42nd MEETING NATIONAL BIOETHICS ADVISORY COMMISSION Hyatt Regency Bethesda

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42nd MEETING
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NATIONAL BIOETHICS ADVISORY COMMISSION
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Hyatt Regency Bethesda
One Bethesda Metro Center
Wisconsin Ave. at Old Georgetown Rd.
Bethesda, Maryland
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Volume I
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July 10, 2000
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Eberlin Reporting Service
14208 Piccadilly Road
Silver Spring, Maryland 20906
(301) 460-8369
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I N D E X
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Opening Remarks
Eric Meslin, Executive Director
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ETHICAL ISSUES IN INTERNATIONAL RESEARCH
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Discussion of Draft Report
Harold T. Shapiro, Ph.D.
Ruth Macklin, Ph.D.
Alice Page, J.D., M.P.H.
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P R O C E E D I N G S
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OPENING REMARKS
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ERIC MESLIN, EXECUTIVE DIRECTOR
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DR. MESLIN:
Dr. Shapiro is on his way and
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he has asked me to open the meeting now.
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still waiting for a couple of commissioners to arrive
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so what I would like to do is inform the commission
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and the public who are here what our agenda is for
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the day and how we are going to proceed.
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We are
This is the 42nd meeting of the National
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Bioethics Advisory Commission and we have a very busy
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agenda ahead of us.
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part of the day, the morning, going over a draft of
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the International Report.
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We are going to spend the first
For the public who are here, I want to make
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it clear to them that if you have picked up these
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materials, as we hope you have, it is our intention
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that the International Report will be going out for
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public comment on or about the 18th of July.
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documents that you are reading are not the public
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comment draft.
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today's meeting and it will be widely circulated
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within about ten days time and I say that just to
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avoid any confusion by the public or the media who
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are here reviewing the materials that you have in
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our hand.
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The
This will be revised following
Let me briefly then go over just a couple of
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other housekeeping items and then we are going to
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turn directly to the agenda.
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You have in your table folders a number of
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additional items, including my Executive Director's
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Report.
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commissioners and the public.
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noncontroversial report reminding you of what our
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public comment process is, identifying a number of
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letters that we have received and correspondence from
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previous reports, informing the commission and others
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that the draft agenda for the Third Global Bioethics
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Summit has been prepared and will be available to
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people.
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You are welcome to review that,
It is essentially a
If there are any commissioners who have
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questions about these items, I am happy to go into
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some detail about them.
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I would also like to inform commissioners
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that as a requirement to the Federal Advisory
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Committee Act we have distributed some materials to
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you from the Deputy Ethics Counselor of the
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Department of Health and Human Services, Hal
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Thompson, through the Ethics Office, and a Mr. Ed
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Swindell, providing you with materials for your
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review and understanding about ethics rules as
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members of federal advisory committees.
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I am encouraged to inform you that you
should and must read these and be aware of them.
If
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you have any questions about those ethics rules,
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please feel free to direct them to me.
Are there any questions or comments either
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about the Executive Director's Report and the
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materials attached, or about the agenda or any other
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parts?
I should inform the public that although we
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are not in full quorum at this point I do want to
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check and see whether Professor Charo is on the
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phone.
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Alta, can you hear us?
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PROFESSOR CHARO:
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DR. MESLIN:
Very clearly.
Right.
Thanks.
Alta was unfortunately
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delayed in Wisconsin due to the thunder storms that
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were out there.
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phone, Alta.
PROFESSOR CHARO:
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We are glad you could join us by
It is a pleasure to be
there.
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DR. MESLIN:
Right.
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I circulated to commissioners, just a couple
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of days ago, some materials that Ruth Macklin and
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Alice Page and I, with Harold Shapiro's input,
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prepared for you to facilitate this morning's
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discussion about the International Report.
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of discussion, we thought we would identify those
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items in the report that based on discussion that the
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commission has had by e-mail and other ways would be
For ease
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crucial to focus on.
This meeting is designed to allow you, the
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commission, to agree that the report itself is
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acceptable for dissemination for public comment.
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Agreement does not entail or require that you agree
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to every single line and word and comma.
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mean that you are comfortable enough with the
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recommendation and with the text that you are
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prepared to have the public comment on those.
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It does
For the public's benefit, our process at the
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commission using a public comment mechanism is we
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will be providing a revised draft of this report on
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the 18th of July.
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up until September the 1st, post-marked September the
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1st, or by e-mail.
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Public comments will be received
There will be a Federal Register notice
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informing the public of this but for those who are
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here, you can call our office, 301-402-4242.
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go to our website, www.bioethics.gov.
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a request to us at 301-480-6900.
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can give you those particulars if you did not take
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them down.
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You can
Or you can fax
Any of the staff
Once the public comments have been received
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and analyzed by staff, and shared with commissioners,
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it is likely that modifications to the report will be
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made, and our timetable has the commission discussing
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the full report again at its October meeting, the
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24th and the 25th, in Salt Lake City, Utah.
With that preliminary introduction, and I
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notice
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- I think we are in quorum if I am not mistaken.
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do want to begin.
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a little bit and many of you know that Bernie has
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given comments already.
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that
Eric Cassell is here so now we are in I
Bernie Lo will be stepping out in
What I would like to do is begin with the
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notes that I sent around to you and just confirm that
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you have all received this note from me from July the
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7th so that you know about which we are speaking.
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And then, Bernie, I am actually going to
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allow you to make some early comments, taking our
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chapters slightly out of order, knowing that you have
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to leave.
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Bernie Lo?
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ETHICAL ISSUES IN INTERNATIONAL RESEARCH
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DISCUSSION OF DRAFT REPORT
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DR. LO:
Thanks, Eric.
My apologies.
I am
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going to have to run, going to come back and then run
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out again, and then come back.
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Metro system here today.
So I am testing the
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I want to thank Ruth and Alice for their
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work and also thank Eric for the six-page memo he
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sent out, which I think really helped me clarify what
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some of the issues are.
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raised seemed to have struck a chord with others and
I think some of the things I
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I am not going to sort of belabor those points, but
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there are two issues where I may just be out in left
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field, in which case that is fine, but I just wanted
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to make sure I tried to be clear on what I was trying
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to say.
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One is an issue of, sort of, how we
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characterize the problems going on in clinical trials
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conducted in some sectors of the U.S., and another is
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really an issue of clarification of one of our
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recommendations in Chapter 5.
On the first point, it seems to me there are
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problems with some clinical trials conducted in the
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U.S. in that the subjects of research are selected to
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be drawn disproportionately from groups that do not
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have good access to health insurance and, therefore,
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do not -- cannot be reasonably expected to be able to
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have access to drugs if proven effective in a
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clinical trial.
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There are a number of studies where
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recruitment is made from people who are homeless,
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people who attend clinics and public hospitals, and
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the level of access to health care outside the trial
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for those people is getting worse, I think, rather
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than better.
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In San Francisco, we are actually closing
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the pharmacy for San Francisco general hospital,
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which means people will not get medicines for high
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blood pressure, diabetes, standard things because of
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budgetary cuts.
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for a sizeable part of the population.
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That is the hospital of last resort
They are recruited into clinical trials and
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sometimes targeted because there is a higher
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prevalence of the condition, and I think I am
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troubled by what sometimes, I think -- I may be
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reading into this -- is the sense that things may
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happen here, but by and large, people do have access.
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My sense is that there are trials here that
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are designed to target people who do not have access,
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and I would just like us to say we think it is wrong
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if it happens in a Third World country and we think
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it is wrong if it happens here.
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problematic either way, and I guess I do not see what
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we lose by saying we have problems in our own back
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yard and we should deal with it.
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It is ethically
You know, again another example:
Earlier on
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there is the example of contraceptive clinical trials
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in Puerto Rico a number of years ago.
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is really in our back yard and so I think we need to
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sort of be willing to say we blew it here, we still
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have problems, we think it is wrong, we object to
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people being entered in clinical trials where the
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likelihood of their having access to a drug if proven
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effective is not very good.
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You know, that
So I just want to sort of leave that out as
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a plea, and I do not think that it weakens our
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argument, but I think it makes us more consistent in
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where we direct our criticism.
Let me just raise one other point which is
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all the way at the end.
I understand that Chapter 5
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is the chapter that has, you know, sort of been not
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as -- we have not had the opportunity to discuss it
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as much.
Chapter 5, Recommendation 5 has the
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recommendation for oversight where -- let me just
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flip to it for a minute.
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in the research protocol a description of the
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mechanisms of oversight at the institutions where the
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research is to be conducted.
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the adequacy of these mechanisms and the review and
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approval process."
Two things:
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"Researchers should include
U.S. IRBs should assess
One I think we need some
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clarification language, and it can be in the
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discussion in the recommendations, what we mean by
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"oversight" because it can mean lots of different
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things.
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oversee what IRBs are doing in the host country.
One is that it could mean are we supposed to
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Another thing is we are going to oversee the
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informed consent process particularly in a situation
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where we are saying that signatures and thumb prints,
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which are the usual means of documentation, may not
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be appropriate.
How then are we going to assure
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ourselves that people were not coerced and understood
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and really comprehended what they were getting into?
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It seems to me that is a big issue.
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The third issue is, is the protocol carried
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out in practice the way it was written when it was
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submitted?
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were a number of respondents who said, "You know, we
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really do not know what actually goes on out there
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once we approve the protocol?"
In Nancy Kass' study there was -- there
It is somewhat true
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in the U.S. as well, but it seems to me we have less
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assurance that we are going to find out, or we may
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have less assurance we are going to find out, if
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there are problems with implementation abroad.
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Finally, I think it is the adverse event
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reporting in a clinical trial which sometimes falls
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under the mechanism of oversight and I would just
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like to say I would like to, sort of, sort that out
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because it seems to me on some of those, I think, we
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can really hold the researchers accountable.
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ought to be accountable for -- if I am a PI doing a
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study in a developing country, I ought to know what
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the consent process is and be able to satisfy myself
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through site visits, through checks, through whatever
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kind of direct independent observation process that
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the consent process is, in fact, a valid one.
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They
I think I ought to be responsible for
assuring that the protocol in the field is actually
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carried out the way it is written.
It seems to me
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there is some quality control things that ought to be
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written in that are standard in a lot of U.S.
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clinical trials and we ought to expect to say that.
I think particularly now with the increasing
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emphasis on monitoring adverse events, I ought to
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have some system in place for monitoring adverse
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events in developing countries.
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So I think I ought to be really responsible
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for that and it seems to me the IRB ought to be able
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to have some judgment into that, although again there
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is a caveat that Nancy Kass' study alluded to that
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U.S. IRBs may be not very expert at judging what goes
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on in developing countries according to some of the
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researchers.
I do not -- I mean, I am a little more
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concerned if by "oversight" we mean someone here is
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going to check up on what an IRB is doing abroad.
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mean, there is a number of nice quotes elsewhere in
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the study that say we do not have a clue what goes on
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there.
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You know, we do not speak the language, it is far
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away, the phone system does not always work,
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whatever.
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a U.S. IRB passing judgment or a researcher in the
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U.S passing judgment on the deliberations of an IRB
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without some greater assurance that there is real
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You know, some of it, I think, is alarming.
But I think I am a little concerned about
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knowledge of what goes on.
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I know that sometimes with a lot of good
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communication you can have a good sense, but what
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bothers me about this recommendation is that it is to
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me something I would like to see.
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is very far off from what goes on now and we need to
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take into account in the accompanying language the
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sense we want to get there, but that we are very far
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from that now and some things are going to be harder
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It seems to me it
to provide oversight over than others.
So I am going to stop there and see if that
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strikes a chord with anyone?
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DR. MESLIN:
Bernie, I am going to ask you
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in a minute if you can make some specific proposals
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for how you want to deal with some of those but I
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know Trish wants to make a comment.
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PROFESSOR BACKLAR:
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DR. MESLIN:
Yes, after --
Oh, I should make the note that
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when you are speaking you should push a button so
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even though you are not going to speak, the next time
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you do push a button.
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Reactions to Bernie's suggestion because we
do want to put it into some context?
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Jim Childress?
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PROFESSOR CHILDRESS:
Well, particularly
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regarding the first one.
It seems to me that since
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our audience is not only researchers and sponsors in
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the U.S. but, in fact, a worldwide audience, that we
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would look rather silly if we do not recognize the
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problems in the U.S.
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our report credible if we fail to see, for example,
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why in the World Health Organization in a ranking of
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health care systems our's is 37th given the great
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quality we have.
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unequal access, and I think failing to build that
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into the report in an adequate way -- and I think we
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actually do at some points later on say more than we
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say up front.
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shifting some paragraphs around.
And it is pretty hard to make
Obviously that is largely due to
It might be a matter in part of
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DR. MESLIN:
Other thoughts?
Bette?
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MS. KRAMER:
My recollection is that we
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discussed this issue in San Francisco and that we had
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decided to incorporate in Chapter 1 some language
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that was very, very much up front and that addressed
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the situation in the United States.
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DR. MESLIN:
Alta, I know you will let us
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know when you want to speak but this might be a good
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chance to check in with you.
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PROFESSOR CHARO:
Thank you.
I would just
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say that I actually did take a try at a paragraph,
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which you reproduced in your memo, on the top of page
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3 of your memo, that I say exactly that.
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DR. MESLIN:
So just so commissioners are
following along, even though Bernie was making
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comments about Chapter 5, Bette was referring to
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earlier explanatory language that now Alta has
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already circulated to us.
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I want to make sure that we are on your
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point, though, Bernie.
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and I want to make sure that we are not getting away
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from your oversight concern.
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DR. LO:
You started with oversight
Alta's, the way I printed it out,
it is the next to the last comment about Chapter 1.
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Is that right, Alta, where it says, "While most
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Americans do have access to the fruits of health
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research."
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PROFESSOR CHARO:
Yes.
And although it is
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now in that memo listed as something for Chapter 1, I
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really did not have any -- I did not have any
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attitude about where it would go.
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to capture the point that was made in San Francisco.
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DR. LO:
Yes.
I just was trying
I guess I would be a little
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more blunt.
I think it is more than controversial.
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It is problematic or troubling or just plain wrong.
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PROFESSOR CHARO:
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DR. MESLIN:
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DR. MIIKE:
That is fine by me.
Larry?
While we are on that specific
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suggested quote by Alta, I do not agree with the last
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sentence of that section, which states boldly that
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our concerns overseas are because of our concerns of
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unequal access in the United States.
It is a
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parallel concern.
I do not think it is one that one
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-- the international area follows because of our
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domestic.
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DR. MESLIN:
Alex?
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PROFESSOR CAPRON:
Sticking with the point
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that Bernie was making, do I understand that on page
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the requirement for assessing the adequacy of host
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country review on the IRB's shoulders, Bernie?
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DR. LO:
I guess I -- that is partly it.
I
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guess I would start by saying I would want us to
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clarify in the accompanying language what we mean by
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oversight and sort of break it out a little, and to
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try and say some of this oversight investigators
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ought to be used to be doing as part of their
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preparation of protocols and IRBs in the U.S. are
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used to reviewing at least in the domestic context.
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That would be the consent monitoring, carrying out
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the protocols, quality assurance and monitoring of
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adverse events.
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Now it is not always done well, obviously,
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given the recent criticisms that we have had over
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gene therapy, but at least it is on the board.
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are examples of how to do it well.
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There
I am more concerned -- you are right -- that
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when it comes to overseeing or judging the
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acceptability of ethical review by the host country
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IRB, I think it -- we ought to know about it and as
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an investigator I ought to have some sense that it
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is done right, but I think that is a very, very new
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task and I am not sure there are parameters on, sort
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of, how to go about doing it or how to set it up.
PROFESSOR CAPRON:
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Well, my sense was that a
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few of the people, perhaps Dr. Pape from whom we
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heard, who themselves move between two institutions,
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have facilitated the American institution in being
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familiar with what goes on in the developing country
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institution, but I think I agree with you that in a
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way it is odd to put this as a responsibility on the
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IRB.
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We have a discussion in here about the
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movement away from SPAs to MPAs and certainly the
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suggestion is that -- whichever U.S. agency it is, if
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it is the Office for Human Research Protections or
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whatever -- that negotiates the assurance is the body
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that has that responsibility.
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course it would not be true, to the best of my
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knowledge, that in the United States were an American
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investigator collaborating with colleagues at another
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U.S. institution that his or her home IRB would be
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passing judgment on the adequacy of the processes of
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the other IRB.
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protocol.
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protocol which had been approved by another IRB but
And in the ordinary
They would pass on the research
They might ask for changes in a research
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they would not be generalizing that to saying that
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the other IRB does or does not have adequate
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processes or mechanisms or anything else.
I mean, it does seem to me that, that is a
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responsibility.
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engage in even if there are examples of some that are
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seen through years of interaction with a particular
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investigator who, in fact, has two home institutions
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to have developed that level of knowledge, and as we
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were told, I believe, even exchanges between the two
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IRBs.
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can have great benefit, but I do not suppose that we
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would require that.
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It would be difficult for an IRB to
And I think that is obviously something that
And I am not sure whether Bernie's comments
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strikes Ruth and Alice as pointing out something
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which they agree would be a problem or if they did,
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indeed, have in mind that we had indicated that we
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wanted the IRB to play that role, because I am
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conscious of the fact that sometimes we have had
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discussions of a point and seemed to have come to a
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conclusion and this is their attempt to convey that
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conclusion.
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So if we have substantively said that we
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thought the IRB rather than OHRP or some other body
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would be doing this, I would be interested to be
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reminded about it if there are countervailing points.
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Otherwise I would agree with Bernie's point and I
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think that the appropriate place to correct the
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discussion is around pages 24 and 25 in the chapter.
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DR. MESLIN:
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DR. MACKLIN:
Ruth?
Yes.
I think we can handle
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this by clarifying.
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words here and, in fact, it is the case that IRBs in
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this country would do an analogous thing with respect
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to a multi-center trial.
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I mean, notice the specific
The wording says, "Researchers should
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include in the research protocol a description of the
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mechanisms of oversight at the institution where the
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research is to be conducted and the IRB should assess
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the adequacy of these mechanisms."
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were no IRB review in the host country.
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be something -- but there was someone else who rubber
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stamped it.
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Now suppose there
That would
In this country if there are collaborating
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institutions or if people are transferring human
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biological materials from one place to another, you
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look to see that there has been IRB approval in
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another institution.
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So, I mean, spelling this out as Bernie
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requests, I think, will handle it.
It surely does
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not imply that the U.S. IRBs are scrutinizing the
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actual work of the other IRB but if it is material --
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if it is information that should be in the research
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protocol then the research protocol should describe
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things like there will be progress reports, there
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will be -- I mean, any of the quality assurance.
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that all the U.S. IRB is looking to see is that the
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protocol that is submitted by a U.S. researcher to
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this country and to another IRB includes the -- some
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description of what is going to be done there and
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that is in the protocol.
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So
It does not follow that the IRB here is
going to determine what the IRB in another country is
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going to actually do.
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points that Bernie makes that investigators are
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capable of doing and not capable of doing, maybe if
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we spell those out it will be a little clearer.
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DR. LO:
No.
So, I mean, with the kinds of
I think this may be a
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situation where just some clarification would be
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useful and I think Alex's, you know, way of framing
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it, I thought, was useful, as was Ruth's.
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PROFESSOR CAPRON:
If I may, Ruth, I am glad
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that we are all intending to say the same thing.
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think the phrase "a description of the mechanisms of
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oversight," I agree with you, is unexceptionable.
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The kinds of examples you gave were not mechanisms of
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oversight as I understood them.
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reports have to come back to the U.S. IRB because a
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U.S. investigator is conducting the research.
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is the U.S. IRB's own obligations and so forth.
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I
I mean, progress
It is the adequacy of the mechanisms.
That
It
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does not seem to me a progress report is a mechanism
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of oversight at the institution.
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oversight is the IRB.
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seems to me would be knowing that it has an assurance
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with an appropriate federal agency is the way that
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you determine its adequacy.
The mechanism of
And assessing its adequacy
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Now I think we can in commentary perhaps say
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more about the value of collaborative relationships.
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We talk elsewhere right from the beginning in Chapter
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review process and this would certainly be something
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that could be cited in an exemplary fashion as -- if
13
that occurs without the suggestion that it is the
14
obligation of the IRB as opposed to the obligation of
15
an OHRP to assess the adequacy of that mechanism.
16
It would certainly be true that that is an
17
important task knowing that the mechanism is not
18
merely a proforma, that the IRB is appropriately
19
constituted, that it has some way of getting the
20
results that are expected of it.
21
22
DR. MESLIN:
Eric Cassell, you had your hand
up before.
23
DR. CASSELL:
24
DR. MESLIN:
No.
I want to just take everyone's
25
temperature and see whether, Bernie, the comment that
26
you started with because you are going to leave
27
shortly and then come back later, hopefully, has that
22
1
been addressed well enough by the commission so that
2
you can leave knowing that you have got an answer to
3
your question at least?
4
DR. LO:
Yes.
5
DR. MESLIN:
6
DR. MACKLIN:
Good.
Ruth?
Just one more point.
7
Following what Alex just said, is the phrase
8
"mechanisms of oversight" the wrong phrase here?
9
other words, do we have to -- there are two options.
10
One is to keep the recommendation and clarify in the
11
text.
12
recommendation so it does not mislead or have the
13
implications that Alex, suggested so I want to know
14
which is better.
15
In
The other is to change the wording of the
PROFESSOR CAPRON:
Well, I was taking your
16
first point to be correct that the IRB locally -- a
17
U.S. IRB would want to know that there is a process
18
and a description of it would be that there is an IRB
19
there that is appropriately constituted and that
20
operates under either an SPA or an MPA at the
21
institution.
22
It is the second sentence that they have to
23
assess the adequacy of that mechanism in the review
24
and approval process that would concern me, and I
25
would continue to be dubious that U.S. IRBs take that
26
as their function vis-a-vis collaborating
27
institutions.
Certainly in multi-center trials they
23
1
look at the protocol.
2
And, as I say, they sometimes -- I mean,
3
people who conduct such trials sometimes pull out
4
their hair because one IRB will look at something
5
that has been approved elsewhere and say, "Sorry, at
6
our institution that consent form or that description
7
of how the project is going to be conducted will not
8
fly."
9
University of X IRB must be inadequate.
But they are not there by saying ergo the
They are
10
simply saying we cannot have our investigator
11
participate under those terms even if he is going to
12
the University of X to do it where they think it is
13
okay.
14
DR. MESLIN:
Bette, and then Bernie.
15
MS. KRAMER:
Bernie, do you want to answer
16
17
Bette?
that?
DR. LO:
Well, yes.
To pick up on Alex's
18
point about oversight.
19
we are saying that researchers have to provide in the
20
protocol and IRBs have to review is a process by
21
which the researcher is going to ensure that ethical
22
issues are addressed adequately after the protocol is
23
approved by the IRB and the protocol actually goes
24
out in the field and is implemented.
25
I mean, it seems to me that
It seems to me I am thinking of things like
26
consent, actual implementation of the protocol, and
27
adverse event reporting, which to me is different
24
1
than oversight at the institution, which really has a
2
ring of sort of compliance with regulations and sort
3
of how the institution works.
4
It is really that the trial itself as it
5
moves forward adequately addresses human subjects
6
protection as it is being implemented.
7
DR. MESLIN:
Bette?
8
MS. KRAMER:
Before Bernie leaves I would
9
like to go back to the first point and that is the
10
attention we are going to pay to domestic research
11
and I wonder -- are the other commissioners satisfied
12
with the language that Alta has suggested?
13
extensive enough?
Is that
14
I am afraid -- as I think about the report
15
and all of the allusions to the -- the allusions to
16
the fact that most Americans have adequate access to
17
health care, I am concerned that this one paragraph
18
of just a few sentences is sufficient to state our
19
position, that that is not the case.
20
DR. MESLIN:
21
opportunity to say something?
22
Alta, was the breath an
PROFESSOR CHARO:
It is possible that if we
23
went through the entire report line by line we would
24
find every reference to the U.S. situation.
25
the point has been made several places that we have a
26
lot of people who do have access and a very
27
substantial minority that do not.
And if we
I think
25
1
continually make both those points, I think, we will
2
be fine.
3
DR. MESLIN:
4
Thanks, Alta.
5
Bernie?
6
DR. LO:
Yes.
Bernie?
I think that, you know, when
7
we see subsequent revisions of -- you know, we will
8
have to just sort of go through and make sure there
9
are not other places where we say something that is
10
not quite what we mean to say.
11
and I think we will just have to look and see as the
12
draft evolves to make sure we have handled those
13
okay.
14
DR. MESLIN:
15
PROFESSOR CHILDRESS:
I noted some of those
Jim?
Bernie, it might be
16
useful if you could give some documentation of the
17
kinds of examples we are talking about where we are
18
actually targeting that population.
19
familiar with them anecdotally but it still might be
20
useful in this kind of report to have documentation.
21
DR. LO:
We are all
I had tried to give a cite, which I
22
do not have, to an article run in the Wall Street
23
Journal a number of years ago about Indianapolis.
24
do not know if that has been tracked down because
25
that was a news story that got a fair amount of play.
26
I just do not have the exact reference.
27
Alice has got it.
I think
I
26
1
PROFESSOR CHARO:
2
DR. MESLIN:
3
PROFESSOR CHARO:
Eric?
Yes, Alta?
I also want to just remind
4
all of us about the reason why we are discussing
5
this.
6
the U.S. health care system.
7
understanding the justifications that have been used
8
for putting people into research situations at all.
9
As I recall the analysis, it was that one of the
It is not entirely about a characterization of
It is about
10
reasons we are comfortable with the notion of making
11
people research subjects is that there is a broad-
12
based benefit that will come back to them eventually.
13
And keeping that in mind I think it is fair
14
to say that the majority of people in the States,
15
most research benefits are likely to rebound to them
16
at some point in the future.
17
absolutely true, as Bernie was noting, that there are
18
substantial swaths of society for whom that is not
19
yet true.
20
So although it is
And keeping that in mind, I think the
21
pressure has lessened a little bit to try and do a
22
kind of complete description of the inadequacy of the
23
U.S. health care system, because the point simply is
24
we have a reason why we justify research on human
25
beings in the United States and where that
26
justification does not exist in the U.S., as in the
27
recruitment of homeless men, we find that it is, in
27
1
fact, quite alarming to us and that is why I wrote
2
that we find -- it should not be surprising that same
3
kind of alarm or distaste is triggered when you look
4
abroad.
5
justification.
I mean, it is about the lack of a
6
DR. MESLIN:
7
DR. CASSELL:
Eric Cassell?
I want to underscore Bernie's
8
first comment about this subject of health care.
9
is not just homeless men.
10
It
It is large populations of
poor people.
11
In general, the report reflects a disease
12
fallacy that when people sicken and die, it is the
13
disease that is the whole issue, when in point of
14
fact it is not the disease, although the disease may
15
be the thing that kills them ultimately.
16
things that go with poverty, the increased death rate
17
from every disease among the poor more than among the
18
comfortable.
19
are targeting where malnutrition and other factors
20
play a much larger part probably than the absence of
21
medical care.
22
All the
And certainly in the countries which we
I think that we just have to make it clear
23
that it is this situation that we are trying to bring
24
good ethical research into, not simply something
25
having to do with a bad thing called a disease and so
26
forth and so on.
27
DR. MESLIN:
Alex?
28
1
PROFESSOR CAPRON:
I have shared the
2
concerns that Alta and Bernie have expressed on this
3
subject and they led me to look back at the first
4
chapter, and right from the beginning to think that
5
it would be good to tie what we are doing in here
6
more firmly with the whole history of human subjects
7
research and, in particular, with some of the
8
discussion that the National Commission had 25 years
9
ago that led to language in the Belmont Report.
10
I have prepared and asked the support staff
11
here to produce a few pages at the beginning, a
12
revision of the way into the report, and I gather we
13
have time this morning for the discussion.
14
rather than read it out to you, it may be easier just
15
if you will expect that there will be this
16
opportunity for people to look at it and we can
17
discuss it.
18
And
I think Alta's suggested language in the
19
memo does belong in here but I think that the sense
20
that we are somehow looking at problems which only
21
occur abroad and that are new to the field because of
22
research which occurs when a rich nation does
23
research in a poor nation can be combatted.
24
And I think the report already has right at
25
the beginning the very firm statement about the
26
premise that research will be relevant to the
27
population and that that emphasis, what was needed,
29
1
and what I tried to bring in was the notion that by
2
looking abroad we then have a perspective to look
3
back at what happens in this country and to be
4
reminded that it is equally a concern here and it may
5
reflect on either the adequacy of the federal
6
regulations or of their implementation.
7
And what I have is simply a draft and I am
8
sure that others will have a lot of improvements in
9
it but it is a suggestion I have for changing the way
10
we begin the discussion, and rather than just make it
11
as a comment, I sat down and tried to write it out to
12
give us something, and I am sorry that I do not have
13
a printer with me so I am dependent upon it being
14
printed out in a few minutes.
15
DR. MESLIN:
16
Ruth?
17
DR. MACKLIN:
18
19
Thank you.
Maybe once we see Alex's pages
it will set this whole discussion to rest.
Alice Page and I looked through the entire
20
report after getting these comments, especially
21
Bernie's comments and the discussion that ensued, to
22
see what we actually say about the U.S. health care -
23
- people's access to treatment in a percentage.
24
Without a lot more empirical information and
25
statistics, we cannot say anything more specific than
26
using words like "some, many or most."
27
fact, those are the words that are in here.
And, in
"Some,
30
1
many or most."
Otherwise, you have to be very specific and
2
3
have some kind of statistical backing.
4
would look ludicrous if we mentioned only homeless
5
men in studies.
6
population.
It is a very small percentage of the
Eric Cassell says, "Well, it is not only
7
8
Surely, it
homeless men.
It is other people, too."
But we really have to have something more
9
10
precise and Jim mentioned earlier that if the report
11
is to be credible we need to acknowledge why it is
12
the United States is 37th in this ranking.
13
Also, in order to be credible, we cannot
14
portray the United States as looking like Uganda.
15
would -- this report would be a laughing stock if, in
16
fact, some of the countries in Africa read this
17
report or people in those countries, and then looked
18
at this and said, "They are trying to say that things
19
are just as bad in the United States as they are
20
here?"
21
We
The reason that things are as bad in this
22
country as they are is that there has been no
23
political will to provide universal health care and
24
we are not going to go down that path in this report
25
but, in fact, no matter what the political will is in
26
Uganda they cannot afford to provide even drugs for
27
tuberculosis and malaria.
In this country you can
31
1
spend $60 billion dollars on some missile to shoot
2
another missile out of the air but they cannot afford
3
or have decided that they are not going to allocate
4
this money for health care.
So I think we would have to say a lot more
5
6
if we want to go down this road of saying, "Gee,
7
things are really bad here, too, and we have the same
8
problems here as you have in Uganda."
DR. MESLIN:
9
Diane, and I apologize.
I had
10
you on the list and I did not recognize you before.
11
I am sorry.
DR. SCOTT-JONES:
12
I just wanted to add a
13
couple of comments to this discussion and I think
14
that in the report we can strike a balance without
15
saying that the United States is as bad as Uganda,
16
uniformly.
17
concern is the differential access to health care and
18
there are pockets in the U.S. where conditions are as
19
bad as in developing countries.
20
access to health care.
21
issues.
22
I think the real issue that is causing
And it is not just
It involves some of the other
For example, on page 3 there is a reference
23
to individuals being incapable of informed consent
24
because they are illiterate, unfamiliar with the
25
concepts of medicine held by the investigators, are
26
living in communities in which the procedures typical
27
of informed consent discussions are unfamiliar.
That
32
1
also characterizes communities within the U.S., as
2
well, and I think it is important for us to make a
3
strong statement in this first chapter about these
4
conditions in the United States that in certain
5
communities are very much like those in developing
6
countries.
DR. MESLIN:
7
8
Eric, were you going to
comment?
DR. CASSELL:
9
Well, I do not think that -- I
10
mean, we can get into an extended discussion of it,
11
but the issue is not simply making us look good or as
12
bad as Uganda.
13
fact remains that there are people in the United
14
States below the poverty level.
15
below the poverty level who do not have access to
16
adequate medical care or medication and so forth.
That is not what the issue is.
There are numbers
It is not that we are terrible.
17
The
That is not
18
the point.
19
a developing nation and us because our people have
20
where their people do not have, is the fallacious
21
contrast.
22
also.
23
That does not change anything in Uganda or what are
24
problems we have to address there.
25
The point is to make the contrast between
We have this problem -- these problems
That does not change the issues in Uganda.
It really tries to take away using us as a
26
contrasting good against that particular bad.
The
27
bad there in terms of consent and all of those things
33
1
remains.
It does not matter what you say about the
2
United States.
3
place is terrible.
4
there are realistic problems here and the contrast is
5
the mistake.
So we are not trying to say that this
We are trying to point out that
6
DR. MESLIN:
Trish Backlar?
7
PROFESSOR BACKLAR:
I just wanted to make
8
the point that when this report goes out for public
9
comment, it is going out at a time when there is a
10
great deal of public discussion about access to
11
medications and drugs.
12
difficult that may be if you do not have the right
13
kind of insurance and certainly there are many people
14
in populations that I am very familiar with,
15
vulnerable populations, who have terrible
16
difficulties in accessing medications because of the
17
type of insurance or lack of insurance that they
18
have.
19
And I personally know how
This is a real problem for many people and
20
we might even have numbers on that.
21
that those are not available to us, but I do want to
22
point out it will be very embarrassing for a report
23
to go out that indicates that we do not have these
24
kinds of problems precisely at the time when we are
25
having a public discussion about this.
26
DR. MESLIN:
27
DR. MIIKE:
I do not know
Larry?
Yes.
I think we are just
34
1
falling into our usual mode about talking about what
2
I consider background and peripheral issues without
3
getting on with the rest of the report.
4
everybody has expressed their concern.
5
some serious problems, do what Alex has done, which
6
is put some suggested language in.
7
on.
8
DR. MESLIN:
9
PROFESSOR BACKLAR:
DR. MESLIN:
10
I mean,
If you have
Well, let's move
Thank you.
Thank you.
Are there any other comments?
11
We are essentially letting Harold get his notes
12
together.
13
return to the memo, which is really where we are now
14
with Chapter 1.
Now that Bernie has left, we are going to
15
Chapter 1 comments?
16
Yes, I am -- so for those -- let's really
17
focus on suggestions for new language, if necessary.
18
Alta has indicated a couple of large blocks
19
of proposed text in a memo that I circulated.
I
20
think it would be useful to get a sense from the
21
commissioners as to whether these blocks of text --
22
realizing that Alex also has some blocks of text to
23
suggest -- are going in the direction that you want
24
them to.
25
those blocks of text and we can do edits to make them
26
more appropriate but in order for us to get through
27
the morning in the most useful way possible, we need
You simply need to agree more or less with
35
1
to get your general consensus on these proposals.
Alta, I do not want to turn back to you
2
3
because you have already -- and spend more time, but
4
is there anything you want to say in the event that I
5
have put your paragraphs in the wrong spot in the
6
memo?
7
two large blocks?
Do you want to say anything more about these
8
PROFESSOR CHARO:
9
DR. MESLIN:
Okay.
No.
Are there any comments
10
from commissioners about whether these -- this text
11
should or should not be incorporated into Chapter 1?
12
Diane?
13
DR. SCOTT-JONES:
It would be helpful if
14
Ruth and Alice or Alta have suggestions for where to
15
place these particular blocks of text because we have
16
read the chapters as given us and it would be helpful
17
to know what they would substitute for, where they
18
would go.
19
DR. MESLIN:
We might want to ask Alta as
20
well but I do not know whether -- Ruth or Alice, do
21
you have thoughts about where they might go?
22
DR. MACKLIN:
Actually our strategy was to
23
see whether or not the commissioners -- they are not
24
going to substitute for anything.
25
addition.
26
DR. MESLIN:
27
DR. MACKLIN:
They would be in
Be insertions.
They would be insertions and
36
1
our strategy was -- rather than redraft any chapters
2
or make those decisions, we wanted to see what the
3
commissioners thought of those paragraphs.
4
can say now is they would go in a suitable place to
5
support or further elucidate what is there in chapter
6
1, but they would not replace any existing text.
7
DR. MESLIN:
8
DR. DUMAS:
So all we
Rhetaugh and then Trish.
Yes.
I would just like to say
9
that I think that the material that has been proposed
10
by Alta is acceptable to me and it is clarifying, and
11
I think it addresses -- although maybe not to the
12
extent that some people would like it -- the issue
13
that we have just heard raised about comparisons
14
between other countries and this country.
15
So I am happy with the statement and I think
16
that the one on page 3 of your report having to do
17
with conditions in the United States is adequate for
18
purposes of this report, as I see it.
19
would make a mistake to get into a lot of detail
20
having to do with comparisons of hardships and bad
21
problems.
22
I think we
I think we need to keep the emphasis on
23
ethics of research involving human subjects, no
24
matter where they are, and when they are in resource
25
poor countries, what kind of provisions, exceptions,
26
or what have you, are warranted.
27
DR. MESLIN:
Trish?
37
PROFESSOR BACKLAR:
1
I just -- I thought
2
possibly that Alta's suggested language should go in
3
somewhere in the section on justification for writing
4
this report, and that starts on page 10.
5
DR. MESLIN:
6
DR. MIIKE:
Larry, and then Eric.
I actually have a constructive
7
suggestion instead of just all lashing out.
On
8
Alta's first quite long excerpt, I have some qualms
9
about it but it is okay with me, and if it is going
10
to be somewhere, it should be in sort of a point
11
counterpoint discussion in Chapter 4 around
12
Recommendation 4, which is the one I suggest we split
13
rather than combining, access to country, because
14
that would be where that discussion should go.
Alta's second quote on the situation in the
15
16
U.S., as I said, I do not agree with the last
17
sentence of that short answer and I would delete that
18
part.
The rest of it I do not have a problem with.
19
DR. MESLIN:
20
DR. CASSELL:
Eric?
On paragraph 3 of Alta's
21
proposed insert for Chapter 1, I am not -- it is not
22
clear to me what that means and I wonder if Alta
23
could make that clearer.
24
you are saying, Alta.
25
PROFESSOR CHARO:
Just make it manifest what
Sure.
I can try to
26
rewrite it and make it more straight forward.
27
Basically if a sponsor is, in fact, the cause of the
38
1
unaffordability of a drug, it would seem that the
2
sponsor's claim that it is now time to test cheaper
3
alternatives is a claim that is weakened because the
4
sponsor is responsible for creating the situation
5
that now leads us to need to look at cheaper
6
alternatives.
7
The rest of the material tries to explain
8
that in most situations the sponsor is not the sole
9
cause of this problem but that there will be some
10
11
times where it is.
DR. CASSELL:
And then how does that impact
12
on the issue of designing the trial so that it is
13
ethically acceptable?
14
PROFESSOR CHARO:
In those situations where
15
the real problem is solely the unaffordability of a
16
particular kind of drug and not the variety of
17
conditions that are identified elsewhere, it seems to
18
me that it is harder to conclude that it is ethical
19
to test cheaper and less effective alternatives
20
because the drug is not affordable, since that is a
21
correctable problem.
22
And it is especially problematic when it is
23
the same company that is making the expensive drug
24
that is now saying, well, now we have got to test the
25
cheaper alternative.
26
Do you understand what I am saying?
27
DR. CASSELL:
I understand it.
I am not
39
1
sure of its applicability here.
PROFESSOR CHARO:
2
3
I am sorry.
I could not
hear you.
DR. CASSELL:
4
I say, I understand what you
5
are saying but I am not sure of its applicability in
6
a report about ethical issues for overseas research
7
that are supposed to impact on the kind of research
8
that is done, and who does it, and how subjects are
9
chosen, and so forth.
PROFESSOR CHARO:
10
Well, let me put it this
11
way.
If drug company, you know, Molly, you know, if
12
Molly makes the right drug and they sell it at a
13
price that is completely unaffordable in both private
14
and public sectors in another country, and then they
15
want to hire a researcher from my institution to run
16
trials on another drug that they are going to propose
17
that is the cheaper and less effective alternative,
18
and I am sitting on the IRB, I think that it should
19
be something I consider.
Should we, in fact, get involved in testing
20
21
a less effective drug than a standard therapy when
22
the sponsor could, in fact, make the right drug
23
available at a price that is affordable.
24
that is a relevant part of my analysis as to whether
25
or not I should approve this protocol as an IRB
26
member.
27
DR. CASSELL:
I think
Well, I actually do not, but I
40
1
mean the commissioners will have to express
2
themselves, but I, myself, find that paragraph not
3
useful.
DR. MESLIN:
4
5
language?
6
DR. SHAPIRO:
7
DR. MESLIN:
8
DR. SHAPIRO:
9
Any other comments on that
On that particular paragraph?
Yes.
I have a comment on the -- I
have a whole series of comments but only one I want
10
to raise now on this first proposed change.
It
11
occurs in the second paragraph here, the one that
12
begins "All these problems."
13
editorial comments.
I will eliminate any
I think in a good deal of the discussion we
14
15
have had, in my judgment, there is a confusion over
16
the ethics of doing research and just what is
17
appropriate or inappropriate in a system governed by
18
various kinds of market organizations, intellectual
19
property rights, patents, et cetera, et cetera.
20
I think those are two different things.
21
would suggest -- and I think confusing them does not
22
help us straighten out where the ethical
23
responsibilities lie.
And
Therefore, I
24
If, for example, the high price of
25
pharmaceuticals is a problem there are many solutions
26
to that.
27
companies ought to behave.
Only one deals with just how pharmaceutical
I mean, it is easy enough
41
1
just to suggest another one that resource rich
2
governments buy these medicines and give them away.
3
I mean, that is just another solution.
4
suggesting it, but it is another solution and it is
5
just as ethical as anything dealing with property
6
rights and changing the system under which these
7
drugs are developed.
8
9
I am not
That leads me to change the second paragraph
here by taking the sentence that begins "One area"
10
and simply crossing out the next seven lines down to
11
the sentence that begins "One recent response."
12
the way I could tie it in to the issue, which is a
13
genuine issue, that is the cost of pharmaceuticals
14
certainly is an issue, I would just write, "One
15
recent response to the cost of pharmaceuticals, for
16
example, has been an agreement to lower..." and so on
17
and so forth because that is a plausible enough
18
response, and it is a serious problem.
19
And
I do not find dealing with issues of
20
protections of licensee's legal rights, fiduciary
21
views of stockholders, profits, and so on, something
22
which we really have thought carefully about or know
23
whether or not this is the source of the problem.
24
may be the source of the solution.
25
It
I do not want to argue that point, but it
26
seems to me it is just unnecessary and the points
27
that Alta makes very effectively here can easily be
42
1
made without taking on that, which is a much bigger
2
subject, which we really have not dealt with in any
3
way.
4
Yes?
5
PROFESSOR CAPRON:
What I am unclear about
6
is whether this is something which is part of the
7
issue in Chapter 1 or in Chapter 3 about the design
8
of studies.
9
there and I turn to the authors to ask if they have a
It seems to me that it might fit better
10
sense.
11
which strike me as honing us in on what is most
12
relevant to our report as opposed to additional
13
problems.
14
15
16
I mean even with the chair's modifications,
Do you think it should be in Chapter 1 if it
is anyway?
DR. MACKLIN:
Well, it should be Chapter 1
17
because Chapter 1 sets up the whole problem to which
18
we return.
19
"See Chapter 3," and maybe that is all that is needed
20
is that note.
21
laying out the various research designs and then
22
saying which ones are acceptable or unacceptable and
23
for what reasons.
24
At various points in Chapter 1 we say,
Chapter 3 is much more specific on
This is a much more general point so I think
25
it should remain or if it goes anywhere with these
26
modifications it should go in Chapter 1 with a
27
reference to Chapter 3 where there is a much more
43
1
specific discussion.
2
DR. SHAPIRO:
3
DR. MIIKE:
Larry?
I had mentioned earlier that I
4
thought it belonged in Chapter 4 and the reason is
5
that --
6
DR. SHAPIRO:
7
DR. MIIKE:
Alta, what a paragraph?
No, no.
I mean the whole
8
quotation because it depends on how you -- what you
9
take away from this discussion.
If we are talking
10
about research design, that is one thing.
But I read
11
this paragraph to sort of say that pharmaceutical
12
companies owe a duty to these countries to make
13
prices -- make things affordable, et cetera.
And if that is the case then it does not
14
15
belong in Chapter 1 and it does not belong in Chapter
16
3.
17
appropriate response in our recommendations about
18
obligations to test subjects versus obligations to
19
country inhabitants.
It belongs in the discussion about what is the
20
DR. SHAPIRO:
21
conclusion into here.
22
read it that way but I have got to agree with Ruth.
23
It ought to fit somewhere in Chapter 1.
24
and we will refer back to it as we go into 3 and 4 as
25
appropriate.
26
27
I, myself, did not read that
I understand how one could
It is useful
Let's go on to the second comment.
Just to
make sure if there is any question regarding the
44
1
second comment that Alta made, and there is a comment
2
with respect to this chapter that is attributed to
3
Larry also, but any comment on what is really on the
4
top of page 3 in the memo that was distributed to us?
If not, then let's -- I have some -- excuse
5
6
me.
I am sorry, Arturo.
DR. BRITO:
7
I apologize.
I have kind of a general comment
8
about it and I was thinking how to phrase it because
9
I -- I think one of the issues here is just right at
10
the onset of this.
We are talking about the
11
paragraph that starts "While most Americans..."
12
right?
13
DR. SHAPIRO:
14
DR. BRITO:
Yes, indeed.
The fact that it goes on to say,
15
"...do not have access to fruits of medical research,
16
many have only limited access and some have near no
17
access at all," we are not really talking about
18
access to medical research, are we?
19
issue here is that because individuals -- or the
20
fruits of the medical research, right?
DR. SHAPIRO:
21
22
23
I thought the
Fruits of medical research,
right.
DR. BRITO:
The confusing thing here is that
24
somehow this deviates.
I guess it depends on where
25
it is going to go but it seems to deviate from -- the
26
issue at hand is that because a substantial number of
27
Americans do not have insurance at one point in time
45
1
or another, not because it is a complex system
2
necessarily, just because the system does not have
3
universal health care -- there is not universal
4
health care.
5
are -- when they lack health insurance are more
6
likely to become vulnerable and, therefore, enroll
7
themselves into research or be subjects of research.
8
Is that not -- maybe I am missing the point of this
9
paragraph here and where it goes but the --
I think the issue here is that people
DR. SHAPIRO:
10
I will turn to Alta in a
11
minute.
12
not feel good about using that population as human
13
subjects since they do not stand to benefit from any
14
of the possible successful results.
15
trying to show that even if this took place in this
16
country we would not feel good about it.
DR. BRITO:
17
18
21
Okay.
It is just
That is -- what I do not
-DR. SHAPIRO:
19
20
My understanding of this is that we would
That is all it is trying to
do.
DR. BRITO:
What I do not feel good about is
22
having somebody not so much because they are not
23
going to bear the fruits of that research but because
24
at the point that they are in the research they are
25
very vulnerable and being taken advantage of, and
26
could suffer consequences during the research.
27
DR. SHAPIRO:
That is an additional point.
46
1
I agree.
DR. BRITO:
2
3
So that is -- So I guess it
depends on where this is going to go but --
4
DR. SHAPIRO:
5
after we adjourn this morning.
Let's turn now to -- any other comment on
6
7
this paragraph?
Let's turn now to the comment attributed to
8
9
Larry.
Larry, do you want to say anything further
10
11
Our authors will work on this
about this?
DR. MIIKE:
12
It was just -- it was more an
13
incidental comment about what -- you know, what we
14
were talking about and were not talking about --
15
problems relevant to a country's population.
16
initial impetus for my making this statement is
17
really a little concern to me, but I do have two
18
other things.
So the
One is that I think that when we get -- once
19
20
we get past that simple statement, then we get into
21
issues like the one I originally raised, which is so
22
what.
23
if it is a problem we can deal with in the U.S., in
24
the population in the U.S., we should do it in these
25
other countries.
26
as you meet the ethical imperatives.
27
If it is a problem that -- are we saying that
And my answer would be, no as long
But there are two other things.
Out of this
47
1
arises -- once we talk about the health needs of the
2
country, then we have two opposing forces.
3
the side that says those who argue -- that says,
4
"Okay, we have to make it affordable in that
5
country," and then all of the issues around lower
6
prices, you know, prediscussions before the trials
7
continue on, et cetera.
8
discussions around Recommendation 4 in Chapter 4.
9
One is on
Issues around my --
The other side is this issue about most
10
effective treatment, and that side impinges on the
11
trial itself where one -- if you are going to take an
12
either/or position, one could argue that those who
13
say that the -- we must have exactly the same ethical
14
standards in the U.S. as in these other countries,
15
and that even though the host country is willing to
16
conduct trials, we are not going to let them do it
17
that way.
18
women trials.
19
come up once you get beyond just the simple statement
20
about health issues relevant to the country.
21
The whole issue about the AZT and pregnant
Those are the kinds of issues that
And I have not looked at the report to see
22
whether that kind of tome is in there, but clearly
23
those are two issues that arise once you get past
24
that initial statement.
25
DR. SHAPIRO:
I agree.
Those issues are
26
going to be right before us very shortly.
My
27
prediction is that it will not be a simple black
48
1
line, yes or no.
There is going to be areas which
2
are going to require decisions as each case goes
3
along.
4
how the commission feels.
That is my own judgment. We will have to see
5
Steve?
6
MR. HOLTZMAN:
7
I think it is important to take Larry's
Thank you.
8
dissention, and let's put aside the second for the
9
moment, which goes to the trial design, and tackle
10
squarely when is it morally acceptable to conduct a
11
trial in another country.
12
There is a sense that I get in reading this
13
-- and I do not think it is intended -- or let me
14
make that a question.
15
gating condition is the health problem being studied
16
(a) has to be relevant to the country in which you
17
are studying it and (b) that there has to be a prayer
18
of a chance at least -- let's just make that gating
19
for the moment -- that the resulting benefit will
20
become available -- will be reasonably available.
Assume for the -- that a
21
And what we need to get clear on at a level,
22
which I do not think we have exactly, is what -- are
23
we saying that if you could as easily study it in the
24
U.S., you ought study it in the U.S., because I think
25
that is where there is not a complete clarity.
26
27
So, for example, on page 7 where we make the
case, we seem to be saying that all things being
49
1
equal, just because it is cheaper over there you
2
should not be able to, or are we saying it is okay if
3
all things are equal.
4
entirely clear on what we are saying on this issue.
5
Now maybe others feel we are but I do not feel we
6
are.
7
DR. SHAPIRO:
And I find that we are not
I will speak for myself on the
8
cheaper issue, which I think is another issue that
9
tends to bedevil us unnecessarily.
It is my own view
10
that if other ethical requirements we laid out are
11
satisfied, substantive ethical requirements are
12
satisfied, that the fact that it is cheaper is sort
13
of an irrelevant issue for us to consider.
14
just my own view.
15
consider.
16
substantive ethical procedures are, in fact,
17
fulfilled.
That is
That is for someone else to
Our concern should be whether the
18
MR. HOLTZMAN:
19
DR. SHAPIRO:
20
MR. HOLTZMAN:
You see -That is my view.
And even the language of
21
cheaper, I think, maybe is the wrong language to put
22
here for the following reason, Harold:
23
real live situation is that for many of these
24
conditions, which exist both here and in the
25
developing countries, your rate of accrual of
26
patients will be faster.
27
DR. SHAPIRO:
I understand.
Because the
50
MR. HOLTZMAN:
1
A consequence of that is that
2
development and hence availability will be
3
accelerated --
4
DR. SHAPIRO:
5
MR. HOLTZMAN:
I accept that.
Right.
But not necessarily
6
other than in very large terms for the developed
7
nation.
8
deal with as opposed to creating, you know, a make
9
believe case that I go to a Third World country
I think that is the hard question we should
10
because it is cheaper per subject.
11
I can get the approval faster.
12
responsibility accrues to us by virtue of taking
13
advantage of that fact, if any?
14
question, I think, we should be tackling.
DR. SHAPIRO:
15
No, the issue is
What moral
That is the
I think that is -- I do not
16
want to take us off that.
I think we do have to get
17
directly to those kind of questions.
18
absolutely right as we formulate our recommendations.
19
I mean, I have my own view on the answer to that.
20
do not know whether this is -- I will share it at
21
some appropriate time.
I think that is
I
We ought to get to it.
22
In general, Larry, I found myself responding
23
positive to the suggestion you made here, and we need
24
to incorporate it in an appropriate way in the
25
report.
26
Okay.
Any other comments?
27
Let's go on then to just taking these.
We
51
1
can circle back to these areas as we go through this
2
but I want to make sure that we get through at least
3
the comments that have been noted in this memo and
4
then we can deal with other issues as they come up.
Bernie had some recommendations regarding
5
6
the repositioning of the recommendations with their
7
justification to bring them closer together.
8
Apparently the staff recommended moving
9
recommendations 1, 2 and 3 to be inserted later in
10
the document.
I, myself, feel not strongly but just
11
12
exactly the opposite way.
13
should be brought forward to where the
14
recommendations are, but that is -- I think we will
15
let the people who are going to actually write this
16
decide that in the end but, I think bringing them
17
together is a good idea.
But are there other comments on that
18
19
Namely the justification
particular issue?
Okay.
20
We will bring those together and
21
leave it, Ruth, for your judgment as to whether to
22
bring them forward or bring the recommendation
23
backward or whatever the right way to describe that
24
is.
25
There is also a proposal.
I think Alta may
26
have been the author of this or at least of this
27
particular language, which essentially takes
52
1
Recommendation 7 in Chapter 2 -- can someone tell me
2
which page that is on?
3
DR. __________:
4
DR. SHAPIRO:
14.
Thank you.
Which is on page
5
14-15.
6
Alta believes is a more effective and less ambiguous
7
way.
But, Alta, let me turn to you to see what
8
9
And tries to articulate it in what I believe
you would like to say about this.
10
Is Alta there?
11
PROFESSOR CHARO:
Oh, yes.
I am sorry.
12
is every once in a while people have been hard to
13
hear.
14
some e-mail traffic between me and Eric on this
15
point.
It
I think it speaks for itself and there was
16
DR. SHAPIRO:
17
DR. MIIKE:
Larry, and then Eric?
In the combination I think there
18
is some confusion being introduced, which may be in
19
the original two recommendations, and that is the
20
line that begins sort of in the middle of the
21
paragraph, "Where local custom requires..."
22
to me that what this thing says the way it is written
23
is that I think it confuses the issue of seeking
24
permission to talk to the woman with not -- with
25
seeking permission from someone else in place of the
26
woman's permission.
27
It seems
I think that if you read this where the
53
1
sentence says, "Where local custom requires a husband
2
or the family be approached for permission before
3
approaching an adult woman," then all these other
4
things follow.
5
that -- this to me is that -- I think we agree that
6
that can go on regardless of what it is as long as
7
the woman's permission is obtained.
Anyway, there is some confusion in there.
8
9
I think what was meant originally was
It is not really clear to me what is being said.
Second of all, it goes back to the original
10
11
recommendation which has been incorporated here by
12
Alta.
13
three.
14
substantial problem, et cetera, but I do not know how
15
one would ever decide when it would be impossible to
16
conduct research under these conditions, and I think
17
that is sort of a condition that I would rather see
18
deleted.
I do not really like condition one of the
I can live with two and three about the
19
DR. SHAPIRO:
Alta?
20
PROFESSOR CHARO:
My goal here was not to
21
change the substance of Recommendations 7 and 8 but
22
just clarify.
If it did not work, it did not work.
23
Larry, the idea here was to very clearly
24
separate the concerns about recruitment processes
25
from the concerns about enrollment, which is why
26
there is not a sub-A on recruitment and a second one
27
on enrollment.
54
As far as the three conditions that are
1
2
listed -- and you may recall from the San Francisco
3
meeting that after that exchange about whether we
4
should abide by local customs that have been
5
documented in which one cannot recruit women directly
6
but must go through their husbands or other family
7
members, that compromise was developed.
8
actually produced some language that was presented to
9
the commission, and as I recall a majority of the
Bernie Lo
10
people thought that it was acceptable, which was say
11
that U.S. researchers should, in fact, approach women
12
the same way they approach men.
13
them directly.
14
recall being mentioned, in which that is not going to
15
be a problem.
16
clinics.
17
That is approach
There will be many settings, as I
For example, reproductive health
Where there is a local custom that says you
18
are not supposed to do that, they should not follow
19
that local custom unless there is a compelling reason
20
to do so, and the conditions that Bernie had listed
21
in this language tried to capture for him and for
22
others what they thought that compelling circumstance
23
would be.
24
DR. SHAPIRO:
Eric?
25
DR. CASSELL:
Well, my problem is with the
26
serious conditions having to do only with women.
27
Tuberculosis, malaria, hepatitis C are serious
55
1
conditions having to do with women and to do research
2
only on men in those conditions, we would find
3
nowadays, after all we have made a similar criticism
4
in the United States, we would find inadequate
5
particularly since many women are pregnant and so
6
this would affect research on women who are pregnant
7
who have these serious deceases.
I think the basic issue is we do not like
8
9
the idea that women somehow are second class citizens
10
and that their consent cannot be obtained like you
11
would obtain the consent of anybody else and that is
12
-- if that is what you are trying to address, the
13
seriousness of the health condition, it is not the
14
crucial issue.
15
women.
It is how you want to approach those
16
I also believe that they should be
17
approached directly where that is possible, and where
18
it is not possible, the justification should be given
19
in the design of the protocol.
20
justification is inadequate then the protocol does
21
not get approved.
22
DR. SHAPIRO:
23
MR. HOLTZMAN:
And if the
Steve?
I would like to follow on
24
Eric's comment to try to see where we are, and it
25
seems to me there are certain things it is very clear
26
we agree on.
27
approached in the same way regardless of gender, and
Such that one wants people to be
56
1
as soon as one departs from that you start asking
2
what are acceptable and unacceptable departures.
In no event may someone -- there be
3
4
substitute consent, so that is very clear.
And that what is articulated by Alta,
5
6
effectively, is a position which says that if the
7
autonomy right of the woman is to be abrogated in the
8
form of seeking an additional consent from the
9
husband, that that is only morally allowable if the
10
condition to be treated or to be studied is one which
11
women benefit from.
12
benefit from, only affects women.
13
notion is that the woman's autonomy, in some sense,
14
is not being overridden because the benefit is
15
accruing to women, and women specifically.
And then it says only women
So effectively the
And what Eric is asking is the question, is
16
17
that the only condition?
18
health condition or health condition which affects
19
men and women, why is it the case that that would not
20
equally be a case of not eroding the woman's
21
autonomy?
22
decide.
23
24
I think that is the question we have to
DR. SHAPIRO:
Any other comments?
I want to
focus on exactly that issue.
25
Alex?
26
PROFESSOR CAPRON:
27
If one considers a serious
Pardon me if I have
missed a crucial part of the discussion just now but
57
1
it -- I thought Alta's revision was preferable.
2
did not see it substantively as that different, and
3
perhaps I have missed something.
4
me it sorted out the issues much more clearly.
5
I
It just seemed to
The present version of Recommendation 7 and
6
8 seems to me to jump from one thing to another and
7
so that if we are looking for the substance of what
8
is expressed, I find Alta's way of expressing it --
9
whether we call it Recommendation 7A or B or
10
Recommendation 7 and 8 is irrelevant but preferable.
11
On the issue of whether the requirement that
12
the problem be one which only affects women, I think
13
Eric raises an appropriate concern that that, of
14
course, would put this research in the same category
15
as a lot of research on common conditions that affect
16
men and women in the United States where for years we
17
had no data on the women.
18
It seems to me that the further condition
19
here, however, that failure to conduct the research
20
would deny the benefits to women in the country may
21
be an adequate safeguard because as I understand
22
that, Eric, it would mean that if you are conducting
23
research on a treatment in X country and the
24
researcher wants to use women whose access into the
25
trial is totally dependent upon their husbands giving
26
permission for them to be in the trial, and the IRB
27
in effect says, "Gee, that is not a condition that we
58
1
can live with," the only circumstance where it would
2
be justifiable to say you should live with that, we
3
should do this, is that not only does the research
4
have to be done in that country because the drug
5
approval process in the country requires local
6
subjects and so forth, but that there will be no
7
other circumstances in which there will be data,
8
which would allow the medical practitioners, as
9
opposed to the drug approval process in the country,
10
feeling comfortable that the results that were
11
gathered in that country on men are applicable to
12
women as well.
13
So that if you can do the research, get the
14
drug approval process by doing it on men in country
15
X, but the doctors in country X will use the
16
treatment on women based upon the fact that it was
17
tested on women through a better consent process in
18
country Y then there -- you should not have women
19
recruited into the process in X and it should not go
20
on there in country X it seems to me.
21
Now I do not know if that is what the intent
22
here is but that is what it seems to say to me and I
23
am not bothered by that.
24
DR. SHAPIRO:
25
MR. HOLTZMAN:
Steve?
To me, Alex, it is clear
26
there is two different ways one can recommend here.
27
The first -- if you -- let's use Alta's language
59
1
because it is clear.
2
starts with the word "health problem that affects
3
only women," whether or not you want the word "only"
4
in there, and that limits everything else that goes
5
on so it is unaffected.
6
and then in point number two, further down, you say
7
"failure to conduct this research with women in the
8
trial would probably deny its potential benefits to
9
women in the country."
10
If you go down to the line that
Or whether you delete "only"
It seems to me those are your two
11
alternatives of how to think about it, right?
12
would go for the first one with the "only women" if
13
you believe the fact that it has to be a woman's
14
condition which could be the sole thing that could
15
override the autonomy right of the woman.
16
one says that that is not necessary.
17
sufficient is that there is a benefit to women.
18
PROFESSOR CHARO:
19
DR. SHAPIRO:
20
21
You
The second
What is
Hand up.
Hands up.
Okay.
Hands up.
You can speak now.
PROFESSOR CHARO:
Let me just remind you
22
that the language about only women is taken verbatim
23
from what was discussed at the San Francisco meeting.
24
If the consensus now is that there ought to be a
25
change and delete the word "only," personally I would
26
not object and leave the rest of it exactly as it
27
stands, and deleting the word "only" I think still
60
1
conveys most of what is currently there and still
2
provides a pretty strong statement about how we want
3
our researchers to go about this in their work.
4
DR. SHAPIRO:
Thank you.
5
Jim?
6
PROFESSOR CHILDRESS:
I would just recommend
7
deleting "only" and going in the direction that Steve
8
suggested.
9
sense of both paragraphs if we take the second
In addition, I think we get a better
10
sentence, "if a potential subject," and put that down
11
at the beginning of B for enrollment because it
12
really is an enrollment question, that is, it is a
13
consent procedures question rather than a recruitment
14
question.
And then it seems to me the whole paragraph
15
16
flows and then the subsequent change that has just
17
been made for me makes it a really strong and helpful
18
paragraph.
DR. SHAPIRO:
19
20
I think my -- I am sorry.
Ruth, I am sorry.
DR. MACKLIN:
21
I just want people to realize
22
the consequences of what this -- of changing it will
23
be.
24
mean, if we go with the strong statement for only
25
women -- conditions that affect only women, if a
26
woman's husband says, "No, you may not be in this
27
trial," then that would preclude the possibility of
If the husband's signature is required -- I
61
1
women being in the trial.
2
Granted we all agree that the husband should
3
not have the authority to enroll the woman, but this
4
gives the husband the authority to deny the woman the
5
possibility of being in the trial.
6
word "only" is in there is -- as I think Alex
7
correctly described it, but without an example, let
8
me just give the example.
9
The reason the
In countries where women may want to use
10
contraceptives, their husbands may not want them to
11
use contraceptives.
12
contraceptive.
13
a contraceptive that could be beneficial to women.
14
The Health Ministry would never introduce this
15
contraceptive unless women in that country were the
16
research subjects.
17
their wives to have 50 babies said, "No, you may not
18
be in this research,” or “we do not think this is
19
right for you to be in this research," you would
20
never have the research being conducted, which goes
21
to Larry's point about it being impossible to conduct
22
the research otherwise.
There is no available tested
Someone comes in and proposes testing
If all the husbands who wanted
23
Now the problem here is that this would be a
24
condition that would affect only women, and I believe
25
Alex is right when he says if you are doing research
26
on TB and you do not have women in there, the
27
practitioners are still going to use that drug for
62
1
women and furthermore -- well, let me just leave that
2
point.
3
So there is a particular purpose of saying
4
only women because there are conditions that affect
5
women, which if they are not -- if the research is
6
not done then you would never have any of those
7
benefits to any of the women in that country.
8
So this is specifically targeted to
9
recognize that autonomy -- the autonomy of the woman
10
or her authority to say I want to be in the research
11
is more important overall than making sure that you
12
have research that has both men and women in it.
13
If you broaden this to conditions that
14
affect women and you take out the word "only" then
15
you have got a general situation in research and you
16
do not deal with that specific problem.
17
18
19
DR. SHAPIRO:
Arturo, and then Eric, and
then Alex.
DR. BRITO:
Ruth, one of the problems -- and
20
I wrote an e-mail to this effect earlier, and I think
21
Alta responded with some of the changes, and I think
22
it is an improvement.
23
with this recommendation is that I think it actually
24
takes away from the substantive ethical principle we
25
are trying to convey here that is mentioned in the
26
first paragraph about the requirement for individual
27
informed consent.
One of the problems I have
63
I do not know if we need -- I frankly do not
1
2
know if we
need
this entire paragraph in this --
3
the second paragraph of research, however, in the
4
recommendation itself.
5
harm than good.
I think it actually does more
I think it takes away from the individual
6
7
informed consent principle because we are talking
8
about things that are more public health issues and I
9
have mentioned this before in other parts of the
10
paper about how sometimes I think the tone is -- we
11
do not stick to individual rights.
12
just an Americanism or American ideal but it is also
13
something that is mentioned in all the international
14
documents.
That it is not
I do not know how what you just said is not
15
16
taken care of by what is mentioned in the first
17
paragraph.
18
replace the requirement of individual informed
19
consent, period.
In no case may a spouse's permission
20
PROFESSOR CHARO:
Hands up.
21
DR. SHAPIRO:
Eric?
22
DR. CASSELL:
Just take the example that you
23
gave.
Contraception in this set of villages.
The
24
husbands all say, "No, there will be no research on
25
contraception.
26
you cannot have research on contraception."
27
other hand, if -- and consequently in that example
You can do all you want to get it,
On the
64
1
the no is still a no.
If you take away the word "only" it does not
2
3
deny it for any serious condition applying only to
4
women.
If you take away the word "only" we will not
5
6
have the situation where practitioners are using
7
treatments that were designed on men, dosages set up
8
for men, and then treating women with them.
9
course, practitioners do it.
Of
I have been a
10
practitioner.
I have done wrong things my whole life
11
thinking it was the right thing to do.
That is not the issue, whether practitioners
12
13
will do it.
The issue is what is the best research
14
strategy that best supports the respect for persons,
15
not just autonomy, respect for persons, and at the
16
same time accomplishes the goal.
17
promote research that is beneficial for -- among
18
other things -- the population of the host country.
19
DR. SHAPIRO:
20
Excuse me.
21
24
Steve?
Alex is next.
I apologize.
Alex is next.
Steve, you are after Alta as a matter of
22
23
Our goal is to
fact.
PROFESSOR CAPRON:
I agree with the concern
25
that Ruth expresses, but it does not seem to me,
26
Ruth, that this recommendation goes to that concern.
27
There is a difference between a researcher saying, "I
65
1
want to override local custom, I want to find a way
2
with adequate protection from the women against later
3
retribution by their husbands to do the necessary
4
research."
5
it and the local -- the host country process is
6
willing to allow something which goes against local
7
custom.
And the local IRB is willing to approve
As I understood it, the question is what
8
9
happens when the local IRB tells the researcher, "In
10
our country you cannot do that study without getting
11
the husband's agreement to allow the wife to enroll."
12
The usual response, I think, without this discussion
13
would be no, no, you cannot, therefore, do the
14
research.
So I think we are talking about something
15
16
different here.
17
which the researcher says, "I am willing to find
18
husbands who are willing to allow their wives to
19
enroll.
20
conduct the research with this additional
21
qualification on the recruitment process or is that
22
an illegitimate qualification?"
23
We are talking about a situation in
I am willing to abide by that custom.
May I
And this recommendation, as I see it, was
24
designed to carve out a way if a project meets
25
certain requirements.
26
with Eric that taking the word "only" out has the
27
advantage of saying if it is possible to set it up in
I guess in the end I agree
66
1
a way in which you are looking at a disease that
2
affects both men and women and you can get women in
3
that country enrolled through this process.
4
be better to have the data on the women but I mean --
5
so I do not think it is contradicting the situations
6
in which you are dealing with a woman specific, i.e.
7
reproductive condition.
8
9
It would
But I do not see this recommendation as
responsive to the example you give as such.
Do you -
10
- and I guess at some point, Harold, I would like
11
some dialogue on this because I am in agreement with
12
Ruth as to the problem but this recommendation seems
13
to me the flip side when the investigator says, "I
14
want to go ahead.
15
will agree to allow their wives in.
16
these data.
17
data in X country and have them approve this drug.
18
Can I do it?"
I think I have found some men who
I want to get
This is the only way I can get these
19
DR. SHAPIRO:
Alta?
20
PROFESSOR CHARO:
First to Arturo's point,
21
if there is a concern that by discussing first
22
recruitment and then enrollment are reducing
23
attention to the very strong statement being made
24
about enrollment, an easy solution is to simply break
25
it into two recommendation.
26
recruitment practices and Recommendation 8 on
27
enrollment practices.
Recommendation 7 on
67
1
With regard to the question of whether or
2
not to continue to use the word "only," in an ideal
3
world I would prefer to keep it in.
4
ideal world and I would be happy to see any progress
5
on this point because it is my impression that
6
currently when investigators from the U.S. go into
7
countries where women are not approached directly but
8
where husbands and other family members are
9
approached to see if it would be permissible then to
10
speak to their wives or daughters or sisters, we are
11
in a situation where we are in a widespread way
12
buying into a practice that is not needed and is
13
insulting.
14
reducing the frequency of that practice and would
15
carve out an exception even without the word "only"
16
in which we are no longer going to insult women this
17
way but we are also not going to penalize them in a
18
concrete fashion when insulting them is the only way
19
to get something that is valuable to them.
20
It is not an
And this would make progress towards
I think that the second condition that
21
Bernie had drafted, which has to do with failure to
22
conduct research would probably deny potential
23
benefit to women in a country, as Alex mentioned, is
24
an important way for IRBs to try and distinguish when
25
they ought to let their investigators buy into these
26
practices and when they ought to tell the
27
investigator no.
If you have to go through the
68
1
husband then do not do it there, do it some other
2
place.
3
DR. SHAPIRO:
4
MR. HOLTZMAN:
Steve?
My understanding of this
5
recommendation is the same as Alex's and so I really
6
would like to understand what Ruth was saying if she
7
has a different understanding.
8
another issue there, it is how do we feel about
9
people undertaking trials for the benefit of a
I think if there is
10
population of women in a manner which would violate
11
local customs if that is what is necessary in order
12
to get the health benefit, which seemed to me was
13
what Ruth was addressing.
14
DR. SHAPIRO:
Diane wants to speak but,
15
Ruth, do you want to answer?
16
this time or do you want to wait?
17
18
DR. MACKLIN:
Make any comments at
Let's hear from Diane first
because there are a lot of points already.
19
DR. SHAPIRO:
Okay.
20
DR. SCOTT-JONES:
Diane?
This may be taking the
21
discussion in a different direction but as I am
22
struggling to fit all of this in.
23
Recommendation 9, which is somewhat parallel to the
24
previous Recommendation 7 and 8, and in this
25
recommendation we agree that it is fine to approach a
26
community leader and ask that person for permission
27
to go ahead and approach individuals.
I am reading
69
1
And at the very least we should make these
2
recommendations consistent with one another.
3
should it be possible to go to a community leader and
4
say, "May I approach the women in your village about
5
enrolling in this study?"
6
the issues that would arise in Recommendation 7,
7
which was formerly 7 and 8?
8
would abide by the local requirements.
9
PROFESSOR CHARO:
10
DR. SHAPIRO:
11
PROFESSOR CHARO:
Why
How is that different from
We are here saying we
Hand up.
Alta?
Diane, I think there is
12
actually a response to your concern.
I do believe
13
there is a difference between community leaders and
14
family members when it comes to saying which person -
15
- which kind of person should be a filter.
16
of community leaders as akin to political leaders and
17
political leaders actually exercise a kind of
18
function all the time.
19
that I sent, the Attorney General of New York State
20
is well positioned to say to certain companies, "You
21
may not approach the citizens of this state with
22
offers for certain kinds of lotteries or sweepstakes
23
or any number of kinds of consumer offers because we
24
think of them as being either exploitative or
25
misleading, et cetera."
26
exercised on behalf of all citizens, not on behalf
27
solely of women or men or the elderly.
I think
As I mentioned in the e-mail
And that is a role that is
70
So to the extent the intent -- I think it is
1
2
now actually Recommendation 8 -- I am looking at my
3
text.
4
the recommendation on community leaders in my mind
5
would be that it is about community leaders speaking
6
on behalf of the entire community and not just
7
segments.
If what we are trying to do there is endorse
8
9
Maybe I have got it wrong but the intent of
the idea that community leaders can say, "Well, you
10
cannot approach the women but you can approach the
11
men," then I would agree with you that that is just
12
ridiculous.
13
But if it is about community leaders saying,
14
"You cannot approach our community," then I think of
15
it as being an appropriate political function as
16
opposed to husbands saying, "You cannot approach my
17
wife," which is simply buying into the rank kind of
18
sex discrimination.
DR. SHAPIRO:
19
I think the issue you raise,
20
Diane, that is there is sort of a lack of symmetry
21
between 7 and 8 and the current 9, the way it is, is
22
an interesting point we ought to address when we get
23
to 9.
24
not mind, we will just put it on hold for a moment
25
and we will get back to it shortly.
I think we ought to just put it -- if you do
26
Ruth?
27
DR. MACKLIN:
I do not want to belabor all
71
1
this.
I mean, the commission has to decide what they
2
want.
Let me say one more thing about only women.
3
If the recommendation is going to be changed, namely
4
changed so that it does not say "only women" and it
5
is conditions for both, then I think we need some
6
additional paragraphs that would require any such
7
research -- where the U.S. IRB would have to look at
8
any such research and see whether or not the results
9
of the research are going to be interpreted, whether
10
there is going to be a stratification, whether the
11
women are going to be broken out from the men, and
12
whether those research results are going to be
13
interpreted so that you can apply them.
14
When the IOM, the Institute of Medicine, had
15
its committee on women in health research, one of the
16
big issues that arose and that was raised by the
17
methodologists is, okay, fine, you want women in all
18
studies, then you have to have a methodology that
19
enables you to apply the results of having women in
20
the studies.
21
You have to look at the differences.
22
analyze those differences.
23
enough population of women and men, et cetera, et
24
cetera.
25
You have got to stratify the groups.
You have to
You have to have a large
If we just make the point that this research
26
should involve women and men without also saying
27
something about the interpretation and analysis of
72
1
the results so that if they are different for men and
2
women, they could be applied differently, then I
3
think we are glossing over an important point about
4
the research and its applications.
5
So if that is the direction the
6
commissioners want to go, then I think we need those
7
paragraphs in order to say that.
8
think about the likelihood that that is going to
9
happen in some of this research, but that is a
10
11
We also have to
separate point.
DR. SHAPIRO:
Well, my judgment is here --
12
and if I am incorrect then the commission should tell
13
me, but we do -- that we do want to rewrite this
14
paragraph.
15
the question of "only," which I think -- at least I
16
am persuaded -- is not the right focus here.
17
other is a suggestion made by Jim that we should move
18
some language back down to (b) which I think is also
19
a good recommendation.
20
There are two key suggestions.
One is
And the
As I understand the recommendations being
21
made here, and it may need some additional text, that
22
is quite possible, it is -- in fact, getting rid of
23
the "only" broadens the issue in what I think is an
24
appropriate way.
25
that, I propose we go that way, and we do have to
26
ration our time here this morning.
27
And so I -- unless people object to
Steve, Larry and Alex?
73
1
MR. HOLTZMAN:
Clearly I agree with that,
2
but I think to Ruth's point about adding the
3
additional paragraphs, whatever, I would like that
4
signalled in the rec where in the line that starts
5
with "failure to conduct this research," I would
6
insert "with women in the trial would probably then
7
deny its benefits," and that would tie into Ruth's
8
clarifitory (sic) paragraphs.
9
DR. SHAPIRO:
10
That is helpful and we are
going to have to work on the language here.
11
Larry?
12
DR. MIIKE:
I think, though, that what the
13
result will be is that first -- well, first of all, I
14
am assuming that any research that -- research that
15
is being done would be addressing serious health
16
problems in these countries so that if one gets rid
17
of "only" you have essentially made the exception to
18
the general rule because if there are going to be
19
serious problems to be addressed then this
20
recommendation without the "only" would open
21
basically any kind of research of a serious disease
22
is through this exception so it becomes the rule and
23
not the exception.
24
DR. SHAPIRO:
This does not bother me
25
actually because the recommendation requires someone
26
to, you know, present --
27
DR. MIIKE:
Yes, I understand that.
74
1
DR. SHAPIRO:
2
DR. MIIKE:
-- reasons.
But then I -- the way it is
3
written it sounds like it is an exception.
4
should say there --
5
DR. SHAPIRO:
6
DR. MIIKE:
Where we
Yes, I understand that.
-- are certain qualifications
7
that need to be met before you continue on with the
8
research.
DR. SHAPIRO:
9
10
Yes, that is reasonable.
Alex?
PROFESSOR CAPRON:
11
Three comments.
First, I
12
think that the point under condition one at the end
13
of the paragraph -- and this is -- I am looking at
14
Alta's recommendation but it is the same language --
15
is unclear if we -- if we move the language that Jim
16
wants to move and so if we do that we have to revise
17
it.
18
Second, I want to make sure in agreeing to
19
this, and I think Steve's modification to point two
20
is now necessary if we take the word "only" out, that
21
what we are talking about here is denying the
22
potential benefits of the research results to women
23
in the country because it is not the potential
24
benefit of being a research subject that otherwise we
25
have just opened up, and if that is agreeable I would
26
say that we change the word "its" before "potential"
27
and say "the potential benefits of the research
75
1
results."
The third concern -- question is on Jim's
2
3
suggestion that we move that sentence.
And, Jim,
4
when you first stated it, I thought that made a lot
5
of sense but if we do that we have to be very careful
6
because look at what will happen.
7
potential subject wishes to involve a spouse or other
8
family member in the consent process researchers
9
should discuss the consequences of such involvement
If we say, "If a
10
with a potential subject and then abide by the
11
subject's wishes.
12
member's permission substitute for individual consent
13
by a competent adult."
14
those circumstances where by tradition an individual
15
regards health decisions as ones which he or she
16
delegates to others, and that is the tradition, and
17
it is an explicit delegation.
18
not allowing husbands to decide for wives.
19
husbands or wives, or whoever, when faced with health
20
choices saying, "These are not my choices.
21
sick person ergo they are the choices of someone
22
else."
In no case may a spouse or family
We would be saying that in
In other words, it is
It is
I am the
We would be saying that is unacceptable.
23
Now if that is what we mean, fine, but there
24
are large segments of the world population which take
25
a very different view and, of course, I would agree
26
that we should not allow that to simply be an
27
assumption that someone else wants the decision to be
76
1
made but where it is explicitly decided I want you to
2
involve this person and I want you to listen to them
3
in choices, we by this recommendation as put together
4
with these two sentences would be saying that is
5
unacceptable.
6
Now if that is what we mean that it is
7
always unacceptable and that research is different
8
than health care in this regard, even research on
9
health care where the subject is also a patient,
10
fine, I guess. I mean, I can see an argument for
11
keeping it separately but I am a little worried about
12
a view towards autonomy meaning I decide for myself,
13
which is not the worldwide cultural norm, and I am
14
not sure I want to say that it is wrong in those
15
countries where the researcher has found explicitly
16
that that is the choice of the subject.
17
MR. HOLTZMAN:
See, I have no problem with
18
that but it has nothing to do with the placement of
19
the second sentence because the problem still is in
20
(b) whether you put it there or not.
21
PROFESSOR CAPRON:
22
MR. HOLTZMAN:
I understand.
So I think we have to address
23
the substantive question but as it now stands the
24
second sentence in (a) just breaks the flow
25
completely and really refers to consent procedures
26
which we are addressing under enrollment rather -- it
27
is really the recruitment question.
77
PROFESSOR CAPRON:
1
2
movement but the movement simply highlighted -MR. HOLTZMAN:
3
4
5
6
I agreed with your
Right, the need to make that
-PROFESSOR CAPRON:
-- the need to make a
substantive decision --
7
MR. HOLTZMAN: Right.
8
PROFESSOR CAPRON: -- are we saying that --
9
MR. HOLTZMAN:
10
I agree with your --
-- exception point, sure.
PROFESSOR CAPRON:
-- the research rules are
11
different.
I mean -- and if in Korean society or
12
whatever, when health care decisions are made the
13
patient expects that the eldest child will make those
14
decisions for him or her, and we are saying, "Well,
15
if you get into research you have to follow the
16
American view that you make your own choices."
17
PROFESSOR CHARO:
18
DR. SHAPIRO:
19
PROFESSOR CHARO:
Hand up.
Yes, hands up.
I think that in some way,
20
Alex, that this is a problem that we are creating by
21
reading too much into the language here.
22
common practice in the United States, for example, to
23
say that individuals have to give consent for their
24
medical treatment but routinely they will delegate
25
decision making authority to somebody else or to a
26
physician and that delegation is what is considered
27
to be their consent.
It is
And I think that we can
78
1
understand the word "consent" here the same way.
Somebody in Peru says, "Well, you know, you
2
3
have my permission to let my husband, father, sister,
4
you know, cousin make these decisions for me."
5
would be our understanding of having given consent by
6
virtue of a delegation but it is a delegation of the
7
individual who is going to be the subject.
8
think that this can probably be handled in the text
9
without having to worry about rewriting the
10
That
And I
recommendation.
DR. SHAPIRO:
11
Well, let's just make sure
12
that we, first of all, understand what we want to
13
say.
14
says as long as it is the individual that decides how
15
their situation is going to be handled and we get
16
permission from that individual to handle it in that
17
way.
18
feel about that.
19
20
21
22
I think my own -- I agree myself with what Alta
That satisfies me but I do not know how others
It is just that they cannot be volunteered
is what we are trying to say here.
DR. DUMAS:
Right.
That is right.
I agree
with that.
23
DR. CASSELL:
24
DR. DUMAS:
25
DR. CASSELL:
That is the essential issue.
Yes.
And I accept this entirely.
I
26
have taken care of populations where whole decisions
27
are a woman's decision, ultra orthodox Jews the women
79
1
make health decisions but they do not volunteer their
2
husbands any more than their husbands volunteer them.
DR. SHAPIRO:
3
4
5
Okay.
I do want to proceed
on.
Eric has handed me a note which I have not
6
yet read from Bernie which also focuses on Chapter 2
7
and let me just read it.
8
it for the first time myself now.
9
10
11
12
I have not -- I am reading
Do people have copies of this?
DR. MESLIN:
distributed.
Yes, they have been
Yes.
DR. SHAPIRO:
All right.
Well, for the
13
purposes of the -- I do not know if it has been
14
distributed otherwise for the purpose of those who
15
are attending today.
16
additional recommendations:
17
indicate in the protocol how they will minimize the
18
likelihood that potential subjects mistakenly believe
19
that the purpose of the research is to administer
20
treatment; and (B) IRBs may approve protocols where
21
documentation of informed consent through a signature
22
or thumbprint is waived provided the investigators
23
have provided adequate justification for the waiver.
24
25
He said, "I would suggest two
(A) researchers should
The first -- I do not know where Bernie
wants to -- I just got this as a statement.
26
DR. MESLIN:
27
DR. SHAPIRO:
Here is an extra one.
I am not sure -- let me make a
80
1
suggestion.
I am not sure where Bernie wants these
2
and how he wants them inputted.
3
Ruth, excuse me.
4
DR. MACKLIN:
I apologize.
That is okay.
No, it is --
5
there was some discussion about this.
Where they
6
would go -- for example, the therapeutic
7
misconception, there is a discussion of the
8
therapeutic misconception.
9
think it was Trish who originally made the suggestion
The statements -- and I
10
that this should rise to the level of a
11
recommendation, there is a discussion in the text
12
that says something very much like this.
13
in the text.
14
It is right
The question is whether to take what is in
15
the text as explanatory or supportive material and
16
make it rise to the level of a recommendation.
17
Similarly, the waiver of signature is in a
18
lengthy discussion of the problems of signing and how
19
people do not sign things in other countries, et
20
cetera, et cetera, and we make the point that the IRB
21
should accept different procedures but not different
22
substance for informed consent.
23
Here again the recommendation -- the
24
suggestion is to make a specific recommendation for
25
waiver of signature rather than leaving that as a
26
discussion in the text.
27
So that is basically moving what is already
81
1
there in the discussion and raising it to the level
2
of a recommendation.
PROFESSOR CAPRON:
3
4
How does this relate to
Recommendation 2 on page 6?
DR. MACKLIN:
5
It actually is a more explicit
6
specification of what that means.
7
relates to it by further elucidating it.
8
sure it adds anything.
PROFESSOR CAPRON:
9
I mean, I think it
I am not
Well, I mean my point was
10
shouldn't we meld these two together?
I mean, I
11
thought when I looked at his (b) here that we had
12
already agreed to that.
13
And so --
It was Recommendation 2.
14
DR. SHAPIRO:
I think that is right.
15
PROFESSOR CAPRON:
And so to the extent that
16
he says these are additional recommendations, I do
17
not see them as additional.
18
only point in raising that.
DR. SHAPIRO:
19
20
right on that.
That was my
Let me -- I think you are
Let me -- I am sorry.
MS. KRAMER:
21
That one.
Bette?
However, it is handled, I
22
thought that both of those subjects were handled very
23
well, the therapeutic misconception beginning on 24
24
and then following with a documentation of informed
25
consent.
26
missing as I completed the language in those -- each
27
of those sections that there was not a final
And I, myself, felt that something was
82
1
conclusion, which rose to the level of
2
recommendation.
3
DR. SHAPIRO:
4
MS. KRAMER:
5
Certainly the supporting
language is there.
DR. SHAPIRO:
6
7
Yes, I think --
So you would support making a
recommendation on the --
8
MS. KRAMER:
9
DR. SHAPIRO:
Yes, I would.
Yes.
PROFESSOR BACKLAR:
10
Trish?
I think that Bernie and
11
I both were thinking of the --
12
DR. CASSELL:
13
PROFESSOR BACKLAR:
I cannot hear you.
I think Bernie and I
14
were both considering that (a) the therapeutic
15
misconception recommendation should go at line 28 on
16
page 26 after the discussion about the therapeutic
17
misconception simply because that is a very
18
thoughtful and well put together discussion, and it
19
seems as though something is lacking as Bette says
20
when you get to the end and there is nothing that
21
attracts your attention to it in a significant
22
fashion.
23
DR. SHAPIRO:
Alex?
24
PROFESSOR CAPRON:
I agree.
And it seemed
25
to me that vis-a-vis the recommendations on page 6,
26
Bernie had already recommended that those be moved
27
back and I guess I wonder from -- again from Ruth's
83
1
and Alice's point of view if there is a problem if
2
there is a problem with either moving the text up or
3
moving the recommendations back, whichever.
4
DR. SHAPIRO:
We discussed that precisely.
5
Ruth and Alice are going to look at that and see
6
whether they want to move one forward or the other
7
backward, however you think about it, but to bring
8
them together.
9
I want to say a word about this therapeutic
10
misconception.
I think in view of the things that we
11
are considering and saying in Chapters 3 and 4, I
12
think it is quite important to say something explicit
13
about therapeutic misconceptions.
14
are doing are going to make this matter worse and so
15
we better straighten it out early on and this is one
16
way to at least highlight it.
17
with that.
18
Steve and then Trish.
19
MR. HOLTZMAN:
A lot of things we
So I certainly agree
With respect to -- this ties
20
to the documentation issue.
21
very clear that signed consent is not necessary and
22
you should just effectively -- what you care about is
23
the substantive requirements of consent as opposed to
24
the specific procedures.
25
I think we are making it
I would just ask Ruth and Alice to think
26
about if you look at, for example, Recommendation 1 -
27
- so page 6, line 13, where you say "consent
84
1
documents should include all the basic elements of
2
disclosure," I think we use documents to mean things
3
like the consent form and also we use to mean the
4
documentation presented, for example, to an IRB that
5
consent took place.
6
so at least when I read this it has made it sound
7
like you need a consent document, e.g. that someone
8
signed and then, oh, by the way, that has to be a
9
signed consent document.
So you just might look at
10
how we use our language.
Okay.
11
All right.
And I think that --
With respect to the therapeutic
12
misconception over on page 26, we cite the confusion
13
potentially arising there between the fact that
14
someone may be getting extrinsic health care in the
15
context of a clinical trial and that can engender
16
therapeutic misconception but what we do not tackle
17
is the case where someone is going into the trial in
18
order -- because they are suffering from something
19
for which there is no good cure and the experimental
20
medicine is the best opportunity.
21
Now is that a therapeutic misconception?
I
22
am not sure how people who know this literature -- is
23
that considered a therapeutic misconception when I am
24
dying of cancer, nothing will treat me and I read
25
that there is a hot new medicine potentially
26
available in a Phase III?
27
DR. MACKLIN:
Yes.
I guess the cancer
85
1
example is not the best to demonstrate the
2
therapeutic misconception because it is Phase III and
3
there is lots of other meds out there and they have
4
been there for a long time.
5
The more telling example is something that
6
is being tested that is of uncertain efficacy and we
7
certainly have enough -- it is a clinical trial.
8
is of uncertain efficacy and there is enough evidence
9
for the number of clinical trials on various drugs
It
10
that never actually get approved because they are not
11
sufficiently efficacious or they are too harmful.
12
So the therapeutic misconception
13
specifically is that the aim of research is to
14
provide treatment.
15
that is the key because somebody is going to go into
16
the trial and get randomized and if they get
17
randomized -- of course, if it is cancer they are
18
going to be randomized against a standard treatment
19
which will give them treatment but if it is in the
20
placebo case -- I mean, in the case of anything with
21
a placebo they are not.
22
The intention of research.
And
So, I mean, as we describe and define the
23
therapeutic misconception it is the belief that the
24
purpose of research is to confer benefit to the
25
individual.
26
Now as a matter of fact, it will be the case
27
that entry into research will for some people confer
86
1
benefit.
Okay.
That is not the misconception.
2
misconception is about the purpose and the intention
3
of research to confer therapeutic benefit directly to
4
individuals rather than to learn something that will
5
contribute to knowledge.
6
DR. SHAPIRO:
7
What time did we get started this morning?
8
DR. MESLIN:
9
DR. SHAPIRO:
10
Other comments?
The
Okay.
8:30 right on the dot.
8:30.
Okay.
I was not here
then.
I want to -- I am going to suggest then we
11
12
take a brief break because I am going to want to skip
13
over now other issues in Chapter 2 and come back to
14
address directly the issues that come up in 3 and
15
again in 4 with respect to placebo controls and
16
establish effective treatment to supply that.
17
we really mean -- this is everywhere in that chapter
18
and unless we straighten out where we feel -- what we
19
feel on that issue it is just hard to make the other
20
-- the rest of the chapter fit together.
So let's take a ten minute break.
21
22
25
If we
can, let's try to reassemble at 20 to.
(Whereupon, at 10:33 a.m., a break was
23
24
What
taken.)
DR. SHAPIRO:
Colleagues, as I indicated
26
just before our break, I wanted to go on to an issue
27
that comes up in Chapter 3 recognizing there are
87
1
other issues in Chapter 2 and as you have before you
2
some suggestions from Alex with respect to dealing
3
with the initial material in Chapter 1, which I hope
4
you will get a chance to review some time today or
5
this evening so that we can deal with it.
6
have an hour tomorrow morning.
7
go through this right now.
It is unrealistic to
And you may have some reactions to that and
8
9
I think we
Ruth and Alice may have reactions to it as well but I
10
do not want to deal with that right at the moment
11
since many of us have not read that material yet but
12
I want to thank Alex for putting it -- taking the
13
trouble to put it together.
I also want to encourage commissioners if
14
15
they have done so, if they have heavily marked up
16
copies of the report, as I do, really to pass it on
17
to Eric so as we begin rewriting, which will begin
18
this afternoon, we can take advantage of some of the
19
observations that you may have.
So if you do have a marked up report that
20
21
you are willing to share, please hand it to Eric at
22
our lunch break and that may be helpful to us as we
23
go ahead.
I want to now focus our attention on one
24
25
particular issue, which as I said before, comes up in
26
Chapter 3 and that is concerns placebo control
27
trials.
It is really quite important that we be
88
1
clear as we can even though we might disagree amongst
2
us as to exactly what we want the report to say in
3
this respect.
I think we all agree that where there is no
4
5
established effective treatment and there are
6
proposed treatments of placebo controlled trials that
7
are entirely appropriate, I do not believe that is a
8
controversial issue.
9
there is an established effective treatment and the
The issue comes up rather where
10
question then is are there any circumstances where a
11
placebo control trial is nevertheless still ethically
12
appropriate.
Where I -- my own view on this matter, which
13
14
certainly could be changed by persuasive arguments,
15
is that where there is an established effective
16
treatment that is presumptively the way a trial
17
should be carried out but there may be good and
18
sufficient reasons in particular areas and particular
19
circumstances to have a placebo control arm, although
20
the researcher would have to justify that in some
21
way.
22
issue but I really would like to get the
23
commissioners' view on that.
24
That is just where I currently sit on that
So, for example, if you look at page 15 --
25
and I do not mean to pick out this particular
26
sentence as the -- except that it happens to be one
27
of the ones that caught my attention as I read
89
1
through Chapter 3, on lines 22 to 24 where it says,
2
"It is generally accepted that a placebo control
3
trial would not be ethical if an established
4
effective treatment that is known to prevent serious
5
harm such as death or irreversible injury is
6
available for the condition being studied," although
7
I am not quite sure what available means and if it
8
means available everywhere or what.
9
sure about that.
10
I was not quite
But if this was meant -- and I may be
11
misinterpreting here -- to be -- to say that placebo
12
controls are never ethically justified in the case
13
where an established effective treatment exists and
14
that -- I may be reading more than was intended here
15
but I am just saying that to highlight the issue and
16
try to see where commissioners are on this issue
17
because I think my own view is that it is central to
18
everything we say -- not everything but many of the
19
things we say in Chapter 3.
20
So let me open the floor for discussion and
21
comments, indications of where you think we should be
22
on this particular issue.
23
Arturo?
24
DR. BRITO:
Once again the only time it is
25
justifiable to do placebo control trials in my mind,
26
unless there is a specific example somebody has, is
27
when you are concerned about a public health of, for
90
1
instance, large populations and large communities.
2
But this is not what this -- what the tone of this
3
whole report is about.
4
individuals.
5
We are talking about
So when it comes to individuals, placebo
6
control trials, I do not think, are justifiable in
7
any situation so
8
- that is just my --
9
I
agree with Harold there.
DR. SHAPIRO:
So I -
Well, in that case I did not
10
express my -- I did not express myself well enough.
11
I apologize.
12
do not speak very well.
In addition to not having good ideas, I
13
DR. BRITO:
14
DR. SHAPIRO:
No, you speak very well.
But the -- my view is a little
15
different than that.
16
treatment is the presumptive control but it can be
17
overridden in certain circumstances.
18
circumstances placebos might be appropriate but that
19
has to be justified.
20
DR. BRITO:
That established effective
So in certain
That is just my view.
Okay.
I would like to hear the
21
examples of when they can be overridden when an
22
established effective treatment is available and
23
maybe that would help.
24
DR. SHAPIRO:
My own view is that if a
25
placebo control trial would answer an important
26
health related problem in that country and the
27
established effective treatment would not, that that
91
1
is perfectly appropriate to think about it.
2
to be -DR. BRITO:
3
It has
Once again then when you are
4
answering that -- you are talking about something for
5
a population.
Therefore --
DR. SHAPIRO:
6
I am talking about information
7
that would be generated out of the trial that would
8
impact the health of the population -DR. BRITO:
9
DR. SHAPIRO:
10
11
DR. BRITO:
16
Right.
But at the cost of the
individual.
DR. SHAPIRO:
14
15
Relevant population,
population of sufferers, right.
12
13
Of the population at --
correct.
Yes.
In that country that is
Alex and then Eric?
PROFESSOR CAPRON:
I guess I would like to
17
have some explanation as to the rationale here.
18
the cases which are cited in the text on page 15,
19
line 24 and following, I understand that the argument
20
is that where you are going to a group of people who,
21
if you were not conducting the research, would
22
receive an established effective treatment, it would
23
be wrong to deprive some of them of that treatment.
24
DR. SHAPIRO:
25
PROFESSOR CAPRON:
26
27
Right.
And I guess it would
require a truly exceptional justification.
DR. SHAPIRO:
Right.
In
92
1
2
3
4
PROFESSOR CAPRON:
I mean, I would like to
have you give a justification in that case.
The cases which have caused difficulty in
the international arena are not those.
5
DR. SHAPIRO:
Right.
6
PROFESSOR CAPRON:
And the argument,
7
therefore, is not one of wrongful deprivation.
As I
8
understand it, the principle concerns are two.
One,
9
that research will be exported to places where there
10
is no established effective treatment as a way of
11
either making the research easier to conduct or
12
making it cheaper to conduct because you are not
13
obliged to give the established effective treatment.
14
And a rule against it in that circumstance would be a
15
prohibition designed to prevent that act which would
16
be seen as an ill motivated act.
17
So the justification in that case would be
18
that is not why we are going there.
19
there because there are other reasons to do the
20
research in that country.
21
We are going
Then you get to the second concern, which is
22
if you are coming from a country in which you would
23
supply the research -- excuse me.
24
established effective treatment, is it wrong to treat
25
the subjects that you are dealing with differently
26
than you would treat subjects in your own country who
27
would by the previous discussion be entitled to
Supply the
93
1
something which they would otherwise have access to?
And here the argument is not that your
2
3
motivation is wrong.
4
have good reasons independently for wanting to do it
5
there but that it is -- it is somehow unfair to
6
people who you are -- on whom you are placing some
7
demand of being research subjects or placing some
8
potential burden not to treat them as well as you
9
possibly could.
10
I got it wrong?
12
Is that correct?
DR. SHAPIRO:
11
We have already established you
Is that -- or have
I guess that is -- I mean, I
was not concerned -PROFESSOR CAPRON:
13
I want to get to the
14
underlying rationale for how we apply it not as a
15
general principle in the U.S. and otherwise, which I
16
agree with your conclusion but what is the rationale
17
for saying that the established effective treatment,
18
which is not now present in the country, ought to be
19
applied?
20
obligation?
21
lies?
Is it the notion of some kind of reciprocal
Is that in the end where the argument
22
DR. SHAPIRO:
23
PROFESSOR CAPRON:
24
25
Let me just try to respond.
Say reciprocal to the
gift that they are giving by being -DR. SHAPIRO:
I -- first of all, to go to
26
the first part of your comment.
I certainly agree
27
that where the established effective treatment is
94
1
what they would have received, it would be
2
inappropriate to deprive them of it.
3
in a country where the established effective
4
treatment is available and they would have benefitted
5
from it, like the U.S. or anywhere like that, then it
6
would be inappropriate to use placebo controls.
7
agree completely with that.
So if they are
I
8
The question is in my mind -- comes up where
9
the established effective treatment is an irrelevant
10
control for that country because it simply cannot
11
meet the needs of -- the health needs in that country
12
in any foreseeable time period.
13
And in those cases other kinds of
14
experiments can be considered.
15
ought to be initiated but can be considered.
16
not think they should be required under all
17
circumstances to import the established effective
18
treatment.
19
I do not say they
I do
Now the people in that particular country
20
cannot be made worse off because of the trial by
21
depriving them of treatment they otherwise would have
22
received.
23
-- it is that case that I am thinking about.
24
I completely agree with that.
PROFESSOR CAPRON:
So that is
I, like you, do not
25
express myself well and I wanted to know whether what
26
the argument is, is that -- not that they -- that
27
such research could be conducted but that if you were
95
1
applying only the first rationale for the not using a
2
placebo, that is to say you would be depriving
3
something of someone, that clearly does not arise
4
here.
5
obligation to bring it in and, if so, does it rest on
6
this notion of treating the subject as well as you
7
possibly can?
8
9
Is there a second obligation -- an affirmative
Now if that means that the established
effective treatment in another country, in the United
10
States, requires medical infrastructure that is
11
totally unavailable, or clean water, which is totally
12
unavailable in the country, and the argument is,
13
well, we cannot do that because we cannot do it, then
14
that is an argument as to why it is an impossibility.
15
But if it is possible but it was simply more
16
expensive and because you are using an active control
17
you require more subjects in total and more expense
18
and more time, do you still have that obligation to
19
do it is what I want to know and, if so, does it rest
20
on this argument that because the subjects are being
21
-- are making their contribution, you should treat
22
them as well as you possibly can?
23
DR. SHAPIRO:
I do not think so.
24
PROFESSOR CHARO:
25
DR. SHAPIRO:
Hands up.
That is just my opinion
26
because I think a competing ethical requirement is to
27
do something of use to the people in that country and
96
1
I balance -- I put that on the scales to think about
2
and do not have just a standard flat rule.
3
PROFESSOR CHARO:
But this is -- that is
4
where you lose me.
5
intervention which could be beneficial to them in
6
that country if it proves useful, the question is
7
what do the controls get?
8
you could do under the circumstances?
9
If you are testing an
DR. SHAPIRO:
Do they get the best that
No, because it may not answer
10
the question of interest.
11
control does not work as well as the established
12
effective treatment may be an irrelevant finding for
13
the health needs of that country.
14
PROFESSOR CAPRON:
To find out that the
But that is not the only
15
finding you will have.
16
how well the tested intervention works, won't you?
17
18
DR. SHAPIRO:
You will have a finding about
Not unless you have a control
somewhere you won't.
19
Eric, and then Carol.
20
DR. CASSELL:
Well, I think it is wonderful
21
of the commission to give both of you the opportunity
22
to polish your skills of articulation.
23
lacking, I have noticed, yes.
24
(Laughter.)
25
PROFESSOR CAPRON:
26
27
Otherwise
Well, you do not have
that problem.
DR. CASSELL:
Thank you.
I agree with you,
97
1
Harold, and I think if we took the famous trial that
2
starts this off in lots of minds, the use of a full
3
four drug regimen for AZT in a population and then
4
that regimen would stop at the end of the same period
5
would -- might briefly benefit somebody's CD4 count
6
but not very long, and it might do a lot of damage.
7
Nobody knows what that does in a malnourished
8
population for one thing.
And that, it seems to me, is an example of
9
10
something in which a placebo control is irrelevant to
11
the population in which it is being studied, number
12
one.
13
population when it is not dangerous in a better
14
nourished population with better medical care and for
15
that population and for that period of time they
16
should not be getting that standard regimen.
17
And, number two, it may be dangerous in that
However, there are not a lot of trials like
18
that and I think that is the point you are making and
19
that is what all the other -- I mean, the fact that
20
the Helsinki and then this one and then that one, and
21
everybody says the same thing does not make it any
22
stronger in cases like that but it does say as a
23
general principle you should not deprive a population
24
of care they might otherwise get.
25
DR. SHAPIRO:
Carol?
26
DR. GREIDER:
Yes.
27
I just wanted to again
agree with what you had said, Harold, and to point
98
1
out that a study can only establish what it sets out
2
to establish and the controls are part of the
3
experiment.
4
regimen that what you are testing against the
5
established effective treatment is less effective,
6
that does not tell you how effective it would be
7
against placebo if your control -- and so how you
8
design the experiment can only give you a certain
9
answer.
So if you find in a study that your
And so in some situations it might be a
10
meaningless result and I think that was a point that
11
you were making.
12
DR. SHAPIRO:
Bill?
13
MR. OLDAKER:
I also agree but I think that
14
what we are talking about is trying to set up the
15
ethical parameters which we already know in developed
16
countries that established effective treatment must
17
always be given.
18
available it seems we would be saying that we are
19
carving out an exception to be looked at.
20
would not be for all cases but it would be certainly
21
acceptable under the proper circumstances where it is
22
not reasonably available to conduct these types of
23
trials.
But in countries where it is not
24
DR. SHAPIRO:
25
MR. HOLTZMAN:
Not -- it
Steve?
I think the genesis of this
26
principle has to do with actually two features.
One
27
is the -- not to deprive of what would otherwise be
99
1
normally available but also is the extent to which
2
there is potential harm because examples -- and we
3
have articulated this in this -- for example, there
4
is nothing wrong with doing a placebo control of a
5
new version of Ibuprofen, for example, because the
6
minimalist harm that will result is the person is in
7
pain for an extra two hours.
8
usual, flat out statements usually do not work as you
9
start to get into the real cases.
10
So I think just -- as
I want to come back to Alex's point, though,
11
as when we move to the case of a country where an
12
effective therapy is not available, though it is
13
available in the world, while it is true that a study
14
will only prove what a study is designed to prove,
15
there -- you can have cases where there are two
16
alternative studies.
17
So, for example, in the case at hand we have
18
heard arguments that a noninferiority study would
19
suffice to justify making the therapy available.
20
would have shown it was effective by showing it was
21
not inferior.
22
one that Alex is focusing on, is if it is the case,
23
right, that you have an alternative study which
24
involves the effective control, first off do you have
25
an obligation to use that.
26
you have -- if that study would not prove what you
27
sought to prove such that you had to do the placebo
You
So I think the ethical question is the
And then the second is if
100
1
2
3
4
control, is it ethically allowable to do so?
And I think if we could just tackle those
two cases.
DR. SHAPIRO:
Well, my own view, Steve, is
5
that the established effective treatment is the
6
presumptive control.
7
control that way and if there are ways to answer the
8
appropriate question that way that is what you do.
9
And you need to build a case for anything else.
Okay.
You always try to
I am
10
just trying to say that I think there probably are
11
cases where that would be allowable and you just have
12
to make the case.
13
and it is not obvious.
14
MR. HOLTZMAN:
It is not an easy case in all ways
But I think that -- I am not
15
going to disagree with you.
16
on this one.
I want to work with you
All right.
17
DR. SHAPIRO:
18
MR. HOLTZMAN:
Yes.
Let's assume you are true.
19
Then I think we need an answer to the critic who says
20
that that effective control is irrelevant in the
21
situation.
22
context that puts a moral obligation on you to
23
provide it as the control since it -- what is the
24
nature of the deprivation?
25
could have it available to you that creates a
26
situation of otherwise you would be depriving?
27
think if we could articulate that it would be the
What is special about the research
Is it the fact that you
I
101
1
basis of your argument.
2
PROFESSOR CHARO:
3
DR. SHAPIRO:
4
PROFESSOR CHARO:
Hand up.
Yes, hands up.
I would like to say that I
5
think Alex has articulated that justification and I
6
would assert that when people are volunteering for
7
research that we do owe them something as a result.
That it would be entirely sensible to say
8
9
that even if the established treatment is not
10
ordinarily effective in country, that it should be
11
provided
12
allow you to answer the scientific question that has
13
to be answered to make the research useful.
if possible unless that is not going to
14
The language that I proposed --
15
DR. SHAPIRO:
16
PROFESSOR CHARO:
Well, I agree with that.
I am sorry.
The language
17
that I proposed on page 5 of Eric's memo attempts to
18
capture these situations and to say that placebos are
19
appropriate when reasonable alternatives have been
20
exhausted and that those reasonable alternatives,
21
which include these other kinds of controls have to
22
be examined to make sure that they do not create a
23
net increase in risk because of some of the design
24
inferiority that can come along with them.
25
DR. SHAPIRO:
26
with you.
27
page 5 which I read.
Thank you.
I think I agree
I certainly agree with your statement on
102
1
Steve?
2
MR. HOLTZMAN:
You see, I think this is
3
going to take us directly back into Chapter 4 when we
4
start talking about justification for, for example,
5
provision of ongoing care and what is the moral basis
6
of that.
7
it health as a primary care?
8
going to have to get into is exploring what is the
9
nature of the relationship between the researcher and
10
the subjects which creates certain moral obligations.
11
That is my sense.
Is it the justice as reciprocity basis?
Is
I think what we are
12
DR. SHAPIRO:
Ruth, yes?
13
DR. MACKLIN:
Harold, if you think there is
14
an inconsistency between the statement on page 15
15
that you read --
16
DR. SHAPIRO:
Right.
17
DR. MACKLIN:
-- and the recommendation,
18
which seems to me to incorporate everything that
19
people here seem to be agreeing on, namely
20
Recommendation 2 on page 40, which sets up the
21
presumption of an effective established effective
22
treatment.
23
It says this should be done whether or not
24
it is currently available but goes on to say in cases
25
where the study design does not provide that then the
26
protocol should include a justification and all of
27
the text before that explains all these factors.
103
1
Now the problem with the statement on page
2
15, I guess, is that it says it is generally agreed.
3
Now in a discussion that Eric and Alice Page and I
4
had about your comments, we thought we would change
5
those words.
6
agreed," to "leading experts agree," because we have
7
Bob Temple, we have Bob Levine, we have the written
8
literature in which even the people who are debating
9
the appropriateness of placebos in some context, all
Instead of saying "it is generally
10
seem to agree on that point.
11
going to have death or permanent disability then it
12
is inappropriate to use the placebo.
13
Namely that if you are
So I think if we focus on the recommendation
14
and we just -- this is meant to be a descriptive
15
statement about the agreement.
16
DR. SHAPIRO:
I did not have any problem
17
with the recommendation at least as I recall it right
18
now and maybe I read more in the statement than was
19
intended.
20
I am trying to at least articulate a
21
position that says there are an awful lot of complex
22
problems out there and a lot of complex diseases and
23
just what the most relevant experiment is to help to
24
address the health needs of a particular area or
25
particular population may not always in various
26
circumstances require the established effective
27
treatment as a control.
104
I do not know.
1
I am just trying to leave
2
room for that to happen.
3
the recommendation does that so I agree with the
4
recommendation.
5
Eric?
6
DR. CASSELL:
That is all.
And I think
Related to the recommendation,
7
I would like to hear an example that would pass the
8
no effective treatment test.
9
would find acceptable, Ruth.
10
11
12
Tell me one that you
DR. MACKLIN:
Say that a little more
DR. CASSELL:
Well, the recommendation says
clearly.
13
you should have concurrent treatment except under
14
certain circumstances.
15
think those circumstances are.
16
DR. SHAPIRO:
17
PROFESSOR CHILDRESS:
I would like to hear what you
Jim?
Let me just build on
18
that, I guess if you are looking at the
19
recommendation on 40, another way to say it would be
20
do we give enough indication in the text to give the
21
kind of richness that would be required for the
22
justification and I am not sure that we do.
23
other part would be do we need to say more in this
24
recommendation itself since many people have looked
25
at the recommendations and do not read the text that
26
carefully.
27
at least kind of an example of the justification that
The
Do we need to build in more of the -- or
105
1
would be acceptable?
2
going in?
Is that the direction you are
DR. CASSELL:
3
Yes.
I think the
4
exemplification is important in this particular thing
5
but more perhaps than in some others because it has
6
been so widely argued.
7
We are generally agreeing that we think you
8
should not have a placebo control trial except under
9
certain circumstances and then we do not say and
10
these are some circumstances that came into our --
11
that we thought were acceptable.
Now IRBs may disagree and so forth and so on
12
13
but these are examples.
DR. MACKLIN:
14
The problem with examples is
15
that then you get bogged down in the examples.
The
16
text that immediately precedes the recommendation
17
sets out criteria.
18
example but it sets out criteria.
It does not provide -- mention an
Once you start with the example, if people
19
20
disagree about the example you do not make any
21
headway.
22
goes to line 7 on page 40 sets out several specific
23
criteria that must be met and otherwise you have got
24
-- you can rebut the presumption.
So what starts on line 25 on page 39 and
25
I do not think we can go -- do any better
26
than that without getting into examples that might
27
turn out to be controversial.
This is supposed to
106
1
provide the framework for determining in any
2
particular case whether or not you have met the
3
criteria.
4
DR. SHAPIRO:
Alex and Steve, then Arturo.
5
PROFESSOR CAPRON:
Ruth has said basically
6
what I would say.
I did have a question about the
7
fourth point on lines 5 through 7 on page 40.
8
not understand what was being advanced there, Ruth,
9
as one of the criteria that could be examined.
I did
The
10
language is a clear case that controls are intended
11
to stimulate the current state of care --
12
DR. MACKLIN:
Simulate.
13
PROFESSOR CAPRON:
14
sorry.
I just misread it.
15
Simulate the current --
Simulate.
Oh, I am
Boy, is that a misread.
16
DR. CASSELL:
(Not at microphone.)
17
PROFESSOR CAPRON:
18
(Laughter.)
19
PROFESSOR CAPRON:
20
too damn articulate diagnostically.
Thank you.
Sometimes you are just
21
That goes to a -- that goes then to a point
22
that I want -- I think we need to make clear earlier
23
on and that is there is a difference between a
24
placebo being justified as a placebo and a placebo
25
being justified because there is no good care being
26
given in the country as it is.
27
argument is that the placebo simulates the current
I mean, if the
107
1
state of care because the current state of care is
2
merely hand holding or whatever, and it does not
3
amount to any known therapeutic valuable
4
intervention, then we are back -- we are in a
5
different realm it seems to me, Harold, because
6
before when it was being discussed the assumption was
7
that is all there was.
There may be situations in which some form
8
9
of treatment is now being given and it is not the
10
world standard but the argument there, it seems to
11
me, is different than the placebo argument.
12
DR. SHAPIRO:
I agree.
13
PROFESSOR CAPRON:
And yet in our earlier
14
discussions to the extent that they influence the way
15
the final draft of this is, those two were being
16
equated.
17
DR. SHAPIRO:
Yes, I agree with that.
18
PROFESSOR CAPRON:
19
DR. SHAPIRO:
20
Let's see.
21
MR. HOLTZMAN:
Yes.
I agree with that.
Steve?
I thought that the work that
22
was done on page 39, lines 25 through page 40, line
23
7, was really wonderful.
24
criteria so I think there is a presentation question
25
that given that we know that the world tends to only
26
read our recommendations, whether this
27
recommendation, we should pull some of that text up
I mean it did lay out the
108
1
into the recommendation.
2
criteria being laid out, which again -- the
3
background against which judgments will have to be
4
made, I thought this nailed it.
5
But I think in terms of the
And I could then imagine a range of cases --
6
Alex's point about it is different than a placebo.
7
But if I -- if I am a big drug company and I can
8
provide an effective treatment and I want to use
9
placebo, I have one set of justifications as opposed
10
to someone else who could not have access to the
11
effective treatment and, therefore -- so I think you
12
cannot nail them.
13
criteria like Ruth and Alice have and look to people
14
to make judgments.
15
You have to just lay out the
DR. SHAPIRO:
Larry?
Let me -- Larry had
16
made a comment about this particular recommendation.
17
Do you want to --
18
DR. MIIKE:
Yes.
I was just looking for
19
simplification.
20
I like recommendations that are short and to the
21
point because when they get too long it kind of gets
22
a little too confusing and the justification should
23
be in the text that follows.
24
current version that we have is changed from the one
25
that I originally talked about but even this one I
26
think is redundant.
27
I mean, contrary to what Steve said.
I think that the
We do not have to say that the experimentals
109
1
have to design it so they justify.
2
say that the IRB has to review it for the
3
justification.
4
more simple way but I have no problems.
5
the message is conveyed and, as I say, I would like
6
something short and simple with the explanation in
7
the text rather than trying to cover everything in
8
the recommendation.
9
10
We do not have to
So I am just -- just state it in a
DR. SHAPIRO:
DR. BRITO:
Okay.
As long as
Arturo?
I think I am going to prefer to
11
make some of my -- I will rank my papers and present
12
them that way because I am a bit troubled by some of
13
the conversation that occurred earlier and I
14
understand, you know, a good study design and the
15
need -- and when you are comparing a nonplacebo trial
16
that you need larger numbers but I am a bit troubled
17
by how that can be interpreted.
18
When I read the recommendation -- except
19
maybe some of the redundancy that it refers to but I
20
am happy with it for the justification.
21
The only comment I make now is I do not know
22
if we need to think about do we need to include in
23
the recommendation a comment that Steve made about
24
when you are talking about things that are not really
25
more than minimal risk.
26
need to be provided for placebo control trials for
27
things that are not life threatening or, you know,
You know, does justification
110
1
can cause severe medical problems down the road?
2
for the other comments I will reframe and then write
3
them.
4
DR. SHAPIRO:
Okay.
5
PROFESSOR CAPRON:
But
Alex?
Do we assert here by
6
quoting Bob Temple and so forth that what we are
7
saying here applies in the United States fully under
8
current interpretation?
9
process 18 years ago or whenever it was, we heard
10
from Temple and other people in the FDA as to why
11
placebo control designs are used and a very strong
12
scientific presentation of them.
13
I mean, when we began our
We are now taking the position that at least
14
as to any serious condition where death or
15
irreversible injury would be involved, placebo
16
control designs are ethically unacceptable unless
17
there are all these kinds of justifications.
18
The justifications do not seem to go to the
19
placebo design.
20
of a known effective treatment, which could mean not
21
the world standard treatment but some other known
22
effective although not very effective treatment in
23
the country in question.
24
They seem to go to the withholding
We are, therefore, saying in the United
25
States that all the companies that do placebo control
26
designs are wrong or is Temple -- is what we say here
27
from Temple and Bob Levine, who is not cited at this
111
1
point, but Ruth says is in support of the same point,
2
that today, in fact, researchers in the U.S. as to
3
serious illnesses do not use placebo controls?
4
that the current -- is that a currently correct
5
statement?
DR. SHAPIRO:
6
7
Steve, did you want to say
anything?
MR. HOLTZMAN:
8
9
Is
I mean, if you think back to
what Temple was pointing out, he was specifically
10
dealing with the example of psychotropic drugs.
11
Right?
12
his point was that because of the variability of
13
response, a noninferiority trial will not do what you
14
need it to do because there -- you will not know
15
whether your control had been effective.
16
it is as effective as your control is irrelevant in
17
terms of is it effective at all.
18
He was dealing with psychotropic drugs and
Hence that
I mean, under current standards, and I think
19
Ruth is right in what she states about the
20
cardiovascular so to use a real live example, my
21
company is conducting or we submitted a BLA with
22
respect to an anticancer drug where the FDA agreed
23
that in some ideal world it would be great to do a
24
placebo control but there is no way you can ethically
25
do a placebo control and it drives the statisticians
26
crazy that we are using historical controls but it
27
would be unethical to do otherwise.
112
So I do not think it is necessarily
1
2
inconsistent.
3
to certain kinds of studies you cannot get the proof
4
unless you use a placebo control.
5
question is it ethical to do so?
6
the case of the serotonin reuptake inhibitors were
7
that it was not such a dire consequence.
8
the, so to speak, spectrum with the Ibuprofen example
9
that could justify it.
PROFESSOR CAPRON:
10
11
I think Temple was saying with respect
Now ask the
And the argument in
It was on
It would have to fit
within that?
MR. HOLTZMAN:
12
It would have to fit within
13
that.
14
withholding life saving therapeutic intervention by
15
giving a placebo you are not allowed to do that and
16
we do not do that.
PROFESSOR CAPRON:
17
18
If it is the case that you would be
with what we said in the report on --
19
MR. HOLTZMAN:
20
PROFESSOR CAPRON:
21
It should be.
-- persons with
diminished capacity.
22
MR. HOLTZMAN:
23
DR. SHAPIRO:
24
And that is consistent
Right.
Hold on a second.
Jim, then
Trish, Arturo.
PROFESSOR CHILDRESS:
25
But along those lines
26
I just want us to be cautious on 17 and in quoting
27
Temple.
When we had his testimony and we were trying
113
1
to develop the other report, I am really concerned
2
that we not think that discomfort does not count as a
3
harm on the top of page 17.
4
discomfort, the context and so on and so forth, and I
5
just do not want us to slip in that trap here.
6
Okay.
7
DR. SHAPIRO:
8
PROFESSOR BACKLAR:
9
DR. SHAPIRO:
It may well be a harm.
DR. BRITO:
10
It depends on the
Trish?
(Not at microphone.)
Arturo?
I have a request that when we
11
speak about placebo control trials, placebo control
12
trials in essence are not unethical.
13
difficulty with is placebo control trials when an
14
established effective treatment is available and in
15
the conversations going back and forth it is very
16
hard to keep up and then when Dr. Temple spoke back
17
then and he -- I am not -- I am confused about when
18
he was speaking about when established effective
19
treatments were available and when they are not
20
available.
What I find the
So if we can just make that clear when we
21
22
are talking about this and the same thing within the
23
text.
24
DR. SHAPIRO:
I think one of the phrases
25
that might be useful, I really ask Steve and Ruth and
26
others to think about it, is Steve used the phrase
27
just a moment ago when the noninferiority trial
114
1
simply does not answer the question, okay, that is a
2
pressing or compelling interest.
3
Then you have to start making -- consider
4
other things and I think maybe that is a useful -- I
5
mean, I find that a useful phrase.
6
know, I am not a physician.
7
the examples.
8
9
10
PROFESSOR CAPRON:
I am not -- you
I cannot give out all
But even there that will
then push us back to the issue, “Is the question
ethically acceptable?”
11
DR. SHAPIRO:
Correct.
12
PROFESSOR CAPRON:
Because from the drug
13
company's point of view, the advantage even when
14
there is an accepted effective treatment, is a
15
noninferiority trial does not answer the question
16
that they want to ask, which they might want to ask,
17
which is does this drug have a greater effect than a
18
placebo, i.e. is it approvable as an effective
19
efficacious intervention even though doctors would
20
like to know is something else that is already around
21
better so that they would not be using it.
22
But I mean a lot of stuff has been developed
23
on kind of a me too basis without proof that it is
24
better than the existing things.
25
understand it there is a -- that is not an unusual
26
practice.
27
I mean, as I
Steve, are you going to tell me it is
115
1
2
unusual?
MR. HOLTZMAN:
Yes, it sure is.
I mean,
3
particularly in a world of pharmacoeconomics
4
considerations and formularies being able to show
5
that it works as opposed to “its at least as good if
6
not better” is absolutely useless these days so I
7
think -- I do not think that is a correct portrayal.
8
So then, in fact, the drug company actually has an
9
interest in showing the superiority or
10
11
noninferiority.
Okay.
PROFESSOR CAPRON:
It may well but doesn't a
12
drug company -- correct me if I am wrong.
13
recently, at least with the economic pressures, a lot
14
of things have been approved and the objective of the
15
drug company was to get the drug approved using a
16
placebo control.
17
it believed it could show that its drug was superior
18
to or comparable than but cheaper than or whatever
19
argument for superiority it wanted to put forward
20
from an established treatment but it was not required
21
by the FDA to show that and, indeed, the FDA could
22
not refuse to approve something simply because there
23
was another established treatment that was more
24
effective.
25
26
27
Until
It could then do further studies if
MR. HOLTZMAN:
The real world has changed
over the last decade.
PROFESSOR CAPRON:
Right, but it has not
116
1
changed because of ethical pressures is my point and
2
so if we say that it is not a -- it is not effective
3
because -- excuse me.
4
answer the question, the relevant question, I just go
5
back to say relevant to whom.
6
DR. SHAPIRO:
7
PROFESSOR CAPRON:
That the design would not
I agree completely.
And you might say that
8
the drug company -- well, if all you are developing
9
is a me too drug and there is no reason that it would
10
be more effective than the existing treatment you
11
should do it and they say but the question for us is
12
do we have an efficacious treatment.
13
MR. HOLTZMAN:
Okay.
14
PROFESSOR CAPRON:
So --
And then we will deal
15
with marketing later, thank you very much, aren't we
16
entitled to do that.
17
MR. HOLTZMAN:
Yes.
Well, with all
18
affection, it is a very abstract argument you are
19
making, is that getting a drug registered is useless
20
if you cannot market it.
21
market it is a function of what is in your label and
22
your label will either say have the comparison to the
23
standards or it will not, and you cannot market
24
outside of the label.
25
trial one does not say how do I get this thing
26
registered.
27
order to make this thing marketable and that has
Whether or not you can
And so when one looks at the
One just says what do I need to show in
117
1
always been the case.
2
DR. SHAPIRO:
That is the real world, Alex.
I think the issue of whether
3
the research question itself suffers from ethical --
4
is a very important one and is everywhere in all
5
trials, and that really needs to be considered.
6
comes up, I believe, in -- I think it is in Chapter 4
7
but Ruth can correct me where you give some examples
8
saying if the central question is this then this is
9
the ethically appropriate trial, if the central
That
10
question is that something else is the appropriate
11
trial, that does not overcome the question of whether
12
the central question itself has -- is ethically
13
acceptable and needs to be addressed.
I mean, I agree with that point that nothing
14
15
should be said here gets around that basic issue as
16
to whether the whole question being addressed has any
17
ethical basis or not.
Okay.
18
19
Any other comments?
You wanted to
read --
20
PROFESSOR CAPRON:
21
DR. SHAPIRO:
22
PROFESSOR CAPRON:
Could I ask one question?
Yes.
As part of the discussion
23
leading up to the point where we were talking on page
24
39 -- and I think I have wide agreement, Ruth, that
25
the language on 39 and 40 is very helpful, there are
26
two -- at the top of that page at line 2 the
27
statement on page 39, to examine the various
118
1
alternatives we need to contrast proposition B with
2
two other candidates.
3
over from an earlier edition because then we go on
4
and say (c) and there is no (d).
5
sure that I was not missing something.
6
question.
7
there a substantive --
8
9
Is that simply something left
PROFESSOR CHILDRESS:
And further there is
after (c) the and as though -DR. SHAPIRO:
11
PROFESSOR CAPRON:
12
DR. SHAPIRO:
13
PROFESSOR CAPRON:
15
It is a
Is this merely an editorial problem or is
10
14
I just want to make
Right.
Yes, exactly.
Right.
Exactly.
Did something
get left out intentionally or otherwise?
DR. MACKLIN:
Yes.
I think we made a
16
revision.
I think we made a revision and did not --
17
we had more propositions in there initially.
18
(a), (b), (c) and (d).
19
them and this needs to be fixed.
We took out one.
20
Pardon?
21
PROFESSOR CAPRON:
22
We changed
We no longer need (d),
whatever it was.
23
DR. MACKLIN:
24
PROFESSOR CAPRON:
25
DR. SHAPIRO:
26
PROFESSOR BACKLAR:
27
We had
No, we no longer need (d).
Okay.
Thank you.
Trish, and then Jim.
Yes.
Can I make a
simple request and that is that -- are we going to
119
1
have another look at this before it goes out for
2
public comment and, if so, it would be
3
extraordinarily helpful if there would be some
4
difference in the changes that you make like bolding.
5
Some way that when we go back to read this just as
6
readers
--
7
DR. SHAPIRO:
Well, I think --
8
PROFESSOR BACKLAR:
9
DR. SHAPIRO:
No, not possible?
Well --
10
PROFESSOR BACKLAR:
11
DR. SHAPIRO:
All right.
No, do not feel that it is not
12
possible but I think you will get a -- I do not know
13
that we will have a chance to sit down in a meeting
14
to go over it.
15
and have some short period for comment before we send
16
it out.
17
18
We can certainly send out a new draft
PROFESSOR BACKLAR:
DR. SHAPIRO:
20
PROFESSOR BACKLAR:
Right.
DR. SHAPIRO:
23
PROFESSOR BACKLAR:
Which one?
Number 2 that has that
paragraph before which lists on page 39 --
25
DR. SHAPIRO:
26
PROFESSOR BACKLAR:
27
And that is that the
recommendation number --
22
24
And then just --
this is two things in one.
19
21
Okay.
Right.
criteria for the assessment.
-- and you list the
In some of the other
120
1
reports we would -- with the recommendation you would
2
still have a little discussion following it and maybe
3
if you do not want to lengthen the recommendation it
4
would be wise to put that paragraph following the
5
recommendation imbedded in there.
6
DR. SHAPIRO:
Eric?
7
DR. CASSELL:
I just want to go back to the
8
set of four -- the four recommendations on the -- not
9
recommendations, the four criteria on the top of page
10
40.
11
cannot do the study at all.
12
not advancing the care of the people in the host
13
country.
14
and then we go back to controls are intended to
15
simulate the current state of care in the host
16
locale.
17
There are three.
Three that have -- one if you
The other is if you are
And then there are two about exploitation
I think if we are going to take exploitation
18
as being one of those things, which is actually how
19
this -- one of the reasons that this all gets fired
20
up, we ought to separate it out.
21
not think it is under beneficence.
22
is a matter of injustice and exploitation as a matter
23
of injustice.
24
think it is injustice.
25
It is not -- I do
For one thing it
But I mean you can make the case but I
And it is a separate issue and it is a
26
clearly important issue that when research is done
27
that exploits people, and that is why there is no
121
1
placebo control because it is cheaper and quicker and
2
slicker and all that stuff.
3
clear that that is a separate set of criteria.
4
would only require actually moving those things to a
5
different position.
DR. SHAPIRO:
6
We ought to make that
All right.
Let's -- before we
7
-- Jim, I have been -- I always have trouble if
8
someone sits right on my right.
9
Please?
10
11
12
13
That
I apologize, Jim.
PROFESSOR CHILDRESS:
Let me agree with
PROFESSOR CHILDRESS:
Another inarticulate
Eric.
person on your right.
14
PROFESSOR CHILDRESS:
15
(Laughter.)
16
PROFESSOR CHILDRESS:
That is right.
Let me agree with Eric
17
and suggest also that in looking back over this, the
18
exploitation plays such a central role we ought to
19
make sure that we really do define it well and work
20
it out that is in the report as a whole.
21
did not go through it as carefully as I could have
22
with attention to that but I have -- before we leave
23
this discussion I would like to go back to pages 15
24
and 16, and we have spent a lot of time discussing
25
the first -- it is generally accepted that a placebo
26
control trial would not be ethical in lines 22 and
27
following.
And I
122
1
But I would also like to just call attention
2
on line 30 at the bottom of 15 and the top of the
3
next page where it is generally accepted that if a
4
clinical trial is testing an experimental
5
intervention for a disease for which there is no
6
available treatment it is ethically justifiable to
7
give research participants a placebo because in such
8
trials there is nothing with which to compare the
9
experimental intervention.
10
But I would just remind us that we had a lot
11
of controversy about the initial AZT trial as to
12
whether we should have simply used historical
13
controls given the fact that there was nothing
14
available then in the antiretroviral area to treat
15
HIV infection or the Ara-A trial in the context of
16
herpes simplex encephalitis.
17
had about a 70 to 80 percent mortality rate.
Again a condition that
18
So what I just want to emphasize is that it
19
may be okay to go ahead in both of these and lay out
20
it is generally accepted as long as we recognize that
21
there will be some difficult questions to arise and
22
we have already dealt with some of those in regard to
23
the first generally accepted.
24
The second observation I would make is --
25
and this just picks up some of the earlier discussion
26
-- is that a lot depends on how much we build in to
27
what is generally accepted and there is a kind of
123
1
specification that has gone on in the first one that
2
has to do with prevention -- established effective
3
treatment that is known to prevent serious harm such
4
as death and so forth, and yet a lot of our
5
discussion focused on the more general level.
6
think it is important for us to be clear that it may
7
set out a general principle or standard and whether
8
we can take it as sort of absolute or presumptive or
9
mere suggestion or guideline.
I
A lot is going to
10
depend on what we build into it and I think a fair
11
amount is built into the first one as a matter of
12
fact.
13
DR. SHAPIRO:
Okay.
Thank you.
14
Let me make a suggestion, Alex, because we
15
are jumping around a bit but there are certain issues
16
I do want to get close to resolution and so we will
17
come back if time allows either later this morning or
18
tomorrow morning to some of the other issues both in
19
Chapter 2 and Chapter 3 and Alex's suggestions
20
regarding Chapter 1.
21
But I do want to move our focus now to
22
another key recommendation and it really comes up
23
under Recommendation 2 in Chapter 4.
24
recommendation, as you know, deals with obligations,
25
post trial obligations, and it is important --
26
critically important, I think, to make sure that we
27
agree with Recommendation 2 or some alternate
That
124
1
recommendation.
And I would just like to open the
2
floor now for discussion regarding Recommendation 2
3
on page 10 in Chapter 4 that deals with post-trial
4
obligations and so on.
5
Eric?
6
DR. CASSELL:
This is one of those areas
7
where I am troubled by it.
I really am because of
8
several things.
9
we have to provide adequate food, which as I
First of all, it does not say that
10
indicated before might make a bigger difference in
11
that intervention.
12
of something like HIV to go two months or three
13
months and then stop.
14
after a one month trial.
15
It does not say ongoing treatment
It is just as bad as stopping
It seems to specify -- it seems to me to be
16
holding people to do something where it would be
17
lovely but we do not -- why are they doing this?
I
18
mean, aside from the fact that it would be nice.
And
19
-- because the minute you specify limits to the doing
20
then you have to justify, well, if those limits are
21
there, why would they do it in the first place.
22
those limits and why not these limits.
23
does not seem to me to be addressing an issue of
24
having to do with the ethics of clinical trials as
25
much as it has to do with what we think we might owe
26
a deprived population and that is another question
27
entirely or what we think the industrial might of the
Or
So that it
125
1
United States should do rather than what it is doing.
2
DR. SHAPIRO:
3
Steve?
4
MR. HOLTZMAN:
Other comments, questions?
I am not sure how I feel
5
about this recommendation.
I know it is a good
6
aspiration but what I feel I do know is that the
7
justification given for it in terms of the Daniels'
8
like argument and justice is reciprocity and saying
9
that it comes from the fact that whence in the trial
10
you have established a new status quo from which it
11
may not be diminished, I find that line of argument
12
wholly unconvincing and that if I were to move
13
forward and we were going to go ahead with these
14
recommendations I would want to ground it in a
15
different line of arguments, which is motioned
16
towards here in terms of the special relationship
17
that is established between the medical community and
18
subjects of research, which imposes an obligation in
19
order to keep intact the meaning of that
20
relationship.
21
DR. SHAPIRO:
Bill?
22
MR. OLDAKER:
Like Steve, I am a little
23
troubled by the justification.
24
as a moral principle if we were saying universally
25
that this had to be done in Watts or in poor parts of
26
the United States, I would probably be empathetic
27
with it.
It seems to me that
I mean but if we are dealing with it as
126
1
something that we are going to do in another country
2
just because we are doing research there, it -- to me
3
the ethical principle is not any different than
4
dealing with an impoverished group here that would
5
not have the follow up health care.
6
that -- I have not thought enough about it to think
7
about whether it should be kind of a universal
8
principle and that we should be talking about it.
I do not know
The second thing in the recommendation
9
10
itself, I am always troubled by kind of open ended
11
things, such as relevant parties and if you are going
12
to negotiate this, and how you really figure it out,
13
but I guess I am troubled by the underlying concept.
14
PROFESSOR CHARO:
15
DR. SHAPIRO:
16
PROFESSOR CHARO:
Hand up.
Alta?
I was comfortable with the
17
original justification but I certainly share Steve's
18
instinct that there is a second line of justification
19
having to do with the special relationship between
20
research subjects and the investigators, and would be
21
happy to see that presented as well as an explanation
22
for why some of us reach the conclusion that is
23
represented in Recommendation 2, which I strongly
24
support.
25
I am less -- I am not troubled as Bill
26
Oldaker is by the open ended nature of it because
27
that open ended nature was a result of compromise
127
1
since it used to have much more specific language
2
that got people uncomfortable and so the
3
recommendation was rewritten to loosen it up and
4
allow for a process of negotiation among whoever
5
seemed to be an appropriate party leaving it to the
6
IRB and the investigator to discuss this when the
7
research protocol was first being presented.
8
it seemed to me like the only compromise we could
9
have rather than if we were not willing to lay down
10
And
very rigid rules.
11
DR. SHAPIRO:
12
Yes, Laurie?
13
MS. FLYNN:
Any other comments?
I just want to offer kind of a
14
two part thought.
Like most of us here I think I
15
kind of like the feeling of this that, in fact, we
16
would want to be able to offer this.
17
concerns that particularly in some of the situations
18
in developing countries that we are familiar with
19
that there is the great potential for further
20
confusion around the therapeutic misconception that
21
we have tried so hard to articulate and that there is
22
some potential for this to be coercive and
23
potentially exploitative depending upon the way in
24
which this is presented.
But I have some
25
So while I understand where we want to go
26
and why we want to go there I do not think we have
27
given sufficient justification to get there.
128
1
DR. SHAPIRO:
Eric?
2
DR. CASSELL:
Also even though Ruth does not
3
like examples, my friends and hers, Stephen Toulmin
4
and Johnson otherwise, here is an example -- here is
5
an instance where an example would be very helpful to
6
me.
7
are you talking about?
8
What population are you talking about?
9
talking about only the clinical trial members or
What drug are you talking about?
What disease
How long would you give it?
Are you
10
their families as well?
After all, if the brother is
11
getting it, why not the other brothers?
12
and so on especially in a community where one person
13
participates.
14
participating.
15
then we get into these issues and I would like to
16
hear an example of it.
And so forth
In point of fact that is the community
It is different than it is here.
17
DR. SHAPIRO:
18
MR. HOLTZMAN:
And
Steve?
Well, actually, Eric, I
19
thought there was a lot of language in this chapter
20
that actually went exactly to all of that and the run
21
up to the recommendation was saying you have got a
22
lot of very complex situations.
23
is the relevant population?
24
the family?
Is it everyone?
Is it
What about the controls?
25
DR. CASSELL:
26
MR. HOLTZMAN:
27
Some would say what
(Not at microphone.)
So I thought -- but anyway,
but I think maybe you could look for examples that
129
1
exemplify the different cases.
What struck me is that we do talk about
2
3
wanting prior agreements, or whatever is the
4
terminology that we would use, with representatives
5
of the relevant country.
6
are stipulating some specifics as opposed to just
7
leaving it to that process.
DR. SHAPIRO:
8
9
10
And I wonder why here we
Let me make a comment on the
recommendation itself and see if it might be of any
help in at least thinking of some people.
With respect to the underlying rationale, it
11
12
is my own view, as Eric and Ruth know, that the
13
primary goods argument and so on really does not
14
provide a solid basis for this nor does, in my view,
15
justice as reciprocity because reciprocity can be
16
expressed in many different ways.
17
particular reason it needs to be expressed in this
18
way.
19
There is no
It is only one of many possible ways.
But the recommendation as it is phrased has
20
two sentences.
The first one says they have to
21
provide something but the second one says at some
22
unknown price and some unknown period of time.
23
seems to me that you are then left with a
24
recommendation that is not operable because it is not
25
clear what anyone is supposed to do or expect because
26
it could be zero price, high price, low price, short
27
time, long time and so on.
It
130
1
It may be that you cannot get around the
2
fact that these things need to be negotiated, as
3
someone said a moment ago, in prior agreements.
4
One way to read Recommendation 2 would be
5
say sponsors should continue to provide at terms to
6
be negotiated, et cetera, et cetera, the research.
7
That would just simply -- that is a much simpler, not
8
necessarily adequate, not -- I am not trying to
9
promote this recommendation, just looking at another
10
11
alternative.
It would just say that this is something
12
that really deserves some consideration and that
13
ought to be part of some prior agreement or some
14
other language like that and then you leave that to
15
the people involved in a case by case basis to decide
16
what is appropriate.
17
Bette?
18
MS. KRAMER:
Picking up on the language you
19
just suggested, what about the possibility of saying
20
whether or not it should be continued -- a sponsor
21
should continue to provide the research product.
22
should be a matter of prior agreement or discussion
23
prior to the initiation of the research.
24
DR. SHAPIRO:
It
Well, I do not think that is
25
different in spirit from what I said.
I have no view
26
on the language.
27
carefully but I think that is -- I am not quite sure
I have not thought about it
131
1
what I am suggesting but, I mean, that -- I am just
2
trying to move the conversation along but that is
3
very consistent with what I just said.
4
Yes?
5
PROFESSOR CAPRON:
Steve earlier pointed to
6
a rationale which we have discussed at previous
7
meetings, which is the fiduciary nature of the
8
physician-patient relationship which carries over
9
into medical researchers' relationship with their
10
subjects.
11
is whether we are establishing unreasonable
12
expectations there which we do not expect are
13
universal, that is to say they would not apply in
14
this country.
15
And the difficulty here, it seems to me,
And I am always -- and I think it is good
16
when our looking at things abroad makes us look back
17
at our practices here.
18
rules would differ but presumptively they ought to be
19
the same.
20
There may be reasons why the
I do not think we have to worry about the
21
researchers and we do talk in Recommendation 2 about
22
sponsors rather than researchers.
23
is not a personal obligation of the researcher,
24
although it arises out of their personal
25
relationship.
26
their agreement with their own research sponsor as to
27
what the sponsor is going to provide.
That is to say it
It is something that would be part of
132
But part of the difficulty I have with that
1
2
is that an example which we mentioned in passing in
3
the text leading up to this is the situation in which
4
the intervention is not useful but the existing
5
established treatment is useful and that is what the
6
controls have been getting but maybe the controls
7
would not have been getting it and do not have access
8
to it or all of them do not from an ordinary medical
9
system.
And this would certainly be relevant if we
10
were talking about trials in the United States as
11
well if you have patients who are recruited, some of
12
whom do not have insurance and so forth but they are
13
in the trial and they are getting the effective
14
intervention.
15
It is equally a breach of their fiduciary
16
relationship to abandon, as it were then, just as it
17
is not to turn around at that point, and to turn to
18
the subjects who are getting the -- as it turned out
19
-- an effective therapy -- research intervention and
20
give them now the established effective treatment
21
that the controls were receiving.
22
So I think we -- I mean, I do not think we
23
can waltz around this.
We can point out that those
24
are issues that have to be done and if we do that
25
then the solution that you and Bette just were coming
26
up with is all that we can say, which is simply these
27
are the considerations and people ought to have
133
1
2
thought about them in advance and negotiated them.
That is not what this says now and it seems
3
to me that we just ought to have a show of hands or
4
something.
5
recognizing that sometimes it will not be possible to
6
fulfill it?
7
than impossibility you would give there but if there
8
is an obligation then it does not seem to me that it
9
is something -- if it is based on this fiduciary
Do we believe that there is an obligation
I am not sure what justification other
10
relationship, it does not seem to me it is something
11
that disappears in a week or a month or whatever.
12
becomes some notion of an ongoing obligation.
13
If that seems too impossible, that is to say
14
there will be no circumstances in which a research
15
sponsor would want to take on that potentially
16
lifetime obligation, then we ought to just to take
17
the weaker view and back away from this.
18
19
20
It
DR. SHAPIRO:
Trish wants to say a few words
in a moment.
With respect to the principle that gives
21
rise to this obligation, Alex and others referred to
22
the fiduciary relationship between the
23
physician/investigator and the subject, and I think
24
that is an important issue, although I have to
25
confess that I am not sure just what the nature of
26
that relationship is everywhere.
27
I mean, it is just a lack of knowledge on my part but
I just do not know.
134
1
I could believe that it is an important fiduciary
2
relationship in many places.
3
There is another argument, which in fact I
4
may be the only one here who has found it somewhat
5
convincing, namely that someone is made better in the
6
trial to -- as someone said to put it in an
7
exaggerated way -- to have them abandoned at the end
8
of the trial, represents in my view some kind of
9
existential loss which cannot be anticipated in the
10
informed consent process, not easily anticipated,
11
since subjects do not know what it is to feel better
12
in some sense.
13
And that is to me at least something worth
14
some serious consideration.
15
the end of the day the weaker version of this
16
recommendation for some of the reasons Alex pointed
17
out because it is difficult and complex.
18
However, I do favor at
Second of all, I think that while we do not
19
want -- sponsors are not simply pharmaceutical
20
companies where that is a model which I think is in
21
people's minds as we have a lot of discussion.
22
the U.S. government is a major sponsor, probably the
23
major sponsor, and some very interesting -- it is not
24
clear that depending on the results that even the
25
government or at least some agency of the government
26
has the capacity to deliver on this kind of thing
27
and, therefore, they would be unable to proceed at
And
135
1
2
all.
It seems to me that one has to think about
3
the incentives in a complicated way here.
And so for
4
those and other reasons that have been mentioned, I
5
do not want to repeat here, I do favor the weaker
6
version of this.
7
but I will not repeat it -- but language that is
8
similar to that really might be as far as we can go
9
and then point out these various issues.
I may not have the right language
10
Trish, you are next.
11
PROFESSOR BACKLAR:
Yes.
I actually favor
12
the weaker version but there are two things.
13
I think that you are moving in the right direction,
14
Harold, because I was thinking that one also wants to
15
say about research subjects that one does not wish to
16
make them worse off than they were during the trial.
17
One is
So you reach the -- they reach a certain
18
point and then if you -- if they get nothing they are
19
actually made worse off.
20
And we actually did discuss this to some
21
extent while we were doing our capacity report and
22
the issue of people with mental disorders getting
23
certain kinds of medications during a trial and then
24
not being able to give it to them afterwards, and at
25
that time as -- if I remember correctly, I actually
26
looked through the capacity report because I had in
27
my mind that we had said somewhere -- I know that
136
1
Laurie pushed this quite hard -- that when people
2
were in trials we should make sure that they were
3
able to get the drugs afterwards.
4
But when I looked through the capacity
5
report recently I could not find that anywhere so
6
exactly what you are saying, Alex, holds.
7
not able to do it here.
8
Or should -- is this an opportunity for us to revisit
9
this problem because it is a real problem?
10
DR. SHAPIRO:
We were
How can we do it elsewhere?
My own view is that -- the
11
fact that we do not do it here should cause us to
12
pause and think it through but not necessarily stop
13
because it may be after all something which we should
14
be doing here and are not.
15
us to pause.
16
It should certainly cause
I have a number of people who want to speak.
17
Larry, Steve and then Eric.
18
DR. MIIKE:
In answer to Alex's question I
19
do think we need to treat the trial participants
20
differently from the host country inhabitants and so
21
the discussion around 2 has to be linked with the
22
discussion around 4.
23
owe trial participants is a negotiated -- negotiation
24
beforehand of whether they get anything or not,
25
rather than a negotiation about what kinds of
26
benefits they would get, then the discussion about
27
the host country participants is useless because if
If we say that all we need to
137
1
we are not going to have any obligation except a
2
discussion before the trial takes place about what we
3
-- what, if anything, is to be provided to the trial
4
participants then nothing is owed.
5
discussion to the -- what might be owed to the host
6
country's inhabitants.
So I think we have to keep in mind 4 while
7
8
Not even a
we discuss 2.
DR. SHAPIRO:
9
Yes.
I think 2 and 4 in my
10
view ought to be more closely integrated on a number
11
of grounds, including what Larry has just said.
12
There is a lot in 2 that is again repeated in 4 and
13
so on.
We need to bring that together.
14
Steve?
15
MR. HOLTZMAN:
I would like to try to piece
16
apart two different strands in Recommendation 2.
17
one that is, is something owed, and I think that ties
18
very closely to 4.
19
which it is determined what form that which is owed
20
should take.
21
The
And specification of a process by
That is distinct from the question -- a
22
different strand which says certain forms of
23
recompense would be inappropriate and the justice as
24
reciprocity in the Daniels' argument, which I do not
25
accept, I think is trying to drive at that.
26
saying that only certain exchanges would be
27
appropriate exchanges.
That is
138
1
I actually agree that that is true but that
2
is where I want to ground it in the relationship of
3
the researcher or the medical doctor to the subjects
4
and what they are doing and how certain forms of
5
recompense would erode that.
6
meaning of the enterprise.
7
It would change the
So, for example, if we were talking here
8
about consensual sex, we would say that it is okay
9
and people can negotiate it.
However, there are
10
certain things we might say are beyond the pale such
11
as money in exchange for the sex.
12
it could not be -- it could be reciprocity there but
13
we think that the nature of that reciprocity erodes
14
what we hold to be as a value in the act.
15
Why?
Not because
And I think that goes to your points,
16
Harold, also about the existential charge of the
17
relationship.
18
And I think we are saying something
19
stronger, wherever we are going to ground it, that
20
says we think certain forms of exchange would be
21
inappropriate and exploitative.
22
DR. SHAPIRO:
23
Eric?
24
DR. CASSELL:
Thank you.
You know, grounding it in the
25
fiduciary relationship of physician and patient, I
26
spent a lifetime in that relationship, and the one
27
thing about it is you have to be very careful that
139
1
you are not Thidwick, the big hearted moose.
I do
2
not know -- Dr. Seuss fans aside, Thidwick allows
3
birds to keep nesting up in his horns you see until
4
finally he can hardly move because there are so many
5
birds nesting in his horns.
Physicians learn very early on that that
6
7
relationship has got to have boundaries.
You are not
8
a family member.
9
not expected to give beyond what is practical for
You give what you can do.
You are
10
you.
11
and, you know, constant and so forth within the
12
limits of ability.
13
You are expected on the other hand to be honest
So that is on the one hand.
The other hand is generally speaking when we
14
talk about the relationship of researchers to
15
subjects, it is not the same relationship.
16
mostly like to see the relationship of the researcher
17
to knowledge be the stronger of the two
18
relationships.
19
up in conflicts in lots of clinical research.
We would
That is one of the things that comes
20
So to move it over and call it the fiduciary
21
relationship of a doctor -- the caring doctor and the
22
patient is, I think, not grounded in the way things
23
actually take place.
24
DR. SHAPIRO:
Trish?
25
PROFESSOR BACKLAR:
And leads to the
26
therapeutic misconception we are so desperate to keep
27
apart from research.
140
DR. SHAPIRO:
1
I think I am going to go to
2
Alex and Bill and then we are going to have to stop,
3
and Jim.
4
on the list now or you speak after lunch?
5
Alex, Bill and Jim.
All right.
Okay.
6
Anyone else now because you get
So it is
Let me just say one thing about this
7
therapeutic -- there is no getting around the issue
8
that if you have post trial benefits for whatever
9
reasons you have, it feeds into that, I think,
10
especially if it is medical care or something close
11
to it as opposed to some other benefit.
12
go.
13
But let's
Alex?
PROFESSOR CAPRON:
Yes.
I want to disagree
14
with that proposition and I thought Ruth articulated
15
it well as I understood it before.
16
difference between inducements, which we may believe
17
are under the circumstances so great that a person
18
gets to the point where they cannot say no because
19
they are just so desperate for all the ancillary
20
things, which could include post trial treatments as
21
well as nuggets of gold after.
22
things could be such inducements.
23
than the therapeutic misconception.
24
DR. SHAPIRO:
25
PROFESSOR CAPRON:
There is a
I mean, all sorts of
That is different
Right.
And I do not think that
26
suggesting that you could have circumstances in which
27
the relationship of a researcher providing a research
141
1
intervention to a subject which manifestly in a way
2
that they both understand has made the subject's
3
condition better is -- will seem to be comparable to
4
a physician.
5
misconception going in but because coming out it has
6
proven that this seems to have made a beneficial --
7
now it may be false.
8
9
Not because there was a therapeutic
It may turn out that you look statistically
and the person is doing no better than the person
10
getting the control but that there is that
11
understanding.
12
Chairman, and there is that understanding.
13
You are calling it existential, Mr.
I like that to that fiduciary relationship
14
in the sense that at that point it would be an
15
exercise of the obligation of nonmaleficence not to
16
withdraw that treatment from that person who is
17
dependent upon it.
18
Now it is perfectly true, Eric, that we can
19
say that the -- that there are reasons for treating
20
the researcher-subject relationship very differently
21
than the physician-patient relationship and that that
22
relationship is time limited and it has to do with
23
the research intervention and it ends when the
24
research ends.
25
description.
26
27
I mean, it is possible to give that
I am simply saying that in -- as experienced
-- maybe existential is the right word -- as
142
1
experienced by people that line -- that sharp
2
distinction between those two relationships, I think,
3
will not wash and there will be circumstances in
4
which either the controls who did well on the
5
standard intervention or the subjects who got the
6
active research intervention who did well will feel,
7
and other people observing it would justifiably feel
8
that there has been an exercise of maleficence there
9
in withdrawing it.
10
I think we have to address that and we have
11
two choices.
12
strong obligation exists or we should say, as Bette
13
and Harold were saying, we should say that this is a
14
serious issue which needs to be thought through in
15
advance, negotiated by the relevant parties and
16
spelled out.
17
We can either say that is wrong and a
And, in effect, that would flip
points 2 --
18
Recommendation 2 and 1 on page 10 because we would
19
say first it needs to be negotiated and secondly you
20
need to be clear to people about what the result of
21
that negotiation is.
22
I just think at some point we should bring
23
the conclusion to -- and give instruction to the
24
staff by having a straw poll as to whether the
25
negotiation or the strong ethical conclusion is the
26
one that we favor.
27
DR. SHAPIRO:
Okay.
We will do that in a
143
1
few moments.
Bill?
MR. OLDAKER:
2
I will agree with that, too,
3
but my -- and I agree that we should use a word like
4
"negotiated" if we are going to do this.
5
if we use "relevant parties" we will have created
6
also a nullity because people will create whichever
7
relevant parties they want.
I think that it -- and it also goes back
8
9
My fear is
into 4.
I do not know if the right entity to be
10
negotiated with is the Ministry of Health or someone
11
else but if it is we should be trying to be somewhat
12
more specific because it is -- I think "relevant
13
parties" is just too ambiguous of a term to figure
14
out who the sponsor is going to negotiate with, and
15
we should be a little bit more specific.
16
PROFESSOR CHARO:
Hand up.
17
DR. SHAPIRO:
18
Jim, you are next.
19
PROFESSOR CHILDRESS:
Just a second, Alta.
I think we have
20
materials in the text and in the lines of argument
21
that Steve and Alex and others have suggested to
22
develop a kind of relationship model without falling
23
into some of the pitfalls that Eric worries about in
24
which we are really talking about a relationship in
25
which we have a kind of partnership, reciprocity,
26
fiduciary concerns and so forth and that would
27
certainly clear the matters that we have already
144
1
talked about of not exploiting people and not making
2
them worse off, of having some obligations that
3
continue by virtue of what was established in that
4
relationship.
5
I think that we have those threads in our
6
discussion today and in the text and I think those
7
threads got lost somewhat because in -- this is a
8
version of a point that Steve was making earlier,
9
too, the Daniels' discussion may mislead us.
It is
10
really brought in to indicate why in a justice is
11
reciprocity mode we should be focusing on health
12
benefits rather than other kinds of benefits.
13
The problem is that obviously food and other
14
things could contribute to health benefits if that is
15
the direction we are going.
16
much that kind of outcome oriented concern but rather
17
the nature of the relationship and that process of
18
interaction.
19
So really it is not so
So I think we could go in that direction and
20
capture most of the concerns and themes that have
21
been raised this morning.
22
we really are making the first step relative to the
23
participants in the research and we still have the
24
further problems to address with the other
25
recommendations.
26
DR. SHAPIRO:
27
PROFESSOR CHARO:
If we do that then I think
Alta?
Since a challenge has been
145
1
laid down that we distinguish -- that we vote
2
essentially on whether we think of this as an ethical
3
obligation or something that is simply a matter of
4
negotiation, I would like to remind us or urge us to
5
keep this in some context.
6
If we were talking about research trials in
7
France, I think negotiation might be the perfectly
8
sensible way to go for a lot of these things.
9
when we are talking about research in totally
But
10
impoverished countries where three or four percent of
11
the GMP is spent on health at best, two percent is
12
already going to AIDS -- you know, care for people
13
who are HIV positive according to the latest stuff
14
out of the AIDS conference in Durbin, I think we have
15
got to keep in mind that the negotiating partners are
16
not in equally powerful positions.
17
That no matter how the Ministry of Health in
18
one of the impoverished countries -- of the country's
19
own self interest, it is not in a position to push in
20
a negotiation the way a country in Northern Europe
21
might be.
22
I mean, if you look at the pharmaceutical
23
pricing schemes, one of the reasons why
24
pharmaceutical prices are lower in the European Union
25
is because Union countries have a negotiating ability
26
to insist on that.
27
are talking about the Southern African countries.
And you do not find that when you
146
1
And the same thing is going to happen with regard to
2
every aspect of a trial, instruction, and the details
3
of what will be made available afterwards, and the
4
infrastructure that will be left behind.
And so for that reason because I do not
5
6
think we actually have a level playing field that is
7
background justification for going to a contractual
8
model in which all parties negotiate and then shake
9
hands, I think that there is a strong argument for
10
laying down some basic conditions that strain the
11
parameters of that negotiation.
Let's say that there are certain things that
12
13
we are simply going to say have to be done if they
14
are at all feasible because we cannot trust all
15
parties to be able to effectively represent their own
16
interests.
DR. SHAPIRO:
17
Before we see how we feel on
18
this, I do want to say that it is -- the choice is
19
not between ethical approaches and negotiation by
20
assumption and nonethical approach, that is simply
21
not the choice that is in front of us.
Ethics deals with taking the interest of
22
23
others into consideration and negotiation may or may
24
not be the best way to do that.
25
matter.
26
27
That is another
But I do not think we should view ourselves
as either taking an ethical or nonethical approach on
147
1
this subject.
PROFESSOR CHARO:
2
That is not my -- Harold,
3
I am sorry but that was not my implication but to the
4
extent that what is being discussed is a move towards
5
saying that everything should be a matter for
6
negotiation rather than saying that there are some
7
limits, that they feel that the position can be no
8
worse than this.
9
at.
10
Right?
That is what I am getting
But I think we should put some constraints on
that negotiation.
11
DR. SHAPIRO:
All right.
12
PROFESSOR CHARO:
If the negotiating
13
partners are not equally well positioned to represent
14
their own interests.
DR. SHAPIRO:
15
Okay.
We are going to break
16
in 30 seconds for lunch.
17
at 1:00 and, therefore, we should try to be back here
18
as close to 1:00 as possible.
Let's take a show of hands right now as Alex
19
20
We do have public comments
has suggested -PROFESSOR CAPRON:
21
As I think about it, are
22
there then three choices?
There is -- that it is as
23
strong ethical obligation, that there is an ethical
24
presumption within which negotiations should take
25
place.
26
negotiation that deserves prior attention and then --
27
but without stating in the recommendation any ethical
And, third, that it is a matter for
148
1
presumption as to what is the right outcome.
DR. SHAPIRO:
2
It seems to me that the --
3
just since we are just trying to clarify
how we
4
think at the moment -- that -- you know, I take the
5
recommendation as it stands.
It really is in some -- in my view the weak
6
7
version because it says prices and time are unknown
8
and, therefore, it is a negotiation although it does
9
not quite say it that way.
That is what it actually
10
says.
At least that is the way -- I should not say
11
that.
That is the way I interpret it.
12
what we -- let me just pose it this way and we may
13
have to refine this as we get to talk about this
14
further.
15
And I think
I had made one recommendation, namely that
16
we look at Recommendation 2, which we will have to
17
integrate with Recommendation 4 later on.
18
get to that.
19
terms to be negotiated, et cetera, down to the end of
20
that first sentence.
21
identify as the weak version of this and I do not
22
mind if we call it that.
We have to
Sponsors should continue to provide at
That is what we have come to
23
So why don't we just have a show of hands of
24
those who would like that kind of a recommendation as
25
opposed to the exact language versus something that
26
is significantly stronger language to be developed?
27
So let's -- those who would favor -- let's put it
149
1
this way:
Those who would favor something
2
significantly stronger than that?
3
(A show of hands.)
4
PROFESSOR CHARO:
5
DR. SHAPIRO:
6
PROFESSOR BACKLAR:
7
DR. SHAPIRO:
8
Hand up.
Hands up.
One, two, three.
Stronger than just --
That is right.
Right.
Okay.
Others?
DR. MIIKE:
9
Let me ask a clarification.
10
Both of these, the strong or the weak, is -- there is
11
the assumption that something is owed to the trial
12
participants, right?
13
DR. SHAPIRO:
14
DR. MIIKE:
15
DR. SHAPIRO:
16
Correct.
Okay.
Correct.
owed is to be negotiated.
17
PROFESSOR BACKLAR:
18
PROFESSOR CAPRON:
And what is exactly
Exactly.
Through prior agreement.
To say that the strong
19
one -- to me the
20
negotiation.
21
strong presumption that that would be the right thing
22
to do.
It is whether you start off with a
DR. SHAPIRO:
23
24
strong one also has to then lead to
What would be the right thing
to do?
25
PROFESSOR CAPRON:
No, to provide --
26
(Simultaneous discussion.)
27
PROFESSOR CAPRON:
To provide those things
150
1
which during the trial have proven to advance the
2
health of the participants in the trial, that there
3
is some --
4
DR. SHAPIRO:
Free of charge indefinitely.
5
PROFESSOR CAPRON:
There
is some ongoing --
6
and that the -- I mean, I do not think it is
7
impossible to say the exact terms of those are
8
subject to the constraints of the ability of the
9
sponsor to provide that.
As you say, some sponsors may not be able --
10
11
but
there
is different -- to me, that I though --
12
the real contrast with what I thought you agreed with
13
Bette that there was a different way of going about
14
this, which basically says the important thing is to
15
negotiate these points out in advance.
16
DR. SHAPIRO:
Correct, I agree with that.
17
PROFESSOR CAPRON:
But that does not start
18
off with a presumption that you ought to be providing
19
it.
20
I mean, that seems to me a legitimate
21
position that is an alternative.
22
saying, no, there is a presumption and it is just a
23
matter of negotiation then we are very close to what
24
was already here.
25
If we are all
It is just a matter of moving --
DR. SHAPIRO:
My own view is that we -- the
26
reason we cannot vote on that is there is really no
27
distinction here because if one does not specify
151
1
time, amount and a whole bunch of other things there
2
is no obligation here.
PROFESSOR CAPRON:
3
But we -- Harold, at
4
other points I think we get to a point as we were
5
just talking about the last set of recommendations,
6
we try to set out criteria which someone will use in
7
judging whether or not the outcome of a process is
8
acceptable.
But we -- so we -- you could -- we provide
9
10
an ethical stance from which you could look at a
11
situation and say they met their ethical obligations
12
or they did not.
13
subject to negotiation, judgment and individual
14
determination.
That still recognizes that it is
There is a different view which is that this
15
16
is just a matter that ought to be thought about and
17
negotiated.
DR. SHAPIRO:
18
Okay.
19
not understand it but okay.
20
DR. MIIKE:
I do not -- okay.
What I am understanding us to
21
vote on, let me just jump to 4 and it makes it
22
clearer.
23
I do
In 4 I would say that we have an obligation
24
to trial participants and the negotiation is over
25
whether -- what the price is and how long the time is
26
but there is an obligation to provide something.
27
Whereas in the host country's inhabitants
152
1
the only obligation is to have a negotiation whether
2
anything is going to be done about it.
3
that is a positive point in the sense that it raises
4
the issue explicitly whether or not they actually do
5
something about it.
6
And I think
So in the Recommendation 2 the distinction
7
to me is about whether they are going to negotiate
8
about some kind of benefit to be determined or
9
whether they are going to negotiate about whether
10
there is or not a benefit.
11
DR. SHAPIRO:
12
MR. HOLTZMAN:
Steve?
I think right from the
13
beginning of this report we articulate as a
14
fundamental principle that one ought not be
15
conducting a trial in a population unless there is
16
reason to believe that if successful the benefit will
17
accrue to that population.
18
DR. SHAPIRO:
Right.
19
PROFESSOR BACKLAR:
20
MR. HOLTZMAN:
Right.
So I think what we are trying
21
to do here is state the presumption -- to start to
22
flush that out.
23
it mean for that presumption to be fulfilled?
24
Okay.
If it is successful what does
So, therefore, I think we can state it in
25
terms of there should be a negotiation but there is
26
presumption that if successful it will be made
27
available in some reasonable time frame in some
153
1
relevant way and that people need to try to figure
2
out how to do that.
So, therefore, I think that is a little more
3
4
-- I understand your logical point, Harold.
5
saying, well, it is just negotiating -- if you have
6
not specified any parameters it is all in
7
negotiation.
8
DR. SHAPIRO:
9
MR. HOLTZMAN:
You are
Right.
But I think one can say --
10
but you are saying it needs to be negotiated as
11
opposed to just saying it is irrelevant and I think
12
that is the presumption we are trying to establish.
DR. SHAPIRO:
13
Well, let's try to actually
14
develop some actual language here rather than try to
15
-- we all have a different kind of sense of what the
16
language is so let's actually try to develop some
17
language and we will see how we feel about it.
MR. HOLTZMAN:
18
I also think that is what --
19
that again ties back to why certain forms of
20
recompense are not appropriate because the
21
precondition that it has to be fulfilled is that the
22
stuff will be made available, that is why you are
23
testing it in this population.
24
DR. SHAPIRO:
25
We are going to have to
break now and let's try to reassemble at 1:00.
(Whereupon, at 12:40, a lunch break was
26
27
Okay.
taken.)
* * * * *