ajh ATDEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

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ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
MEETING BETWEEN THE INSTITUTE FOR
CLINICAL PET AND FDA STAFF
ON APPROVAL PROCEDURES FOR PET DRUGS
Thursday, February 18, 1999
9:10 a.m.
Advisory Committee Conference Room
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Food and Drug Administration
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Rockville, Maryland
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PARTICIPANTS
PET PARTICIPANTS
Peter S. Conti, M.D., Ph.D.
Jennifer Keppler
Val Lowe, M.D.
FDA PARTICIPANTS
Jane Axelrad, J.D.
Florence Houn, M.D.
Ravi Kasliwal, Ph.D.
Patricia Love, M.D.
Brian Pendleton, J.D.
Doug Snyder, Esq.
Victor Raczkowski, M.D.
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C O N T E N T S
Page
Opening Remarks and Welcome
Ms. Jane Axelrad
4
Opening Remarks
Dr. Peter Conti
9
Update on FDG Myocardial Viability and N-13 Ammonia
Dr. Patricia Love
10
Preliminary Results of Safety and Effectiveness
Review of F-18 FDG PET
Dr. Florence Houn
14
Regulatory Procedures for PET
Ms. Jane Axelrad, Mr. Brian Pendleton
55
Status of USP Chapter on PET and PET Monographs
Ms. Jane Axelrad
166
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P R O C E E D I N G S
Opening Remarks and Welcome
MS. AXELRAD:
Good morning.
I am Jane Axelrad,
the Associate Director for Policy at CDER and the Chair of
the PET Steering Committee.
This is the third in a series
of public meetings that we have been holding with
representatives of the Institute for Clinical PET to discuss
issues associated with the development of appropriate
procedures for the approval of PET drugs and appropriate
current good manufacturing practices requirements.
FDA was directed to develop these procedures in
Section 121 of the FDA Modernization Act.
First, I would like to ask my colleagues at the
table and the other people in the room from FDA to introduce
themselves.
DR. LOVE:
Patricia Love, Director, Division of
Medical Imaging, Radiopharmaceutical Drug Products, CDER.
MR. PENDLETON:
I am Brian Pendleton with the
Regulatory Policy Staff.
DR. RACZKOWSKI:
Victor Raczkowski, Office of Drug
Evaluation III in CDER.
DR. HOUN:
Florence Houn, Office of Drug
Evaluation II, also with the Center for Drugs.
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MS. AXELRAD:
If the FDA people around the room
can maybe go to the mikes so they can pick it up.
DR. KASLIWAL:
I am Ravi Kasliwal.
I am a Review
Chemist in HFD 160.
DR. MILLS:
George Mills, Center for Biologics.
DR. LEUTZINGER:
Eldon Leutzinger.
I am the
Chemistry Team Leader in the Division of Medical Imaging.
DR. COLANGELO:
Kim Colangelo, Project Manager in
CDER.
DR. LANGE:
Susan Lange, Office of New Drug
Chemistry Project Manager.
DR. SALAZAR:
Milagros Salazar, Review Chemist,
Division of Medical Imaging.
DR. HUSSONG:
I am David Hussong, Review
Microbiologist, Office of New Drug Chemistry.
DR. LEEDHAM:
R.K. Leedham, Chief Project Manager
with Staff HFD 160 Medical Imaging.
DR. ARNSTEIN:
Nelson Arnstein, Medical Officer in
the Medical Imaging Division.
DR. FARKAS:
Ray Farkas, Group Radiopharmacist,
Division of Medical Imaging.
MS. AXELRAD:
Thank you.
Many of these people have been working very hard
on the documents that we have been producing and the
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presentations that you will be hearing today, and you will
be hearing from several of them over the course of the next
two days.
This meeting has been called by the PET Steering
Committee, a working group created in the Center for Drug
Evaluation and Research to implement Section 121 of the FDA
Modernization Act.
When we began working on PET issues, a little over
a year ago now since the Modernization Act was passed, we
identified the need for a scientific exchange of information
at the working level as we developed the procedures.
In August, at our first public meeting, we
discussed chemistry, manufacturing, and controls issues, and
made a lot of progress in identifying some important
principles that we could carry forward in our work as we
worked on the approval procedures and GMPs.
In November, we presented the preliminary results
of our review of the literature on the safety and
effectiveness of N-13 ammonia for myocardial perfusion and
F-18 FDG for myocardial viability.
At this meeting, we have a very busy agenda.
Copies of the agenda are available in the back of the room.
We will be discussing the preliminary results of our review
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of the literature regarding the safety and effectiveness of
F-18 FDG for oncology indications.
We will explore in more depth the existing new
drug approval procedures to obtain a better understanding of
the possible problems associated with our existing
procedures and to identify areas that we might want to
change.
We will discuss a model that we have developed to
simplify the submission of chemistry, manufacturing and
controls information in an application for FDG, and which,
if this seems to be an workable approach, we may also use
for ammonia and water, and we will discuss a draft outline,
a very preliminary draft outline of possible current good
manufacturing practices for PET.
Copies of all of the relevant documents are
available at the back of the room, and I would like to
stress again that these documents are preliminary working
drafts prepared by the agency as a starting point for the
discussions today and at meetings to follow.
They do not
reflect the official agency position on PET, and may not be
used at this point in time to satisfy regulatory
requirements.
I would also like to just mention a few ground
rules for the meeting.
This is a working meeting between
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FDA staff and the Institute for Clinical PET, however, in
the interest of making this process as open as possible, we
have invited members of the public to attend the meeting as
observers, and some I see have taken advantage of the
opportunity to attend.
Today's discussions will be principally between
the ICP representatives at the table and the FDA staff.
However, members of the audience will be given an
opportunity to comment on the discussion at the end of each
topic.
The purpose of today's meeting is to have a free
exchange of scientific and regulatory information at the
working level.
We are not trying to reach consensus on how
to regulate PET drug products, but rather to exchange
information regarding a scientific foundation on which new
PET approval procedures can be based.
We have quite a bit of material to cover for the
next two days, and I am looking forward to some very
productive discussions.
A little bit about logistics.
We will be breaking
mid-morning, probably after we finish the discussion of the
oncology indications and before we get into the next topic.
We will break for lunch probably around noon.
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There are some restaurants within walking
distance, but it is sort of miserable weather, and for
anybody who wants to, you will have to be escorted, but we
can take you over to the Parklawn cafeteria, and we will
have to get you into the building because of our security,
but we will do that.
There are also vending machines in the room right
across the hall behind us, and if you have any questions,
just ask one of us.
Kim Colangelo is here, right there, and
she is handling the logistics for this.
With that, I would like to turn it over to you,
Dr. Conti, and see if you have some remarks.
Opening Remarks
DR. CONTI:
Just very briefly.
On behalf of Dr.
Barrio, who couldn't be with us today due to an illness and
family circumstances, I want to thank the FDA for again
inviting us to participate in these discussions.
I would like to commend the pace at which things
are moving along on the clinical side.
We are very
appreciative of the reviews and the diligence that has been
put into these evaluations.
It will be a very active discussion as we proceed
for the next two days.
I assume that the majority of the
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activity will focus on the regulatory procedures and the
CGMPs in tomorrow's session.
Again, while we are listed here as the answer to
the clinical PET, I want to remind the FDA and the audience
that we represent the consensus of a number of professional
societies including the USP, including the Society of
Nuclear Medicine in this endeavor.
You all know who I am.
My name is Peter Conti.
will allow the other two visitors here to introduce
themselves.
MS. KEPPLER:
Jennifer Keppler, Institute for
Clinical PET.
DR. LOWE:
Val Lowe, St. Louis University.
DR. CONTI:
point.
I have no other comments at this
I would suggest we just move on to the discussions.
MS. AXELRAD:
First, Dr. Love is going to give us
an update on where we are on the other topics that we are
not going to be discussing today, on FDG myocardial
viability and N-13 ammonia.
Update on FDG Myocardial Viability and N-13 Ammonia
DR. LOVE:
Right.
Again, just briefly, as you
recall, at the end of the last session, we were going to be
considering the language for those two products.
In
essence, we are looking at this moment for FDG, something
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that does relate both ischemia and to some extent viability
determinations and assessments for patients with myocardial
disease or vascular disease, and also looking at ammonia,
perfusion indications, very much along the lines of what Dr.
Houn presented last time, and a way to link the two products
together for expected uses.
At this point, we felt it was best not to come to
final wording on those two because we also need the section
for oncology to look at a final labeled language for an
indication, and we will also have to develop the clinical
trials sections that will go into the labeling, and all of
these pieces are linked.
So, what I am just sharing with you is where we
are at this moment, and certainly we are looking at
considering and linking the functual aspect, the
identification of glucose metabolism abnormalities to all of
these different areas, as well as the linkage to the
existing indication for epilepsy, so we will be having one
composite package insert for all of these areas.
That is where we are with this.
We are also beginning just very preliminarily to
look at O15 water along the same model, although we are not
prepared to discuss that at this time.
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MS. AXELRAD:
I would also like to mention that we
have been presenting our preliminary findings on these at
the series of meetings.
Late this spring or summer, we will
be taking, hopefully, all of them at the same time, if we
can do them all at the same time, to our Medical Imaging
Advisory Committee.
One of the reasons that we don't want to finalize
the labeling is that we do need to present the findings to
the advisory committee and get their input, and they will
also have some input on the labeling issue.
DR. LOVE:
Right.
The other pieces of the label
that will often come into play is any additions or changes
or modifications that might be necessary for a clinical
pharmacology section because of the differences in uptake in
certain tumor areas, and also the heart, plus the
differences in usage, whether or not the FDG imaging is done
in a fasting or non-fasting state.
So, all of those things will have to be modified,
and the persons who are working on those sections are also
here in the audience with us.
DR. CONTI:
Let me just ask a question with regard
to the N-13 stress/rest.
example labeling.
I mean we had submitted to you an
That is actually separate from the FDG
since this is a separate test.
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Where are we with that?
DR. LOVE:
Certainly, we agree that this is used
in both rest and stress situations, and I think we can craft
language that would address that.
I would suggest that you
look at some of the rest/stress labeling that exists for
some of the other radiopharmaceuticals, some of the recent
ones that indicate rest and stress both with exercise, as
well as with pharmacologic stress.
DR. CONTI:
We submitted that.
the labeling.
I think that is what we, in fact, did.
I was just concerned with the hold-up on
With the FDG, I understand because you want
to have that for epilepsy and oncology, but the N-13 is
actually a separate issue in and of itself, separate label.
DR. LOVE:
It is separate, but we generally come
to final labeling language after we write the clinical trial
section, so the team is having labeling meetings at this
point in time, but the final label is not yet finished.
Also, as was just mentioned, we would take it to the
advisory committee, and we would also get input from them.
So, whatever we would have would be preliminary,
but whether the words are exactly the words, and the syntax
and the grammar and which clause comes first has not yet
been determined, but the essence is still myocardial
perfusion with rest and stress.
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DR. HOUN:
Yes, that concept of rest and stress is
acknowledged, as well as what it may be indicative of in
terms of cardiovascular disease.
MS. AXELRAD:
I anticipate that at one of our
other meetings later this spring, probably before it goes to
the advisory committee, we will be discussing our
preliminary, the actual labeling.
When we finish the draft,
we will probably bring it or talk about it at another public
meeting before it is presented to the advisory committee.
DR. LOVE:
Right, and that would be analogous or
similar to our normal procedure with sponsors before
labeling goes to final, the sponsor generally gets a chance
to see the labeling.
MS. AXELRAD:
I think basically, what we are
trying to do here, since we don't have one sponsor, we have
many interested sponsors, is do what we normally do with an
individual sponsor, but in a public forum, so that anyone
who has an interest can follow what we are doing.
DR. LOVE:
With that, I will turn it over to Dr.
Houn, who will be presenting the preliminary results of the
safety and effectiveness review of F-18 FDG PET for
oncology.
Preliminary Results of Safety and Effectiveness
Review of F-18 FDG PET
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DR. HOUN:
My background is I was formerly head of
the FDA program for mammography quality that is responsible
for implementing the Mammography Quality Standards Act.
All
the mammography facilities since 1994 have been certified
and inspected by FDA.
I am also an instructor in oncology at the Johns
Hopkins Breast Surveillance Service where my training was at
the National Cancer Institute in cancer prevention and
control.
So, I am not an oncologist, I actually worked in
the Preventive Oncology Branch.
[Slide.]
I wanted to share with you my review of the safety
and effectiveness literature for oncology indications for
FDG PET, and I wanted to remind folks that we are working as
a team.
There are many members that helped me contribute to
this review, and I really appreciate their hard work.
[Slide.]
I am giving preliminary review conclusions,
preliminary in that as we discuss things, I am sure I am
going to learn a lot from our discussions today and further
discussions, that these conclusions are open for discussion
and can be reviewed.
But in terms of looking at the preliminary
conclusions, I am finding that for FDG PET, there is
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effectiveness in detecting abnormal glucose metabolism to
assist in evaluating malignancy in patients with
abnormalities found by other testing modalities or in
patients with an existing diagnosis of cancer.
The doses that were described in the literature
are between 200 and 740, and that these doses were
administered at least four hours after fasting.
I also found in the review not sufficient data in
terms of how to handle diabetic patients, patients with
hyperglycemia, or the use of furosemide with FDG.
I know
that some institutes and some articles did mention this.
I
will share with you the data to really say much about this
currently.
[Slide.]
My presentation is going to just follow the order
of discussing guidances that FDA issued on clinical
effectiveness in medical imaging, how I derived the intended
use for FDG and oncology indications, discuss a little bit
about the use of pathology as a standard, my search
methodology, selection criteria of the articles, review of
findings of the studies, and preliminary conclusions.
[Slide.]
In terms of when can FDA use published literature
alone in determining clinical effectiveness, back in May of
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1998, FDA did publish a guidance document that stated that
when there are multiple studies that had adequate design and
consistent findings, as well as detailed protocol
information, that objective and appropriate endpoints were
selected carefully, and there was a consistent finding of
efficacy across these studies, and these were conducted with
proper study conditions, that FDA would be able to use
literature in determining safety and effectiveness.
There have been some examples in the history of
FDA in which we relied on literature to find safety and
effectiveness, and the most recent being thalidomide.
[Slide.]
In terms of what is an adequate and wellcontrolled trial, I mean in the medical literature it is
very different from seeing a detailed study protocol, but in
the Draft Medical Imaging Guidance we kind of lay out some
of our thoughts about what should be included in literature
articles, such as the selection of subjects studied should
equal what the target population of the intended use of the
diagnostic is.
That readers should be independent, masked, images
be presented in randomized fashion, separate readings.
That
the diagnostic test is compared to a standard of truth, in
this case, histopathology.
Endpoints are clearly
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delineated.
There is analysis plan, and that safety
information is also important in our review of the
literature.
[Slide.]
In terms of the intended use, I am coming out with
an indication of evaluating malignancy in a diagnostic
population, it is not a screening population, and that this
use of FDG in oncology does not provide a definitive
diagnosis of cancer, but that it will assist in the
evaluation of malignancy.
I derived this in terms of looking at the major
uses that FDG has had in the oncology literature, and to
coordinate with what was published by FDA in the Medical
Imaging Guidance in terms of structuring indications by
anatomical structure, function, diagnostic claim for disease
or patient management claims and outcomes claims.
I am thinking that FDG falls more into a
functional, physiological, or biochemical assessment, and
that is why, in terms of looking at abnormality of glucose
metabolism, that would be included in the indication.
We do think there is a pharmacological basis for
this functional claim.
glycolysis.
Cancer cells do have increased
There is increased hexokinase, lower levels of
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phosphatase in these cells, and that would justify a larger
indication for malignancy.
DR. CONTI:
Just a quick question just from a
logistic point of view.
Would it be better for us to ask
questions as you proceed or wait until the entire
presentation is finished?
How would you like to handle
that?
DR. HOUN:
I guess we could ask while it is
happening, so it is more interactive as opposed to -- yes,
go ahead.
MS. AXELRAD:
I am having a hard time hearing you.
You might move your mike closer.
DR. CONTI:
With regard to the issue on diagnosis
versus evaluating, one of the primary indications that we
use FDG for is in a solitary pulmonary nodule, and, in fact,
it can be considered cost effective for the diagnosis of
cancer in the sense that you could avoid potential biopsy.
So, how would that play into this scenario?
DR. HOUN:
Well, the latter part of your sentence
about preventing biopsy, that is a management claim in terms
of it can do this, and I think we would have to have studies
that actually show that that management strategy is right,
and that probably entails a longer follow-up period than in
most studies that have been presented.
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In terms of diagnostic, it is diagnostic for lung
cancer, diagnostic for malignancy, but you are not actually
saying, you can't really say what the lesion is, what type
of cancer, what cell type, what grade, et cetera, which most
people would say is part of that diagnosis.
So, I think in the larger scheme of things, what
it is doing is saying cancer/no cancer in that case, and
that is why we are saying evaluating malignancy as opposed
to evaluating non-small cell carcinoma versus small cell
carcinoma, very specific diagnoses.
DR. CONTI:
Maybe what we can do is qualify it as
a non-pathological diagnosis, because, in fact, what will
happen in many of these patients, for example, they might go
on directly to resection in which case a biopsy was never
obtained.
You will get the pathological diagnosis obviously
at resection, but you will have avoided the pathological
diagnostic procedure, which includes biopsy, to confirm the
presence of malignancy before an actual therapeutic option
was elected.
DR. HOUN:
I guess I would have to see those kinds
of studies showing that that selection of decision was, in
fact, correct, and how the management strategy was studied
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to say that this can be used in that particular form of
management, avoiding biopsy.
I don't think any of the studies had that specific
study hypothesis.
DR. LOWE:
I guess what I would like to know is,
which at this point I mean it is premature to comment on
what you are thinking about in terms of the indication, but
what is your definition of diagnostic population, just so I
understand that better?
DR. HOUN:
Diagnostic population is a population
that has a symptomatology which could include a previously
abnormal test or they are having actual symptoms of pain,
pleuritic pain, coughing up blood, you know, some type of
symptomatology as opposed to a screening population which is
healthy asymptomatic.
So, a referral population is usually a diagnostic
population because they have a defined problem, they want to
be diagnosed, they want the name to their problem attached.
A screening population has no problems at all.
DR. LOWE:
That sounds fine to me.
I mean we are
talking about, then, people who have no documented
malignancy, but someone has the suspicion that they have
malignancy for some reason, and that you are doing a PET to
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evaluate the chance that there may be malignancy in that
person.
I think that is adequate.
DR. HOUN:
So, I guess we were saying that either
that they have an existing diagnosis of cancer, whether it
was done five years ago and this is being done for followup, or further evaluation of recurrence, or they come in
with an abnormal chest x-ray, and they want further testing
done.
DR. LOWE:
That is very good.
DR. HOUN:
So, that is the existing testing
modality has found an abnormality.
[Slide.]
In looking at the pathology standard, we looked at
published studies that compared PET results to
histopathology, and I chose this because in the terms of
various levels of efficacy, one of the first things
physicians want to know is the diagnostic accuracy of this
test, and so the standard model is to try to obtain
diagnostic efficacy meaning sensitivity and specificity, and
for that you kind of need a standard of truth pathology or
long-term follow-up or people who are testing negative.
Sensitivity and specificity was focused on in the
reviews even though many articles published data about
predictive value, negative predictive value, positive
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predictive value, sensitivity and specificity was focused on
because these are the traditional measures of testing
accuracy, predictive value is derived from them, and is
based on prevalence, and because of the many, many studies
that we have looked at, it is hard to define each study's
disease prevalence in that population, so it became very
complicated, and also sensitivity and specificity allow you
to derive ROC modeling, which is very important, of growing
importance in how imaging is evaluated.
[Slide.]
In terms of our search criteria, we used a similar
search criteria as in the ammonia search, as well as FDG
myocardial viability, recent articles, human clinical trials
published in English that had to be on on-line databases.
We solicited articles from ICP.
We got a lot.
also used references from the above articles.
So, the package that you gave Victor for
Thanksgiving came to my desk.
[Slide.]
In terms of selection criteria, which studies I
would be seriously looking at to contain in this review, I
wanted only prospective studies.
We also made sure that
every PET result was compared to pathology or long-term
follow-up, that the hypotheses in these studies were
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clinically relevant, not scientific investigations on SUV
and theoretical links to performance, but we focused in on
visual interpretation, accuracy of visual interpretation.
We wanted to make sure all the study populations
were well described, that there were at least 50 evaluable
patients.
I know in some previous reviews of the
literature, they have included fewer patients, such as 12,
but we chose 50 to have some greater confidence of the point
estimates that these articles derive.
Whenever there was a larger data set, an article,
many authors wrote several times about their data set, and
we picked the ones that include the most patients, so some
articles in a sense were not duplicate.
We didn't take
duplicates.
[Slide.]
In terms of the published literature review, I am
going to be talking about two studies that are adequate and
well controlled in terms of having a prospective enrollment,
the study population being very similar to the target
population for clinical use, that pathology was used.
One of the studies is a multicentered study, which
we encourage, or the other study had 50 evaluable patients,
and there were details about the interpretative criteria,
how interpreting physicians ranked PET ratings as positive
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or negative was detailed in these studies.
Many studies did
not explain what criteria interpreting physicians used, and
just simply commented that studies were evaluated as
positive or negative.
There was either masking or multiple independent
readers involved in these studies, or both.
We also had 14
supportive studies that were also prospective, also had at
least 50 in the study population, they also had pathology as
a standard of truth, but sometimes their hypotheses of
investigation was a little bit more ancillary as opposed to
primary in terms of clinical performance of PET.
[Slide.]
The adequate and well-controlled studies I am
going to talk about are two studies, one published by Dr.
Lowe, and the other by Dr. Carr.
[Slide.]
The supporting studies are listed here.
[Slide.]
For the Carr study, published in 1998, in a study
done in London, England, on Hodgkin's and non-Hodgkin's
disease patients.
The objective of the study was to look at
how FDG, if it could differentiate between benign and
malignant bone morrow lesions.
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The sample size was 50 patients that were
consecutive, with Hodgkin's disease or non-Hodgkin's
lymphoma.
It was a prospective study.
It used pathology
compared to PET results, and the pathology results were
based on unilateral iliac crest aspirate or trephine biopsy.
This was unilateral biopsy standard practice in the UK.
The image protocol, I have here masked, but
actually, the visual interpretation was done -- whether
masking was done or not was not commented upon, but we did
get from the study that there were three independent nuclear
medicine physicians doing the reading, and that whenever
there was a difference, the final reading would be when two
reports concurred.
The pathologists, on the other hand, there was a
definite remark in the study that they were masked to the
clinical findings and to the PET findings.
The study also
performed by kappa analysis for the interpreting physician
variability, this kappa being 0.64, which reflects good
concurrence.
In this study, 350 was given six hours or more
after fasting, and the sensitivity of PET was 81 percent,
and we calculated confidence intervals around that to be
between 54 and 96 percent, and specificity was 76 percent
with confidence intervals, 59 to 89.
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[Slide.]
The strengths of the studies included that in
workups, physicians are not going to necessarily
differentiate Hodgkin's disease versus non-Hodgkin's, so
that the combining of the patients seemed appropriate.
On the other hand, we do know that Hodgkin's
disease and non-Hodgkin's disease do behave differently and
that in non-Hodgkin's disease there is more bone marrow
involvement than Hodgkin's disease.
Another strength of the studies, there were three
independent readers.
The PET criteria for reading was given
that positive studies were based relative to liver uptake,
Kappa statistic was calculated, and that a fairly detailed
histology protocol was presented in this paper where the
histology was read by two hematologists and one
histopathologist masked to the PET scan results.
Some of the weaknesses of the study include that
there were only 50 patients, that Hodgkin's disease and nonHodgkin's disease encompass a variety of cell types and
grades, which it would be important to make sure that all
these various cell types and grades are adequately studied,
that the pathology was compared to unilateral iliac crest
biopsy or aspirate, and that usually misses 30 to 50 percent
of lesions.
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Many of the studies commented on the discrepant
cases, people that were PET-positive, biopsy-negative, or
biopsy-positive, PET negative, and they attempted to try to
resolve discrepancies just on these, in a 2 by 2 table, they
would be called cross-diagonal cells, and this is a biased
way of resolving discrepancy in that if you resolve cases
this way, it only will allow sensitivity to either stay the
same or get better, and there is no way to take away from
the sensitivity calculation, so just a general comment in
terms of trying to devise a non-biased method of discrepancy
resolution is needed in imaging.
DR. CONTI:
Making a general comment there,
because this is a non-surgical disease, I mean we can't
biopsy every site that is either positive or negative in
these patients, so your comment is well taken that there
needs to be some way of solving that problem.
Do you have
any suggestions?
DR. HOUN:
Well, we know that that is the problem
with using pathology as a standard.
the gold standard.
It is supposed to be
It gives you a tissue diagnosis, but it
is only so good as your sampling.
So, there is a fallacy
with every gold standard.
We look at all the diagnostic tests, even for
culture, that used to be the gold standard, or it still is
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the gold standard in many cases, and yet, you know, now with
the new technology, with recombinant polymerase chain
reactions, is that a better standard, and so there is always
problems with gold standards.
[Slide.]
In terms of the next study by Dr. Lowe, perhaps he
should present.
DR. LOWE:
I have been through it enough, you go
DR. HOUN:
Sometimes it is even hard to recall
ahead.
your studies, I know you have written so many.
This one was published last year, and it focused
on deriving sensitivity and specificity for PET with single
pulmonary nodules that were seen as indeterminant on chest
x-ray or CT scan.
The sample size was 89 patients from nine PET
centers across the country.
There was a total of 105
eligible patients, but 16 were excluded for various reasons
including 8 having no pathology results, 4 not being
indeterminant, 2 not having CT scan results, and in the
paper it says 2 had the nodules in regions not imaged by
PET.
I am just wondering what that means.
Is that
something that the PET scans were not done fully or is there
a particular area of the lung which PET doesn't image?
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DR. LOWE:
It is clearly just a disconnect between
where the nodule was and the physicians didn't clearly
understand where that nodule was when they did the PET scan.
I imagine maybe they were told to do a lung nodule scan, and
it was in the base of one of the lungs, and without being
compulsive about doing your PET scan in the right location,
it is actually fairly easy to miss the exact location where
the nodule is.
So, I guess 2 out of 109 isn't too bad.
Again, some of these places, you know, people may
have been doing some of their first PET scans, I mean within
the first year or two of doing PET scans, so that is just a
difficulty with people getting used to performing the tests
appropriately.
DR. HOUN:
Okay.
The inclusion criteria was very
specific in that lesions that were less than 4 centimeters,
but greater than 0.7 centimeters, and that they had to be
considered indeterminant on CT scan, were included.
The design included comparison of PET scans to
pathology and also an SUV analysis was performed.
[Slide.]
The image protocol was very defined in terms of
the readers being independent, masked.
readers.
There were two
The interpretation criteria was given and that
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positive was defined as any increased uptake relative to the
pooled blood structures in the mediastinum.
Film copies were specified, they were used.
Disagreement was resolved by consensus.
A kappa statistic
was calculated and found to be very high.
prospectively determined for malignancy.
SUV was
Chest x-rays and
CT scans were read by non-site radiologists who were masked.
The SUV was performed by masked readers, as well.
A dose and administration was given, as well as when scans
were taken.
[Slide.]
The results showed that 60 of 89 of single
pulmonary nodules were malignant, 29 were benign.
Of these
60 malignant pulmonary nodules, 50 of them were from nonsmall cell lung carcinoma, 5 were melanoma, and then the
rest were 1 each of Hodgkin's disease, small cell carcinoma,
carcinoid, neural tumor, colon metastasis.
The data was also stratified by size to look at
percent cancer in three groups of three sizes, the group 0.7
to less than 1.5 cm had 44 percent malignant lesions,
greater than 1.5 or less than 3 was 90 percent, and for over
3 cm it was 75 percent malignant lesions found in those by
size.
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In terms of the benign lesions, 7 of 29 were
granuloma, and actually 3 more were necrotizing granuloma.
Eight were fungal lesions, 4 were debris, 4 were
inflammation, 1 fibrosis, 1 hemangioma, and 1 showing
metaplasia.
The visual sensitivity was calculated as 98
percent, 59 out of 60, and in the article, the confidence
interval was defined as 95 to 100 using normal theory
method, and at FDA, we had our statistician, he used the
exact method to calculate the confidence interval given the
smaller numbers in each cell, and we got a confidence
interval between 91 and 100 percent.
Specificity 69 percent as the point estimate for
visual with exact method, confidence intervals of 49 to 85
percent.
In the article, there was comment that 7 diabetics
were enrolled in this study, and that their glucoses, 2 of
them were quite elevated, 300 to 400, and 1 of the elevated
folks had a false positive scan, 1 diabetic who had a normal
glucose level had a false negative scan, but these again
were very small numbers in the diabetic population.
[Slide.]
We had several strengths for the study.
inclusion criteria was very well defined.
The
The pathology
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standard was used.
independence.
The image protocol had masking and
Inter-observer variability was tracked in
terms of reading.
Sensitivity and specificity calculated.
[Slide.]
Dispute resolution was described.
The CT and
chest x-ray readings were controlled, but the 9 centers that
submitted these studies and their readings with the studies
had them reviewed independently.
It was a multicentered trial.
There were many
patients, and there was detailed patient information.
There
was line listing on size, location, and there were 61
patients with glucose information, as well.
[Slide.]
In terms of weaknesses, the overall study had many
more malignant lesions than benign.
Usually, in SPN we
would expect 30 to 50 percent of the lesions to be benign,
so whether this was a different patient population, you
know, raises a question.
There was not enough information I felt about the
pathology reading protocol, and that sampling variations did
exist.
People obtained their histopathology diagnosis
either by the TTNA or open lung biopsy.
[Slide.]
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In terms of the other studies, I am not going to
run through them.
It is just a listing here in alpha order
of studies that helped us look at sensitivity and
specificity in performance of PET in a variety of
malignancies.
As you can see, some of the sensitivity and
specificity point estimates are quite high, although the
confidence intervals would tend to be a little bit larger
because of the numbers.
[Slide.]
The study by Dietlein in thyroid cancer had a
sensitivity, however, of 50 percent, and they suggested that
if they did PET testing in only those with thyroglobulinpositive patients, that they would improve their
sensitivity.
[Slide.]
Overall, from this review, we had a total of 1,311
patients from the 16 studies, we had a total of 1,311
patients from the 16 studies, and these studies also
reflected a variety of cancers - lung cancer, Hodgkin's
disease, non-Hodgkin's lymphoma, colorectal cancer, thyroid,
breast, pancreatic, and various types of metastases.
The problems with looking at the medical
literature include the absence of statistical criteria for
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significance and power in these articles. I mean often the
hypothesis is not crafted in that type of way that we are
usually accustomed to seeing at FDA for a study protocol.
There is less information in published studies
about image handling, reading criteria, pathology criteria,
pathology handling, because most editors are not interested
in looking at this, and that is what unfortunately, you
know, that is some of the important information we look at
in terms of defining an adequate and well-controlled study.
The absence of patient line listing.
Some studies
did present tables of their patients, others did not.
There
is often bias in terms of just looking at the literature.
There is publication bias.
We also just looked at on-line
literature, only English literature, so all these kind of
biases come into play.
Many of the studies didn't control for prior
imaging interpretations from the referring source.
studies used furosemide.
serum glucose.
Two
We know that furosemide increases
We are not really sure.
I don't think there
is enough data, and I would be happy to discuss with you
folks, if there is more data about use of PET in diabetics.
Then, the other problems with relying on the
medical literature is that there are just variations in how
pathology is obtained in the various studies.
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But in weighing all these, weaknesses versus the
amount of studies that we have looked at, these are just the
16 reviewed studies.
I mean there were over 150 studies
that had PET used in oncology indications for diagnostic
purposes.
That is why, in terms of looking at this whole
body of literature together, looking at what FDG is doing in
terms of detecting abnormal glucose metabolism, we are
coming down to a finding, a preliminary review conclusion
that it is useful in evaluating malignancy in patients with
an abnormality found by other testing modalities or with an
existing diagnosis of cancer, as we discussed before, not a
screening indication.
We do know the results varied from study to study,
from site to site, in terms of cancer type from cancer type,
we do know that some cancers may not be as well imaged by
PET, such as bronchi alveolar cancer or low grade nonHodgkin's lymphoma, but for all diagnostic modalities, that
is true, too.
I mean even for mammography, it is well known
that lobular carcinoma is not imaged as opposed to ductal
carcinoma.
So, these again are diagnostic tests.
They are
used to assist in the patient workup for a diagnosis.
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are not pathognomonic, their findings are not pathognomonic
for a disease.
[Slide.]
In terms of safety information, a small amount of
FDG or glucose is introduced into the body.
metabolism and excretion is known.
life.
The pathway for
It has a short half-
There is acceptable radiation dosimetry and radiation
risk associated with this procedure.
We just do not have enough information to assess
its performance with patients who are diabetic or have
hyperglycemia.
Also, with the effects of furosemide, I
don't think have been adequately studied.
[Slide.]
So, again, these are the preliminary conclusions,
and I would be happy to discuss them and learn more from
folks.
DR. CONTI:
of comments.
Maybe we can open it up for a couple
Let me just take on this furosemide issue
head-on, because I think this is something that we need to
clarify.
Lasix is occasionally administered to patients for
clearance of radio tracers, not just FDG, but for other
radio tracers, even very standard ones like TTPA is part of
examinations for clearing the activity from the collecting
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systems and the anticipation of reducing the high levels of
activity that normally would accumulate in those organs for
better visualization of surrounding structures.
Likewise, we occasionally catheterize patients to
remove activity in the bladder.
We may have them drink lots
of fluid, particularly in patients that have difficulty
emptying their bladder.
They may have to get up from the
table from several times and void, again, to reduce the
amount of activity in the bladder, so that we can better
visualize the pelvis.
This is the purpose of the furosemide, if you
will, in this scenario.
It is not necessarily an issue with
regard to serum glucose per se when we use this as part of
the test.
The patient may be on other medications that
certainly could affect serum glucose.
There are a number of
medications that could potentially do that.
So, I just want to clarify that this is not an
issue as to whether we are adding furosemide for the
purposes of manipulating serum glucose.
We are doing it
because it is a methodological approach in an individual
patient that might allow better visualization of the
anatomy.
DR. HOUN:
I know that the studies were very clear
on that, they were trying to decrease false positive
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readings or decrease activity, so they could have a better
reading in the pelvic area.
What my comment is I don't think the labeling is
going to be able to support any mention of that.
DR. CONTI:
percent.
I would actually agree with you 100
I would just leave it, drop it.
That is my point.
I mean I think this is an individual manipulation that a
physician may perform to better evaluate an individual
patient, just like putting a catheter in the bladder to
remove activity.
I don't think that this is something that
really belongs in the label.
DR. HOUN:
Okay.
DR. LOWE:
Florence, I would just like to say
thanks for the review.
I think you ought to have a nice
week off at a sunny beach somewhere.
Actually, we should
put Victor to work.
MS. AXELRAD:
This is a sideline for her in terms
of her other workload.
DR. LOWE:
She just does this in the evenings.
MS. AXELRAD:
DR. LOWE:
Over Thanksgiving.
I agree with your review and really
everything you have said.
There are certain aspects of the
development of PET imaging that we have not published an
update on, and that will be forthcoming, I am sure, and some
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of it may never be answered.
I think what you have said is
entirely correct.
DR. HOUN:
What are your feelings about this
diagnostic indication meaning that I don't know if the
community had wanted something more in terms of screening,
somebody totally healthy, come on in to see if you have
occult cancer.
Is that something that --
DR. LOWE:
At this point, you are correct.
There
is absolutely no data to justify that kind of imaging.
not sure as a society that we are ready for that.
I am
I am not
sure we can afford that.
I mean screening is an issue that we don't know
what to do with breast nodules, and that sort of thing.
I
mean there are a lot of issues that screening is a problem
for, and PET has just not been looked at in terms of
screening.
So, I agree with you.
I think that the diagnostic
population, as you defined it, is really the one that is
really the population that PET should be targeted for, and
at this point, that is all.
DR. CONTI:
There is actually some work out of
Japan looking at screening of patients.
There is a group in
Lake Yamanaka, I believe it is, that is doing this work
where they are actually imaging executives from
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corporations, and things like this, as part of their health
plan.
These folks are being evaluated with PET as part
of their physical exam, if you will, and they are finding
incidence of cancers around 7 percent of the patients that
they see.
DR. HOUN:
Seven.
DR. CONTI:
Seven.
So, it is a low number.
At
least what we have is preliminary information, but I would
suspect that if studies were done that were directed at
patient populations that are at risk for cancer, family
histories, and things like this, that we might be able to do
a bit better, but these are all comers in this group of
people.
That is really the only data that I am aware of at
this point.
DR. LOWE:
And that is a single site.
Again, we
are talking about a population that participates in a golf
club, and they come up there for their health workup, if you
will, and it is a select population, so in terms of
screening the general population, we don't have that
information right now.
DR. CONTI:
issue.
Another comment on the hyperglycemia
I think at this point, those of us in practice would
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generally continue to perform these studies even in the
presence of diabetes.
I have done a number of patients that
are diabetic or have elevated serum glucose, and again we
can visualize tumors in that scenario.
While I am saying that we haven't done formal
studies to look at the presence or absence of hyperglycemia
and its effect on FDG uptake in malignancies, from a
clinical practice point of view, I would not refuse a
patient because they have diabetes to do this examination if
the patient falls into the diagnostic population.
So, I would rather not see it as exclusionary, but
that perhaps it might be a caution at this point rather than
a contraindication to doing a test.
I have conducted some animal studies years ago in
hypo- and hyperglycemia, and really saw no significant
change in distribution of this radio tracer.
There have
been some reports clinically that said there are some
alterations in glucose uptake because of the presence of
high serum glucose clinically, but again, those are not at
the point where we can reliably use that information, but at
least in animal studies that we did, we did not see those
changes.
DR. HOUN:
Do you know if more studies are being
contemplated in the community on diabetics specifically?
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DR. CONTI:
I would venture to say people are
probably thinking about it, but again, is it an issue, and I
think from a clinical perspective for me personally, I could
speak of my own activity, it is not an issue.
I am not going to be concerned whether they have
diabetes to perform this test, so it is not going to be
exclusionary.
If I don't see the malignancy, it may be
because they are hyperglycemic, but it could be because of a
number of other reasons, and to begin to explore all those
other potential reasons to explain a false negative is going
to be quite a challenge in terms of a study design.
DR. LOWE:
I think we would all love to have the
answer to that question as to what to do, but as Peter said,
in my practice, it is a fairly rare occurrence that we see
somebody come through with a glucose value that is over 200
whether they are diabetics, whether they know they are
diabetics or not.
So, one issue is we don't really have the
motivation to put together a study, and number two, it would
be very difficult because of the number of people that we
see are very small, so whether we will ever have the answer
to that, I don't know.
I mean what we do is again, if we have a person
with known malignancy, we will do the scan if it is
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imperative that it be done at that time.
If we see the
tumor, the primary, and we are just staging the malignancy,
for example, then we are home free and we are fine.
We know
that we will be able to identify whatever disease there is.
If we are just trying to find a tumor when there
is no known tumor, if the glucose value is high, sometimes
we will ask the patient to come back on a day when they are
under better control, and that is very simple to say come
back when your glucose is lower, and that is how we deal
with it.
That is a very simple thing to do.
I am not sure
that anybody is going to ever put out the effort to resolve
it more than that.
DR. HOUN:
Thank you.
DR. CONTI:
I want to congratulate you on a very
excellent review again.
It was very well done.
DR. RACZKOWSKI:
Actually, I have a question, and
it arises from something that Flo said and that Dr. Conti
indicated.
With regard to the diagnostic versus screening
indication, one thing that Dr. Conti mentioned was used in
patients who may otherwise have risk factors, be at high
risk, so to speak, but aren't specifically symptomatic.
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Would you be considering the use of PET products,
FDG, in particular, in patients who are at risk, that are
otherwise healthy and asymptomatic?
DR. CONTI:
It is an interesting question because
it actually overlaps a little bit with perhaps something
that Florence put together in her statement.
I was thinking
about this, I didn't know if it was appropriate to bring it
up.
If you have a test, it is actually a question -- I
am going to answer your question with a question to her also
-- other testing modalities, now, the way I would interpret
that would be clinical examination, laboratory tests,
genetic testing, and this now overlaps with what you are
saying.
Now, if I have a patient with a certain expression
of a certain type of gene product that suggests that they
have a higher risk for, let's say, breast cancer, does that
qualify as a test, but not to this category, yet, it still
overlaps with screening.
DR. RACZKOWSKI:
This is an issue.
I would
categorize those sorts of activities more as case findings
perhaps as opposed to screening specifically.
if Flo would agree with that.
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I don't know
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DR. LOWE:
I think what the data supports right
now is the fact that we haven't looked at any populations at
risk, so we don't know what the value of that is going to be
right now.
I think, in general, if somebody referred to me
a patient and said, well, this patient is a smoker, I don't
know if they have got lung cancer, let's just see and do a
PET scan, I would say, you know, let's do a chest x-ray
first and use that as a screen.
I am not sure that anybody, I am not sure that I
would be ready as a practitioner to use it as a screening
test.
I am quite certain the data is not there to support
that in at risk populations, but that is something that we
probably need to look at.
I mean will it be of any benefit in screening
people?
That is possible, but I mean really there is no
data to support it right now, and I don't think we can claim
that.
I think that we would like to look at that is where
we stand right now.
I don't know that we can say much more
about that.
DR. CONTI:
It is difficult.
Again, it overlaps.
If you have an elevated thyroglobulin and history of thyroid
cancer, you would qualify because that is a test and it has
some predictive value as to whether or not you have residual
tumor, so you are at risk because your thyroglobulin is
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elevated, but you have no other evidence of disease, let's
say.
But again, I agree with Val, we haven't done
formal studies in the sort of screening population that
might be at risk because of their occupational exposures to
drugs or to smoking or to things like this.
That has never
been done.
But on the other hand, again, we get into the
nitpicking here because there may be tests that come up over
time, either genetic testing or biological testing, that are
suggestive of being at high risk for cancer or having a
strong family history for cancer that would be worthwhile.
Many of the cancers that we currently have, we
have no screening test for.
Actually, with lung cancer, for
example, chest x-ray has been overwhelmingly disapproved as
a screening test for the presence of lung cancer.
It's not
sensitive enough for the detection of lung cancer.
Again, it is a choice that you make, but we don't
have any formal studies to look at these types of things to
support this use.
DR. HOUN:
Yes, and those studies would be needed.
I mean we are learning more about genetic predispositions to
cancer.
I mean now for BRCA-1 and BRCA-2 mutations there is
a concern.
There is radiation sensitivity to those mutation
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carriers, so people are thinking they should get mammograms
more often, maybe that is the wrong recommendation, they
should have fewer.
So, you have to really study this with that
particular indication.
If we are going to go after folks
with genetic p53 mutations or BRCA-1 and BRCA-2, and use
this in screening, right now it is not clear whether you may
do them more harm, especially if you are screening for
cancer, such as pancreatic cancer, where what are you going
to do when you find it.
There are lots of decisions into how a screening
test is developed, and part of it is what can you do after
you find the results.
DR. CONTI:
I think the consensus, the community
really doesn't want it as a screening tool at this point.
That is probably the fairest.
I think if there was a
specific application that came up in a population that was
studied, we would like to expand that indication to include
that if it was supportive of it, but I think we need a
little bit of flexibility in terms of deciding a patient
should get a test on the basis of some sort of definitive
lab value or something that suggests that they have, in
fact, disease.
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DR. LOVE:
I think that is where Flo's
presentation comes back to that point.
Basically, these
would be patients with either symptoms, as defined earlier,
with your diagnostic population, or patients perhaps with an
abnormal CT, chest x-ray, MRI, and we would try to develop
labeling language that would allow some flexibility, but
would certainly point to the fact that these are patients
that have a reason for further work-up.
DR. CONTI:
I actually have some comments I would
like to make before we get into the regulatory procedures.
MS. AXELRAD:
When we finish this, if you have
additional -- do you have additional comments on this part
of this?
DR. CONTI:
On the oncology.
MS. AXELRAD:
Okay.
Then, let me ask if there is
any members of the audience who would like to make any
comments on this part of the discussion.
[No response.]
MS. AXELRAD:
Okay.
It doesn't look like it.
Do
you want to make comments now or do you want to take a
break?
DR. CONTI:
MS. AXELRAD:
We can take a break.
That is fine.
Let me just mention one thing, and
that is, part of what I am sort of hoping in this discussion
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of the safety and efficacy reviews, is it has sort of got a
twofold purpose.
One is to deal with existing indications that are
well reported in the literature for things that it is
actually being used for now, but it also, I think, can
inform the community on what kinds of things that we look
for in terms of designing trials for new PET products that
might be under consideration for which there isn't much in
the literature.
Whether those studies are reported in the
literature ultimately or simply submitted to us as the basis
of a new drug application, I think that some of the comments
that we made on the weakness of the studies or the strengths
of the studies that were reported in the literature
can be
helpful in future discussions when we get into how are we
going to handle new PET products.
You know, we are trying to deal with things that
are less commonly used out there now for which there is a
lot of literature to base some conclusions, but we also want
to address new things, and we will be probably talking about
that and issuing guidance in the future for what those kinds
of studies ought to look like, so that they can be done in
an efficient way that will produce results that will lead to
additional approvals.
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DR. CONTI:
Yes, I agree.
In fact, that is why I
asked Florence if she had any suggestions on that one topic.
This is the type of information that is very helpful to us,
to go back when we develop new compounds, so we can choose
the parameters that will best suit evaluation in the future
to make this process a lot smoother.
There is no argument
there at all.
Let me just tell you what the comments are going
to be, and then you can decide if you want to take a break.
I was going to bring up the issue of the other radio tracers
and the clinical evaluation of those tracers, the O15 water,
the fluorodopa, and the fluoride ion, so we can decide if we
want to talk about that later or we can talk about that now.
It is up to you.
MS. AXELRAD:
Let's talk about that now.
We are
talking about the clinical evaluation of other things.
DR. CONTI:
MS. AXELRAD:
now.
Right.
I think we should talk about that
Then, we will sort of close out the clinical part of
this and then get on to the other.
DR. CONTI:
With regard to the fluorodopa, this is
the easiest one, that I just want to mention.
You know, Dr.
Barrio has put together or has been possibly putting
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together this review.
This is something that you had asked
us to do as opposed to FDA doing this.
This is undergoing this review at this point, so
we would like to at some point present that to you, perhaps
the next time we discuss clinical applications.
The other two, the O15 water, Dr. Love mentioned
that this is something that you are looking at.
just clarify that.
I wanted to
Is this something that FDA will review
and present back to us?
MS. AXELRAD:
Yes.
MS. KEPPLER:
Do you want us to look at literature
and provide you a Memorial Day present or something?
DR. LOVE:
Maybe even sooner if we want to present
it by Memorial Day perhaps, so as soon as possible, and we
are doing the same type of search, but anything you can
provide would be helpful.
DR. CONTI:
DR. LOVE:
So, we will get on that.
Also, on the F-dopa, were you planning
to submit copies of the literature along with his review at
some point?
DR. CONTI:
Yes, we will send you the literature
that we used.
DR. LOVE:
I think that would be helpful.
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DR. CONTI:
The fluoride ion is a little trickier
of an issue, and I just wanted to bring up a couple of
comments on this.
Historically, as you know, fluoride ion has been
used in bone scanning prior to the use of technetium-labeled
derivatives with bone imaging, and this is something now
that we have to address in terms of a drug that has been
approved for a very long time, it is very old, the
literature is also very old, and we have another issue with
fluoride in the fact that it has been produced traditionally
with reactor material.
We have apparently an active NDA by Amersham for
fluoride, and we need to have some discussion with regard to
what is the approach that we need to take with this
particular drug.
It is established as a bone imaging agent.
Now we are in a scenario where we are going to produce this
material locally for this application.
How do we deal with this in terms of presenting
clinical data or discussing clinical data and also the issue
of how to deal with this active NDA?
DR. LOVE:
set of questions.
We have been concerned about the same
May I ask first are you seeking the same
indication that exists in the approved NDA or something
different?
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DR. CONTI:
Well, I haven't seen the approved NDA,
so I don't know exactly what is in there.
DR. LOVE:
But in the realm of bone scanning?
DR. CONTI:
It will be in the realm of bone
scanning just like we would -- I mean essentially, the
indication would be identical to the technetium NVP, which
is currently used with bone imaging agents, the same issue,
the same applications.
DR. LOVE:
I think we have some background
checking and obviously we need to talk with the sponsor, the
NDA holder, to see what issues exist there, if there are
some concerns.
There are two ways to approach it - the same way
that we are doing now with the other products, and you will
hear a little bit about what those approaches will be
momentarily, but we could either look at it from the
perspective of using literature to support that depending on
what the NDA holder wishes to do.
regulatory approaches.
There are some other
Did you want to mention some of that
now?
MS. AXELRAD:
I would just say I think that if you
are going for the exact same indication for which it is
already approved, then, we would have to explore the
possibility of it being an abbreviated new drug application.
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We are going to go through in detail the
differences between the three different types of
applications that there are, and the ups and downs, what you
have to show for each one.
There is differences in terms of
what has to be there.
Then, while we are doing that, perhaps you could
raise questions that are particular to this one, which is
already approved, which is unlike -- I mean FDG is approved
-- and we should try and at least identify the issues
associated with each of the different substances, so that we
can then go back and talk about it among ourselves and
figure out what we think in terms of the best regulatory
approach to it.
DR. CONTI:
With regard to just the clinical
issues, again, we will get back to the NDA-ANDA issue, but
from the clinical point of view, an NDA has been filed for
these applications.
Is it necessary at this point to do
another literature review in this forum to represent
fluoride ion?
That is really what I am asking.
DR. LOVE:
I understand and that is where we are.
That database, part of it is going to depend on how much is
in the auspices of the NDA holder and how much is in the
public domain, and that is something we have to check.
may be a very simple process.
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DR. CONTI:
It may be very difficult from a
computer point of view, because many of this data could be
on line.
DR. LOVE:
This might be a simple process for us,
it may be a bit more complex.
It shouldn't be any more
complex than what we have already shown in terms of
reviewing literature if it is out there.
If the NDA holder would cross-reference the
database, allow that, then, it isn't a problem at all.
MS. AXELRAD:
On the other hand, if it is eligible
for an abbreviated new drug application because you are
going for the exact same indication, there wouldn't be any
need to do an additional work-up.
DR. LOVE:
Exactly.
MS. AXELRAD:
So, we would have to look at it
carefully to make sure that it, in fact, is eligible for an
ANDA, and if it is, then, you are dealing with chemistry,
bioavailability, bioequivalence, and not safety and
efficacy.
DR. LOVE:
Right.
We have looked a little bit.
We have thought preliminarily about the issue of reactorbased versus cyclotron-based production, and we will sort
through that and see if there are any other issues here.
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DR. CONTI:
Okay.
That is the extent of my
comments.
MS. AXELRAD:
minute break.
With that, why don't we take a 15-
Then, we will come back and talk about the
procedures.
[Recess.]
MS. AXELRAD:
It is looking like the schedule may
be, we will see how it goes here, but basically, the ICP's
people that deal with the chemistry and GMP issues will not
be coming in to town until tonight, so we will not be moving
forward into the chemistry issues when we finish the
procedures.
So, we can sort of take a time check.
idea how long it will take to go through this.
I have no
If we
approach noon, and it looks like we have a lot more to do,
we will break for lunch, but I would suggest that if we
don't have a lot more to do, then, we would just keep going
until we finish it, and then break for the day, and then
come back tomorrow on the chemistry issues.
I guess it is best to work late until the
chemistry people come to talk about the USP chapter and the
monographs also.
Regulatory Procedures for PET
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MS. AXELRAD:
We are now going to be working from
a document entitled, "The Existing Regulatory Framework for
Drug Approval," which is our sort of preliminary attempts to
make sense to you all or to people who are not really
familiar with the regulatory process of our regulations for
approval of a new drug application.
A lot of what we say here, I mean we are going to
try and simplify this in our explanations to sort of reach a
common understanding.
oversimplify this.
It is of concern to me that we may
This is incredibly complex.
People
discuss and negotiate over these in the context of all kinds
of applications.
There are lawsuits over this all the time.
So, what I am saying here is basically it is FDA
Approval 101 as applied or as we think it may apply in the
PET context, and it shouldn't be -- when I say it "shouldn't
be" -- extrapolated to any other application or anything
else.
We are really trying to just sort of simplify this in
a way that we can sort of have a common understanding and to
identify what works and what doesn't.
Basically, what we have done in this document is
try to lay out the regulatory framework for drug approvals,
which translates down to three basic types of applications:
a full application for new drug approval that we call a
505(b)(1) application; a somewhat shorter type of an
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application, a 505(b)(2) application, which generally relies
on the literature for safety and efficacy or on data in some
other application to which the applicant doesn't have a
right of reference; and an abbreviated new drug application,
which, of course, are our generic drug applications.
Now, what I am going to do is sort of go through
this step by step and talk about the different types of
applications, and what I really want to do is have a
dialogue with you, answer any questions that you have about
the different types of applications and the regulatory
requirements for each one, and to get a sense from you as to
which things in here are problematic.
There are a number of issues in terms of how we
structure this and how the applications are going to come
in, who is going to bring in the application, the initial
application, whether multiple sites will bring in
essentially similar applications at the same time, whether
there would be one application approved and then
subsequently abbreviated applications, and as we go through
this, you will understand that there are implications
associated with this.
Just for one example in terms of user fees, a
505(b)(1) application with clinical data pays a full user
fee, a 505(b)(2) application or an application that doesn't
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have clinical data in it would only pay a half of a fee, and
a generic drug application pays no fee.
So, how this gets structured in terms of what
comes in first and what comes in second, and how we do this
will have implications in a number of areas, user fees being
one of them.
DR. CONTI:
Jane, excuse me.
Before you go into
the individual descriptions, is it possible to define for us
who are the current eligible holders of these items, in
other words, in terms of individuals, institutions,
commercial operations?
I think it is important for us to know that
because it will determine who actually does the submission
irrespective of what type of submission it is.
MS. AXELRAD:
that?
Patricia, why don't you comment on
My answer would be I don't think there is any
constraints.
Anyone can bring in an application as long as
they provide the data in the application to support it.
So,
ICP could bring in an application, an individual site could
bring in an application, some kind of a coalition of groups
could probably jointly put in an application.
DR. CONTI:
You don't have to be a specific
manufacturer.
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DR. LOVE:
Right.
It could be the institution, it
could be the hospital, or if it is a free-standing center.
A lot of that would also depend upon whatever legal
arrangements exist with the center and any individuals
involved, and so some of that would just depend, but it is
whoever is basically going to be taking responsibility for
the drug and its preparation, and the like, and developing
the data.
DR. CONTI:
That is the rub, I guess, the
responsibility of a drug.
If the ICP were to submit, they
don't have responsibility for the drug at the individual
sites.
That is where I am going with this.
DR. LOVE:
sort out.
And that is an issue you would have to
It all depends upon what you also may wish to do
in the future in terms of developing other kinds of
liaisons, or you could submit the data and authorize crossreference, as we have talked in other cases.
A group like PETNet, that has multiple sites
throughout the country, might submit an application, and the
other sites might be manufacturing sites.
So, there are a
number of ways to do it.
So, then maybe a group like PETNet wouldn't
necessarily have to submit full applications, just multiple
manufacturing sites, basically chemistry and nothing else.
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So, there are a number of possible combinations and
scenarios.
DR. CONTI:
They would have responsibility of the
drug manufacturing process as a corporation.
DR. LOVE:
Yes.
DR. CONTI:
But I am concerned about the
professional societies holding an NDA and not being
responsible for the actual production.
MS. KEPPLER:
Actually even doing production.
There wouldn't be an ICP site type of thing.
MS. AXELRAD:
I believe that the sponsor of the
application would be held responsible for the manufacturing
that is done under that application wherever it is done.
So, regardless of who actually submitted it, I think the
applicant would be held responsible for it.
MS. KEPPLER:
Could there be an application like
that where there was no manufacturer at the site of the
original NDA, but only manufacturing at the site of ANDAs
that could reference the NDA?
Do you see what I am saying?
So, you could have a sponsor that didn't produce
any drug, a sponsor like the ICP where there would be no one
producing under that one -- I am sorry, NDA -- ICP could
submit an NDA where no one would be manufacturing under that
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NDA, but then other people could reference it from the
standpoint of the NDA.
MS. AXELRAD:
been done.
That certainly I don't think has
I think that is a question -- I think I am going
to make a list of questions that you raise that we can't
answer on the spot.
these coming up.
I think there are going to be a lot of
So, that is something that we would have
to address.
I guess I would say when we go through the types
it will be clear.
If the application, though, were, for
example, going to be for N-13 ammonia for myocardial
perfusion, for the indication that we have outlined here,
and based on some publication, for example, that we might
publish in the Federal Register saying that we think that
based on these articles in the literature, we would support
a finding of safety and effectiveness for this indication,
and welcome applications, all it would be is essentially a
manufacturing application because it wouldn't need safety
and efficacy data, and that could be done by the individual
sites.
You wouldn't need an umbrella ICP application.
For something new where somebody was doing new
clinical data or something, and it wasn't based on the
literature, then, we would have to explore the possibility
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of how you would do that without having individual
manufacturing sites with it.
DR. CONTI:
We are in a little bit of a dilemma.
Some of these, as you say, if you do publish it, we can
reference that information in the Federal Register and go
that route, but the other problem that comes up is that you
have two other scenarios.
One is the proprietary drug or a
commercial institution would take it through an NDA process
or some similar process.
That is one scenario.
The other one would be drugs that are in existence
in the public domain that have no patents or any type of
protection, yet have not been evaluated clinically in a
sufficient number of trials to warrant presentation in the
Federal Register.
Then, the ICP or some other entity may have to
take this issue on, and this is where the dilemma comes in
as to how to handle that because it would be nice, with a
drug that is in the public domain, yet not ready for prime
time, if you will, can we have an umbrella type of approach
that would allow us to get this thing to be developed since
we won't be able to take responsibility for its individual
manufacturing.
I will give you an example.
O15 oxygen.
It can
be produced, it can be used in patients, yet it is not at
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the point where it is an approvable pharmaceutical.
Yet, it
is going to be manufactured all over the country, and yet
you would have to decide how you want to approach that with
an NDA through the ICP, with other sites registering as
ANDAs or some other -MS. AXELRAD:
One option would be that the
clinical safety and efficacy data -- I think this was what
was done actually for the original Peoria application for
FDG -- was that the clinical data could be developed and
placed in a drug master file, and then anyone who wanted to
submit an application would have a right of reference or
could be given a right of reference to that clinical safety
and efficacy data.
Now, that would a 505(b)(1) application because
they would have a right of reference presumably to all the
underlying safety and efficacy data, unlike, in the case
where it is in the literature and they would be relying on
published literature which would lead to a (b)(2).
So, I think that is something that would be
doable, but ICP probably wouldn't be the sponsor of the
application.
Someone else would sponsor the application,
they would submit the manufacturing information and any of
the other information that needed to be in there, but they
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would rely on the data that was developed by a society or
ICP or whoever for clinical safety and efficacy.
DR. CONTI:
So, a society would hold the DMF
basically.
MS. AXELRAD:
DR. CONTI:
Right.
I didn't mean to distract you.
I just
wanted to sort of open that up because it is important for
us to understand who can do what.
MS. AXELRAD:
No, I think this is the real purpose
is to understand the issues, too.
DR. LOVE:
And that is one of several options, it
is not necessarily the only way it would have to be.
MS. AXELRAD:
Normally, the first application for
a new chemical entity is submitted under Section 505(b)(1)
and contains full clinical trials conducted by a foreign
applicant, demonstrating the safety and effectiveness of the
application.
Go ahead.
MS. KEPPLER:
One question that I had when I was
reading this, too, is -- and this is kind of the difference
between PET and traditional drugs -- is that under Section
505(a) of the Act, no person may market a new drug unless it
has an approved NDA or ANDA.
In large measure, we are really not talking about
marketing because we are talking about somebody producing it
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for use within their own facility, as well.
question here is what do you mean by market?
use?
So, I guess my
Is that also
There may not be an answer.
The reason why this gets to be an issue as we
start to talk about some of the more complexities of it is
because we want to set up a process going forward that
allows drug approval in the future to be sponsored by a
commercial entity.
You know, there may be a drug that somebody wants
to run a clinical trial for that sponsors it, so that they
can market it, but if they can market it and then if they
put that together, and then anybody that is out there can
use it in their own facility, there is no financial
incentives for a company to do that.
Alternatively, we also want to be able to set up a
mechanism, so that drugs that are developed at academic
sites can be then shared between many academic sites and
utilized to advance PET.
That is why I was trying to understand what you
meant by "market" there.
MS. AXELRAD:
I am looking at my lawyer.
Introduce yourself because they don't know who you
are.
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MR. SNYDER:
I am Doug Snyder from the General
Counsel's Office, FDA.
Essentially, what marketing would be there is the
commercial use of the drug.
That can be anywhere from the
exchange of money for the drug or simply used in a
commercial setting.
DR. CONTI:
little bit further.
Maybe you can help clarify this a
Would commercial use imply
reimbursement from an insurance carrier?
MR. SNYDER:
MS. AXELRAD:
MR. SNYDER:
DR. CONTI:
Yes.
Only?
No, not only.
I am not talking about distribution,
distribution I understand, and commercial activities I
understand, I am just trying to define if you are using the
exchange of monies and you have to use that as well as the
distribution concept.
MS. AXELRAD:
If you don't get reimbursed, it
doesn't mean you are not marketing it commercially.
If you
inject a patient with the drug, and the patient pays for
that, that scan then is commercial regardless of whether it
is being reimbursed by HCFA.
MR. SNYDER:
That's right.
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DR. CONTI:
Right.
I didn't mean to taint it with
the issue of reimbursement per se, but I mean as long as we
are exchanging some monetary issue here.
MR. SNYDER:
If there is any kind of value being
exchanged regardless of whether it is monetary or not, it is
a commercial use of the product.
DR. CONTI:
So, that would maybe in part answer
Jennie's question, so that individual sites could, in fact,
quote, unquote "market" to their clinicians on site to have
those studies done, and not actually be in the outside of
the campus arena, so to speak.
You can actually go to your oncologist and say you
should use this drug to image these patients because it will
help your cancer diagnosis capability, and that would
constitute marketing.
MR. SNYDER:
DR. CONTI:
That's right.
Does that help?
MS. KEPPLER:
Yes.
I just needed to understand
MS. AXELRAD:
So, normally, the first time an
that.
entity, let's just say N-13 ammonia, if someone were to come
in with an application for N-13 ammonia, and they had done
two adequate and well-controlled clinical trials to support
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its use, and they had all the other data that you needed, it
would be considered a 505(b)(1) application.
However, if they come in with an N-13 ammonia
application and it is based on a literature review on the
published literature or based on an FDA publication in the
Federal Register that indicates the literature would support
this finding, then, it would be considered a 505(b)(2)
application, and I won't get into the fact that the
505(b)(2) application is really a 505(b)(1) application by
another name, but you don't want to get into that.
You just have to know that there is a (b)(1) that
has full studies of safety and efficacy, and a (b)(2) that
doesn't have the full study set.
For at least some of the
required studies, they rely on studies done by somebody else
and to whom they do not have a right of reference.
So, that is the key.
If whoever it is that holds
the application gives them a right of reference, then, that
application becomes a (b)(1).
DR. CONTI:
The NDA held by Peoria is a (b)(2),
correct?
MS. AXELRAD:
DR. LOVE:
No, that was probably --
Actually, yes.
Some literature was
submitted, but not all of it was literature based, but
technically, now, given what we are talking about, it would
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be in the context of a (b)(2), but I think at the time, it
was handled primarily as a (b)(1) because you also needed
all the chemistry, and you needed everything else, so even
though there was some literature for efficacy, a lot of the
other basic evaluation was more in the context of a full NDA
since it was the first one going through.
MS. AXELRAD:
I will say that this distinction
between a (b)(1) and a (b)(2) didn't have a lot of
importance until the User Fee Act passed in 1992, where it
indicated that only certain (b)(2)'s paid, but all (b)(1)'s
paid.
Before that it didn't really -- it is the same
application.
I mean the main difference is the need for a
patent certification, and that type of thing for a (b)(2),
that you don't have in a (b)(1), but that was really the
main difference, but the basic applications were not that
different.
We would just say, you know, we acknowledge
receipt of your application submitted under 505(b), and we
are approving your application under 505(b), and they didn't
indicate whether it was a (b)(1) or a (b)(2), but now they
have to pay attention to that when it first comes in because
of the implications for user fees.
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DR. CONTI:
If you rely on the DMF that uses
literature to demonstrate safety and efficacy, that would
automatically imply that you are dealing with a (b)(2)
application, correct?
MS. AXELRAD:
No -- well, yes, if it is based on
the literature, yes, if the DMF is based on literature, yes,
and there weren't original studies.
DR. CONTI:
MS. AXELRAD:
I am learning.
So, in the document on page 2, we
lay out based on our regulations what needs to be in an NDA,
a full NDA, full reports of investigation showing whether
the drug is safe and effective for use, a full list of the
articles used as components of the drug, a full statement of
the drug's composition, a full description of the methods
used, and the facilities and controls used for the
manufacture, processing, and packing of the drug, samples of
the drug and its components, specimens of proposed labeling,
a patent number and expiration date of any patent that
claims the drug, and there is a whole section that we are
going to come to later on patents and exclusivity, but
basically, the innovator, which is what we call the original
person that brings in an application, has to give
information about their patents, so that other people know
whether there is or isn't a patent on it.
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Then, our regulations in 21 CFR 314.50 lists
exactly what has to be in it.
You have to have an
application form, an index, a summary, various technical
sections, CMC information, nonclinical pharmacology and
toxicology, pharmacokinetics and bioavailability
information, microbiology, clinical data, statistical
evaluation of data, samples and labeling, case report forms.
There is a whole list here of things that need to be in it.
The most recent one -- which we are not going to
really talk about much -- it is a new rule, financial
certification or disclosure statement by clinical
investigators, which is cited here, and you all might want
to get a copy of it, but we are not really prepared to
discuss that in great detail.
It's a new rule.
really been involved in developing it.
I haven't
We can talk to you
later about what that involves.
But basically, that is it.
I think I passed out
to you a copy of our 356(h) form, which is really a very
simple application form, two sides, and as I said, sometimes
400,000 pages of attachments that come with it, but
basically, every application has to be accompanied by this
form, and it tells whether it is an original application or
a supplement, the product description, the established name,
the dosage form, information about the application and the
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applicant, and what is included in the different sections
that are included in the application with a cite to the
regulations that apply.
So, that is your standard -MS. KEPPLER:
How do the DMFs fit into this
equation, since that is what we know about?
MS. AXELRAD:
It is interesting because the drug
master file was originally conceived as a way to share with
the agency information that the owner of the data wanted to
keep confidential, but to still allow someone to take
advantage of the fact that that information exists.
I think it was most often used in a chemistry
context.
I don't think it is very often used at all in the
safety and efficacy context.
What happens is if somebody
manufactures a chemical of some sort or a pharmaceutical,
and they don't want to share with the person who buys that
stuff from them and makes it into a finished dosage form how
they do that, they don't want to share the details of their
synthesis process with them, but obviously, we have to know
that to look at the chemistry manufacturing controls in the
application.
So, they will submit that information in a drug
master file, and they will give the person who buys the
stuff from them a right of reference to the information in
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the file.
it.
The person who buys the material doesn't ever see
We get it, we have it.
When we get an application that
contains a right of reference to it, we go and open it up
and look at it.
We don't review drug master files -- and the
chemists can correct me, my drug master file knowledge is a
little dated -- but the last time I checked, we didn't
review drug master files unless we got an application that
contained a right of reference to it and gave us authority
to look at it.
I gather it has been used in terms of safety and
efficacy information in a similar way.
Somebody developed
the safety and efficacy information, they didn't want to
actually -- the studies weren't published -- they didn't
want to actually give those to everybody, so they maintained
it in a drug master file.
We had access to it, and when
someone submitted an application with an authorization to
reference that, we would go and look at it and review it.
There is a very old guidance on drug master files,
but it dates back in 1987.
fixed.
I don't know if it is being
I am sure it mostly is chemistry.
Again, I am not
sure if it says much about safety and efficacy -- it's all
chemistry, okay.
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DR. LOVE:
I think at the time -- and this is
based on information shared with me -- at the time the DMF
and that process was negotiated, it was primarily to find a
way to develop an NDA that one person could reference just
for the reasons that Jane has articulated, but there were so
many other issues that appeared to be new ground at the
time, that is why some of the approaches that you will hear
described today on how a 505(b)(2) differs from the (b)(1)
and the approaches that we are considering at this point.
Those approaches weren't in use at that moment in
time for that particular application, so it was a more
complex process then.
MS. AXELRAD:
Another way that a lot of DMFs are
container closure systems, again, a manufacturer of a data
closure system doesn't want to put out for all the world to
see how they make that product, because then anybody could
copy it or make it.
So, they put those details in the drug master
file.
We need to see it to make sure that we are satisfied
with the chemistry manufacturing and controls, that the
stoppers are made of appropriate materials, and things like
that.
So, we will go look at it when we have an application
that says I am buying the stopper from Acme Distributors,
and here is my letter of authorization.
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So, there are a lot of those.
called Type 3 DMFs, container closures.
I think those are
There may be
another use of it in this case, too, I don't know.
The second kind of an application is the 505(b)(2)
application, and the main difference between a (b)(2)
application and a full NDA is that a 505(b)(2) application
relies for at least one of the investigations needed to
establish the safety and efficacy of the drug on a study
that was not conducted by or for the applicant, and to which
the applicant has not obtained a right of reference or use
from the person who conducted the investigation.
Now, again, should we get into discussions of
whether something is or isn't a (b)(1) or a (b)(2), who
conducted your studies that you are relying on may be an
issue.
You know, the UCLA PET center conducted both of
the studies that are being relied upon for approval, it
might be hard to argue that it's a (b)(2) instead of a
(b)(1) for UCLA, if UCLA were to come in with an
application.
Again, that makes a difference for user fees.
So, when we talk about how to structure this, you
have to keep in mind, you know, who is doing the studies and
how that will work.
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DR. CONTI:
here?
Can I ask a question on the wording
The applicant has not obtained a right of reference
or use from the person who conducted the investigations.
If
you are relying on the literature, do you need a right of
reference?
MS. AXELRAD:
No, but you wouldn't have obtained
one, and that is what makes it a (b)(2).
Because it's in
the published literature, you don't get a right of
reference, it's in the public domain.
DR. CONTI:
I am just trying to make sure we don't
have to go and ask for it, we could just use it in the
public domain.
MS. AXELRAD:
No, you don't need one if in the
public domain, but that's one of the things that makes it a
(b)(2).
Also (b)(2) issues are again very complex issues.
We have been working on a guidance document to discuss
(b)(2) applications for, I don't know, about five years, and
we still don't have it done yet.
Again, it was a side thing that was originally put
in the 1984 Hatch-Waxman Amendments to the Food, Drug, and
Cosmetic Act that created generic drugs under Section
505(j), and it was sort of based on an original concept of a
paper NDA where people could submit even before 1984 an
application based on literature, but the (b)(2)'s in HatchMILLER REPORTING COMPANY, INC.
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Waxman went beyond the literature, and that is sort of where
the complexities lie, but one of the things that we are
talking about here are mostly literature-based applications,
at least for the things that we are talking about today that
are commonly in use and for which there is literature.
Then, there is two types of (b)(2) applications,
one that involves an application that represents a
modification of a listed drug, that is, an indication or a
dosage form that differs from that of an approved drug and
for which investigations other than bioavailability and
bioequivalence studies are essential to approval of the
change.
For example, an application for the oncology
indication for FDG based on the literature would be this
type of an application, because it is different than the
indication for which FDG is already approved.
Then, the other type of it is as one seeking
approval of a new chemical entity for a particular
indication, like if we were running a new N-13 ammonia
application based on the literature.
We have talked here about sort of what our plans
are in terms of presenting the findings on safety and
efficacy to an advisory committee, and then publishing them
in some way, so that they could be referenced in
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applications, probably in a (b)(2) application, and we have
done that before for adding an indication for emergency
morning-after use for oral contraceptives where we encourage
people - we did a review of the literature, we determined
that certain existing products could be used for that
indication, and we invited people out there to submit
applications.
Now, a 505(b)(2) application has to include
basically the same information, but there are some other
additional things.
It has to have basic safety and efficacy
information, chemistry and manufacturing controls
information, and we will be talking about the model CMC
section that we are going to talk about tomorrow, would
probably be the CMC section whether it is a (b)(1) or a
(b)(2) application, or a (j) application.
There may be some additional things depending on
which pathway we take, but basically, we are talking about
the chemistry section regardless of what route.
Bioavailability.
There has to be either evidence
demonstrating the in-vivo bioavailability of the product or
information to permit FDA to waive the submission of such
evidence.
If the drug product has a different formulation
than that of the listed or already approved drug or the drug
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used in the studies, you still could have a 505(b)(2)
application, but under our current regulations, you have to
characterize and explain the qualitative and quantitative
differences between the applicant's formulation and the
formulation of the listed drug or the drugs used in the
reference studies.
If the formulation difference is substantial,
additional data may be required to show that the applicant's
formulation doesn't adversely affect safety or
effectiveness.
We may get into this tomorrow when we talk about
the chemistry or we might have one of our chemists comment
on this formulation issue now, because obviously, the
studies in the literature were done on a lot of different
formulations.
MS. KEPPLER:
I was going to ask what you meant by
"different formulation."
MS. AXELRAD:
Well, they were probably done under
a variety of different procedures, different places,
different ingredients, and I am not sure how detailed the
information in the literature is even about the formulations
that were used, probably not very.
DR. CONTI:
Particularly if it gets into the micro
amps used on the cyclotron.
These types of things are going
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to be very different all over the board, and it is going to
come up with the fluoride and again with different
cyclotrons and reactor versus cyclotron.
DR. KASLIWAL:
I think what you say we understand
that the method of manufacture could be different.
What we
are interested in the endproduct is same.
DR. CONTI:
Well, that would be very nice if we
could focus on that.
DR. KASLIWAL:
One of the examples that I would
cite is from a radiopharm equivalency biodistribution,
equivalency biodistribution point of view is FDG, you are
making no carrier added versus carrier added where you
generate isomers and the specific activity differences.
If
that was the situation, there will be a burden to prove
equivalence.
MS. AXELRAD:
insurmountable problem.
We don't think this is an
We think that we can develop, we
obviously have developed, it's the standard or model section
for CMC for FDG at least, where we understand the basic
process by which it is produced, and if it is being produced
at the manufacturing, proposed manufacturing site in
accordance with this, we will be fairly comfortable that it
is safe and that the findings of safety and effectiveness
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that are reported for FDG products in the literature would
be attributable to this.
If there are differences from the procedures that
we know, then, they need to be explained in the application,
and our chemists would look at them to determine whether we
thought that they were significant differences or not.
For a drug with different strengths than that of
the listed drug or the drug used in the study showing safety
and effectiveness, you could still -- again, this is a
similar thing -- you could still have a (b)(2) application,
but you might have to address the strength difference and
what it means.
I mean obviously, if it was five times stronger or
something like that, we might have concerns about whether
the safety and efficacy data that we are relying on would
actually apply to this.
We have already talked about the issue of a drug
with a different indication than the listed drug.
You can
come in with a different indication for a listed drug, for
example, if we approved an application for ammonia for
myocardial perfusion, and then there was some new indication
for ammonia that hadn't been done yet, somebody could do
clinical trials to support that indication, and it would
still probably be a 505(b)(2) application because all of the
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other data required for approval would have been in the
literature, but the (b)(2) application would simply address
the difference, which would be the new indication for use.
DR. CONTI:
is a good example.
Let me ask a specific question.
That
Let's suppose that we do have a
505(b)(2) for, based on the literature, for N-13 ammonia,
and referencing the Federal Register, and then we get into
the issue of viability, and N-13 ammonia is a participant in
that evaluation.
Would we have to file another 505(b)(2) to use N13 in the resting perfusion state with the FDG to do the
viability study?
DR. LOVE:
I guess you are asking a hypothetical
that probably won't exist because you would have taken care
of it in the labeling ahead of time, but if you assume that
it was not already resolved, then, yes, someone would have
to submit additional literature for something that is not
already in the database.
MS. AXELRAD:
it approved.
Well, that is if you wanted to get
Once something is out there and approved for
an indication, it is a matter of practice of medicine, and a
doctor can prescribe it to be used for an unapproved use.
DR. LOVE:
Right, which is a separate issue.
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MS. AXELRAD:
Which is a separate issue.
You
couldn't promote it for the unapproved use, you couldn't put
out a pamphlet saying, oh, you know, hey, it is approved for
this, but we think it is great for this, too.
But if a doctor, in the course of his practice,
decided that they wanted to prescribe it for some other use,
that would probably be permitted.
DR. RACZKOWSKI:
Perhaps there is another
dimension to what Dr. Conti was asking.
An indication, for
example, for ammonia might just say that it is useful in
evaluation of perfusion, and may not specifically refer to
its use in the context of evaluation of myocardial viability
with FDG, but the implication would be that in that
situation that wherever a perfusion agent is useful,
regardless of whether it's ammonia or rubidium or one of the
others, those are potential candidates that could be used in
the evaluation of viability.
I am not sure if that is what you were getting at.
DR. CONTI:
question absolutely.
It is within the domain of the
I guess I am just concerned that we
run into a situation where we have probably several
independent applications of these drugs, even if they are
now being considered and would be placed in the Federal
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Register, how the site would have to handle that by filing
for separate applications.
DR. LOVE:
Basically, assuming the Federal
Register Notice identifies all the different indications we
have been talking about in the context of this meeting and
the last meeting, we would then say that we think there is
sufficient evidence for that set of indications.
Now, certainly someone, if they wanted to, could
only ask for one of them, but the idea would be that you
would ask for all of those indications with one application.
DR. CONTI:
DR. LOVE:
Okay.
That is what I was getting at.
Each application does not have to have
a specific separate application.
MS. KEPPLER:
But you would have to have a
separate application for each drug.
DR. LOVE:
For each drug, yes, but you would say I
want FDG application for all the ones cited in 505(b)(2) for
all of the indications for FDG, another one for all of the
ammonia indications.
DR. LOWE:
And then two years later, if you think
there is another indication for that same drug, you can use
that under the practice of medicine without having to submit
-- there is no application if you just don't promote it as
such.
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DR. LOVE:
As long as you don't promote, yes.
MS. AXELRAD:
Probably when you are adding a new
indication anyway to an existing application, it is not a
new application, it's a supplement, which in the user fee
context again has implications.
If it is a supplement with
clinical data, it only pays a half-fee as opposed to an
original application with clinical data that pays a full
fee.
MS. KEPPLER:
daily practice?
What role does the NDA have in your
I was thinking of that in terms of the
different strengths, because I think we have talked about it
in the past, and I saw later in your document here where you
have talked about having a very wide range of strengths,
which could bridge multiple sites.
But as we also have talked before, as long as
there is good product that tests good at the end, even if
only 15 millicuries is made, it will often be used because
you have tested it, it is FDG, and you will use it.
That
might be too small to be within your range of strengths.
Under this approach, can you still use it if, in
your NDA, you have a range of strengths that is higher?
Does that make sense what I am saying?
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DR. KASLIWAL:
Let me understand your question.
I
guess what you are asking is can you sum it in a different
application.
MS. KEPPLER:
clearly.
No, I am sorry, I didn't speak
What you put in your NDA, can you use product that
ends up to be outside of the ranges that are within the NDA,
you know, of a lower strength.
You know, one day it comes
out as a lower number of millicuries per mL than what you
even have in your broad range that is in there.
So, I guess does the NDA dictate -DR. RACZKOWSKI:
I think when you release your
finished product, in order to release it, it has to be
within that stated strength.
The thing is that what we are
trying is at least a lower number.
If it is lower than
that, you probably won't have a dose.
So, we are trying to
keep the lower number as low as possible, so it is
equivalent to one dose that you get out.
That may not be of concern.
The concern is the
upper number, which basically depends on how much you made
in a single batch.
You could go beyond that.
You can
expand that down the road, but that has constraints with
respect to whether it is an abbreviated new drug application
or 505(b)(2).
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MS. AXELRAD:
here.
That is why we raised this issue
I mean what your release criteria are for the drug,
you know, it is sort of a GMP issue.
into that tomorrow.
We will be getting
But the strength issue is important
here because an ANDA, an abbreviated new drug application,
has to be for the same strength.
If it isn't for the same strength, then, you have
to go and file a suitability petition, and that has to go to
a committee, and then the committee has to evaluate whether
that difference in strength is too much that it would
require a new drug application or whatever.
The problem is that for the existing FDG that is
out there, the strength was defined narrowly, and it may not
cover all the other situations, so we have to deal with
that.
MS. KEPPLER:
Let me a different question that
addresses the same issue.
Let's say your O18 supplier runs
out and you have to go to another O18 supplier, and your
chemistry manufacturing and controls application portion has
the specific one that you have listed.
What happens, can you not use the other O18?
DR. KASLIWAL:
Usually, what the manufacturers
would do is in advance they will have multiple suppliers to
cover themselves.
You can, if you look at the chemistry
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application, where it is providing that option to you to
list multiple suppliers in advance.
MS. KEPPLER:
But it has to be one of them.
DR. KASLIWAL:
It has to be one of the approved
suppliers, yes, but you can have multiple suppliers of same
component.
MS. AXELRAD:
You can add suppliers later, if you
didn't think of it, in a supplement.
DR. CONTI:
Let's take the scenario where you have
two suppliers and all of a sudden, they are both out, and
you need to do clinical work, and you find a third supplier,
can you proceed and just notify the FDA of a new supplier
and then you retrospectively review that?
DR. RACZKOWSKI:
I would just explain it
generally, it depends on the component that you have, and
the mechanisms are under 314.70, and basically, the
preapproval or you can have changes being effected in a
supplement.
MS. AXELRAD:
And that is all under review.
DR. RACZKOWSKI:
So, you can submit a supplement
with changes being effected.
MS. AXELRAD:
The whole regulation, there is
another section, a FDAMA Section 116 that deals with
manufacturing changes of just this type and what constitutes
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a major change or a change with moderate potential or a
minor change, and the agency is revising its regulations on
314.70 to talk about which changes have to be reported in a
preapproved supplement, which can be in a 30-day
notification supplement, which can be effective immediately,
and you should be watching for that rule, which will be
published in the foreseeably near future.
DR. CONTI:
That would be very helpful.
MS. AXELRAD:
Since we have a deadline, a two-year
statutory deadline on that, the entire final rule has to be
published by next November, the 21st.
DR. LOVE:
But we also have emergency procedures.
Sometimes there is an immediate need, and we can't handle
that, and we work to expedite it.
DR. LOWE:
On Jennie's comment about the
concentration, I think if we were just able to state a very
wide range, if there is no difficulty with doing that, and
the concentration of the drug changes 8-fold in one day from
the production run, and so really what is important is the
active ingredient, you know, the radioactivity of the
ingredient that we have, not the concentration.
So, if we have to talk about concentration, then,
as long as we can state a wide range, I mean that is no
problem.
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DR. RACZKOWSKI:
That is fine.
I think what we
are recommending is when you make the batch for the NDA, you
make, you know, the worst case scenario at the highest
concentrations and submit that.
covered.
every day.
In that way you are
You don't have to make the highest concentration
Your actual batch can be based on your needs. As
long as it falls within that, that is fine.
MS. AXELRAD:
Now (b)(2), I think is the most
likely route we would use, but then there is the issue of
abbreviated new drug applications.
The requirements for
abbreviated new drug applications are in a separate section
of the regulations, actually several sections, 314.92, 93,
94, and they are fairly specific.
You can submit -- these are applications submitted
under Section 505(j) of the Food, Drug, and Cosmetic Act as
opposed to 505(b), and the drug has to be the same as an
approved drug, and the same means identical in active
ingredients, dosage forms, strengths, route of
administration, and conditions of use.
You can also submit an ANDA for a drug product
that has a different active ingredient if it is part of a
combination drug product, route of administration, dosage
form, or strength if you first submit and obtain approval of
a suitability petition under Section 505(j)(2)(c) of the
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Act, so that is where we were talking about the need if the
strength in the original approved drug was narrow, you would
have to go the suitability route.
Similarly, if you wanted to have -- I can't
imagine that any of these would apply in a different dosage
form or route of administration, I think it is unlikely we
are talking about anything different here -- but you might
do that.
Then, the requirements for an abbreviated new drug
application are set forth in 21 CFR 314.94, and they are
listed on page 7 here.
Now, there are some considerations that apply with
regard to different formulations.
I think these are very
similar, some of them are similar to the (b)(2), but for an
ANDA, a drug product intended for parenteral use has to have
the same inactive ingredients in the same concentration as
the reference listed drug.
But you can get approval of a drug that differs
from the reference listed drug in preservative, buffers, or
antioxidants if the applicant identifies and characterizes
the differences and provides information demonstrating that
they do not affect the safety of the drug.
So, there is a separate provision that
specifically allows for those narrow exceptions.
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DR. CONTI:
block here.
I am just having a philosophical mind
Again, dealing with this concentration and
strength issue, I mean I know we have dealt with this in
many discussions in the past, but when I take a
pharmaceutical, whether it is a prescription or over-thecounter, I know how many milligrams I am taking, I don't
know the concentration of it.
So, I am just having a hard trying to figure out
what you are talking about here in terms of PET
pharmaceuticals.
Are we really dealing with the amount of
millicuries of the tracer that you are giving to the
patient, or are we really dealing with the millicuries per
cc.
I think that this is a fundamental problem that we
are facing that we have got to clarify, you know, for PET
pharmaceuticals, so maybe we need to really look at this
regulation and really deal with this issue head-on.
MS. AXELRAD:
I don't know what the answer is for
PET.
DR. CONTI:
I know what the answer is.
The answer
is millicuries, it is not millicuries per milliliter.
It is
the same with any other nuclear medicine pharmaceutical.
mean you can give 5 cc, 10 cc, it doesn't really matter, 2
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cc, as long as you don't give 4,000 cc.
I mean there is
sort of practical limitations to how we do this.
DR. KASLIWAL:
What we are dealing with, one is
the strength, one is the dose.
DR. CONTI:
That is what I am saying.
Maybe we
need to be looking at the wording here and recreate the
wording that is appropriate for radioactive materials.
DR. LOWE:
What you have to keep saying is that
concentration is irrelevant to these agents.
that, that can be done.
If you want
I mean we can certainly give a
range for these drugs, but I guess the point is that the
millicuries is what is important because it changes.
We can dilute it.
Because it is such a small
amount, whether we present it to the patient in 5
microliters or we present it in 5 milliliters, it really
doesn't matter, but we can give that range.
difficult either.
That is not
I mean we can set up a range, so that
there is a range if that is something that is helpful for
someone.
DR. KASLIWAL:
My understanding of strength is
what is in the vial.
DR. CONTI:
I have got a concentration for you
that maybe might work is disintegrations per minute.
about it in that sense.
Think
If you are looking megabecquerels,
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I mean you are dealing with activity or time, so there is
your new term for concentration for radioactive materials.
You have got to be a little creative here.
can't deal with millicuries per cc.
DR. KASLIWAL:
We
It doesn't work.
If that is the case, it may have
little consequences at the highest concentration that you
are dealing with, but radiopharmacy, in general, our concern
would be if you go too much higher, with the stability, and
all that.
DR. CONTI:
That is a millicurie issue, it is not
a concentration issue.
You are talking about the amount of
radioactivity in the projected dose.
DR. KASLIWAL:
You are right, what concentration,
the total activity, whatever construed the most radiation
dose within the vial.
DR. CONTI:
Generally, in everything else that we
do with bone scans and other imaging agents, the
prescriptions always mention the concentration.
We always
say what it is, and that is, I think, what has always been
done.
I think that our concern would be certainly just the
ability to specify a very wide range.
DR. KASLIWAL:
I think I agree with you.
trying to do that as wide as possible.
We are
It doesn't prevent
you from drawing up and diluting it as you need it.
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DR. LOWE:
Right.
I mean that is the concern, is
if you have got just a few millicuries left, 10 millicuries
left, and you have to flush a number of your remaining vials
to get everything you need, you end up with a large volume,
which isn't a problem, but as long as we can fit that into a
wide concentration range, then that can be used.
I think that is the concern, is that it varies
dramatically, and as long as we can include a wide range for
the dose, it wouldn't be a problem.
We don't feel like it
is terribly important I think is the issue.
DR. CONTI:
dose.
I just think the language needs to be
That would be much more acceptable than to deal with
terms of strength and concentration.
It is just not
appropriate for the radiopharmaceuticals.
I think that
would be a better term.
DR. LOVE:
Just for understanding, what we are
trying to look here is to see how something that is already
in existence would be handled, and there will be a lot of
discussion tomorrow perhaps on the form and how the
different pieces would come in.
So, if we think conceptually for the moment, then,
assuming that we can come to some understanding on
terminology for how the dose is defined, is there a problem
with the concept of what is in this item here?
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DR. CONTI:
No.
Again, it is a philosophical
concept that I am having a problem with, trying to use the
words concentration and strength when I am dealing with
radiopharmaceutical.
DR. LOVE:
That is the issue.
Right.
DR. CONTI:
So, I think that the language would
have to be restructured to deal with radiopharmaceuticals if
we are going to put something together that is going to
work.
DR. LOVE:
I understand.
But assuming we know
what we all are meaning by concentration or strength, which
we have to come to grips with, in terms of what is stated
here in general, though, the point.
This was really just
given as an example of what it might mean, not necessarily
the specific wording here.
DR. CONTI:
It might be a way out for the Peoria
strength issue, because if we then focus on dose, we don't
have to worry about the, quote, unquote, "strength" range
that they identified.
DR. LOVE:
Right.
I think those pieces we will
talk about more tomorrow.
MS. AXELRAD:
The issue is that right now we have
existing regulations that say this is the way you do it.
So, for any of these questions that we are bringing up, the
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question is whether the existing regulations, with the
wording the way it is, allows us room to interpret it in
ways for radiopharmaceuticals or PET that are more practical
or work better for those, but it is still consistent with
the overall regulatory framework and words as they are
written in the rules.
If it won't, and we determine that there is a
problem, then we will have to do some amendments to the
regulations.
DR. CONTI:
Exactly my point.
MS. AXELRAD:
And there may be others of these,
but it is good to identify them.
DR. LEUTZINGER:
Jane is right.
This issue is
partly because of convention of the way we have dealt with
other drug products.
Usually, it's milligrams per
milliliter, grams per milliliter, and I agree with you, we
are going to have to do some thinking about the relevancy to
radiopharmaceuticals.
MS. AXELRAD:
The first thing will be to decide
what we think it ought to be from a scientific perspective,
and then the second question will be do the regulations
allow us enough room to interpret them in such a way that
that would be appropriate under there, and if not, then, how
would we change it to do it.
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The last issue in the document here is the
discussion of if you want any different indication than that
of the originally approved reference listed drugs, and we
are talking here in the abbreviated new drug framework.
You would either have to submit a 505(b)(1)
application if you did all the investigations, we wouldn't
accept an abbreviated new drug application, or you could
submit a 505(b)(2) application, but you couldn't submit an
ANDA for a new indication.
A new indication always kicks it
into the (b)(1) or the (b)(2) realm.
That is basically the issue.
issues, I was just looking for it.
Now, one of the
There is a provision in
our regulations -- Brian, do you remember where it was -there is a provision in the regulations that talks about if
you could come in as a (j), whether you would be allowed as
a (b)(2) application.
MS. KEPPLER:
What is (j) again?
MS. AXELRAD:
Abbreviated new drug application.
An ANDA is a (j), and the others are (b)(1)'s or (b)(2)'s,
but there is a provision that talks about this, and if we
can find it, I will talk about it.
But it is a concern to me if the structure is that
the first one that comes in or a number of them come in as
(b)(2)'s, whether once one is approved as a (b)(2), we would
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be allowed to bring in others as a (b)(2) or whether the
regulations would require that they come in as (j)'s.
MR. PENDLETON:
Right.
It is 314.101(d), and (d)
talks about the agency may refuse to file an application or
may not consider an abbreviated new drug application to be
received, that is, we wouldn't receive an ANDA if any of the
following applies, and then No. 9 under that is that the
application is submitted as a 505(b)(2) application for a
drug that is a duplicate of a listed drug, and it's eligible
for approval under Section 505(j).
That says that we may not consider an ANDA for
that type of product.
MS. AXELRAD:
The reason for that is that they
don't want people to go -- they are talking about
traditional pharmaceuticals here -- they don't want them to
go and do a bioequivalence test that shows that they are not
bioequivalent to the innovator drug, and then therefore
couldn't make it as a (j), and then come in under the (b)(2)
route, so that there will be a whole bunch of different drug
products out there that weren't bioequivalent to each other.
It is not directly relevant in this context, but
the regulations, again we will have to look at how that
regulation would be interpreted in this context and whether
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the regulations give us enough flexibility to allow, for
example, if we chose to do that multiple (b)(2)'s.
I want you to sort of look at this and you may
have additional questions that you want to ask us about
these, so that you fully understand the different routes,
and when you start talking about how you might structure who
is going to do the applications, how you are going to do
multiple manufacturing sites or what you are going to do,
then, we will need to focus in on some of these provisions
to see what works and what doesn't.
Okay.
Patent and exclusivity provisions.
I am
not going to spend I don't think a lot of time on this.
It
is obviously an application under (b)(2) has to include a
certification and also under a (j) actually, that to the
best of the applicant's knowledge, for each patent that
claims the drug, the patent information hasn't been filed or
the patent has expired, the date on which it will expire or
that such a patent is invalid and will not be infringed by
the manufacturing or sale of the new drug for which the
application is submitted, and if applicable, the applicant
must also certify that there are no patents.
I mean they have to come in.
A (b)(2) application
will have to come in with one of these certifications.
don't know if any of this patent stuff is going to be
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applicable, whether any of these drug products will or will
not be patented.
If they are, then, they have to follow
this.
MS. KEPPLER:
Certainly none of the five that you
are talking about, I don't believe, Peter.
MS. AXELRAD:
DR. CONTI:
Right.
No.
It is something we just can't
answer right now, we don't know, maybe in the future
something will be done, but at this point, none are.
None
of these are.
MS. AXELRAD:
Well, if there aren't any patents,
then, probably it would be a paragraph one certification
that such patent information has not been filed.
It would
be a paragraph one certification, and then we would just
move on and that would be the end of that.
If there was a patent, there would be issues
associated with that, that would have to be dealt with.
DR. CONTI:
What about patents for methodology or
application, I mean how would that be dealt with, the same
thing as -- we are talking about patent for the actual
production of the isotope I would assume here.
I am not
sure if someone proposed a unique patentable methodology
using the drug.
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MS. AXELRAD:
There is a method of use.
In No. 2
on page 9, No. 2, we talk about if information was filed by
a (b)(1) applicant regarding a method of use patent that
doesn't claim a use for which the (b)(2) applicant is
seeking approval, then, the 505(b)(2) applicant must submit
a statement that the method of use patent does not claim
such a use.
If it does claim the use, it may glop it.
know that for sure.
I am not a patent expert here.
I don't
We have
another, actually we have a separate lawyer who deals with
patent and exclusivity issues.
We could ask her the
question if it is an issue, but basically, we won't approve
an ANDA as long as there is -- this is again very loosely
speaking -- we generally won't approve an ANDA as long as
there is an outstanding patent with a whole bunch of caveats
about court challenges and things like that.
Generally, if there is a patent outstanding, it
raises a whole bunch of regulatory issues about whether we
can approve subsequent drug products, so if there are patent
issues we will have to really deal with that separately.
The same goes for exclusivity because
theoretically, the first person that comes in with an
application for ammonia or O15 water, would be bringing in a
new chemical entity application and might be subject to some
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kind of exclusivity or somebody bringing in a new indication
would qualify possibly for three years of exclusivity, and
that wouldn't work very well if the first person claimed
that and nobody else could use it.
MS. KEPPLER:
I wrote down in my notes about rush
for the N-13 ammonia application.
MS. AXELRAD:
Right.
But it can be waived, this
kind of exclusivity can be waived.
If the first person that
comes in waives the exclusivity, then, it is no longer an
issue.
MS. KEPPLER:
Is there a mechanism that -- and
this is the same definition of marketing that we found on
the first page, so that it would be that no other (j) could
be filed, so basically, once somebody filed this and claimed
exclusivity, nobody else could file one.
Is there a way they can allow people to file
against it for a fee?
MS. AXELRAD:
and they do that a lot.
Yes, they can license absolutely,
I mean the person that gets
exclusivity can either waive the exclusivity in toto or
enter into licensing agreements with subsequent people to do
that.
MS. KEPPLER:
Which may be a way in the future to
justify somebody putting in the monies, do a clinical trial
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for a new compound if they could then recoup some of the
costs of the clinical trial through a system like this.
MS. AXELRAD:
We have so much litigation on the
patent and exclusivity issues for traditional generic drug
products, it is an incredibly specialized and controversial
area.
We try to give you sort of an accurate picture of
this, but beyond what is written here, we would have to get
somebody here who is really an expert on our patent and
exclusivity issues.
If we get into that, it becomes a
problem.
DR. CONTI:
It is a potential problem, as Jennie
brought up, there is going to be a rush for N-13 ammonia
now, but the issue is, is what is really a new chemical
entity.
N-13 ammonia is certainly not a new chemical
entity, it is just not approved.
MS. AXELRAD:
Well, that to us is a new chemical
entity, unfortunately.
DR. CONTI:
What flexibility do we have in
interpreting that issue?
MS. AXELRAD:
I don't think we have a lot in these
cases because this is statutory.
can't just change this.
This is statutory.
This is the way it is.
want to open up the statute for this.
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They won't
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DR. CONTI:
problem.
Again, it may be a little bit of a
We may have to figure out another way to prevent
what are essentially drugs in the public domain from falling
into this category by creating another vehicle here to get
them -- or some qualification for PET pharmaceuticals if
they go through a (b)(1) or a (b)(2) or even the ANDA route.
MS. AXELRAD:
It has to be approved.
It doesn't
get the exclusivity until after approval.
DR. CONTI:
Understood, but let's say you approve
N-13 ammonia, as soon as it appears in the Federal Register,
it is to be approved for use in those indications.
I mean
that afternoon you will have a 505(b) on your desk
theoretically by a commercial company or something like this
or an entity, whatever, claiming exclusivity, and that would
be devastating to the PET market, so it might be able to
infringe upon other things which, in the regulations, such
as interference with practice or whatever that would prevent
other people from using that drug in their clinical
practice.
Maybe there is some sort of detrimental effect of
that happening in existing practice that we can infer.
MS. AXELRAD:
But it is interesting, it may not, I
don't know, it may be that that is not going to be an issue
here because we can't approve a 505(b)(2) application or an
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ANDA for a drug product that contains the same active
moiety, but we could approve a (b)(1) application.
It may be that this could be interpreted to say
that these would be (b)(1)'s because you would have a right
of reference or somehow to the data.
figure it out.
We would have to
I mean I realize it says it is going to be a
(b)(2) because it is based on the literature, but it is
literature that is in the public domain.
That isn't what this was meant to do.
It was
meant to protect somebody else's work, and we would have to
look into whether that -- we have to talk to our expert on
the statute and see whether it could be interpreted to avoid
that problem, but we will put it on our list of possible
problems.
That is why I wanted to go through this, to
identify all the problems.
MS. KEPPLER:
Again, especially if it is not
possible for somebody like the ICP to identify 505(b)(2)
because we aren't a manufacturing site, we wouldn't have a
production facility.
Then, we have got to find somebody who
are sure to get the first one in that is going to waive the
exclusivity, like what happened with the Peoria, so that the
community could have access.
MS. AXELRAD:
touchy issue.
Right.
Now we come to another
Establishment registration and drug listings.
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I know there has been a lot of controversy associated with
this.
This isn't really an approval issue.
This is anybody
who manufactures a drug is required to register with FDA,
each establishment which manufactures the drug, and to
submit a list of every drug that is in commercial
distribution.
An establishment is a place of business under one
management at one general physical location.
I put on the
back table and I think you should have these are the forms.
Again, they are fairly simple forms for registration of the
establishment and drug product listing.
I think that what seems to generate the
controversy here is that the registration and listing
requirements are seen as a way for FDA to inspect, and it is
true that registered drug establishments are subject to FDA
inspection by statute at least once every two years, or that
is the designated frequency in the statute.
I am not sure
we meet that all the time, but we are supposed to get out
and inspect once every two years.
But there is no fee associated with registration.
It is done annually.
We require you to update a list each
June or December or when a change occurs of drugs.
It is
just a way of keeping track of what is made, where, period.
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Again, I think the forms are fairly simple and not a big
deal.
DR. CONTI:
I think you are aware of the documents
that we had submitted to FDA a while back with regard to
what the community's position was on registration,
particularly for those academic institutions that are using
this for their own purposes.
I am trying to come up with a scenario that might
alleviate some of the community's concerns, and we had
proposed looking at the RDRC or some various configuration
similar to that as a means of registering sites.
It would seem to me that expansion, for example,
of the current RDRC supervision of use of radioactive
materials to include approved pharmaceuticals, approved
radiopharmaceuticals under their jurisdiction, and the
appropriate recordkeeping associated with that could be done
on a local basis without having to register directly with
FDA.
MS. AXELRAD:
What is the issue with registration?
Is it, as I thought, that people don't want to register
because they don't want FDA to come and inspect them or
what?
DR. CONTI:
I think inspection is certainly one of
the major issues, and certainly that could be handled within
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the RDRC mechanism, as well, since they would have authority
to look at those production methods and systems.
So, I think there is an issue of concern about the
inspections, yes.
DR. LOWE:
This is along the same lines.
I know
that our concern, and I think a lot of sites' concerns, is
not necessarily with the inspection per se.
I mean it is
with maybe kind of the process, the whole process of
preparing for the inspection, if you will, or having all of
the paperwork in order for the inspection and feeling like
it is a little overdone for what we are really producing.
I guess that is what most sites are feeling is
that we feel like we have a fairly safe product and that
what really is the benefit to society in terms of cost.
Our
site, for example, I have three employees in the PET center,
and to really prepare for an inspection or to really do
everything that we need to, we are talking about employing
another person, and this kind of stuff, I think it is
obvious what would be entailed.
We are saying that is fine if it really helps
somebody, if we are really doing something that would
benefit the patients that we see, and we are just unsure
that that is really good for society and good for our
center.
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I mean the inspection, we wouldn't mind anybody
coming in and taking a look.
I think the issue is more
preparing for that, the manpower, the cost for the facility,
and preparing everything that is needed for the inspection
where we just don't know that there is -- we have done 5,000
PET scans, and we have never had any problem with anybody.
I mean you have heard this before, I am sure, and
I think there should be regulation, I think we should have
some way to ensure that the products are safe, to ensure
that we do what we say we can do with this test.
I am just kind of in a dilemma as to the
discrepancy between how much benefit we are getting for the
amount of work that we might do in preparing for such an
inspection.
We were one of the only sites, I think, one of the
only private sites that actually prepared an ANDA three
years ago, and so we kind of had a little sense of what
would be involved in doing this.
That is I think our dilemma.
I mean it is not
necessarily the inspection per se, having somebody come by,
that's fine.
I think the issue is more manpower cost, is it
really a benefit.
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DR. HOUN:
I think that that is a legitimate
concern, and that is why have to really work together on the
CGMPs and then the eventual inspection process.
In the mammography program, it was the same thing.
People were very concerned about certainly they wanted to
practice good mammography, they wanted to have good
mammograms, most people, but there were a few facilities
that had terrible quality control and you would not want
them as part of your colleagues or as part of the radiology
community, and those people were forced out of business
because of inspectors coming by.
fact, it is the vast minority.
It is not a majority, in
I mean there are like a
handful.
But in terms of inspection, I do think, you know,
there was a lot of concern in our program about how much
time do people have to prepare for these inspections, how
much cost, so we actually did a survey of 1,000 of the
10,000 mammography facilities.
We did this in 1996 to see how long people were
taking to prepare, the average for mammography inspection,
how long at the facility.
It was between 85 and 90 percent
of the facilities saying that they took an average of six to
eight hours to prepare, so one day of one quality control
technologist's time.
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That is to prepare for the inspection, but we do
know the burden in terms of following all the regulations is
every day, you know, running phantom images, you know,
densitometry, sensitometry testing is every day, and you are
going to do the same kind of quality control every day when
you produce your PET drugs, but I think there is a way to
make it more reasonable.
I think that is what we have to keep our dialogue
on, like what are critical areas that you would want
everybody to have a clean record on, in what area would you
want inspectors to inspect, and what areas are worthless and
they are not going to produce any impact on patient quality
or impact on drug quality that we should be looking at.
So, I think it is a very legitimate concern you
have, but I think also we can try to address it to make it
reasonable, to look at the really important parts that you
would want facilities to be checked because if you were
going to send a relative there, you would want to make sure
they were doing it right in this way.
DR. CONTI:
We certainly don't want to confuse the
issue of performing the PET scan with the inspections
regarding the manufacturing.
I think this is a different
issue that we are talking about here.
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MS. AXELRAD:
similar.
No, we are not, but it is very
I think that we are really lucky to have Dr. Houn
involved in this because what they did in mammography is
very similar to what we are doing here, which is that the
FDA came in and began to regulate what had been an
essentially unregulated industry.
DR. HOUN:
It wasn't the production of the
equipment, but it was the production of the mammogram from
what do you do to monitor your films, what do you do to
monitor your equipment, the radiation output, so it was
those steps in the production.
DR. LOWE:
Can we use that for a model?
MS. AXELRAD:
we are looking at it.
Well, we are looking at it.
I mean
What they did was, what Florence has
laid out is that they did, they focused on what are the
critical parameters or things that need to be controlled,
what do you really have to inspect to make sure that you
have got a sort of level of consistency in terms of quality.
It is not the traditional kind of inspection that
we do when we go out to do a preapproval inspection of a
manufacturing facility that is making a million dosage units
of a drug.
I mean we are starting over.
starting over, as you know, with PET.
The agency is
Downstream, after we
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get the other stuff in place, including the GMP, although it
is starting to come into play in the GMP, we will be working
with inspectors to see what kinds of inspections, what will
they be looking at, what kind of information will they focus
on, what effect is it going to have on the person that is
being inspected, how much time will it take for the person
to prepare, and we can use the sort of experience that the
agency had in going in, in the mammography area and other
areas where we may have come in and essentially begun
regulating what has been an unregulated industry to do it in
a sensitive way, and to do it in a way that everybody agrees
is not unreasonable.
DR. HOUN:
So, in the manufacturing process, what
is reasonable to inspect.
train our inspectors.
We would be obligated to also
I know that is a major issue with the
professional societies, that FDA inspectors are not
necessarily Ph.D. physicists or they may not have the total
training that some of the folks working in the facilities
have, but they can be trained to look at some very
fundamental and important areas of the process.
But what I would say is that if we can keep an
open dialogue, it will be better for us all, for the FDA
inspectors, as well as for the facilities.
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DR. LOWE:
What was the application process like
for each of the mammography facilities to apply to be
certified?
DR. HOUN:
We used a third-party accrediting
system where you had to apply to an FDA-approved
accreditation body, ACR, the State of California, Iowa, or
Arkansas.
They were all approved as accreditation bodies.
They had to submit quality control data for a
year.
They had to submit physics reports.
They had to
submit names, degrees, bios of the doctors and techs.
They
had to submit mammograms to be evaluated by the reviewers of
these accreditation bodies.
After they passed accreditation, they got an FDA
certificate, and then they had to pass annual physics
surveys, and the FDA inspection, as well as the accrediting
body also asked for random images from these facilities.
We are not looking at interpretation or image at
PET.
It is a different focus.
DR. LOWE:
Unless you wanted to see at least that
there was an image, I mean like you were talking about, some
places weren't even producing images.
DR. HOUN:
images.
Right.
The inspector did not look at
The inspector looked to make sure they had medical
records and to make sure that the films were stored and that
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there were logs, those things, but they weren't looking at
the quality of the images or did they interpret this right.
That was done by the accreditation bodies, by the other
radiologists.
DR. CONTI:
What is absent in the current IRB
radiation safety and RDRC approach that would prevent you
from using this as a mechanism?
MS. AXELRAD:
I would like to defer that question
until tomorrow when Tracy Roberts, who is with our Office of
Compliance, involving good manufacturing practices is here.
From my own perspective, I would say one of the things that
is absent is really sort of independence, the idea of having
an independent inspector from the FDA come in and look, and
be able to say things about the process that the RDRC or the
IRB, who is actually a part of the hospital, you know, might
not, but we could talk about these issues perhaps a little
more with her when we start talking about GMPs.
DR. CONTI:
My understanding -- and maybe I am
wrong -- is that the FDA still has the authority to go in
and look at an RDRC or at an IRB, and to evaluate whether or
not they are, in fact, complying with the regulations.
MS. AXELRAD:
But there is a different focus.
I
mean the RDRC and the IRB are sort of looking at the purpose
of the research and the quality of the research, and they
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are usually done in the research context, whereas, the
production of the drug and the distribution of that drug -and I don't mean administration to the patient -- I mean
where you take the vial and you stick it in a box, and you
stick it on a plane and ship it somewhere or whatever is
really not the kind of thing that RDRCs or IRBs are usually
involved in at all.
DR. CONTI:
That is why I am proposing an
expansion of this activity, to look specifically at just
using approved drugs within the context of the RDRC, because
essentially, you have to still submit to RDRC how you are
going to prepare that pharmaceutical and administer it to
patients, whether it is for a research study or a clinical
study.
It could be adding a clinical study to that.
This would still allow you access to monitoring
depending upon what your inspectors come to inspect, and it
would allow the local control of the situation and perhaps
obviate the need to do this additional registration process.
So, this all I am getting at.
I think this is a
concern of the community.
MS. AXELRAD:
Well, they would be doing it.
mean the RDRC and everybody can be doing this.
will be doing it.
I mean they
You said that they will be doing it
anyway.
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DR. CONTI:
Not for approved pharmaceuticals.
What I am proposing is that we expand the current definition
since apparently we are rewriting these now.
This is a good
time to do this, to look at what the RDRC's role is, and if
it could be for internal use of an approved pharmaceutical
to be inclusive in their jurisdiction, it would obviate the
need for a lot of this.
MS. AXELRAD:
It may be that they would do that,
that they could take on some of that role.
talk about this.
We will still
We haven't really talked about this among
ourselves at all even, but I don't think it is likely that
the agency will allow that to totally substitute for
registration and listing and FDA inspection on some
frequency, you know, even if it's once every two years.
That is not very often.
You know, RDRC could maybe deal with production or
whatever, and will be on a daily basis, but to have an FDA
inspection once every two years and to simply require them
to fill out a form that tells us what they are making at
that facility does not strike me as being incredibly
burdensome, and I think that it can be done in a sensitive
way, you know, learning from the agency's experience in
dealing with other industries that have not been regulated,
that would be minimally burdensome to the industry and still
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give us the feeling that we are making sure that the
regulations and things that we have worked so hard to put in
place are being followed.
MS. KEPPLER:
Can I ask about how you would -- I
am sure I know the answer to this except I was reading this
again where it said here that the list is for anything in
commercial distribution -- how do you define that commercial
distribution again, anytime money is exchanged for the
isotope?
Is that it, meaning that patient pays for the -MR. SNYDER:
It is not simply when money is
exchanged.
MS. KEPPLER:
MR. SNYDER:
within the process.
When value is exchanged.
When some kind of value is exchanged
Essentially, it would include just
about everything outside of a research context.
MS. KEPPLER:
Because I would, you know, as an
outsider, would read that and think that if I was using it
in my own patients clinically, that it would be okay, but
what you are saying -MR. SNYDER:
But that is a commercial transaction
that is occurring there unless you are providing a
charitable service.
MS. KEPPLER:
I think I would like to just
reiterate one other point that I have heard from folks in
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the community, the two points that I have heard as far as
the fear.
People get inspected all the time at these sites
by their radiation, you know, safety internal committees
once a month.
My experience was we got monthly inspections
and then annually by the State, and Joint Commission comes
in and inspects.
I don't think it is the process of inspection or
having somebody look over your shoulder that is, in and of
itself, the problem, because I think folks are used to being
inspected.
I think the issue that I have heard from other
people again is whether you are inspecting the right things,
and I think that is what people are concerned about, that a
lot of time will be spent on things that aren't of
importance to the outcome of the drug.
MS. AXELRAD:
I would like to think we have the
opportunity to work that out, the same way we are working
out everything else that has to do with this.
MS. KEPPLER:
The other issue that I have heard
brought up from people that I have talked to is that -- and
I will just throw this out because I have heard it mentioned
-- is that as institutions, they are exempt from
registration, and I still hear that occasionally, that as an
institution, we are exempt from registration.
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That is the
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other response I have heard when we talk about establishment
registration.
MS. AXELRAD:
Well, that gets to the compounding
versus manufacturing issue.
Doug can speak to this, but
basically, you don't want to be in the compounding area.
You are not in the statutory exemptions with regard to
compounding.
You are specifically out of that provision, so
you wouldn't qualify for the compounding exemption that any
compounded drug product would qualify for.
So, if you are manufacturing, which we consider
this to be, then, you do have to register and list.
DR. CONTI:
I don't know if we are going to get to
the fees, the application fees.
MS. AXELRAD:
10 after 12:00.
Well, I was just going to ask.
It's
The question is do you want to press on
through the rest of this or do you want to break?
really up to you.
It is
I mean do you want to take some time and
caucus after lunch?
DR. CONTI:
We certainly do want to talk about
fees.
MS. AXELRAD:
Yes.
The only question is whether
we should talk about it before lunch or talk about it after
lunch.
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DR. CONTI:
Right, and I am just wondering whether
we want to go back and spend more time on the NDA-ANDA
issues and discuss that some more.
If we think we can
discuss all that in an hour, we should just finish it.
Otherwise, we should just take a break and then come back
and maybe end by 2 o'clock or something like that.
MS. AXELRAD:
I think it is really up to you all,
if you want to caucus and assimilate what it is you heard
and ask some more questions.
MS. KEPPLER:
I think we should break for lunch,
because I think what we will do is be able to come up with
additional questions that might be valuable.
MS. AXELRAD:
Okay.
So, we will break and why
don't we come back at about 1:15.
[Whereupon, at 12:15 p.m., the proceedings were
recessed, to be resumed at 1:15 p.m.]
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AFTERNOON PROCEEDINGS
[1:30 p.m.]
MS. AXELRAD:
We are going to reconvene and pick
up on page 11, talking about user fees, and then we will go
through the rest of this document and then we will talk
about the USP chapter and monographs before we adjourn.
Before I start on user fees, do you have any other
issues from what we talked about this morning that you would
like to get into?
DR. CONTI:
I actually had a couple questions on
the clinical side, just to put those out of the way.
I am
sorry this is backtracking a bit.
MS. AXELRAD:
DR. CONTI:
That's fine.
One of the things that we were
somewhat concerned about was the fact that we wanted to try
to put together all the FDG applications, and once we have
had them all together, we would then prepare this label or
this set of indications for FDG.
I felt that maybe we might be neglecting an
important area because we have talked about oncology, we
have talked about cardiology, but we have left out one major
area for FDG, which is neurology, and there are some very
specific applications of FDG in that area.
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In addition, I wanted to make sure we clarified
that brain tumors would be included in the oncology
indication, and I thought that perhaps maybe the way to do
that would be to include some brain tumor literature as part
of the citations that was in the Federal Register supporting
the conclusions that were reached.
So, perhaps we can take one or two brain tumor
articles and we can maybe provide you with those articles.
DR. HOUN:
I would be happy to review.
I couldn't
find any that were prospective, had 50 or more evaluable
patients.
I mean that is the way the other ones are.
If
there are less, I mean I would be happy to read them, as
well, and we could figure out what to do with that.
DR. CONTI:
Some of the classical articles with
FDG by DeChiro and other folks at NIH, actually there are
hundreds of patients that have been studied with FDG.
DR. HOUN:
Okay, so they may be older.
DR. CONTI:
It is in the early to mid-eighties
that most of the literature was published.
There has been
not so much since then, but we do have some more recent
articles, as well.
Actually, we did a recent literature
search in brain tumors, so we can provide that to you, but I
think we can at least give you a couple of sentinel articles
that I think would be appropriate.
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I just don't want to leave that application
hanging, because sometimes it is confused with neuro, and
with regard to neuro, there are at least two or three
applications that we routinely use PET for.
One of those is
in dementia, particularly Alzheimer's versus the multiinfarct dementia presentation.
The second one is in the area of epilepsy, which
is already included in the NDA from Peoria, and then we have
the area of stroke, which is another general application.
This will have some overlap with the perfusion imaging
agent, the O15 water.
As you go through the literature, you
will see O15 water used to evaluate stroke.
So, we want to make sure that at least those
common scenarios are included in the general indications,
and my question now is how do we want to handle that as far
as the reviews.
Do you want to go through this process of
us sending you the articles or how would you see us moving
from here?
DR. LOVE:
I would say that for anything for which
we do not yet have articles, then, we would need the
articles to do that.
dementia one.
So, certainly the stroke and the
For the brain tumor, perhaps we may need to
talk a little bit about it.
If there are articles, as Flo
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suggested, that are prospective or have greater than 50
patients for their brain tumor, that would be important.
I guess the other question is what are you seeing
as different in the labeling indication for brain tumor
specifically as opposed to the more general indication for
malignancy in general.
DR. CONTI:
Nothing.
I mean the issue here is
just to make sure that it is a cancer that is commonly used
with PET, that is at least cited as supporting data.
We are
looking beyond the general application for evaluation of the
cancer patient or diagnostic population to be able to at
least point to third-party carriers that, look, this is the
literature that was reviewed, and by the way, it does
include brain tumor, if there is a question on that, because
we can potentially lose sight of that, particularly because
it falls into the two separate categories of neurology and
oncology.
I want it somewhere that we looked at that.
DR. LOVE:
Are you thinking about the management
type labeling types of discussions, or again, just that
brain tumor patients were evaluated?
DR. CONTI:
No, it is diagnosis.
The vast
majority of the brain tumor patients are going to be ruling
out recurrent tumor from radiation necrosis.
and away the most common application for FDG.
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That is by far
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DR. LOVE:
We may need to talk just a little bit
about that and get back to you on what, if anything, we
would need on the brain tumor.
DR. CONTI:
DR. HOUN:
Okay.
I would like to go ahead and if there
are articles, you know, to gather them.
I do recall those
older articles, and I am not sure if they were prospective
in nature.
DR. CONTI:
They may not have been.
DR. HOUN:
Right, and I do remember they were
DR. LOVE:
That is a little bit of my concern.
older.
The DeChiro articles were submitted to the original NDA.
Many of them were quite small in number, and a lot of the
patients did not have pathology follow-up, so some of them
were just followed in the course of normal treatment, and we
were not able to document a uniform treatment management
program from the database.
Our reviewers doing that review did go to NIH to
try to get the data, so there were some concerns about
whether or not -- I have some concerns about whether or not
we can use all of that literature.
On the other hand, at that time, the indication
was different from what we are talking about today.
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At that
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time, it was a very specific, disease-specific type of
indication, and we were looking at the data in that context,
so we may or may not be able to extrapolate today since it
is a different indication.
DR. HOUN:
We would appreciate that the search
might have overlooked such well-controlled studies, and that
would be great if you have them and could give them.
DR. CONTI:
With regard to the dementia and the
stroke, and the epilepsy, we don't need to deal with because
it already has the NDA, but as far as the other articles,
would you want to do that review yourselves or how would you
like to proceed?
MS. AXELRAD:
ourselves about that.
issue.
I think we need to talk among
I think that we get into a resource
I mean each one of these reviews is very resource
intensive.
So, let us talk about that.
Do you have any idea of how many articles or how
big the literature is on this?
DR. CONTI:
There is probably more on dementia
than there is in stroke.
I can't give you an actual figure.
Also, keep in mind that other nuclear medicine procedures
have been used to look at these applications, as well.
I mean there is a vast literature on SPECT and
Alzheimer's disease, for example, and again, the same basis
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is for the FDG.
We are looking at changes that are
consistent with the pattern seen on SPECT imaging for
Alzheimer's disease, so there is sort of a similarity to how
we review the perfusion imaging with N-13 ammonia with the
perfusion imaging that is done with current SPECT
pathologies like thallium or things like this, so there is
some overlap.
The same with stroke, we are really looking
at a similar disease, which is a different agent.
So, I just don't have a feel for the exact number
of papers at this point.
MS. AXELRAD:
We will talk among ourselves, and we
will get back to you on that.
DR. CONTI:
The only other thing I had was the
issues on the NDA routes and whether or not we wanted to get
into any type of discussion regarding alternatives to the
NDA approach, if there are any that could be considered.
I
mean this is something that -- is the NDA route the only
route that we have to proceed with an approval process for
PET radiopharmaceuticals at this point or is there something
else that can be contemplated.
MS. AXELRAD:
Well, statutorily, we only have
three routes to approve a drug - (b)(1), (b)(2), and (j),
period.
So, I hadn't thought about having a statutory
change.
I think that the existing procedures will work,
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possibly with some minor regulations changes, but I think
that the statutory framework is there, and we can work
within that.
I don't think we need to change that.
DR. CONTI:
I think as long as we have the
flexibility to make the modifications that are appropriate
for these drugs, then, I think we will be comfortable with
that.
MS. AXELRAD:
What I am hoping is that at the end
of the discussions today, you will have a good sense of what
we see as looking like what the application will actually
look like, and then you can let us know whether you think
that an application within our existing regulatory
framework, maybe with some things, we may have to deal with
strength, we may have to deal with that exclusivity
question, but there are a few things that we identified this
morning, but basically, you will see what the application
looks like, and then the question is whether you think that
would be an appropriate framework.
Also, why don't I ask this point before we get on
to user fees, ask anybody in the audience if they wanted to
make any remarks regarding what we have covered so far on
the regulatory framework.
DR. CALLAHAN:
My name is Ron Callahan from Mass.
General Hospital.
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I want to go back to the registration issue just
for a moment to point out another aspect of that, not that
it is onerous or that we might not be able to comply, but I
come from an academic institution that now I have to go and
convince the administration or someone in the institution to
sign this document in some way that says we are now a joint
manufacturer, and that opens up a lot of liability issues,
insurance issues, and the like.
So, that is another aspect of registration that is
far into the PET community and one we have to deal with from
our point of view, it's not your problem, it's our problem,
but it is just something I wanted to bring up.
As far as inspection, I don't think we are too
concerned about the concept of inspection.
We are more
concerned, as was mentioned, about what they will be
inspecting against, i.e., the GMPs and also the training and
direction given to the inspectors, and then whereas, there
were 1,000 mammography out of 10,000, you know, that you
surveyed, or something, there is only a handful of us out
there, and so that resources that might be allocated to
inspect such a small number of specialized sites might be
very small, and we would hope that these inspectors would
have the appropriate charge and background.
MS. AXELRAD:
Thank you.
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DR. CONTI:
Actually, I want to pick up on
something that you said, because that is a very good point.
We are facing actually the same exact issue within the
university that I am at with regard to how do we classify
ourselves as a manufacturer and what the liability issues
are.
There is everything from considering creating
corporations outside the university to handle this
particular business, if you will, to doing it as we have
been doing it all along, and I think that while we now
currently make drugs for use in our patients on site, our
IRBs and institutional committees still require us to file
INDs and still require us to file IRB applications even
though it is for patient studies, clinical use.
So, it has come down to they have allowed us to,
quote, unquote "manufacture" a drug for our own patients,
but we have to do all these other things, but when you get
into the issue of distribution, then, that really throws up
a red flag.
I mean if you are going to do any type of
distribution from your institution, then, you have to really
be careful about these liability issues, because then that
becomes transferable to the outside.
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So, the universities are looking at this very
carefully and I think, as Ron has mentioned, it is of
concern at this point.
MS. AXELRAD:
I don't see a difference in
liability whether it is called manufacturing or not,
whatever you are doing, and you are making drugs and
administering them to patients, and some academic
institutions are also distributing them outside the hospital
and flying them various places, and things like that.
So, you have whatever liability you have now, I
don't see how requiring you to list and register is going to
alter that.
DR. CONTI:
I think it is just a matter of
bringing it to the forefront.
In the past it has been done,
and people have not paid a lot of attention to it, but now,
because of this bringing the piece of paper to be signed,
you end up having a little bit of a problem.
MS. KEPPLER:
It's the physician's liability,
though, versus the institution's liability in part, too -and correct me if I am wrong -- but I would believe that if
the physician is using the drug under what he believes to be
the practice of pharmacy and medicine, he is compounding the
drug under his license as opposed to the institution
registering as a drug establishment.
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I don't know if that helps clarify what people's
concerns are or not.
DR. CALLAHAN:
I would add to that, that, you
know, if the practice of medicine and the practice of
pharmacy is what the institution does and some of the normal
actions that they do on a daily basis within their scope,
drug manufacturing, as formalized by registration and
listing, is outside of the normal functions of a hospital
for which they currently do not have liability protection, I
would assume and I have been told.
So, whereas, if as a pharmacist I screw up, they
have some liability and I have some liability insurance to
cover that, but if there is a litigation against a defect in
the product that was manufactured and listed, that may be
not covered under our risk management portfolio at this
time.
MR. SNYDER:
Basically, what Jane said is correct.
It doesn't matter whether you have to list yourself as a
manufacturer or not under the FDA statute or FDA
regulations.
When it comes down to the fact that somebody is
making the product, under tort liability law, they are the
producer and they may have liability as the producer
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regardless.
The fact that they are manufacturing it would
cause them to have liability if the product is defective.
Now, if the doctor or the pharmacist is an
employee of the hospital or the medical institution or the
university, the university would most likely have liability
also unless it is set up in such a way, as I think Dr. Conti
mentioned, where maybe the hospital may set it up as a
separate corporation to somehow protect itself from
liability, because then that corporation becomes a person
unto itself.
But even those issues, that is not clear because
if it is a wholly-owned subsidiary of the hospital,
potentially, the hospital could be sued and be a defendant
in a litigation also.
Let me tell you that law is not the clearest law
in the world, and basically, let me say, what would happen
is if there is a defective product, you would all be sued.
MS. AXELRAD:
Let me also suggest that perhaps,
you know, the fact of FDA approval and compliance with
current good manufacturing practices that we would establish
might provide some defense for you in terms of the liability
issue.
If you were following procedures and doing exactly
what you were supposed to be doing, and could show that you
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had sort of made every effort to make a high quality
product, that might help.
DR. CONTI:
This is the argument that I have used
actually with our administration.
MS. AXELRAD:
It won't insulate you, but that
would certainly help.
MR. SNYDER:
Well, that is true.
What happens
typically in these litigations is if it was made pursuant to
a process that was approved by the government, that is
evidence of the fact that that is a standard that is
accepted within the community, you couldn't do any better,
and therefore there is no liability there from that
perspective.
I mean patients take on a certain risk when they
take drugs, obviously, or anybody who uses a product takes
on a certain risk.
It is a matter of whether the producer
did something that was negligent in essence when they
produced the product, and if you are following a standard
that has been accepted by the community, it has been
approved by the government, that is a defense.
DR. SWANSON:
Dennis Swanson, University of
Pittsburgh Medical Center.
I apologize, this may have been covered this
morning, but our legal counsel at the medical center has
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clearly read the exemptions from requirement to register as
a drug establishment, and our legal counsel has advised us
that our institution falls under those exemptions.
How do you see reconciling the institutional legal
counsel's perspectives of those regulations?
MR. SNYDER:
I think what I would want to see is
their analysis, and the statute and the regulations require
any manufacturer to be registered unless they are a pharmacy
that is involved in compounding.
DR. SWANSON:
In our institution, it could easily
be said that we are pharmacists involved in compounding
these drugs.
You have defined it as manufacturing in your
previous Federal Register Notice, but this whole issue was
the major issue of conflict between the PET community and
the FDA, to begin with, and I still think that you have a
major area of conflict there, if you are saying everybody
has to register as a drug establishment, that you haven't
resolved.
MR. SNYDER:
If you classify yourself as a
compounder, then, you have certain criteria that you have to
come under, under the new statute for compounding, and that
creates a whole set of other issues for you then.
DR. SWANSON:
Yes, but the new statute on
compounding exempts radiopharmaceuticals.
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MS. AXELRAD:
No, it doesn't exempt them.
It says
that it doesn't apply to them.
DR. SWANSON:
point in time.
It doesn't apply to them at this
The point I am trying to make is your --
your regulations define who is exempted from the requirement
to register as a drug establishment.
Again, I will keep asking, how are you going to
resolve the situation when our legal counsel -- you come out
and say we all have to do this -- and our legal counsel
says, well, wait a minute, their regulations say we don't?
MS. AXELRAD:
We are doing a cut on that.
Our
lawyer is doing an analysis and we will make a cut on that,
and it will appear whatever regulation we do, or whatever we
need to do, we will be making a statement that says whether
we think you do or do not have to register and list.
If somebody out there disagrees, then, they will
have to probably sue us, and it will be resolved in court.
MR. SNYDER:
Of course, just in the process also
of proposing a regulation and putting the policy out there,
you will have the opportunity to respond to the legal
analysis.
MS. AXELRAD:
Yes, there will be opportunity for
comment.
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DR. SWANSON:
It becomes a very critical issue
because then it also ties into Section 704 of the FD&C Act,
which addresses what you can do when you come in for
inspections, because entities that are exempt have different
inspection criteria on what you can do.
MS. AXELRAD:
That, you did miss this morning.
I
mean basically, we had this discussion this morning, and I
was trying to get at my understanding is that the reason
that people are objecting to the registration and listing
requirement is because of what happens with regard to the
inspection.
What we indicated this morning is that we are well
aware of that, and we would expect to work out the details
of what would be inspected and the training of our
inspectors, and all of that, in a sensitive way, the way we
are sort of trying to address all the other PET issues, but
that I didn't think it was likely that at the end of the day
the answer was going to be that you wouldn't be inspected by
the FDA.
DR. SWANSON:
Let me state that, you know, I have
no problem with inspection by the FDA, and I will keep
saying this, as long as that inspection is based upon a
reasonable set of standards for the production of these
agents.
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MS. AXELRAD:
Dr. Houn, who was involved in
setting up the Mammography Quality Standards Act inspection
program, sort of has experience in coming into what has been
essentially an unregulated industry, and setting up an
inspection program to deal with that.
We are learning from her, and she is involved in
what we are doing here, so that at the end of the day, we
hope to have a program that will meet both of our needs.
DR. CONTI:
Again, one of the proposals that is
around the table was this RDRC expansion.
This may, in
fact, provide some additional level of alternative here, if
you will, to allow the universities to again maintain some
control over at least their own operations.
I mean putting aside the distribution concept, at
least if they go through this mechanism, they can continue
to operate and still have the same liability levels that
they currently have with an approved drug now as opposed to
just research drugs.
That might solve some of the issues
that the universities face.
So, again I urge you to consider that as an
alternative.
MS. AXELRAD:
Are there any other comments from
the audience?
[No response.]
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MS. AXELRAD:
If not, we will move into user fees.
Peter, did you have a short answer to this, if
there was a short answer that there shouldn't be any, or
would you like me to explain how they work?
DR. CONTI:
My short answer is no fees.
So, if we
can move on from there -MS. AXELRAD:
Okay.
Then, let me talk to you
about how the statute works and how you might get to that
result, if that is the result which you obviously want.
There are three basic types of user fees.
There
is application fees, product fees, and establishment fees.
There are application fees for an application requiring
clinical data.
That would be a full 505(b)(1) application
which for this fiscal year is $272,282.
If the application did not have clinical data, it
would be half the fee, of $136,141.
It goes up according
to, you know, in the statute, the fees are set in the
statute, and an inflation factor is applied each year.
Certain 505(b)(2) applications do not have to pay
a fee.
If it is a 505(b)(2) application that does not
involve a new active ingredient, in other words, if it is
for something that had already been approved, or a new
indication, then, it doesn't pay a fee.
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The problem with that is that the first ammonia
application, and actually any application that came in until
one was approved, would be for a new active ingredient that
hadn't previously been approved and would be required to pay
a fee.
Once one was approved, they wouldn't have to pay a
fee.
My people are telling me -- we did the billing, my
office, believe it or not, actually does the billings for
user fees.
We actually send out the invoices and
everything, and decide what gets billed, so you are talking,
this is something I know a fair amount about.
If it is based on the literature review that we
did in the Federal Register Notice, it wouldn't be
considered to have clinical data required for approval, and
so it would only pay a half-fee to begin with.
But then there are waiver provisions.
waivers of these fees.
You can get
First of all, if the first applicant
that came in was a small business and qualified under the
criteria in the statute as a small business, which is it has
less than 500 employees and meets the definition of a small
business set up by the Small Business Administration, and we
actually consult them on that, then, the application fee
would be waived for the first application that is submitted.
They can't have any other new drug applications in
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interstate commerce or any distribution, but if they don't,
and they meet the definition, then, they could get the fee
waived, and then once one is approved, nobody else would
have to pay.
So, that is something to sort of keep in mind
when you are structuring it.
The other alternative is to apply for a waiver,
and here, there are very fixed criteria in the statute on
what would constitute a grounds for a waiver or reduction.
It has to be necessary to protect the public health or to
eliminate a significant barrier to innovation because of
limited resources.
Obviously, if an applicant would get a lot of
money from sales of PET drugs or has a significant total
annual revenue in excess of $10 million, or has a corporate
parent, it might not qualify for the waiver.
The waiver program is administered by our office
of the Chief Mediator and Ombudsman.
So, we could talk to
them about a waiver, but we can't just say, oh, well, we
don't think PET should pay a fee.
There just isn't a
statutory basis for us to do that.
DR. CONTI:
That is what we are here to write,
right?
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MS. AXELRAD:
rewrite the statute.
I didn't think we are here to
We are going to do what we can within
the regulations.
DR. CONTI:
Let me ask you a question.
In terms
of the corporations that would qualify on the nonprofit or
not-for-profit, is there some guidance that we could have in
terms of if it's a 501(c) corporation or something like
this, that that would qualify as a not-for-profit and
therefore be exempt, is there any guidance in that area if
the entity were?
MS. AXELRAD:
I don't think there is anything in
existence, but we issue a report on waivers.
I would
suggest that either you, or I, or both of us could talk to
the Office of the Chief Mediator and Ombudsman.
There are reports on the waivers that have been
issued, and there are examples of people who have gotten
waivers, and you can tell by who they are that they have
gotten waivers based on nonprofit.
You know, there are
people that are nonprofit or they get a waiver for some,
because some drugs are not making any money at all by
distributing.
They are essentially distributing them for
free, some vaccines and things like that are distributed by
some of the public organizations.
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But I don't think there is anything written down
in terms of how you actually view it.
We have a very old
guidance document that was put out on waivers in 1993, that
we can get a copy for you on, that says basically, if you
got less than $1 million in annual revenue, you would get a
waiver.
If you got more than 10, you wouldn't, and in
between we would sort of examine it.
But there has been a lot of history since that
guidance was put in place, these decisions are basically
done on a case-by-case basis.
But I would say one of the
things you would want to consider, though, is who is
applying for the application.
We would have to look at, you know, based on if
they were a not-for-profit and what their revenues were, and
then it will play into, you know, if we had one (b)(2), and
a bunch of ANDAs, ANDAs don't pay user fees at all.
DR. CONTI:
That is what I was thinking.
If we
did a (b)(2), you would probably want to do that under a
scenario of whether it is the institution, let's say, ICP,
which is a nonprofit, or even if it is a university, which
is a nonprofit, that would still potentially qualify even
though they may have more than 500 employees.
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I mean if we can get some precedent for types of
entities that would be eligible for this type of waiver,
that would be very helpful, I think.
MS. AXELRAD:
We can do that.
Let me just also
suggest, though, that we will have done a lot of work on
this, work that is normally done by the applicant, and it
might be that it might be possible for the group of people
who are going to be benefiting from that work, and who are
going to be submitting applications, to perhaps share in the
cost.
Instead of working so hard to find a waiver, having
them perhaps come up with a way of paying the fee at least
for the first one that gets approved.
MS. KEPPLER:
136,000 is pretty cheap, right?
MS. AXELRAD:
Divided by 70 it might be.
MS. KEPPLER:
I am not opposed to the fee
structure as it is outlined.
it, though.
I do want to try to understand
When you said that a small business, you said
something about and not having another drug in commercial
distribution, so those are both requirements, that it would
be a small business and no other drug -MS. AXELRAD:
No approved drug.
MS. KEPPLER:
-- no approved drug in commercial
distribution.
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MS. AXELRAD:
Whatever you are doing under your
INDs or whatever doesn't count.
MS. KEPPLER:
Right.
MS. AXELRAD:
And even if you were distributing
generic drugs, that doesn't count, so, you have no other
human drug application in commercial distribution as that is
defined in the User Fee Act.
MS. KEPPLER:
My concern was that if we ended up
with -- because of the way it came out with -- we ended up
having to have 80, 505(b)(2)'s because nobody could qualify
for the (j) ANDA, that that is a huge burden across the
community if everybody had to come up with their own -MS. AXELRAD:
Right, if you wanted to stage it so
that you had one approved that would come in first and pay
the fee, which could be shared by the others, that none of
the others would have to pay a fee, because they would be
not a new active ingredient and not a new indication, that
means for the same indication.
That would be one way of doing it.
The first one
comes in pays the fee, and the rest of them don't have to,
and they could be in as (b)(2)'s, and not pay a fee, they
wouldn't have to come in as ANDA.
MS. KEPPLER:
Oh, that's right, so the second
(b)(2)'s don't have to, it's just the first one.
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MS. AXELRAD:
Right.
The first one, after the one
is approved, though, they don't pay.
DR. CONTI:
But you have to send the fee in during
that approval process until one is approved.
MS. AXELRAD:
Right.
I am just saying suppose one
came in and, you know, was -- you know, we are not talking
about a major substance, I mean we would be looking at the
chemistry, but the safety and efficacy, we wouldn't be
looking at that because it would be based on what we have
already done.
Presumably, the review could be done fairly
expeditiously, and then you would wait until that approval
is in place, and then the rest of them could submit.
I mean
the industry will have a least a two-year period under the
statute to bring themselves into compliance with our new
procedures after the procedures are in place.
So, there might be a way to stage it that way.
One could come in, and then everybody else would come in
after that.
DR. CONTI:
Well, let me throw this out and say
aren't we, in fact, looking at the chemistry for the drugs
that we are talking about here now anyway?
We are looking
through the USP, and looking at FDG, N-13 ammonia, and these
other pharmaceuticals.
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MS. AXELRAD:
DR. CONTI:
Right.
Why do we have to relook at the
chemistry again in the application?
We are going to have
the safety and efficacy in the Federal Register.
We are
spending the time now doing the USP for each of the drugs.
What else is there left to do, and why do we even need to go
through the -MS. AXELRAD:
Because we are required to look at
the chemistry manufacturing controls, which isn't quite
totally covered by the USP.
DR. CONTI:
We are going to work that out.
MS. AXELRAD:
DR. CONTI:
We will be getting into that, right.
We are going to work all these things
out as part of our negotiations.
Why do we have to then
resubmit it and be re-reviewed because we have already
agreed on what we are going to submit?
DR. KASLIWAL:
The thing is that if you look at
the USP methods or other things, they are very broadly
written.
USP.
People don't exactly follow what is written in the
When you do the method in your house, you do it
certain ways, and it depends on how you do it in those
specific things that you do.
DR. CONTI:
So, each application would have to be
evaluated for just those deviations.
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DR. KASLIWAL:
That is something we will discuss
tomorrow, is there are certain common things and there are
certain things that are very specific to your own facility.
DR. CONTI:
I guess my point is that the first
person in the door is going to have nothing more for you to
look at than the 80th person in the door, which is the ANDA.
You are going to have the USP or whatever it ends
up being called, and you have going to have the safety and
efficacy.
The first one in the door comes in with a (b)(2)
at $136,000, you are going to check the eight or nine things
that are going to be some sort of deviation from what the
USP is or some specific things that are done in-house there,
and you are going to do exactly the same thing for the ANDA
that comes in as number two.
MS. AXELRAD:
Well, if it comes in as an ANDA, it
won't pay a fee.
DR. CONTI:
I know, but I guess I am just sort of
having -- I think 99 percent of the work is done.
We have
got to do a quick checklist and see what specific things
have been verified.
DR. KASLIWAL:
The application is simplified, so
that most people can comply, but I am not sure.
individual does their own thing.
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DR. LOWE:
There certainly may be some differences
maybe in irradiation time, something like that, and that may
be something that somebody on an ANDA would want to specify
as a deviation from what was on the (b)(2).
Is that what
you are saying, something like that?
DR. KASLIWAL:
Well, irradiation time is one
thing, but your specific manufacturing process may be
different.
I mean you may be using a different -- the
overall process is the same, philosophy of the process is
the same, but the exact stepwise process is different.
I think it will be a little bit clearer when we go
through the application actually tomorrow.
You can see
where the difference is, I mean where the specificity of the
thing lies and where the commonality lies.
MS. AXELRAD:
At least you understand it.
MS. KEPPLER:
Yes.
MS. AXELRAD:
You may not like it, but you
understand it.
DR. LOWE:
One more question about the fees.
A
lot of PET centers obviously are within a large corporation,
a large hospital, if you will, even though the PET center
itself has a very low, maybe under a million gross per year,
they would still not qualify as a small business because it
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is part of a larger corporate, larger hospital, is that
correct?
Is that the way I am reading that?
MS. AXELRAD:
Yes.
I think that that would
present problems should we try and apply the waiver criteria
the way they are written.
Also, I want to mention so far we have just been
talking about application fees, we haven't been talking
about product and establishment fees.
Two-thirds of the
fees actually that we get come from product and
establishment fees, one-third from product fees and onethird from establishment fees.
These are fees that are assessed annually on
products that are approved under human drug applications and
establishments that manufacture prescription drug products
that are approved under human drug applications.
The establishment fees in particular are fairly
hefty fees.
The establishment fee for FY '99 is $128,435,
so that would be assessed annually.
The good news is that
the first company that gets an approval would pay these fees
on an annual basis until a second one was approved under
either 505(b)2 or (j).
Once the second product is approved,
then, they don't pay fees anymore.
DR. LOWE:
Neither one of them?
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MS. AXELRAD:
Neither one of them.
This was set
up because the way it is now, innovator applicants pay fees,
but generic drug applicants don't, and so it wouldn't be
fair to keep assessing these annual fees on an innovator
applicant when the generic that is competing directly with
it doesn't have to pay a fee at all.
So, the innovator pays until a generic is
approved.
pays.
Once the generic is approved, neither one of them
So, again, if it all happened within a year, the
first person would pay a fee, might not even have to pay a
product and establishment fee if there was generic
competition under either a (b)(2) or (j) within the first
fiscal year that it came on the market.
DR. LOWE:
When is that fee assessed, is it
assessed at the end of the first year?
MS. AXELRAD:
We bill in December of every year.
It is our Christmas billing.
Yes, we get it out around
December 15th, and it is due and payable on January the
31st.
DR. CONTI:
Reading what you have here, though, it
sounds like that we wouldn't be doing this anyway.
MS. AXELRAD:
That what?
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DR. CONTI:
That we wouldn't be paying product or
establishment fees anyway because of the fact that it is a
505(b)(2) or an ANDA.
MS. AXELRAD:
Well, certain (b)(2)'s pay, ANDA's
do not, but the first 505(b)(2) application, if you never
had anybody else on the market, the first ammonia
application is for a new active ingredient, or if there were
a new FDG application that was separate from the existing
application for a new indication, that would pay a fee until
something else comes on that competes with it, a generic.
DR. LOWE:
Is the initiation for the assessment
the approval or the application?
MS. AXELRAD:
DR. CONTI:
Yes, it is the approval.
That is not written in here.
MS. AXELRAD:
It is the approval.
It is from the
day -- it is once it is approved, and, in fact, it is then
eligible for drug listing, too.
The product fee is tied to
drug listing.
DR. LOWE:
So, if the ammonia is approved in
February under a (b)(2), the second institution sends in an
application in June, if that was approved before December,
then, no fee will be assessed at all.
MS. AXELRAD:
approved before.
Actually, it would have to be
You would want it to be approved before
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September 30th.
It goes on a fiscal year basis.
It goes
from October 1 to September 30th is the fiscal year,
whatever happens within the fiscal year.
DR. LOWE:
Would that be possible, do you think,
to do it that way?
MS. AXELRAD:
I think it's possible.
I think we
would have to work it out, so that it would work, but I
think it would be possible to do that.
DR. LOWE:
We are back on page 14.
DR. CONTI:
write-up here.
So, that stipulation is not in your
That is why I was having a hard time
understanding that.
MS. AXELRAD:
DR. CONTI:
MS. AXELRAD:
Which one?
Back to the first, 505(b)(2).
On page 13.2.
Product Fees.
An
exception to the product fee requirement is that no fee will
be assessed if the product is the same as a product approved
in a 505(b)(2) application or an ANDA.
Therefore, no fee
will be assessed on a PET drug that is the same as a PET
drug approved under a 505(b)(2) application or that is the
same as an ANDA approved PET drug.
And the establishment fees, the establishment fees
go to whether you have a prescription drug product that is
assessed a fee.
So, if it is an establishment that is
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manufacturing a product that is not assessed a fee, then,
the establishment isn't assessed a fee either.
MS. KEPPLER:
I am also trying to understand, too.
I am a little lost on the concept of the establishment fees.
Now, a facility would pay that once even if they had five
drugs or they would pay it five times?
MS. AXELRAD:
Once, each establishment pays once.
MS. KEPPLER:
But if we had five products, you
would pay five product fees?
MS. AXELRAD:
Right, but the product fees are very
MS. KEPPLER:
I just wanted to make sure I
small.
understood it, that if you have any drug that you are
manufacturing, and you don't qualify for the exemption of
it, you would pay the 128,435 per year, and then on each
product it is small, it's 18.
MS. AXELRAD:
Right.
Again, once you got one
approved or two approved, then, nobody else would be paying
either of these fees.
Nobody would be paying either of the
fees.
DR. CONTI:
Now, Peoria has a 505(b)(2).
Are they
paying a product fee or an establishment fee at this time?
MS. AXELRAD:
not.
I don't know if they are waived or
I don't know.
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DR. LOVE:
They were waived.
Everything was
waived.
DR. CONTI:
So, for FDG at least, we are not going
to face this, because the next one that comes in is the
second.
MS. AXELRAD:
However, the application for the
FDG, I guess we would say that the application for the FDG
for the new indication would probably, you know, if it were
just submitted by an applicant, period, without being based
on our work, it would pay one-half the fee, you know, it
would be a supplement for a new indication.
Let's say Downstate Clinical PET Center submitted
a supplement to its existing application to add the
indications that we have talked about to the FDG thing.
Normally, a supplement where clinical data is required for
approval pays one-half the fee, but since we have done the
literature review, I don't think it would be assessed a fee.
I would have to check that with my people, but I
am pretty sure that it would not be assessed a fee since we
wouldn't be doing any additional work.
that indication.
So, they could get
It wouldn't be assessed a fee, and then
any other application for FDG would not be paying anything.
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DR. CONTI:
So, really, the only thing we would be
facing would be for the N-13 ammonia or O15 water, something
like that, we would have to go through that process.
MS. AXELRAD:
DR. CONTI:
Right.
So, my understanding is, however, if
we can get a scenario where the original submission is from
a waiver eligible entity, we would not have to pay that, and
therefore we would pay no fees at all.
Am I reading that correctly?
MS. AXELRAD:
Yes.
If you are the first person
that qualified for a waiver under the statutory criteria,
then, they would not have to pay a fee, and then once that
is approved, the next people would not have to pay fees no
matter who they were.
MS. AXELRAD:
requirements.
Post-approval reporting
I wasn't going to spend much time with this.
It has not really been an issue.
This just sort of lays out
what the regulations say.
This applies to anybody who has
an approved drug product.
There are certain reporting
requirements associated with this.
it's in the regulations.
It is straightforward,
If you have questions, somebody
here can try and answer them.
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DR. CONTI:
I just wanted to again reiterate the
issue of the reporting through the current mechanisms that
are available for the research pharmaceuticals.
We do have a mechanism that anytime any drug or
device is used, we report these routinely within our
institutions through our institutional review boards, as
well as the RDRC and Radiation Safety, so there is again a
vehicle in place for adverse events reporting.
If you consider expanding the RDRC, then, you can
include the changes to the CMC's and the other aspects of
the production of the pharmaceutical as another vehicle for
reporting those changes to an FDA authority.
MS. AXELRAD:
DR. CONTI:
MS. AXELRAD:
You would have RDRC report to us?
They do now.
They do now, okay.
They collect
them like a manufacturer collects them.
DR. CONTI:
It would be expansion to include an
approved pharmaceutical in this case.
research pharmaceuticals.
They only deal with
Again, it is another way around
dealing with the in-house utilization of these
radiopharmaceuticals without having to go through the -DR. RACZKOWSKI:
One thing I would like to mention
about the adverse experience reporting, as it is outlined
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here, it says there are 52 different categories.
The first
category is what are called 15-day alert reporting.
Those are really for what are termed serious and
unexpected adverse events, and serious is described as
something that is life-threatening, et cetera, et cetera.
Unexpected means that it is not in the labeling for the
product.
So, those reports only have to come in if a
serious or unexpected event occurs, and the reason they call
it 15-day reports is because those events are of greater
public health implications, so they come in right away.
The
other place where safety data comes in what are from the
annual reports, and that will capture any sort of safety
adverse experience, even those that aren't considered to be
serious or unexpected.
DR. CONTI:
I think also, as in the licensing for
the use of radioactive materials, there are some events that
occur that you report to Radiation Safety, and then they are
either obligated or not obligated to go on and report that
to the State, for example.
The same with IRB, I guess.
Some of these things
they can handle internally without necessarily having to
call the FDA saying such and such happened.
They have the
authority to deal with those issues, and we might be able to
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construct something here that says the only time we need to
actually notify the FDA about any of this is if it meets
some sort of emergent criteria that might have implications
for centers across the country or something of that nature.
But for the most part, again, I thought most of
this stuff could be handled internally by the current review
mechanisms and reporting structure.
Again, it is a level of
duplication that I don't think is necessary since we have
this other process in place.
It is a good way to reduce
user fees, too, reduce the workload.
MS. AXELRAD:
on this part of it.
You don't have to pay any user fees
In fact, the product and establishment
fees sort of helped to support the post-approval inspection
and other processes, although we are not allowed to use it
for postmarketing surveillance.
One of the other pieces of this, you know, we are
sort of focusing on the sort of downstream submitting
applications as part of the process.
At the other end is
the RDRC peer research and the IND issues, which we wanted
to address with you at another time.
We didn't really have time to sort of flesh those
out among ourselves, but we do at some point want to talk to
you about what we are thinking about doing on 361.1 in RDRC,
and we will be considering the suggestions that you have
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made with regard to the role of the RDRC and in the letter
that you sent in, I guess it was in August, about what their
role should be in this process, and then we will talk about
where we are on that in one of our next meetings.
We really haven't talked about INDs either much.
DR. CONTI:
Again, there are some similarities
there, too, because of the nature of the reporting for
adverse reactions and the annual reports, and things like
this, so all that I think could be looked at simultaneously.
I had a question a little further on, on page 16,
I don't know how far, in terms of the clinical data.
Are
you talking about expansion of an indication here or is this
only supporting data with regard to the existing
indications?
DR. LOVE:
This really is any report or study that
is going on by the holder of the NDA, so whether it is a
marketing application, someone exploring a dosage form, it's
for publicity, it doesn't really matter what it is.
It is
any clinical study that was performed by that applicant just
would be reported, the results.
It is not as much detail as
one might see in an NDA, but it is just the awareness of
what else is going on under IND basically.
MS. KEPPLER:
understanding.
I just want to clarify my
So, like if we were to put in an abstract at
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an annual meeting, they talked about stomach uptake of FDG
or something like that, just including the abstract in it is
what you are looking for here.
DR. LOVE:
Right.
MS. KEPPLER:
Not requiring that people continue
to do these clinical studies.
DR. LOVE:
No.
MS. KEPPLER:
It is just if you happen to be, you
are supposed to include it.
DR. LOVE:
It is anything that happens.
DR. CONTI:
What I was getting at was an issue of
whether or not this is sort of a clearinghouse for expansion
of the indications for the drug.
I mean if you are working
with a drug, and you happen to use a different application,
are you interested in having that data submitted through
this process or not?
MS. AXELRAD:
We are interested in knowing you are
going to do it, so we can be aware that you might be
submitting a regular application for it sometime in the
future.
DR. LOVE:
The way the existing regulations are
for any drug, it is just a way of looking at what else is
going on with the development of that product, so you are
looking at safety information, you are looking at the
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reports.
They may be safety reports, they may be clinical
efficacy reports, they could be a variety of things.
They might be cost effective comparisons, a lot of
different things.
So, there isn't any requirement here.
Some of this may be something you want to think
about in terms of how much of this kind of information would
you want to come in under a specific ANDA, holders
information, or how much of this might you want to
centralize, and we can think about that.
DR. CONTI:
That is the part where my concern is,
because what happens is there may be pooling evidence of
safety and efficacy within an ANDA because an investigator
happens to be working with that pharmaceutical, and all of a
sudden, we are in a situation where the others don't have
the access to that information.
I am not sure how that
works.
DR. LOVE:
Some of that is choice because
obviously, the way the regs are currently written, much of
this work is still being done under proprietary INDs, so
everyone isn't aware of it, and you may have individual
investigators who still want to do some work that isn't
public yet, so you want to try to leave some flexibility for
the individuals yet if there is something that is
collective, it doesn't mean that we would want to see the
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same report five times in five different applications -- not
applications, but annual reports.
MS. KEPPLER:
DR. LOWE:
We knew what you meant.
One last question, going back to the
establishment fees and the product fees.
The waiver
criteria, are those the same as what you have described for
the ANDA or for the application fees, are the waiver
criteria similar for the product fees and the establishment
fees as they are for the application fees?
MS. AXELRAD:
Yes, that is exactly the same thing.
The only thing that is different, the small business waiver
is only for the application fee, but all the other criteria,
the public health and innovation are for annual fees, you
could ask that any of the fees be waived under that.
In fact, if you don't qualify for the small
business exception or waiver, you can still say, okay, then,
I want it waived on public health or innovation grounds.
Again, you have to talk to the Office of the
Ombudsman about how they apply these.
They really do it on
a very case-by-case basis.
MS. KEPPLER:
My only other comment about -- which
we talked about earlier, but I guess I am just going to
reiterate -- that it is probably of concern to the
communities for these compounds which aren't going to be,
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you know, these existing ones are the ones that are already
out there that maybe there is not enough clinical data, is
that we try and look at the framework that we have here and
come up with some sort of centralized approach, because I
know the problem that happened with the Peoria FDG NDA
existing.
If we wanted to do a supplement, it needed to be
on the first one.
If we could come up with a community way of
putting forth these paper NDAs through the ICP or through
some other professional association that could do that, that
then people could reference, then the community can expand
it with supplements and things like that, and we are not
beholden to a single institution to expand it in the future.
So, I guess I would just reiterate that if we
could figure out a way to do that, that would be something
that would allow the field the flexibility that it would
need to expand.
MS. AXELRAD:
What you have to do is you have the
safety and efficacy part of it that you would want to be
done by some central organization, but you have the separate
manufacturing processes that would have to be by the
individual manufacturing site.
MS. KEPPLER:
Right.
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MS. AXELRAD:
And that sort of is the trick.
I
mean but it may be that the drug master file is the way to
do that, that you put the safety and efficacy data in a drug
master file that is maintained by some central group and
that everybody else would submit individual applications
referencing the safety and efficacy data for that part of
it, and then providing whatever manufacturing information
and other information they would need, it would be site
specific.
DR. CONTI:
So, what you are saying is if you did
a drug master file, would you be able to go ANDA or do you
still have to file a 505(b)(2)?
MS. AXELRAD:
DR. CONTI:
Yes.
So, someone would still eventually
have to file that.
MS. AXELRAD:
Somebody has to get that thing
approved first as a reference listed drug through a
505(b)(1) or (b)(2) before you can have a (j).
You have to
have a reference listed drug in order to have an abbreviated
new drug application, but that could be not looking much
different than an ANDA would if the safety and efficacy data
is what is reported in the literature.
DR. CONTI:
Right.
We could probably move on.
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MS. AXELRAD:
Does anybody else in the audience
have any comments on the regulatory framework issue?
DR. SWANSON:
A question.
If we in a medical
institution are registered as a drug establishment or a
manufacturer, then, I am assuming we are subject to the same
promotional off-label promotional requirements as a
manufacturer would be.
MS. AXELRAD:
You are subject to the same
promotional requirements whether you are a manufacturer or
anything else.
You can't promote an unapproved new drug or
the off-label use of an approved drug.
DR. SWANSON:
Okay.
Are physicians who work
within our institutions considered to be agents of that
manufacturer, and if so, are they going to continue to be
allowed to use drugs for off-label uses?
MS. AXELRAD:
Oh, my lawyer left.
DR. SWANSON:
Well, you are a lawyer.
MS. AXELRAD:
Right, sometimes.
DR. SWANSON:
If so, that is a problem you need to
be aware of.
MS. AXELRAD:
Let me talk to Doug about it and
maybe we will be able to answer that tomorrow.
DR. CONTI:
Just from experience in terms of
promoting drugs, let's say, for the most part we have not
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had problems that I am aware of, of physicians going out
into the community under continuing medical education to
talk about new developments and availability of tests,
drugs, devices, procedures, or whatever.
So, most folks have not gotten into trouble as far
as I am aware of with regard to confusing that with
marketing.
MS. AXELRAD:
When I was visiting a PET center who
shall remain nameless for these purposes, I noticed a very
nice little brochure that was sitting there about how PET
can be used for all these different unapproved uses.
Of
course, it is not approved for anything except FDG for
seizures, but anyway it was promoting essentially the use of
PET, and it had a number of sponsors on the back, I think
ICP and UCLA PET Center, and the U.S. Department of Energy
was on there.
But anyway that was essentially what I would view
as a promotional piece, whoever it was that was doing that
was essentially promoting the use of an unapproved new drug.
Now, I didn't take this back and immediately
provide it to our Office of Compliance to go out and take
action against that, but that is the kind of thing, you
know, if we ever get this regulatory scheme in place, people
might start looking at promotional things like that.
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DR. CONTI:
Well, you can actually promote the
devices, PET scanners, so if you are clever, you can promote
PET scanning.
MS. AXELRAD:
You can promote the use of a device
for an unapproved use?
DR. HOUN:
No, for the intended use, which was the
intended use that was approved.
MS. AXELRAD:
And was the intended use approved,
what is it, to scan?
DR. HOUN:
I am not sure.
MS. KEPPLER:
I think it was to image positrons or
something like that.
MS. AXELRAD:
that.
Well, this went a little beyond
It showed how you could diagnose various diseases
using the PET.
MS. KEPPLER:
I think that Dennis brings up a very
good, but more subtle point.
I wouldn't be surprised if
most PET centers out there today have some sort of
promotional material whether they are using one that was
produced by another facility or whether they have got a
little flyer of their own that they put out, and that is
definitely one issue that it sounds like Dennis was bringing
up, but there is a more subtle issue which we don't want to
get lost is that the physician that is in a PET facility
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gets asked to go out and give CME, you know, that talks
about it.
The physician is an employee of the institution,
and he no longer gives CME about how he has found that PET
is useful for this off-label, whether it is FDG in infection
imaging or something like that.
I agree with Dennis that is an issue that we
should at least be aware of.
MS. AXELRAD:
I will have to talk to our Division
of Drug Marketing Advertising and Communications.
haven't spoken to them at all.
We
They don't know what we are
doing, and we haven't talked to them about this.
There is a whole guidance and things like that on
continuing medical education and what you can and can't do.
I will talk to them and see what they say about this.
DR. LOWE:
this either.
I don't think we are the initiators of
I mean beta blockers for prevention of
myocardial infarction, I mean there is a lot of things that
physicians talk about that have documented published
benefits.
DR. HOUN:
But those aren't the manufacturers.
DR. LOWE:
That's right, they are not the
manufacturers.
I guess, as a physician, if I went out and
talked about things like that, the use of PET in dementia,
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if that is not approved or whatever, I guess, I don't know
if I would be considered the manufacturer or not.
Would I?
I mean that is the question.
MS. AXELRAD:
With PET, it becomes tricky.
We are getting away from the word manufacturer to
get away from whether you are manufacturing or compounding,
we are going to production, you are producing the drug or
trying to.
DR. MOCK:
I have a question from the audience.
Bruce Mock, Indiana University.
On the annual report requirements for types of
things to notify the FDA about, assuming I have jumped
through all the hoops successfully to get either the ANDA or
the 505(b)(2) manufacturing permits or produce FDG or some
compound and distribute it or make it available, or to use
it clinically, the clinical data, the very last page, No.
16, requirement to notify on an annual basis the FDA, all
published clinical trials of the drug or abstracts either
conducted by or obtained by the applicant must be included
in the annual report.
Now, if I were to conduct a study, I am aware of
that study, maybe I can provide you with a copy of those
results, but what is obtained by me, just because my
institution receives some journal where some article is
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abstracted in there, I am required to notify you of the
reports of the results of that published trial or abstract,
what does "obtained by the applicant" mean?
DR. LOVE:
In the normal context, it would mean
commercial entity is responsible for looking at the
literature and submitting to us other information that might
be published by other sources.
When I was mentioning earlier that we might need
to talk about something centralized in the context of PET,
that was why I was mentioning it, to be obtained by piece is
difficult, and we wouldn't need that to come in, in every
single one of the 60 ANDAs, so that is an issue we need to
clarify for what it would mean.
MS. AXELRAD:
Maybe we could work it out if there
was a DMF in which the safety and efficacy data was there,
that the holder of the DMF would be the one that we would
hold accountable for keeping that DMF up to date with the
latest stuff that was being published.
DR. LOVE:
Right, for the published literature.
MS. AXELRAD:
For the clinical safety and efficacy
of the drug.
DR. LOVE:
But the individual who conducted a
study that wasn't published would be the person who would
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have to tell us about that one.
I agree, it is something
that we have to sort through.
MS. AXELRAD:
I am just throwing that out to make
sure we can do that, you know, see what the regulations say
about that.
Any other comments?
DR. RACZKOWSKI:
Well, typically, what sponsors do
is they just submit copies of the relevant journal articles
that they have gotten through a general search, if that
wasn't clear already.
MS. AXELRAD:
Clearly, we don't want to have 70
people doing the same thing.
That doesn't make any sense.
We do not have all of the people here that would
need to be here to discuss in depth the USP chapter on the
monographs, but do you want us to give a status as to where
we see them at the moment?
Status of USP Chapter on PET and PET Monographs
MS. AXELRAD:
Just to put a little background or
context to this for those who have to be involved in this,
after our initial discussions with ICP last August on
chemistry issues, we began discussing what ought to be in
the general chapter, USP chapter on PET and what the
monographs would look like for the specific PET compounds
that are on the market.
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We sort of continued that discussion in a couple
of meetings under the auspices of the USP with the committee
that is responsible for developing the chapter in the
individual monographs.
Dr. Kasliwal will tell us the status of those
discussions.
We had a couple of meetings under the auspices
of the USP on them, and we have been exchanging comments
sort of through E-mail and other mail processes on the
chapter and the monographs.
[Slide.]
DR. KASLIWAL:
We are talking about the
compounding chapter is 823, Radiopharmaceuticals for
Positron Emission Tomography Compounding.
Basically, there are currently five subsections
and the sixth one to go in there, and all six are listed
there, control of components, materials, and supplies that
are used in the compounding process, compound procedure
verification, stability testing, expiration date, and then
PET radiopharmaceutical compounding for human use, and then
the other one that will go in there is sterilization and
sterility assurance, and finally, the quality control.
My understanding is most issues, control of
components, compounding procedure verification, stability
testing, and the PET radiopharmaceutical compound, and the
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quality control are pretty close to resolution, and my
understanding is that sterilization and sterility assurance
may also be close to finalization.
The others in the room can comment on what the USP
perspective on that is, but that is my understanding.
We
had few comments on those except for sterilization and
sterility assurance.
We had submitted a few comments to
USP, and I am not sure what the feedback is.
Maybe either
Dr. Swanson or -- okay, Dr. Callahan.
DR. CALLAHAN:
The whole background behind this
was that a version of the general chapter made reference to
Chapter 12-11, I think it is, which is aseptic processing
and related sterilization issues in the USP.
There were
some components of that, that we thought should not be
referenced to in this PET compounding chapter.
So, as a result of that, a process was initiated
with David Hussong from your Microbiology Group and myself
to sort of take some of the elements of 12-11 that are felt
to be important and include them, and things that weren't
relevant, take them out.
Over the last several weeks, we have been Emailing a lot back and forth, and I think we are at a stage
where I am comfortable with the document as satisfying our
needs at the practitioner's level, and I am told that it is
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fairly close to meeting the regulatory needs, so that is why
this particular section was not in the original chapter, it
was only to be included in the revised chapter.
David is
not here, but he could add to that, I am sure.
MS. AXELRAD:
Tracy Roberts has also been involved
in this, has indicated that we believe that we are in
agreement with the latest version.
DR. SWANSON:
I might comment that we did send a
version of the compounding chapter to FDA, and you commented
back.
I just got the comments like 15 minutes ago, and
looked over your comments.
I really see no problems in
addressing the changes that you have made on the compounding
chapter.
DR. KASLIWAL:
I thought my comments were fairly
minor editorial things.
DR. SWANSON:
They are just primarily housekeeping
MS. AXELRAD:
Basically, all of this work is just
things.
so that we can get something to USP that they can publish in
the PF, Pharmacopoeia Forum, for comments.
But I think that
we are very close to having something that can be provided
to the USP, that the FDA would not feel the need to make
additional comments on.
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DR. CONTI:
These are with regard to just the
general chapter, the individual monographs.
[Slide.]
DR. KASLIWAL:
Along with the chapter, we also
received the updated monographs on those five drug products,
and I did send my comments, our comments that we went
through and looked at, between OGD and everybody on
fluideoxyglucose F-18 injection.
My understanding is USP had the comments.
haven't received any feedback.
I
I guess we can discuss what
those comments were or if there is a problem with any
specific comment, we can go through that.
We have also reviewed ammonia N-13 injection and
water, although those comments haven't made it to USP yet.
We have to internally go through that and maybe by tomorrow,
we can finalize it, bring it to USP here for discussion on
those two others.
The other two, we haven't had a chance between,
you know, putting together the application and the other
aspects.
My thinking is if we can decide on these three as
a first cut, it will be helpful.
DR. SWANSON:
Again, I just got your comments back
on the FDG monograph, and in looking through them, I do have
some concern.
The comments back, many of them address areas
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where we had lengthy discussion at the USP meeting between
the USP Committee and the FDA.
In fact, I think that on
these comments, we had come to a consensus agreement between
those two groups.
Now I see comments coming back that want
us to deviate from what I thought we had consensus on.
So, I don't know where you want to go with this,
but we are probably going to have to sit down and have
another discussion of these issues.
DR. KASLIWAL:
Right, but understand that since
the last time, the chapter has changed quite a bit, USP
Monograph, some of the language.
DR. SWANSON:
I am talking about here.
But I don't think that is the issues
For example, we had a lengthy
discussion about omitting the term isotonic as part of the
description of FDG, and we had come to agreement on that,
and it was omitted in the monograph, and now you want us to
put it back in again based upon what appears to be what was
in the NDA.
Understand USP monograph standards don't
necessarily have to comply with NDAs.
DR. KASLIWAL:
I guess the reason was we went back
and thought about it, and the reason we suggested that it be
put back is I guess at the time when we were discussing that
isotonic, that it would be suitable for intravenous
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administration, but then if you read that, it says aqua
solution, and if it's aqua solution, it may not necessarily
be isotonic.
DR. SWANSON:
I don't know if this is the forum
for addressing these specific issues.
arguments previously.
We went through these
That is what I am saying, and we had
come to what I thought was a resolution.
Now you are going back against what we had
resolved.
I don't know how you want to handle these.
This
might be the reason why we need to have another meeting to
resolve these issues.
MS. AXELRAD:
I think that we should have another
meeting where we go over the specific comments on the
monographs.
DR. SWANSON:
that.
I think we are going to have to do
That is kind of where we are at on that.
DR. CONTI:
I would make a suggestion that it may
be possible -- I don't know what your schedules are -- but
maybe sometime tomorrow, if we end early, we might be able
to sit down and break out and do that discussion.
MS. AXELRAD:
If we end tomorrow.
I don't know
how long we are going to be taking, thought, in GMPs.
DR. CONTI:
Again, I have a short answer for that.
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MS. AXELRAD:
Oh, great, I don't want to hear the
short answer on that.
[Laughter.]
MS. AXELRAD:
We will agree to try and get
together at some point to discuss the specific comments on
the monograph, but we believe that we are pretty close to
being done, if not completely done, on the overall chapter.
DR. CONTI:
So, the O15 and the N-13, you have
reviewed, you have submitted comments, but you haven't
submitted comments back to USP yet.
DR. KASLIWAL:
No, USP hasn't received.
I think
our hierarchy needs to go through them, and then maybe by
tomorrow -- we are trying, if we can meet the March 4th
deadline for publication.
MS. AXELRAD:
Right, but we have to get it to the
USP in time for them to do whatever they have to do with it,
so we will talk about how we can expedite getting those
comments back on it, and then if we have time to discuss at
least some of them, perhaps we can do that tomorrow after we
break.
Does anybody have any further thoughts before we
adjourn for the day?
Tomorrow, we will take up the model
section of the CMC application and current good
manufacturing practices for PET.
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We will be beginning again tomorrow at 9:00 a.m.
right here.
Thank you.
[Whereupon, at 2:50 p.m., the proceedings were
recessed, to be resumed at 9:00 a.m., Friday, February 19,
1999.]
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