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DEPARTMENT
pz:ll
FOOD
OF HEALTH
AND DRUG
CENTER
INFORMAL
FOR DRUG
AND HUMAN
ADMINISTWiTION
EVALUATION
DISCUSSION
OF SAFETY
SERVICES
AND RESEARCH
OF LITERATURE
AND EFFICACY
FOR PET AlU40NIA AND
FDG
_-
November
Tuesday,
9:00
17, 1998
a.m.
5630
Fishers Lane
Room 1066
Rockville,
Maryland
-
(p-mu
MILLER REPORTING COMPANY, INC.
507 c Street, N.E.
Washington, D-C. 20002
(202) 546-6666
REVIEWS
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___
..
PART ICI PANTS
Moderator:
Jane Axelrad, Associate
Director for Policy,
Center for Drug Evaluation
and Research
INSTITUTE
Jorge
Barrio, Ph.D., Professor,
Medical Pharmacology,
Los Angeles
R. Edward
Peter
Coleman, M.D.,
Duke University
PET
Department
University
of Molecular
and
of California,
Professor
of Radiology,
Medical Center
S. Conti, M.D., Ph.D., Associate
Professor of
Radiology,
Clinical Pharmacy and Biomedical
Engineering,
University
of Southern California
Keppler, Executive
Clinical PET
Jennifer
Ruth Dean
Tesar,
PETNet
CENTER
Jane
FOR CLINICAL
Axelrad,
Director,
Vice President
Pharmaceutical
Institute
and General Manager,
Services, LLC
FOOD AND DRUG ADMINISTIU+TION
FOR DRUG EVALUATION
AND RESEARCH
Associate
Director
for Policy
Florence
Houn, M.D., M.P.H., Deputy
Office of Drug Evaluation
Patricia
Love, M.D., Director of Medical Imaging
Radiopharmaceutical
Drug Products,
111
Offic= of Drug Evaluati.&
Victor
for
Raczkowski,
M.D.,
Office of Drug
Director,
II
Deputy Director
Evaluation
III
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
and
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3
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CONTENTS
Paqe No.
Opening
Remarks
from
Opening
Remarks
Jorge
from the Institute
Barrio, Ph.D.
Background:
Patricia
FDA:
Love,
Jane
Axelrad
for Clinical
of PET Ammonia
M.D.
9
Literature
Presentation
of PET FDG Literature
Victor Raczkowski,
M.D.
Discussion
of PET FDG Literature
Review:
25
Review
48
Review:
65
Review
-
MILLER
PET:
8
Presentation
of PET Ammonia Literature
Florence Houn, M.D., M.P.H.
Discussion
4
REPORTING COMPANY, INC.
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Washingtonr D.C. 20002
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91
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4
1
2
Opening
3
MS. AXELRAD:
4
meeting
5
FDA Modernization
6
Jane Axelrad,
7
Center
8
that has been
9
implementation
to discuss
_c—-%
and asking
12
Then
13
introduce
3eputy
Director
DR.
Wedical
for Drugs
Group
to address
the
by going
around
to introduce
who
the table
themselves.
are here
to
as well.
LOVE:
I am Victor
of Drug
Raczkowski.
Evaluation
Patricia
Love,
Division
Florence
Houn,
Deputy
I am the,
III.
Director,
Director,
Office
II.
DR.
CONTI:
22
DR.
COLEMAN:
23
DR. BARRIO:
24
MS . KEPPLER:
25
to start
in the Office
Evaluation
20
21
of the PET Working
to ask the FDA staff
DR. HOUN:
of Drug
in the
Imaging.
18
19
for Policy
I am
121.
DR. RACZKOWSKI:
16
17
like
121 of the
to PET products.
Director
at the table
themselves
14
15
like
to the second
of Section
in the Center
of Section
everybody
I would
regard
and the Chairman
created
FDA
everybody
the implementation
the Associate
I would
11
from
Welcome
Act with
for Drugs
10
Remarks
Peter
Conti,
University
Ed Coleman
from Duke
of Southern
:alifornia.
~linical
George
Jenny
Barrio
Keppler
from UCLA.
from
PET.
MILLER
University.
REPORTING COMPANY, INC.
507 C Streetr N.E.
Washington, D-C. 20002
(202) 546-6666
the Institute
for
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5
1
Ruth
MS. TESAR:
Tesar
from PETNet
Pharmaceutical
,..
2
Services.
3
[Introduction
4
MS. AXELF?AD:
system.
of staff
Thank
5
of a sound
6
which
7
the Pharmacy
Compounding
8
sound
here.
9
didn’t
The
has only been
system
realize
10
have a sound
11
discovered
12
can all hear
last
used,
and audience.]
you.
time
that
I think
I was
Committee
of happened
I had
to make
special
system
which
is why,
when
wasn’t
each
in this
room
it was
for
and there
on its own
that
there
for the lack
once before,
Advisory
It sort
I apologize
was a
so I
arrangements
we came
one, we rearranged
to
and
the tables
so we
other.
13
But
14
so that
15
can hear
16
table
the people
us.
And
who
This
Meetings
19
invited
to attend.
20
the Institute
21
Like the last meeting
22
really
23
~echnical
issues
24
~fficacy
of some
have
meeting.
and around
there
amount
the room
are mikes
on the
It was announced
Members
However,
for Clinical
We will
up a fair
for the transcript.
calendar.
a fairly
to speak
for the mikes,
is a public
Upcoming
have
are on the sides
also
18
25
we will
for the recording
17
_—
I think
of the public
it is a meeting
PET.
that we had where
free-flowing
associated
with
are
between
It is a working
determining
FDA and
meeting
we are going
discussion,
on the
I hope,
to
of the
the safety
and
of the PET products.
give
MILLER
people
in the audience,
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
should
anyone
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6
1
else
come
2
each
topic
3
going
4
opening
5
background
6
products.
in, the opportunity
session.
to start
Dr.
Then
Dr.
Houn will
8
on the PET ammonia
9
to sort
of open
10
will give
11
of FDG.
12
have closing
15
update
we will
on where
at these
some
PET
on the results
and then we would
Then
like
Dr. Raczkowski
he stands
to discuss
try and break
turn
16
Lugust,
17
~he chemistry
18
1 think
19
~ome of the issues
20
address
21
specifications
first
break
on the review
that.
to the substance
meeting
of this
of the PET products
that we made
a great
Then we will
discussion
is going
tomorrow
where
24
monographs
that
in the USP.
today
we will
we are going
MILLER
an hour.
of the meeting.
sort
of nature
that
are currently
what
products
during
would
In
focused
on
in use.
in discussing
be needed
to
and on the
be developing.
it the USP
are
times
for about
of progress
with
of these
that we would
That
deal
associated
the chemistry
But
at appropriate
for lunch
23
25
to give
some
remarks.
Let’s
22
review
we are
ask to give
a presentation
be able
and we will
our
is going
looking
at the end of
the agenda,
I will
it up for discussion.
We will
the morning
whom
been
give
comments
see from
Love
literature
a status
Then
can
Dr. Barrio
on how we have
13
.
with
remarks.
7
14
As you
to make
to continue,
be discussing
to change
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
I believe,
the PET
our focus
and we
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1
are going
2
the safety
3
commonly
to talk,
really,
and efficacy
sort of for the first
of some
of the PET products
about
that
are
in use.
4
Our approach
5
directed
6
procedures
7
most
8
products
9
to see what
to this--as
by the statute
for the regulation
appropriate
that
from
we can learn
is extensive
literature
11
about
their
and efficacy.
So we embarked
on a review
13
ammonia
14
other
than
15
going
to update
16
where we are so far on those.
and for FDG,
17
for additional
the one for which
you
We feel
18
axercise
19
flewill
20
~eeded
21
products
22
developing
23
=he products
24
Literature.
today
that
of looking
have
come
of these
it is already
we have
it would
on the
in use,
products,
that
approved.
We are
reviews
through
are commonly
understanding
of what
the safety
and efficacy
of these
information
to start
looking
and approvals
for which
that
MILLER
there
sort
isn’t
as much
is
be
products,
in the
of introduction,
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
in use
at how we will
for the newer
and
this
common
that we can use
for
for FDG
of those
gone
and
for which
of the literature
on the status
after
to some
commonly
indications
at the products
to demonstrate
so, with
on some
that
to focus
the literature,
there
12
most
we were
and
We felt
standpoint
in user
from
new policies
of PET.
the agency
are already
safety
you all know,
to develop
10
25
time
I would
like
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8
1
to ask Dr. Barrio
if he would
like
to make
some
remarks.
,.
2
OPENING
3
4
have
5
staff
6
two committee
7
and myself,
8
join us Dr. Coleman
9
of indications,
an awful
also
10
Institute
11
current
on behalf
you,
I don’t
much.
you,
thank
the
but we also
We have
Dr. Conti
invited
expertise
in the area
He is one of the founders
And Ruth
Tesar
to
who
of the
is the
of the ICP.
that
14
wonderful
15
sasy procedures
16
radiopharmaceuticals
17
that final
18
established
this meeting
realistically,
there
radiopharmaceutical
for these
I think
20
~ur exercise
21
opportunity
22
~ome of the issues
23
area.
here
is no point
in having
and assumingly
appropriate
is, I guess,
clinical
that
the agency
that what
regards,
MILLER
to have
and solve
are outstanding
happened
of course.
point
and
indications
.
the overall
and we are delighted
with
of the
get to the final
radiopharmaceuticals
that
to work
I think
importance
for the preparation
if we don’t
is to have
is of great
regulations
or regulations
point
in many
very
the original,
who has enormous
PET.
PET
and friends.
from
of course,
of course.
President
Jane,
FOR CLINICAL
to thank
only here
and Jenny,
to us because,
musual
INSTITUTE
of my colleagues
members
We feel
24
Thank
of Clinical
19
THE
lot to say except
13
25
FROM
DR. BARRIO:
12
.-.
REMARKS
objective
of
the
or resolve
in this particular
with
PET is quite
The technique
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
has been
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1
available
2
FDG,
3
thousands
4
clinical
for more
than
twenty-five
years.
Il@s existed
,..
.
for example,
of papers
6
the time
7
the PET community
8
this because
9
any angle
came
happened
for applying
found
we didn’t
that
11
format
13
is to initiate
14
initiated
15
dilemma
16
proposed
17
for the new ones.
and use
and
animal
models,
like
as we all know,
of how
any support
drug
when
the agency
in a dilemma
for any other
we didn’t
and what
months
these
as examples
Again,
that,
any industry,
a discussion,
several
18
staff .
area,
PET to the clinic,
have
for any of this
20
thousands
and
to do
from
or any other
.
Therefore,
12
was
themselves
is normal
radiopharmaceuticals
would
We have
in the chemistry
But what
19
1976.
studies.
5
10
since
for
ago
five
of what
we were
trying
trial
to do today
I guess,
that,
in order
to resolve
needs
of course,
to be done
of my colleagues
for this
21
any clinical
radiopharmaceuticals
on behalf
to ask you
have
this
that we have
in the future
and
opportunity,
was
friends,
Jane,
we
and your
Background
22
DR. LOVE:
23
noments
is go over
24
co some
extent,
25
:he PET products
What
we are going
a little
is shaping
and being
MILLER
bit
of background
our thinking
able
to do just
for a few
material
that,
as we are looking
to address
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
some
of the
at
aj h
10
1
things
2
fact
3
we going
that you
just mentioned,
Dr. Barrio,
the idea of the
....
that we are
somewhat
to move
in a dilemma
in terms
forward.
4
[Slide.]
5
So we just want
to put
a little
6
on the table,
so that we are all at least
7
the different
perspectives
8
this.
9
a little
So, a few moments
bit
10
and how
11
the options
12
day.
of time
on that.
on some
that will
13
[Slide.]
14
Normally,
were
16
that goes
17
skip this,
just mentioning,
recently
18
through
since
to us,
covered
of some of
forward
with
to spend
and then
come
perspective,
development
information,
just
documents
for the remainder
a drug
a lot of this
you
aware
published
a background
we have
of background
I am going
be considered
from
bit
as we try to move
they may be of assistance
15
of how are
to
of the
as you
process
so I will
it for me quite
just
well.
[Slide.]
19
But
it leads
20
~ltimate
21
naking
22
process
is leads
23
?rovide
useful
24
~ome of the information
25
?articular
goals
sure
to labeling
as we go through
that
to some
type
some
that
so
one of our
all of this process
at the end of the day,
information,
slide,
basically,
if whatever
of labeling,
and the labels
is identified
of the different
Washington, D.C. 20002
(202) 546-6666
the
that would
generally
here
include
on this
information
MILLER REPORTING COMPANY, INC.
soy c1Street, N.E.
is
that
is
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1
here.
2
[Slide. ]
3
Some
4
we have
5
on that.
6
today,
7
a way
been
talking
We will
is somewhat
There
published
products
11
forward
12
for us to move
13
the very
14
towards
that
already
forward
with
with
to be able
Also,
what
is a little
that often
17
YOU are looking
at the data,
18
presenting
information
19
presentation
20
save been
21
seeking
22
experimental
format
focus
as models
and that
in
input
the FDA has used
Often
on the market
other
be unique
products
how
from
to do that.
for us today
of a pre-NDA
the sponsor
is coming
so this
type
and we are presenting
where
and
of
that we
it to you
So, this will
is
phase,
for us in the sense
and guidance.
are
but we are working
unusual
to us,
those
and are coming
so it will
to consider
in somewhat
is unique
reviewing,
products.
approving
ways
we are
of where
the literature,
16
be
and
an
process.
[Slide.]
24
25
literature,
indications,
finding
your
so we won’t
at FDG and ammonia
to approve
been
beginning
that
just mentioning,
the CMC issues,
are a few examples
have
when
was
unique.
as supplemental
15
23
as Jane
at the published
literature
10
about
be looking
and looking
8
9
of the things,
As I mentioned,
~here,
the guidance
there
document
MILLER
are a few documents
for providing
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
clinical
out
evidence
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12
1,
of effective
2
earlier
3
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4
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5
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to that
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and use
t
k
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the evidence
hat
jargon,
it prov “ides some
Thn
is a pr oposed
of thi.s year,
document t
is what
that
iinformation
rule
radiopharmac :eutica,1s us ed as di agnos tics
9
and there
10
developing
11
are perhaps
13
agents
[s ide .1
15
Ju.St a Coupl e of things
16
for the evid [ence
17
sponsors
who
18
process,
wha .t
19
published
nt provides
be
are th,ings that
I just wa nted
about
22
Particularly,
23
conducted
24
common
25
information
Although
as pect
a pproaches
thi s gui.dan.ce
a lot of info ,mmati.on for
by a number
look
for today ist
in that guida nce
publ ished
t:hat
litera ture.
that
inve stiga tors
allows
t hat presen ts cons istent
that ; have
us to hav e anc1 find
resul ts .
REPORTING COMPANY, INC
507 C Street, N.E.
Wa shington, D.C. 20002
(202) 546-6666
MILLER
:he
for mu .ltiple studi e S th~Lt are
o f different
or sim ~ilar desig ns /
of tkle
of this .
to using
one might
endi .ng
th is.
through
to mention
The re is a br ief section
talks
are not
are starti ng at the beginn ,ing part
lit erature
21
they
us as we move
14
20
tha t mi$
affect ing some of our th i.nking
and it can help
points,
we a~
just P ubli~ :hed for
These
ThLey are star ting points,
12
so if: we go
or for moni t:oring,
guidanc e that was
m\edical imag ing
and we
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is our recent
vi
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and biologi
in a,pproxi.ma.tely May
this year,
to refer
drugs
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Another
is the articles
2
level
3
the protocol
4
plan
5
endpoints
that
6
are under
consideration.
of detail
is, how
us to clearly
the patients
a high
identify
are entered,
analysis,
are useful
have
what
and they have
for the proposed
what
is the
objective
indications
that
[Slide.]
8
Also,
generally
come
the guidance
from
opposed
11
So, we look
12
course,
13
particular
site because
14
opportunity
to inspect
to an analysis
at these
one looks
15
be able
17
I won’t
18
I’he comment
19
zhat there
20
with the guidance
21
period
that
that might
articles
analysis
post
as
hoc.
that perspective,
and,
of the authors
generally
the studies
are things
be results
be developed
from
we don’t
there
planned
at the credibility
So, these
that might
noted
the prospective
10
16
allow
for the statistical
7
9
that will
generally
have
as we might
of
and the
the
normally
that we are thinking
do.
about
to be considered.
spend
a lot of time
for that did just
may be some
related
on the proposed
end, but we
comments
that
rule.
do expect
still
come
in
document.
[Slide.]
22
You
are familiar
23
sure, and they
24
Jut whether
25
?adiopharmaceuticals
certainly
PET is going
with
these
fit with
some
to be part
or how
that
definitions,
of the PET products,
of the proposed
is going
D.C. 20002
(202) 546-6666
rule
to be worked
MILLER REPORTING COMPANY, INC.
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Washington,
I am
for
out,
aj h
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1
and is it going
2
still
to be a separate
set that
addresses
this
is
...
yet
to be determined.
3
[Slide.]
4
One of the things
5
address
6
radiopharmaceuticals,
7
effectiveness,
8
going
that
is a set of indications
to talk
9
that
approaches
and also
about
the proposed
rule does
can be sought
for
to the evaluation
for safety.
Today,
for
we are primarily
effectiveness.
[Slide.]
10
These
11
guidance
12
imaging
13
~Pend
things
for industry,
[Slide.]
15
You do have
16
nention
17
14th,
18
~ither
19
1s .
just briefly
so please,
and biologics,
9oing
14
amplified
for the draft
and for drugs
a lot of time
were
over
the comment
to PET or anything
20
[Slide.]
21
The other
you,
some
is that
I don’t
but
23
pidance
closes
24
2trUCtLlral, functional,
physiologic,
25
Ietection,
that
different
or something
groups
is going
to
to
on December
that
please
for some of our discussions
about
want
I did want
the indication
nest relevant
medical
of the guidances.
comments
22
talks
and
period
in general,
in the
for developing
the details
them with
if you have
primarily
are relating
get those
area
today.
to
is probably
The
of indications,
or disease
to be used
MILLER REPORTING COMPANY, INC.
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or pathology
for
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diagnosis
2
diagnostic
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therapeutic
or therapeutic
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Our approach
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in response
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to questions
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Today,
flip side,
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11
recognize
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13
so we will
there
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saying
information
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be looking
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does
We certainly
categories
that
from
that we have,
categories.
of indications
is
to us for how would
is the information
of these
there
categories.
be looking
and overlap
makes
best
of
sense,
at that.
This
brings
us back
then
16
:hat is on the safety
17
?roducts,
18
nodel .
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19
ve will
be look
20
Erom various
reviewers
21
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at the pharmacology,
22
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23
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25
or patient
[Slide.]
15
24
that
for a particular
these
10
14
of workups
to putting
up a product
8
and that ,means
management.
4
9
management,
to our focus
and efficacy
particularly
looking
I mentioned,
of these
at the literature.
has also
We also
have
Dr. Raczkowski
that
MILLER
they
also might
towards
have
about,
support
who have
the pharmacokinetics,
which
and Houn
used
as a
talked
who are in the audience,
to us as we work
)f the information
commonly
at FDG and ammonia
and as Jane
information
for today,
and
be of great
this.
will
be talking
gleaned
REPORTING COMPANY, INC.
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from
about
some
the different
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articles
2
indication
3
remainder
and again
or comments?
This
to stop
Yes .
7
DR. COLEMAN:
9
ongoing
10
and Dr. Barrio
struggle
of the reasons
11
be discussed
I think,
to figure
as the
13
ammonia
14
~dmitted
to a hospital
15
30W many
adverse
16
FDG ?
us several
and FDG.
out,
any questions
material.
that
out,
this has been
PET fits
Dr.
an
in, and is one
was written.
meeting
and he asked
there
as you had pointed
out where
the statute
I remember
Are
just background
pointed
12
several
questions,
We said none.
because
reactions
have
years
ago with
how many
How many
people
of injection
occurred
people
Dr.
Pet,
died
from
have
of FDG?
been
None.
from ammonia
and
None.
17
He said,
well,
18
~valuate
19
oeen the struggle,
20
;oday, because
21
:hese extremely
22
them drugs
because
23
~on’t
-- but has
24
inherent
25
will
there.
is really
6
Love,
that
to get to the
of the day progresses.
I am going
8
at all of this
considerations
4
5
looking
you would
this differently
like
there
safe
in that
But
and
than
I think
think
other
that
has not been
we would
drugs .
a mechanism
has a connotation
some
regulatory
that has
for evaluating
-- I hate
to you
mechanisms
to call
all that we
that
are
term
I think
there
MILLER
needs
to
is why we are here
radiopharmaceuticals
that
And
be able
to be this way
REPORTING COMPANY, INC.
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that you
aj h
17
1
are working
2
drugs,
3
in the literature
4
mechanism
on to look
at these
and hopefully,
that
DR.
6
very
7
and Raczkowski
8
review
9
the different
LOVE:
important
at these
Right.
will
we have
parts
10
presenting
11
I mentioned,
12
from
13
pharmacodynamics
talk
been
and from
from those.
So, yes,
17
to give
of the framework,
18
information
19
?oint,
20
and getting
processes
that
and there
I think
a new
of compounds.
that
it is
and both
Drs.
Houn
in the actual
to do to pull
They
together
will
be
on this.
supportive
As
information
the pharmacokinetics,
and what
is useful
is other
if we are thinking
has been
demonstrated
of my comments
some
simply
of the thoughts,
to us, but
information
is
some
it is not our stopping
that will
be coming
as we go on today.
the details
will
come
from
their
.
DR.
;tatute
is
agree
perspectives
the purpose
on the table
25
on what
to develop
approaches
it is useful
16
Like to get
than
information.
metabolic
24
some
at other
about
23
at this,
the clinical
Particularly,
presentations
based
safe group
trying
15
22
forward
very
about
we are looking
the preclinical
21
about
of the literature.
primarily
some
different
We certainly
for us to look
and what
14
can come
and then going
for looking
5
tracers
COLEMAN:
I think
to is -- and I think
-- is to not be grounded
MILLER
that
this
one concept
I would
is the purpose
in what
has gone
REPORTING COMPANY, INC.
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of the
on in the
ajh
18
1
past,
2
different
3
by the FDA,
4
here
5
radiopharmaceuticals
where
than
drugs,
8
to look
9
as you
that
that have
these
are
typically
through
that will
been
handled
the difference
work
for these
in the future.
I think
we will
that
learn
focusing
from
at a different
that,
process
on the past
but we need
and regular
to move
as we go forward
forward
here,
such
are doing.
10
I think
that
11
to keep
in mind
12
sxactly
in which
13
radiopharmaceuticals
14
~hat might
15
3et down
16
:hese products
17
)e very
one of the things
as we go forward
ways
affect
just
PET drugs
today
may be different
some
approval,
concrete
that
things
can distinguish
try
is to try to clarify
or from any drugs
the drug
that we should
from
in general
but
I think
other
and how
if we can
and characteristics
them,
I think
of
that
will
helpful.
18
—
drugs
to a structure
so,
7
other
and how do we get this
to come
6
.
can we go to the future,
MS. AXELRAD:
I sort
19
me
20
‘OU know,
21
always do, but we are trying
foot
in the past
we are not
22
different
23
!verything,
24
re are straddling
25
hat way.
of view
and one foot
turning
way within
the line
MILLER
in the future
our back
entirely
to address
the constraints
so we are not
it as we have
totally
and trying
for this.
on what
these,
but
to move
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we
you know,
of the statute
changing,
sort of
and
I think
forward
in
in
that
ajh
19
,,—
DR.
1
2
question.
3
proposed
4
there
5
and we have
6
facing
There
rules
was
sort of a housekeeping
are a number
that
of these
are coming
out.
16 deadline
got another
guidances
I think
and
one is actually
that has now come and gone,
December
14th guideline
that
is
us.
We are in a bit
8
trying
to formulate
9
~hemistry
of a quandary
how we are going
and the clinical
10
yet, we have
11
:his process,
12
Iocuments,
13
:ype of approach
documents
side
that
how to do that,
15
MS. A.XELRAD:
would
you
16
)oth of the documents,
17
Juidance
18
Ipply to PET,
19
=uture remained
20
:aid.
document,
iocuments
23
)resent problems
24
;omething
25
problematic,
sort of passing
sure whether
because
the
us by in
to respond
we haven’t
recommend
What
both
to these
structured
our
that
to be determined,
and comment
suggest
on them
for you.
in there,
I think
that
recommend,
the proposed
they might
I would
we do here?
I would
we indicated
and how
22
to deal with
we are
to it.
What
What
here because
of PET radiopharmaceuticals,
are
so we are not
14
21
.—
I have
a November
7
—
CONTI:
they
be applied
which
feel
if it were
that
applied
be good
directly
to PET in the
is what
to the extent
Dr. Love
focus
on the
that
they
there
is
to PET would
if you would
MILLER REPORTING COMPANY, INC.
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in
and the
didn’t
is that you
If you
it would
rule
I think
bring
be
aj h
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that
to our attention.
2
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3
guidance
4
represent
5
indications
6
one,
7
thinking
8
burdensome
9
that
that
document,
certainly
which
the Agency’s
is actually
current
for diagnostic
come
that we felt would
to the market,
10
there
11
than may
12
tried
13
what you
14
trying
15
to supply.
believe
that
really
because
they have
be necessary
to indicate
by breaking
elaboration,
of which
and to clarify
for all radiopharmaceutical
make
products
quite
to get an approval,
those
our
it less
that people
to demonstrate
the
PET is
what
diagnostic
we felt
down
and the
on how they view
pharmaceuticals,
that
rule
a bigger
thinking
and we try to articulate
is in a way
the proposed
out
a bit more
and we
indications
that
.
—
are going
to get determines
16
.
for, what
It is sort
17
lowest
18
management
19
md
20
pharmaceuticals,
21
~oth of those
22
would affect
23
=hat might
24
will do some more
25
~e having
of the sort
claim
I think
what
of like
kind
kind
of a functional
that
thinking
as well,
documents
and
of information
a hierarchy
that determines
that
of an indication
claim
and comment
on them
if they were
to be applied
cause
if they were
applied
other
meetings
MILLER
later
like
of information,
to PET diagnostic
you
you
talking
should
about
to PET,
where
look
problems
and then we
We will
we can talk more
REPORTING COMPANY, INC.
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at
how they
or what
on in this process.
this
of
to a patient
apply
so I think
you have
from a sort
the level
would
you are
aj h
21
1
specifically
2
going
about
in terms
3
what
comments
of finding
DR.
CONTI:
4
the issue
5
becomes
6
going
7
been
8
or what
9
and the deadline
those
back
what
again,
cited
was not decided
10
I have,
11
3oing
12
responding.
just
here
past,
and then
what
may have
is no longer
and the deadlines
a problem,
is now a problem,
so this
of the iterative
it
to be,
the documents,
to be a problem,
and it is
discussions,
is going
originally
is already
in terms
through
these
the consensus
as a problem
in the PET arena.
is the deadlines,
through
re-reviewing
and ,where we are
documents
My concern
of as we proceed
clearer
you make
is a concern
process
that
that we are
that we are facing
for
—
13
so,
I don’t
14
DR.
LOVE:
know
I think
15
Juidance
document,
16
~hat one
is an overall
17
so you
18
~t the moment.
19
eight now
20
~ddress
21
prospective
are looking
22
at this
and then
development,
So, you might
perspective.
24
;tarting
points
25
Joints .
There
The other
from
used
the other
for prospective
two different
products
part
document
is flexibility
gives
but
in how
out,
development,
on the table
and how we can
coming
to think
the
perspectives
is what
new products
want
about
one that went
a set of questions
for literature,
MILLER
that.
thing
the last
guidance
for the commonly
23
the other
particularly
We have
them,
how to address
about
down
the line.
about
it from
us,
as I said,
those
are very
one might
REPORTING COMPANY, INC.
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use
that
general
the
aj h
22
.
1
literature,
2
what
3
use of data.
and
it really
the literature
4
says,
So, they
But even
upon
the literature
because
that
is more
are different
though
5
radiopharmaceutical
6
of that
in the guidance,
7
in that
context.
8
depends
9
them
actually
10
have
left
11
would
12
rule and a new guidance
13
I think
applies
it open
there
and certainly
for the
are
implications
address
your
concerns
it is set up, neither
to PET right
to see whether
be applicable
period
closed,
MS. AXELR-?!D: The way
retrospective
perspectives.
the comment
rule has
and
now,
there
to PET or whether
that would
so I think
are parts
we need
be unique
of
that we
of it that
to do a new
to PET,
and
so
—
___—.
that
14
—
as we go down
Also,
comments
the path
on the guidance
15
though
16
day or 60-day
17
the guidance
document,
18
the comments
in, and we want
19
statutory
20
whatever
21
and the guidance
document
finished
22
but
position
is that
23
guidance
24
final
25
that
we have
a -- whatever
the Agency’s
documents
guidance,
it needs
-- 60-day
comment
to finalize
at anytime,
people
are
to be changed
MILLER
it, we have
like
comments
and even
still
free
in some
21st,
to have
at about
respects,
REPORTING COMPANY, INC.
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to get
a
or
time,
are welcome
on
we issue
to comment
and
on
the rule
the same
after
a 90-
period
we want
the rule by May
’99, and we would
even
do we have
and we do that because
to finalize
it is, of
comments,
it is, 90-day,
on the guidance
deadline
we can do that.
and
a
say
it is sort
ajh
_——=
23
1
of an iterative
2
don’ t want
3
comments,
4
be appropriate
5
But
process.
Obviously,
once we finish
one, we
,,....
to open
it up the very
we will
6
be an open
7
PET is open
8
through
9
get your
consider
to revise
I think,
question
comments,
11
drafting
either
12
document
that would
13
document
for PET.
m
things
those,
16
those
that
could
things
it would
rule
it would
there
into account
or the final
while
to
we are
guidance
for having
so, to the extent
that you
can communicate
a separate
with
us
be helpful.
I would
like
17
thing
18
1 am not
19
would be this meeting
20
tihere we go for indications,
21
3uidance
on exactly
what
22
md
that means
to a commercial
23
>r to the users.
24
discussion
25
Joing forward
sure
talk
are some
the need
that would
to
be good
obviate
it would
to
to apply
and we will
be that
be taken
it is going
are going
but
it may
the final
MS. TESAR:
what
whether
obviously,
happens,
because
small
if we get
it.
and see what
10
15
and decide
you know,
how
day, but
as far as we are concerned,
that
14
them
next
be very
helpful
to make
to us to going
if it is this meeting,
because
I think
of the levels
would
a comment.
I would
I think
be extremely
that
levels
product
helpful
Washington, D.C. 20002
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of claims
mean,
or the industry
and
that would
when
MILLER REPORTING COMPANY, INC.
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on
or some
new to us,
and what
and
it
it has a bearing
it is somewhat
of claims
forward,
hope
is a discussion
the various
One
mean
we are looking
aj h
24
1
at how we want
2
to look
MS. AXELFUID:
3
until
4
because
5
going
to be having
6
more,
sort
7
of indication
8
supports
9
about
10
at our
that
after
that
after
DR.
12
guidances
13
and in the future,
14
am not
15
5ocuments,
16
is going
that we are
illustrate
not,
through
that
and the FDG reviews,
we think
it may
Just
in much
that
sort
the literature
and then we can talk
that discussion,
if
it is just
~as two types
19
guidance
20
tiorking on a guidance
21
Suggested
22
instead
23
~s guidance
for industry
24
compounding
industry
25
?ET community
of guidance,
for reviewers,
guidance
on pharmacy
types
term.
I
of
this
The Agency
for industry
this
We were
and somebody
for compounders
but we decided
in this
is the industry,
and
come up.
compounding,
say guidance
for industry,
case,
REPORTING COMPANY, INC.
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to leave
it
the
and in this
is the industry.
MILLER
industry.
as we go forward,
is a generic
because
now,
in mind.
and we had
it should
through
to these
something,
That
18
come
related
to be kept
MS. AXELRAD:
You produce
PET radiopharmaceuticals
won’t
that means
of guidance
one comment.
The
probably
to be need
that
to hold
how we are applying
gone
for industry.
17
will
and what
_—=
but
like
everybody.
COLEMAN:
sure what
those
we think
having
.
of the discussions
terms
structure,
is okay with
11
some
of concrete
I would
the ammonia
around
and what
that
I think
we go through
I think
indications.
case,
the
. . ...
aj h
-
25
1
2
DR.
COLEMA.N:
SO, an individual,
it ,could be an
industry.
3
MS. AXELRAD:
4
perhaps,
5
side of the table
6
and whoever
a cottage
7
Well,
industry
they
maybe,
as far as we are
are a small
but
they
industry
are the other
concerned,
it’s
the FDA
it is that we are regulating.
We had
the same
8
Advisory
Committee,
9
Actually,
we have
thing
on the Pharmacy
we had an industry
two industry
Compounding
representative.
representatives,
10
representing
the traditional
pharmaceutical
11
representing
the compounding
industry,
12
the term
one
industry
and one
so we had to split
to fit the situation.
13
Presentation
14
DR. HOUN:
15
am the Deputy
16
I am also
17
School
18
Surveillance
of PET Ammonia
Good morning.
Director
19
[Slide.]
20
I am going
at Johns
~ffectiveness
22
who is our
statistician,
23
{ears,
she got her
24
~ashington,
25
>f Public
review
Seattle,
Health
that
Oncology
about
who has been
Evaluation
with
I
II.
Hopkins
Ovarian
Center.
my safety
Sonia
and
Castillo,
at FDA for three
at the University
and did her postdoctorate
at Harvard
Houn.
of the Breast
I did along
Ph.D.
of Drug
at the Johns
Hopkins
to be talking
21
and
in oncology
and Co-Director
Service
Review
I am Florence
for the Office
an instructor
of Medicine,
Literature
University.
MILLER REPORTING COMPANY, INC.
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of
at the School
aj h
-
26
1
[Slide. ]
2
I also want
3
working
4
team.
5
that
together
We have
I drew
on ammonia.
chemists,
upon
[Slide.]
7
The
conclusions,
9
that
first
ammonia
11
there
12
literature,
13
there
14
separated
I want
that we have
are the members
all sorts
to let people
and we did go through
to assess
was
These
pharmacists,
thing
for effectiveness,
10
know
a team
of our
of expertise
to do my review.
6
8
to let people
safety
the literature
an indication
myocardial
it was anywhere
would
perfusion.
in the doses
is our
and found
be for N-13
We also
that were
from
know
used.
found
that
In the
8 to 25 mCi
studied,
and
..—-..
also
studies
between
that
showed
[Slide.]
16
So, how did we do this
17
structured
18
looking
19
is safety.
20
Looked
our review
at existing
at external
We looked
?urely
23
GO understand
24
~ diagnostic
25
in terms
policies
We looked
22
of looking
on what
standards
of how
at many
studies.
others
it performs
performance
We also
review?
usually
were
developed
use
Some
of them were
to allow
to a drug
us
that we had
for.
methodology,
MILLER REPORTING COMPANY, INC.
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We
studies.
comparative
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what
for ammonia.
established
a search
we
at the guidances,
to compare
relative
already
Well,
is effectiveness,
for an intended
investigational,
how
1 I.V. doses,
30 and 40 minutes.
15
21
.-.
were
which
I
aj h
---
27
1
will
talk
about.
2
articles.
3
particularly
4
in bolstering
5
conclusions
We developed
I am going
selection
to review
talk about
our findings
one article
and supporting
criteria
which
for
and
we found
effectiveness,
very
key
and our
.
6
[Slide.]
7
This
8
that Dr. Love
9
were
able
10
N-13
ammonia
11
study
12
findings
13
time.
is, of course,
had talked
about,
to find multiple
were
across
it was
and there
studies,
document
important
that we
in the literature
perfusion.
adequate
many
and
studies
and myocardial
designs
the effectiveness
many
We found
were
about
that
the
consistent
institutions,
and across
-----
14
We also were
15
having
16
?resented.
17
V-13 ammonia
18
:ruth,
19
m.giograms .
very
study
We looked
such
20
detailed
very
impressed
protocol
at how
and
and to their
as coronary
angiograms
21
We looked
22
uere efforts
23
nasking
24
)efore by FDA.
25
.0 evaluate
to minimize
of clinical
external
bias
data,
Secretin
pancreatic
were
standard
The
has been
literature
Bleomycin
MILLER REPORTING COMPANY, INC,
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whether
randomization
and this procedure
function.
was made
of conclusions,
conducted,
including
was used.
results
between
of
or the quantitative
at the consistency
at how the studies
study
the comparison
perfusion
We looked
by some articles
and
there
or
used
was used
and talc were
aj h
.-,
28
1
approved
2
the literature,
3
literature
4
this process
for malignant
pleural
effusion
and doxycycline
was
to get an approval
has been
5
[Slide.]
6
We looked
7
a draft
guidance
8
of what
to look
9
Particular
used
subjects,
11
;arget population
12
~sed.
are
image
it outlined
for in adequate
10
using
in the
of malaria.
So,
before.
and
attention
reviewed
for treatment
at the medical
out,
indications
should
the subjects
which
some points
who are
to selection
studied
the test
part
is being
is
in terms
and well-controlled
be paid
for which
guidance,
studies.
of
of the
intended
to be
.-=
13
We looked
14
:estsr
15
randomization,
16
!ooked at the standards
17
md
the reading
what
18
was done
whether
was written
the readers
independently,
reading
was
of truth,
about
of the imaging
done
masking,
separately.
endpoints,
We also
analysis
plans,
safety.
[Slide.]
19
.-.
whether
We selected
20
)erfusion
21
Lnd the fact
22
lse for the product
23
:nough literature
24
lssessing
25
~e could
based
on a preliminary
that
this
turned
use
that
perfusion
on other
articles
to assess
review
myocardial
of the literature
out to be, we think,
was an important
written
myocardial
draw
the intended
either
use,
and that
related
MILLER REPORTING COMPANY, INC.
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there
directly
or tangentially
to support
the major
this
was
to
to it, that
indication.
aj h
.—=_
29
1
In looking
indication
2
this
3
looking
of to assess
4
that
5
study
6
the spectrum
7
be used
8
that
9
between
zero and 300 cc’s per minute
10
tissue,
so we found
11
basis
there
were
subjects
standards
draft
guidance,
perfusion,
we were
assessment
of truth
indication,
to perfusion,
that we saw in the literature
of disease
in, and this
ammonia,
Imaging
myocardial
at it as a functional
that
it is almost
there
12
[Slide.]
13
Looking
14
a lot of studies
15
there
16
acknowledge
17
narrowing
18
or the viscosity
19
dimensional
20
use
21
a more
22
information.
are problems
didn’t
was
with
of computerized
quantitative
We also
knew
24
FDA for flow and that
25
literature
using
that
there
rubidium
MILLER
rubidium
were
also
and
did
angle,
diffuse
disease
so it is a two-
developed
through
are allowing
of flow using
very
that
diameter
like
has been
So, that was very,
of
to angiography,
and algorithms
evaluation
over
we understood
The writers
things
or takeoff
programs
to flow
pharmacologic
like percent
but what
we knew
100 grams
in comparison
address
would
flow.
standards,
things
of blood
standard,
per
the
did represent
related
angiography.
really
that
of perfusion,
a functional
to detect
used
that using
claim
linearly
at external
were
and
the radiopharmaceutical
functional
for it to be able
23
–—-
at the Medical
angiographic
useful.
had been
studies
as a standard.
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approved
in the
by
for
ajh
-–
30
1
In trying
2
is not
3
We knew
4
products
certainly
5
evaluate
what
6
we looked
7
functional
8
outcome
just
to understand
outlining
there
was
of anatomy,
this
area
were
able
to detect,
at large
aspects,
on stress
it
vessels.
that
PET
and in trying
standard
functional
capacity
looking
perfusion,
of microperfusion
is the external
at some
myocardial
to
for microperfusion,
such as wall
testing,
and even
motion,
clinical
studies.
9
[Slide.]
10
Our
11
search
12
clinical
13
listed
14
perfusion.
search
from January
trials
also looked
17
Cound.
18
we asked
to July
published
got articles
at references
from
for an on-line
1, 1998
for all human
in English
that had to do with
We also
16
1, 1990
articles
databases,
15
criteria,
from
ammonia
from
the
and myocardial
ICP suggestions,
the above
articles
and we
that we
[Slide.]
19
We selected
articles
20
tias a comparison
21
questions
22
relevant
23
iescribed
study
populations,
24
lo reduce
bias,
especially
25
>bserver
based
to an external
the articles
variability
standard
had as main
to myocardial
blood
issues
MILLER
on the fact
study
perfusion,
and
that
earlier
had
that
of truth,
hypothesis
that
there
on when
to be dealt
REPORTING COMPANY, INC.
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they
were
more
with
there
that
the
were
had well-
procedures
interin medical
aj h
31
1
practice.
2
[Slide.]
3
From
this
literature
4
total
5
articles
that we felt were
6
in terms
of adequate
7
they are related
of 17 articles,
8
9
search
of which
we found
very
well
to each
longer
10
were
11
and other
12
hypotheses,
but
13
performance
of N-13
other
controlled
published
that
two,
written,
and well-controlled
the two
well
trial
a
supported
criteria,
other.
One was a preliminary
the follow-up,
we came up with
term
study
study.
published
studies
that were
and another
We also
studies
found
that
that were
that had a wide
also
one was
contributing
there
supportive
variety
of study
to understanding
—
14
We also
15
the quantification
16
[Slide.]
17
so,
looked
and myocardial
at some
algorithm
nore time
talking
about,
that
19
published
in ’86.
This
20
tollow-up
study
there
was
perfusion.
articles
that dealt
is used
for the two studies
18
21
for N-13
ammonia.
that we are going
is a study
to spend
by Dr. Gould,
a preliminary
was by Dr. Demer,
with
study,
published
and the
in 1989.
[Slide.]
22
.-
ammonia
The
23
are Schelbert
24
~ave about
25
listed
here
other
controlled
1982,
Di Carli
nine
other
studies
1994,
supportive
in alphabetical
MILLER
that we have
Gewirtz
studies
1994,
that
order.
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listed
and then we
are just
aj h
32
1
[Slide. ]
2
These
3
were
quantification
of blood
4
[Slide.]
5
I am just
6
article
and spend
7
8
diagnosing
9
ammonia,
10
the studies
more
11
to briefly
time
The Gould
article
coronary
artery
pharmacologic
to look
at the
flow.
going
and it used
that we used
talk
about
on the Demer
article.
was a feasibility
disease
the rest
with
and
the Gould
study
rubidium
stress
test
for
and
format
with
stressing.
The
sample
size
12
the 50 patients
received
13
broken
not
14
although
15
that both
for ammonia
ammonia,
was
small,
23 out of
and the results
were
not
—
up, were
16
were
ammonia
some
17
came
18
going
19
the results
20
dose,
21
coronary
to get this
were
reread
reserve
What
had
being
angiography.
three
and the definitions
flow
was
results
were
24
reading
the captions
25
percent
isocount
similar
enrolled
The
was
in general
the folks
and were
study
times.
agent,
performance.
in that
The
on what
actively
had masking,
study
that
and
did provide
significant
for
was defined.
a little
23
in the paper
was prospective
test were
for coronary
by radiopharmaceutic
comments
and rubidium
The design
22
—_
there
stratified
presented
bit,
though,
in isocounts,
and the figure
reduction
MILLER
and
unclear
was
I am assuming
comments
was proportional
REPORTING COMPANY, INC.
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that
the PET
from
the
to the decrease
aj h
.,-
33
1
in CFR.
2
The preliminary
3
patients
4
diagnosed
5
people
6
coronary
were
identified
disease,
that
21 out of 22
by PET who had coronary
who had negative
PET tests,
angio-
9 out of 9 for
as well
as negative
angiograms.
[Slide.]
8
In terms
specifically
10
evaluate
11
angiography,
had
of the Demer
the hypothesis
accuracy
12
showed
and the specificity,
7
9
results
again
In this
in ammonia
using
case,
tests,
that
the Demer
it was going
PET test,
compared
the rest/stress
about
article,
it
to
to coronary
format.
111 patients
out of 193
—
13
received
14
receiving
15
and we also
16
cases,
17
have undergone
18
there
19
not be comparable
ammonia.
20
was
a significant
the radiopharmaceutic
noted
19 patients
was
This
mdergoing
22
~ide variety,
23
soronary
that
24
~rtery
25
Would be relevant
criteria
disease,
with
disease,
and these
unstable
people
in,
considered
174
would
because
severity
would
defect.
all patients
patients
angina,
with
interested
excluded
stenosis
were
of patients
stenoses,
were
to the PET perfusion
people
only
infarct-related
the residual
catheterization,
artery
data
vascularization,
inclusion
21
that we were
the analyzed
who had
acute
concern
The
that
number
people
suspected
and so this population
included
was what
with
a
known
coronary
we thought
-_
to the actual
intended
use population
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for
aj h
,-
34
1
N-13
ammonia
2
PET tests.
The design
3
which
4
perfusion
5
subjectively
was
was an automated
defect
7
Scales
9
significant
normal,
for coronary
10
perfusion
11
in the opposite
12
and anything
13
coronary
defect
reserve,
versus
PET
qualitatively
Image
that
16
images .
There
17
observers,
interobserver
18
resolution
was
19
how the
20
in the paper.
image
was
3 being
zero
to 5, but
perfusion
defect,
significant
to an SFR of less
outlined
about
and was
what
scoring
variation
described.
protocol
also
severe
we felt we understood
was detail
than
was
So, there
was managed.
from
and for PET
2 was considered
was
presented
less
disease,
comparable
protocol
detailed
and anything
5 being
than
15
rate were
the range
direction,
disease
flow
artery
scores,
greater
artery
21
result,
were
for stenosis
to 5, 5 being
14
which
flow
derived.
[Slide.]
zero
stenosis
quantitative
scores,
6
8
comparing
than
3.
sufficiently
happened
to these
of the two
tracked,
was
dispute
a lot of detail
The dose
on
was presented
[Slide.]
22
The
23
Correlation
24
each patient
25
-- so they
results
were
Coefficient
presented
where
as a Spearman
the most
-- and some patients
severe
had more
stenoses
than
one
of
stenoses
.-—.=
took
the most
MILLER
severe
ones
and compared
REPORTING COMPANY, INC.
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the PET
aj h
—
35
1
score
2
correlation.
with
the SFR score,
3
There
4
193 patients,
5
negatives,
6
performance
7
false
there
and this
of each
positives
8
9
was
and
a statement
were
article
agent,
and false
10
sponsors
11
This
12
figure
13
able
14
false
information,
broke
down
of the
ammonia,
how
the
laid out.
informative
information.
was provided
This
NDA we often
ask
in the article.
as I show you
some
for the
7 false
in terms
in a traditional
however,
that
and
versus
negatives
This
3 that presents
very ,good
positives
rubidium
of information
to provide.
found
in the study
2 false
So, this was very
is the kind
they
and I discuss
of the patient
data,
a
I wasn’t
—
to recreate
positive
totally
[Slide.]
16
so, in trying
13 ammonia
18
aid was
19
Eigure
20
have that,
to understand
PET in comparison
I took
figure
3 is provided
21
of the false
negatives
and
data.
15
17
in terms
and
I will
We took
22
Lhe authors
were
23
dichotomous
scale
24
strength
was
25
iisease,
and what
that
to coronary
3 that
to you
also
figure
trying
the performance
they had
angiography,
a slide
3 and tried
not
to do.
separate.
to have
we did was
to derive
Instead
and
You may
the opposite.
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exactly
of having
this
continuous
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I
of it, as well.
of disease/non-disease,
it tried
what
in the article,
in a handout
show
of N-
what
a
article’s
scales
We tried
of
to make
ajh
.-
36
1
it dichotomous
2
and trying
in terms
of putting
things
in a 2 x 2 table
,.
to derive
3
I am going
4
[Slide.]
5
We will
6
figure
3.
7
vessels.
8
in terms
9
zero
sensitivity
just have
total
perfusion
11
stenosis
12
less
13
disease
defect,
flow
than
of patients
studied
[Slide.]
15
So, what
16
derive
from
17
correspond
18
at for stenosis
19
the disease
20
patients,
21
to your
22
?atients
reserve
using
which
left,
who have
coronary
25
with a flow
artery
rate
So, what
than
The
severe
on
that
is
artery
figure
there
that,
look
of 96
on the column
number
of
3.
of 96 people
remainder,
if you
was a total
than
to
is considered
the total
of less
is to
that we made
we did was
96 patients
a total
disease.
this
3, this
standard,
rate
from
results
coronary
and
rate.
see me outlining
a flow
is
174,
going
Anything
is the table
less
the gold
So, we have
24
3.
are the same
you
to 5.
to do with
and this
to the figure
flow
zero
significant
we tried
was
a very
is the angiographic
going
2 x 2 tables,
5 being
This
top are
is the PET scores
no disease,
a low flow
14
23
number
this
on.
on briefly.
The
3 is considered
with
slide
are patients.
and here
rate,
this
the slide
here
of orientation,
to 5, zero being
10
specificity.
to ask Kim to turn
The bottom
That
and
with
significant
the 78, are people
——
rate
of greater
than
or equal
to 3, and then
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for
ajh
.-
37
1
PET scores
of greater
2
considered
diseased,
3
where
4
patients
5
a negative
6
dashed
7
positive
the dashed
is.
on the figure
To the left
of less
of that
than
are 106, and those
and looked
are the 68
2, considered
and the patients
So, we now have
columns
to 2, that was
to have
to the right
are considered
of that
to have
a
PET scan.
the totals
for a 2 x 2 table,
10
is 1 degree
11
everything
12
columns
of freedom.
else must
for the rows
and this
If I put
is a table
one number
add up accordingly
and
where
there
in a box,
to get the rows
and
totals.
13
So, what
I did was
I looked
14
and the false
negatives.
Those
15
iiiagram.
squared
to the left
16
refers
17
the PET
18
30 above
19
is considered
20
refers
21
legative
22
iisease.
The
to patients
scan
is saying
flow
?eople who
25
Stenosis
are
box here
reserve
boxes
scores
people
and
than
were
told
if you
3, this
for
positives,
over
MILLER REPORTING COMPANY, INC.
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had a score
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that
and yet
who were
score,
line
so this box here
to the false
calculation,
in this
meaning
of less
on angiogram
refers
positives
of the dashed
are disease-free,
on PET scan had a high
flow
squared
by angiograms,
but
at the false
a low PET score,
rate,
negative
by PET scan,
This
they
diseased
to the false
24
box
who have
a stenosis
23
—
line
PET scan,
line
or equal
and we looked
who had a score
8
9
than
2, but
on
of less
than
aj h
38
1
3.
2
right
Those
are error
by the error
3
bars
We decided
4
estimating
that
5
positives,
we put
6
rest
of this
7
8
bars,
and the actual
9
that
in choosing
two out of four
the number
sensitivity
actually
11
positives,
12
presented
in the article.
13
positives
and the 7 false
14
3f 193, and not
15
axcluded
from
16
md
is where,
17
listings
18
some assumptions.
said
that
there
so these
of those
2 here,
actually
were
numbers
174,
error
bar,
patients
and
were
and that gave
false
us the
patient
negatives
we don’t
~cross
21
vhich I am going
the patient
with
what
was
2 false
were
from an n
have
derived
that were
into
NDA data
account,
and line
we are making
we tried
as well
and 2 false
the article,
in the literature,
diagram,
the article
negatives
to be taken
we made,
to try
for patients.
of the people
have
assumptions
20
7 false
do not mesh
so some
when
the 2 x 2 table
fit because
However,
the analysis
of each
The
22
this
and specificity
10
19
are
table.
Now , it doesn’t
this
numbers
in the diagram.
so, that was how we derived
to calculate
patient
to be consistent
as the vessel
diagram,
to show next.
[Slide.]
23
This
is for the vessel
24
:ype of procedure
25
:otals,
and then
diagram.
in terms
of getting
estimating
the error
We did
the rows
bar
column
for a false
MILLER REPORTING COMPANY, INC.
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and
the same
ajh
.
1
negative
exam.
2
[Slide.]
3
SO, in looking
4
derived
5
specificity
6
confidence
a sensitivity
7
gold
9
analysis?
limits,
standard
10
of 98 percent
of 85 percent.
DR.
8
at the totals,
CONTI:
with
What
regard
DR. HOUN:
perfusion,
12
results
13
articles
14
angiograms
will
15
different,
and in trying
16
perfusion,
not
17
which
18
larger
19
matomical
PET products
that
show
only
is something
vessels
20
show
in terms
21
nicroperfusion,
22
:he PET test may
which
;hat is I think
25
Jessels.
They
where
to take
that
case,
because
are not
to give
into
there
are
so much
where
actually
consistent
this
reveal,
be
with,
at
aspect
of
and yet
is perfusion.
was very
at these
concentrating
MILLER REPORTING COMPANY, INC.
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will
is stenosis.
may not
looking
the
definition
and looking
account
the correlation
they
some of the
we are defining
is more
there
at
the same
results,
that,
vessels,
angiography
show
In this
24
have
in looking
of an anatomical
angiography
characteristics
this
and the PET scores
to resolve
that
that
and we have
collaterals,
about
in doing
contradictory
or medium-size
We also
23
results,
actually
for vessels.
to its accuracy
are not going
as angiographic
a
do you make
we do know
it
the 95 percent
same
assumption
Well,
11
the
that
for patients,
We divide
and we did
we find
good,
and
larger
on an area
ajh
-
40
1
where
2
to more
some
of the other
prominence
3
hypothesis
of microperfusion
So, in this paper,
up very
5
we understand
6
a consensus-derived
7
evolves
with
more
8
culture
used
to be the gold
9
looking
more
at DNA amplification
10
so they
evolve.
11
So, when
that
DR.
we are looking
the gold
CONTI:
13
oecause
of the anatomical
14
~ecause
the correlations
15
demonstrative.
article
as sort
at the gold
has
standard,
standard,
as a gold
this up then.
of representative,
It is
that
you know,
and now they
tests
ended
its limits.
For microbiology,
Let me follow
chosen
lead
actually
and it is a standard
technology.
12
this
standard
standard,
will
aspects.
the correlation
4
well.
in the papers
are
standard,
We have
in part
—
16
What
about
17
assay as a better
18
~ategorization
19
Looked
gold
standard
are actually
correlation
gold
with
standard,
of many
here
quite
good
another
and would
of the other
and also
microperfusion
that
papers
and
change
that have
the
been
at?
20
DR. HOUN:
Well,
if we go through
21
?apers,
you will
22
Support
the microperfusion
23
:ind at the end, we do conclude
24
lot just
25
~icroperfusion
large
see from Di Carli
vessel
aspect,
perfusion,
functional
MILLER
aspects
that
some of the
there
and that
is evidence
is why we did
that myocardial
but
are
also
some
supported.
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perfusion,
of the more
to
ajh
41
1
DR.
CONTI:
That
is kind
of why we do the test
... .
2
actually
3
it is important
4
standard
here
5
choosing
the gold
6
demonstrated
7
for certain
8
primary
9
say.
10
is the microperfusion
changes
to understand
is fine,
this
standard
patient
that may
choosing
as large
while
measure
measure.
-- I am sorry
vessel
--
disease
appropriate
is not necessarily
do a stress
looking
So,
the gold
potentially
of why we would
in large
in large
is perfectly
populations,
indication
11
that
on angiography,
We are
issues
the
test,
let’s
for microperfusion
occur.
So, my concern
12
standard
may be something
13
bit more
in detail.
is that
selection
that we need
of the gold
to address
a little
—
14
MS. AXELRAD:
I think
15
for any diagnostic
16
in this
17
tiould support
an indication
18
isn’t
in any way
19
something
case,
like
DR.
21
specific,
22
~e talking
23
:he day,
24
25
since
limited
20
product
CONTI:
I am trying
about
and
this
is what
the bottom
that,
that
vessel
it really
I am just
is an important
just
Look at the radiopharmaceuticals
but
the literature
and it
or
here?
at this not this
we are going
over
concept
one other
the course
to
of
to understand.
comment.
in general,
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standard,
perfusion
because
things
an issue
perfusion,
matter
looking
to generalize
Maybe
is that
for myocardial
a lot of other
DR. LOVE:
is always
is the gold
line
to large
does
that
often
When
we
we come
aj h
42
1
up with
the issue
2
the coronary
3
for the presence
4
give
5
distribution
are raising,
angiography
us some
6
you
study
of coronary
idea
of where
because
we ,recognize
is primarily
artery
a gold
disease,
that disease
and
that
standard
it does
is and the
of the disease.
Then,
when
we look
7
is looking
8
aspect,
then,
9
whether
the angiographic
10
disease
shows
11
microperfusion
12
distribution.
at a radiopharmaceutical
at microperfusion,
smaller
we are making
a correlation
standard
us or correlates
defect,
vessels
that
or some
in general
for the presence
with
the presence
and are they
in the same
other
with
of
of the
.-s-+
13
-_—=,
So, when
14
looking
15
bottom
16
nicroperfusion.
17
~oth looking
18
~isease,
19
information
20
md
21
wall motion
22
:hat changes,
23
Combination
24
25
we analyze
at a combination
line
what
of whether
So,
we are calling
abnormality
lere that do support
to come
of truth
agents
at
for the presence
which
or looking
may
also
at clinical
1here a clinical
(of thing,
to the
set of information,
1that reverses,
sort
DR. HOUN:
things
it is a combined
on perfusion,
of pieces
we are actually
or not you are looking
as control
that
data,
of different
at a standard
as well
these
outcome
ejection
so we take
of the
give
us
outcomes
meaning
a
fraction
a full
of information.
And we have
studies
the functional
MILLER
that we looked
aspects,
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and they
at
aj h
43
1
compare
to stress
2
protocol
or wall
3
standards,
4
support
5
the literature.
that,
study,
7
Conti
8
with, with
9
~etermine
raised
in fact,
when
does
as technology
is what
you do if there
13
md
are very
14
~an discuss
them more.
15
:he guidance
document,
16
3uidance
document
difficult
[Slide.]
18
DR. HOUN:
They
as well,
In terms
cross
the
evolves.
is no gold
and perhaps
on some
the draft
Medical
of the Demer
20
~eflective
in the inclusion
21
:ndpoint
22
:eserve.
Images
were
23
?hey were
masked
to the clinical
criteria
of the target
population.
for PET perfusion
defect,
standard,
later
we
level
in
Imaging
There
were
as well
the
highly
a continuous
as for flow
independently.
data.
differences
and analyzed.
study,
They used
read by two readers
Interobserver
~ere tracked
modality
are addressed
strengths
25
deal
to
and science
problems,
19
24
that Dr.
that was published.
17
laid
trying
in
standard.
evolves
area
to derive
the point
or another
other
is supported
really
That
rhe other
at those
one that we often
agents,
a new gold
in the Bruce
in trying
that
fundamental
an agent
12
these
I think
diagnostic
Line and become
so we looked
this microperfusion
is a very
many
improvement
as the PET result
DR. RACZKOWSKI:
11
.-=
motion
as well
6
10
test performance,
in scoring
was
enough
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of PET images
graphical
data
.1
aj h
——
.—.
44
1
to allow
us to look
2
at individual
patient
information.
[Slide.]
3
There
4
detailed
5
variability.
6
as opposed
7
large
8
largest
9
impressive
was dispute
information
on readers’
The use
of flow
to percent
numbers
area
of patients
study
resolution
performance
reserve
stenosis,
in this
that we looked
for that
The weakness
of the studies
the rubidium
and ammonia
distribution
14
things
15
able to easily
16
~atients
that
of results
look
[Slide.]
18
Other
:he 1982 Schelbert
20
mgio
21
~rtery diagnosis.
study
and PET in terms
This
study
coronary
23
~iagnosed
with
24
is normal
volunteers
25
were assumed
that
results.
not given.
listings
from
controlled
19
was
was
the
was
it did not
The age and sex
These
are kinds
of patients,
at, and we did recognize
excluded
17
22
were
if we had line
were
This
also
reason.
11
13
was
perfusion
were
it certainly
[Slide.]
segregate
for coronary
study.
at, and
There
and on reader
and there
10
12
discussed.
we would
that
the analysis.
studies
that were
that was also
of large
utilized
supportive
a comparison
vessel
patients
artery
coronary
who were
already
disease
on angiogram,
angiograms,
MILLER
anatomy.
as well
but
So, the sensitivity
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was
between
disease,
who did not undergo
normal
be
19
—.—-
to have
of
ajh
.
45
1
and specificity
2
similar
that were
to the Demer
3
[Slide.]
4
Di Carli
here
relationship
6
viability,
and this
7
metabolism
of 18-FDG.
this
9
compare
the results
10
motion,
and N-13
11
results
of this
12
angiographically
13
flow and
14
angiograms
that
15
This
16
terms
17
information
18
nicroperfusion
19
5ifferent
was
with
showed
a paper
wall
very
to look
58 percent
collaterals
as
comes
wall
and the
of
had low N-13
ammonia
shown
on
perfusion.
the capacity
from angiograms,
to
flow,
that had no collaterals
had N-13
and
at was
FDG metabolism,
that
on the
motion,
of coronary
was one of the studies
here
st,udy were
was defined
trying
of angiography
50 percent
that
and that
through
that we looked
PET provides
the issue
about
at in
different
of
-- we are looking
at
things.
[Slide.]
21
This
23
flow,
“viability”
study
defined
20
3etermine
term
study
of addressing
22
blood
perfusion
actually
this
in 1994 published
of collateral
What
from
study.
5
8
derived
other
a minimum
study
by Gerwitz
in 1994 was
to
level
of perfusion
needed
to sustain
nyocardium,
and it looked
at different
zones
of infarction
24
~nd healthy
myocardial
25
iifferent
tissue
to determine
if there
was
----
flow
rates
associated,
and what
they did
MILLER REPORTING COMPANY, INC.
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find was
.
ajh
46
1
a correlation
2
and areas
of wall
3
poor wall
motion
4
studies
flow,
motion,
had
This
6
results
low flow
7
3ifferent
8
areas,
9
information
study
of biologic
standard
nedical
rate
just
here,
that
zones,
that
had
to normal
wall
motion
to our understanding
in terms
motion,
looking
PET is able
is consistent
with
of using
of the
a
at infarct
to provide
our understanding
of the
[Slide.]
12
We also
looked
at other
published
13
them, and I am not going
to go through
14
lad various
Some
15
nyocardial
hypotheses.
blood
flow
16
[Slide.]
17
Others
18
issues,
19
cholesterol,
20
>ecause
21
:ontribute
22
~ariety
23
Ilow, not only
24
ressels,
25
areas
framework.
11
.-
by PET,
scores.
added
wall
as detected
compared
consistency
and supporting
that
perfusion
infarcted
and the PET flow
5
10
between
such
of them
as flow
diet
of their
were
rate
control,
widely
but
in terms
in terms
also
in terms
kinds
and these
of what
of
studies,
helped
PET can do in a
of assessing
myocardial
and medium-size
of a functional
[Slide.]
MILLER
they
to exercise,
hypotheses,
of the larger
but
of
to compare
other
conditioning,
variably
nine
directly.
to study
responding
to our appreciation
of situations
all of them,
of them were
to angiography
studies,
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approach.
blood
aj h
47
So, in doing
1
2
thing
3
literature
4
they may have
5
to get
6
statistical
7
of what
8
type
this
that we commented
reviews
stated
power
Those
10
the published
11
don’t
12
us to read
have
13
2 error
kinds
don’t
It doesn’t
weakness
15
looking
at them
16
ammonia
PET performance.
studies
were
small
you know,
statement
to have
or what
or not.
get translated
mean
that
into
the studies
it is just not available
and then we also
19
~ublication
20
nany authors
21
publication
that we encountered
numbers,
as a whole,
I talked
18
before
bias,
about
for
likely
for a negative
So, those
:erms of literature
24
[Slide.]
the absence
there
positive
for N-13
of source
is a thing
results
to publish
but by
data,
as
get published,
or want
to seek
result.
are just
review
We do conclude
that
10, 20, 30 patients,
that
you know,
are less
were
we got an appreciation
recognized
23
25
protocol
in the literature.
nany
..-
although
the a priori
they wanted
of things
14
22
had,
with
it just means
Another
17
have
one
of doing
scientific
be acceptable
literature.
them,
original
they might
would
of weakness
a lot of the studies,
in their
1, Type
of the literature,
in terms
calculations
of correlation
9
upon
is that
IRB approval,
Type
review
things
we were
aware
of in
problems.
that
from
looking
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at these
various
ajh
,-
48
1
articles,
2
supportive
3
ammonia
4
is consistent
5
diverse
that
there
to assess
We also
8
nicroperfusion,
9
confidence
an intended
use of N-13
many
feel
to the large
perfusion.
studies,
that
We find
long periods
the perfusion
and medium-size
and we had enough
in the performance
10
that
this
of time,
in
indication
vessels,
but also
information
accuracy
is not
to
to have
of this
test.
[Slide.]
11
We also were
12
che published
13
introduced.
14
~rea and to glutamine,
15
~he urine.
16
in the literature,
17
short effective
18
We know
There
that
risk
That
22
I would
information
A small
amount
of ammonia
the metabolism
a short
of ammonia
it is primarily
half-life.
physical
That
from
is
is to
excreted
in
was documented
half-life,
as well
is acceptable,
the
as
half-life.
is also
21
safety
is a short
blood
[Slide.]
to get
and that
The radiation
cadiation
able
literature.
20
25
to give
populations.
limited
24
and enough
myocardial
across
7
23
information
information
6
19
is enough
dosimetry
acceptable.
is our conclusion
be happy
for N-13
to answer
ammonia.
any kind
of questions
~ou have.
Discussion
of PET Ammonia
DR. BARRIO:
Have
you
Literature
in your
assessment
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Review
analyzed
aj h
49
1
or decided
2
perfusion
which
are the many
analysis
3
with
DR. HOUN:
conditions
PET ammonia
of conditions,
5
conditions,
because
6
tested,
some of the studies,
7
so in terms
8
thought
9
functional
10
patient
11
you,
12
because
13
were
and
I think
there
of trying
the best
and not
were
approach
that
each
for clinicians
specific
were
things
very
would
where
you
of investigation,
was very
a variety
limited,
one an indication,
to say for the diagnosis
the literature
were
different
though,
of perfusion
type
there
so many
a
be recommended?
by not limiting
to give
indication
needed
could
In the literature,
4
and
for which
be to have
thought
a
a
that was up to
of a specific
varied
we
in what
entity,
conditions
studied.
14
Some
15
very useful,
16
specific
of them were
and we didn’t
want
experimental,
to really
but maybe
just
limit
it to
conditions.
17
What
18
DR.
19
tiave concerns,
20
think
21
LO
22
is the idea,
23
~ata may
24
night be useful
25
?erfusion
do you
think
BARRIO:
I think
but
about
We think
however,
conceptually
do.
very
that
approach?
it is a good
approach.
of the level
of reimbursement.
and scientifically
it is the right
we will
agree
in terms
be requested
here
I guess
conceptually
of reimbursement,
to specifically
or there,
even
though
marker.
MILLER
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thing
that
more
whether
it still
I
that
sometimes
indicate
We
it
is a
ajh
50
1
.
2
have
3
that does
4
marker,
5
process.
your
I don’t
know
if you
support
here,
if you
the job that
just
6
7
idea
8
to go through
we get
is understood
9
comment
11
Love
12
can derive
13
safety
14
that would
sure
and knowing
a reimbursement
on this.
suggested,
from
that
to
is a compound
to do as a perfusion
facilitate
the
of reimbursement,
your
data would
that
be required
process.
I think
I think
but we like
this
or at least
to the point
MS. AXELRAD:
10
feel
it is supposed
to also make
When
see my point,
that we all probably
that what
we have
is that we are trying
the literature
to
to do, as Dr.
to figure
in terms
want
out what
we
of demonstrating
the
..
and efficacy
15
of these
be going
What
happens
md
17
~ses is a separate
18
as far as we can based
19
~Pecific
indication,
20
Eurther,
then,
21
{OU think
22
sharing
23
~ou to do some
24
suggest
25
=or example,
are going
with
how
after
that
to slice
question,
this
and
if you
we need
need,
and
think
use
more
of reimbursement
into
that we want
with
exactly
that now
about
this,
the way we did
specific,
individual
regard
that you want
to know
I think
of the analysis
would
down
I think
you how we are going
something
in terms
on the literature
but
I think
we would
for a particular
on a label.
16
how they
compounds
a more
be supported.
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what
to go
to the
us to go
claims
that we are
we would
like
that would
specific
claim,
aj h
51
1
I mean
2
this
3
applicant
4
these
5
and we review
is.
I wanted
submits
Application
a New Drug
claims
them
case,
from the literature,
8
axtent .
9
resources
I mean
we are going
11
hugs
they would
a very
like
if we want
13
:hink we are going
14
is you want,
15
cinds of analyses
17
.iterature,
18
:ight now
19
~on’t remember
20
:ollow-up,
21
:etera, put
22
lxamples .
When
I remember
in four
specifically
ammonia
together
I personally
24
Till understand
what
25
.t is perfectly
fine.
you are
what
I
it
review.
have
the ammonia
it in front
of me
situations,
flow,
and
this
but
I think
et
are just
most
to do here,
of us
and I think
is conceptually
MILLER REPORTING COMPANY, INC.
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I
but as a pre-op,
and administration,
trying
I think
used
you do some of these
and
understand
it, and
points,
and know
they were,
control
of
indications.
independent
what
by ability
number
to the finer
I sent you
-- I don’t
-- but divided
tests,
have
ourselves
to a certain
used
on you
that we can then
DR. BARRIO:
all
of the commonly
commonly
to rely
and then perhaps
analyzes
and we are doing
to get down
to have
the
on the label,
do that
to try and do it for some
But
that
large
to do this,
and for some of the more
Usually,
the review
and we can only
it is taking
unusual
them.
we are doing
in the Agency
10
23
that
and critique
7
16
incredibly
to it earlier.
In this
12
how
We sort of alluded
different
6
to stress
the
I
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52
1
right
2
are absolutely
3
question,
4
to make
5
that
is understood
6
with
this
7
in the process
thing
We are a little
right.
There
sure
that whatever
issue,
LOVE:
that you would
10
indication,
11
some of these
12
little
like
agency
have
what
of your
15
sort of diagnostic
16
nay not
17
also perhaps
18
nay or may not need
to go to surgery,
19
Outcomes,
of that
the use with
I think
:alk about
22
?erhaps,
23
vould give
24
indications
meaning
25
nyocardial
perfusion,
in general
but
because
let me ask,
you
specific
a new battle
you
say is
to address
FDG,
that
a
uses.
responses.
I think
infarction,
of a diagnosis
in terms
that part
21
to deal
in the labeled
mentioned,
or presence
something
20
has been
a pre-op
is going
sufficient
rest/stress
sarlier,
motion
no
We like
so let me just pursue
14
include
that
I am hearing
expected
Now , you mentioned
while
too.
to initiate
indication,
questions,
in terms
absolutely
is, is something
to see the language
other
step,
you
going.
I think
the approved
bit
13
by the next
and we don’t
we should,
for literature,
the proposal
to get this
DR.
-- well,
is a second
and the same applies
8
9
to do.
which
may
and FDG is coming,
of triaging,
which
that
or
and
patients
or predictive
sort.
of the indication
it requires
are you
language
it is useful
maybe
both
products
seeking
something
in each
of these
for evaluation
microperfusion,
what
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have
we can
that
of
you,
instead
aj h
53
1
of general
approaches
or categories?
2
DR. BARRIO:
3
DR.
4
general
5
surgical
LOVE:
Or in the evaluation,
in the evaluation
preoperative
6
DR.
7
something.
8
which
9
documented
N-13
of myocardial
something
disorders
We have
ammonia
been
thinking
is a myocardial
in conditions
such
disease,
determine
on coronary
artery
disease,
and with
11
detecting
viable
12
as I was
thinking.
13
so,
myocardium.
that
type
14
yes, it is a perfusion
15
conditions
such
16
DR.
#hen we actually
18
Labeling
19
cry to put
20
nlinical
phase
I think
or
the effect
of
FDG in
wrote
down
here
we are thinking,
and it is useful
The reason
get
functional
disorder
in
22
Language.
We have
23
Eiguring
out exactly
24
zertainly
25
:it with
in time
not actually
in recognition
FDG to some
-- but we usually
in the context
do
of a
of disorders.
anticipate
what
is normally,
-- and we are not at a
evaluation
or group
I would
I am asking
to the labeling
at this moment
this
so,
tracer,
I just
tracer
as.
LOVE:
17
Those
of thing,
about
as suspected
artery
therapy
or
perfusion
coronary
10
more
evaluations?
COLEMAN:
is useful
21
Yes.
that
that
moved
that
would
be some
to that point
language
of the fact
extent,
there
would
that
this
language
MILLER REPORTING COMPANY, INC.
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be,
of
and
also has to
would
wait
until
.
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54
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we have both
2
language
products
DR.
4
precedent.
5
particularly
CONTI:
Citing
a question
of this
part
7
DR.
process,
Citing
CONTI:
in terms
is certainly
in the labeling
DR. LOVE:
certain
I have
examples
6
of the
examples
As we just
of
possible
is that
correct?
you mean?
discussed,
saying
such
as
populations.
DR.
9
10
“such
11
is relative
12
clinical
13
the context
14
was used
LOVE:
Well,
as” in an indication
clear,
trial
but
in a label
the final
CONTI:
16
looking
17
~erfusion
18
to cross-reference
19
Let’s
tracers
per
that
21
question.
22
~hings
23
function.
24
~xercise
Their
That
as it is useful
question,
about
several
We also
would
have
give
a
more
of the data
se, there
too.
Since
are a number
What
as well.
of
that
we are
of other
is the ability
that are used
is sort
of why
I was
has a statement
that
in the evaluation
of pharmacologic
so,
the indication
generally,
imaging?
labeling
It talks
the term
decisions.
exist,
say for thallium
use
Usually,
which
the indications
DR. LOVE:
don’t
and the source
Another
at perfusion
20
section.
of the studies
DR.
we usually
it can be broad.
section
to make
15
25
in terms
and statement.
3
8
completed
rest/stress
stress
of them
MILLER
says
the
such
of myocardial
and response
agents,
have
asking
either
and the like.
different
REPORTING COMPANY, INC.
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sets
of
to
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—
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1
language
based
2
it is usually
3
descriptive
4
on the data
not a “such
that
as,”
it is usually
It describes
5
and that
the effectiveness,
6
accurate
in this kind
7
problem.
8
assess
9
a lot of different
kinds
10
is when
at labeling,
11
from what
12
describe
perfusion,
the study
in this
myocardial
15
coronary
16
theme
17
like we can make
20
two big
ones,
21
therapy
on coronary
22
viability.
25
would
that
to
that
are
and the next
in
step
to make
be supportive
certainly
a jump
to
and
artery
are going
I think
disease
has been
other
those
The people
are having
constant
trouble
But at any rate,
I think
is
to be the
the effect
of
at myocardial
categories
remind
themes
--
are going
and to look
I just
at
a constant
viability,
to be the big
Could
MILLER
of looking
and determine
MS. AXELRAD:
LOVE:
to assess
the broader
The myocardial
that,
like
So, what
is to diagnose
Those
DR.
at this
of studies
in terms
are probably
COLEMAN:
one like
up.
of the test was
is to be able
you know,
that
another
speak
a bunch
disease,
articles.
19
23
studied
now we just have
of populations,
artery
disease,
in all these
DR.
were
label.
perfusion,
artery
these
looking
Right
population
In coronary
14
24
of population,
and we have
we do look
where
the performance
So, you are right.
18
a more
-DR. HOUN:
13
they provided,, but as I say,
everybody
here.
to
hearing.
as I am saying,
REPORTING COMPANY, INC.
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all of
aj h
56
1
these
2
labeling.
3
aspects
4
total
combination
5
would
be looking
6
actual
different
issues
Dr. Houn
has
MS. KEPPLER:
right
now,
9
since
we are learning
10
myocardial
11
would
12
understand,
13
other
14
me
15
3oing to be used
be used,
and
leeded
19
:0 the next
20
:ompleted
21
:hat knowledge
22
~ith FDG, you know,
23
)it more
to have
been
level
that
and we
up with
the
that
is something
some
of the other
how
be useful
this
and we can look
of the evaluation
tracers
it is
terms,
for us to
what
in the literature
because
you know,
it.
in general
different
how that
that people
are,
understood
reading
is
general
you know,
of our concerns
with
be useful
out as a possibility,
if it would
which
is a
if this would
as easily
just
here,
and done,
this
part
I am wondering
18
know
is well
by somebody
you know,
and coming
known,
to be quite
there
is provided,
that
assessments
:alk about,
but
you know,
I guess
17
that
of the specific
the process,
so I think
functional
16
throw
perfusion,
some
we get to final
be used.
I don’t
I might
when
studies,
at all of that
8
25
certain
that would
but
about
of information
language
not going
into play
talked
and highlighted
7
24
come
would
to take
is something
that
have
it
is
at, and then we can use
process
is obviously
as we go forward
going
to be a little
difficult.
DR. LOVE:
)erhaps before
we get
We probably
to that,
MILLER
need
because
to talk
about
FDG
we do recognize
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the
II
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57
relationships,
2
going
to talk
3
maybe
that
4
conversation.
5
and one of the things
about
is the myocardial
can be tabled
MS. TESAR:
6
think
we are coming
7
know,
where
8
I think
back
do these
I think
10
before,
11
this process
12
review.
two different
But
14
concern
15
our issue
16
they
processes.
17
that we are looking
that we need
18
DR.
to what
COLEMAN:
19
say about
20
is my understanding
21
the drug,
I think.
23
bit .
24
results
25
will
In terms
What
we have
today
That
review,
MILLER
comprehensive
know.
side,
Our other
and that
actually
mean,
on top of that,
know
standpoint
we will
be able
is presented
review
will
and we will
how
concerns.
what
we can
it
--
to talk
let me just
is
and I think
the radiopharmaceutical,
of the process,
done
through
as one of our primary
That,
mentioned
So, we don’t
from a commercial
of our review.
be a written
with.
levels
too, about
us, and
you.
we just don’t
I think
MS. AXELRAD:
22
is a very
and thank
to deal
at that
affect
to get
and reimbursement
these
I
is, you
at, as Jane
We want
and this
you know,
before
really
so
of the
us, you know,
I asked
we are looking
is on the HCFA
respond
leads
is
later.
impressive,
then,
of that,
this part
you know,
that
the FDA,
It is very
13
to what
about
aspects
we hear
that
levels,
what
with
until
I think
we can talk
9
that Dr. Raczkowski
about
say a little
the preliminary
be documented.
make
REPORTING COMPANY, INC.
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that
available.
It
ajh
58
1
—
We also will
2
advisory
committee.
3
percent,
but
4
ammonia
I don’t
it is likely
to an advisory
5
That
6
I have
been
7
issue where
8
looked
9
after use
is what
involved
they
of oral
response
11
literature.
want
to commit
we did with
before
to oral
the
was
to that
present
100
both
and efficacy
FDG and
the oral
one that
contraceptives
labeling
of the emergency
and the Agency
petition,
to some
-- the only
contraceptives
contraceptives,
We came
,this to an
committee.
to a citizen’s
12
be presenting
that we will
with
added
at the safety
10
probably
but we looked
conclusions,
or
morningdid
that
in
at the
and we presented
them
—.
13
JO an advisory
14
>ndorsed,
15
indicating
16
safety and efficacy
17
:ncouraged
people
18
.ndication
to the labeling.
19
committee,
and that
that we had made
to submit
nodel here,
21
safety and efficacy
22
Ve will
23
:hen we will
publish
24
md
piece
where
efficacy
some
sort
of following
of these
present
them
something
notice
conclusions
will
make
drugs
about
indication
applications
the Agency
committee
Register
of that particular
so, we are
probably
the advisory
led to a Federal
20
25
which
and
that would
the same
some
sort
findings
for certain
to an advisory
that
the
add
of a
on the
indications.
committee,
can be used
that
and
as a safety
of an application.
It may go so far as to have
MLLLEK
labeling
REEJORrrINGCOMPANY, INC.
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so
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—
59
1
that
the entire
2
will
be these
3
a labeling.
4
the review,
5
but the review
6
detail
7
articles,
8
little
safety
and efficacy
conclusions
or citations
But we will
some
I think
will
have
Florence
also
9
DR.
interested
11
agent,
12
~elow
13
stress
14
~isease,
15
Necessarily
16
it is part
17
~ebulous
18
LO some agreement
19
:hat there
20
indications.
in having
but we are also
that
sort
From
this
to the literature
review,
and I think
and
that
out a lot of her thinking,
discuss
in a little
of illuminate
more
of the
the thinking
see that.
our standpoint,
approved
we are very
as a myocardial
interested
the data
of the application
and the weaknesses
you actually
COLEMAN:
10
that,
laid
of the strengths
when
this
I think
and so that will
more
part
in seeing
support
its use
perfusion
or having
right
for pharmacologic
———
and assessing
the severity
and some of these
a “such
other
as,tt but
of an indication
21
would
be some
MS. A.XELRAD:
22
:hinking
23
Information
24
:he extent
25
~vailable
about,
that would
like
how
it is done
to work
with
on the literature
specific
some of that
be not
other
comments
about
that
to look
imaging
information
you
whether
it
to come
and its analysis
One of the things
on these
artery
in the same paragraph,
it may be impossible
we have
that
things
or just
to us, but we would
based
of coronary
the
I was
at some of the
agents,
and to
may be publicly
—.—.—q
or could
be made
MILLER
publicly
available.
REPORTING COMPANY, INC.
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Since
I
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1
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don’t
know
what
2
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3
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claims
4
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5
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but we could
were
look
documented
DR.
LOVE:
Some
addressing
actually
7
has been
identified.
8
coronary
artery
9
artery
disease
know
whether
to see how
or made,
and we could
6
10
I don’t
then
this
that you are
in some
of the data
the identification
which
was
that
of the
is in the context
and the severity,
of them
see.
are contained
disease,
some of these
and our review
of the pieces
I mean
that would
of coronary
the set of data
that was presented.
11
There
12
I guess
13
here.
14
premature.
15
the labeling
16
extent
17
and then
18
something
19
or something
20
but
what
is information
I am really
The extent
talk
21
what
from
else
I think
what
language
to which
saying
to which
I think
we really
then,
MS. AXELFUU3:
am anticipating
23
is what
24
else.
25
that
we can give
Well , maybe
you,
maybe
we have
I am trying
there
is
article
a lot.
to jump
ahead
because
to say that
to want
REPORTING COMPANY, INC.
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I
this
something
I am just guessing
be the case.
MILLER
can be addressed,
to it at that point,
_——.
just might
see the
is another
are going
not.
about,
at it, and if there
we are going
and you
not, maybe
to do is think
about
we can point
at some point
data may be
be reasonable,
once we look
at this moment
22
need
and the like.
is a lot of data
additional
you are talking
that we need,
motion,
is there
we need
that might
there
else,
on wall
that
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So, what
1
I am trying
2
having
you
to provide
3
having
to go digging
4
at, if we get to that point.
whatever
6
Florence
pointed
7
that
8
interested
9
think
really,
wasn’t
11
indications,
12
can work
I think,
covers
the topics
included
but
with
Eorward
15
specific
16
from
presented
I think
from
this,
areas
then,
we would
let me just
18
The indications
19
mentioned
20
of the labeling.
21
comment
I mean
like
are based
As Florence
22
know,
23
such as perfusion,
24
Qerfusion
agent
25
nedicine,
and there
had
one of the goals
covered,
to see in
we
we go
from us the
or how do we move?
we actually
and which
is to give
go into
your
in the clinical
which
like
I
it
and hopefully
We understand
and that might
is useful,
here
-- well,
how would
said earlier,
here
and as
indication.
I would
do you need
on data,
appears
to get
of it.
Before
briefly.
oftentimes
that
standpoint,
DR. ~CZKOWSKI:
17
of that
in the wording
aspect
that
said,
us
that we are
it is all there
you on that
without
is a lot of data
as part
in the wording
I guess
14
as Patricia
there
presented
13
I think
for
is all I am trying
I mean
it just wasn’t
10
That
out,
in having
out is a way
it is that we need
for it.
DR. COLEMAN:
5
to figure
that,
concern.
has been
trial
section
a lot of times,
a broad
be used
indication,
wherever
is largely
you
a
the practice
of
_—_
may not be a reason
to distinguish
MILLER REPORTING COMPANY, INC.
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——_
62
1
product
from
2
advantages
another
or disadvantages
DR.
3
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5
coronary
artery
6
insert.
Well,
7
to diagnose
8
about
9
reimhrsement
that
how
unless
concern
You know,
payers.
disease,
it says
coronary
that data
one versus
there
and they will
artery
will
are ,some specific
be used
I mean
we get
this
look
to
to diagnose
at the package
perfusion,
disease,
the other.
is when
we are using
to assess
purposes,
there
choosing
COLEP!A3J: Our
4
10
product
it doesn’t
say
and we are concerned
by other
agencies
for
about
it, and
to be blunt
is our concern.
11
If we don’t
have
12
wording,
they are going
13
assesses
perfusion,
14
assess
15
that is in the package
16
~urdle.
the severity
18
discussions
19
3CFA .
20
indications
21
co have
22
~xpectations
23
:hat.
It is going
24
to say, well,
of coronary
artery
insert,
Well,
that
there
to be having
some discussions
are being
What
we will
have
I think
sure
I think
do is talk
to have
if
that
some
scheduled
with
on the oncology
that we will
that
have
everybody’s
is the way
about
to
Whereas,
get us over
a meeting
to make
met,
disease.
is a meeting
for FDG in January.
it
it can be used
that will
we will
specific
the FDA says
say that
I know
.
of the more
it doesn’t
MS. AXELRAD:
17
some
where
I would
put
we are going,
____
25
?robably
not now,
but
I think
MILLER
that
our next
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step will
be to
ajh
63
1
see how
this
2
and then
3
it will
4
next.
have
to translate
some discussions
translate,
5
and then
DR. CONTI:
6
the advisory
7
external,
Jane,
and it will
Medical
11
year.
12
scheduled
heard,
15
views
be a real
Imaging
We will
I have
a labe,l basically,
about
there
how we think
to where
a question
envision
we go
for you about
that,
is that
an
advisory
Advisory
put
be an open public
committee
Committee
meet
this on the agenda
meeting,
meeting.
several
We have
times
a
a
for one of their
meetings.
13
14
you
go from
It will
MS. AXELRAD:
10
with
How do you
panel.
into
internal?
8
9
is going
We will
make
a presentation
the public
will
be invited,
pretty
much
and we will
like you
solicit
their
on it.
16
And
there
committees,
like
DR. RACZKOWSKI:
17
Erom other
18
:ardiorenal
19
someone
from
the Oncologic
20
someone
from
the specific
advisory
Advisory
Committee
MS . AXELRAD :
21
22
the applicant
23
will make
24
presentation,
25
public
make
discussion,
Advisory
use
side
Usually,
a presentation,
a presentation,
you
or,
could,
in this
and then
member
case,
from
the
in the case of FDG,
Committee,
as well,
of it.
we make
a presentation
in this
and if you want
and then
MILLER
may be other
there
they will
case,
to make
will
I guess,
a
be an open
tell us whether
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and
they
we
aj h
—_
64
1
endorse
this
2
3
DR.
COLEMAN:
After
the labeling
discussions
have
occurred?
4
MS. AXELRAD:
5
I want
6
to go with
7
least,
8
ZLt,
9
be presenting
10
or not.
to finish
Probably
-- I don’t
FDG,
too,
you know,
want
whatever
whatever
11
DR.
12
tid present
13
lot discussed
14
applications
to just
way
that
sometime
it to them.
than
the labeling.
I don’t
I mean
do ammonia,
comes
the indications
and so I am envisioning
30 it any earlier
after
out,
I want
for at
are that we look
in the spring
think
we could
we would
probably
the spring.
COLEMAN:
Probably
FDG to the MIDAC,
about
but
seven
oncology
years
ago, we
applications
were
_——.
15
at that
DR. RACZKOWSKI:
what you
17
perspective
18
rou were
19
‘oronary artery
list
said
earlier.
of those
o look
23
ctually
24
he label,
25
abel .
and
cardiologic
disease
would
it would
the
or for use
be helpful
“such
go back
be helpful
as,”
in stress
it would
of products
that
of what
up the way
things
our
that
of
testing,
be useful
having
you would
it will
for you
are out there
want
actually
----
MILLER
from
to
to us.
I think
us language
written
we should
in, if it is for the diagnosis
at the labels
give
I think
exactly
MS. AXELRAD:
22
But
I think
if we knew
interested
21
the necrologic
were.
16
20
time,
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and
to see in
look
in the
aj h
———
..
65
DR. LOVE :
1
2
look
at some of the more
recent
ones.
3
4
And
DR.
that would
COLEMAN :
support
5
The wording
it.
We will
MS. AXELRAD:
6
can continue
7
don’t
with
after
at the data
to you.
that we take
discussion
we take a 10-minute
8
get those
I suggest
this
and looking
a break.
the break,
We
but why
break.
[Recess.]
9
MS. AXELRAD:
10
have
11
on ammonia?
any other
12
issues
Before
we turn
or things
that
to FDG,
they want
does
anybody
to talk
about
[No response.]
13
MS. AXELRAD:
14
Presentation
15
DR. RACZKOWSKI:
16
ammonia,
17
focus
18
:linical
19
nuch less
20
such as chemistry
21
ordinarily
and
I will
Okay,
of PET FDG Literature
and statistical
22
Florence
be talking
of my presentation
emphasis
:hat there
24
~sually
literature
placed
25
:oday will
on some
or pharmacology
go into
a review
are other
include
about
this morning
As I go through
23
Victor.
parts
this
will
review.
N-13
There
will
that
product.
please
keep
disciplines
of drug products.
to the cardiac
MILLER REPORTING COMPANY, INC.
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be
disciplines,
or biopharmaceutics
talk,
The
be on the
of the other
and other
be limited
about
the FDG review.
of any drug
in our reviews
really
talked
Review
in mind
that we
My talk
indications
for
ajh
.——.
66
1
FDG .
2
administratively
3
the cardiac
Our team
is running
from
[Slide.]
5
I want
6
team:
7
want
a
Jordan,
9
have done
Dr.
Sobhan,
helping
11
track
things
12
amount
The other
~ussong;
14
pharmacologist/toxicologist;
15
)iopharmaceutics
R. Kasliwal,
manager,
who
they
in terms
references,
of
helping
organized.
are microbiology,
the chemist;
is Ruby
because
just
things
of the
I particular-y
Leedum,
literature
disciplines
13
project
of work
and keeping
members
also,
and R.K.
of these
down,
and are reviewing
the other
our program
a tremendous
some
team,
the statistician,
and Kim Colangelo,
get
bit behind
currently.
to acknowledge
to acknowledge
10
the ammonia
indications
4
a little
Dr.
David
Laniyonu,
who
is a
Sancho,
who
is the
and Alfredo
reviewer.
16
[Slide.]
17
Like
Florence,
what
18
ny conclusions
19
preliminary
20
:he talk,
21
:his, and from a clinical
22
~ppears that
23
.iterature
24
lyocardium.
25
)ecause that word
I would
at the beginning
conclusions
so you don’t
there
with
like
of the talk
our review
wonder
to do is give
where
or our
at the beginning
we are heading
and statistical
sufficient
evidence
for FDG to be able
to identify
“viable”
the word
“viable”
is sometime
used
MILLER
in quotation
differently
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of
with
perspective,
is probably
I put
you
it
in the
marks
by different
ajh
67
1
people,
and
2
of the implications
3
if you are interested,
ammonia
5
was
6
had dosimetry
7
clinical
review,
about
easier
than
some
the
had a previous
the safety
information
data
was
we already
and so from
safety
8
our review
because
submitted,
talk
of that.
In some ways
4
we could
NDA
perspective
for FDG, we already
that
we already
had
some
on FDG.
[Slide.]
9
The
search
criteria
10
identical
to the search
11
ammonia.
We wish
12
submitted.
13
the talk.
14
criteria
to thank
I will
you
references
16
American
17
Association
guideline
18
circulation
and the Journal
19
~ardiologyr
and from
20
~edicine
for the cardiac
21
to some
that
for the
that
that you
later
source
for FDG came
and the American
statements
are both
of the American
the USPDI
essentially
of those
another
indications
of Cardiology
position
that we used
to comment
15
were
for the articles
be referring
I also want
College
that we used
of
from
the
Heart
in
College
and the Society
in
of
of Nuclear
statements.
[Slide.]
22
This
23
lumber
24
search,
25
indications
gives
of references
and
these
and
you a little
that were
include
for other
MILLER
both
bit
of an idea of the
retrieved
on the literature
references
for cardiologic
indications,
such as oncology
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or
ajh
_—_
68
1
neurology.
..
2
[Slide.]
3
I apologize
4
represents
5
Power
the conversion,
Point
6
When
8
on exactly
9
useful
framework
Medical
Imaging
where
from
our review
Power
be going
for the review
guidance,
but
Point
this
7 to
13
there
14
:hink that
it provides
15
=alk about
a common
16
co approach
these
17
implications
18
Ruture.
is literature
the clinical
with
with
back
Jennifer
framework
to think
products,
for products
and
about
now,
discussed.
it is not
but
in terms
how
I still
for us to.
to review
and how
has
be developed
in the
[Slide.]
20
As Dr. Love
21
lumber of different
22
;hat guidance
23
md
24
diagnostic
functional,
and
has already
potential
document,
therapeutic
My purpose
claims
ranging
biochemical
from
patient
to, there
structural
in
delineation
all the way up to
management
this
are a
that are outlined
assessment,
for showing
MILLER
alluded
slide
REPORTING COMPANY, INC.
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a
for FDG, which
and it certainly
that might
I think
in the draft
been
guidance
and
is reflect
earlier,
for decades
a useful
way
this,
has already
that draft
going
we did
is summarized
which
talking
that we are implementing
from
one of the things
we might
12
25
I guess,
perspective,
As I was
19
___
we began
statistical
11
on the slides,
4.
7
10
for the format
decisions.
is to let you
ajh
—
69
1
know
that when
we did the literature
2
indications
3
thinking
4
maybe
5
alluded
6
category,
more
7
limiting
things
8
our review.
for FDG, we approached
about
which
which
it go into,
to, oftentimes
9
DR.
10
~eveloping
11
m
that
12
one box,
by that,
COLEMAN:
multiple
last
products
but
an open mind,
it into a box,
although
as Dr. Love
fit into more
than
has
one
and so we are not necessarily
this provided
Victor,
claims,
fo,r the cardiac
it with
-- if you had to put
box would
than
review
did you
other
the framework
say you have
claims
with
for
been
the last
two
slide?
DR. RACZKOWSKI:
The question
was did
I say
_—_
13
something
14
nultiple
15
md
16
sxample
17
?erfusion,
18
?athology
19
~rugs or many
20
~iagnostic
21
:ategory.
about
multiple
claims
are is that
for example,
you might
of ammonia,
22
claims
drugs
and perhaps
detection
or other
sometimes
have
-- and
also
or assessment
This
in general
framework
23
jmaging and Drug
24
~ith input
from
25
1 response
in large
Advisory
was
MILLER
cross
I will
use
be useful
the line,
the
for
for disease
-- in other
words,
or many
fit into more
developed
Committee,
or
many
PET products,
than
one
by the Medical
with
the radiopharmaceutical
part
and what
get a claim
radiopharmaceuticals
agents
things
that might
might
claims,
by the Agency
their
industry,
assistance
and
it was
to try to acknowledge
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ajh
—
70
1
some of the thinking
2
We simply
3
that
4
straddle
5
not be encompassed
6
specific
7
the guidance
8
situation,
9
discussions
10
of the diagnostic
sometimes
put down multiple
don’t
more
than
example
neatly
other
by the above,
right
now,
but
is that
to approach
prior
to doing
claims
fit into
one box,
document
just
community.
one box,
claims
and
they may
or things
I can’t
the basic
if you
to acknowledge
think
of a
recommendation
are ever
the Agency
that may
in
in that
and have
some
of the clinical
sort
of overlaps
some
trials
with
it.
11
DR.
12
ammonia
13
~p a little
CONTI:
This
conversation
we had a few moments
.-.
14
bit
on what
Is it your
intention
15
:his draft
guidance
16
)iologics,
is it your
17
:unctional
physiological
18
leal with
19
latter?
20
issues
DR.
21
[uestion
22
let.
23
.ctually had
24
,nd get
25
ee what
that
intention
are more
in terms
an idea
sort
of claims
disease-specific,
in terms
the answer
of what
in terms
and
might
from
that.
MILLER REPORTING COMPANY, INC.
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or does
it
to that
this data
of clinical
use patterns
Washington, D.C. 20002
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first,
the literature
the actual
come
to follow
assessment,
the way we approached
of data,
of what
drugs
to try to assign,
I think
to look
and to pick
said.
imaging
or biochemical
RJICZKOWSKI:
idea was
just
ago,
to the
to, if we are going
for the medical
is no, at least
The
Dr. Coleman
back
were
trials,
and to
ajh
—
71
1
MS . AXELRAD :
2
applicants
3
and to guide
4
a way
5
the various
who are putting
them
that will
6
levels
7
trying
8
be made
9
from you what
to look
is the best
12
ammonia
13
out sort
14
need to have
in fact,
claim
we think
trying
17
looking
18
are really
want
to have
tias because
I think
it just
21
we can talk
about.
It is not
22
Squeeze
23
[Slide.]
24
Some
25
locument
does
see what
that
on the
we came
detail,
we
that.
of the discussions
so that when
we are
by what
you
of a claim.
for showing
a common
this
that
try to
box.
that we Medical
whatever
slide
framework
that we are necessarily
a particular
that
more
we can be guided
provides
of the things
stress,
some
My intent
20
could
exactly
is where
about
earlier,
for in terms
into
this
discussions
DR. RACZKOWSKI:
knowing
and I think
if we want
indications
looking
claim
at it and just
we said
the literature,
something
to support
to make.
easily,
further
the oncology
through
in
in that we are
without
to look
you know,
We might
about
trials
information
we can do here,
of relatively
16
clinical
and to see what
really
you wanted
discussion,
15
their
it backwards
at the literature
some
New Drug Applications,
the necessary
we are doing
So, we were
11
for
of claims.
by it, and,
10
is really, designed
together
in how to design
provide
Here,
19
The guidance
Image
an imaging
MILLER REPORTING COMPANY, INC.
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guidance
agent
does
or
—
aj h
72
-.—
1
PET product
does,
2
by that
to be valid.
has
3
What
4
the drug
5
about
6
agent.
is that
valid
is doing
7
[Slide.]
8
Just
9
the ammonia
nlinical
11
were some very
12
iesign,
13
or interpreted,
14
=he study
15
?opulation
16
md
17
>ias in the clinical
18
similar
that might
~ better
about
21
there
of study
acquired
and so forth,
receive
followed
whether
to the
the imaging
to reduce
agent,
potential
trials.
go into
specific
flavor
were
actually
similar
that
in a
of details
were
sufficiently
ultimately
procedures
I will
20
was
of things
review,
in terms
analyses,
things
of the imaging
a number
images
that
also
of the FDG products,
concerns
how
is simply
and then
at in their
review
statistical
population
it does,
outlined
population,
that, is provided
context
usefulness
looking
and statistical
whether
: talk
it says
clinical
team was
study
in this
as Florence
10
19
means
what
the potential
the information
some
specific
literature
of what
examples
articles,
our thinking
might
of this when
just
to give you
be.
[Slide.]
22
Based
on a number
23
)utlined,
24
“oughly 10 or 11 articles
25
“or FDG
our initial
for myocardial
of criteria
literature
that
which
selection
appeared
viability,
and
I have
boiled
to support
I have
MILLER REPORTING COMPANY, INC.
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down
to
a claim
put asterisks
...-. .
aj h
..—
73
1,
by some
2
Again,
3
examples.
of those
I will
be going
4
[Slide. 1
5
But
6
mentioning
7
review.
8
you know,
9
so what
some
through
is much
it is hard
I thought
I think
about
11
that we have
review
12
claim
specific
it is worth
issues
like putting
about
together
to find definitive
I would
the thinking
by the PET community.
some of these
of the inherent
10
do is give
just
literature
a jigsaw
literature
a sampling
help
support
article,
of some
four or five of the literature
that we think
puzzle,
of
articles
a viability
for FDG.
My intent
14
weaknesses
15
articles
16
take
17
a more
18
actually
some
in talking
of those
or single
risk
look
articles
about
idea
the strength
is not to single
out particular
at doing
concrete
19
20
provided
at this point
This
13
that,
but
authors,
rather,
and
out particular
in fact,
I would
it is to give
of some of the issues
we face when
you
we
at the literature.
MS. AXELRAD:
None
of the authors
are in the room,
I hope.
21
[Laughter.]
22
,.,
that were
DR. ~CZKOWSKI:
23
through
most
24
talking
about
25
Florence,
The next
of the remainder
four
I have
of this
or five different
outlined
MILLER
them
set of slides
talk,
clinical
I will
and
be
trials.
Like
in the way we traditionally
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aj h
74
1
think
2
is to provide
about
these
sorts
of things,
because
the ultimate
goal
.-
3
labeling
for a product.
[Slide.]
4
The
first
study
I will
5
al.,
6
and diastolic
left ventricular
7
artery
grafting
and the objective
bypass
8
9
One
is they
thing
10
them had
11
FDG for viability,
12
Eunction
13
XBG,
14
afterwards
15
:linical
some
sort
done
in terms
so,
17
m
18
nyocardial
19
~one both
20
~yocardial
agent
similar
after
to many
in their
prior,
to some
was
systolic
coronary
of these
design,
both
and most
sort
of
and
of myocardial
sort of intervention,
some
trials
for perfusion
an assessment
of myocardial
perfusion,
perfusion.
prior
of follow-up
function
study,
such as
done
or in terms
rubidium
and FDG was used
Two-dimensional
to and after
of
CABG
was used
to evaluate
echocardiography
in order
as
was
to assess
function.
functions
22
m
23
Jlobal and regional
24
Jew York
25
is common
in this particular
to evaluate
The
that
to assess
et
outcomes.
16
21
is by Carrel,
surgery.
done
there
was
function
of PET imaging,
prior
and then
of the study
that
are all very
talk about
slide,
Heart
There
like
that were
left ventricular
wall
Association
were
evaluated,
motion,
23 subjects
rmmm
ejection
diastolic
functional
with
the endpoints
fraction,
relaxation,
class.
coronary
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artery
both
the
aj h
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disease
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who were
enrolled.
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8
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the PET images
article
is that
of the materials
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echo
mean
specify
readings
to influence
someone’s
interpretation
12
influence
his or her reading
Oftentimes
14
:he clinical
15
sense in which
16
course
17
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18
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19
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20
>f these
articles
21
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to get some
22
md
23
)f these
24
~hether it would
we might
implies
want
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I don’t
know
points
are
of that
I want
to talk
of
want
to
with
That
is the
about
that
and we might
and
things
missing,
it would
find particular
to
be useful
or
it might
on these
in some
be
things,
be useful
for some
important
as to
trying
to get that
people
to take
away
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want
to the extent
information
whether
be worth
we
want
of familiarity
if it would
information,
that you
But also
don’t
as well.
through,
about
you don/t
interpretation
a lack
you get
talk
words,
“blinded,”
“blinded. “
We might
there
and by
you
after
to get
is
of the PET images.
the term
MS. AXELFU.D:
later,
in other
of the subject,
we use
the
of the article
of a 2-D echocardiogram
that
this
the PET or two-
somebody’s
11
about
evaluations,
blinded,
and conversely,
CABG.
make
part
whether
were
to one another,
function,
I will
and methods
VeIItrlCUlar
13
that
before
in the image
10
25
45 percent
One of the comments
4
had left ventricular
information.
that
it would
aj h
76
1
be really
2
studies
3
this have
useful
for new stuff,
that
if you are doing
>.
for new
4
compounds
this
kind
or new
indications,
that we have
of information.
[Slide.]
5
DR. lZACZKOWSKI:
So, the results
6
again,
7
ejection
8
and at exercise.
Wall motion,
there
9
in segmental
motion
before
looking
at the primary
fraction
was
wall
significantly
10
surgery,
11
FDG to predict
12
of the segments
13
which you have
14
lecreased
perfusion
15
;here was
an 84 percent
16
indicates
some
17
flyocardial segment.
however,
endpoints,
score
if you looked
functional
read,
of that
left ventricular
increased
both
at rest
was no overall
and after
improvement,
there
value
was
mismatch
change
CABG
at the predictive
the so-called
study
of
84 percent
pattern
in
.—
18
:egments
20
.ntervals
21
improvement,
22
)attern, which
23
.njury.
24
that were
there
broad
functional
that
only
and
a few number
usually
injured
of
so the confidence
but
there
was
only
implies
sort
some
here
cited
which
irreversibly
in those
I have
or
segment,
there,
improvement,
comment
MILLER
rate
but not
were
here,
oftentimes
just
myocardial
prediction
evaluated,
are very
few papers
of FDG and normal
sort of injured,
I will
he
uptake
to a particular
Conversely,
19
25
increased
because
that
the match
of irreversible
this
actually
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with
25 percent
is one of
looked
at
-.
ajh
77
1
this,
2
evaluated,
3
Heart
but
some
of the clinical
outcomes
were
actually
,,....
and just
Association
[Slide.]
5
Some
improved
of the strengths
6
specifically
7
sometimes
8
this one actually
was prospective,
figure
As
that
I indicated,
Outcomes,
11
neaning
12
nyocardium,
but
13
as ejection
fraction,
14
Further
15
;eart Association
not
only
also
and looking
global
17
;ome of the endpoints
18
>oint afterwards.
19
~chocardiography
was not just
20
~hich is I would
say usually
21
Lrticles,
but
22
:hat sort
of information
23
longitudinal
24
waluating
about
segments
carrying
about
evaluated
that
MILLER
spectrum
of
of the
such
one step
such
as New York
article
at more
evaluated
what
is very
what
this
myocardial
I have
a couple
the graft
study.
function,
might
patency
that
one time
function
with
at one time point,
seen
time points
helpful
was
than
in most
be optimal
was assessed
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of the
evaluated,
in terms
something.
Also,
but
function,
.
25
to
or regions
outcomes,
For example,
data
a whole
it
classification.
thing
were
that
it was a prospective
left ventricular
and then
were
was
the literature,
left ventricular
at clinical
there
all patients.
reading
myocardial
useful
for nearly
it evaluated
functional
Another
the New York
and it is difficult
that
regional
the particular
statement,
of this protocol
out from
indicated
10
16
..
class
4
9
as a general
and
of having
times
for
aj h
78
1
postoperatively.
2
[Slide.]
3
Some
4
see that
5
why I think
6
puzzle,
7
different
8
support
of the weaknesses
a lot in many
when
seeing
there
where
small
were
small
of these
articles.
is, this
is somewhat
the preponderance
articles
actually,
sample
Again,
size.
that
like
small
is
a jigsaw
of the data
with
We
for many
sample
sizes
a claim.
9
It didn’t
say, but probably
10
saying,
11
=chocardiography
12
aata was
13
nyocardial
segment
14
;here were
only
15
father
16
:he patients,
or at least
17
;egments
all the patients,
18
md
19
;egments,
20
:here is always
21
:hat could
22
Irom the trial.
probably
really
than
all those
23
images
left
25
localities,
evaluated
blindly.
some
this
or all those
selected
of bias
two-dimensional
and again
and so
from
with
mismatch
some of the
assessment,
because
segments,
and conclusions
that
technologies
starting
here
echocardiography,
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all
myocardial
in selecting
that we are
two different
of the
one
segments
all the dysfunctional
the results
thing
Only
in the study,
to see an overall
sort
Some
in each patient,
at all the myocardial
match,
influence
.s we have
not read
20 or so patients
and we like
24
were
out in the evaluation.
was
with
Another
of it
the PET and two-dimensional
looking
from
in the lack
and
come
to see a lot of
or two different
trying
to get
.- -. -
..
aj h
79
1
a common
-- when
2
trying
3
you are actually
4
segment
5
was unclear
you
are talking
about
myocardial
segments,
>-..
to align
7
have .
8
~ave just
9
zhink
that you
and
COLEMAN:
I wish
there
it certainly
that was done
that
about
article,
be included
it
at all.
for that
stress
that
the same
is a big problem
answer
and really
a way
we all
one, but you
how you do it, I
how
one has tried
to
those.
DR. RACZKOWSKI:
12
Subsequent
13
~ctually
papers,
And
you will
I think
see that
that
some
some of the
of the authors
did do that.
14
DR. COLEMAN:
15
DR. FUICZKOWSKI:
16
[Slide.]
17
It was difficult
18
information
19
:hings
20
nillicuries
It is not
Right
about
what
dose
or what
There
22
flanuscript, but
23
:eadily
some very
about
was
that was
a reference
basic
some very
actually
the PET protocol
it was
regardless.
absolutely.
of FDG was
was a reference
available
easy
to find
in this manuscript
21
25
are talking
Victor,
should
in such
in this particular
was a good
got to work
11
24
of imaging
how or whether
DR.
relate
sure
of myocardium,
6
10
the planes
fundamental
used,
how many
for imaging.
supplied
in German
in the
that was not
to us.
[Slide.]
The
second
study
I would
like
to comment
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on is the
aj h
80
1
study
2
was
3
to revascularization,
4
be familiar
5
myocardium
6
tissue
7
dysfunctional
8
lack
by Marwick,
to evaluate
et al.,
the metabolic
with
and
response
for those
this particular
is a term
that
and the objective
still
that
has not lost
due to some
study
of hibernating
tissue
in the room who may not
area,
is used
of this
hibernating
to describe
its function,
sort of chronic
myocardial
but
is
insult,
usually
a
of perfusion.
9
The design
was
similar
10
both pre-
and post-assessments,
11
perfusion
with
12
echocardiography
13
functional
14
with echocardiography,
15
perfusion,
16
~efore
17
actually
18
?erfusion
19
intervention.
rubidium,
did
20
that were
that,
this
assessments
21
rhey were
22
particularly
23
:asting
24
lot , that
25
>ur instructions
are
both
it was a small
fasting.
with
or not,
could
Again,
something
or whether
important
those
like
trial,
to know,
to evaluate
did PET studies
both
we write
both
that
of
and post-surgical
only
FDG, whether
because
of
wall motion
16 patients.
are the sorts
the patient
for use when
MILLER
were
be made
pre-
was
and the
is one of the few studies
and of FDG activity
Again,
they
though,
outcomes,
was used
since
There
two-dimensional
evaluated
rubidium
CABG,
case,
functional
and FDG activity,
and after
in this
and also used
to evaluate
outcomes
to the others.
of details,
a patient
is glucose
loaded
they help
a package
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is
or
us write
insert,
you
aj h
1
know,
what
2
should
3
sort
is the optimal
it be glucose
of details
4
The
loaded
are useful
severity
5
in that
there
6
and most
7
the number
8
it did have
9
echocardiography
were
of patients,
10
[Slide.]
11
Basically,
identified
13
motion
14
hibernating.
15
in other
words,
16
Cunction
returned,
17
segments
were
18
5idn’t,
This
but
this
also
both
But among
defects
of which
both
limited
disease,
at not only
of segments,
significant
improvement
22
?erfusion,
and decrease
23
{OU would
24
cecovery
25
it is being
there
were
occurred
has looked
were
and
classified
as
to see whether
if function
did return,
those
if they
as non-hibernating.
in wall
segments,
motion,
is some
there
an increase
in FDG activity,
and if FDG is really
wall
postoperatively,
as bei.ng hibernating,
if there
85 segments
and resting
41 percent
the hibernating
21
trapped
somewhat
for the
perfusion
classified
20
looked
were
and then
[Slide.]
So, those
three-vessel
the results
the author
19
was
the number
readers
classified
expect
without
specification
they were
or what.
under,
for the PET studies.
fixed
disturbances,
the drug
in manuscripts.
did,
some blinded
12
or fasted
patients
and
to use
of the disease
of the studies
with
conditions
all things
sort
of functional
a marker
for viability
in the myocardial
cells
MILLER REPORTING COMPANY, INC.
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because
was
a
in
which
and if
of a
aj h
82
,—_
1
transfer
2
normal
of metabolic
activity
from
lipid
uptake,
which
is
.-.
myocardial
3
route
to glucose
uptake.
[Slide.]
4
As in many
5
classified
6
versus
7
results
8
non-hibernating
9
irreversibly
as being
of these
viable
non-hibernating,
seen
in terms
those,
11
by FDG criteria.
76 percent
12
of what
injured,
10
versus
there
segments,
those
correctly
or hibernating
reciprocal
you would
was
that were
non-viable,
were
those
there
were
studies,
are
type
expect,
the ones
and that
the
that were
a significant
predicted
of
percentage
of
to be non-viable
[Slide.]
13
Again,
14
~valuations
15
1 am sorry
16
~oth pre-operative
17
~ lot of discussion
18
llignment.
19
both
some
of the strengths.
for the PET and
-- for the echo
In this
?DG scans,
21
vas particularly
22
:his was
done
23
:ubidium
scans
24
~mages, but
25
lere, echocardiography
they
rubidium
talked
important
under
fasting
provided
also
evaluations.
in this particular
case,
how
about
article
reference
two different
PET,
aligned
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was
image
with
the
and it
case because
and so the
for the FDG
modalities,
and the author
MILLER REPORTING COMPANY, INC.
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there
about
that was done,
circumstances,
to align
with
and here,
was being
how
--
PET was performed
in this particular
a useful
image
for the FDG evaluations
and post-operatively,
20
but
Blinded
has
..
aj h
83
-_
1
described
2
and in echocardiography
3
to one another.
how
they define
segment
of myocardium
both
in PET
......
4
Again,
6
patients
7
some
8
diversity,
9
evaluated.
were
sample
excluded
from
of the functional
a broad
to be comparable
patients
11
of how
the product
12
disease
severity.
and some
we like
of patients
only want
or the most
size,
the protocol.
claims,
range
We don’t
13
Particularly
are being
to see the least
across
for
to see a broad
that
sick patients.
performs
of the sickest
We want
sick
to have
the entire
an idea
spectrum
of
[Slide.]
14
The
third
15
31.
16
in the evaluation
17
this case,
18
assessment,
19
md
20
were wall
Its objective
:asting,
paper
was
I will
to assess
of pulmonary
instead
of doing
radionuclide
post-CABG.
21
_—
small
10
23
thought
[Slide.]
5
22
that were
and perfusion.
Again,
22 subjects,
image
24
=or the PET and again
25
‘entriculograms
artery
bypass
that were
were
value
et
of PET
grafting.
In
for functional
was done both
evaluated
relatively
undergoing
evaluations
is by Tamaki,
the clinical
ventriculography
motion
The
about
echocardiography
The endpoints
all of them were
talk
small
with
prethat
trial,
CABG.
done
by blinded
readers
blinded
readers
for the radionuclide
for function,
so that
is a good
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thing.
. .
aj h
84
1
[Slide. ]
2
_—.
Again,
I won’t
3
the results,
4
sorts
5
in terms
of viability
6
segments
of myocardium
7
both for wall
but
simply
of things
spend
comment
that were
that
being
the directions
predicted
and non-viability
were
found
talking
about
and the
by the FDG and PET
of particular
in this particular
trial,
motion.
8
[Slide.]
9
I think
10
?articular
11
concept
12
actually
13
IOU can look
14
?re-operatively
15
nyocardial
16
~erms of uptake
17
{OU would
18
:hing is true
this
claim,
is less
although
for a viability
did
and
of claim,
after
segment,
expect,
those
restoration
whether
in that
words,
for the rubidium
20
Strengths.
There
21
:here was more
than
one,
22
rere performed
both
before
23
:eaders,
24
:he PET scans.
not only
I may
some
MILLER
procedure,
were
of
authors
and so
that were
viable
to that
concordant
were,
with
they go down.
The
in
what
same
perfusion.
were
there
these
the FDG changes
multiple
were
blinded
three.
and after
CABG,
for the radionuclide
have
is that
segments
or not
for this
some proof
of perfusion
segment,
in other
[Slide.]
perhaps
the bypass
see whether
with
important
it does provide
type
PET scans
19
25
a lot of time
contradictory
Again,
PET scans
and multiple
scans,
things
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readers,
but
also
here.
for
Here,
.
ajh
-—____
-.
85
1
1 say that
2
can’t
3
earlier
the readers
of the PET
scans
were
not blinded.
I
...
.-
recall
is different
from what
I have
said
or not.
4
DR.
5
DR. RACZKOWSKI:
6
[Slide.]
7
The
COLEMAIS:
final
8
of the manuscripts,
9
illustrative
You
said not blinded.
Thank
study
that
and again
purposes,
approached
11
in the New England
12
A fairly
small
studies,
significant
13
the first
14
studies
the literature,
in segments
17
lot , and whether
18
without
19
~sed to assess
20
~entriculography
21
lsed both
22
pre-
reticle
24
;canning,
25
comparative
is that
motion
it was
et al. ,
I think
or most
was
one of
significant
to determine
indicates
and both
viability
functional
as a perfusion
depending
contrast
to assess
of the patients
at the issue
of information
or radionuclide
patient
were
function.
of this particular
received
of some
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of the
that you might
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or
and FDG was
ventricular
aspects
if FDG
recovery.
agent,
on the particular
and post-CABG
types
by Tillisch,
time.
was used
so this gets
but
it predicts
a subset
for
an idea of how we
studies
One of the interesting
23
in terms
of Medicine.
normal
viability,
to talk about
are just
of the study
or not
Ammonia
these
study,
early
The objective
16
I want
is a study
Journal
at a fairly
you.
so you have
10
15
_-
if that
be able
to
aj h
,--,
.-
86
1
get
2
this
3
to how
from
comparing
case
comparing
FDG might
4
5
two different
how thallium
be able
Seventeen
loaded,
with
viability
compared
viability.
The patients
abnormal
in
motion
were
were
glucose
assessed.
[Slide.]
7
The dose was
8
motion
9
the contrast
and ejection
10
The
10 mCi
PET images
require
12
out a region
of interest,
13
region
of interest
14
people
who
15
results
16
clinical
are doing
of the other’s
status
Again,
per
but
were
wall
used
quantitatively,
se unless
in those
we would
diagnostic
you have
situations
for
that
be blinded
modalities
so
to go
where
recommend
sort of thing
a
those
to the
and to the
of the patient.
they
talked
18
was achieved
between
19
radionuclide
ventriculography
20
evaluated
a reader
that
readers
were
ventriculograms.
were
is drawn,
Endpoints
Blinded
and radionuclide
that doesn’t
17
of FDG.
fraction.
11
about
the different
how regional
types
concordance
of scans,
the
and the PET images.
[Slide.]
21
Again,
22
comment
23
would
24
viability.
25
to one, another,
assesses
to assess
patients.
73 segments
6
agents
that
expect
I won’t
they were
dwell
basically
on the results,
in the direction
to see if FDG is able
to detect
[Slide.]
MILLER
but
REPORTING COMPANY, INC.
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Washington, D.C. 20002
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to
that you
myocardial
aj h
-—__
1
Many
2
touched
3
mentioned,
4
and may be less prone
5
by visual
on already
strengths
- blinded
and weaknesses
image
As I have
evaluation
to possible
I have
evaluations.
this had a quantitative
biases
of PET images
that
are
introduced
analysis.
6
[Slide.]
7
Again,
8
study
9
actually
tried
as part
to indicate
successful
of a proof
whether
or not,
10
a particular
11
you should
see changes
12
concordant
with
13
good marker
14
revascularizing
15
sorts of outcomes.
16
myocardial
what
segment
you would
was
expect
this
was
expect
revascularized,
in that myocardial
for viability,
thing,
revascularization
because
you would
them,
of concept
segment
that
if
then,
that
are
for FDG if it is a
and if it is not
not necessarily
successful
looking
at
for those
[Slide.]
17
That
is my summary
18
:he articles
19
:hinking
that we have
20
[ would
just
21
]riefly
on an abstract
about
22
_—_
of these
when
shift
It was
23
;ommenting
24
:hings, a number
25
cooperative
of just
looked
we review
gears,
just
on because
that
here,
an abstract,
it raises
PET group,
just
and
I thought
to comment
in Heart
but
of some of
we were
articles,
appeared
of interesting
European
at and what
these
right
a sampling
I think
in 1996.
it is worth
a number
of interesting
issues.
This
so it was
done
MILLER REPORTING COMPANY, INC.
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Washington, D.C. 20002
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was done by a
by multiple
aj h
88
-_
1
PET centers
2
some of the results.
3
[Slide.]
4
If you look
this was
at just
sort of trial,
6
the time
of the interim
analysis,
7
appeared,
105 patients
had already
8
evaluated.
It shows
9
from a multicenter
in more
12
the published
13
our review
14
likely
detail,
16
features
that
17
that when
18
protocol
19
so almost
20
prospective
21
whether
22
generating
final
by definition
25
hypothesis
something
that you
many
which
can get
saying
confirming
MILLER
talked
that
out before
it won’t
FDG.
the design
some multicenter
trials,
times
you have
trials,
a common
are working
that means
trial
about
and unless
comes
about
is a desirable
confirming
and then
to note
a particular
versus
I have
objectives,
investigators
It is a difference
find
abstract
completely
manuscript
with
you do multicenter
study,
that
of thinking
wanted
are inherent
we feel that
24
and at
this
it is an abstract,
in our way
that multiple
23
of
achieved
enrolled,
of power
similar
because
I really
versus
been
of the studies
manuscript,
But
that were
at the time
the type
it had very
much
were
analysis
study.
is done,
play
502 patients
you
Like many
11
an interim
the numbers
in this
15
—
and
5
10
,-.
in Europe,
from,
and
it is a
feature
in terms
of
is hypothesis-
a hypothesis.
between
something
data
dredging
upfront
it.
REPORTING COMPANY, INC.
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to try to
about
a
ajh
89
—_
1
The other
2
you get probably
3
because
4
patients
5
institutions
6
nature
7
peculiarities
8
having
9
results
will
10
groups,
as well
11
they are not
12
is a very
aspect
more
represent
who you might
may have
that
trial
be robust
makes
across
about
the
see or different
it more
different
types
dependent
of
Particular
PET procedures
as different
desirable
spectrum
peculiarities
they
the way
so much
see.
particular
t,rials is that
of the results
a broader
otherwise
of the patients
a multicenter
multicenter
generalizability
the patients
about
about
are done,
likely
types
that
the
of patient
of investigators,
on one
and
investigator,
and
so that
feature.
.- ‘-..
13
I really
14
this is something
15
:ountry
16
sxisting
perhaps
for future
types
PET products
17
[Slide.]
18
So, just
19
:alked
20
~ET , there
21
pharmacology
22
?rior NDA,
23
oy Dr.
24
Jlucose
25
just put
about
NDA,
metabolism
Although
want
we know
to emphasize
a lot about
the prior
there
were
for
review
vis-a-vis
dosimetry
MILLER REPORTING COMPANY, INC.
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the basic
for the
that was done
in the heart
lipid
data
I have
that with
FDG review
of how FDG behaves
in the heart
in this
or indications
of the things
as for the current
in terms
that
be developed.
of some
from
I think
be considered
of PET products
I really
of FDG both
Laniyonu
should
that might
a prior
as well
that
a summary
today.
was
this up because
and
metabolism.
in the original
aj h
.-=
90
1
NDA,
some
of the questions
2
pharmacokinetic
3
with
4
widespread
5
diabetic
6
the patients
7
by renal
what
this product
population,
patients
be like when
not particularly
renally
impaired,
by ,our
reviewers
and do we have
to do
it is used
any
in a
information
relevant
since
have
in
to FDG, whether
it is largely
excreted
route.
so,
I think
from
9
preliminary
conclusions
10
nyocardium,
and from
11
preexisting
data
12
articles,
13
my
14
?atient
15
?opulation
16
actually
17
indication
but
reason
are that
the safety
from
an NDA,
the question
to believe
population,
But
we would
raise
here
in that NDA,
cardiac
md
Dr.
Conti,
had to do with
21
md
are
fairly
empirical
22
safety.
23
mimal
24
iata.
by I think
this particular
the patient
even
though
the
about
isn’t
of these
the way we think
data
with
issue
it was by Dr. Coleman
in terms
some
sort
even mentioned
REPORTING COMPANY, INC.
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MILLER
is, is there
and the other
the safety
to see concrete
safety
literature
indication.
and supplemented
Usually,
viable
and that NDA
patients
is the way we think,
20
studies
patients,
than
our
we had
cited
rhich was mentioned
We like
perspective,
be different
earlier
identify
again
for neurological
that
FDG may
cardiac
some
perspective,
which
reviewed
include
was
that
might
that was
did
the efficacy
19
25
are raised
or by pharmaceutics
will
8
18
that
products,
about
of either
of human
even
in
.. _. .-.-.
aj h
91
1
passing
in many
2
it is unclear
3
what
sort
4
5
an adverse
6
and many
7
might
8
really
9
empirical
10
of the journal
if it was
really
of safety
assessments
Oftentimes
individual
event
to some
of these
cardiac
not be ascribed
systematic
data
sort
assessed
in any way
were
11
I will
12
Discussion
stop
disease
are very
but
of safety
a particular
so
at all or
might
of underlying
feel
and
done.
investigators
to the drug,
evaluation
that
that we read,
patients
that we really
the conclusion
articles
process,
sick,
so they
it is only
through
data
and getting
comfortable
drug
ascribe
product
with
a
some
reaching
is safe.
there.
of PET FDG Literature
Review
.K–+-%
13
14
MR.
have
SARVI:
information
about
15
DR.
16
MR. SARVI:
17
DR.
18
the Society
19
tabulation
20
He published
21
ago .
22
Journal
23
coming
24
25
With
Ted Silverstein,
-- who heads
of Nuclear
Medicine,
He has a manuscript
of Nuclear
out?
MR.
I think
SARVI:
tias in the paper
more
the USP Committee
that
it was
It was
than
MILLER
and adverse
50,000
something
about
accepted
Do you know
when
events.
a year
by the
that
injections
like
that.
REPORTING COMPANY, INC.
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for
a running
I think
that has been
Medicine.
--
has kept
form,
do you
yes.
of FDG injections
in abstract
data,
--
Ted Silverstein
COLEMAN:
that
to the safety
the Silverstein
COLEW:
of number
regard
35,000,
is
of FDG.
but
it
aj h
92
.- -.
1
DR. COLEMAN:
2
at one of our conferences.
3
available
4
supply
5
it should
6
journals
for you.
said
that
we will
he would
followed
be in the peer-reviewed
actually
have
be happy
through
literature
to
on that,
but
in the next
few
at least.
DR.
CONTI:
A comment
8
pharmacokinetic
data
9
have you
at calculations
looked
none of the dose was excreted
11
impaired
12
through
13
what kind
14
tiose of the pharmaceutical
15
consideration?
16
MR.
person
of level
<now,
18
renally
19
Iave means
20
~xercise
what
LEE:
David
impaired
~pper limit
24
maintained
25
:he pharmaceutical,
team
that
and only
would
be and
regard
to the
into
leader.
As far as I
as far as dosimetry
is going
that
calculations,
to be with
excreted
the tracer
patients.
to happen,
in
We do
but
that
yet.
I think
if you do your
is going
what
done
CONTI:
23
Lee,
with
or hepatically-impaired
has not been
)ecause
and taking
any information
to speculate
22
have
if
renally
to excrete
calculations
you
impaired,
say, project
in the perfectly
of comfort
I do not have
DR.
to, let’s
those
and the
or renally
that has not ability
the kidneys,
17
on the dosimetry
in the diabetics
10
21
.———..
Ted
that was discussed
So, that data
it, and we just haven’t
7
_-
I think
is very
important,
you will
what
your
all the dose being
by the physical
and then you
know
can go from
MILLER REPORTING COMPANY, INC.
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half-life
there
of
because
aj h
,F.
93
1
if that
2
other
is acceptable,
then,
there
is no need ,to do this
.
exercise.
3
MR. LEE:
4
wanted
5
have looked
6
in renally
to state
7
this upfront,
have already
9
?oint
done
of view,
found
Maybe
those
?harmacokinetics
13
;alking
14
it .
about
15
.
That
16
:enal or hepatic
17
:here has been
18
and from
because
because
we
a dosimetry
of the short
20
~ith these
issues
21
:onditions
in patients
22
;o, I think
with
I don’t
that
other
know
COLEMAN:
blinded
I think
with
I am just
aspect
of
of any data
either
on
patients.
I don’t
guidelines
that
actually
those
technetium
and other
that would
types
be a useful
of
isotopes.
exercise.
you brought
up an issue
importance
for clinical
it is important
to do that,
MILLER REPORTING COMPANY, INC.
.507c Street, N.E.
Washington, D.C. 20002
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in
that deal
to address
and
think
on that.
are some
Jane,
readings,
or
the safety
radiopharmaceuticals
as to how
exploring
issue.
vis-a-vis
There
fIRD, I think,
DR.
the pharmacology
any publications
19
itudies.
data we
information
is maybe
is a different
insufficiency
DR. CONTI:
25
I just
patients.
the reason
with
the dosimetry
DR. COLEMAN:
about
any dosimetry
it is not a problem
12
m
the literature
calculations,
I am not dealing
24
that
for sure,
of the isotope.
11
23
one thing
or hepatically-impaired
DR. CONTI:
~alf-life
but
at, we haven’t
8
10
Right,
early
to get the
aj h
94
1
idea of these
2
themselves
studies,
what
information
is in,them,
by
.....
.
3
But
I have
discussions
4
they don’t
5
them at the time with
6
the information
7
evaluating
8
interesting
9
~tility
10
~aving
like
that.
They
operate
the technology
way
to look
11
blindly
Most
on, which
would
be very
of these
I think
separate
from
13
3roups and who does
14
?erson read
the PET scans,
15
>asis, they
are probably
16
~ind that
what.
I think
that
is
than
of an
that
from
about
the
here,
important.
are going
the echo,
In very
interpreted
is different
so it is sort
but
and
you had,
that we are talking
way, certainly
to be read
just
knowing
few places
do the echo
read blindly,
does
So, just
that
the
the same
on that
but you would
need
to
out .
17
I am sure
18
:hey will
say yes
19
md
would
20
It is just
21
how you
information
at this,
12
there
my clinicians,
to have
itself,
of the procedure
it read
like
whatever
they
with
if you
communicate
or no, and there
be no reason
with
these
is no reason
to say one way
people,
to hide
it,
or the other.
information.
DR. R-ACZKOWSKI:
22
differences
23
jf the way
24
:linical use,
25
jeople from doing
between
images
what
We recognize
is done
are read
versus
and certainly
there
it both
ways.
that
on clinical
what
might
is nothing
In fact,
is
trials
be done
in terms
in
to prevent
oftentimes
MILLER REpORTING COMPANY, INC.
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there
we
ajh
95
.-
1
encourage
2
actual
3
where
4
minimal
that because
effect
really
information
7
somebody
are looking
then you have
might
DR.
imaging
idea
of the
in an environment
at is the image
use
being
11
the United
12
stress
13
baseline
resting
14
viability
type
used
with
States,
where
with
to the real use
practice,
is the so-called
study
they
perfusion,
DISA
and what
might
protocol
I don’t
know
do a resting
to use
set of
be.
use of FDG in cardiac
institutions,
the resting
if you
will,
that
how many,
FDG study
FDG study
as
is
well
as
in
and a
as a
a
of tracer.
Did you
17
Another
in some
sestamibi
anything
more
it in, in actual
days
10
the corresponding
corresponds
COLEMAN:
these
15
-.
all you
that
8
look
at any of those
studies
and do
that?
DR. RACZKOWSKI:
18
focus of the review
19
where the bulk
20
nest widely
21
~rticles
22
nyocardial
23
a clear
of the radiopharmaceutical
And
6
16
you have
information.
5
9
then
was
Not
first
of the evidence
being
that best
used,
and
supported
in any detail.
just
was
then
The real
to try to figure
out
and how the product
trying
that.
to select
In this
case,
is
the
it was
viability.
DR.
COLEMAN:
24
~bout its use with
25
~m not quite
But
DISA,
sure what
MILLER
I wonder
looking
to describe
if we shouldn’t
at resting
myocardium
-- it is looking
REPORTING COMPANY, INC.
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think
-- I
at the
aj h
96
1
glucose
2
comparison
3
certainly
4
don’t
5
certainly
accumulation
with
know
what
that
MS. AXELRAD:
tell me what
DISA
DR.
subtraction,
perfusion
panel
should
Excuse
isotope
11
rest/stress
12
thallium,
13
?atient
14
inject
15
md
then
16
md
one on the 511 KEV photo
subtraction
19
~oronary
20
~iability.
21
:or those
artery
22
24
25
inject
they do one
:hey do these,
23
study,
the sestamibi
18
institutions
think,
my ignorance,
acquisition
now,
but
but
for dual
the
and
I
it is
could
you
study.
or rest/stress
image
isotope
“A” -- acquisition,
the FDG at rest,
-- they don’t
This
It
be discussed.
I forget
10
17
information.
members
It stands
I think.
they
for
is?
COLEMAN:
mibi
myocardium
on in several
the fellow
something
8
9
the stress
is catching
6
7
in the resting
Instead
then,
FDG by itself
one on the sestamibi
disease
So, it is being
a
exercise
the
they
stress,
photo
peak
peak.
collimated
they
and
stress
-- then,
image,
and thus,
using
they
stress
with
of doing
redistribution
during
is done
dual
can use
SPECT
this
imaging
is how
for diagnosis
for determination
of
of myocardial
used
in several
institutions
could
supposedly
do the same
now
indications.
DR. BARRIO:
:hing with
stress
You
ammonia.
MS . AXELRAD :
Is this being
done under
:linically?
MILLER
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research
or
ajh
97
.
1
DR.
COLEPUSN:
Several
institutions
a,re doing
it
.
2
clinically
3
and it has become
4
one
5
nuclear
now.
institution
in the United
SPECT
apparatus
8
very
interesting
9
articles
primarily
11
the device
from
12
15
to see how
16
appropriate
in
standard
about
energy
modifying
photon,
it is a
several
I was approaching
of drug
effect
this
as opposed
to
effect.
I think
that
just
the final
Right,
it.
again
wording
DR. RACZKOWSKI:
flith whether
19
tiith the SPECT
20
sorts of things
21
lltimate
22
md
23
*S well.
the image
performance
so that
:alked about
that
that
was
that
There
is the right
we would
to see if that would
is a potential
is as good,
have
we will
You mentioned
the ammonia
way to
want
be an
circumstance.
to the PET imaging,
could
is the way
an impact
issue
probably
and those
on the
relationships
Earlier,
and issues
MILLER REPORTING COMPANY, INC.
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patient,
be thinking
wording.
here
and so forth,
of the FDG in any particular
is something
DR. LOVE :
I think
in the wording,
resolution
as opposed
actually
and
I think
use of FDG under
18
25
years,
at least
it is their
I do have
that.
the perspective
to leave
go.
I know
issue
that high
about
like
14
States,
and actually,
COLEMAN:
we would
17
one,
DR.
13
it for several
of choice
The whole
to detect
that do talk
10
doing
procedure.
DR. RACZKOWSKI:
7
24
have been
the procedure
cardiology
6
—
They
with
about
we
aj h
98
—
1,
viability,
2
conclusions.
Are
3
have
of wording?
4
rest,
5
and Victor
and now Vic Raczkowski
in terms
viability,
some general
terms
8
does
9
the rest,
of stress
is tried
most
11
an oxygen-limiting
12
tissue
certainly,
the defect
of course,
the anaerobic
is still
I think
alive
that
utilization
of FDG because
15
the defect,
metabolic
16
analogous
17
FDG that
18
suggest
19
epileptic
20
is probably
that,
much
still
and
viability,
what
is done
in
What
the flow portion
more
visible.
probably,
Then
I think
of glucose
under
myocardial
or viable.
is a very
it gives
powerful
a positive
I think
signal
due,
to, again,
this
signal
is conceptually
in epilepsy
at least
animal
the anaerobic
observed
studies
use
for
with
may
of FDG during
seizure.
It is something
21
Conceptually,
22
different
23
But it is always
24
nave a tracer
25
about
in the impaired
defect.
to the increased
earlier
indicate
concept
14
that you
at stress
utilization
situation
his
--
I am talking
to make
10
13
mentioning
is the flow portion.
FDG will,
that
issues
looking
to the fact
DR. BARRIO:
7
Are you
and we were
has alluded
6
-——
-.
there
is indicating
way,
you
can also
already
much
more
that
look
it is important.
at that
low utilization
that gives
I think
that
interesting
you
a positive
is also very
effect
of the fatty
diagnostically
signal.
valuable
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
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in a
in the
acid.
to
the
aj h
99
1
utilization
2
3
the cardiac
4
terms
5
fasting,
or are they
6
that you
think
8
patients
people
glucose
loaded
glucose
and/or
13
protocols
14
checking
15
insulin
16
inject
the FDG,
or just
17
insulin
glucose
infusion
18
~rotocols
19
there
the euglycemic,
both
their
ways,
are used
MS. TESAR:
21
~on’t do the insulin
22
nore looking
23
31ucose
and
at least
that
of
widely,
over
glucose
clamp,
glucose
glucose
with
or may not get
is before
level,
and I don’t
so both
know
one right
at the time,
checking
sugar
Actually,
I have
I mean
found
that
now.
they
I think
is
and doing
levels.
there
that
are very
actually
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
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(202) 546-6666
they
infusion,
out in the community
level
are
loaded,
level
another
loading
so there
an insulin
as much.
going,
euglycemic?
towards
to get a fixed
loading
DR. RACZKOWSKI:
lrticles,
their
I think
then
a direction
is the community
and they may
starting
at the sugar
loading
patients
preferred
20
way
fasting,
levels,
rather
is one being
24
having
on what
of time versus
the preparation
hyperinsulinemic
glucose
depending
about
It is moving
12
in
in?
Which
loading,
DR. COLEMAN:
for
is going
ahead
or is there
about,
of study?
DR. RACZKOWSKI:
11
25
the community
I am sorry,
type
feeling
the way
are moving
for this
is it towards
is your
euglycemic,
DR. BARRIO:
the patient
What
indications,
of having
9
10
use.
DR. ~CZKOWSKI:
7
,-
of FDG for this
few
go into
aj h
100
1
the details
2
different
about
how
images
might
be optimized
with
,.. .
glycemic
3
4
DR. BARRIO:
this
DR.
are right,
7
~ltimate
but
there
9
given
labeling
in terms
recent
There
is not
of how
DR.
a whole
are addressing
COLEMA.N:
and my guess
13
>f -- you
depending
14
vith -- but
15
rays that have
16
;ertain
a couple
been
level
17
when
~ata in the literature
19
~yocardial
20
:ome have
21
)f the technetium
perfusion
24
~ith a myocardial
25
lone
would
be given.
be
That
it is going
there
will
to have
be a couple
indications
we come up
or a couple
of literature
the glucose
related
has been
tracer.
single
I would
)ackage insert,
is that
to have
rubidium-82,
23
of advice
the
I
I think
on what
again
18
so,
about
level
at a
the FDG is injected.
One thing
been
sort
should
of suggested
done
you
helpful.
I agree,
=0 be in there,
know,
I am thinking
the product
is very
bit on that,
lot.
of what
12
22
studies
is a little
Again,
in terms
sort of information
11
,.-
COLEMAN:
DR. RACZKOWSKI:
8
10
More
issue.
5
6
I
states.
you would
tracer.
MILLER
have
have
been
been
all of the
of FDG and a
N-13
ammonia,
sestamibi
or one
emitters.
that
in the indication
probably
perfusion
as a viability
Some
photon
almost
a combination
some
think
to that,
tracer,
want
to have
and
it combined
and not just have
We were
talking
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about
it
with
aj h
101
1
ammonia.
......
2
DR. RACZKOWSKI:
3
that point
4
trial
section
5
rather
than
6
versus
another.
7
yet.
We may
what
8
always
uses
9
?oint,
to determine
a resting
11
order to meet
have
12
agent.
that
14
~o, you may want
15
investigator
16
scan
;uess I was making
18
rould appear
19
;omewhere
that
DR.
21
.ssue of what
22
n a resting
hink
reviewed
that
is the
how you
shake
perfusion
scan
it
in
here.
an N-13
scan
ammonia
or a
or whatever
open-ended
Your
a more
point
technical
in the indication
CONTI:
you
for the
is well
point
or whether
The claim
the claim
understood.
about
whether
that might
perfusion
Victor,
mainly
from
of viability,
is based
scan with
DR. COLEMAN:
25
mibi
one
I
that
appear
else.
20
tudies,
doing
used
to choose.
17
24
are proposed
or resting
DR. IQCZKOWSKI:
23
I think
a resting
it means
to leave
that you
so no matter
with
were
recommending
perfusion
Now , whether
thallium
agents
basically
viability,
at
in the clinical
The data
criteria
:esting
describe
of perfusion
got to deal
13
sure we are really
out and specifically
DR. CONTI:
Xlt , you
simply
types
coming
10
I am not
There
you didn’t
Italy,
has
on, and the claim
an
is based
an FDG study.
actually
go through
where
it is just
they
been
those
just
a couple
today,
but
did FDG alone
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of
I
and
ajh
102
.—.
1
did the prediction
2
don’t
without
the combined
perfusion,
but
I
,..
know
3
that
anybody
does
DR. RACZKOWSKI:
4
felt that
there
5
are moving
6
in that
DR.
this just means
direction
8
now .
that
I think
Iere, and we have
11
m.d finish.
12
md
13
steps and if we want
14
:he rule
and the guidance,
15
:or lunch
and come back.
to choose
I mean
we are sort
16
DR.
17
:alk a little
18
>pen-ended
19
lay make
20
: would
21
md
of here
CONTI:
bit
about
it a little
we want
anything
into
some
it might
we
that.
think
that
in this way
of at crossroads
to keep
else
going
to present,
about
next
about
or we can break
be worthwhile
application,
In the next
have
meeting,
to
an
it
as far as the presentation.
we break
for lunch
and come back
do that.
DR.
COLEMAN:
I think
so, too.
23
MS. AXELRAD:
I think
we need
25
since
of the questions
22
24
I
that we can talk
easier
that maybe
but
we are sort
the oncology
bit
that,
we can do that,
about
and
to be described
have
I thought
discussion
suggest
now,
to get
with
whether
we don’t
so much,
but
--
this needs
10
at some of those,
has been
I agree
MS. AXELRAD:
--
I looked
-- there
COLEMAN:
7
9
was
that
:ay 1:15,
be back
here
[Luncheon
at 1:15.
recess
MILLER
an hour,
taken
at 12:10
REPORTING COMPANY, INC.
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p.m.]
so I would
. .. ---- --
aj h
103
1
AFTERNOON
SESSION
2
[1:15 p.m.]
3
MS. AXELRAD:
4
open
5
next.
6
What
I am going
to you all to set the agenda
We don’t
obviously
is it that we want
7
DR.
8
you are going
9
or 40, 50 very
10
specific
11
oncology.
with
good
of the
14
is going
to be worded
15
specific
indications.
myocardial
18
get into
19
the multiple
20
used
21
cancers
22
COIOreCtal
23
indications,
24
going
I think
as well
we discussed
17
this morning
cardiac
perfusion
I would
was
was
in, and the ability
are quite
cancer,
some
which
as general
relate
to how
rather
rather
we want
to go
to know
where
just gave
you
articles
applications
again
relate
versus
to supply
prevalent,
of these,
but
problematic
used
whereas,
to be quite
as we
because
of
in, is being
a lot of data
the lung
insert
The
straightforward,
it has been
in
to things
the package
indications
30
on
straightforward.
it is more
that
like
review
that
are going
to be orphan
some
and the general
indications
this
presentations.
Jenny
issues
FDG and oncology,
which
any planned
articles,
13
The
as to where
FDG and oncology.
A couple
16
have
to leave
to discuss?
COLEMA.N:
indications,
12
25
I guess
in some
cancer,
some
of the
effective,
are
diseases.
You know,
they
MILLER
are going
to be the sarcomas
REPORTING COMPANY, INC.
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Washington, D.C. 20002
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where,
aj h
104
1
you know,
2
patients
3
-32
- —
L
-,
s~uales
LO
aocumenc
4
there.
a major
a year,
very
—L--
5
center
6
review
7
in these
common
8
of data,
as well
9
just
.,-..
where
to be so much
DR. FQCZKOWSKI:
We are
12
is hard
13
much
of the review
14
with
the literature
15
we talked
still
16
about
would
from the community
19
indications
or what
20
?retty
to go into
21
nuch more
straightforward
22
~estions
that we are trying
I think
25
:his point
about
of this
out.
there
are
question.
review,
I anticipate
of some
with
in time
that may
would
what
so it
that
of the issues
to some of the things
you would
these
like
things
us focus
a clear
our
sense
to see in terms
for, because
open-ended,
if we can into
it with
of
it is
and it is
specific
to answer.
I think
the ammonia,
that
help
be if we had
you are striving
DR. COLEMAN:
zalking
where
a lot
this morning.
18
24
play
be similar
review,
23
to have
is an excellent
in terms
17
hard
see this
how do we factor
we are going
stages
will
One of the things
though,
and then
to be
data?
in the preliminary
would,
of
.
it is going
indications
That
to say how things
.
numbers
is how do you
going,
as the other
11
but yet
to you
indications
mig,ht see 10
to get large
. .
lts
utlllty,
of FDG and oncology
not going
like Duke
difficult
so, my question
10
---
medical
that
again,
it would
FDG is indicated
be our thought
at
for evaluation
of
MILLER REPORTING COMPANY, lNC.
507 C Streetr N.E.
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like we were
aj h
105
.
1
tumors
including
2
neck
3
statement
lung
cancer,
colorectal
cancer,
head
and
----
cancer,
melanoma,
followed
4
lymphoma,
and having
by a specific
indication.
DR. CONTI:
5
for example,
6
subpopulations,
7
whether
8
There
9
actual
I think
of the cardiac
there
you have
FDG with
10
in line with
literature,
are many
is a significant
trial
also
ways
rubidium
amount
some
where
of doing
the nature,
there
ammonia.
within
look
at the oncology
literature
11
same
12
scores
13
with
14
literature,
15
colorectal , head
and neck,
16
those
categories,
17
spectrum
18
higher
spectrum
that we have
done
with
viability,
19
higher
spectrum
that we have
done
with
perfusion.
as a whole
of different
FDG for tumor
not
and
of what
say,
okay,
subpopulations
imaging,
separating
individual
20
the
designs.
One could
fashion
are many
the studies,
or FDG with
of variability
general
we have
that have
and pooling
et cetera,
but
done
this
I think
21
3ata is an interesting
one,
22
situations
is biological
23
lone in situations
where
24
reasons
that
25
a different
there
to believe
state,
there
into
look
evaluated
each
like
the
like
of pooling
the
be
or other
the same way
it is harder
REPORTING COMPANY, INC.
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the
in
or can potentially
is behaving
of
at the entire
can be done
is biological
words,
been
lung,
tracer,
the idea
that
the drug
in other
MILLER
but
been
have
and critiquing
saying
with
there
all of the
it necessarily
DR. RACZKOWSKI:
where
well,
in the
to pool
in
ajh
106
1
things
that
2
common
denominator.
3
4
assume
5
what
6
there
7
of the pharmacology
9
Well,
I read
in your
Well,
documented
parameter
10
31ycolysis,
11
:0 neoplasia,
12
~omfortable
so you have
and this
14
in terms
15
>f tumors
with
of being
that,
the option
is really
able
what
that
concept
about.
feel more
glycolysis,
the different
but
types
-We never
claimed
17
;can is an FDG scan.
We don’t
claim
18
-iterature
21
is accelerated
of accelerated
DR. CONTI:
to do that.
anywhere
An FDG
in any of our
-DR. RACZKOWSKI:
~ou would
is a well
we would
16
20
part
drug.
we are talking
to differentiate
is
in fact,
of this
of extending
I think
the notion
basis
there
that,
is, in part,
and that
in malignancy,
DR. RACZKOWSKI:
13
and that
or pharmacological
If yOU
of FDG, which
and you do know
have
some
is in, in fact.
glycolysis,
tumors
is not
the pharmacology
cardiac,
is accelerated
if there
there
that you understand
19
.,
heterogeneous
DR. CONTI:
8
----
are very
want
So, that
is not
something
that
to --
DR. CONTI:
I think
22
)f accelerated
23
)f the radiotracer
24
:ine points
25
~ould not opt to do, but
glycolysis
you
as the principle
in the tumor,
of what
are dealing
all means
with
for accumulation
and we can argue
in biochemical
the point
is that
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an issue
about
terms,
the
which
the principle
I
of
aj h
107
.—
1
accelerated
glycolysis
2
development
of this
3
not
4
to speculate
5
distinguished
has been
the foundation, for the
......
in the position,
6
nor
from
label
8
concerned
that
9
lymphoma,
sarcoma,
suggestion
if we would
that
11
DR.
12
DR. CONTI:
concept,
14
your language.
but
15
COLEMAN:
trying
about used
17
?resence
18
Eor.
as part
That
of assessment
19
DR. CONTI:
Yes .
20
DR. LOVE:
22
DR.
23
DR. LOVE:
24
:hink would
25
.ndication
CONTI:
replace
out that
suggesting.
We were
neck,
lung,
and
about.
our objective.
the
“such
as”
it so it is acceptable
were
general
for presence
are things
Are you
head,
talking
again
So, if there
and nonmalignant
throwing
differentiation,
were
As examples,
those
nalignant
just
just
is not
to be
et cetera.
implies
really
and we are
in the position,
is going
say including
of neoplasm,
21
was
to package
DR. HOUN:
16
we were
that
you
cancer
cancer,
Coleman
is not something
13
lung
I know
Dr.
purposes,
is the literature
colorectal
DR. HOUN:
that
for oncology
as to whether
7
10
tracer
looking
to
terminology
of tumor,
that you
are looking
to differentiate
lesions?
Yes .
Would
this be something
a biopsy?
Do you
see that as a label
perhaps?
MILLER
that you would
REPORTING COMPANY, INC.
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aj h
108
—
.... .
1
2
DR.
would
CONTI:
It would
on the circumstances
I
think.
3
MS . TESAR :
Not
4
DR.
We have
CONTI:
in all cases.
5
lung cancer
literature,
that
6
the solitary
pulmonary
nodule,
7
versus
benign,
8
~p, which
9
all cases?
being
depend
11
3eneric
to that.
12
MS . TESAR :
13
md
14
>iopsy depending
15
~ou have
16
leed to determine
17
flaybiopsy
the most,
18
lot going
to be doing
19
:0 be biopsying
20
Jet that
21
.t,
22
;hat respect.
what
but
we have
if that
therapeutic
25
:reat a patient
that
options.
or not
cases,
tissue
and the
you a
as an example
replace
but
you
are
are going
to get to, just
yes,
to
you are avoiding
to be tumor
is driven
dependent
in part
we would
regardless
if
so you
so you
but you
a
then
somehow,
lesions,
in
by the
not like
to
of the particular
MILLER REPORTING COMPANY, INC.
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in
in metastasis,
is closest
that
give
and you may
outside
For example,
without
cancer
of the PET scan,
so it is going
Alsor
you do that
situation
a lung biopsy,
so in some
CONTI:
lung
is cancer
maybe
a lesion
Will
for example,
you know,
you are bringing
so I can’t
Medicare,
result,
in not all,
24
with
on the result
diagnosis,
DR.
We can use
done
a positive
with,
where
malignancy
on the clinical
you are dealing
in the
to the point
to what
of biopsy.
:ype of cancer
answer
for example,
differential
can be applied
is the avoidance
It will
developed,
is developed
10
23
depend
aj h
109
.—
1
modality
used
2
examination.
In other
words,
3
chemotherapy,
you will
not make
4
of clinical
5
tissue.
6
to make
the diagnosis
examination
So, again,
clinical
8
you may not necessarily
9
rely more
10
clinical
11
12
neoplasm,
13
nasses,
14
that --
me
17
processes
18
there
19
glucose,
20
glucose.
21
can have
23
or infection,
There
where
will
there
exhibit
of use
from other
is that
elevated
in the brain
are other
or the
something
I mean
where
entities
I mean
of
else
there
inflammatory
glycolysis,
where
a
types
just
the brain
the heart
or disease
like
utilized
utilizes
processes
that
glycolysis.
So, you
are looking
to make
now?
DR. CONTI:
~estion.
data
differentiating
are certain
in the heart
accelerated
well,
but you would
It can be considered.
DR. FQCZKOWSKI:
24
25
cancerous
or issues
need
cancer,
on the imaging
or benign,
is issues
distinction
case
anyway,
either
which
22
do a biopsy
How about
circumstances
You will
on the particular
DR. RACZKOWSKI:
DR. CONTI:
16
depend
or
to treat.
inflammatory
15
alone.
therapy
on the basis
If it is a recurrent
in that
examination
radiation
that decision
or imaging
circumstances.
heavily
to apply
it would
7
or the clinical
It would
I think
depend
on the clinical
if you are going
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to try to
that
aj h
110
1
distinguish
2
lung,
3
you have
4
with
5
distinction.
between
because
it seems
a person
lung
circumstance
8
biological
9
Now , the differential
as a tracer
activity,
act on that
11
to be tuberculosis
12
the next
14
to have
15
aren’t
16
some
17
the lung.
18
you
19
false
step
COLEMAN:
to prove
going
irrespective
or cancer,
management
positives
Those
are going
21
has
22
this particular
23
active
are not very
those
one of the
hard
25
relationship
I mean
still
it turns
to then
out
take
common,
you are going
oncologists
so there
granulomatous
but
will
be
infections
in
they do exist,
but
up to get tissue.
area
that will
-- no test
and that
accumulate
is perfect.
FDG,
Every
is one of the limitations
test
with
test.
DR. RACZKOWSKI:
24
you
said earlier,
go on the PET scan,
with
its limitations,
process.
and you may
of whether
or
in that patient.
so, it is a known
and it is just
in that
disease
it allows
it is cancer.
to follow
20
but
AS Peter
that
to just
exists,
if
that
of metabolism
an active
diagnosis
and
and a patient
to make
level
in the
accepted,
the tracer
of some
displaying
information
DR.
well
tuberculosis
you are using
7
13
active
use an example,
it can be difficult
However,
10
let’s
to be pretty
with
cancer,
6
a person,
to talk about
This
specifics,
to other
but
modalities,
MILLER
is such
a broad
in terms
of PET,
such as where
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area,
it is
FDG in
it fits
in
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with,
2
events,
3
about ?
say, MRI or CT in terms
or is that
4
DR. BARRIO :
5
DR. R14CZKOWSKI:
6
cost , but where
7
have
9
does
an equivocal
8
there,
will
in almost
every
11
sensitive
and specific
have
circumstance,
than
DR. FQCZKOWSKI:
14
Looking
15
modalities
16
Oefore
I mean,
Almost
it may depend
to, let’s
in other
the
words,
to follow
the PET is going
the CT scan
replace
or as an adjunct
to do with
YOU
it up.
that you have
had a CT and a PET scan,
Perhaps
some
what
to be more
result.
I am asking
or situation
of these
to -- and
and
is --
-- are you
other
if it is an adjunct
or after?
17
DR. COLEMAN:
18
:0 replace,
19
>ecause
20
~ays, but
21
Jan replace
but more
CT scanning
22
there
In some
often
is just
are some
getting
circumstances,
it is going
so ingrained
circumstances
a CT scan
;urgeon no longer
24
;canning.
25
Jet a CT, we get
gets
CTS,
In our lungs,
it is going
to be an adjunct,
in oncology
certainly
he is following
where
it
our melanoma
with
if we see a lung nodule,
the PET scan.
these
done.
I can tell you at our institution,
23
So,
of
be thinking
all of the data
on the cancer
say,
sequence
effective?
No, no, nothing
it fit.
10
again,
cost
CT scan and you want
the patients
13
that you would
You mean
DR. COLEMAN:
12
—
something
of the diagnostic
in some
MILLER REPORTING COMPANY, INC.
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PET
we don’t
circumstances,
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it has replaced
2
MS.
3
colorectal
4
prior
5
replaCing
6
circumstances
disease
a rising
may be a PET
scan done
the rising
CEA,
a claim
CT, you know,
it can replace
CT.
think
we have
11
local
custom
12
judgment
CONTI:
other
15
best
16
they will
17
patients
18
micromanaging
words,
place
we want
to use
this
it can image
is.
The
also
have
some
21
make.
22
about
supposed
24
ultrasound,
25
an adjunct
to be used
the high
to do here
tumors,
think
and
are
that
it
that.
I
up to make
is allow
let them
will
on how
we want
decide
look
those
them
in its best
companies
and the
to
form,
what
in
the
at this,
the management
to get
of
into
practice.
We certainly
is what
DR. HOUN:
23
prior,
into
are worked
influence
I don’t
MS. AXELRAD:
are talking
and
some discretion
technology
insurance
medical
to get
the physician
What
go, but
20
want
as to how patients
the option
14
We don’t
to allow
calls.
CEA,
they do replace.
if we can make
10
like
so there
know
19
—
that
recurrent
is sometimes
at CT, too, with
DR.
have
In certain
there
I don’t
replaces
the CT scan.
there
to surgery,
9
-.
TESAR:
cancer,
7
8
getting
There
kind
of claims
definition
MILLER
I mean
like
to
which
to mammography,
ultrasound
mammographic
all we
do you want
are some diagnostics
as an adjunct
to an abnormal
don’t.
was
approved
or indeterminate
REPORTING COMPANY, INC.
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are
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mammographic
2
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3
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7
detected
8
literature.
to CT scan
Most
abnormalities.
though,
11
have
12
try to better
13
be CT,
14
imaging
15
additional
16
of standards,
17
markers
is that
to understand
that.
be most
they
that
is being
whether
they
or
CT
of the
point
are doing
here,
You
to study
finding,
nuclear
the point
used
be a
for the study.
a particular
whatever
will
be characterizing
it may be other
techniques,
and
to
it may
medicine
is, it is an
evaluated
against
are CTS or other,
some
series
or blood
or whatever.
18
In clinical
19
situation
20
may be a real
21
literature
22
I mean
where
or questionable
is an important
characterize
test
will
this
direction,
is the rationale
it may be MR,
that
of the literature
and will
That
that
in that
That
DR. CONTI:
suspect
or for abnormal
of CT and PET,
10
you
supportive
DR. COLEMAN:
9
--—..
and would
is more
5
_—.
image,
where
practice,
the CT is done
dearth
since
Duke
24
abnormality,
25
biopsy,
in melanoma
that was not
That
now.
then
you might
the PET scan,
in that
that
MILLER
have
a
and there
scenario
in the
the objective.
is exactly
what
We get the PET scan,
they will
to document
after
of information
DR. COLEMAN:
23
however,
get a CT to use
it is metastatic
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is happening
at
and if we see an
to guide
disease.
the
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114
1
The
PET scan
is more
sensitive
and can survey
the
,,,. ..
2
whole
body
better
3
don’t
want
to limit
4
practice
6
and
7
adjunct
8
is that what
9
that was
I think
what
that
I think
too,
that
so I think
came after
our literature
the standard
is an adoption
and physician
we are seeing
even
can,
that we
it.
parameters,
practice
is that
patterns,
initially,
a CT most
it was an
of the time,
represents
and we needed
of
right
now,
to compare
and that
because
it to
something.
11
But as you get out
12
center
13
able to evolve
their
14
replacing
they
15
UT scan
that
I am involved
like
into
with,
clinical
you
practice
in the
see the physicians
practice
patterns,
are doing
at Duke,
and they
where
being
start
they don’t
do a
for melanoma.
16
In Our institution,
17
3 PET
18
?rior to surgery
19
:here is other
study,
20
21
the CT scan
MS. TESAR:
5
10
than
so,
ve really
and
DR.
23
:han practice,
24
JET was
25
~ave gone
before
other
I think
write
CONTI:
through,
they
CEAS,
they do
do a PET study
about
doing
a CT if
of tumor.
is a practice
into
a label.
We want
to focus
to focus
to, just
what
rising
think
that
we want
compared
tumors,
they would
suspicion
can’t
22
certain
you know,
like
other
pattern
on that being
on the standards
in the other
tests
thing
were
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rather
at which
studies
being
that
used,
that we
the
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echoes
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3
what
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and things
like
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,..
.
is used
5
of which
as the standard
sort
Once
6
begin
7
the table
itself
regard
MS. TESAR:
9
need
to do?
10
each
individual
11
statement
12
where
13
what
14
cross
In your
that
issues
concept,
that
this
of cancer.
SO, looking
at that,
estimation,
would
do we need
can encompass
you mentioned
before
a question
the tumors
you
study,
then,
tracer
what
we need
to look
can have
of
and
practice.
to imaging
tumor,
that
it’s
out in clinical
at the broad
with
first,
for the particular
we can get over
to look
8
is done
we can
brings
would
to
we
to look
at
at a broad
and then have
a functional
some,
and
--
n
is that
that
15
next
what
17
sense
18
specific
we could
that
up
-- disease
specific,
you might
line.
I don’t
16
level
know
what
other
literature
do to support
that,
but
we would
have
that
a functional,
we can do or
seems
then
to be my
the disease
sort of level.
19
DR. HOUN:
20
mean
21
increased
22
process,
but
23
clinical
claim,
24
possibility
25
conditions?
the function
So,
in terms
is to detect
glycolysis.
in terms
I mean
active
that
of relating
it would
of malignancy
MILLER
of the functional
disease
claim,
process
with
is the biochemical
that
be in order
or neoplasm
to a claim,
to help
a
assess
or inflammatory
REPORTING COMPANY, INC.
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the
I
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116
—_
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2
image,
can you
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MS. TESAR:
DR.
say tumor
CONTI:
4
use terms
5
disease,
6
cancer-related
7
you could
8
3allium
scan,
9
at what
is used
like
use
stage,
scan,
you
use
11
questions
some
evaluate
that
a gallium
#ork up a cancer
you
to therapy.
indications,
10
say
could
We can
for recurrent
These
are generic
if you
aren’t
using
FDG,
or if you
aren’t
using
a
a CT scan.
from an imaging
patient,
examples.
You are just
point
of view
and can we adopt
those
looking
how you
types
of
to the FDG molecule.
12
DR.
13
mentioning
14
~xample,
15
~valuation
16
Jeneral,
17
ve do have
LOVE:
I think
are things
those
statement
for what.
We do need
some
The
there
type
issue
19
will have
to think
20
something
underlying
21
=arlier
22
mother,
23
one tumor
24
:oncern
25
lelp answer
are
just
about.
For
evaluation,
so
of context
that we don’t,
biopsy
and look
can’t
or another
some
type
in
but often
is something
at the data.
one of the comments
you
or question,
think
tumor
some
times
of replacing
but are you more
type
was
you were
of context.
about
is perhaps
terms
we can certainly
the beginning
although
18
We can give
response
now
or can you
imaging?
diagnose,
assess
say assess
distinguish
I think
was making
one tumor
type
apt to have
a correct
is something
that may
be of
the data
would
and going
of those
Victor
that we
through
questions
or at least
MILLER REl?ORTINGCOMPA~, lNc.
507 C Street, N.E.
Washington,D.C. 20002
(202) 546-6666
answer
from
in
try to
determine
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117
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what
information
2
guard
against
3
there
is enough
4
need
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didn’t
include
this
6
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such as carcinoid
9
cancers,
very
of lung
not even
tumor
that
about , there
12
it is less
13
<now, we did a study
14
or three
15
sensitivity
16
:umors
accurate
in, and
MR. CONTI:
18
:he presentation
19
~ diffuse,
20
Lesion.
21
Lesions
22
That
just
.n there
24
~ith regard
25
~ood example
are
may
disease
are differences
forget,
in looking
also,
or certain
starting
of that.
types
to be,
that
I don’t
is two
the decreased
cell
in large
and how
cell
tumors.
measure,
it appears,
as opposed
on
if it is
to a focal
in our ability
to detect
such
issue.
that
there
is some
of update
For example,
There
talking
and there
non-small
depend,
cell
of those.
and bronchoalveolar
at the degree
to prognosis.
cancer,
you were
to show
other
as a technological
Don’t
23
they
of the disease
disseminated
There
at what
types
to the other,
PET
and bronchoalveolar
cell
tumors
cancer,
to call
of 10 or 12 patients,
in carcinoid
compared
-- and really
50 percent
now of that many
that
are some unusual
necessary
is getting
sure
or
to the user.
-- in lung
there
probably
may be certain
studies
of that
of the lung
PET detects
11
but
,to identify
to make
is available
in the literature
sensitive,
I think
17
that
An example
cancer,
that
labeling
of assumptions
information
5
good,
to go into
types
DR. COLEMAN:
10
—
may
is pretty
of the tracer
brain
good
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information
tumors
is a
evidence
about
at
118
.
1
using
2
patients.
3
that.
FDG in brain
tumors
to determine
prognosis
in
,...
There
4
DR.
are articles
COLEMAN:
5
last month
6
ability,
similar
7
starting
to be more
9
10
We just
on FDG uptake
8
to that
example
Prognostic
might
DR.
But, yes;
13
prognostic
14
~ptake
15
the stage
16
~he FDG provides
17
=hing
there
18
is probably
asked
I thought
cancer
And
of the tumor,
me earlier
more
One
20
[rug where
one company
21
.hemselves
from another
22
~roduct-–we
thing,
Iayors in government
a
one.
it.
on the
even
of tumor,
of glucose
if you know
everything
so that
else,
type
to get paid
of
to keep
for a generic
to differentiate
that we do this with
than
Company
to worry
studies
a company
this
Y.
that we need
for these
and when
that we need
at the claims
saying
the level
MILLER
too,
is not going
do this better
25
good
the amount
information,
is that we are looking
So I think
what
available.
.n mind
.s are we going
is
claims.
data
prognosis
the size
additional
24
there
that was probably
to be more
predicts
MS. TESAR:
a very
At the time,
19
23
and its prognostic
tumors.
Someone
is starting
is becoming
in Cancer
cancer
in brain
information.
in lung
an article
be of one of the other
COLENUXN:
12
address
of that.
indicators
11
specifically
had
in lung
DR. RACZKOWSKI:
good
that
might
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about
by third-party
advertise
at
119
1
that,
an individual
company
might
advertise
th,at.
.....
2
3
I don’t
with
see how we are going
this generic
4
FDG.
MS. AXELRJID:
5
with
6
to-head
7
claim,
8
other
traditionally
9
scans
and the MRIs
the existing
against
going
each
other,
head-to-head
and things
11
MS. AXELRAD:
13
of claims
14
advertising,
in terms
you
Certainly,
MS.
KEPPLER:
16
MR.
CONTI:
or some of the
the devices,
the CT
from
the agency’s
this
and for what
to make
have
kinds
in the
significance.
Okay.
We want
17
field here.
We want
18
~ecide which
tests
19
~e want
to make
sure
20
it does
reflect
clinical
21
:hoose a PET scan
22
]atient.
23
:his whole
25
it does
on your
important.
to be allowed
for example,
depending
head-
that.
of establishing
15
24
even
So it is more
are going
That
be,
thallium
like
head-to-head
You are not going
or could
against
KEPPLER:
you are going
agent.
approved--and
MS.
perspective
In a way,
diagnostic
10
12
to go head-to-head
to give
to also
the physician
he or she would
that
like
our claim
practice
or a CT scan
is really
what
level
the playing
the choice
to be able
is not only
options.
to evaluate
I think
to
to use.
accurate
So you
but
can
that particular
we are asking
for in
process.
MS . KEPPLER:
lse of lung
cancer
This
and brain
discussion
tumors,
of the prognostic
and Peter,
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correct
me
at
120
1
if you
feel differently,
2
that
3
to see that
to be in the labeling.
Are
in the labeling,
DR. COLEMAN:
I would
5
MS . KEPPLER:
I just
6
talking
about
7
and I am not
9
it because
so sure
MR.
questions
CONTI:
that
11
well-supported
12
3ut , again,
13
open up that
14
:hen, the literature
15
~xpand on it as we generate
by what
allowing
17
we are
18
snd, but where
19
md
20
what claims
21
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22
regard
23
Je haven’t
24
Literature- -
25
in terms
really
more
material
sort
we need
perfusion
area
gotten
DR. ~CZKOWSKI:
to
be
into
There
be able
This
area
where
the
the ammonia
hear
from you
and,
and for
also,
is something
else.
are other
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
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to
isn’t
for ammonia
if there
anything
will
of summarize
is to really
and,
clearly.
and I think,
of on both
in that
less
.
from you.
to see on the label
to the oncology
to the
of malignancy
and we will
so far sort
What
myocardial
going
to the drug
we need
we stand
you want
different
access
in the area
follow
We were
on that
are many
are
Let me just
of what
the oncology.
literature
you have
for access
MS. AXELRAD:
looking
in time.
sure.
it is in the literature,
will
for
even.
there
obviously,
the use
channel
to make
is some
one can ask once
Lracer
Are you guys
at this point
is a hope,
10
16
want
As I said,
and some of them,
you?
not,
there
that
so sure we are looking
Ed?
4
8
—
I am not
We only
things
like
with
else.
have
at
121
—
1
disease.
2
MS. AXELRAD:
3
DR. RACZKOWSKI:
4
.
Alzheimer’s
interested
We have
MR. CONTI:
6
DR. RACZKOWSKI:
we were
8
giving
9
sections
literature
That
is an area
What
we were
on that.
that you are
in.
5
7
some
debating
you
Yes.
at lunch
the label
for FDG,
that we think
10
you on; what
11
1ike, what
12
actually
what
are the claims
something
does
specific
agency
15
the development
16
?rogram
17
Development
18
labeling
has
talked
about
review
divisions
a label
tailoring
to get to where
you want
so you don’t
19
is over
sol in a way,
20
:hat kind
21
ire your
22
:hat we were
of information
views
23
find
it could
talking
about
That
cardiology.
25
vere going
to be getting
so
development
do your
here
and the
I would
would
for us to get
like
to see what
be one of the things
proposing.
I think
:oday with
be helpful
from you.
that.
24
in advance
your
it is over
at the
there.
about
DR. COLEMAN:
look
so we could
and then
you want
from
from you.
is developing
and then
input
the
preparation
program
program
this--but
to get
patient
that you want,
of doing--
and circling
be useful
It is one of the other
14
of doing
for example,
it would
is the dose,
get
13
the merits
thinking
It was
we had
talked
about
our understanding
our thoughts
together
MILLER REPORTING COMPANY, INC.
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that
that we
and getting
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122
1
them
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3
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preparations
about
what
we would
like
to see th,e indications
..
Again,
thing
at lunch,
could
go on with
to questions
6
In some
7
easy
8
because
9
would
love
10
come
in with
11
you have
in most
other
than
to work
MS. AXELW.D:
13
your recommendations.
First
14
where we are already
on ammonia
15
perfusion.
16
you want
17
really
18
3et into
19
chose directions
20
night catch
21
l_ooking at prognosis
22
that.
So it would
that
think,
I think
what
you
the review,
23
and
ignore
our attention
24
really
25
bit about--one
are
interested
to know
want,
to get
of heard
far off what
we hear
what
for oncology,
and we won’t
waste
are not really
of the things
like
sort
how
then we can sort
And
take whatever
and FDG for myocardial
our review
in.
no; we
we could
really
some of the other
if you
We can focus
we would
the earlier
because
But,
Certainly,
of all, we have
really
is very
in the blanks.
be useful
is.
preparation
or we could
fill
I think
patient
influence.
on that.
it and
be happy
and the FDG uptake
and glucose
our recommendations
hopefully,
We would
those
the patient
you
about,
oncology.
cardiology
with
and discuss
talking
concerning
of those,
of the insulin
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things
Washington, D.C. 20002
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in
that
heard
in
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doing?
DR. COLEMAN:
lnd difficult
to
focal
of how
like pulling
that would
able
some
who has control
do something
generate
We just
So we have
the data
You
claims.
somebody
a protocol
19
25
of a
this.
to do this.
of pulling
multicenter
Can ICP, with
into doing
we do leaves
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are you
30 a prospective,
24
what
proving
12
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has gone
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11
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maybe
can see what
and essentially
to talk to you
want
6
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with.
We are only
don’t
Again,
I think
question.
that
is a very
interesting
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tell you,
ICP has
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124
—
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MS . KEPPLER:
5
MS. TESAR:
6
DR.
Jenny,
Yes;
US at Duke
8
sent in to Duke.
9
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doing
one of which
did we have
Single
pulmonary
et cetera.
sure
That
that
in
nodules.
nodules.
all the coordination.
We made
was
it is in there.
COLEPIAIT: Pulmonary
7
they
would
That was done by
All
got
the studies
were
sent out,
read
be very
difficult
to do
you
“we,”
again.
11
12
so far,
remember,
4
10
DR. RACZKOWSKI:
referring
to Duke
13
14
institutions
15
:0 us,
16
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17
institution,
18
;ent out for blinded
19
ill that was done
.
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clinical
When
Duke
forms.
that were
the CT scans,
collated.
It is all done
22
his
23
Lre PET manufacturers
but
24
leans .
are limited
25
:verything
its resources.
because
The resources
has been
done
with
effort,
is how we have
a drug
company.
are not an Eli Lilly,
so most
of these--
that volunteer
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as a volunteer
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were
came back
through
That
we aren’t
they
the films
readings
coordinated
:hough .
for everything
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21
used
for all of
out at the local
readings.
at Duke,
the PET scans,
We had all of this
filled
to Duke,
MS. TESAR:
Duke
are you
and the participating
had to send
report
send
say
University?
DR. COLEMAIJ:
20
.-
don’t
trials
effort.
done
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by any
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125
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1
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using
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staff
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has been
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know
8
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svery year
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Least help
some
11
:ogether.
13
md
pull
together
but
Duke
and use
We realize
this
is a necessity.
for the ICP and
of these
it is, of course,
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to
for the PET community
trials
volunteers
in terms
and be able
in pulling
as you
know,
to at
this
time-intensive
money-intensive.
14
MS . KEPPLER:
15
:00, is--and
16
:hink the issue
17
JDA for lung
18
:hat you
19
lave to say--$2OO,OOO
20
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21
22
sometimes,
we can do in the future
of funding.
But
by
of volunteerism.
really
7
12
companies
to do that.
what
in the agenda
from
resources
amount
institutions
and resources
6
of help
their
a massive
other
time
bit
if we could
cancer
trying
DR.
23
solve
one of the other
the coordination
that we discovered
is putting
all are used
oy the FDA,
I think
to seeing
with
the data
to put
COLEMAN:
in their
And
it was
problem,
the adjunct
together
it cost us--and
and some which,
issues,
I
to the
in a format
Ed you will
for a series
of
$50 is a lot of money.
found
to be unacceptable
too.
MS . KEPPLER:
24
slinical
25
ione and were
trials.
That
We have
published,
is the other
piece
got the clinical
but
that
trials
is a different
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of the
that were
level
of
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126
—
1
data
than what
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control
3
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was
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forms
you
are used
to seeing.
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....
the publication
putting
$200,000
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and
the Akron
this coming
13
network.
14
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15
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16
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I think
Yes;
about
and they
MR.
CONTI:
are
at the NCI
nechanism
21
in that
22
competitive
23
:ype of thing
24
~oing to be successful
25
~rant, so to speak,
that we need
about,
the NCI-funded--
started,
starting
what
and Barbara
indications,
be able
I think,
is called
Croft
do clinical
specifically
for
to help.
is certainly
at.
The problem
that
It is going
to be a
for access
a
are
That
to look
in
an oncology
to try to help
it is competitive.
process
is at the RSNA,
a new network,
Right .
20
is that
the case
to folks
also
Sullivan
institutions
So they might
19
I
for the lung
taking
meeting
talking
It is for oncology
imaging.
talked
first
are you
Dr. Dan
to be talking
17
you
up December--they
among
was
but
it.
Their
DR. HOUTT:
12
forward,
Branch?
MR. CONTI:
actually,
going
analysis
some which
Have
it had all the right
that,
the quintiles
and analyzing
Imaging
11
18
together
DR. HOUTJ:
9
10
sure
in it as we are learning
7
8
and make
to funding.
that we are doing
in getting
We can’t
in the hopes
funding
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do the
that we are
by applying
to do the trial.
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one
for a
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127
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to be able
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and things
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or the colorectal
a core
of drug
is that
is available
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groups
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for example,
that
in the GI section
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process
sound
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to core
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it is a matter
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16
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18
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19
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20
~or doing
Imaging
networks.
Network
are just
MR. CONTI :
~o up against
23
;veryone wants
24
rith conventional
25
!etera, that
I don’t
is going
that,
know
to accrue
the NCI
to be but a number
fund
of
for example,
or
the infrastructure
trials.
In the radiology
is everyone
wants
nuclear
medicine
groups
group,
what
to do a trial,
to do a ultrasound.
all these
what
pediatrics,
They basically
the clinical
22
of the investigators
the study.
DR. RACZKOWSKI:
17
21
This
a peer-review
is fundamentally
One of the advantages,
7
15
the hypothesis
as an industry
they
to do a tr,ial, we need
to do it and not go through
whether
6
to decide
vying
Everyone
and PET,
an MRI.
wants
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to do it
et cetera,
for a single
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128
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1
money
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three
years,
an application
it may be another
before
DR. COLEm:
6
Dan Sullivan
7
in time,
we get access
8
Siegal
9
Committee
We certainly
well.
there
We know
full year
or
to actual
on Nuclear
at protocols
12
at is through
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planning
14
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15
those
16
nompany
interested
17
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of when
18
chat comes
on doing
like
through
md
21
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that
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24
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25
conclusions.
was
study
that
Siegal’s
be looking
is being
of Surgeons.
looked
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are
and esophageal-cancer
where
saying,
or how.
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if you don’t
it, moving
done
love
and there
mechanisms
We can take
ahead,
have
you have
a
no
is a lot of delay
multicenter
like
studies
to do at ICP.
But
are the problem.
This
this
the literature
But you
to do more
that we would
MS. AXELRAD:
23
Barry
that.
is something
22
know
in doing
So we would
20
in that.
I am on Barry
College
I don’t
it gets
and
there.
a lung-cancer
Peter
Croft
At this point
and PET that will
multicenter
study.
things,
19
Medicine
the American
Barbara
PET protocols
committee.
to be supported
The other
know
that mechanism.
is no specific
is on the main
11
---
down,
to submit
to do a study.
5
10
to have
is really
so far by doing
review
are still
MILLER
the crux
whatever
and coming
left with
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of the
out with
every
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we are
some
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129
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entity.
3
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doesn’t
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The question
4
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ever
6
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DR. BARRIO:
these
five--the
8
about
a new
9
now,
and
particular
12
of the clinical
13
money
trials
the NDA
17
approval
then
spending
18
this
industry
The question
20
;hey are
would
21
:adiopharmaceuticals
22
:hem frequently,
number
23
>f them may
emerge
we have
There
the
is, beyond
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at Washington
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one,
these
to consider
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approval.
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synthesized
most
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we are trying
in between.
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and to go through
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radiopharmaceuticals
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exist
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19
25
thinking
to industry.
whatever
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sure
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radiopharmaceutical
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that,
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because
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it is a lot of money.
really.
MR. CONTI:
A generic
is whatever
and developed
through
drugs
life
is rather
DR. COLEMAN:
MR.
CONTI:
11
4nd we may be stuck
12
m
13
Ievelop
14
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15
>wn public,
16
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the literature
distribute
drug
industry.
And
It has got
would
be
the spectrum
Absolutely.
never
in that quagmire
really
on certain
coming
if you will,
It may
kinds
up with
approach
have
of having
as it is developed
actually
it.
large.
And will
the literature
an owner.
to only
rely
take years
of drugs
as they
the funding
in evaluating
to
to do our
this
in a
trial.
17
MS. AXELRAD:
There
18
:he drug
can be made
19
;etting,
if it is just purely
20
ill, under
21
Lvailable
available
the existing
under
and
RDRC
are options.
under
INDs
research
thing.
First
and not
clinical
Is it possible
to do that,
24
MS. AXELRAD:
25
DR. BARRIO:
setting
under
an IND?
Yes.
And
at
It can be made
setting
in the clinical
of all,
in a research
IND in the clinical
DR. BARRIO:
Lvailable
for anybody
to distribute,
10
23
like
a half
9
22
incentive
something
We can’t
6
patented
do you do with
MS. TESAR:
too short
7
is what
get reimbursed,
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also.
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it
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131
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MS. AXELRAD:
No; not and get
reimbursed.
I was
of taking
I
.....
2
wasn’t
3
stepwise.
going
that
far.
We are getting
4
DR. BARRIO:
5
MS. AXEL~:
7
want
8
that we did or are doing
9
talk about.
smerge
from
13
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14
off to the f-dopa
15
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16
think
research
but
only
18
where
is that
transmitter.
19
complicated
20
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21
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22
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the new
future
So the question
24
.iterature
on that
25
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here
with
sorry.
things
we have
review
to
that
can be done.
that may
sort of
talk
four.
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agent,
my
about
you get
trickier
the receptor
agent.
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it gets more
review
of that.
that at all but we can,
meetings
talk
about
We
at some
the
that.
is, first
developed
of all,
to the extent
is so that you
MILLER
is what
It is non-toxic.
about
associated
and you
of what
a little
it is not
Okay;
talked
setting
to do the work
That
to doing
to do a literature-based
really
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are the ones--you
that gets
No;
to take
the literature
minimum
there
has
it is a receptor
MS. AXELRAD:
23
that
committed
DR. BARRIO:
is a neural
somebody
are not only
12
you want
for these.
is the bare
There
it
I was wondering.
to the clinical
then
I really
for this
11
17
stage
to get reimbursed,
we did
what
But when
the investigational
sort
to that.
That’s
6
10
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can pull
is the
that
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the
from
it?
--.L3Z
at
——
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What
are the difficulties
2
together
from
3
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anything
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somebody
who
do it?
in the PET
can do that?
the literature
and do an
evaluation.
MS. AXELWiD:
analysis.
9
It’s
To do what
DR. BARRIO:
3one it with
11
1 have
12
werything
13
Will be more
14
!nd I understand.
15
~fternoon
been
16
working
else.
~ery difficult
already
To do the
happy
that
the work
you put
is extremely
process.
On the other
We appreciate
hand,
20
lard to fill.
One of the things
21
rane, is, once
we decide
22
:he potential
23
:adiopharmaceuticals
24
:rial, what
25
:ogether
kind
we are left with
MILLER
that process.
and this
This
is a very,
that.
this vacuum
I would
like
of one or two from
that
I
to do it.
on four or five,
end up being
of requirements
considering
Then
for us it is so important
]ecause otherwise
that may
and
well.
us this morning
time-consuming.
19
emergency
very
together
is a field
models
you go through
shown
we have
That
the animal
literature
to help
You have
In fact,
partially.
in for years,
I know
than
This
18
We can do that.
fluoro-dopa
all
we did.
the analysis.
10
17
pulling
on that and who would
ICP or whoever,
MS. TESAR:
7
8
with
we do it or is there
either
5
6
the literature
Would
community,
associated
there
you might
how
is very
to see,
too,
to deal with
this
jungle
of
in the clinical
like
is no incentive
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that
to put
in industry,
at
133
1
no incentive
2
want
3
process
4
under
in the PET community,
to do it, to really
go through
and do it that way,
this
MS. AXELRAD:
6
reimbursement
7
the incentive.
8
incentive
9
from
11
kinds
The
of thing
incentive,
though,
At some point,
to do something.
is what
money
that becomes
in terms
13
or whatever
14
are.
15
iiiagnostic area,
16
diagnostic
is required,
what
vehicle
we choose
We are taking
18
?roductsr
steps
There
19
Erom the ones
20
~implify
21
second
22
:rial based
the ones
that
the requirements
then
is
enough
is given
to us
the
to show,
what
:hings can we clarify
25
me
document
our expectations
in the radiopharmaceutical
are
some
have
radiopharmaceutical
of the same
between
a sort
class
more
that you
or explain?
all the time where
issues.
1 and class
of clear
safety
difficult,
for one category
the question
24
developed
what
can you differentiate
on the claim
And
that
in a guidance
to use,
that are a little
category,
a large
do you have
in the traditional
area.
That
and requirements.
Can you distinguish
23
do
is to get
of implementing
We can try and articulate
17
we could
off of it.
The question
really,
of procedures
12
who really
the clinical-trial
kind
for it and then make
the Congress,
statute,
what
those
circumstances.
5
10
beyond
are going
is what
to a
in a
for.
kinds
of
orphan
are very
MILLER REPORTING COMPANY, INC.
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can you
is required
other
Certainly,
there
profile
as opposed
what
2
small
drugs
at
134
—
1
patient
2
here.
3
a relatively
4
wouldn’t
populations.
Small
companies
There
6
and trying
7
I hope
8
going
9
trials
are ways
to do anything
not a lot of point
11
articulate
understand
14
over
15
We are
16
This
is very
17
back
and reassess
it.
the last
review
20
going
I think
several
what
21
do, how many
22
parameters
with
they
those
if the answer
that
concepts
in a way
that
is nobody
is
do any kind
of doing
of clinical
then
a lot of time
we have
has been
as to what
I think,
whether
words,
it is we are,
it now
there
trying
to make
is
to
the requirements
those
what
type
are.
parameters.
for the community
to go
is doable.
in fact,
what
sure we
a lot of confusion
if we are going
trial
patients,
This
part
or else
of taking
now of defining
important,
of those
and,
there
years
to do a clinical
25
presumably
in the PET area
But
I think
in the process
19
decade
them
in spending
In other
24
new
how you do that.
13
23
of sort
is no way
MR. CONTI:
18
drugs
of money
and you won’t
there
10
something
it.
be applicable.
because
inventing
orphan
amount
to articulate
will
12
develop
reasonable
be doing
5
We are not
to do a literature
expected
to do, if we are
it is we are expected
of study,
what
to
are the
studies.
has escaped
therefore,
to try to figure
the PET community
there
out,
MILLER
has been
“Well,
gee;
very
over
little
we don’t
REPORTING COMPANY, INC.
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the last
on our
know
what
we
at
135
—
1
are going
2
submitting
3
$200,000
4
not in the format
to do.”
We run into
the problem
that we ran into
,,.-..
the lung-cancer
on it.
It goes
That
6
MS. AXELRAD:
7
is not my understanding
9
can’t
about
10
there.
The main
11
like to articulate
12
=he issue
13
communication
14
were saying
16
~hat we were
17
leeded
18
somewhat
19
Tou .
“Well,
this
is
There
to be clear.
That
happened.
I think
clearly
here
Kim called
was
some of this.
you
to try
some miscommunication
is Kim.
Maybe
she would
Kim, we are talking
pulmonary-nodule
that you and Jennifer
study
about
and the
had and whether
we truly
it was not acceptable.
not
saying
saying,
though,
we were
of a pre-NDA
said
MS . KEPPLER:
md
22
~hich raise
23
:an’t get an IND.
24
:omewhere.
isn’t
going
up, which
The
that
was
going
it was not acceptable.
that
that
I think
to go away
more
it in the manner
communication
the crux
with
of the problem
any other
with
So, as we go forward
with
by some
is,
generics
is the ICP or professional
thing
we
it was not acceptable.
It has to be done
same
the information
to review
and we needed
But we had not
21
25
And
issue--and
to review,
20
say,
the record
of what
No.
that.
We were
this
I want
of the single
15
to FDA and they
We spent
happen.
DR. LOVE:
to talk
we submitted.
that we want.”
5
8
data
association
institution
an NDA.
with
the generics,
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if we are
at
137
1
the process
2
process
We haven’t
even
attempted
to, clarify
the
yet.
3
.-
yet.
MR.
CONTI:
4
is as we define
5
for the PET community
6
do.
7
guess
8
community,
9
Nuclear
This
what
that process
to decide
If the parameters
I sort
10
industry
11
trials
in part
there
Medicine,
will
from
that we will
12
be a response
acceptable
14
is a commitment
15
these
by both
groups,
that
be much
easier
I think,
portion
from
and
of the PET
the Society
organizations
to pull
I
together
of
and
the types
of
like.
If the parameters
13
defined,
for a good
be able
the issue
it is we can and cannot
ICP and other
that you would
I think
is, it will
what
are well
of speak
that
is my point.
are designed
we will
I think
such as they
do what
we have
are
we can and this
to make
to FDA to do
trials.
16
DR. LOVE:
17
~ou are
18
:hink that
19
]roblem
20
:ontacted
21
Miscommunication,
saying
And
about
example
I think
our ability
that was
of communication
Jennifer
22
But
23
:he issues
24
md
25
:learly,
where
and
it was
when
we called
to
I think
for that
try
are the things
forward
MILLER
it out.
up exactly
is the important
REPORTING COMPANY, INC.
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that we
the
that both
was miscommunication.
I
was a
reason
to straighten
clearing
what
because
on the table
we recognized
the process,
are we going
it is important
to communicate
just put
because
are and what
there
that
what
of us need
thing.
So,
. ..
at
138
.
1
MR.
2
mechanism
3
use that
term
just
4
publicly
held
or that
5
society?
for a DMF
6
or let’s
Yes.
to be done
through
8
question.
I am certainly
9
can’t do that.
we have
ICP.
I think
MR.
12
MS. AXELFQUI:
CONTI:
if you will--let’s
through
I think
I want
that
can be
a professional
an IND might
to look
not going
into
that
to say right
is an important
I want
13
mybody
14
leld one and you
15
:0 your
16
>f procedures.
17
>roprietarily-held
18
:verybody
19
share it, or somebody
20
And we keep
can hold
data.
;O reference
22
.s done,
23
:hemistry
Yes;
can charge
We can
DMF
is what
you
but
be able
legal
now you
legal
question
could
for granting
them
we want
the traditional
way
is, where
are giving
them access
in terms
of--where
to it and you
us.
it confidential
for clinical
access
you are not giving
it with
people.
though.
be a publicly-
out whatever
shares
it to other
the IND,
the IND--clearly,
there
people
figure
data
not usually
to get beyond
I know,
an NDA.
the data,
21
25
is a
to answer.
11
24
there
of discussion--that
can be done
MS . AXELFQ.D :
that
say an NDA,
for sake
7
10
—
Do you believe
CONTI :
and they give
That
is sort
data,
mostly
a right
of the way
it
in the
context.
We have
lnd we can’t
flexibility.
do anything
that
We have
to watch
is inconsistent
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the statute
with
the
139
at
1,
statute
and there
2
at, but we could
3
do new procedures.
4
sets
MR.
6
have
issue
8
issue.
Bob Wolfangel
9
practically
wants
that was just made
12
of want
to put
13
holder
of an IND and NDA
14
well.
That
in a plug
MS. AXELRAD:
16
MR. WOLFANGEL:
that would
18
PET community.
serve
both
20
ICP’S
21
assume
legal
22
construct
because
what
24
clarifying--in
25
go back
the issues
and
there
for us.
We
to go away.
it a generic-drug
and since
Listening
you.
with
respect
and work
he is
to the
to ICP,
I just
sort
the USP as, perhaps,
through
fact,
would
But
a
that process
certainly
it may,
FDA needs
as
be unusual.
in fact,
and also
offer
The other
be a vehicle
the needs
of the
it as an alternative.
part
and the risks
on that has to do with
that
ICP is willing
are two sides
on this particular
I think
to start
are with
start
that
of the audience--
That
MS. AXELWD:
23
call
for using
So I just
DR. LOVE:
19
to
be unusual.
15
17
not going
Thank
comment
is the issue
to say something
the only member
would
that
We still
11
supposed
to do it by regulation
that
MR. WOLFAJTGEL:
,have to look
we can do that.
I think
CONTI:
MS. AXELRAD:
10
_-
procedures,
we would
We are obviously
If we need
a generic-drug
7
things
do new regs.
out special
5
are certain
we need
this part
of it.
one of the take-away
thinking
about
what
issue.
identifying
We can start
items
kind
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to
I have
of guidance
is to
we
at
140
.
1,
can give
2
developing
in terms
you
of developing
a new
indication
or
-.
a new molecular
3
We are learning
4
reviews.
We know
5
a jigsaw
6
to do two adequate
7
~hat would
8
Fifty patients?
9
What
look
we just
like?
dhat kind
12
sort of try and reach
13
~as to be done
14
;hat you produce,
What
kinds
of analysis
together
like
set out at the beginning
about?
of claims
would
clinical
trials.
Twenty
patients?
:0 learn
17
in the literature
18
reviews.
19
the PET community
20
our phone
how you
What
we have
done
did the literature
review,
you be getting?
so that
if you do it the way,
gets
bills
would
I think
that we can
of what
the product
is okay.
today
review,
We are able
and being
what
we can help
us out of the starting
reimbursed.
are we
of an understanding
that we can articulate
16
How many
you be getting--so
some kind
MS. TESAR:
able
you found
do literature
gate.
That
to start
gets
paying
again.
We are out of the starting
22
#hat we can look
23
#ant to have
24
Lhings
at is that
proprietary
certain
drugs
process
gate.
Then,
entities
will
and that want
and then how do we provide
What
things
Ten patients?
are we talking
11
25
to piece
literature
500 patients?
about?
That
this
and well-controlled
talking
21
.——.
Supposed
10
15
yourselves.
from doing
that we had
puzzle.
they
entity
access
are we going
arise
that
to do these
to those?
to use
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I think
for the new drugs
at
141
-_
1
as we discussed.
2
gate
3
certainly
4
guidelines
that we all agree
5
are going
to do it in a good
6
what
But
I think
to get out of the starting
,, .....
and essentially
help
we’ve
I think
this
my worry
is getting
9
we don’t
have
10
volunteer
review.
11
the people
12
to not have
beyond
the means
effort
I think
the ICP can
If we do it with
on, then you will
fashion
the
trust
and that you
have
can--we
been
those
write
15
who are involved
16
up .
Before
17
sort
of see if there
18
what
sort
19
typical
it anyway.
involved
that we
can review
in doing
know
But what
21
an analysis
some
22
way our own review
23
how--turning
24
just
25
dopa.
that
would
that
exactly
our
Most
Maybe
of
we ought
they are there
in the drug
road,
to
company
do the write-
I would
like
to
What
you
saw from us
typical
but
a more
in to us--it
be done
is done.
around
So we have
you were
you
is similar,
a little
to what
we want
MILLER
But
or less
is done.
comes
say you we decided
it.
of the studies
is some model.
that might
in time where
review.
that
the people
you go too far down
that
I think
type of search.
in writing
I don’t
of typical--not
What
at this point
that.
do it.
I’m sure
FDA review
with
can do literature
people
14
that
help
to do that
MS. AXEL~:
20
done,
we can certainly
8
13
you have
done.
7
—–.
with
what
differently
to look
we would
going
to give
want
but
it is
than
at sort
you
the
of
to--let’s
to do the thing
on f-
us so that we could
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at
142
1,
then
2
focus
review
on that
3
4
thing.
5
are other
6
literature.
7
wrong
That
We would
have
and articulate
MR.
would
help
that
But we would
that
the
as George
to be able
“g” word
8
MS . KEPPLER:
Unproprietary?
9
MS . AXELRAD :
You don’t
10
drug because
11
It is going
12
second
13
call
the first
comes
it a generic,
But
and there
16
I want
that
to be a new drug
one that
15
drug
want
comes
to really
from
Unproprietary?
18
MS . AXELR-AD :
Unpatented?
19
MR.
20
nany of these
21
of that
literature
22
at least
evaluate
23
then we would
24
pharmaceuticals
25
needed
There
is some
agents.
the parameters
we stood
and we would
to be done,
what
MILLER
used
the
to call
it a generic
in isn’t
a generic.
of some
sort.
The
route
and
other
it comes
under
505(j)
with
How about
literature
If we were
in the format
where
to--I
is some
that.
So
the term generic.
MS . KEPPLER:
know
there
and there
associated
17
other
said,
to go that
then
of issues
stay away
CONTI :
important
be a generic.
if it is a generic,
are all kinds
and
for the record.
application
in, if we were
would
at that
is the most
are out there
like
I used
of look
to you.
us because,
drugs
again.
to sort
that
I think
CONTI:
generic
word
14
___
it?
know
able
that?
out there
to compile
on
some
that you are looking
for or
that you
for
on many
what
trials
are looking
of these
other
would
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tests
need
would
be
to be done.
at
-.
_-
143
1
DR. BARRIO:
Then
the first
step would
be for us
.....
2
to help
3
these
you
in whatever
radiopharmaceuticals
4
MR. CONTI:
5
Let’s
6
George.
let them prepare
How
about
8
DR. BARRIO:
I think
MS. AXELRAD:
know
the third
on this.
that
is a good
idea.
do that.
No question
know
the fourth
about
13
MS. AXELRAD:
14
just want
15
what the fourth
16
I don’t
to make
Sodium
20
that
I
is the fourth?
in agreement
on that
I
is
is.
By the way,
sodium
MS. AXELRAD:
articles
fluoride
sure we are all
all available,
18
is.
fluoride.
Sodium
DR. BARRIO:
really
what
one is water.
DR. BARRIO:
21
a compromise
the four and you do the fifth,
We could
12
19
four.
that.
10
17
make
of
that?
MS. AXELRAD:
11
for four--okay,
Let’s
7
9
way we can in the evaluation
exist
most
fluoride
And we were
on FDG;
DR. BARRIO:
of the literature
in 1972,
modest
is
NDA .
in the 2,000
right?
I think
there
are much
more
than
~hat .
22
DR. LOVE:
23
~estions
24
:he two products
25
?OU were
There
or differences
saying
may be some manufacturing
that we would
are similar.
the first
That
thing,
try to make
is what
though,
was
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we need
really
sure
that
to know.
the
at
_———_
144
1
information
2
MS. AXELRAD:
3
to get ammonia
4
if we are going
5
whatever.
6
doing
7
people
9
there,
to get this
done.
and to the advisory
and out so that people
then we will
the other
and such.
We want
and FDG done
And
do the others.
two as soon
as we finish
We want
committee,
can be doing
We can start
these
and have
to do them.
8
We can’t
because
lose
sight
of the chemistry
one of the issues--we
10
that this
11
what exactly
12
me
drug
is safe
were
14
through
15
!Jormally, we know
16
#as made
17
It may
18
~hen there
19
JO the old material
20
studies.
different
and
21
multiple
chemical
exactly
during
discussing
ourselves
the drug
so you
different
That
only made
wasn’t
don’t
:hink it is an insurmountable
23
~mmonia but
24
:hemistry
25
:hese for either
more
ways
is not
trial
the norm.
material
or less
development
of how
to sort
it is something
made
how the clinical
22
what
drugs
the clinical
But we have
time
asking
because
processes.
are measurements
area,
and kept
on this
trials.
it is usually
change
spending
and effective
in these
There
were
and effective
is safe
used
13
-
on the indications
one way.
program
the new material
have
compares
to go repeat
all the
of keep
that
in mind.
problem
with
regard
we will
is the chemistry
an IND or an NDA.
be addressing
going
What
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of
I don’t
to FDG and
in the
to look
kinds
but
like
for
at
—_
145
1
information
2
over
do we need
and what
kind
of control
or controls
,...
the process
3
MR. CONTI:
4
your
sentence
5
To the extent
6
be very
there
7
something
again
8
different
structure
I’m glad
because
I think
and we won’t
that
have
is different
The
and it is like
11
NDA and then you go through
12
then you get the NDA.
You
13
information
to put
14
place which,
15
mder
16
30 an IND .
steps.
You get
to be able
presumably,
RDRC before
MR. CONTI:
18
zhat you would
19
~hat the boundaries
20
#orking
22
md,
23
:evoke when
24
vorking
25
>oundary
a long
since
you
That
address,
doing
important.
it would
and do
it is a
what
have
get
can get the
you have
a certain
done
to point
is another
thing
in chemistry
to do and
amount
some of this
of starting
I would
and
radiopharmaceuticals.
on that.
We were
we started
anything
out,
Congress
RDRC
to
hope
is the RDRC
when
to 361.1
of
in the first
way back
they did everything
MILLER
IDE so you
We are working
put
is under
is you get an IND first
it into humans
ever
too,
ago,
we hadn’t
what
IND in
processes,
to go back
require
are for those
time
on changes
those
the
you will
MS. AXELIW.D:
21
it is really
just because
ideal
10
17
that
of an application.
MS. AXELRAD:
your
you mentioned
that we can overlap
helpful
9
—--——_-
do we need.
else.
doing
PET
didn’t
But we have been
for some
time
and what
isn’t.
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the
146
at
—_
MR.
1
Knowing
CONTI:
2
would
be extremely
3
solve
a larger
problem
4
need
to go down
with
5
communication
helpful
would
these
at one point,
8
MR.
9
MS . AXELRA.D :
meeting.
11
a future
meeting.
12
MR.
new compound
with
that
we are trying
pathways
do we
developments.
important,
to
That
I think.
can you do under
RDRC
and
to go to an IND.
Right .
CONTI :
a future
are doing
is what
How much
do you need
10
which
be extremely
7
you
for us because
here
MS . AXELRAD :
6
what
I think
we should
We can talk about
CONTI:
With
respect
talk about
the chemistry,
to the issue
that at
too, at
of the
—
13
potential
14
one of these
15
of fees
16
are and where
17
for public
DMFs
or NDAs,
and things
you
I think
entity
like
folks
just
or some
maybe
this
are with
19
trials
20
such that we can tie a low barrier
21
these
22
that are proprietary
23
our poverty
but
I do want
non-proprietary
Nhat we do in terms
25
application,
regard
level
and what
Basically,
of user
as defined
fees.
the issue
and see where
we
to say that we have
running
to approach
your
surface
to hold
to fees.
with
this
to access
pharmaceuticals
MS. AXELRAD:
24
bit
in the beginning
already
for you,
equivalent
we should
a little
18
expressed
such
a little
to some
as opposed
opinions
in the statute,
Washington, D.C. 20002
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of
to those
specifies
that a new drug
pays
MILLER REPORTING COMPANY, lNC.
507 C Streetr N.E.
bit
are on that.
the statute
It says
clinical
a fee and the
at
—
147
1
application
2
$267,606
fee for the fiscal
plus
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adjustment
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4
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6
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7
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for FDG or a new active
9
if it were
505(b) (2), which
been
10
example,
approved
based
1999
12
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13
probably
14
safety
15
is we publish.
none
would
16
They
would
17
in the first
18
split between
19
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20
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place,
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21
although
however
many
drugs.
group
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22
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24
:eduction
25
~ssessment
for certain
the main
people
with
were
kinds
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present
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would
on the same
were
it
a fee.
to pay a fee at all
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going
through
charging
to pull
be
to be accessing
for the
it together.
a fee at all,
the statute
and exemptions.
are that a waiver
to protect
of the fee would
want
of waivers
provisions
is necessary
to pay
going
to not pay
pay
come out of whatever
theoretically
be dealt
central
would
doesn’t
entity
a fee.
would
all relying
not have
Now , if somebody
indication
pay
of the others
be generic
which
that
such as the ammonia.
be 505(b) (2) applications
data
something
a new molecular
—
and efficacy
that.
of new drug
such as an oncology
one of those
one pays,
kind
indication,
on the literature
After
pays
on the literature--would
ingredient,
11
is
for inflation.
application
is a special
before
and 2000
we have
one based
Now , the first
the first
years
the public
health,
a significant
MILLER REPORTING COMPANY, INC.
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or
the
barrier
to
at
148
1
innovation
because
2
person,
3
the present
of limited
resources
available
to the
......
that
4
fees
and future
And
5
don’t
have
6
of--well,
7
depend
8
doesn’t
9
who submits
to be paid
there
to worry
the first
on is that
have
10
a person
incurred
about
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it.
the public
that
the labor
but
those
health
is with
community
like
have
and wasn’t
expecting
13
they might
qualify
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15
qualify
for a waiver
16
financial
17
qualified.
18
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19
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20
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21
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22
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23
:or determining
24
>usiness.
for a waiver.
needs
test
There
but now
business
with
some
from
group
to determine
that
hospital
or
from
that.
submitted
it, they might
they would
apply
exception
is submitted.
the Small
Business
of the Small
revenue
the drug,
a small-business
who has
It used
for the
to be a half-
And
that qualifies
less
than
500 employees.
Administration
Business
Administration
who
rules
somebody
qualifies
as a small
Gee,
ICP might
qualify.
the
a
fee.
REPORTING COMPANY. INC.
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MILLER
the person
they were
as someone
MS. KEPPLER:
the application
whether
it is the full
whether
and innovation--
revenue
But , basically,
is also
sort
a lot of annual
a lot of annual
If a not-for-profit
so we
its affiliates.
So if you had a small
12
use
three
It is not only
also
exceed
by the secretary.
one that we never
two,
that
will
is another
a lot of revenue.
something
25
costs
the entity
11
14
by such
a
at
—
149
1
MS . AXELR-AD :
2
But, basically,
3
that
4
setting
5
use
have
up whatever
Like
the first
8
first
9
new indication.
10
DR.
that
or structure
that,
COLEMAN:
about
here
these
going
with
12
MS. AXELRAD:
We are.
13
DR.
These
will
14
MS. AXELRAD:
Yes.
There
COLEMAN:
15
statute.
16
Nell, we think
17
so we are going
18
malysis
19
?arameters
20
:hat.
There
under
23
it would
24
:ee whether
25
;05(b) (2) just
it would
and
to what
ammonia,
pertain
water--
to that,
too.
is no real basis
user
have
say,
fees
“Oh,
for PET
using
or exception
be waivered?
in the
to go through
the statute
for a waiver
be for a
be a problem.
FDG,
We would
Who would
KEPPLER:
an entity
like
or the
to pertain
to waive
for
an
the
to do
Would
it be
!Twho?T!
:he ICP or the first
MS.
be nice
the provisions
MS . TESAR :
entity
at all for us to just
to do that. “
that provide
21
22
is no basis
to
only be an issue
or whatever
today
you are
you are going
it wouldn’t
Are
when
like
to do that.
it would
or something
an analysis
in mind
for a new molecular
After
we are talking
to keep
I think
application
,possibility.
to go through
an application
I said,
application
an interesting
have
process
for submitting
7
11
we would
and you would
6
That’s
I think
like
the NDA
MILLER
she is going
the ICP could
and the
to look up to
be the holder
IND.
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of a
at
,,,
150
1
MS . AXELRAD :
2
couldn’ t.
I don’t
3
ICP wanted
to submit
5
Somebody
6
wasn’t
7
presumed
else
around
that
8
9
that
12
the NDA.
13
NDA .
so I don’t
there
the NDA had
was
why.
I don’t
hold
why, they
about
But
If
could.
the DMF,
holds
that.
I think.
the NDA.
I would
I
have
a reason.
were
some reasons.
Ed, yOU were
remember.
I thought
to be at a site
We could
they
Peoria
know
There
MR. CONTI:
14
15
me, but
DR. COLEMAF( :
11
is an issue
We submitted
correct
at the time.
10
there
the application,
MR. CONTI :
around
understand
think
MS . KEPPLER:
4
I don’t
we were
and that
the DMFs
told
at the time
ICP couldn’t
but we couldn’t
ICP was not actually
hold
hold
the
producing
material.
16
MS. AXELRAD:
17
companies
18
at a contract
19
~id so--
20
submit
DR.
applications
facility.
it at the time and
22
:enter.
I was.
it had
MS. AXELRAD:
24
Legal reason
25
what .
for that
think
here
We were
materials
doing
told
to be the Methodist
I have
Drug
produced
this when
just
Medical
a preference
REPORTING COMPANY, INC.
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they
ICP couldn’t
to find out if there
or if it was
MILLER
that matters.
and their
I wasn’t
COLEMAIN:
21
23
I don’t
was a
or
do
1
at
---.
151
1
DR.
2
certainly
3
we were
4
waiver
I can’t
COLEMAN :
held
told
the DMFs
it had
and we wanted
to be Peoria.
why,
,either, but we
to hold
And
then
the NDA.
But
they
got a
they were
small,
on the fee on the NDA.
MS. AXELFA.D:
5
6
public-held.
7
waivers
Right,
I remember
in ’93, I think
MR.
8
CONTI:
that.
Certainly
be important
and certainly
10
for actually
submitting
11
assessed
12
need
13
It is handled
15
You
16
sort
17
it.
can call
them
reciting
20
annual
21
financial
22
about
23
on behalf
That’s
but
revenue
need
out
is going
to
are the requirements
have
to submit
what
to be
ICP would
I can tell you
of Chief
they
Mediator
grounds
and Ombudsman.
and ask them.
are the ones
and
I can tell you
that
requesting
indicating
that.
actually
do
a waiver,
what
your
is and things
to demonstrate
that you had a
to get this.
You might
to talk
how they would
to think
easy.
it is a letter
the statutory
24
you would
on the phone
Basically,
19
what
that
or for a waiver,
by the Office
of, basically,
18
finding
together.
MS. AXELRAD:
14
The was one of the first
knowing
what
for an exemption
to put
because
it was.
9
25
remember
react
to a trade
want
association
to them
doing
that
of the industry.
MR.
CONTI:
That
about
very
shortly.
MILLER
is a process
that we could
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.
152
DR. BARRIO:
1
2
then,
3
radiopharmaceuticals
4
five NDAs,
5
come
you
envision
from
for these
The
two questions,
four
That
probably
is the first
we already
for FDG, what
is going
to happen
8
your view,
9
present
or how the old NDA will
evaluation
10
of the whole
MS. AXELRAD:
I don’t
11
that at all and
12
see it is, frankly,
that
13
heart
attack--every
PET center
14
would
essentially
15
505(b) (2) application
16
that
I think
is,
right
NDAs.
now,
Those
will
have
with
be put
an NDA
in
that NDA
together
in
with
the
process.
think
we should
every
One
question.
is since
Peoria
about
paper
second
7
Jane.
or five
that we are talking
to be in place,
ICP?
6
I have
we have
talk
about
talked
it.
PET center--don’t
about
The way
have
I
a
~.,
_
NDA,
submit
an NDA what
a literature-based,
for the PET drugs
and the indications
they want.
17
They
18
follow
19
say to reference
20
Register
21
terms
22
products
will
a model.
Notice
all be the same
For the safety
either
or those
That
24
labeling,
25
this is what
will
and efficacy
piece,
it will
or the FDA Federal
it is that
of the safety
all sort of
the FDA produces
and efficacy
in
of those
indications.
would
whatever
They
the FDA review
or whatever
of its analysis
23
.-
be a paper
would
be part
1 of the efficacy
it is that we come
the labeling
is.
The
out with
second
piece
MILLER REPORTING COMPANY, INC.
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and the
that
will
says
be the
at
.
153
1
chemistry.
2
standardized
3
you are using
What
4
we are working
chemistry
5
are using
6
same procedures,
7
it would
8
we can make
9
procedures
there
these
sort
it given
will be other
12
there
13
that any one of them
14
differentiating
15
it is that
16
specifications,
17
that.
might
be.
20
to get
DR. BARRIO:
21
if this
22
presentation
23
?age or two indicating,
24
with our requirement,
25
rather
than
and then
every
really,
there,
but--
1 was
thinking
whether
sending
there
would
operation
that
else
simple
thing
be basically
from whatever
they meet
and things
of this.
the USP
like
We don’t
probably--I
centers
will
this procedure
“ that may be the easiest
center
as
don’t
know
know
if ICP had the standard
the individual
“We use
but
the chemistry.
a very
standards
but
the
standardized
or whatever
envision
of my vision
or not,
that you
differently
ourselves
is and saying
the monograph
is feasible
describes
manufacturing
is sort
if
are a lot of different
among
can do and,
the standard
if we are going
you are doing
that
I really
their
“okay,
to certify
of biopharmaceutics
But
say,
or, if you are not using
there
talked
kinds
That
standard
of standardized--as
out there- -piece
11
19
what
that
We haven’t
18
is some
explain
that would
of a very
do this.”
same procedures
be a very
10
submission
this process,
Either
on is some kind
you a pile
MILLER REPORTING COMPANY, INC.
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and we comply
way
out
of papers.
at
154
1
Right .
MS . AXELRAD :
We could
probably
do that,
..
2
do it in an NDA,
3
is there.
4
My understanding
5
things
6
with
7
processes
they would
is that
somewhat
that
there
this
that
If all you are doing
way as somebody
11
they
12
be how
13
doing
14
have
15
sterile
16
doing
17
for them
are doing
to deal
it differently,
a different
18
an ideal
20
could
21
whatever
22
either
23
deviating
24
that .“
25
blessing
if the bulk
that
have
to come
levels
is perfectly
differences,
if somebody
easy.
It will
box or they
or they don’t
that we would
the way
is actually
a different
it is that
have
they might
have
it is.
the same
said that
that
differently
of procedures.
exactly
already
of synthesis
to grips
the easier
“I am doing
if they have
do
different
the standard,
and we have
of it
they do that.
PET centers
two or three
or whatever
any
be
to find a way
to address.
MR. CONTI:
19
have
method
procedures
entirely
We will
and different
it is okay,
with
to show
is saying,
else,”
whatever,
the 70 different
are at least
for doing
10
have
differently.
The more
8
9
But
do it in a DMF,
scenario
submit
some
where
“We are using
would
envision--let’s
to call
the exact
this
be reviewed.
take
site
or an ANDA
or
it that would
procedure,
“ or,
is the justification
You would
or whatever.
MILLER
just
the NDA and each
information
we may want
by this method;
This
ICP holds
supplemental
terminology
say,
So we could
REPORTING COMPANY, INC.
507 C Street, N.E.
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give
“We are
for
it your
at
.-
155
1,
And
2
DR. BARRIO:
the DMF
also would
be central
wi,thin--
,,,
....
3
that
would
be the easiest
way.
4
MS. AXELRAD:
5
just
6
a DMF.
7
it.
8
it a secret
9
else
10
I think
an NDA.
The
It could
be just
ICP submits
It is not
from
know
DMF
everybody
who would
an NDA.
the N’DA.
like--the
to see what
to use
I don’t
Maybe
when
we don’t
is what
This
is really
else,
be a DMF or
when
they
have
you want
you don’t
is in the DMF but you want
want
them
need
in
to keep
anybody
to be able
it.
11
Like,
12
where
13
want
anybody
14
know
how
15
references
16
have
17
the DMF.
for the synthesis
the manufacturer
of a bulk-drug
of the bulk-drug
substance
substance
doesn’t
—~
to know
they make
it.
how
The drug
about
19
there
except
what
they
20
in the final
drug
product.
21
be done
22
it could
as a secret.
If you
in the DMF and,
have
if we
to the holder
a clue what
to know
in terms
In this
case,
are doing
to
applicant
we talk
doesn’t
need
it but we have
product
the synthesis,
The drug-product
23
they make
the DMF and then we go look
questions
18
—
else
is in
of impurities
it is not going
this
for everybody,
beMR.
24
of the issue
25
to protect
CONTI:
with
that
It should
the user
fees.
so that we can,
MILLER
be open.
Going
then,
And
that
is part
for a DMF would
sell
REPORTING COMPANY, INC.
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of
that
be
to recover
to
at
.
156
1
the user
fees.
2
equation,
3
process
4
the public.
If you
eliminated
then we wouldn’t
to have
that kind
MS. AXELRAD:
5
though .
6
too,
7
charge
8
develop
9
could
the NDA,
reference
10
you authorized
11
whatever.
12
you
them
MR.
protect
a user
NDA
just
the DMF
to
it in the NDA,
fee and you wanted
to spend
money
to
to
do the NDA and then people
for whatever
to reference
CONTI:
the
and it is open
it or you had
could
your
could
to pay
to access
fee, from
to go through
of protection
You
If you had
people
have
the user
they wanted,
whatever
it for, the chemistry,
The existing
NDA
at Peoria,
or
would
---
13
there be a way
14
we would
have
15
to move
to negotiate
MS. AXELF&D:
16
what we would
17
xt
18
Peoria
if there
want
was
to ICP?
with
some
real
Is that
something
that
Peoria?
We would
to do about
in the first
19
have
to talk about
that.
reason
I will
why
have
that
and
to find
it had to come
in from
place.
MR. CONTI:
The
potentially
be bought.
20
!JDA could
21
protect
22
?ublic
auspices
23
~here,
it is accessible
24
:hrow the whole
25
that
it for the public
so that
process
MS. AXELRAD:
only
would
would
And
be to keep
owns
to a purchaser.
in the array
would
be is that
the only way
the community
That
MILLER
reason
And
of the
have
to
it under
it.
the
If it is out
then
that would
“public
access.”
to be addressed.
REPORTING COMPANY, INC.
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the
at
.—
157
1
Whoever
it is, what we would
2
acquires
3
the NDA updated
4
annual
it has to be willing
MR. CONTI:
that we would
7
8
which
is that whoever
to do what
is submitting
it is that
is required
the supplements
to keep
and the
reports.
5
6
want
have
That
would
have
to be a commitment
to make.
MS. TESAR:
That
is a couple
of weeks
of work
a
year.
MS. AXELRAD:
9
We wouldn’t
10
somebody
11
that,
12
llwe haventt
13
years
and we are withdrawing
14
doing
that.
who wasn’t
we send
them
going
to do that.
a notice
gotten
it transferred
And,
in the Federal
reports
annual
want
from yOU
to
if they don’t
Register
do
saying,
for the last
five
—
15
16
like
CONTI:
MS.
KEPPLER:
The
NDA.”
community
I just
would,
signed
one
obviously,
nOt
that.
17
18
MR.
your
would
I find
19
The
505(b) (2) regulations,
those?
MS. AXELRAD:
There
314.
know
20
314, part
21
up and
22
are references
23
provision
24
It is more
25
~ifferent
where
I don’t
see where
to
the
of the statute.
often
than
used
Somewhere
But
MILLER
314.50,
it
there
difficult
terribly
that wants
is the most
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
in
to go look
after
It is not used
That
scattered
I have
it is a very
by a generic
an innovator.
regulations
exactly.
(b) (2) .
(b) (2)s.
are
often.
to be
common
use
of
at
.
158
1
it.
2
It was originally
3
Waxman-Hatch
and there
4
They
5
to do things
wanted
7
a little
8
also
9
the grounds
based
bit.
allowed
Waxman-Hatch
11
an indication
12
then
13
information
14
ANDA,
15
(b) (2) route.
submit
on that
and it has
18
like
that
19
to have.
MR.
CONTI:
with
21
and I have
22
these
approved
23
technetium
24
such as Mallinckrodt
it sort
sort
because
this
99m on a ligand
that
invokes
to be able
for a generic
through
like
certifications
a very
This
is patented
drug,
submit
into
the
a generic
and things
issue
R.K.
is one of
94 for a
by a company
set of problems.
with
that
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
Washingtonr D.C. 20002
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wanted
ligands.
a technetium
to deal
that
interesting
of patented
a certain
on
all out for you.
in the past.
substituting
it
was a phantom
of goes
is also
but
and just
It looks
patent
concept
if a generic
as if there
that
of changed
an application
(b) (2) application
There
about
where
We have
people
for the innovator
We can lay that
to isotopes
issues
in with
complicated.
has
talked
drugs.
and allow
qualify
For example,
certain
20
25
to come
a
generic,
to have
regard
was no
generic
the paper-NDA
indication
It is very
along,
who wouldn’t
that wasn’t
a phantom
17
came
the difference.
they would
to have
there
up a little
It incorporated
of sameness
addressed
when
on the literature.
a generic
10
16
was no way
to sort of loosen
After
6
developed
somehow
at
..-.
159
1
because
2
with
3
process
4
non-proprietary
now we are introducing
a PET radiopharyaceutical
.
an established
is rather
5
6
questions,
7
because
8
don’t
9
components
you would
know
make
12
somebody’s
13
have
14
you and
15
then
16
whatever
a patent
if you
a patent
MR.
CONTI:
is going
20
iodine
21
introduce
PET pharmaceuticals.
22
available
to the community
and things
MS. AXELRAD:
25
application
to
can sue
this.
to wait
You
And
30 months
or
litigation.
complicated.
to be suppressed
the first
they
are doing
in patent
have
problem.
and then
that you
drugs
that
and its
infringing
be a definite
in and we have
What
substitutions
and they would
If you were
19
are going
or the drug
on--I
look.
to look
it is resolved
18
the drug
certification
very
a lot of difficult
was
that would
kicks
It gets
raise
to see if there
the fact
17
fact
as a
(b) (2) route
have
a patent
until
24
developed
the
certification.
the statute
would
but you would
would
challenge
23
that
are going
if it is just
patent,
to file
if it is being
That
look
or what,
They
11
to go through
drug.
especially
even
and how
formidable
MS. AXELRA.D:
10
—
ligand
potentially
like
this
They
could
because
It is sort
new chemical
for ammonia,
MILLER
to happen
because
that
of the
are going
be literally
to
not
of that.
of complicated
entity,
I believe,
is a lot of
say,
would
REPORTING COMPANY, INC.
507 C Street, N.E.
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by the
for the first
qualify
for
at
.-
160
1
exclusivity.
2
their
3
one, would
own clinical
4
literature.
6
same.
7
it qualify
trials?
clinical
9
like
single
10
they
could
trial,
nodules
get three
years
15
which
16
indication.
17
based
if it is
it is not
based
for a new
the
on a
indication
on a new clinical
trial,
of exclusivity.
approval
decision
required
trial.
a clinical
would,
but
something
even
If the final
MS. AXELRAD:
required
do
a literature-based
if anything,
it is possible,
pulmonary
clinical
14
if they didn’t
they get much
If they did
DR. LOVE:
13
think
It is limited,
8
that
If it was
I don’t
MS. AXELRAD:
11
even
they qualify?
DR. LOVE:
5
12
But would
then,
If the decision
trial,
block
DR. BARRIO:
18
think
19
are much,
20
with FDG.
21
going
22
the ICP takes
23
or so difficult
24
~as to be done
25
Discussion
we envision
much
simpler
to do with
anyone
they would
else
Let me go back
NDAs
I still
then
or whatever
than
am not
clear
for everybody
to that
to put
that we are having
MILLER
to this
we like
in my mind
realistically,
that NDA
get exclusivity
from marketing
the NDA process
the old NDA,
that NDA,
on the indication
is probably
to comply
FDG issue.
to call
it that
through
how what
are we
because
even
if
so convoluted
it in the context
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
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I
we went
to that
in a different
for that
something
of this
way,
to look
at
at
161
1
this
and
so on and
so forth.
,,
2
That
3
for me,
4
whatever,
5
NDA that
6
out there,
7
going
if we start
from
I am not
square
so sure.
1, you
and then we can get there.
was part
of the old way
I am not
to get
8
9
is the thing
there
so sure
But with
of thinking,
I really
It sounds
One would
it,
an existing
that
understand
to the old NDA and that,
11
with
the chemistry
like
there
be the chemistry
10
12
can implement
this
is
how we are
for FDG.
DR. LOVE :
questions.
It is clear
I think,
procedures
DR. BARRIO:
Then
are two sets
part
is being
in relationship
taken
care
that we are talking
you mean
of
we are going
of
about.
to cancel
---->.
13
the old procedure?
14
DR.
LOVE:
I am not
15
am saying
16
the fact
17
iifferent
places,
different
18
3ifferent
sites.
So that,
19
oare of in whatever
20
perspective.
we are trying
DR.
22
?rocedures
23
)MF , then.
24
25
COLEMAN:
come
would
address
from
about
will
are
replace
It would
may be different
take
be addressed
saying
into
it somehow.
MILLER
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
at
take
from
that
that whatever
whatever
that
in
different
we can probably
would
But
to deal with
the old NDA,
I think,
So you
it is cancelled.
approaches
processes
procedures
DR. LOVE:
md
to develop
that manufacturing
21
saying
was
in the old
consideration
I
at
.—
162
1
MR.
CONTI:
2
DR.
LOVE:
3
we could
address
4
already
5
that would
been
As an alternative
the existing
approved
The other
7
other
8
indication?
9
what will
indication
manufacturing
in the context
part
have
process
of these
that
of the question
has been
I think
we could
you,
but
that
has
procedures
MS. AXELIUD:
of reference
12
DR.
LOVE:
is what
approved,
talk
be cross-referenced
10
a right
or what
be developed.
6
11
It may be an alternative,.
about
this
the epilepsy
about
that
in terms
of
and the like.
I would
say Peoria
to their
safety
Actually,
that
could
give
people
and efficacy.
is already
in existence
.-—..
13
because,
14
and ICP had originally
15
that is already
when
16
17
rhey have
available
DR. LOVE:
something
20
information
21
:oming
22
~lready
23
:he existing
24
indication.
in new,
a right
Exactly.
have
as well
NDA
to claim
in order
DR. BARRIO:
MILLER
I think
do with
would
to get access
Let’s
just
exclusivity.
claiming
in terms
as whatever
in the DMF
So
reference.
incorporate
they would
it was
of reference
But
be addressed
what
not
for cross
that we can also
would
through,
But not just
to authorize
19
one came
decided
MS. AXELRAD:
18
25
the first
exclusivity.
to those.
that
that
is
in whatever
of anyone
else
the information
we
need
with
to be done
to that particular
say that we are ready
REPORTING COMPANY, INC.
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to
at
.—
163
1
act and
2
think
say,
UCLA
“Well,
would
like
to apply.”,
What
do you
-.
I should
DR.
3
4
We haven’t
LOVE:
talked
5
6
do?
I think
from
7
No,
yOU
9
it is that
owns
10
that
“I give UCLA
11
for their
12
NDA No.
do; get a right
use
Jane
in general
head,
I will
8
says,
I mean
the top of your
MS. AXELRAD:
to
is what
was
saying.
exactly--
DR. BARRIO:
coming
that
without
tell
of reference
the DMF with
in an NDA
terms,
an existing
you what
I would
from Peoria
the safety
just
the right
the safety
and efficacy
like
or whoever
and efficacy
PET Center
NDA.
data
to reference
data
in my
so-and-so, ” period.
~——->
13
DR. COLEMAN:
14
DR.
The
15
NDA is what
16
the information
17
give us authorization
18
.—.
LOVE:
that
19
3MFs , a clinical
20
~een updated
21
~ave to be able
22
olinical
23
<now better
25
So Peoria
is relevant
for whatever
would
and the chemistry,
And
approved
to do is reference
have
ICP would
to your
is there
so that
Somebody
part.
are two
the chemistry
the two DMFs,
currently.
the
to give us
part.
is relevant
My understanding
the NDA was
or NDA?
is in the DMF but
to their
and a chemistry.
after
DMF has
all people
the
else might
but--
DR.
~he NDA,
in the DMF
information
is approved.
MS . KEPPLER:
24
Is that
LOVE:
though,
Some
I believe;
of the chemistry
is that
is actually
not correct?
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
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in
at
—
164
1
MS . AXELRAD :
2
but whatever
3
right
4
efficacy
5
-1 have
6
have
I think
it is, it would
of reference
data
we should
be simply
to the chemistry
a matter
with
the issue
of getting
and the safety
in the NDA and submitting
to deal
chec,k our facts,
and
it in whatever
of making
sure
a
for’m-
it doesn’t
to be a generic.
7
We run into
8
?eneric.
9
it is probably
It has
10
because
11
strength.
12
sameness,
13
that.
all kinds
to be exactly
going
the strength
There
to be a
of problems
the same.
That
the
is why
I say
(b) (2) and not a generic
is an issue,
what
are a lot of issues
and bioequivalence
with
was
the approved
associated
requirements
with
and things
like
So I would
see it
———_
14
It just
15
as a
16
is in the--
(b) (2) that
17
18
DR.
just has a right
BARRIO:
In terms
MS. AXELRAD:
?ieces
of paper
21
22
complicated.
of reference
to whatever
of the procedure,
specifically?
19
20
gets very
that
DR. BARRIO:
nodify,
It would
be a piece
of paper,
or
indicates-Just
indicating
that,
follow
that,
or
a simple--
23
MS. AXELRAD:
24
Eorm that
25
Letter
has
that
A 356(h)
to go with
explains
that
an NDA.
form,
probably.
It is a form.
all of your
information
MILLER REPORTING COMPANY, INC.
507 c Street, N.E.
Washington, D.C. 20002
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We have
And
a
then a
is coming
at
.-—..
165
1
from
some
other
sources.
2
DR. BARRIO:
3
or is the institution
4
to the same
5
written
You are raising
8
yet.
Let’s
9
need
to do.
issues
my next
does
of that NDA
We would
a lot of issues.
get the issues
We need
question
that going,
the modifications
MS. AXELFUU3:
7
10
that
requirements
or how
6
Then
to be subjected
in the way
will
apply.
have
to talk
We haven’t
on the table.
to start
is am I going,
about
gone
That
the discussion
it is
that.
that
is what
far
we
so we get the
on the table.
11
DR. BARRIO:
12
making
13
it will
our views
I think
a little
that NDA being
bit not
so clear
there
in terms
is
of what
.—=
mean
14
MR. CONTI:
15
assumption
16
held,
17
really
18
alternatives
19
just
20
or not--
.-.
that
let’s
I think
to go back.
.
Unless
from
in terms
you have
the NDA becomes
start
It has
scratch--I
of complying.
to make
a public
to be updated,
don’t
Or modified
know
the
document
from there.
it is eliminated
DR. BARRIO:
adapted
centers
say, by ICP and
have
start
21
22
for individual
I think
to a point
is an option
so it could
to-MS . KEPPLER:
Do a 505(b) (2) for FDG as well.
24
MS. AXELRAD:
You don’t
route.
you
and we
23
25
is
and
completely
if that
that
You have
got
that
MILLER
want
on the books.
to go down
Let’s
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.c. 20002
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that
not do that
be
at
.n.
166
1
anymore.
2
need
3
it.
We don’t
to modify
4
it.
saying,
the safety
6
relevant
Plus
8
better
9
anything.
than what
Not
we have
So we really
the
of each
center
’92, PDUFA,
there
was
15
MR. WOLFANGEL:
$60,000
a year.
MS. AXELRAD:
18
MR. WOLFANGEL:
in there
was
is
probably,
of literature
want
to go down
for
that
route
of
to the discussion
your
own NDA,
a requirement
that
Did
fee.
fee.
carry
that
under
for a facility
An establishment
Did
I know,
in
fee which
was,
I
over?
carry
a year.
over
to the
’97
FDAMA?
MS. AXELRAD:
21
MR. WOLFANGEL:
Eee, also
an annual
Yes.
NDA
23
MS. AXELRAD:
24
MR. WOLFA.NGEL:
25
as Victor
but,
$120,000-something
20
22
relevant
Establishment
17
19
don’t
of filing
MS. AXELRAD:
think,
only
Relevant
14
16
to get rid of
information
in terms
MR. WOLF~GEL:
13
we
rid of it.
11
terms
want
of that data,
and efficacy
MS. AXELRAD:
12
some
don’t
We ,do whatever
to his decisions.
7
getting
to get rid of it.
We certainly
DR. LOVE:
5
10
want
m
opinion
discussion.
The
other
thing,
there
was an NDA
fee.
There
was
a product
I am bringing
You are
talking
those
up so we have
about
if we file an
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
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fee.
at
.-q
167
1
NDA,
2
establishment
3
on that.
4
that
you
have
to register
as a drug manufacturing
...
There
is an annual
Plus , each NDA you hold,
in addition
5
6
.
to having
MS. AXELFUU3:
a correct
MR. WOLFANGEL:
8
MS. AXELRAD:
there
is an annual
10
aollars
11
product.
12
I’hose are also
13
talked
about
14
factor
in.
and there
subject
an annual
fee on
report.
That
is not
is not correct?
First
That
Now , one thing
it is legal
18
~ave to be separate,
19
manufacturer
20
seventy
21
~ubmitted
22
manufacturing
We have
never
different
under
what
fee which
product
provisions
we would
individual
or whether
manufacturer
the one NDA
whether
applications
there
could
sites
that we
have
am throwing
I don’t
the statute--is
is on each
it is assessed.
we can explore--I
this.
is is
is 120,000-some
is the way
about
there
fee which
is something
talked
at all under
site
of all,
to the same waiver
earlier.
17
25
No.
is an annual
X_lt.
24
That
establishment
16
23
is another
No, no, no, no, no, no.
It is on each product
15
there
$60,000
statement.
7
9
to file
fee of at least
even
to
this
know
there
would
for the
be just
one NDA and
and information
for all of those
different
sites.
MS . TESAR :
Then
they would
have
to have
Variations .
MS. AXELRAD:
Right .
MILLER
We will
have
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
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if
to look
into
at
.-.
168
1
figuring
out something.
2
will
3
establishment
4
to figure
be an issue
5
structure,
if we were
7
understand
it, going
8
$267,000
facility.
9
indications
for,
To continue
going
back
fee for each
three;
it
worth
of
I think
we will
to clarify
the fee
to have--just
indication,
like,
if we were
FDG which
Alzheimer’s
so that
have
I
to the fees by indication,
would
disease,
MS. AXELFQD:
It is a half.
12
MS . KEPPLER:
It is a half
MS. AXELRAD:
If it were
going
be--say,
tumor
11
13
dollars
but
out somehow.
MS . KEPPLER:
adding
say it for sure,
the 120,000-some
at every
6
10
the
to add
we were
imaging--
for every
additional
one ?
14
15
efficacy
16
indication,
17
data.
18
literature
supplement
which
it is half
These
would
a supplement,
is a supplement
the fee,
for adding
a supplement
be supplements
with
if it is an
with
clinical
a new
clinical
data
albeit
reviews.
19
.-
about
fees
that
I won’t
Like
I said,
20
the problem
21
wouldn’t
22
without
23
Nould not be assessed
with
be a new
a new
the first
the application
indication.
indication
and
a fee.
one
is where
fee.
After
It would
it would
24
MS . KEPPLER:
Oh, okay.
25
MS. AXELRAD:
The
first
have
it
be a 505(b) (2)
a fee.
the first
So every
new
that,
not pay
It is only
we would
other
indication.
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
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It
one.
site.
After
at
—..
169
1
that,
2
time you
3
application
every
other
site would
not have
to pay.
But
the first
.
come
4
fee.
a new
But
5
issues
and we will
6
they would
fare
MR.
indication,
it is only
But the annual
7
have
product
which
9
concerned
about.
Even
10
inherently
safe
species,
11
suits
12
holder
13
contracting
14
choose
to look at it, or something
15
making
this drug,
17
of the public
site,
out with
your
because
20
the table.
22
deal
out how
I think
we would
to have
these
reason,
be exposed
be
are
of law
and what
the
to if a
site,
like
about
if that
that,
is how you
an entity
a problem.
I would
like you
to figure
that
one
lawyers.
That
may be why we went
the way we
of that.
I think
No solutions,
we got a lot of issues
but we have
a lot of issues
on
to
with.
23
MS. KEPPLER:
24
DR. BARRIO:
25
up an issue
are possibilities
or subcontracting
MS. AXELRAD:
21
there
NDA would
were
fees are
and figure
we all know
for whatever
DR. COLEMAN:
did,
that
though
MS. AXELRW3:
18
19
generated
the $250,000-some.
those
brought
liability
being
to an
process.
Ed just
is something
it is subject
and establishment
to address
in the waiver
CONTI:
half
8
16
.—_
in with
one ICP holding
this
That
is good,
I think,
is obviously
MILLER
though.
ideally,
the paper
the easiest
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NDA
for
way without
at
..=
170
1
considering,
of course,
2
we are going
to deal
3
with
The other
for the PET community
5
the registration
6
heated
7
of the FDA,
8
that
9
course,
is the issue
the agency
wanted
far from
concept
a negative
12
or if you go and do this,
13
opposition
way.
sure how
traumatic
to think
of the registration
That
to see,
were
has been
and
a very
In the old view
or saw at the time,
drug manufacturers.
Of
that.
has remained
11
I a,m not
emotional.
PET centers
far,
That
has been
complicated,
the individual
10
that
drug manufacturers.
very
we are
issues.
that.
thing
4
issue,
the legal
If we go out
in many
there
you will
people’s
and discuss
find
a very
mind
this
in
issue,
gut-related
-—.
to that notion.
14
Is there
15
envision
16
without
17
registration?
that would
going
18
—
any alternative
allow
through
us to do exactly
the politically
MS . AXELFUUI :
We will
19
To me,
20
paper
21
application
22
saying
that you are making
23
~rugs,
period.
24
25
drug
every
registration
means
have
difficult
to look
that you
the time
is when
approved
and then
it is at whatever
PET drugs,
lets us know
us the right
MILLER
that you
first
issue
you
of
get your
frequency
are out there
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of
a piece
the following
to go and inspect
thing
at the statute.
submit
you
you may
the same
whatever
That
and it gives
or approach
PET
doing
against
it
at
-_
171
1
whatever
the requirements
2
we were
3
and we were
4
to the PET facilities
5
with
considering
are.
I can understand
PET to be a major
going
manufacturing
to go out and apply
that
that when
facility
210 and 211 literally
that would
not have
set very
well
the community.
6
However,
7
of GMP
8
on whatever
9
complying
with
10
developed
that,
11
community,
if we have
requirements
12
a new,
that we will
frequency
we would
the set of GMP
hopefully,
that
MR. CONTI:
different
be out looking
inspect,
that
requirements
will
it shouldn’t
totally
set
to just
you
see,
are
that we have
be acceptable
to the
be a big burden.
As George
said,
this
is an emotional
—
——
13
issue.
14
DR. BARRIO:
15
MR.
16
issue,
17
to on this
18
nind.
19
~ssumptions
20
nay or may
it is still
side
I think
21
_--=
CONTI:
it is in part
not exist
md
23
Oefore we say--
communication
that
issue.
heard
to me what
this
because
as an emotional
people
I am still
associated
not
there
with
are objecting
clear
in my
are certain
that process
that
in the new configuration.
again,
it is an issue
as to what
MS. AXELRAD:
discussion
having
not clear
that we have
22
25
Even
of the table.
I think,
24
It is an emotional
will
I hope
the community
and won’t
when
will
of clarification
we have
become
be required
the GMP
more
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familiar
and
at
-.-_
...
172
1
there
will
2
going
to be requiring
3
communication
4
safety
5
when
6
understand
7
thing
understanding
with
I really
regard
like
that
that,
problems.
That
10
make
11
compound
12
you are doing.
it so that
building
is
this
such
question,
it gone
people
into place
before.
has
They
can manufacturer
be not much
will
and difficult
the community
we heard
and will
and with
a burdensome
had
PET community
the drugs,
we are
at the end of the day which
I think
is what
of been
what
to
been
DR. COLEMAlf:
about
regard
to address
have
sort
to chemistry
it is not
as it might
developed
as we have
and efficacy,
8
9
be more
in 1995.
its
said we can
the drug,
different
can
than what
.
13
It ends up they went
14
did, basically,
15
whatever.
a Mallinckrodt
community
or Burroughs
just
can’t
16
MS. AXELFU+D:
Right;
17
DR. COLEM.AN:
The FDA had
18
Uan ease up the requirements
19
~ithout
difficulty.
20
,. ._
The
in and inspected
21
revoke
22
grant waivers
23
revoke
24
25
it.
we had
finally
But , anyway,
2MPS .
We are doing
standards.
that.
PET centers
well,
we
can do this
to do that before.
which
we were
it out there
we are doing
a totally
or
us
out that was proposing
to GMPs
got
those
they
to do that but you made
that was
and exceptions
Wellcome
said before,
not able
We tried
We had a rule
after
we know
so that
You were
MS. AXELRAD:
meet
it like
approach
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to
to do that.
a different
different
told
to
approach
to GMPs.
to
at
173
1
It is not going
2
discuss
registration
3
through
some
4
come
5
are going
to look
like because,
6
have
gone
through
the NDA process,
7
many
less
issues
8
out how you are going
9
and lay out the chemistry
into
11
place.
sort
So I think
common
compliance
understanding
or problems,
and,
whatever
those
to me, believe
than
basically,
GMPs
you have
done
13
send us a piece
of paper
and we go and check,
14
as to whether
DR. BARRIO:
16
for your
17
3ocument--I
18
mbelievable
19
?ossible
20
As you know,
understanding
don’t
of what
know,
agonizing
line,
me,
one way
22
lad the opportunity
to express
23
I’here is absolutely
no way
24
lave everybody
25
:ourse,
agreeing
periodically,
we produced
a document
is.
That
a solid
six months
of debating
every
in an
single
like
therapy,
the whole
the fact
themselves
that,
on every
principle
we didn’t.
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community
that people
was very
in one document,
,—
MILLER
is you
the GMP requirements.
or the other,
participated.
was
facility
of this process.
21
That
and efficacy
registration
our position
we spent
process
believe
Almost,
meeting
to figure
in the first
you have
all that,
you
raises
get your
After
15
once
trying
12
you are actually
requirements
me,
the safety
gone
have
the registration
I think,
and,
we have
hopefully,
on what
to go through
with
th,at we should
of at the end when
of the GMP discussions
to some
10
to be the same.
there.
helpful.
we can
And,
of
at
174
1
But , still,
2
expresses
the view
3
SEP,
ACNP
4
issues
5
that
6
certain
7
probably
SNM,
are of concern
11
it.
12
paper,”
This
is supported
But there
it
by
are certain
in individual
registration,
because
presenters,
and there
for example,
are
that
is
out of proportion.
may be simpler
that you
document
to a lot of people
of that
I don’t
10
part.
to manufacturers,
elements
8
9
of the community.
for the most
related
still
it is a consensus
disagree,
than most
perhaps,
people
can go out and say,
This
is going
this
with
think
and that.
but
“Oh, guys;
to be so simple.
Nobody
the notion
it
it is not an issue
don’t
worry
It is a piece
is going
that
to believe
about
of
you.
-
13
MS. AXELRAD:
14
DR. HOUN:
15
open in terms
16
regulations
17
inspect
18
Eield as well,
19
what would
But
of sharing
which
against.
20
I know.
I think
what
We would
to develop
of things,
for new GMP
we would
that
of all these
actually
for the FDA
regulations,
check.
If we are open
and having
21
we
22
:hen, what
23
‘This is what
we are going
24
>e considered
a violation.
25
vithin normal
II
to look
have
is fairly
to develop
from what
a list
we did
we want
are different
we actually
we going
if the process
at, how would
in mammography
MILLER
discussions,
we evaluate
was we told
to look
This
those
at.
is what
This
it.
And
the community,
is what
would
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what
would
be considered
at
175
So they knew
1
2
was.
3
to have
We want
them
to have
DR. BARRIO:
5
misunderstand
6
the opportunity
7
in a way
8
There
good
what
the ,inspection
inspections.
to discuss
We don’t
want
11
very
12
probably
13
details
are certain
sensitive
All
done
that
about
I was
I wanted
discussions.
referring
16
agency
17
anly say the percent
18
there.
19
that everybody
20
nechanism
21
:enter
context
and to make
the intent
We have
sure
that we have
to go and explain
understands
and this
that
is simply
of discussion,
you aware,
people
don’t
very
clearly
somehow
for you
the
out there.
in a
by the
say that.
Don’ t
and leave
it
to make
sure
just
is a very
to know
and
carefully
to register
this
it.
like
here,
it is explained
is, and very
face
to is that
we know,
this has to be explained
general
Let’s
issues
that.
to make
Most
to have
all these
it before.
it anyway--remember,
15
what
and discuss
in this process
issues.
of these
14
thing
items
you knew
this
have
and don’t
We are delighted
no question
The only
there
take me wrong
I am saying.
is absolutely
10
Don’t
that we never
9
innocuous
what
every
is doing.
22
If that
23
DR. HOUN:
25
of time what
problems.
4
24
ahead
nest of these
is the intent,
Do you have
spread
good
it out,
communications
70 centers?
DR. BARRIO:
Oh, yes.
MILLER
saying
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that,
with
at
,—
176
1
DR. HOLIN:
2
get more
3
help
solid
to give
to those
other--
MS. KEPPLER:
5
in terms
6
the road.
7
community
of we have
Right .
why
this
We are probably
we want
it to be.
10
we have
to do.
11
the most
12
the irrational
13
exists
14
Aon’t
15
work.
PR effort
not going
difficult
what
to deal
emotional
with
to make
that
for you
talked
sure
that
about
that
the
it be exactly
is a part
is talking
which
to
thing.
as
of what
about
is the irrational
response,
things
as we get down
to have
George
these
already
is a great
So we realize
I think
when
information
We have
to do a PR effort
understands
9
you
to do our own
We have
8
sense,
to be able
disseminate
4
So, in some
that
is
fear where
is a fact--it
—
and we can say that
have
16
17
So that
going
forward
18
19
to worry
about
20
with
irrational
~ranscript
22
so people
23
1 sort
24
with what
25
2MP area
of hope
that almost
challenge
doesn’t
that we see
that
there
is a basis
behavior.
We are going
hopefully,
that
attend
and
future
be able
the people
they perceive
will
and that you
because--
It is perceived
of this meeting
will,
saying
difficult
the community
MS. AXELRAD:
21
it, but
is a very
MR. CONTI:
for that
it is irrational
who
to be putting
meetings
to follow
have
the future
meetings
the discussion.
concerns
to be doing
in the
that we are going
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up on the Web
particular
that we are going
the
at
——
177
1
to have
2
and understand
3
approaching
on GMP
4
announcements
6
ICP mail
7
communities.
8
will start
meetings,
is called
that with
MR.
reasonable
13
is your
14
should
15
this is because
16
Like to know
17
going
feeling
ask Victor.
out to the
showing
up and we
then we will
think
the oncology
Let me also
add the reason
of the HCFA
meeting
bit more
put
for that?
it would
be
issues?
Maybe
What
I
I am saying
in January.
I would
about
what
FDA is thinking
I heard
that
they were
town meeting.
When
20
situation.
21
ve do it and
I’m sure people
22
:0 do before
they do anything.
25
do you
and visit
neeting,
24
on our
meeting.
when
19
I thought,
I want
But
goes
line
MS. AXELRAD:
23
people
meetings,
on the time
a little
that
which
out from you,
Jane,
to come back
gut
the future
the
and the PETMail.
CONTI:
12
to be putting
more
the next
that up on our pages
18
the discussion
from and how we are
PETMail
So we may have
So once we find
into
can hear
We are going
of these
and what
11
they
we are coming
MS. TESAR:
9
,..
where
so that
the issue.
5
10
issues
hmmm,
to hear
they went
this
what
is a chicken-and-egg
they
want
are going
to hear
and announced
what
They’re
to do before
we are going
it as a public
~lready.
MS . KEPPLER:
having
first.
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meeting
a
at
178
1
MS. AXELRAD:
2
MS. TESAR:
3
are that
4
not a technical
5
going
6
afterwards.
7
what
this
Actually,
advisory
our conversations
committee
committee
It is just
the PET community
is not going
are no decisions
12
presenting.
13
reason
It is
There
have
meeting
them
is not
a discussion
to figure
out
is feeling.
to figure
to be a decision
11
hall
with
meeting.
meeting.
won’t
a town
We are trying
there
based
as a result
is what
on what
So we don’t
out why because
made
is not a decision--that
we were
we are going
know.
We don’t
if there
of this,
told,
and
there
to be
know what
the
is.
14
We are happy
15
that
16
don’t
17
are going
18
papers
there
is going
know
what
that
is going
to give
neeting.
21
3CFA meeting
to come
it our best
Maybe
I said we can’t,
which
again,
this up and
but we really
out of this meeting.
effort
and present
We
a lot of
we could
obviously,
do it around
have
it during
the HCFA
the
is the 20th--
22
MS. TESAR:
23
MS. AXELRAD:
oould do it around
are opening
know.
MS. AXELRAD:
20
they
to be a dialogue
but we don’t
19
25
to go first.
is not an advisory
10
24
get
to be any information--they
8
9
They
We will
all be here.
Everybody
the HCFA
DR. ~CZKOWSKI:
MILLER
will
be here.
Maybe
we
meeting?
The HCFA
meeting
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is two days.
at
—
179
1
MS. TESAR:
2
MS. AXELRAD:
3
DR. lUCZKOWSKI:
4
MR.
unlikely
6
regard
to safety
7
of you
in that
8
hand.
What
9
says will
we are going
sort
maybe
12
llpET Week”
becauser
13
~f envision
doing
14
nhemistry
15
time.
we should
MR.
declare
making
20
Friday,
or Wednesday
24
25
more
whatever
Maybe
the--the
information
is at
gets up and
it.
week
I feel like
is in January
that we have,
indications
I sort
for FDG and
certainly
help
in front
to that.
meeting
fill up the
the West
that Monday
town hall
or Thursday
Coast
or Tuesday,
is what,
Thursday
or something
like
It is Wednesday-Thursday?
do it Monday-Tuesday.
could
that
with
people
one trip.
MS . TESAR :
so you
it is very
you are seeing
to analyze
That would
MS. AXELRAD:
it--
that
that much
So the core
So that would
CONTI:
after
23
than
the oncology
weekend
could
all
at the next
19
22
to present
We have
and GMPs.
though,
21
tell you
of be supplemental
MS . TESAR :
18
be ready?
we get up and say or the community
11
too,
you’ll
I can also
and efficacy
MS. AXEL~:
16
think
It’s possible.
literature.
just
10
and 21st.
Do you
CONTI:
5
17
The 20th
I sort
Actually,
do--Martin
MILLER
Luther
of wouldn’t
the
and
that?
Maybe
mind
we
doing
it is a Wednesday-Thursday
King
Day
is the 18th.
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so you
at
—
180
1
have
2
19th,
3
we have
got
the 19th.
and then we have
observes-~there
and the 21st,
is the
and then
We could
do it the 19th
and the
22nd.
MS. TESAR:
7
MS. AXELRAD:
8
Martin
9
we are not going
Luther
That
is certainly
I had
King week
just
because
to do that
around
told Kim,
it.
“Stay
away
of the holiday, ” but
if the HCFA meeting
from
I guess
is that
week.
11
12
who
got the 20th
MS. AXELRAD:
6
10
know
got Friday.
4
5
I don’t
MS. TESAR:
being
around
That
would
certainly
be your
goal
of
the HCFA meeting.
—
13
MS. AXELRXD:
14
hall meeting
15
I am not
16
are doing
17
really
18
issues,
19
Oncology
20
where
If the HCFA meeting
they
are going
sure how helpful
a more
whether
detailed
we will
whether
I just
21
we are having
22
:ime.
23
+CFA meeting.
24
md
25
:he chemistry
you
I don’t
efficacy
analysis.
So the question
be ready
to discuss
now
be more
come
MILLER
to discuss
efficient
and GMPs
we do it before
We can do one day,
people
is
the oncology
to be ready
in to do chemistry
and then--or
we
the
time.
it would
care whether
from people,
be for us because
at that
think
to be hearing
a town
that would
we can commit
indications
is just
or half
if we don’t
and
want
sit there
as long
at the same
or after
a day,
or safety
to have
to have
for two days,
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
the
we
as
181
at
1
could
do one day on safety
2
chemistry
MS. TESAR:
community
5
safety
that
going
8
cancer,
9
Just as Ruth
wants
colorectal,
They
12
sducate
13
what they
them
Neren’t
16
YOU were
saying,
say,
are going
DR.
:he town
talking
about,
COLEMAN :
meeting,
head
lymphoma
and bring
to Mitch
not
kinds
Burken,
to make
The
meeting.
they
are
and neck
tumor.
Whoever
it is to
any decisions
as to
got through
saying
of specific
indications
accelerated
that you
that
glycolysis.
You may want
that you
to comment
are supportive
I’m not going
on that
at
of that.
to say they
should
for it .
DR. COLEMAN :
21
be at the town hall
indications;
We just
MS . AXELRAD :
reimburse
for the
to be doing.
hall meeting,
19
best
can.
for those
talking
work
it is an open meeting.
on any new data
looking
17
on
in this process.
At the town hall
melanoma,
MS. AXELRAD:
15
will
five
to say something
14
----
was
that would
to be involved
people
to be discussing
11
20
is going
DR. COLEMAN:
7
18
I think
and efficacy
6
10
and on,e day
and GMPs.
3
4
and efficacy
here,
I think,
22
purpose
23
about
24
involve
reimbursement.
25
I don’t
know
how we feel about
what
That
is not
is an open
it.
Some
Some
may
is going
the purpose
discussion
of those
involve
MILLER REPORTING COMPANY, INC.
507 C Street, N.E.
The
to air issues
issues
may
the science
to happen.
Washington, D.C. 20002
(202) 546-6666
here.
of it.
182
MS . AXELRAD :
1
2
the things
that
3
them
to know
4
what
we are doing
5
what
they
6
anything
what
to do is talk
and we need
to know
although,
other
group
9
mismatch
ought
to know
want
to have
of it.
be aware
so that we don’t
I want
bit about
I don’t
side
to at least
anyway.
a little
frankly,
One of
of what
end up with
the
a total
at the end of the day.
DR.
Part
They
the reimbursement
is doing
ourselves.
to HCFA
here.
But we do have
8
among
we are doing
to do with
10
COLEMAN:
That
of our discussion
12
s—
I want
are doing,
7
11
Let us talk
One other
here
is what
relates
comment
we are concerned
about.
to that.
is we have
talked
about
GMPs.
I
.
13
think
that
that
14
lot of people
15
Do we have
to stick
16
about
we go to PET radiopharmaceuticals?
17
be under
when
term has put a bad
in nuclear
MS. AXELRAD:
19
them to be--requires
20
manufactured
21
?ractices .
22
statute
that
term
of a
in PET particularly.
for what
we are talking
It has got to
Yes,
between
any drug
in conformance
I believe
that
that
with
the statute
is approved
current
is actually
requires
to be
good manufacturing
the wording
in the
505.
23
25
with
and
in the mouth
GMPs?
18
24
medicine
taste
We can’t
So I think
invent
we are stuck
MR.
CONTI:
a whole
with
new
statutory
it.
Are we finished?
MILLER REPORTING COMPANY, INC.
507 C Streetr N.E.
Washington, D.C. 2000Z
(202) 546-6666
scheme
here.
at
183
—-.
1
DR.
2
recommendations
3
cardiology,
4
the floor
5
next week.
COLEW:
We will
for indications,
oncology,
with
dopa
Isn’t
outlined
that what
to you
the wording
neurology.
George
our
for the
is going
to head
for you and all the review
you
6
DR. BARRIO:
7
MS. AXELRAD:
We want
DR.
He’s
8
get back
Yes;
by
said?
that’s
what
I said.
a study-by-study
analysis
of
the data.
9
COLEMAN:
DR. HOUN:
10
We will
11
not just
the slides--the
12
Net, but
the actual
medical,
13
now, was
50 pages.
Yours
14
So you
15
strengths
got
it.
No problem.
be publishing
slides
will
a real
review
be available
clinical
review.
of
on the
I think
mine,
—_
can see how
16
17
each
study
and weaknesses
were
But , right
should
be available
18
now,
19
analysis,
20
~ork or literature
21
literature?
how much
would
;hink that
24
:he underlying--
that
with
is the basic
you
to be,
looked
like,
300 pages.
at, how
the
analyzed.
At this
DR. ~CZKOWSKI:
23
was
needs
to the public
DR. BARRIO:
22
is going
clearance
but
that
soon.
stage
of the fluoro-dopa
like
to support
extensive,
actually,
animal
say quite
a bit because
I would
proof
of concept,
your
clinical
so to speak,
of
_-——.
25
DR. LOVE:
For oncology,
MILLER
we are talking
REPORTING COMPANY, INC
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
about?
I
at
___
—
184
DR. BARRIO:
1
2
very
intensive
can be answered
6
discuss
some
7
easy because,
8
certain
9
in animals,
models
Okay;
of this data.
of course,
things
for fluoro-dopa.
are
good.
That
we have
is
demonstrating
cell
count
11
the neural-transmitter
12
5ocumented.
13
patience.
So thank
14
MS. AXELRAD:
15
[Whereupon,
decrease
pathway.
you very
Thank
at 3:20
That makes
we cannot
and terminal
All
much
we can
But
do
then,
this
decrease
is extremely
for your
time
and
you.
p.m.,
it
of data
the meeting
adjourned.]
MILLER
Then
in humans.
amount
that
data.
Wonderful.
we are crazy
a significant
questions
Helpful.
Good .
unless
so many
and animal
that we do in animals
10
16
There
in animal
DR. BARRIO:
5
no, no;
in monkeys.
DR. RACZKOWSKI:
3
4
No,
REPORTING COMPANY, INC.
507 C Street, N.E.
Washington, D.C. 20002
(202) 546-6666
was
and
well
.
185
---
CERTIFICATE
I,ALICE TOIGO, the Official
Court Reporter forMillerReportingCompany,
Inc.,hereby certify
thatI recordedthe foregoingproceedings;thatthe
proceedingshave been reduced to typewriting
by me, or under my direction
and
thatthe foregoingtranscript
isa correctand accuraterecordof theproceedings
to the bestof my knowledge,ability
and belief.
n
A~+
ALICE TOIGO
Printed
by Kim Colangelo
Electronic Mail Message
setlSitiVity:
COMPANY
CONFIDENTIAL
Date:
From:
Dept:
TelNo:
Subject: Overheads
from
Nov.
03- Dee-1998
12: 58pm
Kim Colangelo
COLANGELOK
HFD-160
PKLN 18B09
301-443-5818
FAX 301-443-9281
17 meeting
Good afternoon,
In orderto document ourNov.17
PET public meeting, lneed copies ofyouroverheads
forthe
docket. Electronic copies are preferable(l have paperalready).
Please e-mail meyour
overheads impossible. If not, please letmeknow,
and Iwillsend the hardcopies.
Thankyou!
Kim
.-.
.
.—-
AGENDA
INFORMAL
DISCUSSION
OF LITERATURE
REVIEWS OF SAFETY
EFFICACY DATA FOR PET AMMONIA AND FDG
Tuesday, November 17, 1998
5630 Fishers Lane, Room 1066, Rockville,
Participants
MD
(see attached)
Jane Axelrad, Associate Director for Policy,
Center for Drug Evaluation and Research
Moderator:
Opening Remarks
from FDA
Jane Axelrad
Opening Remarks from the Institute
forClinicalPET
Jorge Barrio
Background
PatriciaLove
Presentationof PET Ammonia
Discussion of PET Ammonia
Presentationof PET FDG
Discussion of PET FDG
Summary
Discussion
LiteratureReview
Florence Houn
LiteratureReview
LiteratureReview
LiteratureReview
and Closing Remarks
Victor Raczkowski
AND
PARTICIPANTS
INFORMAL
DISCUSSION
OF LITERATURE
REVIEWS OF SAFETY
EFFICACY DATA FOR PET AMMONIA AND FDG
AND
INSTITUTE FOR CLINICAL PET
Jorge Barrio, PhD, Professor, Department of Molecular and
Medical Pharmacology,
University of California – Los Angeles
R. Edward Coleman, MD, Professor of Radiology,
Duke University Medical Center
Peter S. Conti, MD, PhD, Associate Professor of Radiology, Clinical Pharmacy,
and Biomedical Engineering, University of Southern California
Jennifer
_—_
Keppler,
Executive
Director,
Institute
for Clinical PET
Ruth Dean Tesar, Vice President and General Manager,
PETNet Pharmaceutical
Services, LLC
FOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION
AND RESEARCH
Jane Axelrad, Associate Director for Policy
Florence
Houn, MD, MPH, Deputy Director,
Office of Drug Evaluation
II
Patricia Love, MD, Director, Division of Medical Imaging and
Radiopharmaceutical
Drug Products, Office of Drug Evaluation 111
Victor Raczkowski,
MD, Deputy Director,
Office of Drug Evaluation
III
Key Aspects of Shdy Protocol
and Reports
Defined C inical Setting
Selection of Subjects
Image Evaluations
Truth Standards
Controls
Endpoints
Analytic Plan
Indication Considerations
.
-FOcus
+ Clinical Safety and Efficacy of Commonly
Used PET Drugs
– FDG and Ammonia Models
– Use of Published Literature Alone
– Support from Pharmacology-Toxicology,
Pharmacokinetics, Pharmacodynamics
,,)
,)
,,,
Developing Medkal Imaging
Drugs and Biologics - Draft
+ Indications
– Structure Delineation
– Functional, physiological or biochemical
assessment
– Disease or pathology detection or assessment
– Diagnostic or therapeutic patient management
)
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U)
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m
n
00
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-
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GUIDANCE FOR INDUSTRY Draft
Developing Medical Imaging
Drugs and Biologics
.
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——__
Intended for use in the diagnosis of a
disease or a manifestation of a disease in
humans
Spontaneous disintegration of unstable
nuclei with the emission of nuclear particles
or photons
Nonradioactive reagent or nuclide generator
that is intended to be used in the preparation
of such article
Proposed Rule - In Vivo
Radiophamaceuticals Used for
Diagnosis and Monitoring
)
)
Published Literature Alone
+ Robust results from prospective analyses
(not post hoc special analyses)
+ Conducted by credible groups with properly
documented operating procedures
Published Literature Alone
+ Multiple studies conducted by different
investigators; adequate designs; consistent
results
+ High level of detail (statistical/analytic
plan, accounting of patients)
+ Appropriately objective endpoints
)
‘1
)
GUIDANCE FOR 1NDUSTR%
Providing Clinical Evidence of
Effectiveness for Human Drug and
Biologic Products
PET Radiopharmaceutical
Approval Procedures - Ongoing
+ Potentially Useful Documents
– Guidance; Providing Clinical Evidence of
Effectiveness for Human Drug and Biologic
Products
– Radiopharmaceutical Proposed Rule
– Draft Guidance; Developing Medical Imaging
Drugs and Biologics
Different Option; Under
Consideration
+ CMC and Microbiology - Ongoing
+ Clinical Safety and Efficacy of Commonly
Used PET Drugs
– FDG and Ammonia Models
– Use of Published Literature Alone
– FDA Review Primary Articles and Develop
Database
Labeling
+ Useful information
– Indication
– Summary of Critical Studies
– Dosing & Administration
– Adverse Events
– Clinical Pharmacology
– Special Population Issues
‘,,,
)
)
Clinical Section
+ Phase 1- safety in humans (normal
volunteers or patients); dose ranging
+ Phase 2- preliminary efficacy data; dose
finding; developing hypothesis; additional
safety data
+ Phase 3- confirmation of hypothesis;
expansion of safety database
Introduction
+ Objective
+ Background
+ Potentially Useful Documents
– In Vivo Radiopharmaceutical Proposed Rule
– Industry Guidances
+
Options
1,,,,
,,,,1
N-13 Ammonia PET:
Safety and Effectiveness Review
Florence Houn MD MPH
Sonia Castillo PhD
November 17, 1998
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N-13 Ammonia S&E Review
Conclusions
●
Effectiveness
To assess myocardial perfusion
●
Safety
– Single doses up to 25 mCi studied
– 2 IV doses up to 20 mCi each studied
N-13 Ammonia S&E Review
on ClinicalEffectiveness/Medical
●
Gukkmes
●
Intended Use of NJ-l3 Ammonia
●
External Standards
●
Search Methodology
●
Selection Criteria
Review of Findings
c Conclusions
●
)
Imaging
.
)
N-13 Ammonia S&E Review
Guidance on Clinical Effectiveness-Use
Literature Alone
c Multiple studies/adequate
design/consistent findings
●
Detailed protocol
c Objective and appropriate
endpoints
of Published
“ Consistent conclusions of
efficacy
Q Conduct of studies with
documented operating
procedures
“ Examples: secretin,
bleomycin and talc,
doxycyline
N-13 Ammonia S&E Review
Adequate/Well-Controlled (Med. Imaging Guidance)
Selection of subjects=Target population
●
Readers: independent, masked, randomized,
separate
●
●
Standards of truth
●
Endpoints
●
Analysis plans
●
Safety: toxicity and radiation assessment
)
,,)
,)
,,,
1
N-13 Ammonia S&E Review
Intended Use: To assess Myocardial Perfusion (MP)
●
Preliminary review for major uses
Q “Developing Medical Imaging Drugs and
Biologics” draft guidance
– “Functional, Physiological, or Biochemical
Assessment”
QValidated to a standard of truth
“ Spectrum of disease and normality tested
QPharmacological
basis of “functional claim”
,,!
N-1 3 Ammonia PET
External Standards for MP
●
Vessel Anatomy, CAD, and blood flow
– Coronary Angiography
– Rubidium-82
“
Coronary microperfhsion
– Functional As~ects
Wall MotionA
Functional Capactity (stress testing)
Clinical outcomes (survival)
)
,/
,i
}
N-13 Ammonia PET
Literature Search Methodology
●
Criteria for Search
– January 1, 1990 to July
1, 1998
– Human clinical trials
– English
– On-line databases: Medline, Cancerlit, Derwent Drug
File, Biosis Preview, International Pharmacology
Abstracts, and Embase
– PET community suggested articles
– References cited in above articles
N-13 Ammonia PET
Literature Search Methodology
●
Selection Criteria
—
N-13 ammonia PET results compared to
appropriate clinical standard of truth
—
Relevant study question to MBP
—
Well-described study population
—
Procedures to reduce bias
,,’)
}
,1
N-13 Ammonia S&E Review
Published Literature
●
Adequate/Well-Controlled
—
Prospective enrollment
Clinical Trials
(2J
- Study Hypothesis related to intended use
— Study population similar to target population for clinical use
Q Other Controlled Published Studies
—
Various study hypotheses
— Retrospectively
selected patients; normal volunteers assumed CAD-free
Q Other Published Studies(9)
— Wide variety of study hypotheses
●
(3)
MBF Quantification Algorithm
(3J
N-13 Ammonia S&E Review
Adequate/Well-Controlled
●
●
Studies
Gould LK, Goldstein RA, Mullani NA, et
al. J Am Coil Cardiol 1986; 7:775-89.
Demer LL, Gould LK, Goldstein RA, et al.
Circulation 1989; 79:825-35.
N-13 Ammonia S&E Review
Other Controlled Studies
●
●
Schelbert HR, Wisenberg G, Phelps M et al Am J
Cardiol 1982; 49: 1197-1207.
Di Carli M, Sherman T, Khanna S et al. J Am Coil
Cardiol 1994; 23:860-68.
Q Gewirtz H, Fischman AJ, Abraham S et al. J Am
Coil Cardiol 1994; 23:85 1-59.
N-13 Ammonia S&E Review
Other Supportive Studies
Beansland RSB, Muzik O, Melon P, et al. J Am Coil
Cardio 1995;26: 1465-75.
●
Czernin J, Barnard RJ, Sun KT, et al. Circulation
1995; 92:197-204.
●
Di Carli MF, Davidson M, Little R, et al. Am J Cardiol
1994; 73:527-33.
●
Gould LK, Martucci JP, Goldberg DI, et al. Circulation
1994; 89:1530-38.
●
Gould LK, Ornish D, Scherwitz L, et al. JAMA
1995 ;274:894-901 .
●
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)
i,
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N-13 Ammonia S&E Review
Other Supportive Studies
●
Haas F, Haehnel CJ, Picker W, et al. J Am Coil
Cardiol 1997; 30: 1693-1700.
‘ Laubenbacher C, Rothley J, Sitomer J, et al. J
Nucl Med 1993; 34:968-978.
●
Sambucetti G, Parodi O, Giorgetti A, et al. J Am
Coil Cardiol 1995; 26:615-23.
c Soufer R, Dey HM, Lawson AJ, et al. J Nucl Med
1995; 36:180-87.
N-13 Ammonia S&E Review
MP Quantification Algorithm
●
●
●
Krivokapick J, Smith GT, Huang SC, et al.
Circulation 1989; 80: 1328-37.
Hutchins GD, Schwaiger M, Rosenspire
KC, et al. J Am Col Cardiol 1990; 15:103242
Gerwitz H, Skopicki HA, Abraham SA, et
al. Cardiology 1997:88:62-70.
)
,,,
N-13 Ammonia S&E Review
Adequate /Well-Controlled:
.
●
●
●
●
dlect ive : Feasibility
study for diagnosing CAD
with RblNH3 using
rest/stress testing
Goul d [1986)/Demer
“ pose: 2 IV 10-20 mCi
N-13 ammonia or 30-50
mCi Rubidium
●
Sample size: 23/50
patients received NH3
,-,:
Prospective;
compared angio and PET
Image Proto CO1:Masked,
Reread x 3
(1989)
●
Significant CFR defined
<3.() on angio; 0/0 isocount
reduction assumed
proportional to YOdecrease
CFR
Sensitivity 21/22 (95Yo)
Aecificity 9/9 (100%)
N-13 Ammonia S&E Review
Adequate/Well-Controlled:Demer
●
●
●
uIect ive : Accuracy
of N- 13 NH3 in
evaluating CAD using
rest/stress testing
compared to coronary
angiography
Aamtie Size: 11 1/193
pts received N- 13
NH3 (n=l 74 analyzed)
,,)
(1989)
c Inclusion Criteria: All
patients undergoing
cath (population
suspect for disease but
some do not have it).
“ -:
Compare
stenosis flow reserve
(SFR-automated) vs.
PET defect scores
“)
N-13 Ammonia S&E Review:
Adequate and Wel -Controlled: Demer (1989)
●
●
-:
SFR ().5
(5=nl;<3=signifo
CAD) PET defect
scores O-5 (5=severe
perfision defect;>2
signif. CAD, SFR<3)
Imag e Proto COI:masked,
independent, reread x 2,
rest/stress read side by
side
●
●
Scores for PET
averaged, interobs.
variation defined and
tracked, dispute
resolution described
J)ose: 2 IV 10-20 mCi
NH3 /30-50 mCi Rb
,,,
,,,f
N-13 Ammonia Review:
Demer (1989) Con’t.
o Results
- Spearman Correlation Coefficient 0.77 (~0.06)
for patients’ scores of most severe PET/SFR
scores
– RblNH3: For N=193, 2 false positives (1
Rb/lNH3); 7 false neg (2 Rb/5 NH3)
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c Patients
- Sens=98% (95% CI: 92. 1=99.7%)
- Sp=85% (95% CI: 74.7-91.7%)
●
Vessels
- Sens=99% (95% CI: 94.9-99.9%)
- Sp=74% (95% CI: 64.5-81.7%)
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– Dispute resolution
●
– Detailed information on readers’ performances
– Detailed information on reader variability
– Use of SFR for coronary perfusion from angio
– Large number of patients
‘)
,,‘)
N-13 Ammonia S&E Review
Demer (1989) Con’t.
●
Weaknesses
– Rubidium/NH3
– Age/Sex distribution
—
19 patients excluded from analysis “because
they had undergone revascularization during
acute infarction causing residual stenosis
severity that would not be comparable to the
severity of the fixed perfision defect.”
N-13 Ammonia S&E Review
Other Controlled Studies
Schelbert (1982)
.
dlect ive: Correlate angio and N-13 ammonia PET.
amde Size: N=32 CAD/N= 13 normal volunteers.
●
●
●
Design: PET compared to angio. 1lCAD pts stress-than.
●
Image P r otoco 1: 2 readers (consensus), masked, agreement
tracked
●
●
Dose: 2 IV doses of 0.22~0.09 mCi
●
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Sp assumed as 100% (0/13). Thallium identified 11/19
stenosed vessels versus 17 PET+/19 stenoses vessels.
,)
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II
N-13 Ammonia S&E Review
Other Controlled Studies
Di Carli (1994)
●
●
●
ulect ive : Relationship of collateral flow, wall motion,
and viability (defined by metabolism of 18-FDG).
sample Size: N=42 cons. patients (78 vessels) w/ CAD
(angio) and LV dysfunction
●
Design: Comparison
●
Image Protoco 1: PET semiquant.,2 observers (consensus)
●
Dose: 20 mCi
●
-:
58% wktngio
collaterals had $ N- 13 flow; 50%
w/no angio collaterals had N- 13 flow.
N-13 Ammonia S&E Review
Other Controlled Studies
Gerwitz (1994)
●
.
●
dlect ive : Determine minimum level of MP.
for than
J amnle Size: N=26 pts with chronic MI refened
and PET.
●
-:
●
Comparison of wall motion and PET FDG/NH3
Image Proto CO1:Quantified PET readings; Visual analysis
for Ventriculography, echocardiograms
●
-:25
●
rnCiNH3/7.5 mCi FDG
-:
Perfusion correlates with wall motion. Results
demonstrate biologic consistency.
●
)
,,
,)
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,)
N-13 Ammonia Review: Other Published Studies
Study
Beanlands
(1995)
Czernin
(1995)
Di Carli
(1994)
.
Obj .
To study
MBF
reserve
and angio
T-sample
Size
N=5 VO1.
N=7 vol.
mid-aged
N=l 5 CAD
on angio
To study
N=13 vol.
4/13 CAD
MP
response to N=8 nr/nc
conditioning
I Controls
To predict N=93
consec. pts.
survival
using
w/severe
PET/angio LVdysfhn.
Design
Image
Protocol
Correlation
of results
Quantit.
Dose
Safety/
Efficacy
20mCi
diameter)
R= -0.56
(%area sten)
Intervention;
Assess
exercise
Capacity
‘ Semiquant.
Survival;
Semiquant.
FKJ avg
‘2 ohs.
13.6 mons Masked
(2-3 lmons) Independ.
2 IV doses
oflo-15
mCi
20 mCi
Improved
flow and
cardiac
endpts.
supports
microperfi
sion use of
PET.
N-13 Ammonia Review: Other Published Studies
Study
Obj.
Sample
Size
Design
Image
Protocol
Dose
Safety/
Efficacy
Gould
(1994)
TO assess
N=15
cm
Rand. to 3
program;
control-Rxcontrol
sequential
trial.
Rand.
con~olled
trial
Quanti.
2 Iv
doses of
18 mCi
PET correl.
Gould
(1995)
perfhsion
after chol
program
To assess
CAD with
angio and
PET
prelpostrisk
Haas
(1997)
)
modif.
To assess
PET’s
correl. w/
outcomes
CABG
decisions
N=20
active
N=15
usual care
N=76 pts
w13VD
Quanti. at
initial and
5 yrs
18 mCi
NH3 or
40-50
~’)~tier
exercise
capacity
Correlation
of PET and
angio results
mCi Rb
Survival
study; use of
PET data on
outcoomes
1
Semiquant.
740 MBq
(20 mCi)
PETresults
;~;d
selection—
survival >
angio
)-
..—=,
0
C6
m
I
z
I
In
i
I
I .
,
.—
N-13 Ammonia S&E Review
Weaknesses of Literature
●
Absence of statistical criteria for
significance and power
●
Small numbers of subjects
●
Absence of source data
●
Bias (publication bias, subjectivity of
readers scoring, patient selection)
,,)
N-13 Ammonia PET Review
Conclusions
●
Efficacy
– Intended Use: To assess myocardial perfision
– Consistent findings, diverse populations
– Sensitivity and specificity calculated
– Blood flow and microperfusion
N-13 Ammonia S&E Review
Conclusions
●
Safety (Ammonia/Radiation)
– Small amount of NH3 introduced
– Know metabolism and excretion
– Short physical half-life (1 Ominutes)
– Acceptable radiation dosimetry
– Acceptable risk of radiation
,)
,;)
)
)
N-13 Ammonia S&E Review
Conclusions
●
Effectiveness:
– To assess myocardial perfusion
‘ Safety:
– Single doses of up to 25 mCi studied
– 2 IV doses up to 20 mCi each studied
)
830
Cjmhtion
VO179, No 4. April 1989
.[&:
2+
--*4
5
g,
.-
i
1
0
2
3
4
s
H
SU2.XCTIVEPCT OCfECTSEVERITY
L’li
10b
?4
_—__
SW.KCTIWS PETOEt=cffSEw3wY
.,
.-=
F[GURE 3.
Top panel: Plot of the ddort
&twwen
arwiographic
stenosis JYow resetve and sdjedve
RET
defect sewtity in tk.e conespondittg anatomk @ott&r
243 stenoses. Mean vahu of SFR k pbtted as ●$bndon
of PETd~ect
seve@
77te ho fizonta! daskd &es ktifi the rangesof nonnm( mildly reduced and signijlcantty reduced stenosis flow reserve. l%e vertical dashed
SCOof 2 or tnomprrdut
iine indicates thatPETde@t
th.#presence
of mild or s@ificant
stenoses. 2k.e urvr
bars represent 90% confidence intends.
7?te number of
patients
represented
k shown adjacent to each p&t.
Right-hand column lists the numbers ofpatients found in
each intewal
of SF~ to i!lustmte the distdution
of
corvnary disease in this population. SFR is pioited an a
reve~e scale (5 to O) to pam!k! stenosis severity. NO
error bans are shown for the point representing
a si@e
stenosis.
Bottom panel: Plot of the relation between
artetz”ographic stenosis flow rescnw and subjectiw PET
The most severe stenosis
defect severity in 174 patients.
was compared with (he most severe PET defect f~ each
patient. Mnctecn patients with revasculari.uztion
dwjng
acute infaxtion
were txc(uded
because
the mstika[
stcnosu sevcn”ty would no; be com~mbic
to the s~”q
of the /i.red perfusion
defect. As for the top ~
C&
horizonta! dashed Iines identify the mtgges of ~
mildly reduced. and significant dy reduczd szemosiz
d
rcscrvc.
7hc vcrdcal dashed [it-w indicates
that P&T
defect scorcx of 2 or more predict the prcscncc of mild or
I(P ifica nt stcnoxcs.
,.
..-——.
1
“i
PI
m
OQ
la
a)
a)
&
● ?4
m
L’
,,
●P-(
●
a
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Q
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m
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.
u
cl
la
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●
●
●
●
)’4
o
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●
n
.
—
—
.
[
n
14
00
a
cd
.
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.
Q
●
b
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&
6
U2
e
0
0
●
I
o
o
☛
m
a)
●
●H
A
I
F-1 8 FDG PET
Results of Literature Search
Database
Medline
Embase
Derwent
Cochrane
Cancerlit
Biosis
HSTAR
)
,,1
Number of References
250
274
38
33
25
9
3
I
F-18 FDG Cardiac PET
Framework for Literature Review
“ Draft Guidance for Industry: “Developing
Medical Imaging Drugs and Biologics”
– Federal Register Notice of Availability
63 FR 55067
– Internet
http://www.fda.gov/cder/guidance/index.htm
.
F-18 FDG Cardiac PET
Framework for Literature Review
Consideration of Potential Claims:
Structure delineation
Functional, Physiological, or Biochemical
Assessment
Disease or Pathology Detection or Assessment
Diagnostic or Therapeutic Patient Management
Multiple Claims
Other Claims
)
,;)
.
F-18 FDG Cardiac PET
Framework for Literature Review
“ Validity of information provided by
F-18 FDG Cardiac PET
Appropriate truth standards in studies, and/or;
Contribution to beneficial patient outcomes
●
Potential clinical usefulness of information
.
.
.
.
—
F- 8 FDG Cardiac PET
Framework for Literature Review
“ Sufficient detail of study design, study population,
doses used, endpoints, image acquisition, Image
interpretation, statistical analyses, etc.
.
●
●
Study population sufficiently similar to the
population for which F-1 8 FDG is intended
Procedures to reduce potential bias: e.g., blinded
image evaluations, randomization
“II
,,,I
F-18 FDG Cardiac PET
Initial Literature Selection
●
●
●
Baer FM, Voth E, Deutsch HF, et al. J Am
Coil Cardiol 1996;28:60-9.
Carrel T, Jenni R, Haubold-Reuter S, et al.
Eur J Cardio-Thorac Surg 1992;6:479-84.*
Gerber BL, Vanoverschelde JJ, Bol A, et al.
Circulation 1996; 94:65 1-9.
.
.
F-18 FDG Cardiac PET
Initial Literature Selection
Gropler RJ, Geltman EM, Sampathhmaran
K, et al. J Am Col Cardiol 1993;22: 1587-97.
Knuuti MJ, Saraste M, Nuutila P, et al. Am
Heart J 1994; 127:785-96.
Lucignani G, Paolini G, Landoni C, et al. Eur
J Nucl Med 1992; 19: 874-81.*
.
,)
)
.
.
F-18 FDG Cardiac PET
Initial Literature Selection
●
●
●
Maes AF, Borgers M, Flameng W, et al. J
Am Coil Cardiol 1997;29:62-8.
Marwick TH, MacIntyre WJ, Lafont A, et
al. Circulation 1992;85: 1347-53.
Tamaki N, Yonekura Y, Yamashita K, et al.
Am J Cardiol 1989;64:860-5.*
F-18 FDG Cardiac PET
Literature Selection
●
Tamaki N, Ohtani H, Yamashita K, et al. J
Nucl Med 1991; 32:673-8.*
“ Tamaki N, Kawamoto M, Tadamura E, et
al. Circulation 1995;9 1:1697-705
Q Tillisch J, Brunken R, Marshall R, et al. N
Engl J Med 1986;314:884-8.*
,;)
,)
,
.
F-18 FDG Cardiac PET
Carrel et al.
“ Objective: Post-op
assessment of systolic and
diastolic LV finction after
CABG
Segments: One segment
per subject analyzed.
MM=l 9; Match=4
w
●
●
c Desi-gn: Prospective; PreCABG 82Rb and 18FDG;
Pre- and post CABG 2-D
Echo
●
“ Subjects: n=23, CAD,
LVEF<45%, pre-CABG
Dose: Not in text
Endpoints: LVEF, globs”
and regional wall motion,
diastolic relaxation,
NYHA fictional
class
Image evaluations: Not
specified if PET and 2-D
echo readings were
blinded
F-18 FDG Cardiac PET
Carrel et al.
●
Results:
— LVEF: Significant increase at rest (from 34% to 52%).
Significant increase during exercise (from 3 l% to 58Yo)
— Wall motion: No change in overall segmental wall
motion score. Functional improvement in 16/19
(84.3%) segments with mismatch, and 1/4 segments
(25%) with match.
— Diastolic relaxation: Significant reduction in time
constant of diastolic relaxation.
— NYHA Class: Nearly all patients improved
,)
-
,1,,
F-18 FDG Cardiac PET
Carrel et al.
●
Strengths (not all inclusive)
– Prospective
— Evaluated a range of outcomes: regional LV fimction,
global LV finction, clinical outcomes (NYHA
fictional
class)
—
2-D echo evaluations performed at more than one time
point (7 days and 3 months after surgery)
– Graft patency was assessed post-operatively
F-18 FDG Cardiac PET
Carrel et al.
●
Weaknesses (not all inclusive)
— Small Sample Size
— PET and 2-D Echo images probably not read blindly
— Incomplete evaluation of segments (only one per
patient)
— In wall motion analyses: unclear if, or how, 2-D Echo
images were aligned with PET images to ensure that
corresponding segments were being evaluated
’11
j’
.
.
F-18 FDG Cardiac PET
Carrel et al.
●
Weaknesses (not all inclusive)
— Postoperative PET not performed
— Doses, PET protocol, glucose-loading,
etc. not
specified in manuscript, but presumably in reference.
Reference (in German) not readily available.
F-18 FDG Cardiac PET
Marwick et al.
Objective: Evaluate
metabolic response of
hibernating tissue to
revascularization
Segments: 85 segments
pre-op with perfhsion and
wall-motion disturbances
Desi-gn: Pre- and postCABG rest-stress
(dipyridamole) 82Rb, pOStexercise 18FDG, and
digitized 2-D echo
Endpoints: Wall motion,
8FDG
gzRb “per~sion,”l
activity
.=,:
n=l 6, fasting,
previous MI, no diabetes,
no 3-vessel disease
)
Dose: 4-10 mCi 18FDG
Image evaluations: Two
blinded readers for 82Rb
PET, 18FDG PET, and 2-D
echo
)
‘
1
F-18 FDG Cardiac PET
Marwick et al.
“ Results:
— pre-op:
85 segments identified with fixed perfbsion
defects and resting wall motion disturbances
— post-op:
35 (41%) classified as hibernating, 50 (59Yo)
as non-hibernating
.
.
F-18 FDG Cardiac PET
Marwick et al.
●
Hibernating
segments (n=35)
– Significant improvement in wall motion, increase in
perfkion, and decrease in (super-normal) 18FDG
activity (comparing post-CABG to pre-CABG)
—
10 segments still had abnormally high 18FDG activity
— 25 (71%) were conectly predicted to be viable by FDG
criteria
,.
F-1 8 FDG Cardiac PET
Marwick et al.
●
Nonhibernating
segments (n=50)
—
No significant difference in wall motion or perfision
(comparing post-CABG to pre-CABG).
—
Significant decrease in (super-normal) ‘8FDG activity
(Comparing post-CABG to pre-CABG)
—
38 (76Yo) were correctly predicted to be nonviable by
FDG criteria
,1.
!
.
F-18 FDG Cardiac PET
Marwick et al.
“ Strengths (not all inclusive)
—
Blinded image evaluations
. PET performed pre-op and post-op
—
Image alignment:
●
PET with PET: 82Rb andl 8FDG scans performed in
same position; 82Rb and 18FDG images
superimposed
. Echo with PET: Defllned segments of myocardium
that were comparable to those obtained with the
other imaging modality
F-18 FDG Cardiac PET
Mar-wick et al.
●
Weaknesses (not all inclusive)
— Small sample size
— Endpoints evaluated at only one time point after CABG
— Determination of whether segments were hibernating
was done retrospectively
predicted prospectively)
(i.e., hibernation was not
— Sickest patients excluded from protocol (e.g., no threevessel disease).
.
I
I
)
F-18 FDG Cardiac PET
Tamaki et al. (1989)
●
●
●
Objective: Assess the
clinical value of PET in
the evaluation of CABG
●
Design: 13NHq,,18FDG,
and radionuclide
ventriculography (RNV)
pre- and post-CABG
●
.-:
n=22, fasting,
undergoing CABG
●
Segments: 51 segments
with pre-CABG perfusion
defect; 46 segments with
pre-CABG wall motion
abnormalities
s Dose: 2-7 mCi 18FDG
End~oints: Wall motion,
Perfusion
Image evaluations: 3 nonblinded readers for PET
scans; 3 blinded readers
for RNV
.
F-18 FDG Cardiac PET
Tamaki et al. (1989)
●
Results
– Wall Motion
46 segments with abnormal pre-CABG perfision:
●
●
●
23 segments predicted to be ischemic. Wall motion
improved in 18 (78°/0) of these segments.
23 segments predicted to be scar. Wall motion
improved in 5 (22°/0) of these segments.
Predictive accuracy of PET for wall-motion
improvement is 78°/0 for ischemic segments and
78% for scarred segments (p<O.001).
)
)
,1
II
F-1 8 FDG Cardiac PET
Tamaki et al. (1989)
—
Wall Motion (cent):
“ 19 asynergic segments had increased FDG uptake
before CABG.
●
Of these 19 segments
– decrease in 18FDG uptake in 13 (68Yo) after
CABG, all of which showed improvement in
asynergy
– persistent 18FDG uptake in 6 (32Yo) after CABG,
half of which showed improvement in asynergy
(p-=o.ol)
F-18 FDG Cardiac PET
Tamaki et al. (1989)
“ Wall Motion (cent):
— In contrast, 4 out of 5 segments (80Yo) showing new
FDG uptake after CABG had fiuther wall motion
abnormalities
.
F-18 FDG Cardiac PET
Tamaki et al. (1989)
c Results
– Perfision
51 segments with abnormal pre-CABG perfusion:
●
●
●
21 segments predicted to be ischemic. Perfusion
improved in 13 (62°/0) of these segments.
30 segments predicted to be scar. Perfision
improved in 8 (27°/0) of these segments.
Predictive accuracy of PET for perfision
improvement is 62°/0 for ischemic segments and
73% for scarred segments (p<o.os).
F-18 FDG Cardiac PET
Tamaki et al. (1989)
c Strengths
(not all inclusive)
—
Multiple blinded readers for radionuclide
ventriculography (evaluation of wall motion)
—
PET scans performed both before and after CABG
—
Multide
readers for PET scans
s Weakne~ses (not all inclusive)
– Small sample size
— Readers of PET scans were not blinded
,)
F-18 FDG Cardiac PET
Tillisch et al.
“ Objective: To determine
if 18FDG uptake in
segments with abnormal
motion indicates viability,
and if uptake predicts
functional recovery
●
-:
13~3
and
18FDG pre-CABG;
Contrast or radionuclide
ventriculography pre- and
post-CABG; subset 201Tl
n=l 7, resting
c -:
wall-motion abnormality,
pre-CABG, glucose
loaded
●
Segments: 73 segments
with abnormal wall
motion pre-CABG
.
F-1 8 FDG Cardiac PET
Tillisch et al.
●
●
●
Dose:
10 mCi 18FDG
Endpoints: Wall motion,
ejection fraction
Image evaluations: Three
blinded readers for
contrast and radionuclide
ventriculograms.
,,)
●
Image evaluations (cent):
PET images evaluated
quantitatively, and counts
in each sector compared to
normal values for each
sector. PET images
reconstructed and
correlated with
ventriculograms to ensure
regional concordance
,)
F-1 8 FDG Cardiac PET
Tillisch et al.
c Results
Of 73 segments with abnormal wall motion:
— 46 segments predicted to be reversible. Five excluded
because of inadequate revascularization. 41 segments
analyzed.
— 27 segments predicted to be imeversible. One excluded
because of inadequate revascularization.
analyzed.
26 segments
F-18 FDG Cardiac PET
Tillisch et al.
●
Abnormal wall motion (AWM)
—
Reversible segments
AWM in 35 of 41 segments correctly predicted by PET
to be reversible (85Y0 predictive accuracy)
—
Irreversible segment
AWM in 24 of 26 segments correctly predicted by PET
to be irreversible (92Y0 predictive accuracy)
—
,,’)
No difference in mean wall-motion score after the
operation compared to score before the operation
.
.
F-18 FDG Cardiac PET
Tillisch et al.
“ Ejection Fraction
— Mean LVEF increased significantly in the study
population from 32% (before the operation) to41 YO
afterward
—
In 11 patients, resting wall motion improved
postoperatively in two or more regions. Mean LVEF
increased from 30°/0(before the operation) to 45°/0
afterward in this group.
F-18 FDG Cardiac PET
Tillisch et al.
Strengths (not all inclusive):
— Blinded image evaluation of contrast and radionuclide
ventriculograms
●
—
Quantitative evaluation of PET images maybe less
prone to possible bias
— To increase segmental concordance, regions on contrast
or radionuclide ventriculograms were correlated with
reconstructed PET scans
)
,)
ii
)
F-18 FDG Cardiac PET
Tillisch et al.
●
Weaknesses
(not all inclusive):
—
Small sample size
—
Attempt was made to assess whether adequate
revascularization of an abnormally contracting region
was achieved, but this was not confirmed routinely by
postoperative angiography. Improvements in wall
motion may be due to factors other than satisfactory
revascularization.
F-18 FDG Cardiac PET
European Multicenter Study
. Abstract:
Louvain B, Lyon F, Groningen NL et al.
Predictive Value of FDG Imaging in 502
Patients with Chronic Ischaemic Lefi
Ventricular Dysfunction Enrolled in a
Prospective European Multicentre Viability
Study. Heart 1996; 75(5):P68
)
)
.
.
*
F-18 FDG Cardiac PET
European Multicenter Study
●
Objective: To ascertain the value of quantitative 18FDG
PET to identi~ chronically dysfunctional LV segments
whose function improve after coronary revascularization.
●
Interim analysis:
Complete follow-up on 105 patients
●
Notable Design Features
– Multicenter
– Prospective
—
Euglycemic hyperinsulinemic
clamp
— Endpoints include LVEF and Regional wall motion
F-1 8 FDG PET
Literature Search
Q Search Criteria for all Uses
– January 1, 1990 to July 1, 1998
– Human clinical trials
– English
— Medline, Embase, Cochrane Controlled Trials Register,
Cancerlit, Derwent Drug File, HSTAR, Biosis
Previews, International Pharmacology Abstracts
– Articles provided by PET community
—
References cited in above articles
— Cardiac: References in ACC/AHA Guidelines, USPDI
,)
,)
,,)
II
,)
)
F-18 FDG Cardiac PET
Preliminary Conclusions
●
Efficacy
— Efficacy supported by basic pharmacology
— Any dosimetry/pharmacokinetic
data in diabetics?
renally impaired?
— F-18 FDG may identi~ “viable” myocardium
●
Safetv
—
—
P~ior NDA data (cardiac patients any different?)
No evidence that it was even considered in most journal
articles
‘)
Guidance for Industry
Developing Medical Imaging
Drugs and Biologics
DRAFT GUIDANCE
This guidance document
-
isbeing distributedfor comment
purposes only.
Comments and suggestions regarding this drafi document should be submitted within 60 days of publication
of the Federal Register notice announcing the availability of the draft guidance. Submit comments to
Dockets Management Branch (HFA-305), Food and Drug Administratio~ 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. All comments should be identified with the docket
numberlisted
inthenotice
of
availability
that
publkhes
intheFederal Register.
Additional copies of this draft guidance document are available from the Drug Infowation Branch, Division
of Communications Managemen~ HFD-2 10, 5600 Fishers Lane, Rockville, MD 20857, (Tel) 301-8274573, or fi-omthe Internet at http://www.fda.gov/cder/guidance/indexhtm.’
Copies also are available from the Office of Communication, Training and Manufacturers Assistance, HFM40, CBE~ FDA, 1401 Rockville Pike, Rockville, MD 20852-1448, or from the Internet at
http://www.fda.gov/cber/guidelines.htm. Copies also can be obtained by fax horn I-888 -CBERFAX or 301827-3844 or by mail from the Voice Information System at 800-835-4709 or 301-827-1800.
For questions on the content of the draft document contact (CDER) Robert K. Lee&am Jr., 30 1-443-3500;
or (CBER) George Q. MNs 301-827-5097.
U.S.Department
ofHealth and Human Services
Food and Drug Administration
CenterforDrug Evaluationand Research(CDER)
CenterforIliologics
Evaluationand Research (CBER)
October 1998
Clin#
_——_
J:lk3uIDAhfc\1210Dm. WPD
iO/2/98
-~
$
Federal Register / VO1.
(3) Ifitcannot
bedetermined
that
the
fasteners
arecorrectly
installed
withwet
remove and inspect the specified
sealant,
number of additional fasteners in that zone,
ovecsize the holes, apply primer, and instafl
new, oversize fasteners with wet sealant, in
accordance with the alert service bulletin.
(i) If, after removal, all additional fasteners
inspected in that zone are found to be
correctly installed with wet sealant, no
further action is required for that zone.
(ii) If, after removal, the fasteners in that
zone are found to be incorrectly hwtalled,
remove all other fasteners in the zone,
oversize the holes, apply primer, and install
new, oversize fasteners with wet sealant, in
accordance with the alert service bulletin.
(b) An alternative method of compliance or
adjustment of the compliance ttme that
provides an acceptable level of safety maybe
used if approved by the Mamger, Seattle
Aircraft Certification Office (ACO), FAA,
Transport Airplane Directorate. Operators
shall submit their requests through an
appropriate FAA Principal Maintenance
Inspector, who may add comments and then
send it to the Manager, Seattle ACO:
Note 2: Information concerning the
existence of approved alternative methods of
compliance with this AD, if any, may be
obtained from the Seattle ACO.
(c) Special flight permits may be issued in
accordance with Ss 21.197 and 21.199 of the
Federal Aviation Regulations (14 CFR 21.197
and 21. 199) to operate the airplane to a
location where the requirements of this AD
can be accomplished,
Issued in Renton, Washington, on October
7, 1998.
Darrell M. Pederson,
Acting Manager, TransportAirplane
Directorate, Aircraft Certification Service.
[FR Dec. 98-27481 Filed 10-13-98; 8:45 am]
BILLINGCODE
4910-134
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 315 and 601
[Docket No. 98NA040]
Regulations for In Vivo
Radiopharmaceuticals
Used for
Diagnosis and Monitoring; Extension
of Comment Period
AGENCY: Food
and Drug Administration,
HHS.
ACTION: Proposed
comment period.
rule; extension
of
SUMMARY: The Food and Drug
Administration
(FDA) is extending to
November 16, 1998, the comment
period on a proposed rule that was
published in the Federal Register of
May 22, 1998 (63 FR 28301). The
document proposed to amend the drug
and biologics regulations
by adding
63,
No.
1!38
/
Wednesday, October 14, 1998/Proposed
provisions that would clarify the
evaluation and approval of in vivo
radiopharmaceuticals
used for diagnosis
and monitoring. The agency is taking
this action to provide interested persons
additional time to submit comments to
FDA on the proposed rule.
DATES: Written comments by November
16, 1998.
ADDRESSES: Submit written comments
to the Dockets Management Branch
(HFA-305), Food and Drug
Administration,
5630 Fishers Lane, rm.
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Rules
55067
comments are to be submitted, except
that individuals may submit one copy. ‘-=
Comments are to be identified with the
docket number found in brackets in the
heading of this document. Received
comments may be seen in the office
above between 9 a.m. and 4 p.m.,
Monday through Friday.
Dated: October 2, 1998.
William K. Hubbard,
Associate Commissioner for Polky
Coordination.
~R Dec. 98-27494 Filed 10-13-98845
MMNG
cODE
am]
4160-01+
FOR FURTHER INFORMATION COt4TA~
Dano B. Murphy, Center for Biologks
Evaluation and Research (HFM-17),
Food and Drug Administration,
1401 Rockville Pike, Rockville, MD
20852-1448,301-827-6210,
or
Brian L. Pendleton, Center for Drug
Evaluation and Research (HFD-7),
Food and Drug Administration,
---5600 Fishers Lane, Rockville, MD
20857,301-594-5649.
SUPPLEMENTARY INFORMATKIN: In the
Federal Register of May 22, 1998 (63 FR
28301), FDA published a proposed rule
to amend the drug and biologics
regulations by adding provisions that
would clarify the evaluation and
approval of in vivo
radiopharmaceuticals
used in the
diagnosis and monitoring of diseases.
The proposed regulations would
describe certain types of indications for
which FDA may approve diagnostic
radiopharmaceuticals.
The proposed
rule would also include criteria that the
agency would use to evaluate the safety
and effectiveness of a diagnostic
radiopharmaceutical
under the Federal
Food, Drug, and Cosmetic Act and the
Public Health Service Act. FDA
provided until August 5, 1998, to
submit comments on the proposed rule.
In the Federal Register of August 3,
1998 (63 FR412 19), FDA extended the
comment period on the proposed rule
until October 15, 1998, to allow
interested persons additional time to
submit comments on the proposed rule.
FDA ffnds it appropriate to further
extend the comment period to
November 16, 1998, to permit interested
persons the opportunity to consider the
proposed mle in light of the agency’s
draft guidance for industry entitled
“Developing Medical Imaging Drugs and
Biologic.” Notice of the availability of
this draft guidance is published
elsewhere in this issue of the Federal
Register.
Interested persons may, on or before
November 16, 1998, submit to the
Dockets Management Branch (address
above) written comments regarding this
proposed rule. Two copies ofany
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 315 and 601
[Docket
hJo.
----
98 D-0785]
Draft Guidance for Industry on
Developing Medical Imaging Drugs and
Biologics; Availability
AGENCY.
Food and Drug Administration,
HHS.
ACTION:
Availability
of guidance.
.-=
The Food and Drug
Administration
(FDA) is announcing the
availab~ity of a draft guidance for
industry entitled “Developing Medical
Imaging Drugs and BiologicS.” This
draft guidance is intended to assist
developers of drug and biological
products used for medical imaging, as
well as radiopharmaceutical
drugs used
in disease diagnosis, in planning and
coordinating the clinical investigations
of, and submitting various types of
applications for, such products. The
draft guidance also provides
information on how the agency will
interpret and apply provisions in the
proposed regulations for in vivo
rad iopharmaceuticals
used for diagnosis
and monitoring, which published in the
Federal Register of May 22, 1998 (63 FR
28301).
DATES: Written comments on the draft
guidance may be submitted by
December 14, 1998. General comments
on agency guidance documents are
welcome at any time.
ADDRESSES: Submit written requests for
single copies of the draft guidance to the
Drug Information Branch (HFD-2 10),
Center for Drug Evaluation and Research
(CDER), Food and Drug Administration,-+_
5600 Fishers Lane, Rockville, MD
20857, or the Office of Communication,
Training, and Manufacturers
Assistance
(HFM-40), Center for Biologics
Evaluation and Research (CBER), 1401
SUMMAFW
‘1’
55068
.—_
Federal Register /Vol. 63, No. 198/Wednesday, October 14, 1998 /F’roPsed
Rockvi Ile Pike, Rockville, MD 208521448, FAX 888-CBERFAX or 301-8273844. Send two self-addressed
adhesive
labels to assist the office in processing
your request. Submit written comments
to the Dockets Management Branch
(HFA-305), Food and Drug
Adminis~ation,
5630 Fishers Lane, rm.
1061, Rockville, MD 20852. Requests
and comments should be identified with
the docket number found in brackets in
the head ing of this document. See the
SUPPLEMENTARY lNFORMATtON section for
electronic access to the draft guidance
document.
FOR FURTHER INFORMATION CONTAW
Robert K. Leedham, Jr., Center for Drug
Evaluation and Research (HFD-160),
Food and Drug Administration,
5600
Fishers Lane, Rockville, MD 30857,
301-443-3500,
or George Q. Mills,
Center for Biologics Evaluation and
Research (HFM-573), Food and Drug
Administration,
1401 Rockville Pike, Rockville, MD 20852-1448, 301-8275097.
SUPPLEMENTARY INFORMATION:
1.
Description
of the Guidance
FDA is announcing the availability of
a draft guidance document entitled
“Developing Medical Imaging Drugs and
Biologic.” It references other CDER and
CBER guidance documents that relate to
the development of medical imaging
drugs and biologics, including CBER’S
‘aPoints to Consider in the Manufacture
and Testing of Monoclinal
Antibody
Products for Human Use” (62 FR 9196,
February 28, 1997). The draft guidance
is intended to assist developers of drug
and biological products used for
medical imaging, as well as
radiopharmaceutical
drugs used in
disease diagnosis, in planning and
coordinating the clinical investigations
of, and submitting various types of
applications for, such products. The
draft guidance applies to medical
imaging drugs that are used for
diagnosis and monitoring and that are
administered in vivo. Such drugs
include contrast agents used with
medical imaging techniques such as
radiography, computed tomography,
ultrasonography,
and magnetic
resonance imaging, as well as
radiopharmaceuticals
used with
imaging procedures, such as singlephoton emission computed tomography
and positron emission tomography. The
.._ draft guidance is not intended to apply
to possible therapeutic uses of these
drugs or to in vitro diagnostic products.
CDER’S Division of Medical Imaging
and Rad iopharmaceuticaI
Drug Products
presented a preliminary version of this
draft guidance document to the Medical
Rules
requirements of the applicable statutes,
Imaging Drug Advisory Committee
regulations, or both.
(MIDAC) on October 26, 1996.
Following that meeting, FDA worked
H. Comments
with MIDAC to develop this draft
Interested persons may, at any time,
guidance. As part of this process, FDA
submit to the Dockets Management
considered proposals submitted by an
ad hoc group representing contrast agent Branch (address above) written
comments on the draft guidance
manufacturers and by the Council on
document. Two copies of any comments
Radionuclides and
are to be submitted, except that
Radiopharmaceuticals,
Inc.
individuals may submit one copy.
On November 21, 1997, President
Comments should be identified with the
Clinton signed into law the Food and
docket number found in brackets in the
Drug Administration
Modernization Act
heading
of this document. The draft
of 1997 (the Modernization Act).
guidance document and received
Section 122(a) (1) of the Modernization
comments may be seen in the Dockets
Act directs FDA to issue regulations on
Management Branch between 9 a.m. and
the approval of diagnostic
4 p.m., Monday through Friday.
radiopharmaceuticals.
In the Federal
Register of May 22,1998 (63 FR 28301),
III. The Paperwork Reduction Act of
FDA published a proposed rule on the
1995
evaluation and approval of in vivo
This draft guidance contains
radiopharrnaceuticals
used in the
information collection provisions that
diagnosis and monitoring of diseases.
are subject to review by the Office of
The proposed rule describes certain .. . .... Management and “Budget (OMB) under
types of indications for which FDA
the Paperwork Reduction Act of 1995
would approve diagnostic
(the PRA) (44 U.S.C. 3501-3520). A
radiopharmaceuticals
and lists factors
description of these provisions is
that the agency would consider in
provided in the following paragraphs
evaluating the safety and effectiveness
with an estimate of the annual reporting
of a diagnostic radiopharmaceutical
burden. Included in the estimate is the
under the Federal Food, Drug, and
time for reviewing the instructions,
Cosmetic Act (the act) or the Public
searching existing data sources,
Health Service Act (the PHS Act). This
gathering and maintaining the data
draft guidance document provides
needed, bnd completing and reviewing
information on how FDA intends to
each collection of information.
interpret and apply various sections of
FDA invites comment on the
the proposed rule.
following: (1) Whether the proposed
In the Federal Register of August 3,
collection of information is necessary
1998 (63 FR 4 1219), FDA published a
for the proper performance of FDA’s
document extending the comment
functions, including whether the
period on the proposed rule on in vivo
information will have practical utility;
radiopharmaceuticals
from August 5,
(2) the accuracy of FDA’s estimate of the
1998, to October 15, 1998. In a separate
burden of the proposed collection of
document published elsewhere in thjs
information, including the validity of
issue of the Federal Register, FDA is
the methodology and assumptions used;
further extending the comment period
(3) ways to enhance the quality, utility,
to November 16, 1998. FDA hopes that
and clarity of the information to be
the issuance of this draft guidance on
collected; and (4) ways to minimize the
medical imaging drugs and biologics, in
burden of the collection on respondents,
conjunction with the extension of the
including through the use of automated
comment period on the proposed rule,
collection techniques, when
will assist interested persons in
appropriate, and other forms of
preparing their comments on the
information technology.
proposed rule. Persons will have
Title Draft Guidance for Industry on
additional time to submit comments on
Developing Medical Imaging Drugs and
the draft guidance after the comment
Biologics
period on the proposed rule closes.
Descrbtiorr FDA is issuing a draft
guidanc~ on the developmen~ of
This draft level 1 guidance is being
medical imaging drugs and biologics.
issued consistent with FDA’s good
guidance practices (62 FR 8961,
The draft guidance is intended to assist
developers of drug and biological
February 27, 1997). It represents the
agency’s current thinking on the
products used for medical imaging, as
development of medical imaging drugs
well as t-adiopharmaceutical
drugs used
and biologics. It does not create or
in disease diagnosis, in planning and
coordinating the clinical investigations
confer any rights for or on any person
and does not operate to bind FDA or the
of, and submitting various types of
public. An alternative approach maybe
applications
for, such products. The
used if such approach satisftes the
draft guidance provides information on
Federal
Register /VoI. 63, No. 198/Wednesday,
how the agency will interpret and apply
provisions of the existing regulations
regard ing the content and format of an
application for approval of a new drug
(21 CFR 314.50) and the content of a
biological product application (21 CFR
601.25). In addition, the draft guidance
provides information on how the agency
will interpret and apply the proposed
rule on the evaluation and approval of
in vivo radiopharmaceuticals
used for
diagnosis and monitoring (63 FR 28301).
The proposed rule, by adding part315,
would clarify existing FDA
requirements for the evaluation and
approval of drug and biological
rad iopharmaceuticals
already in place
under the authority of the act and the
PHS Act.
Existing regulations, which appear
primarily in parts 314 and 601 (21 CFR
parts 314 and 601), specify the
information that manufacturers must
submit so that FDA may properly
evaluate the safety and effectiveness of
new drugs and biological products. This
information is usually submitted as part
of a new drug application (NDA) or a
biologics license application (BLA), or
as a supplement to an approved
application. This draft guidance
supplements these regulations. Under
the proposed rule and the draft
guidance, information required under
the act and the PHS Act and needed by
TABLE
October 14, 1998/Pro~sed
FDA to evaluate safety and effectiveness
would still have to be reported.
Description
of Respondents
Manufacturers of medical imaging drugs
and biologics, including contrast drug
products and diagnostic
radiopharmaceuticals.
Burden I&hate
The proposed rule
used
on in vivo radiopharmaceuticals
for diagnosis and monitoring sets forth
an estimated annual reporting burden
on the industry that would result from
that rulernaking (63 FR 28301 at 28305
to 28306). This draft guidance on the
development of medical imaging drugs
and biologics is in part intended to
explain how FDA will interpret and
apply the proposed rule. Thus, the
estimated annual reporting burden of
the draft guidance, as provided in the
chart below, is the same as that of the .
proposed role, with one change. In
addition to the diagnostic
radiopharmaceuticals
that are the
‘subject ‘of the “proposed rule, the draft’
guidance also addresses the
development of contrast drug products,
which FDA evaluates and approves
under part 314. but which are not
affected by the proposed rule.
The chart below provides an estimate
of the annual reporting burden for
diagnostic radiopharmaceuticals
and is
based on the estimate described in the
proposed rule (63 FR 28301 at 28306).
The chart also provides an estimate for
1.—ESTIMATED
ANNUAL
Annual
Frequency per
Response
No. of Respondents
Diagnostic Radiopharmaceuticals
8
COf_IIKiSt
1
hI@
REPORTING
Rules
55069
reporting burden for contrast.%
drug products. FDA estimates that the
potential number of respondents who
would submit applications or
supplements for contrast drug products
would be one. Although FDA did not
apprmfeany NDA’s for contrast drugs
(there are no biological contrast drug
products) in fiscal year 1997 (FY 1997),
for purposes of estimating the annual
reporting burden, the agency assumes
that it will approve one contrast drug
each fiscal year. The annual frequency
of responses for contrast drugs is
estimated to be one response per
application or supplement. The hours
per response, which is the estimated
number of hours that an applicant
would spend preparing the information
to be submitted for a contrast drug in
accordance with this draft guidance, is
estimated to be approximately 2,000
hours.
the annual
‘
The draft guidance would not impose
-any additional reporting burden because
safety and effectiveness information is
already required by existing regulations.
In fact, clarification by the draft
guidance of FDA’s standards for
evaluation of medical imaging drugs
and biologics is expected to reduce the ~_
overall burden of information
collection. FDA invites comments on
this analysis of information collection
burdens.
BURDENI
Total Annual
Responses
Hours per
Response
1
1
8
1
Total Hours
2,000
2,000
16,000
2,000
18,000
Total
1There are no capital costs or operating and maintenance costs associated with this collection of information.
In compliance with section 3507(d) of
the PRA (44 U.S.C. 3507(d)), the agency
has submitted the information
collection provisions of this draft
guidance to OMB for review. Interested
persons are requested to send comments
on this information collection by
November 13, 1998, to the Office of
Information and Regulatory Affairs,
OMB, New Executive Office Bldg., 725
17th St. NW., rm. 10235, Washington,
DC 20503, Attn: Desk Officer for FDA.
IV. Electronic
Access
An electronic version of this draft
guidance document is available on the
Internet using the World Wide Web
(WWW) at “http: //www.fda.gov/cder/
guidance/index. htm” or “http://
www. fda.gov/cber/gui delines. htm”.
Dated: October 6, 1998.
William
DEPARTMENT
OF JUSTICE
K. Hubbard,
Office of Juvenile Justice and
Assocfate Commissioner for Policy
Delinquency
PreventIon
Coordirratfon.
[FR DOC.98-27495 Filed 10-13-98; 8:45 SIIIl 28 CFR pan 31
elUING
CODE
4160-01-f
[OJP (OJJDP)-1
158]
RIN1121-AA46
Juvenile Accountability
Block Grants
Incentive
AGENCK Office of Juvenile Justice and
Delinquency Prevention (OJJDP), Office
of Justice Programs, Justice.
.-%
ACTION: Notice of proposed rulemaking.
SUMMARW This document proposes
procedures under which an eligible
State, or unit of local government that
receives a subgrant from the State, is
TABLE OF CONTENTS
I.
INTRODUCTION
m
.....0...............**2
SCOPE: TYPES OF MEDICAL
IMAGING DRUGS
A.
. . . . . . . . . . . . . . . . . . . . . 2
ContrastDrug Products. . . . . . . . . . 00...,...
DiagnosticRadiopharmaceuticals
.....*.**...*..*.*. ..............2
B.
.................................................... 1
●
●
●
m.
INDICATIONS
FOR MEDICAL
IMAGING DRUGS
.......... ............3
A.
StructureX)elineation
.....00.00.0040..... 0.0......
. ...0.....
..*.
4
B.
Functional,
Physiological,
or BiochemicalAssessment..................5
Disease or PathologyDetectionorAssessment ....................,...6
c.
D.
Diagnosticor TherapeuticPatientManagement ...0........*.........7
E.
, MultipleClaims .........................0......................7
F.
Other Claims .......*.*.**...**.........*... ...0....
8
. . . . . . . . . .,
●
●
Iv.
ESTABLISHING
CLAIMS FOR MEDICAL IMAGING. AGENTS
. . . . . . . . . ...8
A.
Clinical Usefulness . ...0.....
. ..*..*..*
. . . ...*..
................8
B.
Validity of Information Provided by a Medical Imaging Drug . . . . . . . . . . . 9
Defined Clinical Settings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
c.
D.
Establishing
Effectiveness
forSpecific
Claims .......................11
●
v.
GENERAL
CONSIDERATIONS
FOR SAFETY ASSESSMENTS
OF h!133DICAL
IMAGING
DRUGS
.........* ..*..........*.............. .......... 15
A.
Dose or Mass .......*.....*.........................*........*.15
B.
Route ofAdministration.................. ..................... 15
Frequency of Use . . . . . . . . . ...*....
c.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
D.
Biological, Physical, and Effective Half-Lives . . . . . . . . . . . . . . . . . . . . . ...16
●
●
●
●
VI.
NONCLINICAL
SAFETY ASSESSMENTS
. . . ...*..
.**.....
. . . . . . . . . *. 16
A.
Nonclinical Safety Assessments for Biological Products . . . . . . . . . . . . . ...17
B.
Nonclinical Safety Assessments for Non-Biological Products . . . . . . . . . ...17
WI.
GENERAL CONSIDERATIONS
MEDICAL IMAGING DRUGS
A.
Phase 1 Studies . . . . . . . .
B.
Phase 2 Studies . . . . . . . .
Phase 3 Studies . . . ...*.*
c.
VIII.
●
SPECIAL CONSIDERATIONS
EFFICACY
. . ...*...
. . . .
IN THE CLINICAL
......... .......
.................
. . ..*.....
.......
●
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
●
EVALUATION OF
. .* *.....
. . . . . . . . . . . . . . 20
. . . . . . . . . . . . . . . . . . . . . . . 21
. . . . . . . . . . . . . . . . . . . ..*. 22
. . . . . . . . . . . . . . . . . . . . . . . 22
IN THE CLXNICAL EVALUATION
.
...0.
.
.
.
J: VGUIDANCU21ODFT WPD
10/2/98
i
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
...*....
OF
.
.
.
.
.
.
.
.
.
23
,.
A.
B.
c.
D.
E.
Selection of Subjects . . . . . ...* . .
............
Image Ewluations
Truth Standards (Gold Stmuirzrd$
Controls . . . . . . . . . . . . . . . . . . . .
Endpoints . . . . . . . . . . . . . . . . . . .
....
....
....
....
....
.
.
.
.
.
.....
.....
.....
.....
.....
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.....
.....
. ...*.
.....
.....
.......
.......
. 0,...,...
.......
.......
.....
.....
.
.....
.....
.
.
.
.
.
.
.
.
.
.
31
ISSUES IN IMAGE ACQUISITION AND HANDLING . . . . . . . . . . . . . . . . . . ...32
A.
Image Acquisition
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...32
. . . . . . . . 32
B.
Image Handling Procedures . . . . . . . . . . . . . . . . . . . . . ..0......
x.
STUDY ANALYSIS
XI.
CLINICAL SAFETY ASSESSMENTS
A.
Group 1 Medical Imaging Drugs
B.
Group 2 Medical Imaging Drugs
c.
Radiation Safety Assessment for
. . . . . . . . . . . . 32
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . *.......
. . . . . . . . . . ...*....
●
. . . . . ...0
. ..**...**
. . . ...0..
..............
. . . . . . . . . . ..0......
.............
. . ...***.
. . . . . . . . . .. *...*.
........
All Diagnostic Radiopharmaceuticals
-.. .. .
●
●
.
.
.
.
...0.
.
...0....
●
.*
...*..*
●
*.*...
33
34
35
36------------------40
-
J: UGUlDANC\121ODPT.UTD
10/.?/98
‘,
23
24
29
30
lx.
GLOSSARY
c
,>
Draft - Not for Implementation
GUIDANCE
FORINDUSTRYI
Developing Medical Imaging Drugs and Biologics
I.
INTRODUCTION
This guidance is intended to assist developers of medical imaging drug and biological products in
planning and coordinating their clinical investigations and preparing and submitting investigational
new drug applications (INDs), new dtug applications (NDAs), biologics license applications
(BLAs), abbreviated WAS (@As),.
and supplements .tci~As
or. Baas . . .... ..... . .. ... . .. ... .. . .. ..
_—
Medical imaging drugs are generally governed by the same regulations as other drug and
biological products.2 However, as described in this documen; many medical imaging drugs have
special characteristics that can help guide developmental efforts. This guidance discusses some of
these special characteristics and how drug development for medical imaging drugs can be tailored
to reflect those characteristics. Specifically, this guidance discusses the following items:
1.
Potential claims for medical imaging drugs and the nature of “promotional materials
for such claims?
.
2.
Methods by which each of these claims maybe established.
3.
Special considerations in the clinical evaluation of eflicacy.
4.
Special considerations in the clinical evaluation of safety.
1Thisguidance
hasbeenprepared
bytheDivision
ofMedical
Imaging
andRadiophannaeeutkd
DrugProducts
in
theCenter for Drug Evaluation and Research (CDER) and the Office of Therapeutics Research and Review in the
Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. This guidance represents
the Agency’s current thinking on developing medical imaging drug and biological products. It does not create or confer
any rights for or on any person and does not operate to bind FDA or the public. An alternative approach maybe used if
such approach satisfies the requirements of the applicable statute, regulations, or both.
2 Sponsom developing medical imaging drugs should be familiar with Agency regulations and guidances pertaining
to the development of drugs and biologics.
.—
3 The terms claim, indication, and indication for use are used interchangeably in this guidance.
.
Draft - Not for Implementation
Inresponse
totherequirements
oftheFDA Modernization
Actof 1997,FDA recently
proposeda
ruletoamend thedrugandbiologics
regulations
foronecategory
ofmedicalimagingdrugsby
addingprovisions
fortheevaluation
and approval
ofinvivoradiopharmaceuti
calsusedinthe
diagnosis
ormonitoring
ofdiseases
(63FR 28301,May 22,1998).Thisguidanceelaborates
on
theconcepts
contained
intheproposedruleon radiopharmaceutical
diagnostic
products.
Once
theproposal
isfinalized,
theAgency willrevise
this
guidance,
ifnecessary,
toensurethath is
consistent
withthefinal
rule.
SCOPE:
IL
TYPES OF MEDICAL IMAGING DRUGS
Thisguidanceapplies
tomedicalimagingdrugsthatareusedfordiagnosis
ormonitoring
andthat
areadministered
invivo.Theseinclude
medicalimagingdrugsusedwithmedicalimaging
techniques
such as radiography, c.ornputed tomography. (CT), ultrasonography, magnetic
resonance imaging (MRI), and radionuclide imaging. The guidance is not intended to apply to the
development of therapeutic uses or to in vitro diagnostic uses of these drugs.
Medical imaging drugs ean be classified into two general categories:
-
A.
Contrast Drug Products
:
Contrast drug products are used to increase the relative difference of signal intensities in
adjacent parts of the body and to provide additional information in combination with an
imaging device beyond that obtained by the device alone. These products include, but are
not limited to, the following: (1) iodinated compounds used in radiography and CT;
(2) paramagnetic metallic ions (such as ions of gadolinium, iron, and manganese) linked to
a variety of molecules and used in MR.I; and (3) microbubbles, microaerosomes, and
related microparticles used in diagnostic ultrasonography.
B.
Diagnostic Radiopharmaceutica1s4
4 As defined in the proposed rule for diagnostic radiophannaceuticals, and as used in this guidance, a diagnostic
is (a) an article that is intended for use in the diagnosis or monitoring of a disease or a
radiophannaceutical
manifestation of a disease in humans and that exhibits spontaneous disintegration of unstable nuclei with the emission of
nuclear particles or photons or (b) any nonradioactive reagent kit or nuclide generator that is intended to be used in the
preparation of such an article. The FDA interprets t.hk deftition to include articles that exhhh spontaneous
disintegration leading to the reconstruction of unstable nuclei and the subsequent emission of nuclear particles or
photons (63 FR 28301 at 28303).
J:\!GUIDANC\121 ODFT WPD
10/2/98
.--5+
-
Draft - Not for Implementation
Diagnostic radiopharmaceuticals are radioactive drugs that contain a radioactive nuclide
that may be linked to a Iigand or carrier.5 These products are used in planar imaging,
single photon emission computed tomography (SPECT),
positron ernksion tomography
(PET), or with other radiation detection probes.
Diagnostic radiophannaceuticals
1.
A radionuclide that can be detected in vivo (e.g., technetium-99m,
iodine-1 23, iridium-l 11). The radionuclide typically is a radioactive
molecule with a relatively short physical half-life that emits radioactive
decay photons having sufficient energy to penetrate the tissue mass of the
patient. These photons may then be detected with imaging devices or other
detectors.
2.
A nonradioactive component that delivers the molecule to specific areas
within the body. This nonradionuclidic portion of the diagnostic
radiophannaceutical often is an organic molecule such as a carbohydrate,
lipid, nucleic acid, peptide, small protein, or antibody. In general, the
purpose of the nonradioactive component is to direct the radionuclide to a
specific body location or process.
—
III.
used for imaging typically have two distinct components:
INDICATIONS
FOR MEDICAL IMAGING DRUGS
Because medical imaging drugs are used clinically in many diverse ways, this guidance outlines
certain types of potential claims for these drugs. For example, some medical imaging drugs are
not intended to provide disease-specific information, as characterized by measures such as
sensitivity and specificity, but are intended to characterize structural or functional manifestations
common to several diseases. In such cases, the proposed indications for these products may refer
to structural or fictional
assessments that are common to multiple diseases or conditions.
Indications for medical imaging drugs may fall within the following generaJ categories:
●
●
●
●
Structure delineation
Functional, physiological, or biochemical assessment
Disease or pathology de[ection or assessment
Diagnostic or therapeutic patient management
5 In this guidance, the ten-m ligand and carrier refer to the entii nonradionuclidic portion of the diagnostic
radiopharmaceutical.
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Theseclaimsneed not be mutually exclusive, and approval maybe possible for claims other thaq
those listed. Each of these claims is described in the following sections as is the nature of
promotional materials for each of these claims. Ways in which each of these claims maybe
established are described in Section IV.
A.
Structure Delineation
As described in the following sections, two types of claims for structure delineation may
be possible: (1) locating and outlining normal anatomic structures and (2) distinguishing
between normal and abnormal anatomy.
1.
Locating and Outlining Normal Anatomic Structures
A medical
locate and
clari@ the
other body
imaging drug approved for this type .ofclairn..sh.ould,be,& le.to-help.
outline normal anatomic structures. The product also should help
spatial relationship of the visualized normal structure(s) with respect to
parts or structures.
Such a medical imaging drug maybe developed to distinguish a normal structure
that may not be seen well with other imaging drugs or modalities. For example, a
contrast drug product may be developed to delineate the no~al gastrointestinal
tract to distinguish it from other abdominal structures or an abdominal mass.
Similarly, a diagnostic radiophannaceutical may be developed to image the normal
parathyroid glands, which could help a surgeon plan and perform surgery for a
mass in the thyroid gland. Products that help delineate normal anatomic variants
also may be included here. An example of this type of product is a drug that
delineates normal variants of coronary anatomy.
Promotional materials based on thk claim may describe how the medical imaging
drug enhances visualization of the normal anatomic Structure, or its variants, and
how it facilitates an understanding of the relationship of the normal visualized
structure to other structures, However, promotional materials based on these
claims should not imply that use of the product helps distinguish normal and
abnormal anatomy, or that the product aids in the detection or assessment of
disease or pathology. The materials should not imply that these products have
been shown to facilitate appropriat~ diagnostic or therapeutic management
decisions in patients. These types of uses fall within other claims.
2.
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Distinguishing
Between Normal and Abnormal Anatomy
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A medical imaging drug approved for this type of claim should be able to help
locate and outline both normal and abnormal anatomic structures. The product
also should help to clari& the spatial relationships of the normal and abnormal
anatomic structure(s) with respect to other body parts or structures. This type of
claim applies to situations where the mechanism by which the abnormal anatomy is
visualized is sufficiently similar to the mechanism by which the normal anatomy is
visualized. This type of claim does not apply to products whose mechanism of
visualization is dependent on the presence of an abnormality.
Examples of thk type of product include a medical imaging drug being developed
to identifi bronchiectasis. The drug might be able to distinguish dilated bronchi
from normal bronchi and categorize the bronchiectasis anatomically (e.g., as
cylindric, sacculated, or fisiform). Similarly, a medical imaging drug might be
developed to evaluate meniscal cmIigamentous injuries-of-the knee -Preduots that
help delineate anomalous variants
ofnormalanatomymay alsobe included
here
(e.g.,
a productthathelps define the anatomical relationships of a vascular sling
that compresses the trachea or esophagus).
Promotional materials based on such a claim may describe how the medical
imaging drug helps distinguish between normal and abnormal anatomy or aids in
identification of variants or anomalies of normal anatomy. Promotional materials
based on these claims should not imply, beyond the description of the abnormal
anatomy, that the product aids in the detection or assessment of disease or
pathology. The materials should not imply that these products have been shown to
facilitate appropriate diagnostic or therapeutic management decisions in patients.
_—
A medical imaging drug that is intended either to (a) delineate
structures such as tumors or abscesses or (b) detect disease or
anatomic structure should seek a claim of diseaxe or pathology
assessment or diagnostic & therapeutic patient management,
claim.
B.
Functional,
Physiological,
nonanatomic
pathology within an
detection or
rather than this
or Biochemical Assessment
A medical imaging drug that is intended to provide functional, physiological, or
biochemical assessment should be able to evaluate the function, physiology, or
biochemistry of a tissue, organ system, or body region. Functional, physiological, and
biochemical assessments are designed to determine if a measured parameter is normal or
abnormal. This type of claim applies to drugs used to detect either a reduction or
magnification of a normal fictional, physiological, or biochemical process.
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Examples of functional, physiological, or biochemical assessments include measurement of
cardiac ejection fraction, assessment of regional cerebral blood flow, evaluation of
myocardial wall motion, and assessment of anaerobic metabolizes to evaluate tissue
ischemia.
Promotional materials based on this type of claim may describe how the medical imaging
drug facilitates assessments of fimction, physiology, or biochemis~.
Promotional
materials based on these claims should not imply that the use of these products aids in the
detection or assessment of disease or pathology. The materials should not imply that these
products have been shown to facilitate appropriate diagnostic or therapeutic management
decisions in patients.
The claim offinctional, physiolo~”cal, or biochemical assessment is limited to assessment
of normal fictional,
physiological, or biochemical prmesses when disturbances of these
processes are common to several diseases or conditions and they are not diagnostic for
any particular disease or condition. When these circumstances are not present claims of
disease orpatholo~
detection orassessment or diagnostic or therapeutic patient
management should be sought. For example, a claim of diseaw or pathology detection or
assessment should be sought by sponsors who wish to develop a medical imaging drug to:
●
Establish a diagnosis by detecting or assessing the function, ~hysiology, or
biochemistry of a tissue, organ system, or body region;
●
Detect or assess an abnormality of fimction, physiology, or biochemistry that is
diagnostic for a disease or condition;
●
Detect or assess an abnormality of function, physiology, or biochemistry that is
diagnostic for a specific disease or condition in the defined clinical setting for
which the test will be indicated and used (see Section IH.C);
●
Detect or assess functional, physiological, or biochemical processes that are not
expressed by the normal organ system, tissue, or body part.
c.
Disease or Pathology Detection or Assessment
A medical imaging drug that is intended for disease or pathology detection or assessment
should be able to assist in the detection, location, or characterization of a specific disease
or pathological state in a defined clinical setting.G
6 See Section IV.C for a definition of defrned clinical setting.
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Examples of medical imaging drugs for this type of indication include (1) a peptide
that
participates
in an identifiable transporter fimction associated with a specific neurological
disease; (2) a peptide that is specifically metabolized and is used to evaluate an abnormal
cell’s residual metabolic function in a particular disorde~ and (3) a radiolabeled
monoclinal antibody that attaches to a tumor antigen and thus detects a tumor.
Promotional materials based on this claim may describe how the medical imaging drug
facilitates detection or assessment of a specific disease or pathology in the defined clinical
setting in which it was studied. Promotional materials based on this claim should not
imply that use of these products leads to particular changes in diagnostic or therapeutic
patient management or in clinical outcomes.
D.
-
Diagnostic or Therapeutic Patient Management
A medical imaging drug that is intended to assist in diagnostic or therapeutic patient
management may be studied explicitly for its ability to provide imaging or related
information leading directly to appropriate diagnostic or therapeutic management
decisions in patients in a defined clinical setting. In this contex$ explicitly means that the
hypotheses of how the medical imaging drug might be useful in diagnostic or therapeutic
management should be specified in the protocol. Hypotheses should be tested
prospectively in the clinical study and should be evaluated with endpoints that assess the
appropriateness of patient management or clinical outcomes.’ For example, a medical
imaging drug may assist in appropriate deterrhination of whether patients (1) should
undergo diagnostic corona~ angiography (i e., the test results aid in a diagnostic
management decision); (2) will have predictable clinical benefit from coronary
revascularization (i.e., the test results aid in a therapeutic management decision); or
(3) should undergo resection of a tumor or undergo chemotherapy (i.e., the test results
aid in therapeutic management decisions). Labeling indications for these examples might
include statements that a drug is indicated to help determine the needjor coronary
angiography or to assist in the”evacuation of tumor resectabiIity.
Promotional materials for this type of claim may describe how the medical imaging drug
assists in diagnostic or therapeutic patient management.
E.
Multiple Claims
The indication categories outlined above are flexible, and claims for medical imaging drugs
need not be mutually exclusive. For example, a diagnostic radiopharmaceutical may be
7 As used in this
guidance, clinical outcomes refers to changes iDpatient symptoms, functioning, or survival.
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developedasan aidinthediagnosis
oflungcancerfora claimofdisease or pathology
detection or assessment. This diagnostic radiopharmaceuti cal could also be evaluated for
its ability to provide information that leads directly to appropriate therapeutic management
decisions (e.g., helping to determine, based on test results, what combination of surge~,
radiotherapy, and chemotherapy might be appropriate).
Clinical studies should usually evaluate the effect of the imaging agent on both structure
and fhnction when both are commonly evaluatd together in clinical practice (e.g., as
during ultrasonography). For example, an ultrasound contrast drug used to assess stenotic
blood vessels could be approved for both structural delineation and fictional
assessment
if appropriate clinical studies were performed. In this case, clinical studies could be
designed so that structural delineation of blood vessels is evaluated with two-dimensional
ultrasonographic imaging. The Iimctional assessment of the hemodynamic consequences
of the obstructions could be-evaluated with Doppler interrogation of the-same vessels.
--F.
Other Claims
For a claim that does not fall within the indication categories identified above, the
applicant or sponsor should consult FDA on the nature of the desired claim and how to
establish effectiveness for it.
Iv.
ESTABLISHING
-
CLAIMS FOR MEDICAL IMAGING AGENTS
To establish a claim for a medical imaging drug, a sponsor or applicant should characterize the
drug’s
clinical usefulness and demonstrate that the information provided is valid and reliable.8
Clinical studies should be performed in defined clinical settings. These overarching principles are
discussed in this section, as are the methods of establishing effectiveness for specific claims.
A.
Clinical Usefulness
The principal reason for performing an evaluation with a medical imaging drug is to
determine that the diagnostic results will be useful to the patient and the health care
provider. As is the case with therapeutic drugs, claims for medical imaging drugs should
be supported with information demonstrating that the potential benefits of the use of a
medical imaging drug outweigh the potential risks to the patient. Potential risks include
8 As used in t.lis guidance, validi(y is a global concept that encompasses the quzdityof bias. Valid measurements
are close to the truth (have small bias). Reliability is a concept that encompasses the quality of precision. Reliable
measurements are reproducible (have small variance).
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both the risks related to administration of the dtug and the risks of incorrect diagnostic
information. Incorrect diagnostic information includes, but is, not limited to, inaccurate
structural, fi.mctional, physiological, or biochemical information; false positive or false
negative diagnostic determinations; and information leading to inappropriate decisions in
diagnostic or therapeutic management.
A medical imaging drug that is clinically usefhl provides information that contributes to
the appropriateness of diagnostic or therapeutic patient managemen$ contributes to
beneficial clinical outcome, or provides accurate prognostic information.
In additio~ for a contrast drug product to be considered clinically useful, the product used
in combination with an imaging device should provide useful information beyond that
obtained by the imaging device alone. Stated differently, imaging with the contrast drug
product should add value when compared to imaging without the contrast drug product.
A plan for establishing clinical usefulness should be incorporated into the development
plan of a medical imaging drug. In general, clinical usefulness should be evaluated
prospectively in the principal clinical studies of efficacy (e.g., by incorporation into Phase
3 protocols).g
B.
Validity of Information Provided by a Medical Imaging Drug
A medical imaging drug maybe shown to provide valid information in at least two ways:
1.
Comparing the results yielded by the medical imaging drug with those of a
truth standard (gold standar~.l”
2.
Demonstrating
outcomes.
that the use of the product contributes to beneficial patient
In instances where a truth standard does not exist or cannot be assessed practically, the
focus of the study should be to evaluate the effects of the product on clinical outcomes.
For example, clinical outcomes could be assessed in a study designed to evaluate the
effects of the medical imaging drug on diagnostic or therapeutic management (see
Section IV. D.4).
9 In some situations (e.g., measurement of cardiac ejection fraction), clinical usefulness maybe documented by a
critical and thorough analysis of the medical literature and any historical precedents.
.-
10See Glossary and Section VIII.C.
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c.
Defined Clinical Settings
A defined clinical setting should reflect the circumstances and conditions under whtch the
medical imaging drug is intended to be used. It delineates the patient population, relevant
available medical and diagnostic data, and diagnostic questions that characterize the
circumstances under which the medical imaging drug is intended to be used. For example,
a medical imaging drug for duodenal ulcers could be developed for use in different defined
clinical settings. The drug might be developed to identi~ or exclude duodenal ulcers in
patients with gastrointestinal bleeding to confirm a suspected duodenal ulcer in patients
with equivocal findings on radiographic examination of the upper gastrointestinal tract to
evaluate healing of duodenal ulcers in patients after initial treatment or to help determine
whether patients with duodenal ulcers should undergo surge~ or remai n on maintenance
medical therapy.
The circumstances and conditions under which the medical imaging drug is intended to be
used should be evaluated in a clinical trial and maybe described in the labeling using the
following mechanisms.
1.
Specifying aspects of the medical history and physical examination that are
pertinent for determining the likelihood of the disease or condition that is in
question. For example, a medical imaging drug inteqded to detect breast
cancer might be evaluated for use in the assessment of (1) otherwise
healthy women over 40 years of age, (2) women presenting with palpable
breast masses, or (3) women with a family history of breast cancer.
2.
Specifying
sequence.
to evaluate
Iaboratoxy
and extent
3.
Specifying any other diagnostic assessments that are to be performed in the
evaluation of this patient population. This delineation should include
describing how the medical imaging drug should be used with respect to
other diagnostic tests or evaluations, including (1) whether the medical
imaging drug is intended to be used together with, or as a replacement for,
other diagnostic tests or modalities, and (2) how the use of the medical
imaging drug is influenced by the results of other diagnostic evaluations.
For example, in the evaluation of suspected pulmona~ embolism, a medical
imaging drug COU1
d be developed either as a replacement for ventilati on-
_+
a patient population that is at a particular step in the diagnostic
For example, a diagnostic radiopharmaceuti cal may be intended
patients in an emergency room with equivocal clinical and
findings of a myocardhd infarction, or to evaluate the location
of a myocardial infarction in patients with definitive findings.
__-=
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pefision scanning orasanadjunct
toventilation-pefiusion
scanning. E
the medical imaging drug is developed to be an adjunct to ventilationperfiusion scanning, its intended use will likely be influenced by the scan
results (e.g., intended for use in patients with scan results that are
indeterminate and not for patients with knv-probability or high-probabili~
scans).
Clinical trials should prospectively evaluate relevant hypotheses about the demarcated
patient population in the clinical setting in which the drug is intended to be used.
D.
Establishing
Effectiveness for Specific Claims
The following sections describe how each of the types of claims summarized in Section III
may be established.
1.
Structure Delineation
Methods by which claims for structure delineation maybe established are
described below.
—
a.
Locating and Outlining Normal Anatomic St~ctures
A claim of delineating normal anatomic structures maybe established by
demonstrating in clinical studies that the medical imaging drug can reliably
locate and outline normal anatomic structures and reliably clari$ the spatial
relationship of these structures to other body parts.
In clinical studies, the validity of the delineation should be demonstrated by
comparing the performance of the medical imaging drug with that of a
reference product’or procedure of known htgh validtty (i.e., a truth
standard). Ideally, the high validity of this reference product or procedure
should be thoroughly and critically documented before initiating the clinical
efficacy studl es.
In some cases, valid reference products or procedures may not be available
or cannot be used. In these cases, the validity of the medical imaging drug
may be demonstrated with clinical studies documenting that the product
provides information that is consistent with known anatomic and structural
facts about the tissue, organ, or body part in question. The sponsor should
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discuss
theseanatomicand structural
facts
withtheAgency and carefully
detail
and documentthem prior
toinitiation
oftheclinical
eflicacy
studies.
b.
Distinguishing Between Normal and Abnormal Anatomy
A claim for distinguishing between normal and abnormal anatomy maybe
established by demonstrating in cliniczd studies that the medical imaging
drug can reliably locate and outline both normal and abnormal variations of
an anatomic structure, and that the product is able to clarify the spatial
relationships of the normal and abnormal anatomic structures with respect
to other body parts or structures,
The validity of this distinction should be supported by studies in which
sufficient numbers.of subjects with and without abnormalities are
appropriate y represented. Appropriate representation means that the
studies should generally include subjects that adequately represent the
spectra of normality and abnormality (e.g., including subjects with chronic
bronchitis, pneumonia, asthmq and cystic fibrosis; and also subjects with
localized and diffuse disease for a drug intended to assess bronchiectasis)
as well as the fill range of disease severity (e.g., from mild to severe
disease, or from early to advanced disease).
Appropriate preclinical studies in relevant animal models, if available, may provide
additional information to support structure-delineation claims.
2.
Functional, Physiological, or Biochemical Assessment
This type of claim maybe established by demonstrating in clinical studies that the
medical imaging drug can reliably measure a finction or a physiological or
biochemical process. These measurements should generally be validated by
comparing the performance of the medical imaging drug with that of a reference
product or procedure of known high validity (i.e.; a truth standard). Ideally, the
high validity of this reference product or procedure should be thoroughly and
critically documented before its use in clinical studies.
These studies should provide a quantitative or qualitative understanding of how
the measurement varies in normal and abnormal subjects or tissues, including the
parameter’s normal range, distributio~ and confidence intervals in these subjects or
tissues. When possible, the minimum detectable limits and reproducibility of the
measurement should be assessed.
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The parameter should be evaluated in sufficient numbers of both normal and
abnormal patients. These patients should adequately represent the full spectra of
normality and abnormality (e.g., including patients with inflammatory, neoplastic,
and infectious intracranial processes for a dmg intended to assess regional cerebral
blood flow) and the fill range of fictional, physiological, or biochemical
dysfi.mction (e.g., from minimal or no perfhion to luxwy perfusion).
The drug’s pharmacology in the setting of various fictional,
physiologic, or
biochemical processes also should be documented from appropriate studies in
relevant animal species, if available. These might include approaches such as
induction of pharmacologic perturbations in the system to be evaluated
(e.g., administration of a specific receptor antagonist that results in altered binding
of the medical imaging drug); correlation with other accepted means of measuring
particular parameters (e.g.,. evrdmtiw-.@hwardiac
ejection fraction by
comparison to results obtained with radionuclide ventriculography); and in vivo or
in vitro analyses (e.g., tissue autoradiography). Documentation should be obtained
in at least one appropriate and relevant animal species, if available, in which the
particular finction, physiolo~, or biochemistry is sufficiently similar to that of
humans. For example, for a medical imaging drug being developed to evaluate
receptors within the central nervous system, full biochemical characterization of
rodent brains by tissue autoradiography may be appropriate. ~
3.
Disease or Pathology Detection or Assessment
A claim of disease or pathology detection or assessment maybe established by
demonstrating in a defined clinical setting that the medical imaging drug is able to
identi& or characterize the disease or pathology with sufllcient validity and
reliability. In this conteW the term validity refers to the overall diagnostic
performance of the product as measured by factors such as sensitivity, specificity,
positive and negative predictive values, accuracy, and likelihood ratios. Reliability
in this context means that the overall diagnostic performance of the product has
precision. The phrase sujfcient validity and reliability means validity and
reliability that are good enough to indicate that the product could be useful in one
or more defined clinical settings.
Data demonstrating validity and reliability should be obtained from patients in
defined clinical settings reflecting the proposed indications. Patients may present
for diagnostic evaluation of a specific disease or condition in various clinical
settings. Even though these patients may have the same dkease or condition, the
clinical usefulness of the medical imaging drug and the likelihood that patients have
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the disease or condition will likely be different in each clinical setting. Therefore,
the medical imaging drug should be evaluated in representative settings for which
use is proposed. In most disease or pathology detection or assessment indications,
pooling of efilcacy data across defined clinical settings would likely be of limited
value, and the medical imaging drug should be separately evaluated in suficient
numbers of patients in one or more of such settings. A claim for disease or
pathology detection or assessment may specifi the defined clinical setting and
speci& that the medical imaging drug is to be used in conjunction with other tests.
4.
Diagnostic or Therapeutic Patient Management
A claim of diagnostic or therapeutic patient management maybe established in
clinical studies by demonstrating that in a defined c!iniczd setting the testis usefhl
in guiding appropriate patient management.. -Appropriate patient management
means that diagnostic or therapeutic management decisions are validated as being
proper based on the correct diagnosis of the patient or on clinical outcomes. The
correct diagnosis may be documented by comparison with valid assessments of
actual clinical status (e.g., a histological diagnosis of malignancy), through patient
follow-up, or by evaluation of clinical outcomes.
Medical imaging drugs may seek the claims disease orpatho~ogy detection or
assessment, or diagnostic or therqveutic management, or both. A clarification
of
thedistinction
betweentheseclaimsisappropriate.
The claimdisease or
pathoIo~ detection or assessment can be obtained by demonstrating, in a defined
clinical setting, sufficient validity and reliability of the medical imaging drug to
imply clinical usefulness. The claim diagnostic or therapeutic management will
likely be more diflicult to establish, given the same defined clinical setting.
Generally, it will require prospectively designed trials with the objective of
evaluating a specific hypothesis of how the medical imaging drug might be useful
in diagnostic or therapeutic patient management in a defined clinical setting. The
trials might include randomization (whether to receive the medical imaging drug),
with an endpoint measuring appropriateness of management (given the ultimate
correct diagnosis) or clinical outcome. Alternatively, all patients may receive the
study drug if it is possible to determine both what the management would have
been had the medical imaging drug not been used, and what the management
would be because of information provided by the medical imaging drug. The trials
should demonstrate that management based on findings using the medics! imaging
drug is superior to management without use of the medical imaging drug. A
patient management claim may speci~ that the medical imaging drug is to be used
in conjunction with other tests to affect a patient management decision.
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v.
GENERAL CONSIDERATIONS
JIWAGING DRUGS
FOR SAFETY ASSESSMENTS
OF MEDICAL
The safety evaluation of a medical imaging agent is generally similar to those of other drugs and
biologics. However, in many cases, the special characteristics of medical imaging drugs allow
nonclinical and clinical safety assessments to be relatively effkient. The following sections discuss
the special characteristics of a medical imaging drug that may lead to a more focused safety
evaluation. These characteristics include its dose or mass, route of administration, frequency of
use, and biological, physical, and effective half-lives.11
A.
Dose or Mass
Medical imaging drugs may be administered at low mass doses. For example, the mass of
a single dose of a diagnostic radiopharmaceutical may be relatively small because device
technologies can typically detect small amounts of a radionuclide. When a medical
imaging drug is administered at a mass dose that is at the low end of the dose-response
curve for adverse events, dose-related adverse events are less likely to occur.
B.
Route of Administration
}
Some medical imaging drugs are administered by routes that decrease the likelihood of
systemic adverse events. For example, medtcal imaging drugs that are administered “as
contrast media for radiographic examination of the gastrointestinal tract (e.g., barium
sulfate) may be administered orally, through an oral tube, or rectally. In patients with
normal gastrointestinal tracts, many of these products are not absorbed. According y,
systemic adverse events are less likely to occur in these patients. Therefore, after a
sponsor demonstrates that such a product is not absorbed systemically in the population
proposed for use, the product may be able to undergo a more efficient safety evaluation
that primarily assesses local organ system toxicity, toxicities that are predictable
(e.g., volume effects, aspiration), and effects after intraperitoneal exposure (e.g., after
gastrointestinal perforation). However, if the product will be used in patients with
gastrointestinal pathologies that increase absorption, more complete nonclinical and
clinical safety evacuations should be performed.
11See also the proposed rule on developing diagnostic radiopharmaeeuticals (63 FR 28301, May 22, 1998). When
a medical imaging drug does not possess any speeial characteristics, complete standard drug safety assessments should
be performed.
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c.
Frequency of Use
Many medicalimagingdrugs,
including
bothcontrast
drugproducts
and diagnostic
radi
opharmaceuticals,
areadministered
relativel
y infrequently
andin single doses.
Accordingly, adverse events that are related to long-term use or to dmg accumulation are
less likely to occur with these drugs than with drugs that are administered chronically.
Therefore, the nonclinical and clinical development programs for such products may
generally omit long-term, or traditional, repeat-dose safety studies. However, in clinical
settings where it is likely that the medical imaging drug will be administered repeatedly
(e.g., to monitor disease progression), repeat-dose studies should be performed to assess
safety and efficacy.
D.
Biological, Physical, and Effective Half-Lives’z
Diagnostic radiopharmaceuticals “mayuse radionuclides with short physical half-lives or
may be excreted rapidly. The biological, physical, and effective half-lives of diagnostic
radiopharmaceuticals are incorporated into radiation dosimetry evaluations that require an
understanding of the kinetics of the distribution and excretion of the radionuclide and its
mode of decay. Biological, physical and effective half lives should be taken into account
in planning appropriate safety and dosimetry evaluations of diagnostic
radiopharmaceuticals (see Sections VI. and XI. C).
VI.
NONCLINICAL
SAFETY ASSESSMENTS
The special
characteristics
ofmedicalimagingdrugsdescribed
abovemay allowfora more
efficient
nonclinical
safety
program.The nonclinical
development
strategy
fora drugshouldbe
basedon soundscientific
principles;
thedrug’s
uniquechemist~(including,
forexample,thoseof
itscomponents,metabolizes,
andimpurities);
andthedrug’s
intended
use.Sponsorsare
encouragedtoconsult
withtheAgency beforesubmission
ofanIND application
andduringdrug
developmentforrecommendations
and adviceabouttheoverall
nonclinical
developmentplanand
proposednonclinical
protocols.
Inpart,
thenumber andtypesofnonclinical
studies
thatshould
‘2 Biological ha~-l:~e is the time needed for a human or animal to remove, by biological elimination, half of the
amount of a substance that has been administered. Effective half-lt$e is the time neededfor a radionuclide in a human or
animal to decrease its activity by half as a combined result of biological elimination and radioactive decay. Physical
ha~-li~e k the time needed for half of the population of atoms of a ptiicular radioactive substance to disintegrate to
another nuclear form.
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be conducted depend on the phase of the drug’s development, what is known about the drug or
its drug class, its proposed use, and the indicated patient population.
In the discussion that follows, a distinction is made between biological products and drug
products. Existing specific guidance for biological products is referenced but not repeated here.
A.
Nonclinical
Safety Assessments for Biological Products
Many biological products raise relatively distinct nonclinical issues (e.g., immunogenicity
and species restrictions), To ensure consistency with section351 of the Public Health
Service Act the following documents should be reviewed for guidance on the preclinical
evaluation of biological medical imaging agents:
●
S6 Preclinical Safety Evacuation of Biotechnology-Derived
ICH, November 1997.
●
Points to Consider in the Manufacture and Testing of MonocIonal
Products for Human Use, Februaty 27, 1997.
B.
Nonclinical
Safety Assessments for Non-Biological
Pharmaceuticals,
Antibody
Products
The following sections describe ways in which nonclinical assessmen~ of safety may be
performed for non-biological contrast drug products and diagnostic radiophamaceuti cals.
1.
Contrast drug products
Because of the characteristics of contrast drug products and the way they are used,
nonclinical safety evaluations of such drug products may be made more efficient
with the following modifications:
●
Long-term, repeat-dose toxicity studies in animals usually can be
eliminated.
●
Long-term rodent carcinogenicity studies usually can be omitted.13
●
Reproductive toxicology studies can often be limited to an evaluation of
embryonic and fetal toxicities in rats and rabbits and to evaluations of
13Circumstances in which careinogenicity testing maybe recommended me summarized in the ICH guidance S 1A
The Need for Long-Term Rodent Careinogenicity Studies of Phannaeeuticals, March 1, 19%.
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reproductive organs in other short-term toxicity studies. 14 However, a
justification should be provided for any studies of reproductive toxicolo~
that are not performed and a formal request should be made to waive
them.ls
Additional safety considerations for contrast drug products may include the
following: their large mass dose and volume (especially for iodinated contrast
materials that are administered intravenously); osmolality effects; potential
transmetalation of complexes of gadolinium, manganese, or iron (generally MEU
drugs); potential effects of tissue or cellular accumulation on organ finction
(particularly if the drug is intended to image a diseased human organ system); and
the chemical, physiological, and physical effects of ultrasound microbubble drugs
(e.g., coalescence, aggregation, marination, and cavitation).
2.
Diagnostic Radiopharmaceutic~s
Because of the characteristics of diagnostic radiopharmaceuticals and the way they
are used, nonclinical safety evaluations of these drugs may be made more eficient
by the following modifications:
●
Long-term, repeat-dose toxicity studies in animals ty~ically may be
eliminated.
●
Long-term rodent carcinogenicity studies usually maybe omitted.
●
Reproductive
toxicology
studies
may generally
be waivedwhen adequate
scientific
justification
isprovided.lG
●
Waiversfor the performance of genotoxicity studies maybe granted when
scientifically justified.1’
‘4 See S.5.4Detection ojToxicity
lo Reproduction forMedicinalProducts
De[cction of Toxicity to Reproduction for Medicinal Pwducts:
(ICH),
September, 22, 1994, and S5B
(ICH), April 5,
Addendum on Toxici& to Male Fertility
1996.
15Waiver regulations for INDs are set forth at 21 CFR 312. 10; those for NDAs appear at 21 CFR 314.90.
16See ICH S5A and ICH S5B.
17See S24 SpeclJc Aspects of Regulatory Genotoxici~
Genotoxici~:
A Standard Bat[e~ for Genotoxici~
J: LtGUlDANC\121 ODFT WPD
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April 24, 1996, and S2B
November 21, 1997.
Tests for Pharmaceuticals (ICH),
Testing ofPhannaceuticals
18
(ICH),
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In reproductive toxicology and genotoxicity studies, components other than the
radionuclide should be considered separately because they may be genotoxins or
teratogens, causing effects that may exceed those of the radioactivity alone.
Special safe~ considerations for diagnostic radiophannaceuticals may include
verification of the mass dose of the radiolabeled moiety; assessment of the mass,
toxic potency, and receptor interactions for any unlabeled moiety; evaluation of all
components of the final formulation for toxicity potential (e.g., excipients,
reducing drugs, stabilizers, anti-oxidants, chelators, impurities, residual solvents);
and potential pharmacologic or physiologic effects due to molecules that bind with
receptors or enzymes.
“3.
Timing of Nonclinical Studies Submitted to an IND Application
Appropriate timing of nonclinical studies should facilitate the timely conduct of
clinical trials (including appropriate safety monitoring based upon findings in
nonclinical studies) and should reduce the unnecessa~ use of animals and other
resources 18 The recommended timing of nonclinical studies for medical imaging
drugs is summarized below.
a.
Completed Before Phase 1:
●
Safety pharmacology studies. Particular emphasis should be placed
on human organ systems in which the medical imaging drug
localizes andon organsystemsthattheproductisintended
to
visualize,
especially
iftheorgansystemhasimpairedfunction.
●
Toxicokinetic and pharmacokinetic studies (see ICH guidances).
●
Single-dose toxicity studies. Expanded acute single-dose toxicity
studies are strongly recommended.19 However, if short-term,
repeated-dose toxicity studies have been completed, nonexpanded,
single-dose toxicity studies may be sufllcient.
~
18 See M3 Nonclinical SaJety Studies for the Conduct o/Human Clinical Trials for Pharmaceuticals
November 25, 1997.
19 See Single Dose Acute Toxici~ Testing for Pharmaceutical,
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(ICH),
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●
For medical imaging drugs that are administered intravenously: (I)
local tolerance and irritancy studies, including evaluations of
misadministration or extravasation, (2) blood compatibility studies,
including evaluations of hemolytic effects, and (3) effects on
protein flocculation.
●
Radiation dosimetry, if applicable.
●
In vitro genotoxicity studies (see Section VI.B.2 for diagnostic
radiopharmaceuticals).
b.
Completed Before Phase 2:
●
Short-term, repeated-dose toxicity studies.
●
Immunotoxicity
●
In vivo genotoxicity studies (see Section VI.B.2 for diagnostic
radiopharmaceuti cals).
c.
Completed Before Phase 3:
studies.
Reproductive toxicity studies if needed (see Section VI.B.2 for diagnostic
radiopharmaceuti cals).
VII.
d.
Completed No Later Than the End of Phase 3:
●
Drug interaction studies.
●
In vivo or .in vitro studies that further investigate adverse effects
seen in previous nonclinical studies.
GENERAL CONSIDERATIONS
MEDICAL IMAGING DRUGS
J.4!GUIDANCU21ODFXUTD
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in ICH and FDA
guidance documents.zo The principles described in these documents also apply to the
development of medical imaging drugs. These general developmental considerations include, but
are not limited to, the demonstration of safety and efficacy; the procurement of adequate doseresponse, pharmacodynamic, and pharmacokinetic data to support licensing; and special issues
such as consideration of drug metabolizes, drug-drug interactions, and special populations.
Many
considerations
in the overall
clinical
development
of drugs
are summarized
These documents also discuss issues of trial design, conduct analysis, and reporting of individual
clinicaJ studies. The principles described in these documents apply to individual clinical studies of
medical imaging drugs. Relevant topics include, but are not limited to, study objectives, study
design, selection of subjects, dosage evaluation selection of control groups, numbers of subjects,
response variables (ie., endpoints or outcome measures), methods of minimizing or assessing bias
(e.g., by randomization and blinding), and issues in statistical analysis.
However, the development of medical imaging drugs for diagnostic “purposes may also raise issues
somewhat different from those raised during the development of therapeutic drugs. These issues
deserve special attention. The following sections discuss some issues that are particularly relevant
to medical imaging drug development. Considering them during the product development process
may increase the efficiency of the clinical development of these products.
-—.
A.
Phase 1 Studies2’
;
Phase 1 studies can include, but are not limited to, assessments of the safety of single,
increasing doses of a drug and evaluations of human pharmacokinetics. Depending upon
the drug and its potential toxicities, these trials may begin in healthy volunteers or in
patients. Screening for potential human toxicities may include serial evaluations of clinical
laboratory tests (e.g., hematology, clinical chemist~, urinalysis), other laboratory tests
(e.g., electrocardiograms), and adverse events. Pharmacokinetic evaluations should
address the absorption, distributio~ metabolism, and excretion of all components of the
drug formulation and any metabolizes. Sponsors are encouraged to consult with the
appropriate FDA review division on pharmacokinetic issues. Evaluation of a medical
imaging drug that targets a specific metabolic process or receptor should include
assessments of the drug’s potential effects on directly related functions.
20 See ICH efficacy guidances available on the Internet at http://www.fda.gov/eder/guidance./iidehtm,m,or
http:llwww.fda. govlcberfguidelinesliidex .htm.
21 See also guidance for industq, Content and Format of Investigational New Drug Applications @!Ds) for
Weli-Characterize~
Therapeutic, Biotechnolo~-Derived
Products, November
1995.
Phase-1 Studies of Drugs, Including
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For diagnostic
radiopharmaceuticals,
organ/tissue
distribution
dataovertimeshouldbe
collected
tooptimizesubsequent
imagingprotocols
andcalculate
radiation
dosimetty(see
Section
XI.C). Whenever possible,
pharrnacokinetics
andpharrnacodynamic
evaluations
shouldbe made notonlyforthediagnostic
radiopharmaceutical
itself,
butalsoforthe
radionuclide
and forthecarrier
orligand.
The effects
oflargedosesofthediagnostic
radiopharmaceutical
(including
thecarrier
orIigand
andothervialcontents)
shouldusuallY
be assessed.
Thiscanbe achieved,
forexample,
by administering
largedosesofthe
medicalimagingdrugwithlow specific
activhy,
by administering
thecontents
ofan entire
vialofthemedicalimagingdrug(assuming
thatthisapproximates
a worst-case
scenario
in
clinical
practice),
orboth.
B.
Phase 2 Studies
Goals of Phase 2 studies of medical imaging drugs can include, but.are not limited to,
refining the product’s clinically useful dose range or dosage regimen (e.g., bolus
administrate on or infusion), answering outstanding pharmacokinetic and pharmacodynamic
questions, providing preliminary evidence of efficacy, expanding the safety database,
optimizing techniques and timing of image acquisition, and evaluating other critical
concepts or questions about the drug.
Dose considerations include the following: adjustment of the character or amount of
active and inactive ingredients, amount of radioactivity, amount of nonradioactive ligand
or carrier, specific activity, and use of different radionuclides. Methods used to determine
the comparability, superiority, or inferiority of different doses or regimens should be
discussed with the Agency. To the extent possible, the formulation that will be used for
marketing should be used in Phase 2 studies. When a different formulation is used,
bioequivalence and other bridging studies may help document the relevance of data
collected with the original formulation.
Phase 2 trials should be designed to define the appropriate patient populations for Phase 3
trials. To gather preliminary evidence of efllcacy, however, both subjects with known
disease (or patients with known structural or functional abnormalities) and subjects known
to be normal for these conditions maybe included in clinical studies. Methods, endpoints,
and items on the case report form (CRF) that will be used in critical Phase 3 trials should
be tested and refined,
c.
Phase 3 Studies
The goals of Phase 3 eflicacy studies typically are to confirm the principal hypotheses
developed in earlier studies, demonstrate the efficacy and continued safety of the drug, and
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validate instructions for use and for imaging in the population for which the drug is
intended. The design of Phase 3 studies (e.g., dosage, imaging techniques and times,
patient population, and endpoints) should be based on the findings in Phase 2 trials. The
to-be-marketed formulation should be used, or else bridging studies should be performed.
When multiple efllcacy studies are performed, the studies maybe of different designs.22
To increase the extent to which the results can be generalized, the studies should be
independent of one another and should use different investigators, clinical centers, and
readers that perform the blinded image evaluations (see Section VUI.B).
VIII.
SPECIAL CONSIDERATIONS
EFFICACY
.
IN THE CLINICAL EVALUATION
OF
The following sections describ”e special considerations “forthe eviduation of efficacy in clinical
trials for medical imaging drugs.
A.
Selection of Subjects
The subjects included in critical Phase 3 clinical studies should be representative of the
population in which the medical imaging drug is intended to be used.
1.
For claims (a) structure delineation, or (b)jimctional, physiological, or
biochemical assessment, adequate numbers of subjects should be enrolled. The
fidl range of severity of the structural or functional abnormality (e.g., from mild to
severe disease, from early to advanced disease) should be appropriately
represented. This is to provide adequate estimates of the validity and reliability of
the medical imaging drug over the fill range of conditions for which it is intended
to be used. The spectrum of other conditions, processes, or diseases
(e.g., inflammation, neopIasm, infection, trauma) that may confound interpretation
of the results for the disease or condition of interest also should be appropriately
represented.
Subject selection may be based on representative diseases that involve similar
alterations in structure, function, physiolo~, or biochemistry if it appears that the
results may be extrapolated to other unstudied disease states based on a known
common process. Appropriate models should be selected on a case-by-case basis.
22 See guidance for industty, Providing Clinical Evidence of Effectiveness for Human Drug and Biological
Products,
May 1998.
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Data to justifi inclusion of a particular disease should be thoroughly documented,
as should the data to support why the resu!ts obtained from the models can be
extrapolated to other diseases,
Adequate numbers of normal or unaffected subjects should be enrolled dufing drug
development in appropriately designed trials to establish the performance for the
imaging drug in this population.
2.
For claims (a] disease or pathology aktection or assessment, or (b) diagnostic or
therapeutic patient management, adequate numbers of subjects should be enrolled
to demonstrate the validity and reliability of the information provided by the
medical imaging drug. Because the validity and reliability of the medical imaging
drug may vary depending on the characteristics of the patients and the clinical
setting, the enrolled patients should be evaluated in defined clinical settings
reflecting the proposed indications. For example,”if a dtig is to-be used as a tool
to aid in the diagnosis of patients suspected of having Alzheimer’s dtsease, studies
should not be limited to patients in which Alzheimer’s disease is already known to
be present or absent.
The pretest odds and pretest probabilities of disease should be estimated for all
subjects to aid subsequent clinical use of the medical imaging drug. Whenever
possible, these odds and probabilities should be derived from ~respecified criteria
of disease (e.g., history, physical findings, results of other diagnostic evaluations)
according to prespecified algorithms.
B.
Image Evaluations
Because of the many ways that imaging data maybe acquired, reconstructed, processed,
stored, and displayed and because of the diversity of imaging modalities, the following
sections use the term images in a general way. Images include, but are not limited to,
films, likenesses or other renderings of the body, body parts, organ systems, body
fi,mctions, or tissues. Because of this heterogeneity, the general recommendations
delineated below for image evaluation in clinical trials may need to be customized to be
applied to a specific medical imaging drug or imaging modality. For example, an image of
the heart obtained with a diagnostic radiopharmaceutical or an ultrasound contrast agent
may in some cases refer to a set of images acquired from dtfferent views of the heart (e.g.,
short-axis and long-axis views). Similarly, an image obtained with an MRI contrast agent
may in some cases refer to a set of images acquired with different pulse sequences and
interpulse delay times.
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The specific ways that images will be acquired, reconstmcted, processed, stored,
displayed, and evaluated in clinical studies should be documented clearly in the study
protocol. Special emphasis should be placed on the particulars of the blinded image
evaluation. Study reports should reiterate much of this information and should highlight
any differences from the protocol in the conduct of the study, including any changes in the
execution of the b!inded image evaluations.
1.
Characteristics
of the Readers
In studies that are intended to demonstrate efficacy of a medical imaging drug,
evaluations of images should be performed by readers that are both independent
and blinded (as defined below). Independent blinded image evaluations may not
be entirely representative of the conditions under which the test drug will
ultimate] y be used clinically, but they. compel-the. readers to rely on obj ective.image.
features in their assessments of the effects of the drug. These independent blinded
image evaluations are intended to limit possible biases that could be introduced
into the image evaluation by non-independent or unblinded readers.
Independent readers are those who have not otherwise participated in the Phase 3
studies (e.g., as investigators) and who are not otherwise affiliated with the
sponsor or with institutions at which the studies were condupted.
Blinded readers are those who are unaware (1) of treatment identity (particularly
in studies where images have been obtained with more than one treatment) and (2)
of patient-specific clinical information or the study protocol, That is, in clinical
studies of medical imaging drugs, blinded readers should be blinded in several
ways, including ways that may not be encompassed by the usual definitions of the
term in therapeutic clinical trials. First, blinded readers should be unaware of the
identity of the treatment used to obtain a given image. This is the common
meaning of blindtng in therapeutic clinical trial s.” For example, in a comparative
study of two or more medical imaging drugs (or two or more doses or
administration regimens), the blinded readers should not know about the identity
of the drug (or dose or method of administration) used to obtain the particular
image. For contrast agents, this a!so may include lack of knowledge about which
images were obtained prior to drug administration and which were obtained after
drug administration, although sometimes t.hk maybe apparent upon viewing the
images.
z See E8 General Considerations for Clinical Trials (ICI-I), December
Clinical Trials (ICH),
September 16, 1998.
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25
17, 1997, and E9 Statistical Principles for
..
.
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Second, blinded readers also should be unaware or have Iirnited awareness of
patient-specific clinical information or of the s~dy proto~l. Anatomic orientation
to the images should be minimal. This meaning of blinding differs from the
common way the term is used in therapeutic clinical trials. However, blinding in
this sense is a critical aspect of clinical trials of medical imaging agents. For
example, blinded readers should general] y not have knowledge of the patients’ final
diagnoses and may have limited or no knowledge of the results of other diagnostic
tests that were performed on the patients, including the results of other imaging
studies. In some cases, blinded readers should not be familiar with the inclusion
and exclusion criteria for patient selection that were specified in the protocol.
At least two independent, blinded readers (and preferably three or more) are
recommended for each study that is intended to demonstrate efficacy. This
provides a better basis for.subsequent generalization of the. findings in the studies.
All images obtained in the study (i.e., not just those determined to be evaluable)
should be read by the readers, including images of test patients, control patients,
and normal subjects. Each reader should read the images independently of the
other blinded readers and independently of any on-site readings performed by the
investigators. Consistency among readers should be measured quantitatively (e.g.,
with the kappa statistic). Consensus reads may be done after the readings are
completed, but should not be performed for primary efilcac~ evaluation of the test
drug. Readers may be trained in scoring procedures using sample images from
Phase 1 and Phase 2 studies. Meanings of all endpoints should be clearly
understood for consistency.
Sequential unbinding (i.e., providing more and more clinical information to the
readers) might be used to provide incremental information under a variety of
conditions that may occur in routine clinical practice (e.g., when no clinical
information is available, when limited clinical information is available, and when a
substantial amount of information is available). This may ’be used to determine
when or how the test drug should be used in a diagnostic algorithm.
2.
Presentation
of the Images to the Readers
Images may be presented to the readers in several ways. As described below, this
image evaluation should usually consist of randomized readings that are separate,
combined, or both. Randomization of images refers to merging the images
obtained in the study (to the finest degree that is practical) and then presenting
images in this merged set to the readers in a random sequence. For example, when
the efficacy of several diagnostic radiopharmaceuticals are being compared (e.g., a
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comparison of a test drug to an established drug), the readers should generally
evaluate individual images from the merged set of images in a random sequence.:
a.
Separate Image Evaluations
Separate image evaluations should generally be performed by independen~
blinded readers in the eflicacy evaluation of a medical imaging drug. Such
image evaluations may not be entirely representative of the conditions
under which the test drug will ultimately be used clinically. However, these
conditions compel the readers to evaluate each image on its own merits,
without reference to any other image, and help to limit possible biases that
could be introduced into the image evaluation by a nonrandomized or
combined image evaluation.
Separating images refers to segregating the images (to the fullest degree
that is practical) from other images that were obtained in the same patient
at different times or under different conditions. These segregated images
can then be presented to the readers in random sequence so that images are
not viewed simultaneous y. For example, when both unenhanced and
enhanced images are obtained as part of a study of a contrast drug product,
the images obtained before administration of the con~ast drug product
(i.e., the unenhanced images) should generally be mixed with the images
obtained after administration of the drug (i.e., the enhanced images).
Individual images in this intermixed set should then be read in random
sequence so that the unenhanced and enhanced images are not viewed
simultaneously. Alternatively, in some cases, the individual unenhanced
images may be evaluated in a random order, followed by an evaluation of
the individual enhanced images in a random order. In settings where the
unenhanced image will not be used in clinical practice, images should be
evaluated in a separate fashion, to show, for example, that the information
from the enhanced image, alone, is clinically and statistically superior to the
information from the unenhanced image, alone.
b.
Combined Readings
Combined readings by independent, blinded readers may also be useful in
evaluating the efficacy of a medical imaging drug because this type of
evaluation often resembles the conditions under which the drug will be
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used clinically .24 Combining the images refers to simultaneous, or nearly
simultaneous presentation to the reader of two or more images that were
obtained at different times or under different conditions. Sets of combined
images can then be presented to the readers in random sequence. For
example, in studies of contrast drug products, both unenhanced and
enhanced images may be obtained. The images, which were obtained at
different times and under different conditions, may be viewed
simultaneously by the reader. Similarly, for a diagnostic
radiopharmaceutical, serial images may be obtained after drug
administration to determine the optimal time for imaging. These images
may be viewed in a combined fmhion.
However, when this type of reading is performed, it is often advisable that
an additional separate image evaluati~n be completed on at least one of the.
members of the combination. In this way, differences in the evaluations of
the combined reading with those of the separate reading maybe assessed.
The combined images and the separate image may then be evaluated
statistically with a paired comparison, For’contrast drug products, these
differences should demonstrate that the information from the combined
images is clinically and statistically superior to information obtained from
the unenhanced image alone. For example, if a combined image evaluation
is performed in a two-dimensional study of blood vessels with a
microbubble ultrasound contrast agent (e.g., evaluation of the unenhanced
and enhanced images side by side or in close temporal proximity), another
evaluation of the separate, unenhanced image of the blood vessel
(i.e., images obtained with the device alone) may allow the microbubble
effects on the image to be assessed.
These combined evaluations should be designed to minimize the likelihood
that the readers will know (or be able to recall) their assessment of the
separate image assessment (or vice versa). Thus, different pages in the
CRF should be used for the combined and separate evaluations, and the
combined and separate image evaluations should usually be performed at
different times without reference to prior results.
When differences between the combined and separate images are to be
assessed, the combined CRF and separate CRF should contain items or
24If a randomized, combined reading is the only evaluation that is done, labeling of the medical imaging drug (e.g.,
the INSTRUCTIONS FOR USE) should speci$ that combined evaluations should be performed in clinical practice.
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thatareidentical
inordertoallowdifferences
tobe calculated.
For example,on theseparate
CRF fora contrast
drugproductseekinga
structural
delineation
claim,
thereaders
may be askedtoratetheclarity
of
borderdelineation
ofa structure
on an ordinal
scale(e.g.,
O,1,2,3,4).
The combinedCRF shouldaskthesame question
and thedifference
in
gradescouldbe calculated.
The purposeofthisapproachistominimize
potential
biases
thatmay arise
iftheCRF contains
onlyquestions
oritems
thataskforrelative
judgmentstobe made. Ifdesired,
however,additional
comparative
questions
and itemsmay be addedtothecombinedpagesin
theCRF. For example,thereaders
maybe askedtoratetherelative
clarity
ofborderdelineation
inthesecondimagecomparedtothefirst
(e.g.,
better,
same,worse).
questions
c.
Truth Standards (Gold Standard$
A truth standard provides an independent way of evaluating the same variable being
assessed by the investigational drug. A truth standard is known or believed to give the
true state of a patient or true value of a measurement. Truth standards are used to
demonstrate that the results obtained with the medical imaging drug are valid and reliable.
1.
To minimize potential bias, determination of the tme state of the subjects
(e.g., diseased or nondiseased) with a truth standard should be petiormed
without knowledge of the test results obtained with the medical imaging
drug or test agent.
2.
For contrast drug products, the results of the unenhanced images should
generally not be incorporated in the truth standard. This is to decrease
possible spurious correlations that may result from an ima~ng modality
agreeing with itse[$ Stated differently, the truth standard should provide
an assessment of disease status that is independent of the imaging modality
for which the medical imaging drug is intended. For example, for a CT
contrast agent intended to visualize abdominal masses, unenhanced
abdominal CT images generally should not be included in the truth
standard. However, components of the truth standard might include results
from other imaging modalities (e.g., ~
ultrasonography).
From a practical perspective, diagnostic standards are derived from procedures
that are considered more definitive in approximating the truth than the test drug.
For example, histopathology or long-term clinical outcomes maybe acceptable
diagnostic standards for determining whether amass is malignant. Diagnostic
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standards may not be error free, but for purposes of the clinical trial, they are
regarded as definitive. The choice of the standard should be discussed with the
Agency during design of the clinical trials to ensure that it is appropriate.
As noted in the proposed rule for diagnostic radiopharmaceuticals, a valid
assessment of actual clinical status maybe provided by a diagnostic standard or
standards of demonstrated validity. In the absence of such diagnostic standards,
the actual clinical status may in some cases be established in another manner,
e.g., through patient follow-up. However, when a suitable diagnostic standard is
unavailable or cannot be assessed practically, consideration should be given to
changing the focus of the study to evaluate the effects of the product on clinical
outcomes (see Section IV.D.4).
Truth standards may be other diagnostic tesk. (e.g., tissue biopsy to evaluafe,
whether a mass is malignant) or appropriate combinations of other clinical data and
diagnostic tests. For example, a definitive determination about whether a patient
enrolled in a clinical trial experienced an acute myocardial infarction could be
obtained by evaluating the combination of patient history (e.g., nature and location
of pain), 12-lead electrocardiogram (e.g., Q waves or not), and serum levels of
cardiac enzymes (e.g., creatine phosphokinase) according to a prespecified
algorithm. Using these data, a panel of experts that is blind~ to the medical
imaging results yielded by the test agent could then make the definitive
determination about the presence or absence of disease (i.e., an acute myocardial
infarction).
D.
Controls
As in other adequate and well-controlled clinical studies, clinical trials of medical imaging
drugs may be controlled for different purposes and in a number of different ways. Before
selecting the controls, discussions with the Agency are strongly recommended.
1.
Comparison to Establish Performance in Relationship to a Drug or
Modality Approved for a Similar Indication
In the event that the test drug is being developed as an advance over an approved
drug or other diagnostic modality, a direct, concurrent comparison to the approved
comparator should be performed. The comparison should include an evaluation of
both the safety and the efficacy data for the comparator and the test drug.
Information from both test and control images should be compared not only to one
another but also to an independent truth standard. ‘lMs will facilitate an
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assessment of possible differences between the test dmg and the comparator and
will complete the assessment of diagnostic validity (e.g., sensitivity, specificity,
positive and negative predictive values, accuracy, and likelihood ratios) between
the two. Note that two medical imaging drugs could have similar values for
sensitivity and specificity in the same set of patients, yet have poor agreement rates
with each other. Similarly, two medical imaging dtugs could have good agreement
rates, yet both have poor sensitivity and specificity values.
When a medical imaging drug is being developed for an indication for which other
dregs or diagnostic modalities have been approved, a direcf concurrent
comparison to the approved drug or diagnostic modality is encouraged. However,
prior approval of a drug for use in a particular indication does not necessarily mean
that the results of a test with that drug may be used as a truth standard. Note that
For example, if a medical imaging dmg has been approved on the basis of
sufllcient concordance of findings with truth as determined by histopathology,
assessment of the new drug should also usually include determination of truth by
histopathology.
2.
Placebos
.--,
Whether the use of a placebo is appropriate in the evaluation~of a medical imaging
drug depends upon the specific drug, proposed indication, and imaging modality.
In some cases, the use of placebos may help minimize potential bias in the conduct
of the study, and may facilitate unambiguous interpretation of efilcacy or safety
data. However, in some diagnostic studies (such as ultrasonography), products
that are generally considered as placebos (e.g., water, saline, or the test drug
vehicle) can have some diagnostic effects. These should be used as controls to
demonstrate that the medical imaging drug has an effect above and beyond that of
the vehicle.
E.
.. . . ..—.
Endpoints
In the evaluation of images, objective, quantifiable endpoints should be used whenever
possible (e.g., signal-to-noise ratios, delineation, opacification; size of lesion, number of
lesions, density of lesions). These endpoints maybe complemented by other endpoints that
ask the blinded readers to interpret the meaning of the objective image features (e.g., to
make an assessment about whether a mass is malignant or benign). For example, data on a
lesion’s features may be complemented with additional assessments that demonstrate the
impact of the drug on the physician’s diagnosis.
J: UGUIDAA’CI121
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31
—
.=—
Draft - Not for Implementation
Imaging
CRFS
features
of the images
interpretations
information
gather
should
be designed
as well
of findings
derived
information
from
without
to capture
as the location
should
be supported
the images.
introducing
items
imaging
endpoints,
of, and interpretation
by objective
on the CRF
technical
Of, findings.
quantitative
should
a bias that indicates
including
or qualitative
be carefully
the answer
Subjective
constructed
to
that is being
sought.
The proposed labeled indication should be clearly derived from specific items in the CRF
and from endpoints and hypotheses that have been prospectively stated in the protocol.
lx.
ISSUES IN INL4GE ACQUISITION
A.
Image Acquisition
AND HANDLING
.
In studies that compare the effects of a test drug with another drug or imaging modality,
images taken before study enrollment with the comparator drug or modality should not be
used to determine whether a patient is enrolled in the study. These images also should not
be part of the database used to determine test drug performance. Such baseline enrollment
images have inherent selection bias because they are unblinded and based on referral and
management preferences. All images used to determine the efllcacy. of the test dmg and
the comparator drug (or imaging modality) should be taken after stu~y enrollment and
within a time frame when the disease process is expected to be the same.
B.
Image Handling Procedures
Ideally, all images should be evaluated by the blinded readers. In some cases where large
numbers of images are obtained or where image tapes are obtained (e.g., cardiac
echocardiography), sponsors have used image selection procedures. This is strongly
discouraged because the selection of images can introduce the bias of the selector. In
cases where preelection is thought to be needed, the sponsor is encouraged to clearly
identifi and discuss the selection procedures with the appropriate Agency division before
their implementation.
x.
STUDY ANALYSIS
Many imaging agent trials are designed to provide dichotomous or ordered categorical outcomes,
and it is important that appropriate assumptions and statistical methods be applied in their
anal ysis. Statistical tests for proportions and rates are commonly used for dichotomous
J:l!GUIDANC1l210DFi7 WT’D
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and methods based on ranks are often applied to ordinal
data.Additional
analyses
basedon odds ratios can provide further insight. Study outcomes can often be stratified in a
natural waY, such as by center or other subgroup category, and the Mantel-Haensze125 procedures
provide effective ways to examine both binomial and ordinal data. Exact methods of analysis,
based on conditional inference, should be employed when necessa~. The use of model-based
methods should also be encouraged. These techniques include logistic regression models for
binomial data and proportional odds models for ordinal data. Log-linear models can be used to
evaluate nominal outcome variables.
outcomes,
Dichotomous outcomes in studies that compare images obtained after the test drug to images
obtained before the test drug are often analyzed as matched pairs, where differences in treatment
effects can be assessed by using methods for correlated binomial outcomes. These studies,
however, may be problematic because they often do not employ blinding and randomization. For
active- and placebo-control studies, including dose-response studies, crossover designs can often.
be used to gain efficiency. It is important that subj ects are randomized to order of treatment. If
subjects are not randomized to order of treatment, a crossover analysis applied to the images may
still be informative. Study results from a crossover trial should always be analyzed with methods
specifically designed for such trials.
Diagnostic validity can be assessed in a number of ways. With pre- and post-images, for example,
each could be compared to the truth standard, and the sensitivity and specificity of the pre-image
compared to that of the post-image. Two different active agents can be compared similarly.
Diagnostic comparisons can also be made when there are more than two outcomes to the
diagnostic test results. Common methods used to test for differences in diagnosis include the
McNemar test and the Stuart Maxwell test.2b In addition, confidence intervals for sensitivity,
specificity, and other measures should be provided in the analyses. Receiver operating
characteristic (ROC) analysis is another approach that can be used to evaluate diagnostic
,
accuracy.
XI.
CLINICAL
. .. . . .
‘-
SAFETY ASSESSMENTS27
-25
For more on this topic, see Fleiss, Joseph, L., Statistical MethodsJorRa[es and Proportions, 2nd cd., 1981, John
Wiley and Sons, New Yorlc;and WoolsOn,Robeti, StatisticalMethoa!s for the Ana/ysis of Biomedical Data, 1987, John
Wiley and Sons, New York.
26Ibid.
27 See also guidance for industry and reviewem, Content and Format of the Adverse Reactions Section of Labeling
March18,1998;
and the final rule, “Expedited Safety Reporting
Requirements for Human Dmg and Biological Products,” October, 7,1997 (62 FR 52237).
for Human Prescription Drugs, and Biologics,
-=
J:\!GU1DANC\1210DFT WPD
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Clinical safety assessments of both contrast drug products and diagnostic radiopharmaceuticals
may be tailored based on their characteristics (e.g., dose, route of administration, frequency of
use, and biological half-life), on the results of nonclinical safety assessments, and on the results of
clinical pharmacokineti c+%iopharmaceutics studies.
This guidance defines two categories of medical imaging drugs: Group 1 and Group 2. The
extent of clinical safety monitoring and evaluation differs for these two categories. Medical
imaging drugs classified as Group 1 medical imaging cikgs may be able to undergo a more
efilcient clinical safety evaluation during development. Group 2 medical imaging dhgs should
undergo a complete clinical safety evaluation. Both Group 1 and 2 diagnostic
radiopharmaceuticals should undergo complete radiation dosimety assessments.28 Preliminary
categorization of medical imaging drugs into one of these two groups may be based on findings in
nonclinical studies.
A.
Group 1 Medical Imaging Drugs
Group 1 medical imaging drugs have been shown to be biologically inactive in nonclinical
studies and to have undetectable levels of biological activity in human studies when
administered at dosages that are similar to those intended for clinical use. Group 1
diagnostic radiopharrnaceuti cals are a subset of this group.n~ 30
To be included in Group 1, a medical imaging drug should have the following:
1.
An adequately documented margin of safety between nonclinical and clinical use.
The no-obsewable-effect level (NOEL),31 as appropriately adjusted in suitable
28See Section XI.C.
29This classification conforms with the pro~”sed rule for diagnostic radiopharrnaceuticals, which states that
diagnostic radiopharmaceuticals may be categorized based on defined charackristics related to their risk.
30 Group 1 diagnostic radiopharmaceuticals may include radionuclides, ligands, and carriers that are known to be
biologically inactive. This group may include radionucIides, ligands, and carriemused at radiation do=s or mass
dosages that are similar to, or less than, those used previously. This group also may include radionuclides, ligands, and
carriers that have been documented not to produce adverse reactions.
31 In this guidance, the no-observable-effect
level is defined as the dosage level of a medical imaging drug at which
no biological effects are obscmed. These biological effects include, but are not liiited to, those that are biochemical,
physiologic, pharmacologic, or structural. These biological effects do not nexssarily have to be adverse or (oxic.
Adverse and toxic effects should be evaluated in the most susceptible species with the most sensitive assay. For
Pvses
of ~ls ~idance, localization of a m~ical imaging drug in a target organ or targettissue(e.g.,by binding to a
J:\!GUlDANC\1210D.W. WPD
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,
n.
Draft - Not for Ikvplementation
animal species, should be at least one thousand times greater than the maximal
dose and dosage to be used in human studies. To establish this margin of safety
the NOEL should be determined in each of the following nonclinical studies:
::
c.
expanded-acute, single-dose toxicity studies
short-term, repeated-dose toxicity studies
safety pharmacology studies
Appropriate~ a@sted means that dosage comparisons between animals and
humans are suitably modified for factors such as body size (e.g., body surface
area) and otherwise adjusted for possible pharmacokinetic and toxicokinetic
differences between animals and humans (e.g., differences in absorption for
. products that are administered orally).
2,
Completed and fully documented Phase 1 clinical trial experience in appropriately
designed trials that are consistent with the animal data. The medical imaging drug
should not demonstrate any biological activity in human trials. The human
pharmacokinetic trials also should provide data that allow adequate comparisons
of exposure to be made between humans and the animal species used in the
nonclinical studies.
Alternatively, to be included in Group 1, a medical imaging drug should have a history of
sufficient clinical use orofprevious
clinical
trial experience that adequately documents the
following:
a.
No clinical] y detectable allergic, immunologic, biochemical, physiologic, or
pharmacologic responses at clinical doses or dosages; and
b.
No known dose-related toxicological risk or adverse event profile at
clinical dosesordosages.
For Group 1 medical imaging drugs, reduced safety monitoring in Phases 2 and 3 of drug
development is justified. However, if toxicity is noted during clinical development
appropriate clinical safety monitoring should be performed.
B.
Group 2 Medical Imaging Drugs
tissue reeeptor) is by itself not considered to be a biological effec~ unless it produces demonstrable perturbations.
J: I!GUIDANCU21ODIWWPD
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Group 2 medical imaging drugs have been shown to be biologically active in animal
studies or in human studies when administered at dosages that are similar to those
intended for clinical use. Group 2 diagnostic radiopharmaceuticals are a subset of this
group .32
Group 2 medical imaging drugs include the following:
1.
Any medical imaging drug that does not meet the criteria for a Group 1 medical
imaging dtug;
2.
All biological medical imaging drugs; 33’34
3.
Any diagnostic radiopharmaceutical
or beta decay.
containing a radionuclide that undergoes alpha
For Group 2 medical imaging drugs, standard safety evaluations and monitoring should be
performed in clinical trials.
c.
Radiation Safety Assessment for All Diagnostic Radiopharmaceuticals3S
Radiation safety assessments should be documented for both Group ~1and Group 2
diagnostic radiopharmaceuticals.
The radiation safety assessment should establish the
radiation dose of a diagnostic radiopharmaceutical by radiation dosimetry evaluations in
humans and appropriate animal models. Such an evaluation should consider dosimetry to
the total body, to specific organs or tissues, and, as appropriate, to target organs or target
tissues. The radiation doses of diagnostic radiopharmaceuticals should be kept as low as
reasonably achievable (ALARA). The maximum tolerated radiation dose need not be
32 Group 2 diagnostic radiopharmaceuticals may also include radionuclides and carriers that are known to be
biologically active. This group includes radionuclides and carriers used at radiation doses or mass dosages that are
higher than those used previously, including radionuclides and carriers that have been documented to produce adverse
reactions.
33Biological medical imaging products, such as radiolabekd monoclinal antibodies or monoclinal antibody
fragments, are classified within Group 2 because of their potential to elicit immunologic responses.
34 See also the final rule, ‘Adverse Experience Reporting Requirements for Licensed Biological Products,n October
27,1994 (59 FR 54042).
35This section is based largely on the radiation dosimetry section of Points to Consider in ~heManufacture and
Antibo& Products for Human Use. February 27, 1997.
Testing ofMonoclonal
—
—
J: VGUIDANC\121ODIT.
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established. For diagnostic radiopharmaceuti cals, estimates of the organ dosimetry should
be performed in animals prior to the first Phase 1 study. Phase 1 studies of diagnostic
radiopharmaceuticals should include studies that will obtain sufficient data for dosimetry
calculations (21 CFR312.23(a)(10)(ii)).
1.
General Considerations
An IND sponsor should submit sufficient data from animal or human studies to
allow a reasonable calculation of radiation absorbed dose to the whole body and to
critical organs upon administration to a human subject (21 CFR312.23(a)(10)(ii)).
The following organs and tissues should be included in dosimetry estimates: (1) all
target organs/tissues; (2) bone; (3) bone marrow, (4) liveq (5) spleen; (6) adrenal
glands; (7) kidney; (8) lung (9) heart; (10) urinary bladdeq (11) gall bladder;
(12) thyroid; (13) brain; (14) gonads; (15) gastrointestinal tract; and (16) adjacent
organs of interest.
The amount of radiation delivered by internal administration of diagnostic
radiopharmaceuticals should be calculated by internal radiation dosimetry. The
absorbed fraction method of radiation dosimetry has been described by the Medical
Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine
and the International Commission on Radiological Protection (ICRP) (see also 21
CFR 361.1 (be)).
The methodology used to assess radiation safety should be specified. The
mathematical equations used to”derive the radiation doses and the absorbed dose
estimates should be provided along with a fill description of assumptions that were
made. Sample calculations and all pertinent assumptions should be listed and
submitted.
Safety hazards for patients and health care workers during and after administration
of the radiolabeled antibody should be identified, evaluated, and managed
appropriate y.
2.
Calculation of Radiation Dose to the Target Organ(s) or Tissue(s)
The following items should be determined based on the average patient:
a.
The amount
organ(s).
of radioactivity
J:1(GU1DANC\121ODFZUPD
10/2/98
37
that accumulates
in the target tissue(s)
or
.
-
Draft - Not for Implementation
b.
The amount of radioactivity that accumulates in tissues adjacent to the
target tissue(s) or organ(s).
c.
The residence time of the diagnostic radiopharmaceutical
tissue(s) or organ(s) and in adjacent regions.
d.
The radiation dose from the radionuclide, including the free radionuclide
and any daughter products generated by decay of the radionuclide.
e.
The total radiation dose from bound, free, and daughter radlonuclides
associated with the diagnostic radiopharmaceutical, based upon immediate
administration following preparation and upon delayed administration at
the end of the allowed shelf life.
3.
Maximum Absorbed Radiation Dose
in the target
.
The amount of radioactive material administered to human subjects should be the
smallest radiation dose that is practical to perform the procedure without
jeopardizing the benefits obtained.
—
a.
-———.
7,7-;ANCV21
The amount of radiation delivered by the internal administration of
diagnostic radiopharmaceuticals should be calculated by internal radiation
dosimetry using both the MIRD and ICRP methods. When making the
radiation dosimetty safety assessment the higher calculation of the two
should be used.
b.
Because of known or expected toxicities associated with radiation
exposure, dosimetry estimates should be obtained as described above.
c.
Calculations should anticipate possible changes in dosimetry that might
occur in the presence of diseases in organs that are critical in metabolism or
excretion of the diagnostic radiopharmaceuti cal. For example, renal
dysfunction may cause a larger fraction of the administered dose to be
cleared by the hepatobiliary system (or vice versa).
d.
Possible changes in dosimetry resulting from patient-to-patient variations in
antigen or receptor mass should be considered in dosimet~ calculations.
For example, a large tumor mass may result in a larger than expected
radiation dose to a target organ from a diagnostic radiopharmaceuti cal that
has specificity for a tumor antigen.
ODFZWPD
38
Draft - Not for Implementation
e.
The mathematical equations used to derive the estimates of the radiation
dose and the absorbed dose should be provided along with a fill
description of assumptions that were made. Sample calculations and all
pertinent assumptions should be listed.
f.
Calculations of dose estimates should be performed assuming freshly
labeled material (to account for the maximum amount of radioactivity) as
well as the maximum shelf life of the diagnostic radtopharmaceutical (to
allow for the upper limit of radioactive decay contaminants). These
calculations should (1) include the highest amount of radioactivity to be
administered; (2) include the radiation exposure contributed by other
diagnostic procedures such as roentgenograms or nuclear medicine scans
that are part of the study; (3) be expressed as gray (Gy) per megabecquerel
(MBq) or per millicurie (mCi) of radionuclide; and (4) be presented in a
tabular format and include doses of individual absorbed radiation for the
target tissues or organs and the organs listed above in section XI.C. 1.
.
.-.
J: LlGUIDANC\1210DFT UTD
10127’98
39
Draft - Not for Implemei2tation
GLOSSARY
Note: Subjects in trials of medical imaging agents may often be classified into one
of four groups depending on (1) whether disease is present (often determined with
a truth standard or gold standizrd) and (2) the results of the diagnostic test of
interest (positive or negative). The following table identifies the variables that will
be used in the definitions.
Test Result:
Disease:
Present (+)
Positive (+)
a
true positive
Negative (-)
c
false negative
nl = a+c
total
with disease
Absent (-)
.,
ml=a+b
b
total
false positive
d
with
positive
test
m2 = c+d
true negative
total with
n2 = b+d
negative
test
N = a-t-b+c+d
total without disease
;
total in study
Accuracy: A measure of how faithfully the information obtained using a medicrd imaging agent
reflects reality or truth as measured by a truth standard or gold standizrd. Accuracy is the
proportion of cases, considering both positive and negative test results, for which the test results
are correct (i.e., concordant with the truth standard or gold standhr~. Accuracy = (a+d)/N.
Likelihood ratio: A measure that can be inte~reted either as (a) the relative oukk of a diagnosis,
such as being diseased or nondiseased, for a given test result or (b) the relative probabilities of a
given test result in subjects with and without the disease. This latter interpretation is analogous to
a relative risk or risk ratio.
1.
For tests with dichotomous results (e.g., positive or negative test results), the likelihood
ratio of a positive test result may be expressed as LR(+), and the likelihood of a negative
test result may be expressed as LR(-). See equations below.
2.
For tests with several levels of results (e.g., tests with ordinal results), the likelihood ratio
may be used to compare the proportions of subj ects with and without the disease at each
level of the test result.
~——1
3:i.~Gl.J1DAtJC1121
ODtT. WPD
10[.?/98
40
Draft - Not for Implementation
a
a
—
sensitivip
~~(+)=z=
—b
n2
. TruePositiveRate
1 -specljicity
FalsePositiveRate
~
PostTestO&(+)
=—=
PreTestO&
n]
—
n2
c
—
nl
LR(-)=7=
—
n2
LR(+):
c
1 -sensitivip.
FalseNegativeRate
specl~ci~
TmeNegativeRate
~ PostTestO&(-)
=—=
nl
PreTestOdds
—
n2
Interpreted as re[ative oakk: LR(+) is the post-test odds of the disease
(among those with a positive test result) compared to the pretest odds of
the disease.
Interpreted as reiative probabilities: LR(+) is the probability of a positive
test result in subjects with the disease compared to the probability of a
positive test result in subjects without the disease.
~
LR(-):
Interpreted as relative oahk: LR(-) is the post-test
(among
those
with
a negative
test result)
odds
compared
of the disease
to the pretest
odds
of
the disease.
Interpreted as
test result
negative
relative
in subjects
test result
probabilities:
with
the disease
in subjects
without
LR(-)
is the probability
compared
of a negative
to the probability
of a
the disease.
Negative predictive value: The probability that a subject does not have the disease given that
the test result is negative. Synonyms incIude predictive value negative. Negative predictive value
= dlm2.
Odds: The probability that an event will occur compared to the probability that the event will not
occur. For dichotomous events (e.g., for test results that are either positive or negative), the odds
are defined as follows: Odds= (probability of the event)/(1 - probability of the event).
J:l!GUlDANC\121 ODFXWPD
10LY98
41
‘-
.
Draft - Not for Implementation
Odds ratio: A measure of the amount of association between the presence or absence of disease
and the dia~nosti c test results. Synonyms
include cross-product ratio.
a
——
ml
a
nl
77
——
OddsRatio=@-=
-f$- =adbc
c
——
m2
n2
77
——
m2
n2
Positive predictive value: The probability that a subject has disease given that the test result is
positive. Synonyms include predictive vajue positive. Positive predictive value= a/ml.
Post-test odds of disease: The odds of disease in a subject after the diagnostic test results are
known. Synonyms include posterior o&% of disease. For subjects with a positive test result, the
_.——. post-test odds of disease= rdb. For subjects with a negative test result, the post-test odds of
disease = c/d. The following expression shows the general relationship between the post-test
odds and the likelihood ratio: Post-test odds of disease= Pretest odds of disease x Likelihood
ratio.
Post-test probability of disease: The probability of disease in a subject after the diagnostic test
results are known. Synonyms include posterior probability of disease. For subjects with a
positive test result, the post-test probability of disease= a/m 1. For subjects with a negative test
result, the post-test probability of disease= c/m2.
Precision: A measure of the reproducibility of a test including reproducibility within and across
drug doses, rates of administration, routes of administration, timings of imaging after drug
administration, instruments, instrument operators, patients, and image interpreters, and possibly
other variables. Precision is usually expressed in terms of variability, using such measures as
confidence intervals and/or standard deviations. Precise tests have relatively narrow cofildence
internals (or relatively small standard deviations).
Pretest odds of disease: The odds of disease in a subject before doing a diagnostic test.
Synonyms include prior oah% of disease. Pretest odds of &ease = nl/n2.
.-
J:~lGulD.4NCl121
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42
Draft - Not for Implementation
Pretest probability of disease: The probability of disease ina subject before doing a diagnostic
test. Synonyms include prevalence of disease and prior probability
of disease.
Pretest
probability of disease= nl/N.
Probability:
(inclusive).
The likelihood of occurrence of an event, expressed as a number between Oand 1
Sensitivity: The probability that a test result is positive given the subject has the disease.
Synonyms include true positive rate. Sensitivity = ahl.
Specificity: The probability that a test result is negative given that the subject does not have the
disease. Synonyms include true negative rate. Specific@= dhil
Truth standard (gold standard): An independent method of measuring-the same variable being
measured by the investigational drug that is known or believed to give the true value of the
measurement.
.. .
.
——._
J: I!GUIDANCIJ21 ODPT WPD
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43
.
.
Draft - Notfor Iinplemenlation
_@-..
-
J:UGUIDANCU21ODFT. WPD
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44
Federal Register /Vol. 63, No. 99/ Friday, May 22, 1998 /Proposed
whichever
occurs later, and thereafter at
intervals not to exceed 3,000 landings,
inspect the wing front attachments (both the
wing sides and fuselage sides) in accordance
with Socata Service Bulletin No. SB 10-08157, Amendment 1, dated August 1996.
(b) For all affected airplanes, accomplish
the following on the wing front attachments
on the wing sides:
(1) If no cracks are found on the wing front
attachments on the wing sides during any
inspection required by paragraph (a) of this
AD, upon accumulating 12,000 landings on
these wing front attachments or within the
next 100 landings after the effective date of
this AD, whichever occurs [ater, and
thereafter at intetwals not to exceed 6,000
landings provided no cracks are found during
any inspection required by paragraph (a) of
this AD, incorporate Modification Kit OPTIO
911000 in accordance with Socata Technical
Instruction No. 9110, which incorporates the
following pages:
Pages
I
Revision
level
I
Date
~
(2) If a crack(s) is found on the wing front
attachments on the wing sides during any
inspection required by paragraph (a) of this
AD, prior to further flight. incorporate
Modification Kit OPT lO 911000 in
accordance with Socata Technical Instruction
No. 9110. Incorporate this kit at intervals not
to exceed 6,000 landings thereafter provided
no cracks are found during any inspection
required by paragraph (a) of this AD.
(c) For Modeis TB9 and TB1O airplanes,
with a serial number in the range of 1
through 399, or with a serial number of 4 13;
that do not have either Socata Service Letter
(SL) 10-14 incorporated or Socata
Modification Kit OPT lO 908100
incorporated, accomplish the following on
the wing front attachments on the fuselage
sides:
(1) If no cracks are found on the wing front
attachments on the fuselage sides during any
inspection required by paragraph (a) of this
AD, upon accumulating 6,000 landings on
these wing front attachments or within the
next 100 landings after the effective date of
this AD, whichever occurs later, and
thereafter at intervals not to exceed 12,000
landings provided no cracks are found during
any inspection required by paragraph (a) of
Modification
KitOPTIO
this AD, incorporate
919800in accordance with Socata Technical
Instruction of Modification OPT lO 9198-53,
dated October 1994.
(2) If a crack(s) is found on the wing front
attachments on the fuselage sides during any
inspection required by paragraph (a) of this
AD, prior to further flight, incorporate
Modification Kit OPT lO 919800 in
accordance with Socata TechnicaI Instruction
of Modification OPTIO 9 198–53, dated
October 1994. Incorporate this kit at intervals
not to exceed 12,000 landings thereafter
provided no cracks are found during any
inspection required by paragraph (a) of this
AD.
(d) For Models Tf39 and TB1O airplanes,
with a serial number in the range of 1
through 399, or with a serial numberof413;
that have either Socata Semite Letter (SL)
10-14 incorporated or Socata Modification
Kit OPT 10908100 incorporated, accomplish
the following on the wing front attachments
on the fuselage sides:
(1) [f no cracks are found on the wing front
attachments on the fuseIage sides during any
inspection required by paragraph (a) of this
AD, upon accumulating 12,000 landings on
these wing front attachments or within the
next 100 landings after the effective date of
this AD, whichever occurs later, and
thereafter at intervals not to exceed 12,000
landings provided no cracks are found during
any inspection required by paragraph (a) of
this AD, incorporate Modification Kit OPTIO
919800 in accordance with Socata Technical
Instruction of Modification OPT lO 9198-53,
dated October 1994.
(2) If a crack(s) is found on the wing front
attachments on the fuselage sides during any
inspection required by paragraph (a) of this
AD, prior to further flight. incorporate
Modification Kit OPTIO 919800 in
accordance with Socata Technical Instruction
of Modification OPT1 O9 198–53, dated
October 1994. Incorporate this kit at intervals
not to exceed 12,000 landings thereafter
provided no cracks are found during any
inspection required by paragraph (a) of this
AD.
(e) For Models TB9 and TB 10 airplanes,
with a serial number in the range of 400
through 412, or with a serial number in the
range of414 through 9999; accomplish the
following on the wing front attachments on
the fuselage sides:
(1) If no cracks are found on the wing front
attachments on the fuselage sides during any
inspection required by paragraph (a) of this
AD, upon accumulating 12,000 landings on
these wing front attachments or within the
next 100 landings after the effective date of
this AD, whichever occurs later, and
thereafter at intervals not to exceed 12,000
landings provided no cracks are found during
any inspection required by paragraph (a) of
this AD, incorporate Modification Kit OPTIO
908100 in accordance with Socata Technical
Instruction of ModificationOPTlO918
1-53,
Amendment 2, dated October 1994.
(2) If a crack(s) is found on the wing front
attachments on the fuseIage sides during any
inspection required by paragraph (a) of this
AD, prior to further flight, incorporate
Modification Kit OPTi O908100 in
accordance with Socata Technical Instruction
of Modification OPT lO 918 1–53, Amendment
2, dated October 1994. Incorporate this kit at
intervals not to exceed 12,000 landings
thereafter movided no cracks are found
during an; inspection required by paragraph
(a) of this AD.
Note 3: “Unless already accomplished”
credit may be used if the kits that are
required by paragraphs (c)(1), (d)(1), and
(e)(1) of this AD are aleady incorporated on
the applicable airplanes. As specified in the
AD, repetitive incorporation of these kits
would still be required at intervals not to
exceed 12,000 landings provided no cracks
are found.
(t) Special flight permits may be issued in
accordance with sections 21.197 and 21.199
Rules
28301
of the Federal Aviation Regulations (14 CFR
21.197 and 21. 199) to operate the airplane to
a location where the requirements of this AD
can be accomplished.
@ An alternative method of compliance or
adjustment of the initial or repetitive
compliance times that provides an equivalent
level of safety maybe approved by the
Manager, Small Airplane Directorate. FAA,
1201 Walnut, suite 900, Kansas City.
Missouri 64106. The reques[ shall be
forwarded through an appropriate FAA
Maintenance Inspector, who may add
comments and then send it to the Manager,
Small Airplane Directorate.
Note 4: Information concerning the
existence of approved alternative methods of
compliance with this AD, if any, may be
obtained from the Small AirpIane
Directorate.
(h) Questions or technical information
related to the service information referenced
in this AD should be directed to the
SOCATA—Groupe AEROSPATIALE, Socata
Product Support, Aeroport Tarbes-Ossum
Lourdes, B P 930, 65009 Tarbes Cedex,
France; telephone: 33-5 -62-4 1-76-52;
facsimile: 33–5–62–4 I –76–54; or the Product
Support Manager, SOCATA Aircraft, North
Perry Airport, 7501 Pembroke Road,
Pembroke Pines, Florida 33023; telephone:
(954) 893-1400; facsimile: (954) 964-1402.
This service information may be examined at
the FAA, Central Region, Office of the
Regional Counsel, Room 1558,601 E. 12th
Street, Kansas City, Missouri.
Note 5: The subject of this AD is addressed
in French AD 94–264(A), datedDecember7,
1994.
in Kansas City, Missouri, on May
Issued
14, 1998.
Michael Gallagher,
Manager, Small Airplane Directorate, Aircraft
Certification
Service.
[FR Dec. 98-13653 Filed 5-21-98:8:45
BILLING
CODE
am]
491 WI 3-P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 315 and 601
[Docket No. 98 N-0040]
Regulations
for In Vivo
Radiopharmaceuticals
Used for
Diagnosis and Monitoring
AGENCY: Food
and Drug Administration,
HHS.
ACTION: Proposed
rule,
SUMMARY: The Food and Drug
Administration
(FDA), in response to
the requirements
of the Food and Drug
Administration
Modernization
Act of
1997 (FDAMA), is proposing
to amend
the drug and biologics regulations
by
adding provisions
that would clarify the
evaluation
and approval of in vivo
.
28302
Federal
Register /Vol.
63, No. 99/ Friday, May 22, 1998 /Proposed
Rules
..
b
radiopharmaceuticals
used in the
diagnosis or monitoring of diseases. The
proposed regulations would describe
certain types of indications for which
FDA may approve diagnostic
radiopharmaceuticals. The proposed
rule also would include criteria that the
agency would use to evaluate the safety
and effectiveness of a diagnostic
radiopharmaceutical under the Federal
Food, Drug, and Cosmetic Act (the act)
and the Public Health Service Act (the
PHS Act).
DATES: Submit comments on this
proposed rule on or before August 5,
1998, Submit written comments on the
information
collection
provisions by
June 22, 1998. See section IV of this
document for the proposed effective
date of a final rule based on this
document,
ADDRESSES: Submitwritten
comments
totheDocketsManagement Branch
(HFA-305),Food and Drug
Administration,
12420ParklawnDr.,
rm, 1–23, Rockville, MD 20857. Submit
comments of the information collection
provisions to the Office of Information
and Regulatory Affairs, OMB, New
Executive Office Bldg., 725 17th St.
NW., Washington, DC 20503, Attn: Desk
Officer for FDA.
FOR FURTHER INFORMATION CONTACT:
Dano B, Murphy, Center for Biologics
Evaluation and Research (HFM-1 7),
Food and Drug Administration,
1401
Rockville Pike, Rockville, MD 208521448, 301-827-6210;
or Brian L.
Pendleton, Center for Drug Evaluation
and Research (HFD–7), Food and Drug
Administration,
5600 Fishers Lane,
Rockville, MD 20857, 301-594-5649,
SUPPLEMENTARY INFORMATION:
I. Introduction
Radiopharmaceuticals
are used for a
wide variety of diagnostic, monitoring,
and therapeutic purposes. Diagnostic
radiopharmaceuticals
are used to image
or otherwise identify an internal
structure or disease process, while
therapeutic radiopharmaceuticals
are
used to effect a change upon a targeted
structure or disease process,
The action of most
radiopharmaceuticals
is derived from
two components: A nonradioactive
delivery component, i.e., a carrier and/
or ligand: and a radioactive imaging
component, i.e., a radionuclide,
Nonradioactive
delivery ligands and
carriers are usually peptides, small
proteins, or antibodies. The purpose of
ligands and carriers is to direct the
radionuclide to a specific body location
or process, Once a radiopharmaceutical
has reached its targeted location, the
radionuclide component can be
detected. The imaging
usually is a short-lived
component
radioactive
molecule that emits radioactive decay
photons having sufficient energy to
penetrate the tissue mass of the patient.
The emitted photons are detected by
specialized devices that generate images
of, or otherwise detect, radioactivity,
such as nuclear medicine cameras and
radiation detection probe devices.
On November 21, 1997, the President
signed FDAMA into law. Section
122(a) (1) of FDAMA directs FDA to
issue proposed and final regulations on
the approval of diagnostic
radiopharmaceuticals
within specific
timeframes. As defined in section 122(b)
of FDAMA, a radiopharmaceutical is an
article “that is intended for use in the
diagnosis or monitoring of a disease or
a manifestation of a disease in humans
* * * that exhibits spontaneous
disintegration of unstable nuclei with
the emission of nuclear particles or
photons[,] or * * * any nonradioactive
reagent kit or nuclide generator that is
intended to be used in the preparation
of any such article. ” Section
122 (a)(1)(A) of FDAMA states that FDA
regulations will provide that, in
determining the safety and effectiveness
of a radiopharmaceutical
under section
505 of the act (for a drug) (21 U.S.C.
355) or section351 of the PHS Act (for
a biological product) (42 U.S.C. 262), the
agency will consider the proposed use
of the radiopharmaceutical
in the
practice of medicine, the
pharmacological
and toxicological
activity of the radiopharmaceutical
(including any carrier or ligand
component), and the estimated absorbed
radiation dose of the
radiopharmaceutical.
FDAMA requires FDA to consult with
patient advocacy groups, associations.
physicians licensed to use
radio pharmaceuticals,
and the regulated
industry before proposing any
regulations governing the approval of
radiopharmaceuticals.
Accordingly, in
the Federal Register of February 2, 1998
(63 FR 5338), FDA published a
notification of a public meeting entitled
“Developing Regulations for In Vivo
Radiopharmaceuticals
Used for
Diagnosis and Monitoring. ” The notice
invited all interested persons to attend
the meeting, scheduled for February 27,
1998. and to comment on how the
agency should regulate
radiopharmaceuticals.
In particular,
FDA invited comment on the following
topics: (1) The effect of the use of a
radiopharmaceutical
in the practice of
medicine on the nature and extent of
safety and effectiveness evaluations; (2)
the general characteristics of a
radiopharmaceutical
that should be
-=
considered in the preclinical and
clinical pharmacological
and
toxicological evaluations of a
radiopharmaceutical
(including the
radionuclide as well as the ligand and
carrier components); (3) determination
and consideration of a
radiopharmaceutical’s
estimated
absorbed radiation dose in humans: and
(4) the circumstances under which an
approved indication for marketing
might refer to manifestations of disease
(biochemical, physiological. anatomic,
or pathological processes) common to,
or present in, one or more disease states,
Approximately 50 individuals from
industry, academic institutions,
professional medical organizations, and
patient advocacy groups attended the
February 27, 1998, public meeting and/.
or submitted comments in response to
the notice. FDA has considered all of
these comments in drafting this
proposed rule.
The proposed rule applies to the
approval of in vivo
radiopharmaceuticals
(both drugs and
biologics) used for diagnosis and
monitoring. The proposed regulations
will not apply to radiopharmaceuticals
used for therapeutic purposes. The
regulations include a definition of
-n=
diagnostic radiopharmaceuticals
(which
includes radiopharmaceuticals
used for
monitoring) and provisions that address
the following aspects of diagnostic
radiopharmaceuticals:
(1) General
factors to be considered in determining
safety and effectiveness, (2) possible
indications for use, (3) evaluation of
effectiveness, and (4) evaluation of
safety.
To establish these regulations, FDA
proposes to add a new part 315 to title
21 of the Code of Federal Regulations
(CFR) and to rename subpart D and add
SS 601.30 through 601.35 in part 601 (21
CFR part 601). These new provisions
would complement and clarify existing
regulations on the approval of drugs and
biologics in parts 314 (21 CFR parts 314)
and 601, respectively. In addition to
these regulatory changes, FDA is in the
process of revising and supplementing
its guidance to industry on product
approval and other matters related to
the regulation of diagnostic
radiopharmaceutical
drugs and
biologics. This guidance will address
the application of the proposed rule.
FDA will make such guidance available
in draft form for public comment in
accordance with the agency’s Good
Guidance Practices (see 62 FR 8961,
‘+.
February 27, 1997).
Positron emission tomography (PET)
drugs are a particular type of
radio pharmaceutical.
Section 121 of
FDAMA addresses these products
Federal Register/Vol. 63, No. 99 I Friday, May 22, 1998/Proposed
separately from other diagnostic
=— radiopharmaceuticals and requires FDA
to develop appropriate approval
procedures and current good
manufacturing practice requirements for
PET products within the next 2 years.
Although FDA expects the standards for
determining the safety and effectiveness
of diagnostic radiopharmaceuticals set
forth in this proposed rule to apply to
PET diagnostic products under the
approval procedures that FDA intends
to develop for those products, the
agency will address this issue when it
publishes its proposal on PET drugs.
II. Description of the Proposed Rule
The proposed rule would add a new
part 315 to the CFR containing
provisions on radiopharmaceutical
drugs subject to section 505 of the act
that are used for diagnosis and
monitoring. Corresponding provisions
applicable to radiopharmaceutical
biological products subject to licensure
under section 351 of the PHS Act would
be set forth in revised subpart D of part
601. Both proposed regulations are
discussed in the following section of
this document.
.—.
A. Scope
Proposed s~ 315.1 and 601.30 define
the scope of the diagnostic
radiopharmaceutical
provisions, i.e.,
that they apply only to
radiopharmaceuticals
used for diagnosis
and monitoring and not to
radiopharmaceuticals
intended for
therapeutic uses. FDA intends that these
regulations will apply only to diagnostic
radiopharmaceuticals
that are
administered
in vivo. In vitro diagnostic
products generally are regulated as
medical devices under the act, although
they may also be biological products
subject to licensure under section 351 of
the PHS Act (see21 CFR 809.3(a)).
Some radiopharmaceuticals
may have
utility as both diagnostic and
therapeutic drugs or biologics. When a
particular radiopharmaceutical
drug or
biologic is proposed for both diagnostic
and therapeutic uses, FDA will evaluate
the diagnostic claims under the
provisions in part 315 (for drugs) or
subpart D of part 601 (for biologics) and
evaluate the therapeutic claims under
the regulations applicable to other drug
or biologic applications.
B. Definition
The proposed ruling in SS315.2 and
=_y 601.31 would include a definition of
- “diagnostic radiopharmaceutical”
that
is identical to the definition of
‘‘radiopharmaceutical”
in section 122(b)
of FDAMA. Thus, a “diagnostic
radiopharmaceutical”
would be defined
as an article that is intended for use in
the diagnosis or monitoring of a disease
or a manifestation of a disease in
humans: and that exhibits spontaneous
disintegration of unstable nuclei with
the emission of nuclear particles or
photons; or any nonradioactive reagent
kit or nuclide generator that is intended
to be used in the preparation of such
article. FDA interprets “disease or a
manifestation of a disease” to include
conditions that may not ordinarily be
considered diseases, such as essential
thrombocytopenia
and bone fractures. In
addition, FDA interprets the definition
as including articles that exhibit
spontaneous disintegration leading to
the reconstruction
of unstable nuclei
and the subsequent emission of nuclear
particles or photons.
C. General Factors Relevant to Safety
and Effectiveness
In 5~315.3 and 601.32, FDA proposes
to incorporate in its regulations the
requirement in section 122 of FDAMA
that the agency consider certain factors
in determining the safety and
effectiveness of diagnostic
radiopharmaceuticals
under section 505
of the act or section 351 of the PHS Act.
These factors are as follows: (1) The
proposed use of a diagnostic
radiopharmaceutical
in the practice of
medicine; (2) the pharmacological and
toxicological activity of a diagnostic
radiopharmaceutical,
including any
carrier or ligand component; and (3) the
estimated absorbed radiation dose of the
diagnostic radiopharmaceutical.
Other
sections of the proposed regulations
describe how the agency will assess
these factors. In addition, FDA intends
to provide further information in
guidance to industry.
D. Indications
In ~S315.4(a) and601.33(a), FDA
proposes to specify some of the types of
indications for which the agency may
approve a diagnostic
radiopharmaceutical.
These categories
of indications are as follows: (1)
Structure delineation; (2) functional,
physiological, or biochemical
assessment: (3) disease or pathology
detection or assessment; and (4)
diagnostic or therapeutic management.
Approval may be possible for claims
other than those listed. (In these and
other provisions on diagnostic
radiopharmaceuticals
in the proposed
rule, the terms “indication, ” “indication
for use,” and “claim” have the same
meaning and are used interchangeably,)
A diagnostic radiopharmaceutical
that
is intended to provide structural
delineation is designed to locate and
outline anatomic structures. For
Rules
example, a radiopharmaceutical
be developed
to distinguish
a
28303
might
structure
that cannot routinely be seen by any
other imaging modality, such as a drug
designed to image the lymphatic
of the
small bowel.
A diagnostic radiopharmaceutical
that
is intended to provide a functional,
physiological, or biochemical
assessment is used to evaluate the
function, physiology, or biochemistry of
a tissue, organ system, or body region.
Functional. physiological, and
biochemical assessments are designed to
determine if a measured parameter is
normal or abnormal. Examples of a
functional or physiological assessment
include the determination
of the cardiac
ejection fraction, myocardial wall
motion, and cerebral blood flow.
Examples of a biochemical assessment
include the evaluation of sugar, lipid,
protein, or nucleic acid synthesis or
metabolism.
A diagnostic radiopharmaceutical
that
is intended to provide disease or
pathology detection or assessment
information assists in the detection,
location, or characterization
of a specific
disease or pathological state. Examples
of this type of diagnostic
radiopharmaceutical
include a
radiolabeled monoclinal
antibody used
to attach to a specific tumor antigen and
thus detect a tumor and a peptide that
participates in an identifiable
transporter function associated with a
specific neurological disease.
A diagnostic radiopharmaceutical
that
is intended to assist in diagnostic or
therapeutic patient management
provides imaging, or related,
information leading directly to a
diagnostic or therapeutic patient
management decision. Examples of this
type of indication include: (1) Assisting
in a determination
of whether a patient
should undergo a diagnostic coronary
angiography or will have predictable
clinical benefit from a coronary
revascularization.
and (2) assisting in a
determination of the respectability of a
primary tumor.
Proposed ~S 315.4(b) and 601 .33(b)
reflect the intent of section 122(a)(2) of
FDAMA, which states that in
appropriate cases, FDA may approve a
diagnostic radiopharmaceutical
for an
indication that refers to “manifestations
of disease (such as biochemical.
physiological, anatomic, or pathological
processes) common to, or present in,
one or more disease states. “’Where a
diagnostic radiopharmaceutical
is not
intended to provide disease-specific
information, the proposed indications
for use may refer to a process or to more
than one disease or condition. This
would allow FDA to approve a product
. .
.
28304
FederaI
Register /Vol.
63, No. 99/Friday,
May 22, 1998/Proposed
Rules
. .
for art indication (e.g., delineation of a
particular anatomic structure or
functional assessment of a specific
organ system) that would encompass
manifestations of disease that are
common to multiple disease states. An
example of a manifestation that is
common to multiple diseases is tumor
metastasis to the liver caused by various
malignancies.
E. Evaluation of Effectiveness
Thespecific
criteria
that
FDA would
usetoevaluate
theeffectiveness
ofa
diagnostic
radiopharmaceutical
are
stated
in proposed ~S 3 15.5(a) and
601.34(a). These provisions state that
FDA assesses the effectiveness of a
diagnostic radiopharmaceutical by
evaluating its ability to provide useful
clinical information that is related to its
proposed indication for use. The nature
of the indication determines the method
of evaluation, and because an
application may include more than one
type of claim, FDA might need to
employ multiple evaluation criteria.
FDA would require that any such claim
be supported with information
demonstrating that the potential benefit
of the diagnostic radiopharmaceutical
outweighs the risk to the patient from
administration
of the product.
Under proposed 55 315,5(a) (1) and
601 .34(a) (l), a claim of structure
delineation would be established by
demonstrating the ability of a diagnostic
radiopharmaceutical
to locate and
characterize normal anatomic
structures. In ~~ 315.5 (a) (2) and
601 .34(a)(2), FDA proposes that a claim
of functional, physiological. or
biochemical assessment would be
established by demonstrating
that the
diagnostic radiopharmaceutical
could
reliably measure the function or the
physiological, biochemical, or
molecular process. A reliable
measurement would need to be
supported by studies in normal and
abnormal patient populations,
consistent with the proposed claim and
would require a qualitative or
quantitative understanding
of how the
measurement varies in normal and
abnormal subjects.
The agency proposes, in SS315,5 (a)(3)
and 601.34 (a) (3), that a claim of disease
or pathology detection or assessment
would be established by demonstrating
in a defined clinical setting that the
diagnostic radiopharmaceutical
had
sufficient accuracy in identifying or
characterizing the disease or pathology.
The term ‘“accuracy” refers to the
diagnostic performance of the product
as measured by factors such as
sensitivity, specificity, positive
predictive value. negative predictive
value, and reproducibility
of test
interpretation. The term “sufficient
accuracy” means accuracy that is good
enough to indicate that the product
would be useful in one or more clinical
settings. FDA believes that the data
demonstrating accuracy must be
obtained from patients in a clinical
setting(s) reflecting the proposed
indication(s). For example, if a claim is
for diagnosis of tumor in patients with
a negative computed tomography (CT)
scan for disease and a borderline serum
carcinoembryonic
antigen (CEA), the
accuracy of the diagnostic
radiopharmaceutical
should be assessed
in such patients rather than only in
patients with CT-diagnosed disease or
hi h serum CEA.
b rider proposed 55315,5 (a) (4) and
601 .34(a)(4), for a claim of diagnostic or
therapeutic patient management, the
applicant must establish effectiveness
by demonstrating in a defined clinical
setting that the test is useful in such
patient management. For example, an
imaging agent might be studied in a
manner that would demonstrate its
usefulness in directing local excision of
cancer-laden lymph nodes and sparing
a wide area of nondiseased lymphatic
tissue.
In !jS315.5(a) (5) and601.34(a) (5).
FDA proposes that, for claims that do
not fall within the indication categories
in SS 315.4 and 601.33, the applicant
may consult with the agency on how to
establish effectiveness.
Proposed SS 315.5(b) and 601 .34(b)
specify that the accuracy and usefulness
of diagnostic information provided by a
diagnostic radiopharmaceutical
must be
determined by comparison with a
reliable assessment of actual clinical
status. To obtain such a reliable
assessment, a diagnostic standard or
standards of demonstrated accuracy
must be used, if available. An example
of such a standard is a tissue biopsy
confirmation of a site of a diagnostic
radiopharmaceutical
localization. If an
accurate diagnostic standard is not
available, the actual clinical status must
be established in some other manner,
such as through patient followup.
FDA intends to develop a guidance
document that will provide more
detailed guidance to industry on the
types of clinical investigations that
would meet regulatory requirements for
obtaining approval for particular types
of indications for diagnostic
radiopharmaceuticals.
The guidance
may address such matters as appropriate
clinical endpoints and suitable
diagnostic standards, For indications
that are common to multiple disease
states, the guidance may address
clinical trial design and statistical
analysis considerations
for patient
populations that provide a range of
representative disease processes.
‘-
F. Evaluation of Safety
FDA’s proposed approach to the
evaluation of the safety of diagnostic
radiopharmaceuticals
is set forth in
~~ 315.6 and 601.35. Proposed
!jS 3 15.6(a) and 601.35(a) state that the
safety assessment of a diagnostic
radiopharmaceutical
includes, among
other things, the following: The
radiation dose; the pharmacology and
toxicology of the radiopharmaceutical,
including any radionuclide, carrier, or
ligand; the risks of an incorrect
diagnostic determination:
the adverse
reaction profile of the drug: and results
of human experience with the
radio harmaceutical for other uses.
In { S315.6(b) and 601.35(b), FDA
proposes that the assessment of the
adverse reaction profile of a diagnostic
radiopharmaceutical
(including the
carrier or Iigand) include, but not be
limited to, an evaluation of the
product’s potential to elicit the
following: (1) Allergic or
hypersensitivity
responses, (2)
immunologic responses, (3) changes in
the physiologic or biochemical function
of target and non-target tissues, and (4) =-=
clinically detectable signs or symptoms.
Proposed SS 315.6(c)(1) and
601 .35(c) (1) state that FDA may require,
among other information, the following
types of preclinical and clinical data to
establish the safety of a diagnostic
radiopharmaceutical:
(1) Pharmacology
data, (2) toxicology data, (3) a clinical
safety profile, and (4) a radiation safety
assessment, Other information that may
be required to establish safety includes
information on chemistry,
manufacturing, and controls.
Under proposed 55315.6 (c) (2) and
601.35(c) (2), the amount of new safety
data required would depend on the
characteristics of the diagnostic
radiopharmaceutical
and available
information on the safety of the product
obtained from other studies and uses.
This information might include, but
would not be limited to, the dose, route
of administration,
frequency of use,
half-life of the Iigand or carrier, half-life
of the radionuclide of the product, and
results of preclinical studies on the
product. Proposed s~ 3 15.6(c) (2) and
601.35(c) (2) further states that FDA will
categorize diagnostic
radiopharmaceuticals
based on defined
characteristics that relate to safety risk
+
and will specify the amount and type of
safety data appropriate for each
category. The paragraph states, as an
example, that required safety data
would be limited for diagnostic
-.
Federal
Register/
Vol. 63, No. 99 JFriday,
May 22, 1998 I Proposed
28305
Rules
,.
—_
radiopharmaceuticals with wellestablished low-risk refiles.
Proposed !%+
315.6 fd) and 601.35(d)
discusses the radiation safety
assessment that will be required for a
diagnostic radiopharmaceutical. FDA
proposes that the applicant for approval
of a diagnostic radiopharmaceutical
establish the radiation dose of the
product by radiation dosimetry
evaluations in humans and appropriate
animal models. Such evaluations must
consider dosimetry to the total body, to
specific organs or tissues, and, as
appropriate, to target organs or target
tissues. FDA notes that the use of
limits
occupational
radiation dosimetry
is not required in performing such
evaluations. The maximum tolerated
dose of the diagnostic
radiopharmaceutical
need not be
established.
FDA intends to provide guidance on
safety assessments for diagnostic
radiopharmaceuticals.
Such guidance
may include a classification of
diagnostic radiopharmaceuticals
based
on quantity administered,
adverse event
profile, and proposed patient
population. The guidance would allow
the safety information required to meet
regulatory requirements to vary
according to the class of the
radiopharmaceutical.
The guidance will
also address evaluations of radiation
dosimetry.
III. Analysis
of Economic
Impacts
FDA has examined the impact of the
proposed rule under Executive Order
12866, under the Regulatory Flexibility
Act (5 U.S.C. 601-612), and under the
Unfunded Mandates Reform Act (Pub.
L. 104-1 14). Executive Order 12866
directs agencies to assess all costs and
benefits of available regulatory
approaches that maximize net benefits
(including potential economic,
environmental,
public health and safety,
and other advantages, distributive
impacts and equity). Under the
Regulatory Flexibility Act, unless an
agency certifies that a rule will not have
a significant economic impact on a
substantial number of small entities, the
agency must analyze significant
regulatory options that would minimize
any significant economic impact of a
rule on small entities. The Unfunded
Mandates Reform Act requires (in
section 202) that agencies prepare an
assessment of anticipated costs and
benefits before proposing any mandate
that results in an expenditure by State,
local, and tribal governments, in the
aggregate, or by the private sector, of
$100 million in any I year.
The agency has reviewed this
proposed rule and has determined that
the rule is consistent with the principles
set forth in the Executive Order and in
these two statutes. FDA finds that the
rule will not be a significant rule under
the Executive Order. Further, the agency
finds that, under the Regulatory
Act, the rule will not have a
Flexibility
significant economic impact on a
substantial number of small entities.
Also, since the expenditures resulting
from the standards identified in the rule
are less than $100 million, FDA is not
required to perform a cost/benefit
analysis according to the Unfunded
Mandates Reform Act.
The proposed rule clarifies existing
FDA requirements for the approval and
evaluation of drug and biological
products already in place under the act
and the PHS Act. Existing regulations
(parts 314 and 601) specify the type of
information that manufacturers are
required to submit in order for the
agency to properly evaluate the safety
and effectiveness of new drugs or
biological products. Such information is
usually submitted as part of a new drug
application (NDA) or biological license
application or as a supplement to an
approved application. The information
typically includes both nonclinical and
clinical data concerning the product’s
pharmacology, toxicology, adverse
events, radiation safety assessments,
chemistry, and manufacturing and
controls.
The proposed regulation recognizes
the unique characteristics of diagnostic
radiopharmaceuticals
and sets out the
agency’s approach to the evaluation of
these products. For certain diagnostic
radiopharmaceuticals,
the proposed
regulation may reduce the amount of
safety information that must be obtained
by conducting new clinical studies. This
would include approved
radiopharmaceuticals
with wellestablished low-risk safety profiles
because such products might be able to
use scientifically sound data established
during use of the radiopharmaceutical
to support the approval of a new
indication for use. In addition, the
clarification achieved by the proposed
rule is expected to reduce the costs of
submitting an application for approval
of a diagnostic radiopharmaceutical
by
improving communications between
applicants and the agency and by
reducing wasted effort directed toward
the submission of data that is not
necessary to meet the statutory approval
standard.
Manufacturers of in vitro and in vivo
diagnostic substances are defined by the
Small Business Administration as small
businesses if such manufacturers
employ fewer than 500 employees. The
agency finds that only 2 of the 8
companies that currently manufacture
or market radiopharmaceuticals
have
fewer than 500 employees. 1 Moreover,
the proposed rule would not impose any
additional costs but. rather, is expected
to reduce costs for manufacturers of
certain diagnostic radiopharmaceuticals,
as discussed previously. Therefore. in
accordance with the Regulatory
Flexibility Act, FDA certifies that this
rule will not have a significant
economic impact on a substantial
number of small entities.
IV. Proposed
Effective Date
FDA proposes that any final rule that
may issue based on this proposal
become effective 30 days after the date
of its publication in the Federal
Register.
V. Environmental
Impact
The agency has determined under 21
CFR 25.24(h) that this action is of a type
that does not individually or
cumulatively have a significant effect on
the human environment. Therefore,
neither an environmental
assessment
nor an environmental
impact statement
is required.
VI. The Paperwork
1995
Reduction
Act of
This proposed rule contains
information collection provisions that
are subject to review by the Office of
Management and Budget (OMB) under
the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). A description of
these provisions is shown below with
an estimate of the annual reporting
burden. Included in the estimate is the
time for reviewing the instructions,
searching existing data sources,
gathering and maintaining the data
needed, and completing and reviewing
each collection of information.
FDA invites comments on: (1)
Whether the proposed collection of
information is necessary for the proper
performance of FDA’s functions,
including whether the information will
have practical utility; (2) the accuracy of
FDA’s estimate of the burden of the
proposed collection of information.
including the validity of the
methodolo~
and assumptions used; (3)
ways to enhance the quality, utility, and
clarity of the information to be
collected; and (4) ways to minimize the
burden of the collection of information
on respondents, including through the
use of automated collection techniques.
when appropriate, and other forms of
information technology.
I Medical and Hmlthcam Ma!.ke[place CuldLL
Dorland”s Biomedical. sponsored by Smith Barney
Health Care Croup, 13th ed 1997 to 1998.
28306
Federal
Register \ Vol. 63, No. 99 I Friday, May 22, 19981 Proposed
‘fltle: Regulations for In Vivo
Radiopharmaceuticals
Used for
Diagnosis and Monitoring.
Description: FDA is proposing
regulations for the evaluation and
approval of in vivo
radiopharmaceuticals
used for diagnosis
and monitoring. The proposed rule
would clarify existing FDA
requirements for approval and
evaluation of drug and biological
products already in place under the
authorities of the act and the PHS Act.
Those regulations, which appear in
primarily at parts 314 and601, specify
the information that manufacturers must
submit to FDA for the agency to
properly evaluate the safety and
effectiveness of new drugs or biological
products. The information, which is
usually submitted as part of an NDA or
new biological license application or as
a supplement to an approved
application, typically includes, but is
not limited to, nonclinical and clinical
data on the pharmacology, toxicology,
adverse events, radiation safety
assessments, and chemistry,
manufacturing and controls. The
content and format of an application for
approval of new drugs and antibiotics
are set out in S 314.50 and for new
biological products in S 601.25. Under
the proposed regulation, information
required under the act and the PHS Act
TABLE
21 CFR Section
315,4, 315.5, and 315,6
601.33, 601.34, and 601.35
Total
and needed by FDA to evaluate safety
and effectiveness would still need to be
reported.
Description
of Respondents
Manufacturers of in vivo
radiopharmaceuticals
used for diagnosis
and monitoring.
To estimate the potential number of
respondents that would submit
applications or supplements for
diagnostic radiopharmaceuticals,
FDA
used the number of approvals granted in
fiscal year 1997 (FY 1997) to
approximate the number of future
annual applications. In FY 1997, FDA
approved seven diagnostic
radiopharmaceuticals
and received one
new indication supplement; of these,
three respondents received approval
through the Center for Drug Evaluation
and Research and five received approval
through the Center for Biologics
Evaluation and Research. The annual
frequency of responses was estimated to
be one response per application or
supplement. The hours per response
refers to the estimated number of hours
that an applicant would spend
preparing the information referred to in
the proposed regulations. The time
needed to prepare a complete
application is estimated to be
approximately
10,000 hours, roughly
one-fifth of which, or 2,000 hours, is
estimated to be spent preparing the
1.—ESTIMATED
ANNUAL
No. of
Respondents
REPORTING
portions of the application that are
affected by these proposed regulations.
The proposed rule would not impose
any additional reporting burden beyond
the estimated current burden of 2,000
hours because safety and effectiveness
information is already required by
preexisting regulations (parts 314 and
601). In fact, clarification by the
proposed regulation of FDA’s standards
for evaluation of diagnostic
radiopharmaceuticals
is expected to
streamline overall information
collection burdens. particularly for
diagnostic radiopharmaceuticals
that
may have well-established
low-risk
safety profiles, by enabling
manufacturers to tailor information
submissions and avoid conducting
unnecessary clinical studies. The
following table indicates estimates of
the annual reporting burdens for the
preparation of the safety and
effectiveness sections of an application
that are imposed by existing regulations.
The burden totals do not include an
increase in burden because no increase
is anticipated, This estimate does not
include the actual time needed to
conduct studies and trials or other
research from which the reported
information is obtained. FDA invites
comments on this analysis of
information collection burdens.
.
n.
BURDEN1
Annual
Frequency per
Response
3
5
8
Rules
Total Annual
Responses
1
1
3
5
8
Hours per
Response
Total Hours
2,000
6,000
2,000
10,000
16,000
‘There are no capital costs or operating and maintenance costs associated with this collection of information.
Interested persons and organizations
may submit comments on the
information collection requirements of
this proposed rule by June 22, 1998, to
Office of Information and Regulatory
Affairs, OMB, New Executive Office
Bldg., 725 17th St. NW., Washington,
DC 20503, Attn: Desk Officer for FDA.
At the close of the 30-day comment
period, FDA will review the comments
received, revise the information
collection provisions as necessary, and
submit these provisions to OMB for
review, FDA will publish a notice in the
Federal Register when the information
collection provisions are submitted to
OMB, and an opportunity for public
comment to OMB will be provided at
that time. Prior to the effective date of
the proposed rule, FDA will publish a
notice in the Federal Register of OMB’S
decision to approve, modify, or
disapprove the information collection
provisions. An agency may not conduct
or sponsor, and a person is not required
to respond to, a collection of
information unless it displays a
currently valid OMB control number.
List of Subjects
VII. Request for Comments
Administrative
practice and
procedure, Biologics, Confidential
business information.
Interested persons may, on or before
August 5, 1998, submit to the Dockets
Management Branch (address above)
written comments on this proposal. Two
copies of any comments are to be
submitted, except that individuals may
submit one copy. Comments are to be
identified with the docket number
found in brackets in the heading of this
document. Received comments may be
seen in the office above between 9 a.m.
and 4 p.m., Monday through Friday.
21 CFRPart 315
Biologics, Diagnostic
radiopharmaceuticals,
Drugs.
21 CFR Part 601
Therefore, under the Federal Food,
Drug, and Cosmetic Act, the Public
Health Service Act. the Food and Drug
Modernization Act. and under authority
delegated to the Commissioner of Food- .and Drugs. it is proposed that 21 CFR
chapter I be amended as follows:
1. Part 315 is added to read as follows:
Federal
.
*
Register jVol.
,.. PART 316-DIAGNOSTIC
RADIOPHARMACEUTICALS
S4a.
315.1 Scope.
315.2Definition.
315.3 General factors relevant to safety and
effectiveness.
315.4 Indications.
315.5 Evaluation of effectiveness.
315.6 Evaluation of safety.
Authority
21 U.S.C. 321,331,351,
352,
353, 355, 356, 357, 371, 374, 379e; sec. 122,
Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C.
355 note).
~ 315.1
Scope.
The regulations in this part apply to
radiopharmaceuticals
intended for in
vivo administration
for diagnostic and
monitoring use. They do not apply to
radiopharmaceuticals
intended for
therapeutic purposes. In situations
where a particular radiopharmaceutical
is proposed for both diagnostic and
therapeutic uses, the
radiopharmaceutical
shall be evaluated
taking into account each intended use.
~ 315.2 Definition.
For purposes of this part, diagnostic
radiopharmaceutical
means:
(a) An article that is intended for use
-–—--in the diagnosis or monitoring of a
disease or a manifestation of a disease
in humans; and that exhibits
spontaneous disintegration of unstable
nuclei with the emission of nuclear
particles or photons; or
(b) Any nonradioactive
reagent kit or
nuclide generator that is intended to be
used in the preparation of such article
as defined in paragraph (a) of this
section.
~ 315.3
General factors relevant to safety
and effectiveness.
FDA’s determination
of the safety and
effectiveness of a diagnostic
radiopharmaceutical
shall include
consideration of the following:
(a) The proposed use of the diagnostic
radiopharmaceutical
in the practice of
medicine;
(b) The pharmacological
and
toxicological activity of the diagnostic
radiopharmaceutical
(including any
carrier or Iigand component of the
dia nostic radiopharmaceutical);
and
(~ The estimated absorbed radiation
dose of the diagnostic
radiopharmaceutical.
.-
S 315.4 Indications.
(a) For diagnostic
.radiopharmaceuticals,
the categories of
proposed indications for use include,
but are not limited to, the following:
(1) Structure delineation.
(2) Functional. physiological, or
biochemical assessment.
63, No. 99/Friday,
May 22, 1998 I Proposed
(3) Disease or pathology detection or
assessment.
(4) Diagnostic or therapeutic patient
management.
(b) Where a diagnostic
radiopharmaceutical is not intended to
provide disease-specific information.
the proposed indications for use may
refer to a process or to more than one
disease or condition.
~ 315.5
Evaluation
of effectiveness.
(a) The effectiveness of a diagnostic
radiopharmaceutical
is assessed by
evaluating its ability to provide useful
clinical information related to its
proposed indications for use. The
method of this evaluation will vary
depending upon the proposed
indication(s) and may use one or more
of the following criteria:
(1) The claim of structure delineation
is established by demonstrating the
ability to locate and characterize normal
anatomical structures.
(2) The claim of functional,
physiological, or biochemical
assessment is established by
demonstrating reliable measurement of
function(s) or physiological,
biochemical. or molecular process.
(3) The claim of disease or pathology
detection or assessment is established
by demonstrating in a defined clinical
setting that the diagnostic
radiopharmaceutical
has sufficient
accuracy in identifying or characterizing
the disease or pathology.
(4) The claim of diagnostic or
therapeutic patient management is
established by demonstrating in a
defined clinical setting that the test is
useful in diagnostic or therapeutic
patient management.
(5) For a claim that does not fall
within the indication categories
identified in S 315,4, the applicant or
sponsor should consult FDA on how to
establish the effectiveness of the
diagnostic radiopharmaceutical
for the
claim.
(b) The accuracy and usefulness of the
diagnostic information shall be
determined by comparison with a
reliable assessment of actual clinical
status. A reliable assessment of actual
clinical status may be provided by a
diagnostic standard or standards of
demonstrated accuracy. In the absence
of such diagnostic standard(s), the
actual clinical status shall be
established in another manner, e.g.,
patient followup.
5315.6 Evaluation of safety.
(a) Factors considered in the safety
assessment of a diagnostic
radiopharmaceutical
include, among
others, the following: The radiation
Rules
28307
dose; the pharmacology and toxicology
of the radiopharmaceutical,
including
any radionuclide, carrier, or ligand; the
risks of an incorrect diagnostic
determination;
the adverse reaction
profile of the drug; and results of human
experience with the
radiopharmaceutical
for other uses.
(b) The assessment of the adverse
reaction profile includes, but is not
limited to, an evaluation of the potential
of the diagnostic radiopharmaceutical,
including the carrier or ligand, to elicit
the following:
(1) Allergic or hypersensitivity
responses.
(2) Immunologic responses.
(3) Changes in the physiologic or
biochemical function of the target and
non-target tissues.
(4) Clinically detectable signs or
symptoms.
(c) (1) To establish the safety of a
diagnostic radiopharmaceutical,
FDA
may require, among other information,
the following types of data:
(i) Pharmacology data.
(ii) Toxicology data.
(iii) Clinical adverse event data.
(iv) Radiation safety assessment.
(2) The amount of new safety data
required will depend on the
characteristics of the product and
available information regarding the
safety of the diagnostic
radiopharmaceutical
obtained from
other studies and uses. Such
information may include, but is not
limited to, the dose, route of
administration,
frequency of use, halflife of the ligand or carrier, half-life of
the radionuclide, and results of
preclinical studies. FDA will categorize
diagnostic radiopharmaceuticals
based
on defined characteristics
relevant to
risk and will specify the amount and
type of safety data appropriate for each
category. For example. for a category of
radiopharmaceuticals
with a wellestablished low-risk profile, required
safety data will be limited.
(d) The radiation safety assessment
shall establish the radiation dose of a
diagnostic radiopharmaceutical
by
radiation dosimetry evaluations in
humans and appropriate animal models.
Such an evaluation must consider
dosimetry to the total body, to specific
organs or tissues, and, as appropriate, to
target organs or target tissues. The
maximum tolerated dose need not be
established.
PART 601—LICENSING
2. The authority citation for part 601
is revised to read as follows:
Authority: 21 U.S.C. 321.351, 352, 353.
355.360, 360c-360f. 360h-360j, 371, 374,
.
28308
,’.
Federal
Register /Vol.
379e. 381:42 U.S.C. 216.241.262.263:15
U.S.C. 1451-1461; S12C. 122, Pub. L. 105-115,
111 Stat. 2322 (21 U.S.C. 355 note).
~601.33
[Redesignated
as ~ 601.28]
3. Section 601.33 Samples for each
importation is redesignated as ~ 601.28
and transferred from subpart D to
subpart C, and the redesignated section
heading is revised to read as follows:
63, No. 99 I Friday, May 22, 1998 I Proposed
(b) The pharmacological and
toxicological activity of the diagnostic
radiopharrnaceutical
(including any
carrier or ligand component of the
dia nostic radiopharmaceutical);
and
(~ The estimated absorbed radiation
dose of the diagnostic
radiopharmaceutical.
5601.33
Indications.
For diagnostic
radiopharmaceuticals,
the categories of
proposed indications for use include.
but are not limited to, the following:
(1) Structure delineation.
(2) Functional, physiological, or
biochemical assessment.
(3) Disease or pathology detection or
assessment.
(4) Diagnostic or therapeutic patient
management.
(b) Where a diagnostic
radiopharmaceutical
is not intended to
provide disease-specific information.
the proposed indications for use may
refer to a process or to more than one
disease or condition.
(a)
~ 601.28
Foreign establishments and
products: samples for each importation.
****
*
4. Subpart D is amended by revising
the title and adding ~~ 601.30 through
601.35 to read as follows:
Subpart D--Diagnostic
Radiopharmaceuticals
Sec.
601.30
601.31
601.32
and
601.33
601.34
601,35
Scope.
Definition.
General factors relevant to safety
effectiveness,
Indications.
Evaluation of effectiveness.
Evaluation of safety.
Subpart
D—Diagnostic
Radiopharmaceuticals
~ 601.30
Scope.
This subpart applies to
radiopharmaceuticals
intended
for in
vivo administration
for diagnostic and
monitoring use. It does not apply to
radiopharmaceuticals
intended for
therapeutic purposes. In situations
where a particular radiopharmaceutical
is proposed for both diagnostic and
therapeutic uses, the
radiopharmaceutical
shall be evaluated
taking into account each intended use.
~ 601.31 Definition.
For purposes of this subpart,
diagnostic radiopharmaceutical
means:
(a) An article that is intended for use
in the diagnosis or monitoring of a
disease or a manifestation of a disease
in humans; and that exhibits
spontaneous disintegration
of unstable
nuclei with the emission of nuclear
particles or photons; or
(b) Any nonradioactive
reagent kit or
nuclide generator that is intended to be
used in the preparation of such article
as defined in paragraph (a) of this
section.
~ 601.32
General factors relevant to safety
and effectiveness.
FDA’s determination
of the safety and
effectiveness
of a diagnostic
radiopharmaceutical
shall include
consideration
of the following:
(a) The proposed
radiopharmaceutical
medicine;
use of the diagnostic
in the practice of
~ 601.34 Evaluation of effectiveness.
(a) The effectiveness of a diagnostic
radiopharmaceutical
is assessed by
evaluating its ability to provide useful
clinical information related to its
proposed indications for use. The
method of this evaluation will vary
depending upon the proposed
indication and may use one or more of
the following criteria:
(1) The claim of structure delineation
is established by demonstrating the
ability to locate and characterize normal
anatomical structures.
(2) The claim of functional,
physiological, or biochemical
assessment is established by
demonstrating reliable measurement of
function(s) or physiological,
biochemical, or molecular process.
(3) The claim of disease or pathology
detection or assessment is established
by demonstrating in a defined clinical
setting that the diagnostic
radiopharmaceutical
has sufficient
accuracy in identifying or characterizing
the disease or pathology.
(4) The claim of diagnostic or
therapeutic patient management is
established by demonstrating in a
defined clinical setting that the test is
useful in diagnostic or therapeutic
patient management.
(5) For a claim that does not fall
within the indication categories
identified in S 601.33, the applicant or
sponsor should consult FDA on how to
establish the effectiveness of the
diagnostic radiopharmaceutical
for the
claim.
(b) The accuracy and usefulness of the
diagnostic information shall be
Rules
determined by comparison with a
reliable assessment of actual clinical
status, A reliable assessment of actual
clinical status may be provided by a
diagnostic standard or standards of
demonstrated accuracy. In the absence
of such diagnostic standard(s), the
actual clinical status shall be
established in another manner, e.g..
patient followup.
S 601.35
Evaluation
---
of safety.
in the safety
assessment of a diagnostic
radiopharmaceutical
include, among
others, the following: The radiation
dose; the pharmacology and toxicology
of the radiopharmaceutical,
including
any radionuclide, carrier, or Iigand: the
risks of an incorrect diagnostic
determination; the adverse reaction
profile of the drug; and results of human
experience with the
radiopharmaceutical
for other uses.
(b) The assessment of the adverse
reaction profile includes. but is not
limited to, an evaluation of the potential
of the diagnostic radiopharmaceutical,
including the carrier or Iigand, to elicit
the following:
(1) Allergic or hypersensitivity
responses.
(2) Immunologic responses.
‘(3) Changes in the physiologic or
biochemical function of the target and
non-target tissues.
(4) Clinically detectable signs or
symptoms.
(c) (1) To establish the safety of a
diagnostic radiopharmaceutical,
FDA
may require, among other information,
the following types of data:
(i) Pharmacology data.
(ii) Toxicology data.
(iii) Clinical adverse event data.
(iv) Radiation safety assessment.
(2) The amount of new safety data
required will depend on the
characteristics of the product and
available information regarding the
safety of the diagnostic
radiopharmaceutical
obtained from
other studies and uses. Such
information may include, but is not
limited to, the dose, route of
administration.
frequency of use, halflife of the Iigand or carrier, half-life of
the radionuclide, and results of
preclinical studies. FDA will categorize
diagnostic radiopharmaceuticals
based
on defined characteristics relevant to
risk and will specify the amount and
type of safety data appropriate for each
category. For example, for a category of ~
radiopharmaceuticals
with a wellestablished low-risk profile, required
safety data will be limited.
(d) The radiation safety assessment
shall establish the radiation dose of a
(a) Factors
considered
Federal
.
Register lVol. 63, No. 99 I Friday, May 22, 1998/Proposed
.——diagnostic radiopharmaceutical
by
radiation dosimetry evaluations in
humans and appropriate animal models.
Such an evaluation must consider
dosimetry to the total body, to specific
organs or tissues, and, as appropriate, to
target organs or target tissues. The
maximum tolerated dose need not be
established.
Dated: April 15, 1998.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Dec. 98-13797 Filed 5-20-98; 11:44 am]
91LLING
CODE
4160-01 -F
ENVIRONMENTAL
AGENCY
PROTECTION
40 CFR Part 89
[FRL-6014-4]
RIN 2060-AH65
Control of Emissions
of Air Pollution
from New Cl Marine Engines at or
Above 37 Kilowatts
Environmental
protection
Agency (EPA).
.—- ACTION: Advance notice of proposed
rulemaking,
AGENCY:
EPA is issuing this Advance
Notice of Proposed Rulemaking
(ANPRM) to invite comment from all
interested parties on EPA’s plans to
propose emission standards and other
related provisions for new propulsion
and auxiliary marine compressionignition (CI) engines at or above 37
kilowatts (kW). This action supplements
an earlier action for these engines
initiated as part of an overall control
strategy for new spark-ignition
(S1) and
CI marine engines (Notice of Proposed
Rulemaking (NPRM) published
November 9, 1994, modified in a
Supplemental
Notice of Proposed
Rulemaking (SNPRM) published at
February 7, 1996). The engines covered
by today’s action are used for
propulsion and auxiliary power on both
commercial and recreational vessels for
a wide variety of applications including,
but not limited to, barges, tugs, fishing
vessels, ferries, runabouts, and cabin
cruisers. This document does not
address diesel marine engines rated
under 37 kW, which are included in a
proposed rulemaking for land-based
nonroad CI engines published at
September 24, 1997.
DATES: EPA requests comment on this
ANPRM no later than June 22, 1998.
Should a commenter miss the requested
deadline, EPA will try to consider any
comments received prior to publication
SUMMARY:
-
of the NPRM that is expected to follow
this ANPRM. There will also be
opportunity for oral and written
comment when EPA publishes the
NPRM.
ADDRESSES: Materials relevant to this
action are contained in Public Docket
A-97-50, located at room M- 1500,
Waterside Mall (ground floor), U.S.
Environmental Protection Agency, 401
M Street, S. W., Washington, DC 20460.
The docket may be inspected from 8:00
a.m. until 5:30 p.m., Monday through
Friday. A reasonable fee maybe charged
by EPA for copying docket materials.
Comments on this notice should be
sent to Public Docket A–97–50 at the
above address. EPA requests that a copy
of comments also be sent to Jean Marie
Revelt, U.S. EPA, 2565 Plymouth Road,
Ann Arbor, MI 48105.
Rules
28309
individual mobile sources. Both of the
new emission programs referred to
above, for on-highway and nonroad CI
engines, are anticipated to reduce
ambient PM levels, either through a
reduction in directly emitted particulate
matter or through a reduction in indirect
(atmospheric) PM formation caused by
NOX emissions.
Domestic and ocean-going CI marine
engines account for approximately
4.5
percent of total mobile source NOX
emissions nationwide. However,
because of the nature of their operation,
the contribution of these engines to NOX
levels in certain port cities and coastal
areas is much higher. To address these
emissions, today’s action outlines a
control program for CI marine engines at
or above 37 kW that builds on EPA’s
programs for on-highway and landFOR FURTHER INFORMATION CONTACT:
based nonroad diesel engines identified
Margaret Borushko, U.S. EPA, Engine
above, EPA’s recent locomotive rule,
Programs and Compliance Division,
discussed below, and the International
(734) 214-4334.
Convention on the Prevention of
SUPPLEMENTARY
INFORMATION:
Pollution from Ships (MARPOL 73/78),
Annex VI—Air Pollution developed by
I. Purpose and Background
the International Maritime Organization
A. Purpose
(IMO).~ If the emission standards and
Ground level ozone levels continue to other requirements for those CI marine
engines that use the same technologies
be a significant problem in many areas
reflected in EPA’s on-highway, landof the United States, In the past, the
based nonroad, or locomotive rules are
main strategy employed in efforts to
implemented as discussed in today’s
reduce ground-level ozone was
action, EPA would expect to see NOX
reduction of volatile organic compounds
and PM reductions on a per-engine basis
(VOCS). In recent years, however, it has
comparable to those achieved by
are
become clear that NOX controls
engines subject to those rules. The
often
amoreeffective
strategy
for
reducing
ozone.
Asaresult,
attention numerical levels that EPA is considering
hasturned
toNOX emission
controls
as applying to very large CI marine engines
thekeytoimproving
air
quality
in many were intended by IMO to result in a 30
percent NOx reduction. EPA continues
areas of the country. Building on the
to investigate IMO’S anticipated
emission standards for CI engines
promulgated in the early 1990s, EPA has reductions for those engines. based on
the age and other characteristics
of the
recently promulgated a new emission
U.S. fleet.
control program for on-highway CI
engines and proposed a new program
B. Statutory Authority
for nonroad CI engines. 1,z Both of these
programs contain stringent standards
Section 213 (a) of the Clean Air Act
that will greatly reduce NOX emissions
(CAA) directs EPA to: (1) conduct a
from these engines.
study of emissions from nonroad
Similarly, particulate matter (PM) is
engines and vehicles: (2) determine
also a problem in many areas of the
whether emissions of carbon monoxide
country. Currently, there are 80 PM– 10
(CO), oxides of nitrogen (NOX), and
nonattainment
areas across the U.S.
volatile organic compounds (VOCS,
(PM- 10 refers to particles less than or
including hydrocarbons (HC)) from
equal to 10 microns in diameter). PM,
nonroad engines and vehicles are
like ozone, has been linked to a range
significant contributors to ozone or CO
of serious respiratory health problems.
in more than one area which has failed
Levels of PM caused by mobile sources
to attain the national ambient air quality
are expected to rise in the future, due to
standards (NAAQS) for ozone or CO:
the predicted increase in the number of
and (3) if nonroad emissions are
determined to be significant, regulate
! [n this notice, the term “land-based nonroad”
those categories or classes of new
and ‘‘nonroad’”refers to the land-based CI engines
and equipment regulated under 40 CFRpatt
89.lt
doesnotinclude
locomotive
engines.
J A copy oFMARPOL 73/78 Annex VI and the
associated NOX Technical Code is available in this
ZSee62FR54694
(October
21,1997)
and62FR
docket.
(September 24, 1997).
50152
..
825
utc.
tric
)tor
dar
md
ys-
Assessment of Coronary Artery Disease
Severity by Positron Emission Tomography
Cci:tal
59;
Comparison With Quantitative Arteriography in 193 Patients
sed
nJ
Linda L. Demer, MD, PhD, K. Lance Gould, MD, Richard A. Goldstein, MD,
.st?
Richard L. Kirkeeide, PhD, Nizar A. Mullani, Richard W. Smalling, MD, PhD,
ns-
Akira Nishikawa, MD, and Michael E. Merhige, MD
M:
m‘ed
‘he
:Ie
~86
Iar
ed
dy
tic
1st
‘uIte
:r—
.
Withthe technical assistance of Ma~ Haynie, ~,
and Richard L. Holmes, RT
To assess the accuracy of positron emission tomography (PET) for evaluation of coronary artery
disease (CAD), cardiac PET perfusion images were obtained at rest and with dipyridamolehandgrip stress in 193 patients undergoing coronary arteriography. PET images were reviewed
by two independent readers blinded to clinical data. Subjective defect severity scores were
assigned to each myocardial region on a O (normal) to 5 (severe) scale. Results were compared
with arteriographic stenosis severity expressed as stenosis flow reserve (SFR), with continuous
values ranging from O (total occlusion) to 5 (normal), calculated from quantitative arteriographic dimensions using automated detection of the vessel borders. There were 115 patients
with significant CAD (SFR < 3), 37 patients with mild CAD (3< SFR <4), and 41 patients with
essentially normal coronaries (SFR>4). Whh increasingly severe impairment of stenosis flow
reserve, subjective PET defect severity increased. Despite wide scatter, a PET score of 2 or more
was highly predictive of significant flow reserve impairment (SFR < 3). For each patient, the
score of the most severe PET defect correlated with the SFR of that patient’s most severe
stenosis (r,= O.77&0.06). For each of 243 stenoses, PET defect score correlated with the SFR of
the corresponding
artery (r,= O.63A0.08). PET defect location closely matched the region
suppIied by the diseased artery, and readers agreed whether the most severe PET defect was less
than or more than 2 for 89% of patients. (Circulatiorz 1989; 79:825-835)
M
yocardial perfusion imaging is widely used
for noninvasive assessment of stenosis
severity. Knowledge of the diagnostic
accuracy of these tests is important for proper
clinical application and interpretation. Most previous reports of the diagnostic accuracy of myocardial perfusion imagingl-d have used sensitivhy-
specificity analysis to describe the relation between
image defects
and arteriographic
disease.
This
method requires binary (positive or negative) clas-
sification of both imaging and arteriographic results.
Arteriographic results have usually been described
in terms of percent diameter narrowing, with a
threshold value of 5070 as the criterion for presence
of coronary disease.
From the Division of Cardiology, Department of Medicine,
There are three limitations to this use of sensitivityand Positron Diagnostic and Research Center, University of
specificity analysis for assessing accuracy of noninTexas Medical School, Houston, Texas.
vasive tests for coronary disease. First, coronary
College
of
Presented in part as an abstract at the American
disease is not an all-or-none condition; binary clasCardiology
Scientific
Session,
March28,1988.
Supported
h part
byGrants
RO1-HL-26862
andRO1-HL-26885 sification requires arbitrary threshold criteria and
fromtheNational
Institutes
of Health;
DE-FG05-84ER6021O creates artificial distinctions in coronary artery disfromtheDepartment
ofEnergy;
andasa joint
collaborative
ease that, in actuality, has a continuous spectrum of
research
project
withtheClaytOrr
Foundation
forResearch,
severity.
Houston,
Texas.
Threshold values that yield optimal sensitivity
Addressforcorrespondence:
LindaL. Demer,MD, PhD,
Division
ofcardiology,
UCLA School
ofMedicine,
47-123
CHS,
and specificity values for one test may yield falsely
10833LeConteAvenue,LOS Angeles, CA 90024-1679.
lower values for a different but more accurate test if
Addressforreprints:
K. Iarrce
Gould,MD, Dkisionof
its detection threshold is different. For example, an
School, P.O. Box
Cardiology,
University
of TexasMedical
imaging test capable of detecting 4070 stenoses may
20708, Houston, TX 77225.
Received June 7, 1988; revision accepted December 6, 1988.
have low specificity according to a 50% stenosis
1
&
..
826
11
‘~
~~
:,
~“
1
!
I
Circulation
Vol 79, No 4, April 1989
criterion but high specificity according a 40’%0stenosis criterion.
Second, sensitivity and specificity values are also
determined by the disease distribution of the study
populations A sample population with a high frequency of mild disease will be distributed centrally
near the threshold values where scatter is more
likely to lower sensitivity and specificity. The sensitivity and specificity found in one population may
not apply to a different population. To overcome
these limitations, analysis of test results as continuous variables has been proposed.b
Finally, recent reports by Marcus and others7,6
have indicated that percent diameter narrowing is
not an adequate standard for quanti~ing stenosis
severity in clinical studies. It does not account for
the effects of diffuse disease, inherent eccentricity,
stenosis length, viscosity, cross-sectional
area,
entrance and exit angles, and absolute dimensions
on flow impedance; and it is limited by substantial
interobserver and intraobserver variability .g-ll Proposed alternative approaches include quantitative
arteriographic methods based on the Brown-llodge
methodlz to calculate stenosis flow reserve 13 and
direct measurement of corona~ flow velocity by
Doppler catheter. 14
In an earlier study, Wijns and colleaguesls used
quantitative arteriographic and direct physiologic
measurements to assess the accuracy of planar 20~TI
imaging, but they retained the conventional threshold criteria to classify arteriographic severity and
perfusion defect severity as positive or negative.
The feasibility of clinical PET perfusion imaging has
also been addressed in previous work by Schelbert
and colleagueslb and, with quantitative arteriographic flow reserve, by our group.lT These studies
also retained the binary classification system and
involved small numbers of patients.
The purpose of the present study was to reevaluate the accuracy of positron perfusion imaging in
assessment of coronaty disease severity with scales
covering the range of disease severity rather than
binary classification, direct correlation rather than
sensitivity-specificity analysis, and quantitative arteriographic flow reserve rather than percent diameter narrowing, in a large series of patients.
Methods
Study Patients
Subjects consisted of 193 patients (143 men, 50
women) undergoing diagnostic cardiac catheterization. The patient sample included 50 patients previously reported in a study where binary classification
and sensitivity-specificity analysis were used. 17Clinical indications for arteriography included chest
pain syndromes, myocardial infarction, abnormal
stress tests, coronary angioplasty, thrombolytic therapy for acute infarction, evaluation before renal
transplant, before and after cholesterol lowering
programs, or as part of screening feasibility studies.
,.
Sixty-six patients were clinically diagnosed as hav.
ing a previous myocardial infarction. From an initial +
group of 209 patients, 12 early patients were exclud~~
because part of the heart was not imaged due to
positioning error, and four PET images were not
interpretable due to camera or computer malfunction. Patients were not enrolled if there was evidence
of unstable angina or active bronchospasm with
theophylline bronchodilator therapy, which are conAfter
traindications to intravenous dipyrklmck.
informed consent was obtained, coronary arteriography and PET imaging were performed according to
protocols approved by the University of Texas Committee for Protection of Human Subjects.
Quantitative Ai-teriography
Cheangiographic frames of orthogonal views were
digitized for each stenosis involvimz a maior arterv.
including diagonal, obtuse marginal, ramu”s intermedius, and acute marginal branches. Absolute and
relative stenosis dimensions were measured with a
computer program providing automatic detection of
vessel borders (Figure 1), with an accuracy of t 0.1
mm. The theory and equations for predicting stenosis flow reserve from these dimensions have been
described previously .ls.ls In brief, the coronary perfusion pressure distal to each stenosis was calculated
as a function of flowlg,~ according to the equation:
<7
P~,=PAO- (fQ + SQ2)
where P~r is distal coronary pressure, PAOis aortic
pressure, Q is flow, f is 8w7rL/A~, s is p((l/AJ - (1/
A.))*, & is minimum absolute area, An is absolute
area of normal adjacent artery, w is blood viscosity,
p is blood density, and L is stenosis length.
This relation, shown as the curved line in Figure 1,
lower panel, was compared with the known pressureflow relation for conditions of maximal coronary
vasodilation, shown as the diagonal line. Stenosis
flow reserve (SFR) was defined as the intersection of
these two relations (i.e., flow at maximum coronary
vasodilation) relative to rest flow, under standardized
hemodynamic conditions. In comparison with direct
measurements by electromagnetic flow meter, the
95% confidence interval was *0.66 with a reproducibility of 2–3Y0.1SThe advantages of SFR over other
methods of describing stenosis severity have been
discussed in detail in a recent editorial.zl
Coronary arteries were considered normal if patent
bypass grafts supplied the arterial bed (two patients).
Five patients having their PET study after acute
myocardial infarction, with normal coronary arteriography after revascularization
of chronic occlusions, were considered to have total occlusions for
the purposes of patient-by-patient analysis. Infarctrelated stenoses of 19 patients who had undergone
acute revascularization were excluded from this analysis because the residual stenosis severity would not
be comparable to the variable degree of resultant
perfusion defect; the remaining stenoses in these
patients were included in the regional analysis.
...
Demer et al
Cardiac PET and Quantitative Arteriography
FIGURE1.
827
Top paneI:Automtededge-
detection analysis ofacorona~arteriogram. Bottompanel: Quantitativeartenographicdataforanotherpatient
including
plots of diameter and cross-sectional
Iumenarea asfunctions ofm”alposition
(lower Iefi); parameters calculated from
dimenswns including minimal,proxima~
dista~ andpercent diameter ineach view
(DI,DJ, minimal, proxima~ diktal, and
percent cross-sectional
area, volume,
length and relative length of the stenosed
segment, entrance andm”tangles (aand
Q), predicted rest flow (Q,), and viscous
and expanswn kms coejicients {C,, C,,
&
&) @PPerlefi); and the derived
pressure-jlow relatwn and stenosis flow
reserve (upper n“ght). The diagonal line
crossing the pressure-flow curve represents the condition of maximal arteriolar
vasodilation. As j?ow increases, pressure
distal to the stenosk decreases, until it
reaches a minimum at the point of maximal vasodilatkm. Stenosis jlow reserve is
defined as that maximum value of j70w
relative to restingjlow (Q/Q,) under standardized hemodynamic conditions, where
normal stenosis flow reserve is 5.
Ouantltatiue
1 -SEP-88
fiRT0132177
%~eriography
UTHSCHiCard
RCR
10 logy
28-aPR-88
UCIN #3
100
Prox
Flin
-------------------------
Dl(mm)
D2(mm)
R(mm2)
! 2.65
! 2.79
! 5.88
L(mm)
~lpha
Rn(mm2)
Qr(cc/s)
17.0
-19.8
7.9
1.6
0.87
1.29
0.89
L/Dn
Omeg
Ku
Cu
Dist !%Redl
3.I32
3.33
7.91
5.4
13.7
2053
2.15
! 71
! 61
I 89
Norm
---! 3.I32
! 3.33
! 7.91
U(mm3)
69.8
Ke
Ce
1.40
5.36
Pcor
mnHg
I
1
G!/Qrest
16
fl
/-TU--f3X[f+L
POSITION
(trim)
.- -
60
,
c
.
828
Circulation Vol 79, No 4, April 1989
FIGURE 2. Positron emission tomographic 82Rbimages acquiredfrom a patient with proximal disease of the lefl anterior
descending artety before (top row of upper and lower images) and after (bottom row) intravenous dipyridamole with
handgrip stress. The views are oriented in the obl@e semi-long axis and arranged in vertical orderfiom base (upper left)
to inferior wall (lower right). Each slice is viewed from above so that the apex is at the top, the lateralfiee wall on the
left, the valve ring at the bottom, and the interventricular septum at the upper right of the horseshoe-shaped
Iejl
ventricular slices. In the color coding, white is the highest, red next highest, yellow intermediate, and green and blue
lowest uptake. l%ere is a la~e anterior, septal, and apical defect. The right ventricular wall is not normalJy visualized
on PET imaging due to its thin walls,
Positron
Emission
Tomography
Patients were fasted for 4 hours, and caffeine and
theophylline were withheld for 8 hours before imaging to prevent interference with the hyperemic
effect of dipyridamole. Fluoroscope was used to
mark the cardiac borders for proper patient positioning. Scans were performed with the University
of Texas multislice tomograph17.zz with a reconstructed resolution
of 14 mm full-width halfmaximum. Transmission imagei were performed to
correct for photon attenuation. Emission images
were obtained with 82Rb produced by a portable
generators or, when 82Rb was not available, 13N
ammonia. 17,Zd,~Eighty-two patients received 82Rb
and 111 received 13N ammonia. The tracer was
injected through a 20-gauge catheter inserted into
an antecubital vein. To allow for blood 001 clearante, there was a l-minute delay after !’2Rb and a
3-minute delay after ammonia administration. After
this delay, data were acquired for 5–8 minutes for
82Rb and 15–20 minutes for 13N ammonia. After
isotope decay, 10 minutes after administration of
the first dose of 82Rb or 40 minutes after 13N
ammonia, dipyridamole
(O.142 mg/kg/min)
was
infused for 4 minutes. Two minutes after the infusion was completed, 25% of the predetermined
maximal handgrip was begun as described by
Brown.zs
At 8 minutes from onset of the infusion, a
second dose of the same amount of the same tracer
was injected, and imaging was repeated. Data
were acquired over the same period. Radiation
doses involved in these procedures
have been
described previously .z7-zgFor those patients developing significant angina, aminophylline (125 mg)
was given intravenously.
I
-
Demer et al
image
I
,
I
TMMX1.
Inteqoretation
As previously described,17 rest and stress images
with nine tomographic slices each, were displayed
in an isocount color format. This format consisted
of five primary colors (white, red, yellow, green,
and blue) in order of highest to lowest counts, each
divided into 3% gradations of shade. Images were
visually interpreted by two independent readers
(KLG, RAG) blinded to clinical data. In two cases,
only one interpretation was available due to loss of
data files. Rest and stress images were displayed
either side-by-side or superimposed with adjustable
color scales (Figure 2).
Seven regions of each cardiac image (anterior,
apical, anteroseptal,
posteroseptal,
anterolateral,
posterolateral, and inferior walls) were evaluated.
Perfusion defects, defined as regions of subjectively
lower counts in at least two contiguous slices compared to the remainder of the heart, were graded on
a O to 5 scale defined as normal (0), possible (l),
probable (2), miId (3), moderate (4), and severe (5)
defects, respectively. One score was assigned to
each region. Each step of the scale corresponded to
approximately one primaty color step. For example,
in general, a red region adjacent to a white region
was not considered a definite defect; however, yellow adjacent to white was considered a definite
defect. Relative size of the defect was also included
in assigning the scale to allow for pixel noise. The
average of the two readings was taken for each
region, in effect resulting in an Ii-point scale (O
through 5 in 0.5 increments) of PET defect severity.
Interobserver
Differences
Scan Interpretation
in PET
PET defect scores assigned to each region by the
two readers were compared for variability according to the criteria shown in Table 2. A similar
method has been used to assess interobserver differences in interpretation
of thallium perfusion
images.zg Due to overlap of some portions of the
seven cardiac regions defined above, minor differences in the description of regions contiguous to a
large defect were allowed. For example, if a defect
were described by one reader as having a grade 4
defect in the anterior, apical, and anteroseptal
regions and O in the anterolateral region, whereas
the other reader assigned a score of 4 to all four
regions, then the readings were considered in essential agreement despite the difference in scores for
the anterolateral region.
In eight cases, the qualitative interpretations differed markedly, and the readings were repeated
independently. On repeat reading, the interpretations remained in disagreement except in two cases.
The new readings were used for these two patients.
For the other six, a mean of the divergent scores
was used, as for the remaining patients.
I
Cardiac
Artery in
PET and QuantitativeArteriography
Relation of PETDefect Location
One-Vessel Disease
829
to Stenosed Coronary
LAD-diagonal
Anterior
Anterolateral-anteroseptal
11
7
Anterior and inferior
2
Anteroseptal and posterolateral
2
None
SFR >3
SFR<3
Circumflex
Posterolateral
Posterior
orlateral
Anterior
13
2
10
4
1
None
SFR<3
Right coronary
1
Inferior
8
Inferolateral
Inferoapical-apical
2
6
Inferoseptal
2
Anterolateral
1
None
SFR>3
1
SFR <3
2
LAD, left anterior descending coronary artery; SFR, stenosis
flow reserve.
Comparison of PET defect location with site of coronary
artery narrowing for patients with one-vessel disease with SFR <4.
Analysis
To determine the relation of PET defect severity
to stenosis flow reserve, two analyses were used.
First, the PET defect score was compared with its
presumed corresponding artery for each defectstenosis pair. Only the most severe stenosis was
considered for each artery, and patients with neither
stenoses nor PET defects were counted as only a
single data pair rather than three pairs to prevent
overweighting the extreme normal end of the scale.
The anterior, septal, and anterolateral regions were
associated with the LAD; the posterolateral region
was associated with the circumflex, and the inferoposterior region was ‘associated with the right coronary artery. Diagonal and ramus intermedius branches
were associated with the same region as the LAD.
Second, because it may be difficult to determine
with absolute certainty which artery corresponds to
a given region, the data were also analyzed by
comparing the most severe PET defect with the
most severe SFR for each patient. The nonparametric rank correlation coefficients, standard errors,
and confidence intervals were determined by the
Spearman method and reported as the Spearman
correlation coefficient, r,, f two times the SEE.
Least-squares method was used to calculate the
regression coefficients. Fisher’s exact test was used
to compare results of the two perfusion tracers.
830
Circulation
Vol 79, No 4, April 1989
I
4s
I
16
II
]1] ~
I
‘$1 [
~
-
t2
$3
0
. ,’
G
L
‘“
10
,9
4
~
I
15
56
w
II
13
T
L
m
:2
Results
N
0
t3
Significant
-–––-––
————
———.
25
—— --
3?
Mild
167
gp––.l-l––l–i–
5
35
I
I
I
2
SUBJECTIVE
3
PET
4
5
DEFECT SEVERITY
N
‘f
Coronary artery stenoses with flow reserve values less than 4 were found in 137 patients. Thirtyseven of these patients had stenosis flow reserve
values between 3 and 4, consistent with mild
disease. Fifteen had myocardial infarction with
revascularization.
Occlusive disease was present
in 34, involving 42 vessels.
PET Defect
25
5
0
Artenography
–––––––––––––~
,“
-twfmal
Coronary
i
~ 40
I
Severity Versus Stenosis
Seventy
for
Each Artery
For the 243 stenosis-defect pairs among the 193
patients, PET defect score was compared with arteriographic severity of the corresponding coronary
stenosis (Figure 3, top). With increasing impairment
of flow reserve, subjective PET defective severity
increases. Although there is wide scatter, a PET
defect score of 2 or more, indicated by the vertical
line in Figure 3, top, is highly predictive of significant
flow reserve impairment (SFR < 3). PET score rank
correlated significantly with SFR (r, = 0.63 f 0.08).
Lhear regression yielded the equation:
1~]1
[!~
M
5
,6
12
—
7
——_
14
9
II
5
——
12
1
.—— — —
10
22
——— ———
15
————
predicted SFR =3.91 -0.55 (PET defect rank)
16
25
I
51
0
I
SUBJECTIVE
2
3
4
5
PET DEFECT SEVERITY
FIGURE 3. Top panel: Plot of the relation between
arteriographic stenosis flow reserve and subjective PET
defect severity in the corresponding anatomic region for
243 stenoses. Mean value of SFR is plotted as a jimction
of PET defect seven”ty. The horizontal dashed lines identifi the ranges of normal, mildly reduced, and significantly reduced stenosis j?ow reserve. The vertical dashed
line indicates that PET defect scores of 2 or more predict
the presence of mild or significant stenoses. The emor
bars represent 90% confidence intervals. The number of
patients represented is shown adjacent to each point.
Right-hand column lists the numbers ofpatients found in
each interval of SFR, to illustrate the dktribution of
coronary disease in this population. SFR is plotted on a
reverse scale (5 to 0) to parallel stenosis severity. No
error bars are shown for the point representing a single
stenosis. Bottom panel: Plot of the relation between
arteriographic stenosis jlow reserve and subjective PET
defect severi~ in 174 patients. The most severe stenosis
was compared with the most severe PET defect for each
patient. Nineteen patients with revascularization during
acute infarction were excluded because the residual
stenosis seven”~ would not be comparable to the severity
of the jixed pe@usion defect. As for the top panel, the
horizontal dashed lines identi~ the ranges of normal,
mildly reduced, and significantly reduced stenosis flow
reserve. The vertical dashed line indicates that PET
defect scores of 2 or more predict the presence of mild or
significant stenoses.
with standard errors for the coefficients of 1.4 and
0.04, respectively. This regression equation is provided for description rather than for calculations;
because of the scatter in the relation, direct calculation of any individual value of SFR from PET defect
score would not be accurate. Mean values are shown
for clarity because of overlap of the large number of
data points; regression was performed with the raw
data. Although the correlation coeffkient is negative,
the slope is positive in Figure 3, top, because the
vertical scale was reversed in the figure for convenience so that SFR would parallel stenosis severity.
PET Defects Compared
With Arteriographic
Severi~ for Each Patient
To determine whether PET defects identify
patients with coronary disease, irrespective of location, the SFR of the most severe stenosis was
compared to the score of the most severe PET
defect for each patient over the entire range of
disease severity (Figure 3, bottom).
As in the preceding figure, increasing impairment
of flow reserve corresponds to increasing PET
defect severity. Although there is wide scatter, a
PET defect score of 2 or more (indicated by the
vertical line in Figure 3, bottom) is predictive of
significant flow impairment (SFR < 3). The SEMS
are larger for the middle range of stenosis severity
(from 2 to 4) than for the extremes. This is attributable in part to the smaller numbers of PET defects
in this range. In addition, several of these defects
correspond to lesions in diagonal arteries or in distal
portions of the larger arteries, affecting small regions
of myocardium. The severity of such small defects
.- ?.
Demer et al
Interobserver Differences in PET Scores
TABLE2.
culty
distinguishing normal
mild perfusion defects.
Maximal score
Classification
Difference
Rest scans
Stress scans
Agreement
Identical
o
75 (40%)
59 (31%)
Essential
1
66 (35%)
86 (45%)
Near
2
14 (7%)
14 (7%)
Disagreement
Mild
3
19 (lo%)
16 (8%)
Moderate
4
4 (2%)
3 (2%)
Marked
5
11 (6%)
11 (6%)
Percent in parentheses.
Interobserver differences in subjective scoring of PET scans
by two independent readers blinded to angiographic and clinical
data. Results are tabulated according to the maximum difference
in scores assigned to each region by the two readers. Only one
reading was available for two patients.
may be blunted by the partial volume effect which is
a function of camera resolution.
PET defect severity correlated significantly with
arteriographic stenosis severity (r, = 0.77 k 0.06). Linear regression yielded the equation:
predicted SFR = 4.14-0.70
___
B
(PET defect rank)
with standard errors for the coefficients of 0.14 and
0.04, respectively. As above, this equation is provided for description rather than for calculations.
As for Figure 3, top, mean values are used for
clarity; regression was performed with the raw
data. The problem of false-positive scans is described
below.
Special
Cases
Cardiac PET and Quantitative Arteriogmphy
and Exceptions
One patient with a long intramyocardial portion
or “muscle bridge” of the proximal left anterior
descending artery had a moderate PET defect of the
anterolateral wall. Two patients had defects of the
resting PET scan which normalized with stress; one
of these two patients had an arterioatrial fistula; the
other had no evident coronary disease.
Results of nine patients deviated significantly
from the pattern. Two patients with minimal stenosis severity (S FR>4) had PET defects with scores
more than 2. One with a stress PET defect score of
4.5 reported smoking five cigarettes immediately
before the imaging. A repeat scan performed after
the patient quit smoking was normal. The other
patient with a PET defect score of 3 had undergone
recent transluminal coronary angioplasty with subsequent angiographic dissection of the artery supplying the region of the PET defect, suggesting
early restenosis or closure.
Seven patients with significant CAD (SFR < 3)
had PET scores less than 2 or no defect. None of
these seven cases involved proximal disease; in
five, SFR was greater than 2.5. Mild LAD and
diagonal lesions ‘were more often missed than mild
disease of other arteries, possibly due to diffi-
PET Defect Location
Corona~ Direase
apical thinning
Compared
831
from
W2th Site of
PET defect location was compared to arteriographic localization for each patient. Results for
patients with one-vessel disease are shown in Table
1. For patients with multivessel disease, 55 of 77
had multiple PET defects. In patients with mild or
significant right and left circumflex coronary
stenoses, five of 11 inferoposterior
defects had
associated lateral defects. In combined LAD-RCA
disease, 11 of 13 patients had both anterior and
posterolateral defects. Overall, anterior PET defects
were associated with LAD or diagonal disease and
posterior defects were associated with either left
circumflex or right coronary disease.
Rest PET Defects Compared
Myocardial Infarction
With
Sixty-six patients had a clinical diagnosis of previous myocardial infarction. Fifty-one (77%) of these
had resting PET defects and 18 of these had addi- .
tional or more severe defects with stress. Fifteen
patients with previous infarction had normal rest
scans. Of these 15 exceptions, eight had undergone
acute intervention with intravenous or intracoronary thrombolytic agents and/or transluminal balloon coronary angioplasty. Another five of the
exceptions had non–Q wave infarctions only. The
remaining two had well-developed collaterals.
Rest PET defect severity was less than two in 100
of 127 patients (79%) with no clinical diagnosis of
myocardial infarction. Eight of the 27 exceptions
had complete occlusions of at least one epicardial
coronary artery. Three had regional wall motion
abnormalities documented
by gated nuclear or
contrast ventriculography.
Another eight had
severe coronary stenoses, with SFR values less
than two. There was no evidence of previous
infarct in the remaining eight patients with abnormal rest scans; in two of these eight patients,
scans normalized with stress, and the remaining
six had abnormal stress scans as well.
Interobserver
Differences
Scan Interpretation
in PET
In 82% of rest scans and 83% of stress scans, the
two numeric scores were in agreement (Table 2).
For 89% of patients, readers agreed on the overall
interpretation of the presence (PET score > 2) or
absence of defects (PET score <2) in the rest/stress
scans. Disagreement most often involved the apex
and inferoposterior wall. Forty-eight of 75 rest
scans with identical readings were normal, and 40 of
59 stress scans with identical readings were normal.
Comparison
JWh Thallium
Scinti&-aphy
This study did not specifically compare PET imaging to other, more widely available, methods such as
832
Circulation
Vol 79, No 4, April 1989
‘*TI scintigraphy. Available data are not directly
comparable because of the limitations of sensitivity/
specificity analysis described in the introduction.
One recent study, by Zijlstra and colleagues,JO
reported the sensitivity and specificity of exercise
thallium compared with radiographic coronary flow
reserve in 38 patients with one-vessel disease. It is
not directly comparable because of major differences
in methods, including binary classification, number
and selection of patients, coronary flow reserve
compared with stenosis flow reserve, and exercise
compared with dipyridamole stress. However, this is
the only previous study, to our knowledge, in which
imaging data are compared with a continuous scale
of flow reserve (FR), permitting indirect comparison
to the present results. 1) For moderate to severe
stenoses (FR < 3), 7290 (18 of 25) of thallium scans
compared with 945Z0(108 of 115) of PET scans were
negative. 2) For intermediate stenoses (FR = 3–4),
O% (Oof 9) of thallium scans compared with 49% (18
of 37) of PET scans were positive. 3) For minimal
stenoses (FR > 4), 100% (4 of 4) of thallium scans
compared with 95% (39 of 41) of PET scans were
negative. Three categories were compared because
the small number of patients in the thallium study did
not permit finer divisions, and correlation coefficients were not available for the thallium data. The
intermediate range of 3–4 is used for simplicity, but
it closely approximates the 95% confidence internal of
stenosis flow reseme at the cut-off value of 3.4–3.5
established by other investigators. JO,slThis comparison is limited because of the small number of thallium
patients, especially in the range of normal and less
severe disease; the specificity of thallium may be
overestimated because of the small proportion of
women, reducing the effect of attenuation artifacts.
Compation
of 82Rb with 13N Ammonia
Images obtained with glRb and 13N ammonia
tracers were qualitatively similar. The two false
Bow
cases included one ‘3N ammonia and one
R Image. Of the seven false negative scans, five
were ammonia scans and two rubidium. Thus, 79 of
82 rubidium images and 105of111 ammonia images
were consistent with the arteriographic results. These
ratios were not significantly different (p= 0.73).
Discussion
The accuracy of positron perfusion imaging of the
heart has been reported in previous studies of the
feasibility of clinical dipyridamole-PET
imaging.
Schelbert and colleagueslb compared PET scan
results to percent diameter narrowing and found
sensitivity and specificity values of 97’ZOand 100Yo.
According to standard statistical tables,sz the lower
limits of the 957. confidence intervals for these
In a study of
values are 84% and 75Y0, respectively.
50 patients by Gould et al,lT PET scan results were
compared with quantitative arteriographic stenosis
flow reserve, and sensitivity and specificity were
found to be 95% and 100%. The corresponding
STENOSIS CFR VS. % DIAMETER
““
.
.
.
. >..
..
.: .:...
.
“. ““ ..” “.. .
“..
“.”
.
.“
,.
.
+{.
.
.”
.“.4.
.
.“
.
. .
‘.. x. “.”..
.“
.
“..
“.
“.
““ .:.
.“.
\
.
.
“..
.
.
0
0
m70m
,020304050
“
.
.“
-
..... ..
\ .
. .
go,&
% DIAMETER NARROWING
FIGURE 4. Plot of the relation between stenosis jlow
reserve and percent diameter narrowing, both calculated
from quantitative arteriographic measurements, in the
first 100patients. Because percent diameter narrowing is
only one of several factors used to calculate stenosis flow
reserve, the scatter in thk relation indicates the importance of those factors other than relative diameter that
influence j?ow impedance of a stenosis.
lower limits of the 95% confidence intervals are 77%
and 66Y0. The lower limits of the 9970 confidence
intervals are 71% and 5670. The overlap of these
wide confidence intervals with the sensitivity and
specificity values reported for planar thallium imaging, and even electrocardiographic exercise testing,
indicate the need for larger numbers of patients for
statistical accuracy.
The present study differs from earlier reports
of perfusion imaging accuracy in the combined use
of quantitative
arteriographic
stenosis flow reserve rather than percent diameter narrowing as
the gold standard, the large number of patients,
and the use of correlation
rather than binary
sensitivity-specificity
analysis.
Stenosis Flow Reserve
Flow Reserve
Compared
W7th Coronaiy
It is important
to distinguish
stenosis flow
reserve,sJ which is calculated from static quantitative arteriographic dimensions, compared with coronary flow reserve, which is derived from direct
measurement of the instantaneous ratio of hyperemic to rest flow. Coronary flow reserve depends
on perfusion pressure, coronary venous pressure
and/or arteriolar tone, and strength of the hyperemic stimulus; two stenoses of exactly the same
geometry may have entirely different values of
coronary flow reserve in different patients, or even
in the same patient under different hemodynamic
conditions. SFR, in contrast, is independent of
hemodynamic conditions. It describes the conductance of the stenosis itself as if the arterial segment
were excised and studied in vitro under controlled
conditions. In the present application, this feature is
advantageous because it allows comparison between
patients. Neither measurement is superior; each
.
Demer et al
measures a different aspect of the stenosis, and
each is applicable to a different clinical question.
Stenosis Flow Reserve
Diameter
Compared
With
Narrowing
The advantages of SFR over percent diameter
narrowing, including the use of all relevant dimensions and absolute dimensions to allow for diffuse
disease, have been described previously.zl To assess
the importance of dimensions other than percent
diameter narrowing that enter into the equation for
stenosis flow reserve, calculated SFR was plotted
as a function of percent diameter narrowing for the
first 100 patients (Figure 4). Further patients were
not included because of overlap of data points. The
scatter in this relation represents the effect of factors other than relative diameter, such as length,
absolute cross-sectional area, and expansion angle,
that determine stenosis flow reserve.
These data reveal important limitations of the use
of percent diameter narrowing as the sole indicator
of stenosis severity, even when it is measured
accurately. For arteries with 50% diameter narrowing, stenosis flow reserve ranges from 2.8 to 4.5.
The spread is even wider for 60?Z0narrowing. Many
stenoses with more than 50% diameter narrowing
have only mild or minimal reduction in SFR. Of 107
stenoses with more than 50% diameter narrowing,
30% had only mild SFR reduction (SFR>3), and 8%
had nearlv. normal coronaries C3FRZ4).
.
/ Thus, truenegative perfusion scans associated with such lesions
would be labeled as false-negative, if 5090 diameter
reduction alone were used to define significant
coronary disease. In some studies, the criterion for
significant coronary stenoses is 75% diameter narrowing. This cut-off point, or even 7090 diameter
narrowing, classifies a large number of stenoses
with a significantly reduced SFR as negative. One
third of stenoses with less than 75% diameter narrowing had significantly reduced stenosis flow
reserve (SFR < 3), and 1690 of these were severely
narrowed (SFR < 2). As a result, true-positive scans
associated with such lesions would be labeled as
false-positive, were 75% diameter narrowing alone
used to define significant coronary disease.
PET Defect Severity
Stenosis Severity
Compared
With
PET defect severity correlated significantly with
arteriographic stenosis severity in both the regional
and patient-by-patient analysis. However, there was
considerable scatter in these relations which maybe
attributable to the subjective scoring of PET defects
or other limitations described below.
Rest PET Compared
With Myocardial
Infarction
The relation between PET defects and myocardial infarction has been previously described in a
smaller group of patients.sq The present results
confirm that resting perfusion defects seen by PET
correspond to clinical myocardial infarction.
Cardiac PET and Quantitative Arteriography
Interobsemer
833
Agreement
Interobserver
disagreement occurred primarily
in scans of patients with mild coronary disease
and those with small defects. The finding of 75%
and 76% identical or essential agreement
for
rest and stress scans, respectively, is comparable
with ‘the 7970 exact or essential interobserver
agreement reported for 201TIimages with a slightly
different analytic method.ZT
Potential
Limitations
The use of a subjective scoring method for PET
defect severity most likely accounts for much of the
scatter in the relations in Figure 3. Quantitative
methods for describing PET defect severity have
been described, such as measurement of relative
myocardial perfusion reserve.ss However, this technique was not practical for the large number of
patients in the present study because it requires
subjective border delineation for regional analysis
and assumes the presence of a normal region of
myocardium in each patient. Technical limitations
of quantitative PET imaging include cardiac motion,
patient motion, partial volume errors, and decreased
extraction of perfusion tracers at high flows.sG,sT
Subendocardial infarction may add to apparent error
by introducing a partial-thickness perfusion defect
without a correspondingly severe stenosis in the
supply artery.
Stenoses in series may not have been accurately
assessed. Only the single most severe stenosis was
used to represent each artery because stenoses in
series do not necessarily behave as additive resistances, due to intervening branches, and criteria for
quantitative analysis of such lesions have not been
established.
Anatomic variations in the coronary tree and
overlap of perfusion beds limited the accuracy of
matching each stenosis to a corresponding defect.
For this reason, an additional analysis was performed to compare results for individual patients
irrespective of defect location. This effect would
tend toward underestimation of the relation between
PET defect and stenosis severity by contributing to
scatter. In addition, variation in perfusion bed size
may cause arteries with equally severe stenoses to
have variable sizes of PET defect.
Stenosis flow reserve may not correspond to PET
perfusion reserve in the presence of altered physiologic conditions such as very high or low perfusion
pressure and heart rate, collateral flow, increased
resting flow, ventricular hypertrophy,
abnormal
venous pressure, or inadequate vasodilatory stimuIus.ss Although direct measurement of coronary flow
reserve reflects these conditions, except for collateral flow, it may not be advantageous because hemodynamic conditions are likely to change between the
times of catheterization and PET imaging.
834
Circulation
Vol 79, No 4, April 1989
Summary
Traditionally, noninvasive tests for the detection
of coronary artery disease have been compared
with percent diameter stenosis using binary classification and sensitivity-specificity
analysis. 1-4,39
Recent analysess,G’8’li’m have indicated the need for
comparison to a more accurate gold standard and
the use of continuous rather than binary outcome
variables. In the present study, subjective PET
defect severity and quantitative arteriographic stenosis flow reserve, a more physiologic gold standard, were compared over the full spectrum of
coronary disease severity. Results indicate that
subjective severity of regional PET perfusion defects
correlates significantly with the calculated stenosis
flow reserve of the corresponding coronary arteries.
Acknowledgments
We are grateful
to Jeffrey Gornbein, DrPH, for
assistance with statistical analysis; to Barry Elson,
Martin Buchi, and Yvonne Stuart for technical
assistance; and to Claire Finn and Kathryn Rainbird for assistance with the manuscript. Intravenous dipyridamole
was kindly provided by
Boehringer Ingelheim, Inc.
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KEYWOaDS ● cardiac PET ● quantitative coronary artenography
●
corona~ stenosis ● perfusion imaging