41st MEETING NATIONAL BIOETHICS ADVISORY COMMISSION Volume I

41st MEETING
NATIONAL BIOETHICS ADVISORY COMMISSION
Volume I
Hyatt at Fisherman's Wharf
555 North Point Street
San Francisco, CA
94133
June 6, 2000
Eberlin Reporting Service
14208 Piccadilly Road
Silver Spring, Maryland
20906
(301) 460-8369
I N D E X
Opening Remarks
R. Alta Charo, J.D.
1
ETHICAL AND POLICY ISSUES IN THE OVERSIGHT
OF HUMAN SUBJECTS RESEARCH
Panel IV:
Independent IRBs
Erica Heath, President,
Independent Review Consulting,
San Anselmo, California
Panel V:
5
Purpose of Regulation
Harold Y. Vanderpool, Ph.D.,
Professor in the History and
Philosophy of Medicine, Institute
for the Medical Humanities,
University of Texas Medical Branch
Galveston, Texas
53
Jonathan D. Moreno, Ph.D.,
Kornfield Professor and Director,
Center for Biomedical Ethics,
University of Virginia
72
Donald Magnus, Ph.D., Assistant
Professor and Director of Graduate
Studies, Center for Bioethics,
University of Pennsylvania
89
Recommendations - Purpose and Structure
164
3
1
P R O C E E D I N G S
2
OPENING REMARKS
3
PROFESSOR CHARO:
We are going to begin with a
4
few words from Eric Meslin on some housekeeping matters
5
and after that we will proceed albeit a little bit
6
late, and I apologize to the first presentation of the
7
morning.
8
9
So, first, good morning.
will be chairing this morning.
I am Alta Charo. I
To my right is
10
Professor Alex Capron, who will be chairing this
11
afternoon.
12
13
14
I would like to begin the meeting with Dr.
Meslin's Executive Director's comments.
DR. MESLIN:
Just very quickly as a reminder
15
to those who were here yesterday and to the people who
16
have arrived for today's session, we are going to be
17
splitting the day up in reverse order from what was
18
discussed yesterday, beginning with a discussion of our
19
oversight report, and then moving on in the afternoon
20
to a discussion of the international report.
21
We will be having a working lunch, which is to
22
say that the Commission will be functioning during the
23
lunch hour and they will be discussing Chapter 3 of the
24
International Report during the lunch hour.
25
Immediately following the lunch hour, just as
4
1
you are keeping note on the agenda, we will have a
2
very, very short discussion of the revised
3
recommendation that Dr. Macklin and Dr. Lo circulated
4
late yesterday afternoon to you.
5
sheet of paper that says "alternatives."
6
a very short discussion.
7
It is a one page
That will be
If you are following along in the agenda, what
8
we propose to do at 1:30 is stick with the schedule and
9
discuss Chapter 4.
10
There will be a break at 3:00.
It is Ruth Macklin's wish and my pleasure that
11
Commissioners should be informed that the discussion of
12
Chapter 4 will principally focus on the memo that
13
Harold Shapiro faxed to you yesterday for discussion
14
and comment.
15
exercise as discussing the chapter itself since these
16
are issues that in Harold's absence he wanted to have
17
discussed.
18
We thought that would be as useful an
And then from 3:15 until the end, we will be
19
discussing Chapter 5.
20
agenda, we have removed the 4:45 p.m. item that says,
21
"Chapters 2, 3, 4 and 5, Revisited."
22
revisiting those chapters.
23
talking about Chapter 4 and 3:00 until the end talking
24
about Chapter 5.
25
Thanks.
So if you are annotating your
We will not be
We will spend 1:30 to 3:00
5
1
ETHICAL AND POLICY ISSUES IN THE
2
OVERSIGHT OF HUMAN SUBJECTS RESEARCH
3
PROFESSOR CHARO:
4
Okay.
Thank you, Eric.
We are going to begin this morning with
5
something that I think is quite welcome by way of
6
information.
7
Ms. Erica Heath is the President of
8
Independent Review Consulting here in California and
9
has prepared a paper for us on the history and the
10
future of independent Institutional Review Boards,
11
something about which, I think, we all would like to
12
learn more.
13
14
15
Thank you very much, Ms. Heath, and my
apologies again for keeping you waiting.
PANEL IV:
INDEPENDENT IRBs
16
ERICA HEATH, PRESIDENT
17
INDEPENDENT REVIEW CONSULTING
18
SAN ANSELMO, CALIFORNIA
19
MS. HEATH:
Well, thank you very much.
It is
20
with some pride that I talk about Independent
21
Institutional Review Boards.
22
IRBs for approximately 30 years, speaking at PRIM&R and
23
ARENA, and writing about IRBs.
I have been working with
24
The development of Independent IRBs has been
25
of interest because they have developed within a large
6
1
framework.
2
(Slide.)
3
What I want to do this morning is talk about
4
four things:
5
independent IRBs within the world of IRBs; the
6
evolutionary changes that brought about the
7
independence; some information on the structure and
8
function; and then a little bit about the history.
9
The place and the position of
(Slide.)
10
To take a very simplified view first, there
11
are basically two systems.
12
and that is where the NIH through OPRR, the Office for
13
Protection from Research Risks, reaching an agreement
14
or an assurance with the institution.
15
you could substitute any federal funding agency that
16
signed on to the Common Rule.
17
18
One is the assurance system
And for "NIH"
The FDA is a regulatory agency and regulates
through a compliance mechanism through the sponsor.
19
Where are the investigators in all of this?
20
The investigators can be found almost
21
anywhere.
22
(Slide.)
23
The investigators there in pink can be found
24
in a lot of places.
25
institutions.
They can be found within
That is very traditional.
In hospitals
7
1
of any size, with or without assurances.
2
find investigators located within foundations, clinics,
3
in their private practices, within sponsored companies.
4
5
6
We can also
I think you heard yesterday about General
Motors.
The area of private practices is the area that
7
I think is growing quite rapidly and is projected to
8
grow even more rapidly.
9
10
(Slide.)
How do all of these investigators then relate
11
to the FDA and the NIH?
12
institution relates through the institutional channels
13
to -- through the assurance and the guidance that they
14
receive is through the institutional means.
15
Well, obviously the one in the
All of the investigators that are working on
16
studies of regulated products are in a compliance
17
network with the FDA.
18
of those investigators pretty much at any time.
FDA can come out and audit any
19
(Slide.)
20
So in this big picture where are the IRBs?
21
The red IRBs there are again located all over.
22
is one in every institution that has an assurance.
23
actually has one in-house.
24
have them.
25
the right.
There
FDA
Some sponsors and companies
And then there is the independent IRB to
As the research world expanded, the
8
1
number of independent IRBs increased.
2
IRBs relate to the investigators?
How do those
3
(Slide.)
4
The IRB in the institute relates directly with
5
the investigator in that institution.
6
IRB relates directly with the site and the investigator
7
being reviewed.
8
9
The independent
I have dotted lines there to the investigators
in the boxes.
Those boxes are institutional
10
organizations.
11
places but only with the permission of the
12
administration of that institution.
We can review investigators from those
13
(Slide.)
14
How does the FDA relate to all of these IRBs?
15
Again it is a direct compliance relationship.
The FDA
16
can and does go out and audit each of those IRBs.
17
independent IRBs get audited using the same general
18
framework and investigation policies that are used for
19
all IRBs.
The
20
(Slide.)
21
And finally how do each of these IRBs relate
22
to the NIH?
23
directly through a Multiple Project Assurance.
24
25
Again the ones in the institutions relate
In smaller institutions that do not do as much
research, there is a Single Project Assurance that can
9
1
be negotiated for each study.
2
small institutions that are getting grants such as
3
Small Business Innovation Research Grants, who have no
4
IRB, and really have no interest in setting one up.
5
They may be very small.
6
knowledge or experience to set one up and they are
7
contracting with independent IRBs.
8
still holds the assurance and is responsible for the
9
protection of subjects but they work directly with a
10
They may not have the
The institution
more knowledgeable IRB.
11
12
There are some very
That is pretty much where we exist in the
larger world of IRBs.
How did we come about?
13
(Slide.)
14
I think there were four major events or
15
changes that were important in the evolution of
16
independent IRBs and the first were changes in health
17
care delivery.
18
When DRGs came in, the Diagnostic Related
19
Coding Groups, and reimbursement for patient days went
20
down, there were shorter hospital stays, fewer hospital
21
stays, hospital census went down.
22
patients go?
23
setting.
24
25
Where did all those
They were treated in an ambulatory
One cannot keep on doing research on
institutionalized patients, patients in hospitals, if
10
1
the care is being delivered outside that context.
2
more and more research was being done in new ambulatory
3
centers.
4
Those centers became quite skilled. There are
5
new ambulatories or new ambulatory centers,
6
surgicenters, diagnostic centers.
7
in freestanding units.
8
staffing those units were graduates of the major
9
medical colleges.
You could find MRIs
And the people who were
Quite often they were people who had
10
done research and they were quite skilled.
11
interested in doing research.
12
13
So
They were
There were expansions in multi-center trials.
They happened about the same time.
There were
14
expanded expectations but also abilities to do large
15
scale research.
16
handling the data.
17
There were new technologies for
There were new communication modes.
There was easier travel for monitoring and there was
18
an expectation that more and more subjects, more
19
populations would be included in trials.
20
An interesting one is the patient demand for
21
access to clinical research and we can stress two words
22
there.
23
"Demand and access."
Patients were demanding that they be -- that
24
it was their right to participate in research.
25
think the best example is in the AIDS area where
And I
11
1
instead of being afraid of being recruited, patients
2
were demanding access.
3
The second part of that, the access, is that
4
they were demanding access not in cities remote to them
5
but in their own communities.
6
given where they were in communities that were not
7
necessarily blessed with having a local institutional
8
IRB.
9
They wanted the care
The fourth event was a regulatory change in
10
1981 with the FDA.
11
but in 1981 the FDA expanded the regulations, expanding
12
the IRB coverage to all research, all human subjects in
13
studies of regulated products.
14
only required IRB review if there was an IRB in the
15
institution where the research was being done.
16
I have mentioned that in the paper
Previously they had
They recognized that when they expanded that
17
coverage there might not be IRBs available and they
18
suggested that new alternatives might arise.
19
(Slide.)
20
So what is an independent IRB?
An independent
21
IRB is an IRB which reviews research for the purpose of
22
assuring adequate protection of human subjects, that is
23
all standard, for entities that are generally not part
24
of the same organizational structure as that IRB, and
25
that is a critical part.
12
1
The organizational structure of the
2
independent IRB is a different organizational structure
3
from the site being reviewed; that is the site may be a
4
private practice, remote from the IRB.
5
a neighboring but the organizational structure is a
6
different business unit.
7
similarities and that difference is important.
It can be even
I think recognizing both the
8
(Slide.)
9
There is no typical IRB but thinking about
10
what could be said to be typical, one of the baseline
11
concepts is that an independent IRB is, in fact, part
12
of a corporate institution.
13
incorporated in one of the states, has at least two
14
units.
15
IRB review side.
16
receipt of protocols, respondents, human resources, all
17
the business aspects of running a business.
That institution, usually
One is the administrative side and one is the
18
The administrative side takes care of
The IRB is more isolated.
They are expected
19
to convene, to review submissions, to make decisions,
20
but are not part of the business side. That is done
21
purposefully to address the potential for conflict of
22
interest or interference, ideas about whether the
23
business could affect the IRB decisions.
24
most cases, again typical, they are kept quite
25
separate.
I think in
13
1
(Slide.)
2
Addressing for a moment the strengths and the
3
weaknesses of independent IRBs, I think I hit the first
4
weakness just now and that is it is a fee for service.
5
Just like lawyers get paid for their services and
6
doctors, IRBs are professional.
7
professional.
8
we keep that separate.
The members are
They get paid for what they do and again
9
We do remote review and I think all of the
10
independent IRBs are set up to address the issues of
11
remoteness.
12
13
14
And I know an issue in many people's minds is
IRB shopping.
Personally I do not see very much of it.
We ask, I think, every independent IRB and, hopefully
15
now, every IRB is asking the history of a protocol;
16
that is whether it has ever been submitted to another
17
IRB and what that determination was.
18
is an internet discussion group where that comes up
19
occasionally.
20
I know that there
Our strengths we see as being a much longer
21
list.
22
a void left in the research area that would be unfilled
23
if there were no independent IRBs.
24
25
First of all, we fulfill a need.
There would be
We offer efficient and prompt service.
is what we do.
That
Just -- we are accused sometimes of
14
1
being too speedy but that is the role of an independent
2
IRB.
3
offering quality service but in a timely manner.
That is all they do.
4
They concentrate on
Independent IRBs can actually be more
5
objective.
6
institutional structure that is receiving the grant.
7
They are not tied into institutional politics and they
8
can be more objective about what they are seeing.
9
The members are not part of the
They can offer uniform standards for multi-
10
site studies.
11
done in a number of institutions, there are a number of
12
consent forms.
13
number of IRBs.
14
going into any number of IRBs, all of which get a
15
sampling.
16
That is when you have a multi-site study
There are a number of changes by a
There are a number of adverse events
With an independent IRB, it is one site that
17
sees one consent form and sees what changes each site
18
wants to make so it is a more uniform service.
19
We also offer review of research that is
20
otherwise unregulated.
21
behavioral research that is not now regulated but many
22
investigators, particularly those trained in academic
23
institutions, know that IRB review is a part of doing
24
good research and they are happy to find a quality
25
independent to submit their research to.
This could fall into areas of
15
1
Finally, more recently, independent IRBs have
2
offered support and "breathing room" to institutional
3
IRBs that have found themselves in some sort of
4
difficulty.
5
(Slide.)
6
What kinds of studies do we look at?
I think
7
basically we look at the same broad range of studies
8
that any academic IRB sees.
9
work is usually clinical studies of FDA regulated
The major amount of our
10
products.
11
usual kinds of FDA regulated studies.
12
Those are all phases of products and the
We occasionally see compassionate use or
13
humanitarian device studies.
14
happen in the hospitals.
15
single use compassionate articles are in hospitals.
16
And we occasionally see such requests.
Not all emergencies
Not all requests to use
17
We are seeing an increasing number of social
18
and behavioral studies, as I mentioned, a huge rise in
19
studies of biological specimens, some international
20
studies, some records review studies, and I said other.
21
I would imagine that anything that an academic IRB has
22
seen some independent IRB has probably seen.
23
(Slide.)
24
The future, I think, is kind of wide open.
25
There will be an expanding need for a variety of IRBs.
16
1
2
Not just independent IRBs but IRBs in a wide variety
of research settings.
3
They are going to serve a rapidly expanding
4
number of sites.
5
clinical research is going to expand.
6
prediction that within five years we are going to have
7
double the number of investigators than there are now.
8
9
10
Every prediction I have heard is that
I heard one
That calls for a rapid increase in the number -- in
the infrastructure, the entire infrastructure for
research.
11
We are going to need to serve new areas.
12
Genetics is an obvious one.
13
that is going to be done.
14
be served, not quite new, but there is more research on
15
the elderly and on children and other special
16
populations.
17
There is internet research
There are new populations to
And then there is more technology available to
18
perform that review.
19
for a reasonable cost to video conference, to evaluate
20
sites, to look a web information, to share information,
21
and more abilities to assess the information that we
22
receive.
23
There is more and more ability
I think that is a very quick overview of
24
independent IRBs and of where we are in the world, what
25
we do, how we exist, and I welcome your questions.
17
1
2
3
4
PROFESSOR CHARO:
Thank you very much.
That
was very informative.
We have approximately a half an hour for
questions and discussion.
5
Diane, and then Steve.
6
DR. SCOTT-JONES:
Hi.
I have several
7
questions to just get more information about what you
8
have already laid out for us.
9
10
First, how much turnover is there typically in
the IRB membership?
11
MS. HEATH:
12
that is on for quite a while.
13
years, ten years.
14
several members that have been on ten, twelve years.
15
Those members are very well educated in IRB
16
responsibilities, study design.
17
Typically there is a core group
That core group -- two
There are, I think, on each IRB
And then there is another group that is on for
18
two years, three years.
19
information when something new is developing.
Often they offer specialty
20
DR. SCOTT-JONES:
Can I keep --
21
PROFESSOR CHARO:
Yes, please.
22
DR. DUMAS:
23
PROFESSOR CHARO:
24
25
Rhetaugh has her hand up.
Okay, Rhetaugh.
you on the list.
DR. DUMAS:
Thank you.
I will put
18
1
DR. SCOTT-JONES:
2
external audits of independent IRBs?
3
mentioned on page 17 that there have been external
4
audits --
What is the outcome of the
5
MS. HEATH:
6
DR. SCOTT-JONES:
7
What has been the outcome of that?
8
9
MS. HEATH:
You have
Yes.
-- of the independent IRBs.
Well, I think the outcome is very
much similar to the outcome of all the audits.
Many of
10
the audits have found no identifiable problems.
I do
11
not think FDA will ever say you meet every criteria.
12
They will say, "We could find no problems."
13
have, I think, seen as many of those letters as any set
14
of IRBs.
15
There have been untitled letters.
And we
Are you
16
aware of the various levels of letters?
17
untitled letters and then there are warning letters.
18
"Untitled letters" need a response but they
19
are short of warning letters.
20
warning -- excuse me.
21
letters" to independent IRBs as well.
22
There are
And there have been
There have been "untitled
I have heard it said that there were
23
independent IRBs that were out of business after but I
24
have heard that said of some academic or institutional
25
IRBs as well and I cannot substantiate it.
19
1
2
So I think it is pretty much the same as the
wider set of IRBs.
3
4
DR. SCOTT-JONES:
And then how do you ensure
some sort of community representation on the IRB?
5
PROFESSOR CHARO:
Excuse me.
Diane, if you
6
can speak even more closely to the mike, it will help
7
those on the phone.
8
DR. SCOTT-JONES:
I am sorry.
9
PROFESSOR CHARO:
Ms. Heath, we have two
10
Commissioners on the phone, Trish Backlar and Rhetaugh
11
Dumas.
12
DR. SCOTT-JONES:
13
MS. HEATH:
14
DR. MESLIN:
15
DR. SCOTT-JONES:
16
17
I am sorry.
Okay.
Do it again.
I will repeat the question.
How do you ensure community participation in the
independent IRB?
18
MS. HEATH:
I think each of us look at
19
community input slightly differently.
20
have a wide variety of members on the board meeting at
21
our site.
22
within the board.
23
First of all, we
So there is a wide diversity of opinion just
We have probably a longer and more complete
24
application form than most IRBs and a lot of questions
25
on that form are about the community, the type of
20
1
community, demographics, literacy levels, languages
2
spoken.
3
the kind of population from whom the subjects -- from
4
which the subjects are being recruited.
That sort of thing so that we get a feel for
5
If we have a concern, if in reviewing the
6
study we identify a concern, for instance, in
7
recruitment or advertising or whatever, then we hone in
8
on that area.
9
networks.
At that point we have pretty good
I have been known to pick up the phone and
10
call an IRB colleague in another city and ask about the
11
investigator or about the community, about advertising
12
media in that area.
13
I think there are a lot of various means and,
14
of course, the web now is giving us a lot more options.
15
Does that --
16
PROFESSOR CHARO:
Do you have any further,
18
DR. SCOTT-JONES:
I have one last question.
19
You mentioned that you also review proposals
17
20
Diane?
from the social and behavioral sciences.
21
MS. HEATH:
22
DR. SCOTT-JONES:
Correct.
Could you say a little bit
23
about how the review of that type of research is
24
different from the other kinds of studies that you
25
review?
21
1
MS. HEATH:
Yes.
Obviously it is different.
2
Quite often it is qualitative instead of quantitative
3
research.
4
that they need a wider diversity of membership to
5
evaluate the different designs that are presented by
6
social and behavioral research.
7
In many IRBs along the way they have found
We have had to add members again to account
8
for the differences -- for the new fields being
9
reviewed.
So I think that is the number one change is
10
that the membership was diversified again -- yet again
11
to better understand the kinds of research we were
12
seeing.
13
DR. SCOTT-JONES:
Thank you.
14
PROFESSOR CHARO:
Ms. Heath, you are very
15
popular.
16
would like to ask questions to make sure that I have
17
been told about everybody's hand.
18
I want to go through the list of people who
I have Steve, Rachel, Rhetaugh, Bernie, David,
19
Arturo, Eric Cassell.
20
point.
21
the list, and Bill Oldaker as well, and Alex.
22
right.
Arturo is passing at this
Something must have been -- and I put myself on
You are going to get the --
23
MS. HEATH:
24
PROFESSOR CHARO:
25
(Laughter.)
Are we serving dinner?
That is right.
All
22
1
PROFESSOR CHARO:
2
MR. HOLTZMAN:
3
I have two questions.
4
clarification question.
Very good.
Steve?
Madam Chair, is it Madam Chair?
Is that okay?
5
PROFESSOR CHARO:
6
MR. HOLTZMAN:
The first is a
Please.
Okay.
I am trying to
7
understand a little bit more about the organization of
8
your business because you have put up a slide which
9
said over here we have what in my business we call the
10
useless overhead.
11
people who do the work.
12
Us types.
And then you have the
So that -- but am I to understand that you
13
have a single IRB or that effectively that you
14
constitute IRBs depending on what proposal you are
15
going to be reviewing so that you can have the
16
appropriate expertise?
17
Number one.
And, number two:
Are the members of the IRBs
18
or IRB, depending on the answer to that first question,
19
are they employees of your company or are they like a
20
bull pen of outside experts who you bring in on a
21
consulting basis?
22
MS. HEATH:
The IRB is a standing committee as
23
it, I think, is in most institutions and it is the same
24
membership that meets regularly so it is one IRB.
25
MR. HOLTZMAN:
Okay.
23
1
MS. HEATH:
We do have a list of consultants
2
to the IRB that we can count on for any particular area
3
where we have questions but it is a standing board.
4
The members of the board are independent
5
contractors.
6
from their IRB membership.
They have professional lives quite aside
7
MR. HOLTZMAN:
8
MS. HEATH:
9
Okay.
Many of them are fully employed.
Otherwise, some are retired.
None of them are
10
dependent upon what they receive from the IRB as their
11
means of living.
12
MR. HOLTZMAN:
Okay.
So my question is what
13
do you say to the portrayal, which I have certainly
14
heard of the last couple of years, that this is a blood
15
for money kind of business, that these IRBs really
16
should not exist, that it should only be in the
17
pristine institutions that there should be these IRBs,
18
and this is really about, you know, buying approval of
19
protocols that, you know, if it were not for the money
20
no one would be able to buy?
21
MS. HEATH:
Well, we have put away our rubber
22
stamp of approval. We try never to use it.
23
heard that myself.
24
professional.
25
reputation.
No, I have
The independent IRBs are
We exist based on our continuing
If an independent IRB's opinion could be
24
1
bartered, I think it would lose any professional
2
reputation it had very quickly.
3
lose my integrity.
4
have worked very hard for many years to keep.
And certainly I would
It is a professional standing I
5
PROFESSOR CHARO:
6
MR. HOLTZMAN:
7
PROFESSOR CHARO: Rachel?
8
DR. LEVINSON:
9
Okay.
Thank you.
Thank you.
In your remarks,
you have mentioned that the independent IRBs are set up
10
to deal with remoteness and Diane asked a question
11
about community participation or representation that
12
seemed to go to that, and then Steve asked about
13
whether or not you had a pool of people with which you
14
could draw upon that perhaps could be called upon to
15
represent the locale of the research that you are
16
reviewing.
17
But it does not look as if that is one of the
18
ways you deal with remoteness, because you said you
19
have a core standing body.
20
in, I would assume, are nonvoting.
21
Consultants that would come
So could you expand, I guess, on the point
22
that you made in your talk about how you deal with
23
remoteness as far as voting membership?
24
25
MS. HEATH:
Yes.
Well, first of all,
remoteness, I think, was anticipated by the FDA and
25
1
there is an information sheet on remote reviews in the
2
FDA information sheets.
3
my report.
4
review from any institution might be remote and, in
5
fact, the first times I encountered remote review was
6
when I was the IRB administrator at the University of
7
California in San Francisco, and we were reviewing
8
studies in Malaysia and Zaire so it was not unheard of.
9
I noted it and attached it to
It recognized that there are times where
As I said, on the application form we look for
10
the kinds of communities.
11
study and the kinds of issues that might be raised.
12
If there are any kinds of issues that are
We look at the kinds of
13
brought forward, any eyebrows raised, then we are -- it
14
is very easy to pick up the phone to call a local
15
consultant in that area.
16
voting members.
17
IRB, we would have to be changing the roster with every
18
meeting or every vote.
19
to the standing board, which that board can then use in
20
making their decision.
21
Those consultants are not
If they were voting members on any
DR. LEVINSON:
They give information and input
I have one quick question.
22
Thank you.
23
at as multi-site versus single site, the proportions?
24
25
Can you tell us how much research you look
MS. HEATH:
The multi-site studies are quite
big so if you have three or four multi-site studies
26
1
they can equal 20-25 small studies.
2
different for every IRB.
3
percent, I think.
Our's are probably up 40
4
DR. LEVINSON:
5
MS. HEATH:
6
PROFESSOR CHARO:
7
Forty percent.
Multi-site.
MS. HEATH:
9
PROFESSOR CHARO:
Yes, please.
Rhetaugh Dumas on the
telephone.
11
12
We will not hold you to that
number strictly.
8
10
I would -- it is
DR. DUMAS:
Oh, okay.
I cannot hear you too
well.
13
PROFESSOR CHARO:
14
DR. DUMAS:
My apologies.
I wonder if the speaker would say
15
something about what they perceive to be the potential
16
for factors such as bias and conflict of interest and
17
how they manage that.
18
MS. HEATH:
The question as I heard it was
19
about conflict of interest and bias.
20
PROFESSOR CHARO:
21
MS. HEATH:
Okay.
How you manage it?
Yes.
How we manage it?
Well,
22
first of all, by recognizing it.
23
recognition of conflict is the first step in
24
recognizing any interests.
25
DR. DUMAS:
I think the
What controls do you have that
27
1
would help you identify it?
2
MS. HEATH:
Among members?
3
DR. DUMAS:
Among the members of the IRB.
4
MS. HEATH:
Well, first of all, we ask -- just
5
as, I think, all IRBs do -- that any holdings in any
6
company that we review be revealed.
7
academic institutions there is a disclosure form.
8
ask for annual disclosure of any holdings that somebody
9
might have that could bias them in terms of review of
I think in
We
10
any sponsored studies and then not only annually but if
11
it comes up with any particular company.
12
We have sometimes less conflict of interest
13
than an institutional board because the members are not
14
involved with the institutional politics and biases.
15
16
And then I think members have personal biases
as all members of all IRBs do.
17
PROFESSOR CHARO:
18
Bernie Lo?
19
DR. LO:
20
illuminating presentation.
21
Holtzman's questions about sort of the actual nuts and
22
bolts of how independent IRBs work.
23
Thank you.
I want to thank you first for a very
I want to follow-up Steve
As you know, there is a lot of discussion as
24
to whether IRBs have sufficient resources and support
25
to do their task.
So, I was wondering, if I could ask
28
1
first what do you charge the sponsors of research to
2
review their research?
3
example, to a big, you know, 50-site clinical trial as
4
opposed to a smaller study?
5
can give us a range.
6
independent IRBs pay their consultants?
7
these are not volunteers but are consultants.
8
pay them and how much do you pay them?
9
MS. HEATH:
Do you charge more, for
Secondly -- just -- you
And, secondly, what typically do
I take it
Do you
The fees that we get -- I think
10
each of us publicly post our fee schedules somewhere.
11
Our's is on our web site.
12
would charge by the action.
13
review, initial review of a protocol and so much for
14
initial review of each independent site.
15
large multi-center study is that much more expensive
16
than a one-site study.
17
review and each action.
18
I decided years ago that we
That is so much for
Therefore, a
We charge for continuing
I took that route because I think it is unfair
19
to penalize those sponsors who have thought ahead.
20
Their protocol is well thought out and they have no
21
modifications by charging so much that I cover the
22
costs of all those that modify every week so it is by
23
the action.
24
25
A friend came up with a aphorism, I think,
that is quite true and that is it is the simple
29
1
protocols that will get you.
2
say, "Well, I just have a simple protocol.
3
charge less?"
4
have discovered that that is a wise thing to do.
5
6
Somebody will call in and
Can you
We charge by the action and over time I
DR. LO:
Could you tell us what the dollar
numbers are?
7
MS. HEATH:
The -- we charge $1,000 for an
8
initial review of a protocol and $275 for initial
9
review of a site, and I think every independent IRB is
10
different and I am sure you can look up their web sites
11
for their fee schedules.
12
The fees are based on the fact that we have
13
costs.
14
secretaries, for copies, for phones, for everything,
15
rent, and all of those costs have to be covered.
16
We have costs to go to meetings, costs for
The second part of your question was payment
17
to reviewers and that is proprietary but we pay the
18
reviewers for again the work load, not the decisions.
19
I tend to pay for attendance at a meeting and the size
20
of the agenda so, that if there are ten items, they are
21
paid more than if there is one item.
22
work load question.
That is simply a
They are expected to do more.
23
Does that answer sufficiently?
24
PROFESSOR CHARO:
25
DR. LO:
Yes.
Can you give us a range of what --
30
1
2
PROFESSOR CHARO:
Bernie, you need to be near
the microphone for those on the phone.
3
DR. LO:
I am sort of a quantitative person.
4
I was wondering if you could give us a range of what --
5
if not your own IRB -- other independent IRBs might
6
charge?
7
we talking about $100 an hour for a full day, $1,000 an
8
hour?
9
I mean, the sort of order of magnitude.
MS. HEATH:
Are
Pay for their members?
10
DR. LO:
11
MS. HEATH:
12
PROFESSOR CHARO:
13
DR. COX:
Yes.
No, I cannot.
Yes.
I do not know.
David Cox?
I, too, want to thank you very
14
much for this because it has been extremely difficult
15
for NBAC to collect even qualitative data, let alone
16
quantitative data, on certain subjects and independent
17
IRBs has been a difficult one.
18
So, I noticed that you stated, in the
19
beginning of your paper that you are really speaking
20
for yourself and your experience.
21
So my first question: “is how did you go about
22
collecting this information about all of the different
23
independent IRBs”?
24
there?
25
MS. HEATH:
Like, for instance, how many are
Well, first of all, it is a very
31
1
2
small world.
We all tend to run in the same circles.
We see each other at IRB meetings, the PRIM&R
3
meetings, the ARENA meetings so we run into each other
4
a lot.
5
Just as there is no complete list of all IRBs,
6
I do not think there is a complete list of independent
7
IRBs.
8
one on HemaNet, which I mentioned in the paper, but I
9
must admit that on their list there are a couple of
10
The best most complete list I have seen is the
IRBs that I have never heard of.
11
DR. COX:
12
MS. HEATH:
13
DR. COX:
14
MS. HEATH:
15
DR. COX:
16
MS. HEATH:
17
DR. COX:
So how many in total are there?
They must be very small.
About?
Between 20 and 50 but that is --
But that -Twenty is those I could name.
And is there any sort of mechanism
18
besides just people knowing each other and passing each
19
other at meetings and stuff that sets a standard for
20
the field?
21
discussion was as though there was a standard because
22
you make some statements that are sort of really
23
important.
24
person involved with the institution that was on the
25
IRB.
Is there a standard?
I mean, your
For instance, that there would never be a
So how are those kinds of standards set
32
1
2
3
universally for all the independent IRBs?
MS. HEATH:
I am not sure I said never.
I try
to shy away from never.
4
DR. COX:
5
MS. HEATH:
6
DR. COX:
7
MS. HEATH:
Okay.
But --
I may have misunderstood you.
Again, I was speaking for myself
8
and those independent IRBs I know of and for the most
9
part what I know is that there has been an evolution.
10
When independent IRBs were first evolving in the early
11
'80s after the FDA regulation and in some cases even
12
before, I think there was a much closer interaction
13
between board and administration.
14
15
Each of the independent IRBs was quite small.
There were a limited number of people and there was
16
not as much awareness.
17
last 20 years and I think definitely that the trend is
18
towards complete separation.
19
independent IRBs certainly have that separation.
That has been changing over the
20
PROFESSOR CHARO:
21
DR. COX:
Yes.
The leading IRBs, leading
Anything further?
So do you -- this issue of
22
sort of standardization is a really vexing one in the
23
context of non-independent IRBs.
24
MS. HEATH:
25
DR. COX:
Yes.
So do you think that it is an issue
33
1
for independent IRBs and, if so, then what should be
2
the mechanism or how would you suggest -- I mean, you
3
are clearly a very knowledgeable person about this -- -
4
- about how to go -- about should there be a
5
professional organization for this or how should this
6
go about?
7
MS. HEATH:
Well, first of all, bottom line,
8
we all have to meet the same regulatory standards.
9
least anybody who -- or any independent IRB that is
10
reviewing FDA regulated research.
11
line.
That is the bottom
The minimum standard just as it is everywhere.
12
13
At
Knowing that we are about to have an audit
keeps one having -- adhering to that line.
14
Beyond that there is professional reputation,
15
competition.
16
speed, which clearly is an issue, but also in terms of
17
quality.
18
who come back and say, "We appreciate the quality," and
19
it is a selling point, if you will.
20
quality.
21
Not only are we competing in terms of
I know that there are a number of our clients
We depend on that
As to whether there is an organization, there
22
is several IRB organizations.
23
is ARENA.
24
subgroups and there is a way for independent IRBs to
25
meet within that subgroup, and there is a consortium of
The leading one of which
Most of us are members of ARENA.
They have
34
1
independent IRBs that meets pretty regularly
2
PROFESSOR CHARO:
Okay.
I have on my list
3
myself, Eric Cassell, Bill Oldaker, Alex Capron.
4
Anybody else?
And Steve has an additional question.
5
MS. KRAMER:
6
PROFESSOR CHARO:
7
DR. CASSELL:
8
PROFESSOR CHARO:
9
10
the list.
Alta?
Bette, thank you.
I am taking myself off the list.
You are taking yourself off
Okay.
The questions that I had actually follow
11
directly on from David Cox's questions about the
12
standardization of responses, etcetera.
13
regulatory requirements form a minimum but those of us
14
that have served on IRBs know that each IRB tends to
15
react idiosyncratically to things that go beyond the
16
regulations.
17
example, those IRBs that have additional protections
18
that they have chosen to implement for people whose
19
capacity to make decisions has been impaired.
20
Certainly the
There are supererogatory duties, for
And then there is room for interpretation of
21
the regulations.
22
researcher wanted to replicate a study from another
23
country that had been done only on people of one race.
I remember seeing a protocol where a
24
The question had to do with whether or not that was
25
appropriate or inappropriate since this is clearly a
35
1
disease that touches people of all races in the United
2
States, things like that.
3
The first question: “is whether in your
4
experience your independent IRB or others tend to
5
develop a set of interpretations or supererogatory
6
duties that they then use as precedence so that there
7
is internal consistency within the IRB across time as
8
to how it approaches these problems”?
9
It does happen at institutions sometimes that
10
way and I did not know in your case if it happens with
11
your's.
12
MS. HEATH:
I think the short answer is yes.
13
I think independent IRBs can be as idiosyncratic as any
14
IRB and I know that as a standing IRB they tend to look
15
for what they have done before to set precedent and to
16
build upon.
17
PROFESSOR CHARO:
Then the question that
18
arises from that is the following:
19
IRB there is a local culture of knowledge so that
20
people know what that IRB's policies tend to be.
21
sense it is published informally within the
22
institution.
23
interpretations so that those who are deciding to go to
24
your IRB versus another could anticipate how your IRB
25
might handle these questions that are subject to
In an institutional
In a
Is there any formal publication of those
36
1
interpretation?
2
MS. HEATH:
Yes.
Number one, it is a small
3
world and I think people talk a lot.
4
we published guidances for our applicants.
5
on what an independent IRB is, a guidance on how to
6
write a protocol, a guidance on how to write a consent
7
form.
8
our clients have seen because I sent it to them on how
9
to write consent forms.
10
But, number two,
A guidance
I just published an article that I know a lot of
PROFESSOR CHARO:
Those are fairly general
11
compared to the kinds of things I have been talking
12
about.
13
14
15
16
MS. HEATH:
Well, yes, but that is examples.
It is examples.
Then we also -- most of us have web sites
where we can publish recent information and opinions.
17
PROFESSOR CHARO:
18
MS. HEATH:
Opinions?
Not naming any client but we have
19
been seeing a lot of studies on biological specimens.
20
What do we require?
21
arising and how have they been decided?
22
What are the issues that are
PROFESSOR CHARO:
That is very much the kind
23
of thing I was wondering about.
24
very much.
25
Very good.
Thank you
The next person on my list would be Alex.
37
1
Sorry, Bill. Okay.
Bill?
2
MR. OLDAKER:
3
Again I appreciate your testimony.
4
5
Thank you.
It is very
helpful.
Let me ask a question which you may not be
6
prepared to answer but if you would try I would
7
appreciate it.
8
or licensure of IRBs or alternatively the certification
9
of licensing of the members of an IRB?
10
What do you think about certification
MS. HEATH:
Thank you.
I am on an
11
accreditation committee for accrediting IRBs and I
12
think that obviously if done correctly it could be a
13
real asset to our whole field.
I think it is probably
14
something whose time has come.
As a member of the
15
accrediting -- the committee looking at accreditation,
16
I am, of course, looking at how the opinions and
17
policies being discussed, alternatives being discussed
18
would apply to us.
19
that we would be able to meet the standards as well as
20
an academic IRB albeit differently.
21
And what I am seeing now is
As to accreditation or certification of
22
members, I do have some problem with it.
23
members should be educated as to some parts.
24
the Belmont Report should be required reading, that is
25
that they should be knowledgeable about the regulations
I think
That is
38
1
and the source of regulations.
2
Beyond that, each of the members is asked to
3
be on any IRB based on their backgrounds.
4
bring ethics or religion or law or pediatrics to the
5
board.
6
would serve a good purpose if we have accreditation.
7
So I am hesitant, although I am open to it.
I am not sure if
8
MR. OLDAKER:
9
PROFESSOR CHARO:
10
MR. OLDAKER:
Whether they
certification of members
If I might ask one more.
Sure.
In most professions when one
11
looks to accreditation or certification, one looks to
12
the training and the continuing education of those
13
professionals.
14
that issue if the IRB was the sole certified or
15
accredited organization?
How would you propose to take care of
16
MS. HEATH:
17
MR. OLDAKER:
18
MS. HEATH:
One of the -Thank you.
-- proposals is that the
19
accreditation would take the form of looking at the
20
entire program, not just the IRB.
21
program would include education, training, training of
22
investigators, and again we have taken some pains in
23
that area.
24
25
And, as you say, the
And I think that what you would look at is the
overall functioning of the IRB rather than the
39
1
knowledge of the individual members because it operates
2
as an entity.
Each one contributing to that entity.
3
MR. OLDAKER:
4
PROFESSOR CHARO:
Thank you.
Thank you.
We have got
5
about, oh, seven or eight minutes unfortunately before
6
we are going to have to move on.
7
I have Alex, Bette and Steve.
8
Alex?
9
PROFESSOR CAPRON:
Thank you for your
10
testimony and your paper, Erica.
11
Commission is fortunate to be hearing from one of the
12
pioneers in this entire field.
13
MS. HEATH:
14
PROFESSOR CAPRON:
It is a -- the
Thank you.
And while there is always
15
some risk with anecdotal information, I think there
16
would be no one in the field who would be more familiar
17
than you.
18
I have three questions.
The first is just a
19
question of clarification.
20
FDA's recognition of the need for noninstitutional or
21
nontraditional academic institutional IRBs as the
22
origin of the process in some ways.
23
MS. HEATH:
24
PROFESSOR CAPRON:
25
You described 1981 and the
The turning point.
The turning point.
And yet
the FDA directive that you cite here does not mention
40
1
independent IRBs.
2
Can you clarify that for me, please?
MS. HEATH:
The FDA requirement before was
3
that any research done in an institution that had an
4
IRB had to go through that IRB.
5
studies that were done that were not required to go
6
through an IRB.
7
would apply, the same protections should apply to all
8
subjects.
9
should be given that same protection.
10
11
That left a lot of
In 1981 they said that that regulation
It did not matter where they were but they
And so they
said, "You are going to have IRB review."
They did not establish where that IRB review
12
would occur.
13
in the preamble.
14
societies would or regional societies or professional
15
societies.
16
those populations.
17
They had a few ideas which they mentioned
They mentioned perhaps medical
They never did come up with large IRBs for
In fact, I was working at UCSF and I had the
18
idea for starting this.
19
that was an obvious given.
20
Medical Society and asked if they had any interest in
21
doing it because it would be terrible to try to compete
22
against a group like that.
23
independent IRBs grew up because there was a void.
24
25
I waited because I thought
PROFESSOR CAPRON:
I actually went down to the
There was no interest so
When you spoke of letters
and untitled letters and warning letters, were you
41
1
referring to the FDA or the OPRR?
2
MS. HEATH:
3
PROFESSOR CAPRON:
FDA.
Throughout your discussion
4
you have seem much more focused on the FDA.
5
fact, end up doing much research approval that involves
6
OPRR as opposed to FDA?
7
MS. HEATH:
We do some.
Do you, in
It is a very minimal
8
part of our work load.
9
historically, OPRR would not consider an IRB that was
As I mentioned -- well,
10
external to the institution.
11
very traditional presumption that the IRB was
12
institutional, institutional review board.
13
The presumption was the
More and more grants began going to entities
14
that did not have a review board.
15
either go to a local board, an academic board, at a
16
time when resources were becoming very, very tight and
17
the academic boards were saying, "No, thank you.
18
not need the extra work."
19
They were forced to
Their other alternative was to set up one in-
20
house.
21
have the experience.
22
did not want to go to the annual meetings.
23
could do an IRB.
24
was optimal.
25
We do
They did not have the knowledge.
They did not
With one or two protocols they
They
They could meet the regulation.
So, what?
Three years ago?
It
Four years ago?
42
1
There was the first Single Project Assurance issued to
2
an institution that was contracting with an external
3
IRB.
4
seven.
5
portion.
6
funding agencies as professionals but it is not a major
7
part.
Those continue now.
It might be up to ten but it is a very minor
8
9
I think we have six or
We are pleased to be recognized by the
PROFESSOR CAPRON:
And the final question is
you spoke of being involved with accreditation.
I
10
gather that is the PRIM&R activity in that, is that
11
correct?
12
MS. HEATH:
13
PROFESSOR CAPRON:
Correct.
Would you think as part of
14
that accreditation that the standards would reach the
15
kinds of issues that have raised particular concern
16
about independent IRBs such as the forum shopping
17
issue?
18
suggest that it is common among independent IRBs to
19
inquire whether something has been previously submitted
20
and reviewed and what action was taken by another IRB
21
or one assumes that an unfavorable action if that.
22
But you did not say that response an IRB
That is you describe your own practice and you
23
should have when it learns that information.
24
thinking now around accreditation reach to questions of
25
appropriate standards for a response in that situation
Does the
43
1
and the other kinds of issues, the financial conflicts
2
and so forth, that do get raised?
3
MS. HEATH:
Well, as I said, I do not know
4
what will eventually result.
5
standards that were under discussion were quite broad.
6
I know the performance
They set a standard that I hope is flexible enough
7
that the issue would be looked at but with an open mind
8
because there are a number of ways of handling money
9
but many other issues as well.
10
11
Shopping.
So I am not sure I could predict an outcome
but I think it will.
12
As to shopping, again as I mentioned on the
13
evolution of IRBs, with the administration and the IRB,
14
this is something that is being recognized more and
15
more and more.
16
of the IRB discussion group on the internet but there
17
have been questions recently.
18
such and such protocol, is anybody else concerned,
19
write to me."
20
I do not know if all of you are aware
"We are concerned about
There are times when it is acceptable.
I have
21
received protocols that the applicant said, "This has
22
been reviewed by somebody else and we are moving it."
23
The most recent case I can think of was they were very
24
concerned because they did not think that IRB was
25
adequate.
They could not get records.
There was not
44
1
an appropriate membership.
2
protocol for review.
And we accepted the
3
PROFESSOR CAPRON:
4
PROFESSOR CHARO:
5
MS. KRAMER:
6
PROFESSOR CHARO:
7
We are down to only very quick questions.
8
Thank you.
Betty?
Pass.
Betty passes.
I
apologize.
9
Steve?
10
MR. HOLTZMAN:
It occurred to me as you were
11
speaking that I used to think that there were two
12
universes of IRBs, the institutional IRBs and the
13
independents.
14
third universe, which is the sponsors having their own
15
IRBs.
16
is 20 to 50.
17
universe of nonindependent sponsored ones are?
But as you are speaking, there is a
So you have said your universe of independents
18
Do you have any sense of how large the
MS. HEATH:
I was actually surprised and I
19
tried to get here yesterday to listen to the person
20
from General Motors.
21
one.
22
I had never heard that they had
MR. HOLTZMAN:
Do those folks show up at
23
PRIM&R and ARENA and whatnot?
24
MS. HEATH:
25
might be.
I have never met them but they
I mean, there were over 1,000 people last
45
1
year and I did not meet them all.
2
So --
3
MR. HOLTZMAN:
4
MS. HEATH:
5
MR. HOLTZMAN:
6
PROFESSOR CHARO:
You do not have a sense?
I do not have a sense of it, no.
Okay.
I have one last brief
7
question if I may and that has to do with liability and
8
insurance.
9
high quality work, avoiding liability and keeping
10
insurance premiums low is another spur, and I was
11
wondering how your corporate counsel had structured
12
your arrangements in order to capture what was
13
perceived to be a potential liability and how the
14
insurance industry has responded?
15
Reputation is clearly the greatest spur to
MS. HEATH:
Well, thank you for mentioning
16
another way of keeping us towing the line.
17
liability concerns are large.
18
insurance policy.
19
it several times and I am happy with it.
Certainly
We do have a rather good
We have negotiated -- renegotiated
20
PROFESSOR CHARO:
21
MS. HEATH:
I guess --
We have indemnification agreements
22
with the sponsors that we work with that we are
23
obviously responsible for anything that we are
24
negligent about but are not for issues raised due to
25
actions by the sponsor or the investigators.
46
1
PROFESSOR CHARO:
2
MS. HEATH:
3
PROFESSOR CHARO:
I guess to be --
Does that --- really clear, what I mean
4
is this:
5
history or a large enough database for there to really
6
be historically based ratings, how you have performed
7
in the past, whether or not you have had claims, an
8
insurance company might look to indirect markers to
9
predict whether claims would arise in the future.
10
11
12
In an area where there is not a long enough
So that with drivers they look at age, sex,
location, et cetera.
To your knowledge, has the insurance company
13
reacted by creating its own -- in essence, its own
14
criteria that they think indicate you have an IRB that
15
is less likely than another one to generate some
16
problem that would result in a claim?
17
MS. HEATH:
You know, I do not know how they
18
set the rates.
19
know that the history and all the reports I have heard
20
is that there are fewer problems among research
21
subjects than patients, which should play well but I do
22
know that our premiums are way higher than I should
23
think necessary.
I do not know what goes into it.
24
PROFESSOR CHARO:
25
MS. HEATH:
I do
And don't we all?
But that is for my car insurance,
47
1
too.
2
3
PROFESSOR CHARO:
questions for this session?
4
5
6
7
In that case I would like to thank you very
much.
It was very informative and very, very helpful.
We appreciate you coming.
MS. HEATH:
8
9
10
11
Are there any other brief
PANEL V:
Thank you.
PURPOSE OF REGULATION
PROFESSOR CHARO:
We move now albeit just a
little bit late to our second panel of the morning.
Dr. Harold Vanderpool from the University of
12
Texas Medical Branch, Galveston, will be our first
13
speaker on "The Unfulfilled Promise:
14
Report can amend the Code of Federal Regulations."
15
16
17
How the Belmont
Dr. Jonathan Moreno from the University of
Virginia on "Protectionism in Research."
And Dr. David Magnus from the University of
18
Pennsylvania on "The Justifications for Human
19
Research."
20
21
22
Thank you, gentlemen, for coming and thank you
for your patience this morning.
The way we would like to have this portion of
23
the morning go is as follows:
24
present your papers.
25
or less 15 minutes, is that correct?
If you would each
I understand you were told more
48
1
DR. VANDERPOOL:
2
PROFESSOR CHARO:
3
DR. VANDERPOOL:
4
PROFESSOR CHARO:
5
DR. VANDERPOOL:
6
PROFESSOR CHARO:
7
DR. MORENO:
8
PROFESSOR CHARO:
9
And we will ask the Commissioners to restrict
How many minutes?
Say what?
Twenty minutes.
Twenty minutes.
Okay.
So --
Twenty-five?
Between 15 and 20 minutes.
10
their questions after each paper solely to
11
clarification of a point that was made because there is
12
-- following a break after all three papers there is an
13
hour for discussion of all three papers because they
14
are obviously interrelated and we will certainly invite
15
the authors back to collaborate with us in that
16
discussion and questions can be directed at them or you
17
can interject while we are speaking.
18
So with that, Dr. Vanderpool?
19
HAROLD Y. VANDERPOOL, Ph.D.
20
PROFESSOR IN THE HISTORY AND
21
PHILOSOPHY OF MEDICINE
22
INSTITUTE FOR THE MEDICAL HUMANITIES
23
UNIVERSITY OF TEXAS MEDICAL BRANCH
24
GALVESTON, TEXAS
25
DR. VANDERPOOL:
Thank you, Dr. Charo.
49
1
2
Thank you all.
you today.
3
4
I am truly pleased to be with
So little time, so much to summarize and
accent.
5
I have been charged by your committee and
6
staff to provide an analysis of the relationship
7
between the Belmont Report and the federal
8
regulations, and include a discussion of the link
9
between the Belmont and the federal regulations, and
10
what those ought to be.
11
12
I have also been asked to make clear concise
recommendations with respect to these linkages.
13
Through these highlight remarks about my
14
paper, I will indicate how I have fulfilled these
15
charges.
16
My paper's thesis -- and I will be walking
17
through it with highlights, so join me please -- is at
18
the top of page three.
19
The power of the Belmont Report to amend the
20
Code of Federal Regulations has never been realized.
21
This paper will indicate how and why an incorporation
22
of the content and spirit of Belmont into the body of
23
the Federal Regulations can rectify major problems in
24
the regulations, strengthen the protection of human
25
subjects, and accent the inescapable role of moral
50
1
judgments for assessing when research involving human
2
participants is permissible.
3
I take the word "participants" back.
I
4
believe they should be called "subjects" but that is
5
perhaps another separate discussion.
6
This thesis is defended in the topics listed
7
on page two of the outline, which I will follow very
8
carefully, and I have developed each of the topics by
9
giving sustained and exceedingly careful attention to
10
the actual text of the Belmont and the Federal
11
Regulations in light of careful use of a host of
12
commentaries, some from some of you present, and
13
historical materials.
14
Topic I begins at the bottom of page 3 and
15
notes that both Belmont and the Federal Regulations
16
share the over arching purposes of promoting research
17
as well as protecting human subjects.
18
The promotion of research is not explicitly
19
stated in the document that it clearly evidenced by its
20
content.
21
the PHS-DHEW guidelines for the protection of human
22
subjects, it was fostered and fueled by the NIH's
23
concern to protect its research integrity.
If you read the history of the development of
24
If you look at the bottom of page 3, and I
25
invite you to read all the footnotes you wish, there
51
1
are many, you will note that the promotion of research
2
is a de facto purpose in the Belmont Report, including
3
being a moral obligation.
4
On pages 4 and 5 I just point to the most
5
notable differences between Belmont and the
6
regulations, which are really quite obvious.
7
regulations focus on rules that need to be followed as
8
well as attention to organizational and enforcement
9
mechanisms, laudable mechanisms even though you may
The
10
wish to change some of them, while the Belmont Report,
11
of course, focuses on principles -- ethical principles
12
and guidelines.
13
Topic II beginning on page 5 and following
14
gives an overview of Belmont's purposes and content.
15
At the bottom of page 5 you will note that Belmont's
16
objective is to provide an analytical framework for the
17
resolution of ethical problems arising from research
18
involving human subjects.
19
given on page 6 and includes, of course, its principles
20
and its applications.
21
This familiar framework is
On page 7 I invite us all to look at the
22
Federal Regulations through the lens of the Belmont
23
Report starting near the top of page 7.
24
vantage points of Belmont the present Federal
25
Regulations contain a number of major problems, all of
From the
52
1
which can be rectified by using the report to amend the
2
regulations.
3
The problems include a negligible influence on
4
ethics, a disorganized set of rules that easily confuse
5
and confound researchers and IRB members as they seek
6
to discover what the regulations want them to do; an
7
irresponsible view of the sources that define and
8
discuss research ethics; a seriously flawed
9
understanding of the ethics of research; blind spots
10
with respect to important protections accented in
11
Belmont; a preoccupation with rule stating and rule
12
following to convey the message that the Common Rule is
13
a bureaucratic document without a soul; a distortion of
14
the elements of informed consent found in the Belmont
15
Report.
16
17
PROFESSOR CAPRON:
What is it you do not like
about the regulations?
18
DR. VANDERPOOL:
I do, Professor Capron,
19
appreciate the regulations a great deal but I think the
20
Belmont gives the regulations a very tough time,
21
indeed.
22
Now on page -- on Topic III -- this is a good
23
question.
24
specific about these but on Topic III beginning on page
25
7, I talk about the meaning of Belmont's principles,
We can discuss those and I will be very
53
1
2
which I take to be widely misunderstood.
I do not consider them as -- in fact, I am
3
working with the text -- it is not what I believe but I
4
think it is what the text says.
5
principles that serve as the ultimate foundations of
6
ethical reflections.
7
many bioethicists and pragmatists realize, are easily
8
set -- a set of easily grasped moral standards rooted
9
in cultural belief and tradition for persons of diverse
10
11
They are not abstract
The Belmont principles are, as
background and training.
It is as if the Belmont framers and
12
bioethicists and pragmatists and others are looking
13
around at this host of rules and regulations and
14
requirements and they are saying these are all
15
connected with right making and wrong making
16
characteristics of human actions.
17
How are we goign to make sense of these?
You
18
make sense of these by saying, "Oh, well, there is this
19
division that deals with truth telling and there is
20
this division that deals with justice, and there is
21
this whole set that deals with non-maleficence, with
22
protecting people from harm, and there are these that
23
deal with beneficence and these that deal with
24
gratitude."
25
That is what the principles are.
They are summaries of those elements,
54
1
constitutive, comprehensive elements of human morality.
2
Now Belmont is rather unique about these.
3
They do deal with beneficence and they do deal with
4
justice but they are -- the Belmont's principle of
5
respect for persons is a sort of an amalgamation.
6
has got some philosophy in there, a little bit of kant
7
(sic) but it has got some more things.
8
things from law, from constitutional law, and it has
9
got some things from religion, and it has got some
10
It
It has got some
things for other things about culture.
11
So it is not clean philosophically but it is
12
one of those principles that is supposed to draw in a
13
whole set of things regarding how to regard people with
14
respect.
15
Now you will notice at the bottom of page 10,
16
beginning at the bottom of page 10, that we see Belmont
17
applications and its principles are seen as ethical
18
requirements.
19
ethical requirements.
20
position that I want to argue and I think it is correct
21
-- I stand to be corrected on any of these positions if
22
I take too strong a position then for you -- by all
23
means, let me think -- let me know that you think it
24
may be too strong.
25
Both are seen as equally strong sets of
And then I want to make a
But in the middle of page 11, what I say is
55
1
the equally strong moral requirements of principles and
2
applications and the interplay between them directly
3
relates to the protections provided by the Belmont
4
Report.
5
The most noteworthy feature about the
6
protections for human subjects promulgated by Belmont
7
is that at critical points the protections are far
8
greater in the applications section of the report than
9
in its basic ethical principles section, which a lot of
10
people have not really recognized.
11
The crucial place in which this occurs entails
12
protections pertaining to respect for persons.
13
According to Belmont the respect for person principle
14
requires that persons should be treated as autonomous
15
agents which involves giving weight to the opinions and
16
choices of individuals who are capable of deliberating
17
about and acting in accord with their personal goals.
18
Respect also requires refraining from heavy
19
handed disrespect such as repudiating considered
20
judgments of perspective judgments or denying their
21
freedom to act in these judgments.
22
Now to give weight to a research subject's
23
opinions and choices implies that the authority to
24
weigh and judge resides with someone other than the
25
subject.
It is in the principle section of the report.
56
1
The phrase undercuts the ethical and legal
2
understanding of autonomy, namely that individuals in
3
the research arena are free and self-determining agents
4
who have the final authority to decide what should
5
happen to them.
6
But now what the principles of Belmont under
7
respect for persons denies the applications supply.
8
All persons, all subjects must be granted the
9
opportunity to choose what shall or shall not happen to
10
them, must be given all the information.
11
volunteers would need to know whether they wish to
12
participate, must comprehend this information, which
13
involves how it is organized, the time needed, the
14
communicating that needs to be incurred, what level of
15
communication with respective to subject's intelligence
16
and so on.
17
Reasonable
Patients must be -- subjects -- prospective
18
subjects must be situated in conditions free of
19
coercion, free of undue influence, unjustifiable
20
pressures -- these are carefully defined in Belmont --
21
over either the prospective subject or through
22
controlling influence of a close relative.
23
All these are accents in the Belmont Report,
24
which shows that the subject's choice should be free
25
and final except in just a couple of places where
57
1
Belmont makes a couple of exceptions.
2
Now I think these are very powerful -- a
3
powerful point where the applications secure with -- in
4
a stronger way what it means to respect research
5
subjects than do Belmont's principles.
6
Now you will note on page 13 that I set up
7
this argument:
8
that the principles of beneficence and its applications
9
and the principles of justice and its applications are
I think one can look at Belmont and say
10
in a sense gatekeeper roles.
11
IRBs must use to determine which research projects and
12
protocols are acceptable enough to move to the stage of
13
subject enrollment.
14
They are the criteria
These serve, therefore, as essential but
15
nevertheless initial moral screens prior to the ethical
16
bedrock of Belmont's human subjects protections, the
17
vital protections surrounding informed consent.
18
And I maintain that Belmont's great reliance
19
upon informed consent accord with the fundamental
20
dynamics of the values of free and democratic society.
21
You can -- and I think that in a sense we
22
said, "Well, we have talked informed consent language a
23
lot," but I think we need to strengthen informed
24
consent.
25
between protections, make protections and enhancements
Either one goes with narrowing the distance
58
1
of research more of a zero sum gain or one can accent
2
informed consent and do it right and allow for the
3
greater possibility of risk and harms in research.
4
As specified on pages 14 and 15, the Belmont
5
Report is a flawed and cracked earthen vessel.
You can
6
see the ways in which I identify that as true.
But in
7
spite of its manifest flaws, it can serve as a powerful
8
basis for revision for the Federal Regulations.
9
Its power to do this is linked to its legal,
10
historical and revered status as well as its intrinsic
11
virtues, which are found on pages 15 and 16, and many
12
of those are very powerful.
13
populations, insightful connections between ethics and
14
research, and so on.
15
Protection of vulnerable
Now Topic IV, this is where Dr. Capron's
16
question -- where the rubber hits the road.
17
here very specifically with the ways the Belmont Report
18
could be used to revise our present Common Rule and
19
here is where what I -- what seemed to be maybe
20
overstated charges on page 7, I think are accurate
21
charges, accurate concerns.
22
First of all, Belmont -- the Federal
23
Regulations hardly mentions ethics at all.
24
the main body of the material.
25
I deal
One time in
Second, beginning on page 17, the Belmont has
59
1
-- the regulations contain irresponsible standards
2
pertaining to sources that define an articulate
3
research ethics.
4
Now how does this occur?
In the one place where ethics is mentioned in
5
the main body of the Federal Regulations, Section
6
46.103(b)(1) says, "The statement of principles for the
7
protection of rights and welfare of human subjects is
8
required in assurance of compliance agreement."
9
But if we notice about what this statement is,
10
the actual content of such a statement is not taken
11
seriously and its uses are not even addressed.
12
Here is the wording about the statement that
13
is required:
14
appropriate existing code, declaration or statement of
15
ethical principles or a statement formulated by the
16
institution itself."
17
"This statement may include an
Now this is problematic.
18
by itself will not do.
19
will not do.
20
institution often will not do.
21
well, any of these will do.
22
The Nuremburg Code
The Declaration of Helsinki
Some statement drawn up by the
But this assumes, oh,
And let's say you chose the Nuremburg Code.
23
If you did you would go against Belmont Report that
24
argues that ethical principles are necessary to
25
interpret the rules of Belmont, Helsinki, of the
60
1
Nuremburg code and Helsinki and otherwise.
2
you simply have in the body of the regulations a sort
3
of, oh, comme si, comme sa, develop the regulations you
4
want.
5
And I propose very specific things.
And so
In the
6
middle of page 18 I propose that instead of this open
7
ended phrase with a variety of documetns can do, the
8
phrase -- as you can see in the underlined parts of
9
that midsection on page 18 -- the statement of ethical
10
principles should include at minimum the tenets of the
11
Belmont Report.
12
ongoing basis for training programs and protocol
13
evaluations by the institution's IRB members and
14
investigators.
15
16
17
This statement should serve as an
That is not in the present regulations.
Nothing is said about how the assurance compliance
agreement should be applied.
Now, if anything, it is even more serious,
18
Section, Part III, middle of page 18 is even more
19
serious because the regulations contain a flawed
20
understanding of research ethics.
21
regulations, 46.147(a) under the heading "IRB
22
membership."
23
This is found in the
And this is in the Federal Regulations.
In addition to possessing the professional
24
competence necessary to review specific research
25
activities, the IRB may be able to ascertain the
61
1
acceptability of proposed research in terms of
2
institutional commitments and regulations, applicable
3
law, and standards of professional conduct and
4
practice.
5
Now this is critical.
How do you ascertain
6
the acceptability of proposed research in the
7
regulations by the vague unspecific category of
8
institutional commitments and regulations?
9
have been the Nuremburg Code.
Who knows?
That might
It does not
10
even mention ethics or sound ethical reasoning.
11
could be just sound deliberative reasons.
12
assumes that the standards of professional conduct,
13
presumably professional codes of ethics, directly
14
relate to the ethics of research.
15
It
And falsely
As we know in looking carefully at the final
16
report of the Advisory Committee for Radiation
17
Experiments, what the committee members argued was a
18
historical record and their contemporary projects,
19
which they did in the last part of this huge report,
20
indicate that the distinction between the ethics of
21
research and the ethics of clinical practice was and is
22
unclear and that many of the problems of the past and
23
the present may be due to a failure to distinguish
24
between these two.
25
Now what I propose -- and again these are not
62
1
elaborate proposals but they give an entirely different
2
cut the regulations -- is in the middle of page 19 that
3
this wording should be the following:
4
research in terms of -- should be -- you ascertain the
5
acceptability of proposed research in terms of sound
6
reasoning.
7
distinguishing the ethics of research from the ethics
8
of clinical care, applicable law and each institution
9
statement of ethical principles and rules specified
That proposed
It could be ethical reasoning.
But
10
under 46.103(b)(1) and that is what we just reviewed in
11
terms of specifying the Belmont Report.
12
PROFESSOR CHARO:
13
DR. VANDERPOOL:
14
PROFESSOR CHARO:
Excuse me, Dr. Vanderpool.
Yes.
It is hard to believe it but
15
the time has been flying and it has been about 20
16
minutes.
17
this to read for approximately five or six days, could
18
I ask you just to commend to us for a second reading
19
those items in the remaining part of the paper that you
20
think are especially important to us?
Since we have been fortunate enough to have
21
DR. VANDERPOOL:
22
I think the other parts of the paper that are
Thank you.
Thank you.
Yes.
23
especially important would be Appendix B, which is in
24
light of the criticisms of the sections of the
25
regulations that deal with what IRB members and
63
1
2
researchers should do.
What I do in Appendix B is to indicate how --
3
is to answer this long standing question, which I have
4
heard this committee ask, about how do you make
5
research -- how do you make informed consent a process
6
rather than a document.
7
present Federal Regulations because it says -- the
8
Federal Regulations say that the basic elements of
9
informed consent are as follows, and they are all
10
And it is a document in the
informational, and they all belong on informed consent.
11
So informed consent forms.
12
So if you spend all your time really focusing
13
on what the basic elements of informed consent are, you
14
spend your time focusing on informed consent forms.
15
And what I offer in Section B is the process.
16
The process is not -- to throw away the basic elements
17
of consent in the present regs and talk about the three
18
basic elements of consent, voluntary-ism,
19
comprehension, understanding.
20
into a process.
21
So this makes consent
The other point would be that in the final
22
section I have long been concerned about what is that
23
regulations, and including regulations the Belmont
24
Report is communicating pragmatically to IRB members
25
and researchers, and I think it is probably that --
64
1
what it is communicating now is problematic.
2
think the proposals I make here indicate that it should
3
communicate a clearer set of things they should do to
4
protect human subjects.
5
And I
These are found on page 24. It should make
6
thoughtful deliberations and so on and these -- I think
7
every one of these elements on page 24 will serve to
8
protect human subjects better and these directly relate
9
to what the Belmont Report is about.
10
And on all of these grounds I offer two
11
recommendations to you.
12
opportunity to appoint an expert task force to finally
13
utilize the Belmont Report to inform the Federal
14
Regulations.
15
Belmont II for the sake of articulating a clearer and
16
more comprehensive understanding of the ethics of
17
research.
On page 25, first, seize the
And, second, consider -- to call for
18
Thank you very much.
19
PROFESSOR CHARO:
Thank you and I apologize
20
that the shortness of time precluded a fuller
21
presentation of what is obviously a detailed and
22
careful paper that was provided to us.
23
DR. VANDERPOOL:
And please understand I did
24
not want to assume that you had not read the paper but
25
I think when I read a paper it is helpful for an author
65
1
to say, "Okay, now this is the thing that has punch."
2
PROFESSOR CHARO:
I think we all agree.
3
DR. VANDERPOOL:
And I hope I was able to
4
convey that.
5
PROFESSOR CHARO:
I think we all agree
6
completely.
7
after you have given us the paper.
8
DR. VANDERPOOL:
9
PROFESSOR CHARO:
That is the purpose of having you come
Absolutely.
Thank you.
May I first just ask if
10
there are any points of clarification rather than
11
discussion or expansion?
12
13
If not, then we will turn to Jonathan Moreno
for a presentation on protectionism.
14
JONATHAN D. MORENO, Ph.D.,
15
KORNFELD PROFESSOR AND DIRECTOR
16
CENTER FOR BIOMEDICAL ETHICS
17
UNIVERSITY OF VIRGINIA
18
DR. MORENO:
19
I have some overheads that I am going to be
20
referring to.
21
22
Thank you, Alta.
PROFESSOR CHARO:
staff?
Can we get some help from
Thank you.
23
DR. MORENO:
24
pleasure to be back with NBAC.
25
Good morning.
It is always a
My charge was to develop the idea of
66
1
protectionism as it appears in the Common Rule and I
2
really tried very hard to do that.
3
say that I felt, as I will say this in San Francisco,
4
it may be appropriate, the ground is somewhat shifting
5
beneath my feet over the last several months because --
6
or perhaps my butt as I was writing this because, in
7
fact, I think the moderate protectionism that is
8
characterized as the Common Rule -- what I am calling
9
moderate protectionism, we might be seeing the end to
10
the era of moderate protectionism.
11
elaborate on that as I go on.
12
Although I have to
And I want to
In fact, what I have to say to you is in a
13
certain sense more a study of protectionism as a case
14
study in the history of ideas rather than a
15
philosophical paper per se.
16
a philosopher I often think the history of this area is
17
more illuminating than the philosophy.
Even though I am only
18
(Slide.)
19
Clearly there are two extremes that could set
20
the boundaries of a philosophical discussion of
21
protectionism in human subjects research.
22
extreme we could prohibit human subjects research all
23
together.
24
protectionism.
25
political reasons we have decided not to do that.
At one
That would be the most powerful form of
For various philosophical, economic and
67
1
Harold mentioned the Belmont Report's position on that.
2
At the other extreme we could permit all human
3
experiments, come what may, willy nilly, without any
4
protections at all.
5
defense attorneys did not accept that proposition.
6
They claimed that even their clients sought volunteers
7
in the concentration camps.
8
9
Well, even the Nazi doctors'
So it turns out that nobody at least in public
accepts either of the extremes.
What we have instead
10
is some several flavors of protectionism that stand in
11
the middle.
12
who are subjects in human experiments -- and I am, by
13
the way, going to use the term "human experiments"
14
because it is historically the most generic term even
15
though it has fallen in and out of favor over the
16
decades.
17
There is general agreement that persons
People who are subjects in human experiments
18
deserve protection from undue risks.
19
is not controversial.
20
This proposition
What is controversial is who bears
21
responsibility for protecting them, how should we weigh
22
or balance, and those terms have different
23
significance, weigh or balance societal interests
24
versus individual interests?
25
of medical practice is a way of merging, of meshing the
And, by the way, the idea
68
1
idea of societal interests to the advancement of
2
medical knowledge and individual interest in being
3
protected from undue risks.
4
And it seems to me that both of these
5
questions can be merged through a certain theme that
6
characterizes my historical account of protectionism.
7
The theme is the idea of the discretion of the
8
investigator.
9
about who to bring into research, how to decide that
How much discretion in making judgments
10
they are truly volunteers, how much risk to expose them
11
to and so forth, how long to keep them in the study,
12
many questions.
13
familiar with can be brought under the heading of how
14
much discretion should be allowed to the individual
15
investigator.
16
All these questions that we are
And I think that it is the ebb and flow in the
17
story -- in this story, the story of investigator
18
discretion that is the story of protectionism in
19
medical research.
20
Now in my first slide I have tried to
21
characterize what I think again are the critical
22
issues.
23
subject and those of science and future patients.
24
25
The relationship between the interests of the
Secondly, whether and in what manner the
conduct of the investigator may be monitored or
69
1
controlled by third parties.
2
issue of investigator discretion and a corollary to
3
this is what special arrangements should be made for
4
certain vulnerable populations.
5
This really goes to the
By the way, the idea of a vulnerable
6
population is very much historically based.
7
years the only people who were thought to be really
8
vulnerable were children.
9
late 19th Century through the early -- through the
For many
Antivivisectionist from the
10
1930's anyway -- singled out children for special
11
protection.
12
singled out for special protection.
Rarely were others such as mental patients
13
(Slide.)
14
I am going to dwell on this slide for just a
15
moment.
16
there are several levels, for want of a better term, of
17
protectionism.
18
It seems to me, as I have indicated, that
Under what I have called weak protectionism,
19
the investigator has a great deal of discretion over
20
all the issues that I have mentioned, recruitment, how
21
to get consent or how to ensure voluntariness, when to
22
decide that somebody should not be in a study, how to
23
assess risks and benefits, and there are at best
24
informal constraints.
25
What Henry Beecher, himself, as a matter of fact,
What we might call guidelines.
70
1
called guides.
Guides.
2
I think that the era of weak protectionism
3
really lasted up to about 1980 and 1981 and that the
4
period 1947 to 1981 was an era in which gradually weak
5
protectionism was being challenged and finally gave way
6
to what we have today, which itself may be under
7
attack, which I call moderate protectionism.
8
Under moderate protectionism there is limited
9
investigator discretion but there is nevertheless still
10
a lot of discretion.
11
necessary contemporaneous monitoring of study practices
12
themselves under moderate protectionism and there are
13
formal constraints or rules.
14
rigid rules, which he did not like.
15
Nuremburg Code in the category of rigid rules that he
16
did not like, which is why Beecher preferred Helsinki
17
to the Nuremburg Code.
18
oriented according to Beecher.
19
There is, for example, no
What Henry Beecher called
And he put the
Helsinki was more guidance
And then, of course, it follows as the night
20
to day that if there is weak and moderate positions
21
there must be a strong position and the strong position
22
would be severely limited investigator discretion with
23
formal interventions to ensure that the rigid rules, so
24
to speak, are being followed.
25
This might go so far, for example, not only to
71
1
include independent review of capacity assessment.
2
might also tell investigators who they can have in
3
their study.
4
they not even have a role in the recruitment process
5
itself.
6
it, would be quite severe indeed.
They might not -- we might require that
So strong protectionism, as I conceptualize
7
(Slide.)
8
There are, of course, alternatives to
9
We
protectionism other than the sort of horizontal ones
10
that I have mentioned, which would be to allow anybody
11
to be in research under any conditions and to prohibit
12
research entirely.
13
There are also -- you might think of as
14
vertical alternatives.
15
standpoint you could have a position called -- we might
16
called accessionism.
17
position that there is a very strong interest, if not a
18
right to be in research if you want to be.
19
For example, from the subject's
That is to say you could take the
And I think there are two versions of
20
accessionism.
21
activists in the late '80s and early '90s, which I call
22
therapeutic accessionism, which is that -- essentially
23
that research also is a treatment.
24
cry of ACT-UP and that, therefore, people should have
25
access to that medical treatment as well as any other.
That embodied in the position of AIDS
This was the action
72
1
There is also what might be called scientific
2
accessionism, the position that women and children, and
3
others who have traditionally been excluded from
4
research should get in for good scientific reasons.
5
And then there is the philosophical view, not
6
usually very clearly articulated, that underlies those
7
defenders.
8
investigator discretion.
9
moral virtue, the moral uprightness, the integrity of
The position of those defenders of
Which is that the virtue, the
10
the individual investigator is ultimately the last line
11
and best line of defense against abuses of human
12
subjects.
13
It seems to me that it is this view that is
14
very central to the traditional notion of individual
15
investigator discretion.
16
"virtue ethics."
One might call the position
17
Can I have the next slide, please?
18
(Slide.)
19
Now I am going to just run through these very
20
briefly and I want to -- and this -- obviously
21
everybody has their own highlights or their own
22
landmarks in this history.
23
The point that I want to make is that every
24
single item on this list, every single policy item, was
25
preceded by a public scandal or a tragedy of some sort.
73
1
I was really impressed by Don Chalmers' remark
2
yesterday afternoon that Australia did not have this
3
pattern but nonetheless in the United States I think it
4
is very clear that we have responded to a series of
5
scandals or incidents.
6
(Slide.)
7
We do not have to perhaps go through -- some
8
of you are familiar with these incidents and the
9
scandals and tragedies that preceded them but I think
10
you will see that in each case there was a specific
11
incident or series of incidents that finally called
12
forth a public response.
13
(Slide.)
14
And I have added only a few days ago the new
15
DHHS initiatives and perhaps new legislation, and I
16
want to return to that at the end of my remarks.
17
(Slide.)
18
The period that I have referred to as, I
19
think, the critical era in which moderate protectionism
20
with a lot of investigator discretion was being broken
21
down was the period, as I said, from 1947 to 1981.
22
period that has as its beginning the results of the
23
Nazi doctors' trial in 1947 and it is conclusion the
24
DHHS rules in 1981.
25
A
And I think it is quite interesting that if
74
1
you take six major commentators in the 1960's through
2
the 1970's on human research ethics you see the
3
controversy within the community of distinguished
4
commentators on the issue and you see the breakdown of
5
traditional investigator discretion.
6
Take three distinguished physicians.
For
7
example, I have already mentioned Beecher.
8
I have told you and as many of you know, was opposed to
9
the Nuremburg Code.
Beecher, as
He considered them to be rigid
10
rules.
11
Army contract for Harvard in 1961 and '62 but he
12
embraced Helsinki as guides.
13
the individual investigator as the last and best
14
offense against the abuse of human subjects but Beecher
15
was not alone.
16
He opposed the Nuremburg Code as part of an
He defended the virtue of
Other distinguished medical commentators took
17
the same position in the '60s and '70s.
18
we can see that what they were doing was defending
19
moderate protectionism against the critics, against the
20
attacks that were on their way, and that were coming in
21
waves as each new scandal appeared in the '60s and
22
'70s.
23
In retrospect,
Walsh McDermott, for example, said in 1967,
24
"Medicine has given society the case for its rights in
25
the continuation of clinical investigation."
He uses
75
1
rights language perhaps not wholly self-consciously but
2
interestingly, I think.
3
(Slide.)
4
Lou Lasagna said in roughly the same period,
5
"How many of medicine's greatest advances might have
6
been delayed or prevented by the rigid application..."
7
Again the word rigid application "...of some currently
8
proposed principles to research at large.
9
ethical experienced investigator no laws are needed and
10
11
For the
for the unscrupulous incompetent no laws will help."
So that Lasagna took this position as a matter
12
of fact during the early '70s when there was criticism
13
of prison studies and Lasagna said of the national
14
commission's recommendations with respect to prison
15
research, which were by the way much more permissive
16
than the rules that we finally came out with, he said,
17
"This is a terrific example."
18
editorial.
19
people with some really stupid ideas."
He said this in an
"A terrific example of some really smart
20
So here we have Beecher, Lasagna and
21
McDermott, the great eminences of commentators on human
22
research ethics trying to hold the fort against the
23
attacks on moderate protectionism in the '60s and '70s.
24
On the other hand --
25
(Slide.)
76
1
-- we have people like Hans Jonas, Paul Ramsey
2
and Alan Donagan.
3
Ramsey in 1970 in the Patient as Person writes, "No man
4
is good enough..." and now presumably woman either
5
"...to experiment upon another without his or
6
presumably her consent."
Theologians and philosophers.
Paul
7
In the epigram to the paper that you have in
8
front of you, I used this very powerful statement from
9
Jonas around 1972, "We can never rest comfortably in
10
the belief that the soil from which our satisfaction
11
sprout is not watered with the blood of martyrs."
12
Wonderfully Talmudic language here full of survivor
13
guilt.
14
undeserving beneficiaries to ask, 'Who is to be
15
martyred, in the service of what cause, and by whose
16
choice?'"
"But a troubled conscience compels us, the
17
Or in a rather more hard hitting and even
18
biting statement -- series of statements in a paper
19
that he published in 1977, the analytical philosopher,
20
Alan Donagan basically compared the position that
21
Beecher and Lasagna and McDermott took by name to the
22
defense of the Nazi doctors as crass utilitarianism.
23
Now I argue in the paper that that position
24
that Donagan took -- Donagan was not a marginal figure
25
by any means.
The position that Donagan took was
77
1
intellectually respectable in the late '70s after the
2
scandals and tragedies, and particularly after
3
Tuskegee, and in the midst of the writing or just
4
before the writing of the Belmont Report, and that was
5
only from the standpoint of the history of ideas an
6
acceptable position in the late '70s.
7
have been a respectable position in the early '70s and
8
certainly not in the 1960's.
9
It would not
So what I am arguing in summary with respect
10
to this historical tour is that the period '47 to '81
11
we see a critique and an attack mostly by nonphysician
12
commentators, theologians and philosophers on the
13
tradition of weak protectionism that predominated in
14
the history of this and in 1981 we have the
15
institutionalization of what I call moderate
16
protectionism, our current system.
17
Now in the spirit of moderation, I did
18
articulate some recommendations at the end of the
19
paper.
20
part of the paper.
21
They are all moderate but I think there are more
22
interesting questions that face us right now and it is
23
one that I foreshadowed earlier and I am going to end
24
with these sort of rhetorical questions.
25
Frankly, to me they are the least interesting
You can read them if you like.
Is it possible that perhaps beginning with the
78
1
UCLA schizophrenia study scandal in '94, continuing
2
with the TD case in New York, continuing with the
3
Gelsinger case a few months ago, embodied in the
4
Secretary of DHSS initiatives and the Kennedy bill and
5
the Getty bill that are both being introduced soon, and
6
the report that this Commission is developing, and the
7
transition in OPRR, and so forth.
8
we are witnessing the end of a very awkward, roughly 20
9
year, compromise called "moderate protectionism?"
10
Is it possible that
And that we are entering an era suggested
11
perhaps by some of NBAC's own recommendations in the
12
Mental Disorders Report of a more interventionism in
13
investigator-subject relations.
14
not strong, protectionism.
15
might be expected to have, for example, a liaison who
16
will actually go unannounced to the research site and
17
observe the way consents are being done, observe the
18
way subjects are being recruited, observe capacity
19
assessments.
20
An era of stronger, if
An era in which every IRB
This would be, at least in a matter of degree,
21
if not of kind, a strengthening of what I would call
22
moderate protectionism leading us perhaps to a --
23
ultimately to a very interventionist position with
24
respect to investigator-subject relationships.
25
Now there are some dangers in strong
79
1
protectionism, at least as an idea, and it is an --
2
there actually is a particular danger that was
3
illuminated by the writers of what we have come to call
4
the Nuremburg Code itself.
5
responsibility is perceived by investigators as having
6
been taken from their shoulders and instead that more
7
responsibility transformed into legal and regulatory
8
responsibility for other parties, the IRB, the risk
9
manager, the Vice President or Provost for Research at
Namely that the -- if more
10
the university and so forth, the nursing liaison from
11
the IRB, if the responsibility for the welfare and
12
interests and rights of the subject is perceived by the
13
investigator not to rest finely on his or her shoulders
14
because a system has been created that is supposed to
15
ensure that those rights and interests and welfare are
16
respected, then will investigators begin to divorce
17
themselves from the traditional sense of moral
18
responsibility that at least in principles -- in
19
principle from the Hippocratic era to the present --
20
physician investigators are supposed to have with
21
respect to those in their care.
22
So there is a temptation, I think, to see --
23
and I think to some extent it is happening -- to see
24
the history I have described moving us inexorably in
25
the direction of strong protectionism.
80
1
I think that 20-30 years from now people like
2
us may find themselves sitting around a table like this
3
in a hotel like this reflecting on the consequences of
4
that trend and bemoaning the loss of a sense of moral
5
responsibility among physician investigators and other
6
scientists who are responsible for the well-being of
7
their subjects.
8
Thanks.
9
PROFESSOR CHARO:
Thank you very much.
I can
10
only say in 30 years I suspect we will be doing it by
11
video conferencing and we will not have the pleasure of
12
one another's company over breakfast and lunch.
13
Questions of clarifications?
14
Okay.
Our third presentation, Dr. Magnus from
15
the University of Pennsylvania on "Ethical
16
Underpinnings."
17
backwards.
In some ways I suppose this is rather
Your's was the most general of all papers.
18
DAVID MAGNUS, Ph.D.
19
ASSISTANT PROFESSOR AND DIRECTOR OF
20
GRADUATE STUDIES, CENTER FOR BIOETHICS
21
UNIVERSITY OF PENNSYLVANIA
22
23
DR. MAGNUS:
Right.
This is, I think, the
most general paper.
24
Thank you very much for giving me the
25
opportunity to speak to you about this subject.
81
1
Over the past several years, public response
2
to gene therapy and other innovative therapies have
3
been very interesting, especially in light of the
4
recent death of Jesse Gelsinger at Penn.
5
The public for several years has demanded that
6
new and better therapies, including gene therapies, be
7
developed as quickly as possible. Many articles have
8
been written bemoaning the obstacles to getting
9
patients enrolled in clinical trials and the barriers
10
to getting research out to develop products.
11
At the same time the response to the Gelsinger
12
death suggests that the public also believes that no
13
persons should be harmed in the process of research,
14
and I might add it would be nice if no animals were
15
hurt either.
16
On the surface, to those with knowledge about
17
research, these would be seem to be contradictory
18
desires and evidence of a schizophrenic attitude on the
19
part of the public.
20
This is not necessarily the case.
The two statements only conflict provided an
21
adequate understanding of the necessity of human
22
subjects research even without possibility of benefit
23
and substantial risks that must be undertaken to make
24
medical
25
conveyed to the public.
advances.
This has simply not been
82
1
If computer models, animal models, research at
2
the cellular level and theorizing were together
3
sufficient for a full understanding of the impact of
4
new therapies on humans for good and ill, there would
5
be no contradiction between the two public demands.
6
The biomedical research community, including
7
the bioethics community, has failed to convey the need
8
for human subjects research to the public.
9
of variables in research on humans is far too great,
10
the human body far too complex a system for us to be
11
able to predict what the impact of a given therapy will
12
be on most humans.
13
The number
Treatments that work well on animals and even
14
on human cells often fail to benefit when applied to a
15
human subject.
16
This not only happens, it is the norm.
Similarly, it is difficult to understand all
17
the risks that a human will be exposed to until a trial
18
has actually been performed.
19
effects and dynamic interactions may not reveal
20
problems until much later.
21
Even then long-term
In the comments that I will be making I will
22
be considering the case for -- the fundamental case for
23
and against the value of research in human subjects at
24
all, and try and derive a few conclusions, particular
25
conclusions about protections from them.
But I think
83
1
it is important to remember that in the end the best
2
safeguard to protect subjects is ensuring that they
3
have a better understanding of the nature of the
4
benefits, risks and burdens of research and that a
5
well-informed public that engages in subjects as
6
subjects in research, and to an increasingly large
7
degree, is in the end much better than any form of
8
protection that we could really offer.
9
First, what is the value of research on human
10
subjects?
11
justifications about why we should allow research on
12
human subjects.
13
intrinsic value to the research. We are interested, in
14
general, in knowing things about the universe.
15
the reason why we -- one of the major reasons for
16
justifying science at all.
17
human subjects deals with issues that are of particular
18
concern to us and, therefore, there is a great deal of
19
intrinsic value in research on human subjects.
20
Fundamentally there have been two sorts of
First, there is scientific or
It is
And, of course, research on
Secondly, there is also instrumental value
21
attached to research on human subjects and this often
22
goes without saying but it is important to remember
23
that this is an important moral good to society as we
24
develop better therapies, better preventative agents,
25
better palliative agents that all come about as a
84
1
result of research.
2
In addition, we also as we develop more
3
knowledge -- I mean, it also goes without saying, we
4
learn more about some of the problems associated with
5
other kinds of treatments that we already offer.
6
about the research that gave rise to the discovery that
7
Phen-Fen had some deleterious effects in terms of heart
8
valves.
9
Think
Clearly, these are important and in some sense
10
it means that scientific research, including research
11
on human subjects represents a kind of social good.
12
is important to note that it is only a contingent good,
13
that it is a good that society as a whole has deemed of
14
value and something that it is willing to make a
15
commitment in as a social good but not necessarily
16
something that is necessary.
17
medical research in order to continue to survive as
18
long as the death rate and the birth rates remain more
19
or less in balance.
20
research is absolutely necessary.
21
It
Society does not require
There is no way in which this
Given that this is a social good, there are
22
nonetheless problems that arise for research that
23
really call into question whether or not the extreme
24
view that Jonathan presented a little bit, the extreme
25
form of protectionism, namely we should not allow it
85
1
all, does not, in fact, have some philosophical
2
justification.
3
This particularly is a problem when you
4
consider research that has no -- is not designed to
5
provide any therapeutic benefit but conveys risks to
6
subjects engaged in research.
7
For research without any -- with any
8
substantial risk of harm to the subjects or even a
9
highly uncertain risk, researchers and would be
10
regulators face an acute moral dilemma.
11
Phase I research can be done, whenever
12
possible, on healthy volunteers.
13
exposing people to risk for no possible direct benefit.
This involves
14
Allowing medical practitioners to knowingly harm or
15
risk harm to healthy subjects without any prospect of
16
their personal benefit runs counter to some of the most
17
central ethical tenets of the practice of good
18
medicine.
19
entrenched in the ethos of health care.
Do no harm is a moral norm that is firmly
20
The ethical picture concerning the
21
justification of research becomes even darker when we
22
realize the motivations for many of the subjects of
23
this kind of research.
24
25
Financial gain:
Paying research subjects
either monetarily or in services has become an
86
1
increasingly important part of Phase I research.
2
Payment may produce several problems, including
3
subjects who do not attend closely to the nature of the
4
risks involved in participation, bias sampling in the
5
selection of research subjects, and injustice as those
6
with financial need are asked to risk their health for
7
the benefits of others.
8
there may simply not be enough volunteers for research
9
to be feasible.
10
Without payment, however,
The second harm in the dilemma of whether
11
research can be ethically justified at all can be seen
12
if the pool of subjects for Phase I protocols is
13
restricted, when possible, to those who are already
14
afflicted with a condition or disease whose treatment
15
is being sought.
16
For therapies with substantial risk of serious
17
harm, it is common to restrict research to subjects who
18
are terminally afflicted with a disease.
19
There are serious problems with using the
20
dying as a way to avoid the conundrum posed by
21
undertaking research that is not intended to benefit
22
the subjects.
23
subjects possible.
24
patients who have become reliant on the medical
25
community for any kind of hope and for the alleviation
First, these are the most vulnerable
They are sick and often desperate
87
1
of suffering.
2
suggestions put to them by clinicians regardless of
3
their values in decision making when in a more
4
empowered position.
5
They may be too ill to refuse
Moreover, the desperation of many of these
6
patients means that they are looking for benefit even
7
when it really is not there.
8
occurs due to two complimentary factors.
9
This often arises and
First, the desperation of the patients may
10
mean that they cling to a desperate hope that a trial
11
with no real possibility of therapeutic value will make
12
them well and represent their best last hope for a
13
cure.
14
Second, clinicians who want to offer something
15
to the dying are tempted to play to this desperation
16
and often obfuscate the line between research subject
17
and medical patient.
18
fundamental problem with the ethics of research for
19
Phase I research on human subjects.
20
been alluded to but the line between subject and
21
patient is something that is typically obscured in much
22
Phase I research.
23
I think this is, in fact, a real
This has already
Researchers usually believe in the trials they
24
pursue.
25
Indeed, many researchers defend the need to convey hope
This is often conveyed to the subjects.
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1
to patients.
2
designed informed consent forms and say the right
3
things to patients may also convey a sense of hope and
4
cautious optimism that reinforces the things that the
5
patients are looking for.
6
Even careful researchers who have well-
This seems to reinforce the desperate hope of
7
the patient.
8
may or may not help you.
9
value on any chance that it will help you.
Using vague and misleading language this
We cannot put a numerical
It can
10
certainly help to reinforce the impression that the
11
subject is a patient receiving therapy, not a subject
12
in an experiment designed primarily to test the safety
13
of a treatment, and with virtually little -- no or
14
little chance that it will benefit the subject and a
15
much greater chance that it will cause some form of
16
harm.
17
Empirical studies have shown that as many as
18
85 percent of patients, cancer patients enrolled in
19
Phase I trials are under the impression that they are
20
receiving therapy.
21
being done by some of my colleagues, they have found
22
that patients enrolled in -- cancer patients enrolled
23
in Phase I trials not only typically believe that they
24
are receiving therapy but you can actually identify
25
very clearly things that the clinician said that helped
And in some qualitative research
89
1
to reinforce those beliefs.
2
If the primary reason for using terminally ill
3
persons in research that lacks any real prospect of
4
benefit is that they cannot be harmed.
5
are patients who are beyond harm or subjects that are
6
beyond harm.
7
experimenting on the same subjects for treatments that
8
are unrelated to the condition that afflicts them.
9
That is these
And that reason could be used to justify
In short, terminally ill patients would be
10
utilized as human guinea pigs for any and all dangerous
11
research projects on the grounds that they are beyond
12
harm.
13
doubt on the strength of this justification for using
14
the population.
15
This grisly prospect would seem to cast some
Moreover, the assumption that this population
16
is beyond harm is also false.
17
differences in the way people die.
18
they may well be better off preparing for the end at
19
home rather than desperately clinging to a false hope
20
while suffering indignities in a medical setting.
21
others, dying will be far less burdensome outside an
22
invasive safety study than in such a study.
23
There are important
For some patients
For
One other problem with using the terminally
24
ill in safety studies is that in the end the Phase I
25
studies may not really scientifically be of much value.
90
1
Depending on how ill a patient is, death may be a
2
foregone conclusion so that little about safety is
3
gleaned and it makes it easy to blame the underlying
4
condition rather than the therapy for at least some
5
trials.
6
The recent revelations of a number of
7
undisclosed gene therapy deaths nationwide shows the
8
problem with this approach.
9
reported death from gene therapy, Jesse Gelsinger, who
In fact, the first
10
died at the trial at the University of Pennsylvania,
11
revealed new safety concerns about the type of vector
12
being used in that trial.
13
Had the patient been an infant with a
14
devastating liver disease, OTC deficiency -- these
15
infants are typically born with a life expectancy of
16
often a few days, it is doubtful that any serious
17
safety problems of the sort that came out as a result
18
of the Gelsinger death would have been detectable.
19
In spite of all these objections, clinicians
20
often behave as if it were irrational not to enroll in
21
a trial, even a Phase I trial, if there are no other
22
plausible treatment options.
23
This is especially problematic for conditions
24
which are rare.
25
from a very small pool and they may convey a
Researchers need to enroll subjects
91
1
therapeutic goal and a false promise of hope when none
2
really exists.
3
is misleading for what are really gene transfer
4
experiments with no real hope of therapeutic benefit at
5
the present time.
6
In fact, even the name "gene therapy"
Now are there solutions to this dilemma?
7
There are several possibilities.
8
people to engage in -- sorry.
9
engage in risky behaviors all the time.
We let people
10
ski.
We let people
11
smoke.
12
principle, allow genuine volunteers, healthy
13
volunteers, to be the test pilots of medical research
14
as long as you really truly have informed consent and
15
no coercion, and this might possibly require little or
16
no monetary considerations.
17
will serve as a larger pool of research subjects than
18
is commonly believed.
One, we could allow
We allow people to
We let people become test pilots.
There is no reason why we could not, in
It may be that this
19
Second, we could consider changing the way we
20
do Phase I research when we are dealing with situations
21
with terminally ill patients and possibly combining
22
Phase I and II research at the same time so at the same
23
time we are starting to do safety studies on
24
individuals.
25
particular individuals to higher dosages so that we
We can also be going quickly for
92
1
might at least have a potential that there might be
2
some therapeutic benefit to them.
3
Above all, we need better informed subjects.
4
Informed consent must be a part of any system of
5
regulation but it must move beyond the current
6
understanding of the concept.
7
clinician to state that a trial is a safety study and
8
that there may be no benefit.
9
It is not enough for a
That is done now.
All the right sorts of things typically are
10
said and all the tapes we review of Phase I informed
11
consent processes, the right things are said, the right
12
things are in the informed consent form, but the
13
underlying assumption of the research and the subtle
14
cues involved in the interaction often nonetheless
15
manage to convey to patients that this is their best
16
bet and that this, in fact, is therapeutic and not --
17
then they are not simply subjects in experiment that
18
has very, very little chance of having any benefit to
19
them.
20
Better communication of benefits and risks and
21
burdens of different kinds of research must be conveyed
22
to patients and it must be done so through conveying
23
information to the public as a whole.
24
introduce the conditions necessary to create an
25
obligation on the part of the public to serve as
This helps
93
1
research subjects.
2
People who benefit from cooperative social
3
schemes are obligated to bear the risks and burdens of
4
participating in the activities that the cooperative
5
endeavors require.
6
about free riders who allow others to take on the risks
7
and burdens when they fully intend to take advantage of
8
these sacrifices.
9
There is something problematic
For example, the decision to use a tertiary
10
care teaching hospital can serve as quite a cooperative
11
social endeavor and that means anybody who chooses to
12
go to that kind of an institution agrees in principle
13
to serve as a subject for demonstration and teaching
14
purposes.
15
In terms of biomedical research, if someone
16
benefits from care in a research institution, that
17
would seem to suggest at least a prima facia obligation
18
to participate as a research subject, and again this
19
applies to patients who freely and voluntarily choose
20
to receive care in a research setting.
21
But this means that patients need to have a
22
much better understanding of the benefits and burdens
23
of being a patient in certain kinds of settings and
24
that any expectations need to be made clear at the
25
outset.
Moreover, curtailed power to choose the kind
94
1
of institutions patients want to utilize underscores
2
again the importance of the willingness of patients to
3
participate voluntarily in research.
4
The upshot of these arguments is the
5
importance of informed consent of subjects is still an
6
important aspect of protection from abuse although it
7
may need a revamping and I think the sort of pernicious
8
influence of language like autonomy has actually been
9
problematic in seeing that simply conveying the right
10
sorts of risks is sufficient when it clearly is enough,
11
and it may mean that we need a successor notion to the
12
concept of informed consent to do the work that
13
informed consent currently does.
14
Second, patients need a better understanding
15
of research prior to participation.
16
medical system is a cooperative activity.
Engaging in the
17
Third, current protections of relatively
18
healthy volunteers from engaging in risky research
19
needs to be reexamined.
20
think extreme protectionism could be problematic and
21
run counter to the sort of libertarian argument that is
22
really essential to being able to justify research on
23
human subjects.
24
25
This is the one area where I
Fourth, it may well be that Phase I research
on very ill terminal patients is problematic, and in
95
1
extreme cases, an argument could be made for combining
2
Phase I and Phase II research and really changing
3
fundamentally the way we do research on terminally ill
4
patients.
5
6
PROFESSOR CHARO:
Thank you.
Thank you very
much.
7
Questions by way of clarification?
8
No matter how fast you talked it is still
9
clear.
10
Okay.
11
DR. MESLIN:
12
PROFESSOR CHARO:
13
DR. BRITO:
It is 10:25.
I would like us --
Arturo?
Excuse me.
Yes, Arturo?
Dr. Vanderpool's paper makes
14
reference to Appendix A and B but only -- only A is out
15
there and B is nowhere to be found.
16
PROFESSOR CHARO:
17
It was -- the electronic
version had it and --
18
DR. BRITO:
19
PROFESSOR CHARO:
Yes.
I was not able to -I am happy to provide my
20
copy to you during the break.
21
photocopies for you of Appendix B.
22
Okay.
Okay.
And we will make
I would like to propose that we be back
23
here and start promptly at 10:40 and then we will shave
24
five minutes from discussion with the presenters and
25
five minutes from our own discussion to get back on
96
1
track for the international report at 12:30.
2
(Whereupon, at 10:26 a.m., a break was taken.)
3
PROFESSOR CHARO:
We are on the record again
4
and I do know that some people are still grabbing the
5
last cup of coffee or taking their seat.
6
As they do, I would like to just clarify what
7
we will be doing at this point is a kind of combination
8
of discussion as well as question and answer.
9
on the Commission should feel free to simply make
People
10
observations without specifically directing questions
11
to the speakers or to direct questions.
12
extent that a real dialogue develops among
13
Commissioners, I would like the speakers to feel free
14
to ask to be recognized so that they can intervene as
15
well.
16
17
And to the
First, let me ask if there is anybody who
would like to start the discussion from the Commission?
18
Bernie Lo?
19
DR. LO:
First, I wanted to thank our
20
panelists for their thoughtful papers and
21
presentations.
22
23
DR. MESLIN:
Bernie, could you go right into
the mike for the people listening?
24
DR. LO:
25
DR. MESLIN:
Yes.
Sorry about that.
97
1
DR. LO:
I wanted to ask a question which is
2
actually a little different than what you have talked
3
about.
It is almost the flip side.
4
It strikes me as I read your papers,
5
particularly Dr. Magnus' paper, that we do not have a
6
very clear explanation of the rationale for doing
7
research.
8
is something I guess you would not want to agree with.
9
But it seems to me one of the things that is
What is the moral justification?
Obligation
10
striking, for instance, when Jonathan talks of
11
protectionism, what we hear from some segments of
12
society is that they want more research and they think
13
being in a clinical trial is the fastest way to get
14
therapy for a condition for which effective therapy
15
does not now exist.
16
And at least among some people, some
17
clinicians, there is tremendous pressure to do more
18
research, and it is not viewed as something optional
19
that we can sort of forego if you have ethical scruples
20
about it.
21
So I would like you all -- each of you to
22
comment on that.
23
since it was more in your papers.
24
also tie specifically to the issue of HIV research in
25
developing countries?
Maybe particularly David and Jonathan
And could you
I think if there is a situation
98
1
that rises to moral urgency, it seems to me there you
2
have an epidemic which is really causing a lot more
3
than just quality of life.
4
But in Dr. Magnus' paper I was struck with,
5
you the discussion you had of -- I guess going back to
6
Hans Jonas saying that, you know, as long as you have
7
got more people being born than dying, you do not
8
really need research, the cycle can go on.
9
I mean, I am not sure that view would be
10
accepted today where quality of life as well as just
11
mere survival is at stake.
12
Also, does that hold for Sub-Sahara in Africa
13
and the AIDS epidemic where, at least in some
14
countries, the projections are the population is going
15
to take a tumble?
16
So, I think what is -- the other part of this
17
is what is, -- where can we find a coherent persuasive
18
articulation of the morality of not doing research when
19
-- and foregoing the goods that might occur?
20
DR. MAGNUS:
Okay.
Well, clearly I definitely
21
agree that research has -- is an important value in our
22
society.
23
survival underscores the fact that it is a contingent
24
value, that is it is something that is not necessary to
25
survival.
I think the fact that it is not necessary to
It is not something that, therefore, there
99
1
is sort of a very -- that in some ways it limits the
2
claim of an obligation on people to enroll as research
3
subjects.
4
so society has decided that this is something that is
5
important.
6
But nonetheless it is of societal value and
Now HIV research is interesting in lots of
7
ways.
8
That speaks to it as a -- perceived as a social good
9
and perceived that the research is important and that
The demand for more research is clearly there.
10
it is a social good.
11
have to be concerned when people want the research for
12
its therapeutic benefit.
13
therapeutic benefit and see a therapeutic benefit to
14
enrolling as a research subject.
15
But at the same time I think we
That is for its immediate
And that speaks, I think, to the failure that
16
the biomedical community has to communicate the nature
17
of Phase I research to the public.
18
Phase III research.
19
understanding of anybody who walks into a doctor's
20
office.
21
Phase I, Phase II,
These should be part of the common
This should be common language that everybody
22
understands and it is not.
23
so the trade off is between wanting to get to the final
24
value, and wanting to get the end therapies that
25
research requires, and the -- and making sure that, on
So I think that the -- and
100
1
the other hand, that patients understand what they are
2
doing and what the value is of engaging in the
3
research.
4
DR. LO:
5
One of the other reports we are working on is
Alta, if I could ask a follow-up.
6
an International Report, and a lot of the impetus for
7
that concerns the ethics of HIV research in developing
8
countries where these are not by and large Phase I
9
trials.
These are trials sort of -- trials of
10
interventions that are well tested and shown effective
11
in the developed countries, and are modifications of
12
dosage and administration and the like.
13
We are also considering proposals,
14
recommendations that would require researchers to give
15
-- help me with the phrase here -- effective and
16
established therapies to the control group so that, in
17
fact, in those countries, people would get a
18
considerable clinical benefit from enrolling in trials.
19
So these are not the Phase I studies you so nicely
20
wrote about, but we are trying to develop guidelines
21
that would cover both reports, in a lot of situations,
22
and if you could help us there it would be --
23
24
25
DR. MAGNUS:
Yes.
Actually I want to say two
things about that.
For HIV research, obviously one of the
101
1
exceptions, even Jonas in his original article, made an
2
exception for plagues.
3
something that is really a scourge, that is
4
sufficiently dangerous and lethal.
5
can actually make a case for a much, much stronger
6
obligation because it is necessary for survival and you
7
might be able to make a case that HIV represents such a
8
scourge in developing nations.
9
something that is of clear value.
10
But
Obviously, if you have got
In those times, you
Clearly that is
I want to say, when you are thinking
11
about
12
would not want to overstate the value of that for those
13
societies since, in developing nations, 80 percent of
14
deaths are a result of waterborne pathogens and
15
pollutants.
research in developing nations, I certainly
16
If you are thinking about bang for your buck,
17
there is a lot better ways to spend resources than on
18
research for improving the health of the populations
19
overall.
20
21
PROFESSOR CHARO:
did you want to add any comments?
22
23
DR. VANDERPOOL:
I would like to add a
comment.
24
25
Drs. Moreno and Vanderpool,
It seems -- Dr. Lo has asked an excellent
question.
What is the real rationale?
I think it is a
102
1
very complex and interesting cultural rationale.
2
Part of it is seen in the rhetoric we use.
3
Alot of the rhetoric is war related rhetoric.
4
exterminate hook worm disease.
5
cancer.
6
culture, then it has its own power.
7
Let's
Let's declare war on
And once that rationale gets interred into
And I want to relate that rationale -- that
8
rhetoric, to one concern I have for protection.
9
hear Dr. Moreno's paper, I hear that part of what he
As I
10
would mean by greater protection would be greater
11
surveillance.
12
But I think there are other avenues to greater
13
protection.
14
have a more careful scrutiny of the research
15
initiatives that go forward.
16
Richard Nixon declared war on cancer in 1971, we have
17
had a war on cancer and we have had the SWOG group meet
18
every few months in the Southwest part of the United
19
States, and they approve hundreds of research protocols
20
on cancer patients.
21
And one avenue to greater protection is to
I mean, when -- after
The thing about it is these research protocols
22
are incremental, at best, incremental changes.
23
change a little cisplatinum there, a little bit of
24
something else here, and let's hope to get a slightly
25
better percentage.
And so you have to recruit
Let's
103
1
thousands and thousands of cancer patients into these
2
protocols for, at best, incremental changes, that over
3
time have not made a heck of a lot of difference.
4
So I think protectionism needs to consider
5
what research initiatives will really be effective and
6
not keep enrolling and enrolling patients into
7
initiatives that are surrounded with war time rhetoric
8
that are not going very far.
9
analysis.
10
11
So that is a cultural
I could have some other points to add to that
but I think I have made one important point.
12
DR. MORENO:
I think that is well taken.
13
Although I am not sure -- I think Harold and I would
14
have to talk about the boundary between scrutiny and
15
surveillance.
16
initiatives for research programs would count as a form
17
of surveillance of what physician-investigators were
18
actually intending to do but that is a semantic
19
question and it does not need to concern us.
20
It seems to me that deciding on national
But back to Bernie's really interesting
21
question.
22
religious or philosophical tradition that does not
23
encourage medical experimentation for the greater good.
24
With the exception perhaps of a faith tradition, like
25
Christian Science, that takes itself out of the secular
It is very hard to find, I think, a
104
1
medical tradition entirely, it is really hard for me to
2
think of one.
3
the point of view of wisdom traditions -- kind of at a
4
loss to know where to look for a compelling argument in
5
favor of the morality of fully foregoing research.
6
And, therefore, I am -- at least from
Even Jonas and Ramsey were not in favor of
7
completely foregoing research.
8
with consent.
9
time, was a radical position and now would be
They wanted to do it
And Ramsey, himself, took what, at the
10
considered a very moderate position on kids in
11
research.
12
13
14
So I think it is very hard to find a
rationale.
Can I say something, though, about -- if I
15
may, Alta, about the liberty argument?
16
raised a very interesting point that you could argue
17
that protectionism -- stronger protectionism-should not
18
apply to healthy volunteers for the reason that people
19
ought to be able to express their altruism or get
20
involved in science, whatever it is.
21
I think David
But it is interesting, that liberty argument
22
historically has applied to patient subjects, not to
23
normal subjects.
24
that patients -- and this goes back to the access issue
25
as well -- that patients ought to have the right to
And the argument can go both ways,
105
1
decide whether they want to take the chance and get
2
into research.
3
As a matter of fact, the earliest arguments in
4
favor of strong protectionism in the 19th century came
5
with respect to normal subjects in vaccine studies.
6
And by the way, vaccine studies are a context in which
7
normal volunteers can potentially benefit. And so there
8
are significant questions of compensation in those
9
studies.
Historically, there have been.
10
PROFESSOR CHARO:
11
Steve Holtzman?
12
MR. HOLTZMAN:
13
This was going to be a question directed to
Thank you.
Thanks to all of you.
14
Dr. Magnus and Dr. Vanderpool's last remarks about the
15
cancer trials that may play into it, and it has to do
16
again coming to this notion of a therapeutic
17
misconception.
18
And what I am having trouble squaring is the
19
descriptions I hear from philosophers talking about
20
this, which is the phenomenology of my experience when
21
we are doing Phase I trials.
22
And what I mean by that is, when we are going
23
into a Phase I with healthy normal volunteers with a
24
5LO inhibitor for potential use in asthma, and all we
25
really care about is looking at PK and PD, it is very
106
1
2
clear to the subjects what is going on there.
On the other hand, when we are doing a Phase
3
I, with deathly ill cancer patients with a proteosome
4
inhibitor; yes, we are looking for, the dose limiting
5
toxicities but those people are there, also quite
6
rationally, hoping against all odds that maybe their
7
metastases will shrink and a couple of times it does.
8
9
10
All right.
misconception?
So why is that a therapeutic
Why are we being dishonest?
All right.
We are not and I just -- the phenomenology that you
11
guys sometimes describe here, you are talking about
12
these "trials," thousands of trials to just adjust the
13
cisplatinum, and it is not. These people are dying.
14
All right.
15
modifications.
16
You have got to go in and you are making
It is not a lot different than the practice of
17
medicine where you are trying to make the adjustments
18
so I am just having trouble because I live this stuff.
19
DR. MAGNUS:
That seems to me to be exactly
20
what the problem is, though.
21
I trials, especially the early -- I mean, it is a
22
continuum.
23
I trial where you are starting off at 1/1,000th of the
24
dose necessary to have any effect according to your
25
animal studies, there is -- I mean, there is no chance
If you think about Phase
If you think about the beginning of a Phase
107
1
that this is going to help these patients and it also
2
depends on the therapy.
3
Think about all the gene therapy trials on
4
cancer.
5
doing a Phase I trial on HSTKGCV system, there is not
6
going to be any therapeutic value to that.
7
you that right now.
8
By now it is pretty clear, that if you are
Somebody might get better.
I can tell
You might get a
9
little too much shrinkage.
They might get that if they
10
take some laetrile, right.
We do not apply -- I think
11
we do not apply the same standards of evidence when we
12
think about the potential value of Phase I research
13
that we have applied to, say, unproven, complimentary
14
medical systems.
15
If we had the same attitude and the same
16
critical scrutiny of value -- of therapeutic value of
17
Phase I research that we do to those other things, we
18
would see that, really, it is not therapeutic and we
19
need to draw a sharp line there.
20
If the patients are there because the --
21
MR. HOLTZMAN:
But my objection is, you keep
22
saying it is a Phase I research. Phase I research
23
covers an enormous gambit.
24
DR. MAGNUS:
25
MR. HOLTZMAN:
That is true.
All right.
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1
DR. MAGNUS:
2
MR. HOLTZMAN:
3
Okay.
Sure, you are absolutely right.
I mean, we walk into that knowing, right, that most
4
drugs fail.
5
a lower than expected dose, it is not working.
6
building up to your maximum tolerated dose.
7
one species of the genus (sic), is Phase I research.
All right.
8
DR. MAGNUS:
9
MR. HOLTZMAN:
And when you are starting with
You are
That is
That is right.
It is another when I am going
10
in at full bore, okay, to someone who is going to die
11
in two weeks.
12
their metastases.
13
we can be with appropriate disclosure, not misleading
14
them in saying, "Look, most drugs fail."
15
All right.
And, in fact, we revert
That person can very rationally, and
DR. MAGNUS:
Okay.
Okay.
Our experience -- again,
16
I think it is a continuum, but I also think looking at
17
the tapes and the conversations of the Phase I trials,
18
at the qualitative research that has been done, the
19
right sorts of things have been said. You are right.
20
But the way it is presented, and other sorts of things
21
that are said convey, you know, I think a far greater
22
sense of optimism and of therapeutic value than really
23
exists.
24
25
The probability even for late Phase I research
on cancer -- for, you know, late -- depending on how
109
1
far the metastases is -- is extremely, extremely low
2
that this is really going to help them.
3
And so if they really think this is their best
4
chance, and that they are in it primarily for a
5
therapeutic value, it seems to me that they are in it
6
for the wrong reasons, and that is misleading them.
7
These are very vulnerable subjects, who have been taken
8
advantage of, and especially when you add all the
9
incentives on the part of the researchers to do the
10
research, both economic incentives, publishing,
11
promotion, all those sorts of things, it seems to me
12
that has created a system where we feel very
13
comfortable allowing patients to feel that there is a
14
therapeutic value when there really is very, very
15
little or none.
16
PROFESSOR CHARO:
17
MR. HOLTZMAN:
18
PROFESSOR CHARO:
19
20
21
Eric Cassell?
Can I just -Very, very briefly.
Only
because with three people on the panel, it is tough.
MR. HOLTZMAN:
Yes.
Go ahead.
Never mind.
It is okay.
22
PROFESSOR CHARO:
23
DR. VANDERPOOL:
Are you sure?
I tend to agree with Mr.
24
Holtzman, though, and that is that I think for some
25
patients in Phase I cancer trials, this is their hope.
110
1
It may be thin.
And then the challenge is to give
2
fully informed consent about the hope, and for the
3
physician to recognize that at this point, you are a
4
researcher and you would be very wary about
5
recommending that, yes, if I were in your situation, I
6
would go on it because that is when the consent form
7
may as well be tossed out, because that physician trust
8
is communicated as researcher trust, and that is
9
difficult to do.
But for some patients it is the
10
chance they have and they still want to go for it
11
rather than go fishing.
12
DR. MORENO:
Can I just add I think that the
13
question of therapeutic misconception needs to be
14
treated as a psychological question and I do not know,
15
Diane, if any psychologists have taken up this question
16
but you could, in theory, if it were ethical, and you
17
could get it passed by the IRB, manipulate the
18
variables in such a way that you could find out what it
19
was about the situation that led to people, if they do,
20
led to people being misled or allowing themselves to be
21
misled.
22
For example, what if you had brought somebody
23
into an office building, being met by somebody who did
24
not have the M.D. diploma on the wall and was not
25
wearing a lab coat, rather than a hospital and the lab
111
1
coat and all the paraphernalia and so forth.
2
that make a difference in the way people feel about the
3
situation, and would they be able to filter the
4
information, without the impress of the great medical
5
institution into which they have just been taken up on
6
the elevator and passed all the offices with all the
7
impressive looking scientists and laboratories?
8
Would
So it seems to me that there is -- this is
9
partly an empirical question and that we can identify
10
whether the elements of -- if there is already such a
11
thing as therapeutic misconception, which I take there
12
to be, if those elements can be modified or managed.
13
PROFESSOR CHARO:
14
DR. CASSELL:
15
Eric Cassell?
It is tempting to jump into that
but I do not want to do that.
16
Jonathan, you make a point about the changing
17
intensity of -- I will call it -- investigator virtue,
18
over the period of time and how, as we go to strong
19
protectionism, we may act to diminish further that
20
virtue.
21
virtue has, in fact, diminished -- appears to have
22
diminished?
23
know.
24
so forth and so on, on up the -- but nobody has, so
25
far, suggested that if we decrease the protection that
But don't you really understand that this
Also, it is an empirical question, you
So we are driven to increase the protection and
112
1
2
it is going to increase the virtue, have they?
DR. MORENO:
Well, we might this morning.
3
Look, I do not think that there is a direct -- an
4
inverse proportion between the virtue of people who in
5
a certain era happen to be in the medical profession or
6
in medical science, medical research, and the amount of
7
regulation that society imposes.
8
9
In other words -- and I certainly do not have
any reason to think that my colleagues today in
10
Charlottesville or anywhere else in the country, at
11
least, are any less virtuous than their predecessors
12
100 years ago or 2,000 years ago.
13
So I do not think that any alleged --
14
(Phone tone.)
15
DR. MORENO:
16
17
18
I am busy now.
I am
talking about the -DR. CASSELL:
It is the wrong answer.
That is
what that is.
19
(Laughter.)
20
DR. MORENO:
21
I am sorry.
It is Henry Beecher calling to
support me.
22
(Laughter.)
23
DR. MORENO:
24
DR. CASSELL:
25
DR. MORENO:
From the great beyond.
You did not know him very well.
So I do not think that the
113
1
decrement -- any alleged decrement, or speculative
2
decrement of virtue among physicians, is the reason we
3
find ourselves where we are in our regulatory system.
4
I think it is because of alot of social, economic and
5
political developments, and to some extent
6
philosophical evolution.
7
physician-investigators are necessarily less virtuous
8
than they were 50 or 2,000 years ago.
9
DR. CASSELL:
Not because doctors or
Just one quick follow-up.
You
10
said you did not know of any faith tradition where --
11
which did not support research.
12
this scholastic era when all knowledge was really
13
knowledge of the evidence of God, investigation into
14
the natural world just was not part of it and did not
15
come along until Roger Bakken and that is already by
16
the 13th century.
17
18
Well, actually during
But since that time, it is not about research.
It is about knowledge.
It is a position about
19
knowledge and secular knowledge versus purely
20
theological knowledge.
21
DR. MORENO:
Well, they still supported
22
observational research à la Aristotle.
23
still supported classification.
24
DR. CASSELL:
25
DR. MORENO:
I mean, they
Oh, no.
They preserved.
They preserved
114
1
the science classification.
2
3
DR. CASSELL:
They preserved that but they did
not do their own.
4
DR. MORENO:
5
DR. VANDERPOOL:
6
PROFESSOR CHARO:
Yes, Dr. Vanderpool?
7
DR. VANDERPOOL:
-- a footnote to this?
8
The Jewish tradition in the wisdom of Bensark,
9
Well, they did some.
Could I add --
(sic) 200 years before the rise of Christianity,
10
blessed the physician as an instrument of God.
11
Christianity comes in as a healing cult and beats the
12
Clupeine (phonetic) cult, and Muslims developed
13
institutions and so on.
14
So I think Dr. Moreno's point is secure that
15
religious traditions really are pro-healing for a whole
16
host of different reasons, but part of it is the sake
17
of special -- specialty needy people and one is giving
18
a particular kind of blessed concern when one cares for
19
the sick.
20
21
So I very, very much agree with his point on
that score.
22
PROFESSOR CHARO:
23
DR. CASSELL:
Alex Capron?
Except the Christian tradition
24
was anti-medicine until quite late into the era and
25
religion -- and priests were conjoined not to
115
1
participate in medicine.
2
DR. VANDERPOOL:
3
DR. CASSELL:
4
DR. VANDERPOOL:
Right.
Healing, yes.
But medicine, no.
Christian happens just to
5
capture it by superstition about the Fourth and Fifth
6
Century and beyond.
7
important question about physician's virtues, and I do
8
not think we just should let that go.
9
our training programs -- another way to protect is to
But I think you raise a really
I mean, I think
10
protect at a national level, in terms of what research
11
initiatives can go on.
12
Another way to protect is to protect through
13
training programs, and there -- in my own university,
14
we have had very good responses to physicians and
15
fellows, as they explore research ethics and see who
16
they are and what they can do in this arena.
17
So I think we -- too long we have just kind of
18
let it slide instead of seeing this as a special
19
calling for physicians to exercise their minds and
20
their hearts at the same time.
21
PROFESSOR CHARO:
22
Alex Capron?
23
PROFESSOR CAPON:
Thank you.
I am going to forebear from
24
engaging in this theological discussion.
25
take you back to your basic framework, Jonathan, first
I want to
116
1
as a question.
2
Yesterday we heard from Jeff Kahn, reminding
3
us that his view of the post-Belmont era is one of the
4
movement from the protection to inclusion, and a view
5
of -- emphasis of the benefits of research, and you
6
have in your own paper that quote from even research is
7
treatment or some such phrase from ACT-UP.
8
9
And it seems to me that what we see in all of
this, is a question of whether we favor type one or
10
type two errors.
11
of an unwilling or unwitting person as a subject in
12
research, without full information and voluntary
13
consent, and a type two error is the prevention of a
14
research project in which there are willing volunteers
15
but it is judged to be unacceptable.
16
If a type one error is the inclusion
In the early days of the space program serious
17
thought, as you know, was given to sending up a manned
18
vehicle, that would not be capable of returning, and
19
that would create, in effect, glorious heroes of those
20
who undertook that trip to the moon and there would be
21
no lack of volunteers among the astronaut corps for
22
that.
23
And yet NASA concluded that it could not
24
do that.
25
thought that, in the end, the public would not be fully
Partly it was public relations that they
117
1
supporting.
2
it was -- that was a type two error that they did not
3
want to commit.
4
But they also concluded, I believe, that
And it seems to me that you are -- you are
5
suggesting that we are in an era of moving more towards
6
trying to prevent type one errors if I understand you
7
correctly.
8
-- if you are looking at a historical sweep of things,
9
that is the direction?
10
Is that right?
DR. MORENO:
I mean, that is the way you
I think that is right, yes, in
11
the long run, and I would say that the emergence of
12
inclusionary efforts -- what I call sessionism --
13
PROFESSOR CAPON:
14
DR. MORENO:
Yes.
-- not in the therapeutic sense
15
but in the scientific sense, is to say justified, by
16
the need to know more about how drugs and devices
17
affect populations who have not historically been
18
included in systematic research.
19
compatible with protectionism as I understand it.
20
PROFESSOR CAPON:
That is completely
I guess this is simply a
21
question of -- for which no one has any answer but it
22
is, in a way, exploring what you raised with one of the
23
earlier questions.
24
that if we move in that direction we would 30 years
25
from now bemoan, as you put it, the lack of virtue.
And that is why we would expect
118
1
The late Grant Gilmore famously remarked about
2
in heaven there would be no laws and the lion would lie
3
down with the lamb and in hell all activities would be
4
regulated.
5
(Laugher.)
6
PROFESSOR CAPON:
But what he -- it is not
7
clear from that kind of a remark whether it is -- that
8
heaven is achieved by the absence of laws, or rather in
9
a situation in which you have only virtuous persons,
10
who are fully angelic, that you would have no need for
11
that, that the lion in heaven would not eat the lamb.
12
I do not see the connection running the other
13
way.
14
we have laws against certain activities, in fact, makes
15
people less virtuous because they decide to be law
16
abiding, that they -- I mean, it is sort of a view that
17
all they are doing is obeying the law and they have no
18
virtue, and they become unregulated were it not for the
19
fear of the law.
20
I mean it does not seem to me that the fact that
I guess that is your -- but I want to
21
understand is, that your suggestion that that is the
22
direction in which things inevitably move, as we try to
23
be more protective?
24
25
DR. MORENO:
Well, not to be outdone in
reference to the great sages, that great protectionist
119
1
philosopher whose work also emerged in the 1960's,
2
Woody Allen, observed that the lion shall lie down with
3
the lamb but the lamb will not get much sleep.
4
(Laughter.)
5
DR. MORENO:
6
your interesting question.
7
(Laughter.)
8
DR. MORENO:
9
Which is absolutely irrelevant to
Look, I think the question which
Harold indirectly related also in his remark about
10
education, can virtue be taught, or are some simply
11
born with it, or do they acquire it in some mysterious
12
way, perhaps by inspiration from God.
13
that I am prepared to answer this morning, nor do I
14
know, therefore, under what circumstances there would
15
be a decrement of virtue in an individual or group.
16
It is not one
It is entirely possible that, what you say is
17
correct, and that it would not make any difference if
18
say, people on hard money at an academic medical center
19
who were not involved with the research, had the job of
20
recruiting the subjects and doing the consents and
21
doing the reviews and observing all the research
22
maneuvers and procedures and functioning like a DSMV
23
and deciding when they should be in or out and
24
basically stay on the back of the investigator
25
literally continuously.
120
1
That may make absolutely no difference with
2
respect to the way that the investigator sees his or
3
her moral relationship to the patients or subjects.
4
is entirely possible.
5
again.
6
It
It is an empirical question
But I will bet you that if we move to a system
7
like that, 30 years from now, somebody like Eric
8
Cassell will be sitting at a table or perhaps simply
9
communicating through the ozone through our brain top -
10
- brain inserted computers to each other at the next
11
Commission that something bad happened recently.
12
the reason is that we moved to this system where these
13
guys are constantly being tailed by people, who have
14
taken the moral responsibility for their relationship
15
with their patients or subjects from their shoulders.
16
Now will that person be right or not?
And
I do
17
not know and we are playing what Isaac Asimov called
18
"The Future History," a kind of parlor game.
19
20
21
22
Again, I think it is a psychological question.
I am not really prepared to do anything but speculate
about it.
DR. CASSELL:
But you were not arguing against
23
the education of investigators like Harold suggests?
24
You are not suggesting that that might diminish their
25
knowledge of ethics and so forth, are you?
121
1
DR. MORENO:
Well, I think it
certainly
2
enhances and contributes to their knowledge of the
3
history of research ethics, of philosophical issues, of
4
the rules and so forth.
5
How it actually influences their conduct, I do
6
not think anybody knows.
7
the outcomes of ethics training in the professions.
8
9
10
11
PROFESSOR CAPON:
It is very hard to measure
It has not been done much,
right?
DR. MORENO:
It has not been done and I am not
sure we are very good at knowing how to do it.
12
PROFESSOR CHARO:
13
DR. MESLIN:
14
PROFESSOR CHARO:
Arturo?
Harold?
15
wanted to make a comment?
16
DR. VANDERPOOL:
Oh, I am sorry, Harold.
Yes.
Just one comment.
You
I
17
think that I am very wary, though a historian, of ever
18
predicting what the future will be.
19
basically a set of surprises.
20
I think it is
But I think one can construct just the
21
opposite argument historically built on Eric Cassell's
22
interesting survey of the degree to which clinicians
23
have been regimented through managed care.
24
25
We could face a backlash against, that in the
coming years, and the orientation could be, please get
122
1
off of our backs.
2
deserve your getting off of our backs but get off of
3
our backs.
4
We will do what is necessary to
And so I would hate for researchers to be, --
5
first of all, you regimate medicine through managed
6
care and then you regiment research medicine through a
7
whole set of surveillance mechanisms.
8
tread carefully on that if there are other ways to do
9
it.
10
PROFESSOR CHARO:
11
DR. BRITO:
I mean, I would
Arturo?
This has to do with -- actually it
12
kind of comes full circle here because this has to do
13
with Steven's concerns earlier in a conversation, and
14
something you mentioned, Jonathan --
15
you -- during your talk about the therapeutic
16
misconception from the investigator side.
17
Kahn made mention of that yesterday.
18
I think it was
And Jeffrey
As far as I am aware, there is -- there are no
19
psychological studies of physicians, who are also
20
investigators at some point in time, of how they
21
contribute to that therapeutic misconception, and I
22
think it is an interesting point and something that
23
needs to be looked at.
24
just something that needs to be looked at and some
25
education for the physicians themselves in that area.
Not necessarily regulated but
123
1
2
I, myself, have found myself in that position
at times.
3
I wanted to go back to the process, Dr.
4
Vanderpool, about the -- that you have talked about and
5
written about the process of informed consent, and that
6
is something that I have -- I have thought about for
7
quite a bit and read a bit that Appelbaum and others
8
have written about that, and more from a longitudinal
9
point of view.
10
How does one go about assuring, in a
11
regulatory fashion, that that process is adhered to
12
when we know that, at the onset people get a document,
13
a written document, and it is very hard to absorb all
14
that information and understand it regardless of your
15
educational level or your point of vulnerability?
16
How does one regulate, or not regulate, but
17
how does one make suggestions for regulations that do
18
that?
19
it is in there.
20
period of time, you know?
21
in that?
22
I just got the appendix now but I do not think
Any suggestions of over a longer
DR. VANDERPOOL:
Do you have any suggestions
Well, my belief is that, if
23
one revises the Federal Regulations where the basic
24
requirements of consent are no longer informational
25
items on a consent form, that you already have gotten
124
1
somewhere.
2
If what you look at, day after day, is the
3
three items -- basic elements of informed consent, are
4
voluntarism, comprehension and information -- the IRB
5
is going to spend some time on voluntarism,
6
comprehension and information.
7
process of consent.
And that to me is the
8
Now whether that will ever get back to the
9
research subjects, it is still there, day after day.
10
It is what they are supposed to be doing as they review
11
protocols and as they structure protocols.
12
So what I am saying is, try to insert
13
institutionally the kind of conceptual apparatus and
14
the language that goes with it that make it a process.
15
See right now we preach about Belmont, and we
16
preach about process, but when you look at the Federal
17
Regulations, the Federal Regulations have a primarily
18
rule orientation towards consent forms.
19
most IRBs, the ones I have concern about, have gotten
20
the message.
21
make sure they say the right things, and you spend a
22
lot of your time just making sure that consent form is
23
right.
24
25
And, by golly,
Let's refine the consent forms, let's
And so it seems to me that just very basic
things can restructure the way you look at consent and
125
1
if the three elements, as I say, are voluntarism,
2
comprehension and understanding, and you are pretty
3
clear about what this is, then you are going to be
4
asking in your committee meetings, do we think these
5
people are really in a situation to volunteer.
6
Do we think they comprehend what is going on?
7
Do you think there is a test we need to have the
8
researcher do, in order to see if comprehension is
9
occurring?
10
And then what is on the consent form in terms
11
of comprehension, and do we give them time and what all
12
to do that comprehension?
13
That is my point.
I am not for preaching
14
anymore.
15
regulations that make it into a process ipso facto as
16
it is being analyzed.
I am for plowing something into the
17
PROFESSOR CHARO:
18
DR. MESLIN:
19
on something Jonathan had said.
20
chance to either confirm that this is what he meant,
21
because he was referring to NBAC, and then maybe ask a
22
question of the panel.
23
Eric Meslin?
First, just a point of commentary
I want to give him a
Jonathan, in one of your overheads you
24
included NBAC's Capacity Report as part of the
25
historical legacy of some of these issues.
Because
126
1
there has been much discussion about the impact of that
2
report, as being one that is proposing a significant
3
increase in the types of protections for a particular
4
population, I would be interested to know whether you
5
were implying that that is the exclusive legacy of
6
NBAC's four reports, or you are only including the
7
Capacity Report as an example of that version of
8
protectionism.
9
in the literature to which letters have been written in
10
response, that NBAC's HBM report goes the other way and
11
offers too little protection in the way of consent and
12
such.
13
Because clearly some have argued, even
So I am just giving you an opportunity to
14
either clarify that point because then it will allow me
15
to ask David another question.
16
DR. MORENO:
It was only with respect to that
17
report and, indeed, only with respect, as I say in the
18
paper, to the recommendation concerning independent
19
capacity assessment for nonbeneficial higher risk
20
studies.
21
DR. MESLIN:
So the good news is for
22
Commissioners, as we are watching how our reports are
23
being interpreted out there, I do not -- I would not
24
want the public or Commissioners to assume that there
25
is a linear progression that NBAC simply is writing
127
1
reports about protection.
2
DR. MORENO:
Not yet anyway.
3
DR. MESLIN:
Not yet.
4
PROFESSOR CAPON:
5
DR. MESLIN:
6
(Laughter.)
7
DR. MESLIN:
We are all over the map.
Yes.
So here is -- my question really
8
is focused to David but could go to all three.
9
is if you could imagine -- although it is not in your
And it
10
paper, but could you imagine what the strongest
11
possible case would be, philosophically strongest case
12
would be, for inclusion of individuals in research?
13
What might that look like?
I mean, it follows
14
up on something Bernie asked really at the outset, and
15
you touch on it in various places, and I am not asking
16
for a dissertation.
17
11:00 and we have other questions to go but --
18
I mean, it is 20 minutes after
DR. MAGNUS:
Well, I think it is a combination
19
of the perceived good of the research combined with the
20
libertarian argument.
21
engage in risky behaviors for bad reasons, given that
22
this is a socially desirable end, allowing people to
23
genuinely, in an informed voluntary manner, engage in
24
research.
25
-- what there could be to stand in the way of accepting
I mean, we allow people to
That seems to me to be difficult to see why
128
1
that.
2
PROFESSOR CHARO:
3
DR. SPEERS:
4
Others?
Marjorie?
I have a question that I would
like the three of you to address.
5
When we undertook this project, this oversight
6
project, we began by asking some very basic questions.
7
One of those questions was, what is the purpose of a
8
federal oversight system, and the purpose of federal
9
regulation.
10
As a result of asking that question among
11
ourselves, we asked the three of you to write your
12
papers on the various positions.
13
Having heard your papers today and thinking
14
about this topic, and knowing now that the Commission
15
needs to move forward and make recommendations, it
16
makes -- it causes me to raise the question of what is
17
the purpose, what ought the purpose of a federal
18
oversight system should be.
19
purpose?
20
enhance research, or promote research to protect
21
individuals who participate in research, and to
22
promulgate ethical principles, or try to make us more
23
ethical perhaps than in our research endeavors.
And can it be a multiple
Can it have multiple purposes?
That is, to
24
My question is, can we -- could we have a
25
system, an oversight system and regulation that can
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1
meet those three purposes?
2
DR. MORENO:
3
(Laughter.)
4
DR. VANDERPOOL:
Yes.
Yes.
I think we can and I
5
think Belmont does a pretty good job of it.
6
a perfect job but a pretty good job of it.
7
does not promulgate ethical principles just to be
8
promulgating ethical principles.
9
ethics of research in order to protect subjects and
It is not
Belmont
Belmont is doing the
10
protect research.
11
for.
12
purposes, and it seems to me those two purposes say
13
that we need to both promote research, protect research
14
and we need to protect human subjects.
15
I think that is what it is there
It just uses ethics as a tool.
For those two
So it is not an easy challenge that you all
16
have to find that balance, an effective balance.
17
would like to see the protections increased but the
18
research enterprise preserved.
19
a lot of research that probably is superfluous, in
20
terms of dangers, and perhaps these people have a loss
21
of confidentiality and so on.
22
I
But I do think there is
So I think the research purpose -- the
23
research enterprise will need to be modified at a
24
certain point and expanded at other points but the
25
research enterprise itself will continue but I think we
130
1
need them both.
2
think we should see ethics in the spirit of Chalmers'
3
last comments.
4
superfluous to both these purposes, the promotion of
5
research and the protection of human subjects.
I think we need them both and I do not
We should see ethics as something
6
PROFESSOR CHARO:
7
DR. MORENO:
Jonathan Moreno?
I will expand on that at the risk
8
of sounding facetious.
9
theme that you identify, that unites those elements as
I think it is in the underlying
10
the public's trust in the research enterprise, and
11
since the New Deal anyway, federal regulation has been
12
regarded by the general public as a way of ensuring
13
that, more or less, public institutions are operating
14
according to some standards of integrity.
15
Those regulations were not often -- in fact,
16
were not usually the result of some incident that was
17
directly relevant to them.
18
new authority for the FDA that it had before
19
thalidomide.
20
reason that prison research has been so contained.
21
there were political and sociological factors that
22
seemed to impel the need for regulation.
Thalidomide gave rise to
Prison research scandals were not the
But
23
So it seems to me that that is the underlying
24
motivation, and now the question is, in 2000, what kind
25
of system will insure the public's trust.
That is what
131
1
is really going to drive, I think, what comes out of
2
this era more than any specific incident.
3
way that that incident is processed in the public mind,
4
and the response that government regards as necessary
5
to allay public anxiety.
6
drive this.
7
It is the
That is what is going to
PROFESSOR CHARO:
We have approximately
8
between 10 and 15 minutes left for discussion, and the
9
people I have left on my list are myself, David Cox,
10
Bill Oldaker, Alex Capron.
11
would like to get on the list, the infamous list?
12
13
DR. VANDERPOOL:
Are there other people who
Could I make one quick
footnote to Jonathan's comment about the public trust?
14
PROFESSOR CHARO:
15
DR. VANDERPOOL:
Sure.
To me the looming problem
16
will be the degree to which industry becomes involved,
17
and co-opts many things in the research enterprise,
18
including the privacy of research data.
19
just a huge problem and I think we are looking at new
20
anti-industry -- and we may end up returning to the
21
'60s when people said, you know, "Power to the people."
22
And that is
But, I mean, we see already against the
23
Organization of American States and the World Trade
24
Organizations, we see the anti-industry approach.
25
Well, industry is getting the reins of research in an
132
1
unprecedented way, and one of your real challenges is
2
to say, how do you keep the public's trust in research
3
when industry is doing more and more of it and keeping
4
the results to themselves?
5
PROFESSOR CHARO:
So it would be fair to say
6
that there is another goal here, which is to make sure
7
that the lamb can sleep regardless of whether it would
8
get eaten?
9
DR. MAGNUS:
Can I --
10
PROFESSOR CHARO:
11
DR. VANDERPOOL:
12
Yes, Dr. Magnus?
It is your metaphor and I
love it.
13
DR. MAGNUS:
Two things.
One, again I just
14
want to reiterate the point that one of the problems
15
that could erode public trust, is the fact that the
16
public does not understand the nature of research.
17
if they do not understand the nature of the research,
18
they do not understand why people are hurt or die.
19
And
I mean, if the public thinks that most --
20
initial research where most of the most important facts
21
are able to be done for safety before you ever get to
22
human subjects, that is going to be a real problem in
23
terms of public relations, if you will, when you have -
24
- when people are hurt during the course of Phase I
25
research.
133
1
The second thing I want to say, though, is
2
about the general issue about regulation and a sort of
3
caveat about the ability to be able to construct
4
regulations that are going to be able to achieve all of
5
the goals that you laid out.
6
It seems to me it is sort of history and some
7
of the history that Jonathan was talking about earlier.
8
The regulations that we have got now are a legacy of a
9
historical context that was developed in response to
10
certain kinds of scandals and they do a pretty good job
11
of stopping those sorts of things from happening again.
12
We have got a system really that does a great
13
job of making sure Tuskegee does not happen again.
14
it is not clear that the concepts of that, and the
15
basic framework that we utilize, it seems to me, is
16
going to be adequate for moving forward.
17
really hard, once you have got a framework in place, to
18
do more than just tinker with what you have already
19
got.
20
But
But it is
A sort of analogy would be the typewriter.
21
The QWERTY system, the standard typewriter, was
22
designed to be not an optimal keyboard, but a keyboard
23
that was optimal in the early 20th Century when, if you
24
typed too fast, the keys got stuck.
25
something that would go fairly fast but not too fast.
So they designed
134
1
Well, we have been stuck with it ever since,
2
even though we now could -- now we do not have to have
3
that problem and we could have much, much more optimal
4
keyboards.
5
So I worry that we are just going to be
6
tinkering with something that is really designed with
7
problems that are outdated.
8
PROFESSOR CHARO:
9
DR. COX:
David Cox?
First of all, I found this panel
10
incredibly instructive and to the point, so I would
11
like to thank all three of you.
12
focus me.
13
It has really helped
Specifically on this point that, ironically,
14
ethics are not part of the regs.
15
in my experience as a biomedical researcher that, when
16
I speak with most of my colleagues that is, the
17
fundamental problem, is that they do not actually see
18
that the regs have anything to do with ethics.
19
that they do not understand how ethics is involved with
20
research.
21
I will just reflect
And
So all three of you have said that and I would
22
just like to put on the record that that is a
23
fundamental thing that we have to deal with or else
24
that we are not going to either advance research or
25
protect human subjects.
135
1
Now my question, though, is to David because
2
it was the most troubling thing to me, and it squares
3
with the reality that I have experienced.
4
You can say the right things and you have all
5
the things in the informed consent, but it is the wink
6
and the nod that basically causes the problem.
7
If
we simply focus on saying the right
8
things, and even if we focus on the process, it will
9
not deal with the wink and the nod issue.
10
So how can we even begin to deal with that at
11
a practical level?
12
an implementation level, because this is the part that
13
worries me the most.
14
Not on a philosophical level but at
DR. MAGNUS:
Well, there are obviously several
15
different things that can be done ranging from not
16
doing certain kinds of research, and the way that we do
17
on those subjects who are vulnerable to also
18
guaranteeing more quality assurance for those patients
19
ranging from making sure that it is not the
20
investigators doing the informed consent process.
21
Some institutions, when they are doing
22
research on HIV patients, to avoid these kinds of
23
problems, they have people who are not the clinicians
24
themselves doing the informed consent process to make
25
sure that they do not have those kinds of problems.
136
1
You could also tape the informed consent
2
process.
3
colleagues at Penn were taping informed consent
4
processes, and doing analysis, and doing coding schemes
5
of them, which were not very hard to do, to see the
6
sorts of things that were said both -- and you could
7
detect the wink and the nod in the course of taping
8
those things.
9
I mean, it was really illuminating when my
I mean, if we did something like that where it
10
was commonly -- where these were commonly taped and
11
maybe randomly just examined -- not necessarily for an
12
oversight or policing purposes but just from an
13
informational point of view, where somebody could say,
14
look, here is where you might have misconveyed
15
therapeutic value of this to the patient right here,
16
that might be helpful.
17
DR. COX:
So just to reflect back, because I
18
think Steve Holtzman has really, you know, said in a
19
very nice way numerous times, he reminds us of the
20
richness and the texture -- textural complexity of what
21
we are doing.
22
So what you are saying is that we have to also
23
keep that in mind, and so have a textured level of
24
regulation.
25
is the vulnerability of the population.
But your primary basis for the texturing
137
1
DR. MAGNUS:
Right.
2
DR. MORENO:
Can I also jump into this, David,
3
just to respond to your observation, which I think is
4
right, as Harold points out that our physician -- our
5
investigator colleagues do not perceive the ethics in
6
the regs.
7
It is worth asking ourselves how human
8
subjects research, and the activities of researchers,
9
acquire moral integrity in the eyes of the public and
10
in the eyes of the profession before the regulations.
11
And it is striking but I think that the most important
12
way that happened was that in very novel, cutting edge,
13
controversial -- potentially controversial research,
14
people self-experimented, and that was widely
15
publicized by the profession.
16
DR. COX:
17
DR. MORENO:
Indeed.
And I mean we have Walter Reed
18
that inspired -- an example that inspired several
19
generations of later researchers to do the same thing.
20
Even, as for example, in the first polio vaccine
21
trials in the early '30s when it made no difference
22
because it would not affect them at all, the two
23
investigators publicized the fact that they inoculated
24
themselves.
25
DR. COX:
Right.
138
1
DR. MORENO:
And this gave people confidence
2
that this was okay prior to an era of regulation.
3
Now, of course, auto-experimentation is
4
frowned on today.
5
more irrelevant perhaps than vaccine research.
6
is something that I have sometimes thought about.
7
if we encouraged colleagues to engage in self-
8
experimentation again rather than frowning on it the
9
way IRBs do?
Often it is simply irrelevant.
Even
But it
What
What would that say to the public about
10
the deep commitment that investigators had to their
11
work?
12
13
14
DR. VANDERPOOL:
I think Dr. Cox is exactly
right about the wink and the nod part of it.
A real challenge we have, and I think this is
15
primarily due to the final report of the Advisory
16
Committee on Human Radiation Experiments, that floored
17
me at first, and that is, how trust between researcher
18
and subject is a problem, is a real problem.
19
And I think the question would be, if you
20
really do have some good training about the
21
distinctions between clinic practice and research, the
22
doctor-patient relationship and the researcher-subject
23
relationship, you are probably going to need to really
24
-- you will have to spend some time on that trust and
25
what all you can do to undermine informed consent, both
139
1
2
facially, both by body language and by words.
And unless that is done, unless you really do
3
-- unless we think much more seriously about those
4
distinctions, there are going to be some connections,
5
too, but some distinctions.
6
in-training have to think.
7
have made a mistake if I do this with my subject.
8
9
Physicians and physiciansYou know, well, wait, I
Until you get to that level of sensitivity, it
is going to continue.
The wink and the nods are going
10
to continue and then the consent form -- it will not
11
matter whether it is five pages long, two pages long or
12
what is on it, it is going to get signed.
13
PROFESSOR CHARO:
14
MR. OLDAKER:
Bill Oldaker?
Let me ask a question, if I
15
might, that deals with -- emanates out of what David
16
said about Phase I clinical trials having almost no
17
hope of having any productive outcomes but some risk.
18
But looking -- and I guess that is something
19
that is necessary.
20
is a necessary part of research?
Is that right?
Would you say that
21
DR. MAGNUS:
Yes, under normal circumstances.
22
MR. OLDAKER:
Let me ask a broader question.
23
To deal with that and make sure that people are
24
informed, how do you create a regulatory framework that
25
will inform people of that, because I guess that is
140
1
what informed consent is supposed to do, without
2
causing the ability of research to go forward or
3
without negating the ability of research to go forward?
4
DR. MAGNUS:
Well, I mean, some of the things
5
that we have already talked about are ways of
6
guaranteeing that we have a better process.
7
making sure that researchers do a better job of keeping
8
in mind that they are conveying, in very clear terms,
9
that their patients are subjects, not that -- sorry,
10
that those are subjects enrolled in trials, they are
11
not patients, and that that needs to be conveyed very
12
clearly.
13
I think
I think there are framing issues that are
14
important and that we need to do a better job of
15
educating researchers of those sorts of things. IRBs
16
might be able to play a role in that.
17
There also might be ways, as I suggested, that
18
for, at least some trials, that you could combine Phase
19
I and Phase II so that you could have a more plausible
20
claim to at least some therapeutic value in at least
21
some cases for the individual.
22
off at very low dosages, but for that individual, raise
23
the dosages so that you can make a more plausible claim
24
that there is going to be some therapeutic value.
25
You might be starting
Again the biggest problem is for the first
141
1
patients.
2
do not have those first few patients, and it is for the
3
first patients that the problem is most acute because
4
for them especially there is really no therapeutic
5
value.
6
I mean, you cannot do research at all if you
DR. MORENO:
You could also prohibit the
7
therapist from -- that is to say the primary care
8
doctor from doing research on his or her own patients,
9
and as in some European countries, I gather, separate
10
those roles so you would have a continuing advocate for
11
the therapeutic side for the patient and a very much
12
more expensive system that I do not think we are going
13
to see tomorrow but that is another option.
14
MR. OLDAKER:
15
DR. VANDERPOOL:
Thank you.
The other comment I need to
16
add to this is that I hope this helps you rethink what
17
the vulnerable populations should be.
18
of ethnic minorities and the poor.
19
vulnerable, in many research settings, are those who
20
are desperately sick and this is a major population,
21
vulnerable population, for your committee to think
22
about.
23
PROFESSOR CHARO:
We tend to think
The most
I would like to take
24
advantage of an opportunity to ask a question of my own
25
if I may, and it is something that is pertinent to the
142
1
2
International Report as well as the Domestic Report.
The Belmont Report and the International Codes
3
consistently treat medical -- participation in medical
4
research as fundamentally different than participation
5
in other physically risky or psychologically risky
6
activities, so that there is a demand that there be a
7
scientific justification and risk minimization, and
8
often a concrete benefit anticipated in the future to
9
society as a whole, before one can even offer to
10
individuals the opportunity to agree to participate,
11
often in exchange for filthy lucre as it was called
12
yesterday.
13
In the International Report, this has actually
14
come to be quite relevant in our discussions about the
15
point at which it is appropriate to say that people
16
can, in fact, be invited to enroll, regardless of
17
whether there will be any medical benefit by virtue of
18
participation in the study, or any realistic
19
expectation that interventions are products that are
20
successfully developed would eventually appear in that
21
population or for those research subjects.
22
I understand the history here and the
23
political history here, but at this moment in time, do
24
you think that a case can be made and, if so, how would
25
it be made that participation in human subjects
143
1
research is different than volunteering for pay to be a
2
stunt man in Hollywood, or a stunt woman, I suppose --
3
I have to be consistent with yesterday, right -- stunt
4
person, there we go -- or any other kind of activity
5
that we recognize as being dangerous, and often with
6
very little significant public benefit, although great
7
public entertainment in that case.
8
DR. VANDERPOOL:
9
10
question.
Alta, that is a tough
I mean, there are offers you cannot refuse.
You and I can refuse -- I think you can, I am not sure
11
about me -- a $10 bill. But you give a $10 bill to
12
someone in Guatemala and they are going to take the
13
stunt option.
14
coercive, those kinds of things so that is my biggest
15
concern about research in other settings.
16
And I think those can be very
Often times the patients do not end up getting
17
the pay anyway. It is going to be the village chief and
18
so on.
19
So the OPRR, as you know, has the standard
20
that you have to do -- use equivalent standards in the
21
field that you use in the United States.
22
some discussion about what those equivalent standards
23
are.
24
25
PROFESSOR CHARO:
Now there is
But, Harold, I am sorry but
if I can be -- if I can clarify my point.
144
1
DR. VANDERPOOL:
2
PROFESSOR CHARO:
Okay.
I want to focus on a point
3
that is prior to the moment at which we begin to feel
4
like it is a Godfather offer, where somebody could, in
5
fact, refuse and choose to earn money another way, but
6
they are being offered this opportunity to earn money.
7
The current approach in this area is to say,
8
that that offer cannot be made for one dollar or fifty
9
cents until there has been a prior review that has
10
minimized the risks, and that has determined that there
11
is some gross societal benefit or scientific benefit
12
that justifies making the offer at all.
13
So we do not treat it like an ordinary offer
14
of employment, and my question really is in a
15
noncoercive setting, is there a reason why we should
16
continue to treat this in a singular manner?
17
DR. MORENO:
I think the question, Alta, goes
18
to the question why do we sequester medical activities
19
from the usual moral hazards of other forms of human
20
commerce?
21
is realistic or not -- we like to put medical -- the
22
profession and medical activities in a different moral
23
category.
24
integrity that is -- needs to be preserved against the
25
day that you and I will need to rely on our -- in our
And I think the answer is that -- whether it
We like to think of it as having an
145
1
last days and moments on a representative of that
2
fraternity.
3
4
5
I think that is why we do things that way and
I think otherwise we cannot justify it.
We conclude that there is a difference in
6
quality between the values of the medical profession,
7
and the values of other human pursuits, and in spite of
8
the short-term consequences, which can be baleful for
9
many people, of holding medicine to a different
10
standard, we think that in the long run, it is better
11
for everyone that it be so.
12
PROFESSOR CHARO:
13
DR. MAGNUS:
Other -- David?
I would just like to agree with
14
that completely.
15
addition to the sort of professional community of
16
medicine, which gives rise to a sort of special ethic
17
that is at stake here, it is also important to remember
18
that medicine is dealing with the care of the body, and
19
there is also a tradition of thinking of the
20
specialness of the body in a certain way.
21
outside the realm of the medical, it is one of the
22
reasons why, you know, the things that I make I can own
23
and I can sell and I can do certain things to, but I
24
cannot for my body.
25
medical realm but also legally, you know, I do not have
I might just also add that in
And even
That is true both within the
146
1
any property interest in my body parts.
2
3
So -- I cannot own -- I do not own my body.
That is --
4
PROFESSOR CHARO:
Just on the record as -- on
5
the record from a lawyering point, let's just say that
6
the law is horrendously unclear on this point, and
7
quite varying from state-to-state.
8
9
Harold, did you want to add anything before I
turn to the last question?
10
11
12
Alex, you will have the last word before we
move on.
PROFESSOR CAPRON:
I have a question for David
13
Magnus but I wanted to note that, while I agree with
14
this last exchange that medicine makes research -- even
15
nonmedical research seem special, I think if we were
16
sitting here with people with deep experience in
17
securities transactions and labor law and employment
18
practices, they would tell us that there are endless
19
restrictions on free exchange of activities and money
20
for all sorts of things.
21
And the picture that you painted, Alta, of
22
this being so different, I think they would simply take
23
strong exception to.
24
25
The question I had for David was in response
to a question from Eric Meslin, who asked you to
147
1
summarize your reasons why research is justified.
2
did not repeat something which you had -- I understood
3
you to have said when you were presenting your paper,
4
which was this notion of a social obligation that
5
people have, if they avail themselves of modern
6
medicine, which is built on the prior efforts not only
7
of scientists, but of prior subjects.
8
DR. MAGNUS:
9
PROFESSOR CAPRON:
You
Right.
And I wanted to know if you
10
included that and, if you did, given other points in
11
your paper where you turn to Hans Jonas' work and his
12
writings on the subject, I recall Jonas as arguing
13
against that view.
14
DR. MAGNUS:
15
PROFESSOR CAPRON:
16
DR. MAGNUS:
17
PROFESSOR CAPRON:
That is correct.
And very strongly.
That is correct.
You do not entail that.
18
There was a vigorous debate between Dick McCormick and
19
Paul Ramsey around the use of children in research, and
20
part of the argument entailed there, too, was whether
21
parents might reasonably consent on the basis that a
22
child looking at what his life was, including his life
23
as a subject, would say, "You did the right thing
24
because I was fulfilling my obligation to society."
25
And again, too, that was very controversial.
148
1
DR. MAGNUS:
Right.
Given the time
2
limitations, I did not take time to go through the
3
different versions of the social contract argument, but
4
that is right.
5
social contract argument that I think Jonas very
6
persuasively argues against and that is laid out in my
7
paper.
8
9
There is, at least, one version of the
The sort of fair play argument, I think, is
another justification for doing research.
It is not
10
just -- that -- I did not mention that because that is
11
not -- that is even more than just a justification for
12
research.
13
good argument for suggesting that, under certain
14
circumstances, there is at least a prima facia
15
obligation to engage in research under certain
16
circumstances.
That is in some sense, I think, a pretty
17
PROFESSOR CAPRON:
18
DR. MAGNUS:
19
PROFESSOR CAPRON:
20
21
And you accept that?
I do accept that.
Thank you.
RECOMMENDATIONS - PURPOSE AND STRUCTURE
PROFESSOR CHARO:
We are going to move on to
22
the next session but I would like to invite those
23
panelists that can to please remain and participate, as
24
seems appropriate, as we try to segue from the purposes
25
of research to the structures that might accomplish
149
1
2
3
those purposes.
So the conversation is certainly going to be
one that integrates those two sets of concerns.
4
I would also like to mention that, as you can
5
see, I am a squirmer up here, and I have already gotten
6
one request for stretch time.
7
Since we must end promptly at 12:30, I am
8
going to suggest we continue the conversation but we be
9
quite tolerant of one another getting up and stretching
10
and walking, and listening while they are walking so
11
that we can make sure that our limbs do not become
12
frozen permanently in place.
13
Marjorie, would you like to say a couple of
14
words to start us off on the structures, their
15
alternatives, and maybe get people thinking of how they
16
tie into the purposes they most want to accomplish?
17
DR. SPEERS:
18
We are going to switch gears somewhat here,
Yes.
Okay.
19
from our previous discussion where what we have been
20
hearing about and discussing has been the purpose of
21
regulations, and based on that purpose then one would
22
write a set of regulations and concentrate on the
23
substance of those regulations.
24
25
What we want to discuss now is the structure,
the federal regulatory structure, and this takes us
150
1
back to several meetings ago, where we have been
2
discussing the current regulatory structure in terms of
3
the Common Rule, some of the issues in trying to
4
implement the Common Rule, and -- the roles of the
5
various federal agencies in our current regulatory
6
structure.
7
At least one meeting ago if not two meetings
8
ago, we shared with you a wheel, a red and blue and
9
black wheel, that graphically displayed the current
10
regulatory structure.
11
of material that chart.
12
if you can refer to that chart.
13
You should have in your packets
So I think it will be helpful
We have blown up that chart as well as others
14
for our discussion today and they are posted in the
15
back of the room so that others can follow along.
16
Let me walk you through these charts.
What
17
am not doing is going over the background material and
18
I am not doing that in the interest of time.
19
I
In your packet, what we have done is we have -
20
- as I said -- provided you with the same chart, the
21
same wheel that we looked at a meeting or two ago, that
22
describes our current regulatory system.
23
The second chart in your packet is the same
24
current federal regulatory system minus the additional
25
rules and regulations that the various federal agencies
151
1
have.
2
in the back of the room for you.
3
And for those in the audience that chart is not
It was not posted.
We just gave you this one to take out the
4
superfluous information and to leave you with the
5
current regulatory structure under the Common Rule.
6
The next three charts that are in the back of
7
the room describe the types of changes that could be
8
made to the current system, and those changes are based
9
on three key decisions that you need to discuss and
10
decide where you want to go.
11
One of those decisions is -- one basic
12
decision is whether the administration of the oversight
13
system -- whether that should be a centralized function
14
or a decentralized function.
15
Another basic decision is, whether the system
16
should be extended beyond its current scope, and we can
17
talk about scope in terms of extending federal
18
regulation to other federal agencies that conduct
19
research, who are now not part of the Common Rule, or
20
even extending it beyond to include the private sector.
21
And the third basic decision is whether the
22
regulatory structure should be uniform across all
23
agencies and departments that are part of the Common
24
Rule.
25
the protections, additional protections for vulnerable
This specifically addresses the issue of whether
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1
populations should be common across all agencies as it
2
is currently not.
3
So the possible changes that we have given in
4
change number one in this model -- the current subparts
5
would become uniform across all agencies.
6
that would entail would be altering the Common Rule so
7
that the Common Rule now becomes subparts A, B, C and
8
D, and then each of the federal agencies who are
9
signatories to the Common Rule would have to codify
10
11
And what
regulations of the federal policy.
The second change is one that would occur only
12
within the Department of Health and Human Services, and
13
that is simply to bring the FDA regulations and the HHS
14
regulations together under one uniform set of
15
regulations.
16
And then the third possible change is
17
expanding authority to all human research and doing
18
that through a single set of regulations coordinated
19
from a central office.
20
There are many possible changes.
We have only
21
given you three of them to try to make the points and
22
to begin discussion.
23
Various permutations of these are certainly
24
possible but they certainly -- what they do lay out for
25
you, is moving from perhaps what I will call modest
153
1
change, in terms of simply putting FDA regulations and
2
HHS regulations together which could be done, for
3
example, by a directive from the Secretary of HHS, to a
4
more extensive change that would require an executive
5
order by the President to request, or require, all of
6
the current signatories of the Common Rule to adopt the
7
subparts, to a major change that would require
8
congressional authority to create a new regulatory
9
structure involving one set of regulations that expands
10
perhaps all of the Federal Government and could
11
potentially include the private sector.
12
PROFESSOR CHARO:
13
Would anybody like to get us started
Thank you very much.
14
contemplating which of these seems to accomplish which
15
purposes and best?
16
Bill Oldaker and Bernie Lo, first of all?
17
MR. OLDAKER:
18
DR. LO:
19
Go ahead, Bernie.
Well, Marjorie, I want to thank you.
I always love seeing color charts.
It really sort of
20
wakes me up and makes me focus, and this is really
21
helpful.
22
23
It seems to me you are posing a couple of
questions which are interrelated but separable.
24
One is who should fall under federal
25
regulations concerning human research, and do we extend
154
1
-- the issue we face is, do we extend it to projects
2
that are not now under the Common Rule?
3
4
5
A second question which I think we have not
really dealt with is, what should those regulations be?
I mean, the way we have it here, we are sort of
6
starting with the current Common Rule and the other
7
subparts to 45 CFR 46, but there is also the
8
possibility that, maybe, that is the wrong approach to
9
take.
10
11
Although it has served us well for these many
years, maybe we need a fresh approach.
A third question which you posed was, who
12
should sort of oversee, coordinate, enforce, whatever
13
the verb is?
14
And it strikes me that there is a big
15
overriding question here, which is do we become very
16
practical and say let's be realistic and figure out
17
what is most likely to happen and go for that?
18
Or do we say that this is an opportunity to
19
really take two giant steps back and say, what would a
20
more ideal system be and leave it to others to sort out
21
the pragmatics of whether any of this feasible?
22
I mean, I am really torn personally between
23
not wanting to recommend something people would just
24
look at and say, "Oh, that is nice.
25
bunch of dreamers.
These guys are a
They are in San Francisco on the
155
1
two sunny days in June."
2
just --
3
PROFESSOR CHARO:
4
DR. LO:
5
(Laughter.)
6
DR. COX:
7
DR. LO:
8
DR. COX:
9
DR. LO:
You know, obviously this is
It is sunny?
It is sunny outside.
It is foggy.
It is foggy.
It is not nice outside.
Or are we going to say, you know,
10
what is really needed here -- it is kind of a
11
reorientation, a wake up call, sort of a fresh way of
12
looking at it, that just tinkering with regulations in
13
an incremental way, is not going to address some of the
14
issues that the panel posed, namely there is no ethics
15
in the regulations or the -- you know, it is just -- it
16
is misguided in some way.
17
I feel that we need to think about where we
18
are headed, what our big goal is before we can really
19
start addressing the three very substantive issues you
20
are proposing.
21
DR. SPEERS:
22
PROFESSOR CHARO:
23
24
25
respond, sure.
Do you want me to respond or --
Of course.
DR. SPEERS:
Yes.
If you feel the need to
Marjorie, do you want to?
Two responses.
One is that
one can proceed by looking, perhaps at structural
156
1
issues as we are doing now, and then deal with some of
2
the substantive issues.
3
feel as comfortable as if we had started with some of
4
the substantive issues and then come back and looked at
5
structure.
6
That does not necessarily
However, one of the reasons for deciding to
7
move in this fashion, in addition to logistical issues
8
of when papers were available and when we could discuss
9
certain things, is that even playing out various
10
scenarios of what substance might be, the various
11
options for structure seem to be the same under various
12
scenarios for substance.
13
14
15
I think we end up at the same place so that is
point number one.
Second, I think that the Commission can do two
16
things and needs to do both in a sense.
17
opportunity for this group -- for this body to think
18
very broadly and strategically and to make
19
recommendations of what the system ought to be, what an
20
ideal system would be, to address some of the issues
21
that we are hearing from the researchers and IRB
22
community that sweeping change is needed, that tweaking
23
is not going to be enough.
24
make those kinds of statements.
25
This is an
This is an opportunity to
At the same time I think that there could be
157
1
recommendations that would say this is the ideal.
2
you cannot do the ideal, here are some other things
3
that could be done.
4
the options that have been given here, it does not have
5
to be pick only one, but it could be, here is the first
6
tier and here is the second tier.
If
So that, for example, even with
7
PROFESSOR CHARO:
8
MR. OLDAKER:
Bill?
At the risk of, seeming to, I
9
guess, speak at speed or decibel, at least in theory,
10
more than we are at this time, it seems to me we want
11
to be somewhat radical.
12
will have an impact for change and actually have some
13
lasting events.
14
We want to do something that
Now my problem -- Bernie laid it out at the
15
end -- my problem is, I do not think we have stated
16
basically what we view that we are trying to cure at
17
the current time.
And I think we have to set that out.
18
There is a -- in my mind, and I sit more distantly
19
than the rest of you from these issues, but I think
20
there is an issue now with public perception, and with
21
credibility, with a type of research that if it is not
22
taken care of, could have a caustic effect on
23
biomedical research.
24
try and state that -- what the problem is we are trying
25
to deal with first and then attempt to rectify that
And I think it -- but we should
158
1
problem with -- at least my initial feeling is with
2
some fairly dramatic recommendations.
3
recommendations because I know the body politic
4
generally disregards alternative recommendations.
5
recommendations that would stand out and set a mark
6
that we would hope people would try to meet, and that
7
would also gain the appreciation of the general public
8
as a way to actually build their confidence in the
9
system.
10
Not alternative
But
So, you know, I guess it is a two step process
11
in my mind.
12
should identify what we think the problem is currently,
13
and then we should try and -- that is not an easy
14
process necessarily.
15
solution at that problem, realizing that we may be
16
doing some other things, instead of looking at kind of
17
a scattershot governmental issue and maybe that is part
18
of the problem, too.
19
to solve all of the problems that the government may
20
have in this area.
21
We cannot solve all problems, but we
And then we should aim our
I do not know but -- and trying
PROFESSOR CHARO:
But if we understand you
22
correctly, Bill, one of the problems that you would
23
agree we have, is the problem of maintaining public
24
trust in the research enterprise?
25
correctly?
Did I understand you
159
1
MR. OLDAKER: Correct.
2
PROFESSOR CHARO:
3
Cox?
Okay.
Alex, and then David
Anybody else?
4
DR. CASSELL:
I want to underline what Bill
5
just said.
6
testimony the last couple of days, and I am still
7
trying to say what is the problem that we are going
8
after.
9
regulations, that is a problem.
I have been sitting here listening to
The fact that there is an uneven set of
We could bring people
10
under one set of regulations that are poor, and I do
11
not think that would be very helpful.
12
13
So I would like, also, to hear much more
clearly what do we think is the problem.
14
PROFESSOR CHARO:
15
PROFESSOR CAPRON:
Okay.
Alex?
Well, this is very much in
16
line with what Bill and Eric just said.
17
that the kinds of issues we have seen, Marjorie, cut
18
across both structure and the activities that are
19
carried out within that structure.
20
from the Office of the Inspector General of the IRB
21
system is, in part, a criticism of IRBs not having the
22
resources they need, being over worked, not necessarily
23
all being as well informed about the regulations.
24
it is, in part, of course, a criticism of the assurance
25
model, which is the predominant model from the Federal
My sense is,
And the criticism
But
160
1
Government.
2
And I do not think it takes fully into
3
account, how that model does or does not achieve goals
4
that are different than the compliance model, much less
5
what we have been talking about of an accreditation
6
model.
7
It would seem to me that responding there
8
might have some implications for the structure as well
9
because an accreditation system makes a lot more sense
10
if you are thinking of a single central office that has
11
the responsibility, than trying to design an
12
accreditation system that involves a lot of different -
13
- 20 or so different agencies, each with their own
14
responsibilities.
15
What are some of the other concerns we have
16
seen?
17
embody a very clear set of ethical precepts.
18
Eric just said, you could centralize with bad
19
regulations, or you could have good regulations without
20
centralization.
21
hand.
22
Well, the fact that the regulations do not
Again, as
Those do not necessarily go hand in
But I have the sense that one of the reasons
23
we have the problems with the regulations that we do is
24
this divided structure.
25
major reports, that we thought about ways in which
Every time, in our first two
161
1
changes really ought to be made to take into account
2
the mentally disabled or human biological materials, we
3
kept coming up against the Common Rule problem.
4
That is to say, try to suggest how these can
5
be reinterpreted but do not -- please do not suggest
6
any changes in the regulations themselves.
7
do, think of it as a new subpart, that is totally
8
optional, and is not part of the central -- because you
9
will never be able to get these baronies to agree.
10
11
12
Or if you
There are times when you need a monarch and
this may be one of them.
Now, obviously -- and you have that nice list
13
in the little handout that we have -- the results to
14
avoid include rigidity, bureaucracy and
15
disproportionate burden.
16
suppose, that a central office might tend in that
17
direction, but it is also part of the experience of
18
people that, having different departments and agencies,
19
including the differences between the FDA and the rest
20
of HHS, amounts to some excessive burdens because you
21
have to adjust what you are doing depending upon which
22
regulatory structure you are having to deal with.
23
There is some risk, I
The fourth thing that you said we should avoid
24
is redundancy.
25
departments taking up different places in the Federal
Well, certainly having all these
162
1
Register, with their little curly Q's built into them,
2
leads to a good deal of redundancy.
3
So, I mean, I think that some of the
4
weaknesses we have seen in the present system, some of
5
the problems with the quality of the regulations, and
6
particularly, the ability of the regulatory system to
7
respond to new findings from empirical research about
8
what works and does not work in informed consent, to
9
new ethical thinking about what is important and how it
10
should be balanced.
11
heard about over the last 15 years -- it is not the
12
last time we are going to have a paradigm shift.
13
is a pendulum, and it will always be swinging, and in
14
response to those swings people will perceive new
15
problems.
The paradigm shift that we have
This
16
I mean, I was trying to say the difference
17
between the type one errors and the type two errors.
18
Well, you can substitute different errors in there and
19
it is always a matter of saying, how do we not get too
20
many of one but while we are trying to avoid the other.
21
A system that has central authority on its
22
face is more able to adapt to those changes and adopt
23
change in language as that becomes necessary.
24
25
The final thing is, it does seem to me that a
centralized office would be in a better position to
163
1
marshal the overall resources necessary for education
2
and outreach.
3
To the extent again that responsibility is
4
spread around, there is always the issue of, well, why
5
do I, Secretary of X, Y, Z, want my budget to have to
6
be, you know, boosted up by this and I have to defend
7
why I want money for this.
8
doing it?
9
Let them take care of it.
10
Why isn't that other office
They do more research than we do anyway.
And so I think that it is possible for us to
11
identify weaknesses with the present system and most of
12
those weaknesses, it seems to me, would be better
13
addressed by the model that we have talked about over
14
the last three years as a possibility, which I do
15
favor, of having a government-wide office.
16
DR. MESLIN:
17
DR. COX:
18
David?
Yes.
I agree.
I really agree with
--
19
DR. CASSELL:
20
DR. COX:
I do, too.
-- what all the different speakers
21
have said that -- and I really agree with what Bill
22
said, which is figuring out what the problem is.
23
will say for myself, you know, there is no single
24
problem but we have to prioritize what we think is most
25
important.
So I
So, for me, the biggest problem that I
164
1
would like to see solved, is this one of putting ethics
2
back into this issue because it is not in there right
3
now.
4
And I do that out of the desire to have both
5
the actual protection of the patients, and the pursuit
6
of the research both go on, and my sincere belief is
7
that, if we do not put ethics back in, neither will
8
happen and we will be in big time trouble.
9
So that is the logic of my motivation here.
10
So given that, that then precludes any quick fix to
11
this problem or -- and it precludes anything but a
12
really sort of drastic shake up of the system.
13
Now I am leery of drastic shake ups of
14
anything and I would go to great lengths not to have
15
drastic shake ups but in this situation I do not see
16
very many other options.
17
DR. SPEERS:
Thank you.
This conversation is
18
actually very helpful because it says a couple of
19
things to me and to staff as we work on this.
20
that of those various options, at least what I have
21
heard from three of you here, is that you are leaning
22
towards a more dramatic change rather than a tweaking
23
of the system, and that is important for us as we
24
proceed along and need to do some of the background
25
work.
One is
And I certainly agree we do not want to move --
165
1
we do not want to make drastic change and have bad
2
regulation.
3
So these two go together, these two issues of
4
the structure, and the purpose or substance of the
5
system and the regulations, which is where these two
6
are moving along -- these two issues are moving along
7
together and, hopefully, they will become very clear to
8
you in the next few months.
9
And we will lay out very clearly what the
10
problem is, what we think the problem is because we
11
have -- you have heard testimony.
12
background papers and then we have been hearing from
13
IRBs.
14
perception of what some of the problems are in July.
15
We have some in
You are going to hear from IRBs -- from their
I would like to ask for the other three
16
Commissioners at the table if I could just get a sense
17
of where you are on this issue of tweaking versus
18
dramatic change.
19
DR. MESLIN:
And as you are thinking, if
20
Rhetaugh and Trish are still on the phone, and wish to
21
weigh in, please let us know.
22
Eric Cassell wanted to make a comment.
23
DR. CASSELL:
Well, I do not think we should
24
tweak.
25
lot of complaints about the way it is working from
I mean, we are hearing a lot of noise from -- a
166
1
outside.
2
being.
3
do.
4
of it and I, myself, believe that we have to make major
5
change and drastic is always -- doctors get nervous
6
with the word "drastic."
We have a system that sort of came into
We understand a lot more what it is supposed to
We are aware that ethics is somehow dribbled out
7
DR. MESLIN:
8
DR. CASSELL:
9
And I also feel that, whatever we end up with,
Major.
Major change.
I like that.
10
that a central regulatory agency is a better one merely
11
out of matters of power, and that is an issue that we
12
have to consider because an agency -- a set of
13
regulations and an agency that has no power is in
14
difficulty and that is one of the current difficulties.
15
DR. SPEERS:
Thank you.
16
DR. MESLIN:
Bernie?
17
DR. LO:
I like the idea of a major, not
18
necessarily drastic, change.
19
we get the major change right, because the problem is
20
when you make a major change, you can do a lot of good
21
or you can do a lot of harm.
22
I just want to make sure
So I would suggest that we look at the big
23
picture.
24
the problems are, one way to think about it is that we
25
do not really have any assurance that the individuals
I mean, as I sort of think about what I hear
167
1
and organizations who are responsible for protecting
2
human subjects actually do the job they are supposed to
3
do.
4
medicine, we are looking for outcomes, performance and
5
things like that.
6
which means IRBs, OPRR and individual investigators.
7
Just as in every other branch of clinical
We ought to hold people accountable,
I think another thing we keep hearing about is
8
the -- how much of this really depends on what David
9
calls the wink and the nod, but it is that interaction
10
between the physician-investigator and the subject,
11
which is so important in determining what the potential
12
subject thinks, and whether they are going to enroll or
13
not, which is totally different than the emphasis on
14
consent forms.
15
It seems to me the inference I want to draw
16
from that is, that education about clinical research
17
has got to be part of your training as a clinical
18
researcher and you do not finish a fellowship without
19
doing that any more than you finish your cardiology
20
fellowship without learning how to do your angiograms.
21
You do not get an NIH grant until you show that you
22
have understood research ethics the way you do not get
23
the grant unless you know biostatistics.
24
25
So I think there are big picture issues that
we can deal with.
I am not prepared to say how you
168
1
educate, who -- what kind of model you use but I just
2
think these notions of, holding IRBs accountable,
3
making sure investigators really learn what we think --
4
what somebody thinks they should learn are the sorts of
5
things which I think would be fairly major. I mean,
6
this does not happen and, I mean, I -- the stuff that
7
is on my computer, this is public -- I cannot say it is
8
public record but there are a lot of NIH training
9
grants and program grants that are given out that do
10
not have in place anything more than boilerplate as to
11
training of investigators in research ethics.
12
And everybody knows it, the study section
13
knows it, the PIs know it, the people whose names are
14
down to do the teaching know it.
15
is more than a wink and a nod.
16
asleep at the wheel.
17
And, you know, that
That is sort of falling
So, yes, I would go for major changes but to
18
not be so presumptuous to think that we know all the
19
little steps that need to be taken.
20
21
DR. CASSELL:
"education."
But I did use the word
I just want to reemphasize that.
22
(Laughter.)
23
PROFESSOR CHARO:
Diane?
24
DR. SCOTT-JONES:
I would agree with what has
25
been said so far.
I would agree that we should think
169
1
about major changes but very carefully.
2
we should take into account all the stakeholders, try
3
to consider the perspectives of researchers, of people
4
who participate in research, and I think we should give
5
careful consideration to the social sciences.
6
that Marjorie is very aware of the importance of this.
7
I agree that
I know
I think we should consider carefully children
8
and adolescents as distinct from children.
9
with Bernie and, of course, with the point that Eric
10
often makes, that we should plan for education about
11
any changes and educating again all stakeholders, IRBs,
12
students, new investigators, and the public generally
13
who participate in research.
14
PROFESSOR CHARO:
15
MR. HOLTZMAN:
And I agree
Steve?
Let me start with the
16
structural question first.
17
human subjects protections, that the impetus for it
18
starts with the word human subject.
19
nothing to do with what agency is doing it.
20
absolutely nothing to do with where the money came
21
from.
22
is centralized and deals with humans per se makes all
23
the sense in the world to me, and so I would be very,
24
very supportive of it.
25
I think if one thinks about
It has absolutely
It has
And the idea that there ought to be a locus that
I think getting it right is actually -- it is
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1
an opportunity for it to be much more flexible and not
2
have a single univocal sense of what are the
3
appropriate kinds of protections but actually could
4
work with those different agencies to say, okay, you do
5
social science work.
6
we be evolving for that?
What kind of protections should
7
So, again, when I think of centralization, I
8
think of rather something that can integrate diversity
9
as opposed to come down with a single monolithic set of
10
11
rules.
So I would be very supportive of that.
And I think it would go a long way to starting
12
to try to mend the problem of the public trust because
13
I know for those of us who try to do it right and still
14
get nailed to a cross, it would be nice to have a place
15
you could go to and say, "We are doing it right."
16
I mean, I could point you to accusations that
17
are now on the web about things that researchers have
18
done, where we know OPRR investigated it and found that
19
it was groundless, but it is out there on the web and
20
you are getting interviewed by the Washington Post
21
about these accusations.
22
With respect to the education component, I
23
mean there the issue is what can we do other than
24
hortatory kinds of things.
25
important thing we could do.
But it is clearly the most
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1
2
Dr. Cassell, education is the most important
thing.
3
And I was struck in the discussion earlier,
4
that in encouraging the teaching of research ethics it
5
is not a matter of teaching people rails or teaching
6
people nails, it is actually teaching people how to
7
think and bring a set of questions and considerations
8
to their research which are not in their minds
9
intrinsic to the research.
10
11
12
Questions from an ethical
perspective of why am I doing the research?
How am I performing the research?
All right.
And what will be
the distribution of the fruits of the research?
13
I think that is what we are trying to do.
An
14
education that gets people to say those questions are
15
as important questions as questions about whether I
16
should use this or that restriction enzyme.
17
then giving them a framework in which to say that that
18
needs to be thought about and justified.
19
PROFESSOR CHARO:
Okay.
And
I had a few comments of my
20
own but first let me ask if there are others who wanted
21
to speak at this point.
22
23
24
25
DR. MESLIN:
Have you heard from Trish and
Rhetaugh?
PROFESSOR CHARO:
still there?
Trish and Rhetaugh, are you
They may have gone away for the moment.
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1
Let me intervene, and I am sure other people
2
are going to have comments, too.
3
way, about ten minutes before we have to break,
4
unfortunately.
5
We have got, by the
What I have heard people talk about today, and
6
over time, has absolutely included public trust and I
7
think it was Bernie or Bill who called it "uneven
8
regulations," inconsistent regulations or simply
9
differing regulations that make it complex.
10
major harms, so far occasional major harms,
11
inefficiency particularly in the collaborative research
12
area.
13
Occasional
And one thing that may be a little bit more
14
controversial as a "problem", that we would have to
15
decide if we think needs attention,
16
is able to better influence research so that there is a
17
just creation and just distribution of benefits as well
18
as distribution of burdens, and that goes to the
19
historical problems of the inclusion of women, and to
20
some extent racial and ethnic minorities in research so
21
that we are confident we understand how these new
22
products operate with people whose physiology or
23
circumstances are different.
24
25
is a system that
All of which suggest to me that you would
absolutely want a central authority in the Federal
173
1
Government for the purpose of being able to simplify --
2
first to make rules consistent as well as, as Steve was
3
saying, to facilitate a more efficient way of amending
4
those rules or particularizing those rules to special
5
situations.
6
because of the multiplicity of agencies involved in
7
amendments.
8
9
Something that is now very difficult
It also seems like it would suggest the need
for such a central office to have the capacity to
10
rapidly respond to a changing environment as to what
11
constitutes harm.
12
are worried about today now focus much more on privacy
13
than they had before and yet we do not have the
14
capacity to respond quickly to that.
15
We heard that the harms that people
It also strikes me that ideally a system ought
16
to take advantage of incentives and enforcement
17
measures that go beyond simple regulatory enforcement
18
with fines or shut downs.
19
where, for example, accredited IRBs or licensed
20
investigators, as if you got a driver's license, are
21
subjected to a simplified set of rules or a simplified
22
set of auditing procedures as compared to those that
23
have not been pretested and found to be presumed
24
competent to handle these problems.
25
There are incentive schemes
And it also means that it might be worth, in
174
1
my opinion, examining the role of state governments and
2
state law, since if we wanted to focus on major harms,
3
which would suggest perhaps focusing more attention on
4
major risks and beginning to clear out minor risks more
5
efficiently from the system, there is a role in state
6
law, which covers things like battery, the unconsented,
7
offensive or harmful touching of somebody else, that
8
could be called into service to provide back up for
9
those areas where there was some retreat at the federal
10
level, none of which would be inconsistent with
11
maintaining a decentralized system that is, at its
12
heart, professional self-regulation with sufficient
13
central guidance, oversight and occasional intervention
14
to maintain public trust.
15
Bernie?
16
DR. LO:
A couple of thoughts.
First, you
17
know, I have a computer so I play around with charts
18
and things.
19
each made a list of what we think the problem is, that
20
we are trying to deal with, and circulated them and get
21
a sense if there is commonality or are we just sort of
22
all over the board here.
23
I think it would be really helpful if we
And, secondly, I really would like to think
24
through the notion of professional responsibility.
25
mean, it seems to me, one of the things that is
I
175
1
different from the traditional deference to physicians
2
and other professionals, is that we now have the
3
ability or some ability to compare actual performance
4
to stated expectations and goals.
5
And to the extent, again in the clinical
6
arena, doctors are being held accountable for all kinds
7
of outcomes and getting used to the fact that someone
8
is looking over your shoulder, we should -- and there
9
is a whole sense at least in ideal theory, if not in
10
practice, that people ought to look at their -- take a
11
hard honest look at what they do with a view to quality
12
improvement as a whole and mistakes literature now.
13
I think we should try and piggyback on to that
14
and say, we are not talking about trust in the sense
15
that we know more and you should just trust and defer
16
to us.
17
But trust now, I think, can be backed up with
18
some sense of outcomes related to performance and even
19
if it is just a procedural outcome, in terms of passing
20
a licensure exam or certification or something, it
21
seems to me that is better than just saying, you know,
22
you have got an IRB that somehow has a piece of paper
23
that gives you a Multi-Project Assurance.
24
25
So to the extent we can build in the selfimprovement through looking at outcomes, that would
176
1
give people more of a rational basis to trust the
2
investigators.
3
PROFESSOR CHARO:
4
MR. OLDAKER:
Bill, and then Alex.
I think Bernie's idea is a good
5
idea to the extent that we can put out there what the
6
problems are, but I would think it would be good, also,
7
to have Marjorie or others put together a statement
8
that we could look at as far as whatever those problems
9
are.
10
And then we set aside two hours to really
11
debate them because, to me, if we do not come to grips
12
with what the problem is up front, it is going to be
13
very difficult for us to progress to a place where we
14
actually get something done.
15
So I think, you know, it is -- I think it is
16
wonderful and it has been very instructive to hear from
17
a number of the witnesses but I think with the
18
diversity we have here, it would be worthwhile for us
19
to really thrash out a common vision of the problem we
20
are trying to solve.
21
I mean, just -- you know, as an over arching
22
thing I know that we agree on a number of things but I
23
do not know if agree that this should be a very broad
24
and cover more areas than it currently covered or not,
25
and I think those are the kinds of things that if we do
177
1
not touch up front, we are going to be constantly
2
spending more time trying to figure out how to go down
3
those alleys.
4
PROFESSOR CHARO:
5
PROFESSOR CAPRON:
Alex?
I concur with both of those
6
comments.
7
have not directly talked about in the last few minutes
8
as an example of something else.
9
I wanted to actually raise something that we
We have heard a good deal of discussion about
10
the therapeutic misconception that has been raised as
11
an example of a problem and we have heard some fairly
12
widely differing views about that.
13
as everybody was endorsing the notion of education, and
14
I thought that both Steve and Bernie gave a nice
15
endorsement of that, what would be the education on a
16
topic like that.
17
And I was thinking
Would investigators be cautioned as part of
18
David Magnus' testimony this morning about the ways in
19
which they subtle feed that, or is feeding it really
20
quite all right because that is part of the hope that
21
Eric Cassell talked about at one point and so forth.
22
I wanted to know whether it is our sense that
23
in this report as part of the process of examining the
24
present system we would intend to address substantive
25
issues of that sort or whether we intend to flag those
178
1
kinds of issues, explain why they are difficult, and
2
suggest that that is one more reason why an ongoing
3
structure is needed, through which issues like that can
4
be thrashed out publicly and with input from people who
5
realize that those issues are on the table.
6
I do not think the average person who is an
7
IRB or an investigator knows that that is necessarily
8
before us, for example, but if there were an office
9
that says, you know, this is a big issue and we want to
10
prepare appropriate educational materials, or we want
11
to put something in the regulations, or in the guidance
12
documents that are given to IRBs or whatever.
13
So do we have a sense that in this report we
14
are going to get to issues like that or would we get to
15
them in this latter way that I described of sort of
16
saying, here are a bunch of issues that are current
17
issues, and the only real way to address them is
18
through some ongoing process?
19
PROFESSOR CHARO:
Let me just warn you because
20
Marjorie needs to leave as scheduled at 12:30 that
21
there will not be time to answer your question from
22
members of the Commission right now.
23
PROFESSOR CAPRON:
24
PROFESSOR CHARO:
25
Just on the record.
But if Marjorie would like
to have any closing comments about things people should
179
1
think about in addition to that so that when we pick up
2
the discussion we are ready to respond, feel free.
3
DR. SPEERS:
4
As I envision this report and the types of
Thank you.
5
recommendations that will be made, I think of them as
6
the Commission dealing with the broader issue.
7
opening the doors that then another body, whoever that
8
would be, can go into much more detail on it.
9
not think that we -- I do not think we have the time,
10
the luxury of time to go into detail on some of those
11
issues, but we can certainly open the doors.
12
PROFESSOR CHARO:
13
excuse Marjorie and --
14
DR. CASSELL:
15
PROFESSOR CHARO:
Sort of
But I do
With that, I would like to
You are excused, Marjorie.
-- to turn the chair back
16
over to Alex as we shift gears back to the
17
International Report.
18
approximately a 10 minute discussion on an amended
19
recommendation.
As I understand, there will be
20
I know that Ruth and Alice will be back in
21
momentarily and presumably lunch will arrive at some
22
point for everybody to have here at their favorite
23
seat.
24
25
PROFESSOR CAPRON:
Feel free to move.
Why
don't -- does staff know whether the food is about to
180
1
be delivered?
2
their legs for five minutes and if you have not checked
3
out, you better do so immediately and so forth and so
4
on.
5
6
7
8
9
10
11
12
13
14
Okay.
Why don't we let people stretch
(Whereupon, at 12:30 p.m., a break was taken.)
* * * * *