0001
 1          DEPARTMENT OF HEALTH AND HUMAN SERVICES
 2              SECRETARY'S ADVISORY COMMITTEE 
                 ON HUMAN RESEARCH PROTECTION
 3   
 4                          MEETING
 5                          FRIDAY
                       DECEMBER 12, 2003
 6   
                 The Advisory Committee met in the Franklin
 7   Room in the Sheraton Four Points Hotel, 1201 K Street,
 8   N.W., Washington, D.C., at 8:30 a.m., Ernest Prentice,
     Ph.D., Chairman, presiding.
 9   
     PRESENT:
10   ERNEST D. PRENTICE, Ph.D.        Chair
     BERNARD A. SCHWETZ, DVM, Ph.D.   Acting Executive
11                                      Secretary
12   CATHERINE SLATINSHEK, M.A.       Executive Director
     THOMAS L. ADAMS, CAE             Member
13   MARK BARNES, J.D., L.L.M.        Member
     CELIA B. FISHER, Ph.D.           Member
14   ROBERT G. HAUSER, M.D.           Member
     NANCY L. JONES, Ph.D.            Member
15   FELIX A. KHIN-MUANG-GYI,Pharm.D. Member
     SUSAN KORNETSKY, M.P.H.          Member
16   
     MARY L. POLAN, M.D.,Ph.D., MPH   Member
17   SUSAN L. WEINER, Ph.D.           Member
18   Ex Officio Members:
     HOWARD L. BRADLEY, Social Security Administration
19   KATHRYN LYNN CATES, U.S. Department of Veterans
           Affairs
20   
     ROGER CORTESI, U.S. Environmental Protection Agency
21   PATTY DECOT, U.S. Department of Defense
     ANITA EISENSTADT, J.D., National Science Foundation
22   DAVID LePAY, M.D., Ph.D., Food and Drug Administration
     AMY PATTERSON, M.D., National Institutes of Health
23   JAMES SHELTON, U.S. Agency for International
           Development
24   
     DAVID SHORE, National Institutes of Health
0002
 1                         I N D E X
 2                                                   Page
 3   ADDITIONAL SUBCOMMITTEE BUSINESS                   4
 4     Ernest Prentice, Ph.D.
 5   INTERNATIONAL RESEARCH ISSUES PANEL:
 6     International  Activities & Challenges          20
       Melody Lin, Ph.D.
 7     Deputy Director, OHRP
 8   
       Experiences & Challenges in International       28
 9         Research
       David Borasky, CIP
10     Family Health International
11     Infrastructure and Management of                42
12         Non-Domestic IRBs
       Helen McGough, M.A., IRB
13     University of Washington
14   ADVERSE EVENT REPORTING ISSUES - PANEL #1
15     Overview of Regulatory Requirements             98
       Michael Carome, M.D. OHRP                         
16   
       David A. Lepay, M.D., Ph.D.                       
17     Food and Drug Administration
18     IRB Perspective                                121
       John Zaia, M.D., 
19     Beckman Research Institute of City of Hope
       Patricia Scannell, B.A., CIP
20   
       Washington University
21   
     ADVERSE EVENT REPORTING ISSUES - PANEL #2
22     Drug Industry Perspective                      177
       Peter K. Honig, M.D., M.P.H.
23     Merck Research Laboratories
24   
0003
 1   INDEX (Continued)
 2                                                   Page
 3     Device Industry Perspective                    190
 4     Barbara Westrum
       Medtronic
 5   
       NIH Perspective                                210
 6     Army Patterson, M.D.
 7     National Institutes of Health
 8   
 9   
10     Role of Safety Monitoring Boards               222
11     Susan Ellenberg, Ph.D.
12     Food and Drug Administration
13   
14   
15   PUBLIC COMMENT                                   263
16   
17   
18   
19   FUTURE BUSINESS ISSUES                           269
20   
21   
22   ADJOURNMENT                                      277
0004
 1                   P R O C E E D I N G S
 2                                            (8:47 a.m.)
 3               CHAIRMAN PRENTICE:  We are going to get
 4   started.  I would like to welcome everybody to the
 5   second day of the SACHRP meeting.
 6               Okay.  The first section of this morning's
 7   meeting is going to be dealing with additional
 8   subcommittee business.  Yesterday at the end of the
 9   day we had decided at the next SACHRP meeting that we
10   were going to address two additional areas via panels,
11   and those were going to be Central IRBs and HIPAA, in
12   particular tissue and data banking.
13               We had identified individuals on SACHRP
14   who were going to assume responsibility for organizing
15   those panels.  You have had an opportunity to think
16   about our agenda for next year over the evening, I
17   assume.  Therefore, I would like to open it up for
18   further discussion as necessary.
19               DR. GYI:  In reflecting back on the issues
20   that we have put on the table at the end of the
21   evening, I wonder if I might ask the committee to
22   reconsider the role of litigation, since it appears to
0005
 1   be more of an issue that we really gave it a chance to
 2   evolve into yesterday.
 3               CHAIRMAN PRENTICE:  You can.  Mark, you
 4   are the lawyer on the committee.  What do you think?
 5               MR. BARNES:  Well, obviously -- I mean, I
 6   agree with Felix, and I would -- I'll say what I
 7   think, but I would also defer to other members of the
 8   committee who may have reactions themselves.
 9               In thinking about it overnight, I also
10   think that maybe we should -- I would endorse the idea
11   of focusing a third panel on the liability issues in
12   general.  But before I sort of go forward, I'd like to
13   give other people a chance to say anything.
14               DR. POLAN:  Well, yesterday I made a
15   comment about the litigation issue, which I think
16   dampens pervasively the processes on IRBs, and
17   actually medical care in general.  So I would be very
18   supportive of having a third panel on litigation
19   issues.
20               CHAIRMAN PRENTICE:  Yes, Susan?
21               DR. WEINER:  Mary, can you clarify
22   perhaps, this time not by analogy, how the litigation
0006
 1   really has -- litigation issues have a direct impact
 2   on patient care and on the protection of research
 3   participants?
 4               DR. POLAN:  With pleasure.  There are two
 5   general ways, and one has to do with something Mark
 6   mentioned yesterday, that quality assurance committees
 7   sit and review cases and have the responsibility of
 8   discussing privileging for physicians and hospitals.
 9               Mark made a statement that the law has
10   protected those people on committees from being sued
11   and has made confidential their processes.  Well,
12   actually, in fact, at least in California, those
13   processes are not confidential, can be subpoenaed, and
14   everybody knows that, and people get sued.  
15               They don't get sued for having decided to
16   take somebody off a hospital staff, but they get sued
17   for things like restraint of trade.  So that it
18   dissuades people from serving on committees.
19               I have a department to run.  We have a
20   quality assurance committee.  I have to twist arms
21   every single time I need somebody on a committee. 
22   It's very difficult to get people to sit on
0007
 1   committees.
 2               That was the case in clinical review
 3   processes.  It is now becoming the case in IRB work. 
 4   I have seen it become very intimidating to people who,
 5   by right, should be evaluating physicians and their
 6   care, and they want nothing to do with the process,
 7   because it is so onerous.  
 8               That's beginning to happen in IRBs, and I
 9   can see the possibility of sort of a slippage, so that
10   people don't want to sit on IRB committees, because
11   they put themselves in the position of possibly being
12   sued, and it's not, yes, you have -- You are backed up
13   by your institution, so your legal costs are covered,
14   but anybody who has been -- any physician who has been
15   sued will tell you that it is a very painful process,
16   and it gets in the newspapers, and people just don't
17   want to be involved in it.
18               So it's hard to get people to serve on
19   committees when it takes their time, there is no
20   remuneration, and they put themselves in a very
21   serious situation of jeopardy from law suits.
22               CHAIRMAN PRENTICE:  Tom?
0008
 1               DR. ADAMS:  Yesterday I expressed some
 2   skepticism as to the role of the committee in this
 3   particular issue.  Having reflected on that, I think
 4   there is a time when you need to do the right thing. 
 5               Clearly, there is a problem here which
 6   needs to be addressed.  I think it's actually sort of
 7   -- almost a Sunshine issue, to be able to create an
 8   atmosphere at IRBs where individuals want to be on the
 9   IRB, want to participate, and bring in more of the
10   public.
11               So I would support putting this back on
12   the agenda.
13               CHAIRMAN PRENTICE:  Susan?
14               MS. KORNETSKY:  I think there is another
15   focus.  At PRIM&R one of the questions, when we sort
16   of did a Firing Line type thing, was were IRBs being
17   over-reactive to certain types of things.  I think a
18   lot of this is drawn from sort of a litigious
19   environment, that people are afraid of doing things,
20   and IRBs are spending a lot of time being overburdened
21   in doing things because of this fear of litigation at
22   all levels.
0009
 1               So I think it is not only IRB members, but
 2   it's something that is pervasive in the environment. 
 3   So I would support that as well.
 4               CHAIRMAN PRENTICE:  Mark?
 5               MR. BARNES:  My point of view has been
 6   expressed by different people around the table, and
 7   that is that, as a committee and, I think, just from
 8   the institutional perspective of OHRP, what is most
 9   important is that IRBs do the job they were designed
10   to do, which is protect human subjects, not be driven
11   by the goal of evading liability but be driven by the
12   goal of protecting subjects and having adequate,
13   effective and rigorous oversight of research.
14               So I think that we ought to tackle this
15   issue.  I don't know exactly what we will do or what
16   we should do, but I think the way to start it off is
17   by having a presentation from two or three people who
18   are sophisticated about the issues and thought about
19   the issues, and there are people out there.
20               So I would propose that we get that panel
21   together for next meeting.
22               CHAIRMAN PRENTICE:  Are we talking about
0010
 1   three panels next meeting or two panels?  Can we
 2   accommodate three?  That was a point of discussion
 3   yesterday.
 4               DR. FISHER:  I think it gets back to what
 5   the process is going to be at the next panel for those
 6   types of topics to which we may not have time to have
 7   a subcommittee or the funds to do so.
 8               So although I know with the HIPAA that
 9   yesterday you had said that they might be able to put
10   into effect a short term group, I think the question
11   we want to ask is, in terms of one or two groups,
12   whether or not we really want to spend the second day
13   discussing in depth two issues rather than being
14   exposed to three.
15               So I am certainly for prioritizing HIPAA
16   and litigation.  So now the question is can we do
17   service to centralized IRBs on that second day or do
18   we want to save that for the next time?  
19               I would love for us to do the work and to
20   really be able to maintain a panel throughout a
21   morning on a specific issue.  As we said, if each of
22   the panels are coming to us with very specific
0011
 1   recommendations that at least we can digest and think
 2   about in a practical sense, I think that would be very
 3   useful.
 4               CHAIRMAN PRENTICE:  Mary Lake?
 5               DR. POLAN:  I would support what Celia
 6   suggested, that we have two panels and that we be able
 7   to have plenty of time to discuss and talk about the
 8   possibility of generating either some recommendations,
 9   if we feel that it is appropriate, or a further
10   investigation, or how we want to go forward with it,
11   rather than trying to cover too many things in too
12   brief a time.
13               CHAIRMAN PRENTICE:  Susan?
14               DR. WEINER:  There is time sensitivity to
15   the central IRB issue.  There are real world and daily
16   consequences to the delays in multi-institutional
17   trials that, to be sure, are felt by the pediatric
18   oncology community, and the sooner that gets resolved,
19   the sooner there are clear recommendations, the sooner
20   kids will have access to better treatments and the
21   research will advance.  So I'm in favor of three.
22               CHAIRMAN PRENTICE:  You are in favor of
0012
 1   three?  Anybody else in favor of three?
 2               MR. BARNES:  Ernie, if we were committed
 3   to having a rather lengthy session on the afternoon of
 4   the first day and going a little later than we perhaps
 5   normally would.
 6               CHAIRMAN PRENTICE:  We can.
 7               MR. ADAMS:  I guess, for the chairs of the
 8   other two committees, what is the likelihood of having
 9   actual action items for the committee at that meeting?
10               DR. FISHER;  We will have -- Our goal is
11   to say something about multi-site studies, to come to
12   you with a recommendation for a specific panel
13   process, to come to you with recommendations about
14   non-Federally funded or non -- you know, for types of
15   projects that are not Federally funded and what the
16   407 process should be.
17               I know there is a fourth, and we are
18   committed to coming with specific recommendations.  So
19   I would look at that to be at least as long a
20   discussion as we had yesterday, if not longer, because
21   I hope we can make decisions about more than one thing
22   at our SACHRP meeting.
0013
 1               MR. BARNES:  And I can tell you, Tom, that
 2   we -- I mean, we ought to have a draft report and have
 3   a discussion about -- hopefully, with the full
 4   committee endorsing the recommendations.  So that is -
 5   - I mean, that could take up a good deal of time,
 6   depending on how much discussion there is about the
 7   prison issues.
 8               MR. ADAMS:  I would assume that there
 9   would probably be greater public input at that point,
10   too, in terms of testimony.  So I tend to think that
11   perhaps, if we concentrated on the two issues at the
12   next meeting, giving us time to have discussion which
13   could then expedite the work that anyone might do to
14   come back with definitive proposals on that, would
15   meet everyone's needs.
16               CHAIRMAN PRENTICE:  Robert?
17               DR. HAUSER:  Where are we going to deal
18   with the adverse event issue in all of this?  I mean,
19   we've got the 407 to deal with, the prisoner.  We've
20   got -- already lining two or three panels, plus we
21   have the adverse event issue.  We got a lot on our
22   plate.
0014
 1               CHAIRMAN PRENTICE:  It is likely that the
 2   adverse event panel will result in a subcommittee.
 3               DR. HAUSER:  But that is going to be part
 4   of the March meeting.  Correct?
 5               CHAIRMAN PRENTICE:  Not necessarily.  We
 6   are going to hear, as you know, panel presentations on
 7   adverse events today.  We will identify the issues,
 8   and then we are going to have to decide how we want to
 9   approach it.  But we will not appoint another
10   subcommittee until March, because right now we have
11   made a commitment to only having three subcommittees
12   because of the workload.
13               So, clearly, we are going to pursue
14   adverse events.  The whole idea of panels is to air
15   the issues, so we know what they are, and then to
16   decide how we want to pursue them.  Susan?
17               MS. KORNETSKY:  Just from my experience on
18   NHRPAC and stuff, I appreciate the concerns about the
19   adverse events and the central IRB issue.  If we put
20   too much on our plate, I think, and can't do something
21   after hearing about those things, then I think we are
22   going to leave some momentum.
0015
 1               I would rather take a couple of topics and
 2   be able to work through them and then move on, because
 3   every time we have a subcommittee, it's all of us that
 4   are going to have to serve on that.  In the end, when
 5   you are spread too thin, you are not going to spend
 6   enough time on each topic.
 7               So I would think the -- I would suggest
 8   limiting it to two next time, but taking the other two
 9   topics and definitely making that priority for the
10   next meeting.
11               CHAIRMAN PRENTICE:  Okay, let's bring this
12   discussion to a conclusion.  Is there a motion?
13               DR. FISHER:  I will make a motion for two
14   topics on the second day, HIPAA and litigation, and
15   with the assumption that we are going to move ahead
16   with adverse events in a subcommittee the following
17   meetings and also take up possibly at that point the
18   centralized IRB.
19               CHAIRMAN PRENTICE:  Is there a second?
20               DR. GYI:  Second.
21               CHAIRMAN PRENTICE:  Any further
22   discussion?  All those in favor, signify.  Raise your
0016
 1   hands.  Any opposed?  Any abstentions?  Okay.
 2               MR. BARNES:  Ernie, there is one other
 3   matter that we just wanted to bring to your attention,
 4   or actually wanted to bring to the attention of the
 5   audience, which is that we are very proud to say that
 6   last week our Chair, Ernie Prentice, was awarded the
 7   Roselle Award in San Antonio for excellence in the
 8   care of laboratory animals in regard to animal welfare
 9   and experimentation.
10               He, along with Charlie McCarthy who was in
11   the audience yesterday and I don't believe is here
12   today, is actually only the second non-veterinarian,
13   and we are very proud of Ernie for that.
14               (Applause.)
15               CHAIRMAN PRENTICE:  Thank you.  Chairman's
16   prerogative to make one comment with regard to
17   litigation.  With the exception of perhaps Mark
18   Barnes, I think I probably have more experience in
19   this area.  Even though I am a non-lawyer,
20   universities often hire me to be a consultant when
21   they get sued, and I've got to tell you that in the
22   process of working with attorneys that defend
0017
 1   universities in litigation, and reviewing records,
 2   every time I come home I try to dot more I's and cross
 3   more T's, which causes my IRB staff more work.
 4               I really have to question the translation
 5   of all of that work into real enhanced protection of
 6   human subjects.  So I think this is a real serious
 7   issue, and I'm happy that the Committee has decided to
 8   address this particular issue.  I don't know how much
 9   we can accomplish, but we should probably make a
10   statement.
11               All right.  Now we are five minutes behind
12   schedule.  As you know, I am a bit of a task master. 
13   We now are going to move into our panel discussions. 
14   You can see here on the slide, we've got a number of
15   panels, specifically three:  One on the international
16   research, and then two are on adverse events.
17               I want to recognize the individual members
18   of SACHRP who have been involved in trying to organize
19   these particular panels.  So thank you very much for
20   all of your work.
21               Now I am going to introduce the members of
22   each panel, beginning with the international research. 
0018
 1   You all have their complete bios.  I am not going to
 2   go through the entire bio, but I am going to go
 3   through a little bit of the highlights of each
 4   person's bio, and I am going to introduce, I think,
 5   all of the individuals simultaneously as opposed to
 6   before each person's talk, if that is acceptable.
 7               I am going to move to my position over
 8   there, and Melody, you are up first.  
 9               DR. LIN:  Good morning.  Can you hear me
10   in the back?  Mr. Chairman, are you going to introduce
11   me or shall I start?
12               CHAIRMAN PRENTICE:  No, don't start yet. 
13   I am going to introduce you.  
14               We have three distinguished panelists to
15   discuss issues related to international research.  We
16   have Dr. Melody Lin, who is the Deputy Director of
17   OHRP.  As Deputy Director, she is responsible for the
18   management of OHRP policy, personnel and budgetary
19   matters, but probably more importantly, she is very
20   involved in international research issues.
21               She is also a Captain -- She doesn't have
22   her uniform on today, but she had that on yesterday --
0019
 1   and a member of the Academy Senecas -- I probably
 2   didn't pronounce that right, Melody -- National
 3   Genetic Program Advisory Committee in Taiwan, and she
 4   is also the U.S. liaison to the Canadian Medical
 5   Research Council standing ethics committee.
 6               We also have Helen McGough, who is at the
 7   University of Washington.  She has been there for over
 8   19 years.  Helen and I know one another very well.  We
 9   do a lot of educational activities together.
10               She has been involved at the
11   international, national, regional, local level in
12   terms of educational activities in a variety of topics
13   related to protection of human subjects.
14               Then we have David Borasky, who is the
15   Human Protections Administrator at Family Health
16   International.  He has occupied that position for the
17   last five years.  He has provided consultation and
18   technical assistance to IRBs in numerous developing
19   countries in Africa and Asia and, most recently, he
20   has become the President of ARENA.  So
21   congratulations, David.  
22               We are delighted to have all three of you
0020
 1   here.  Melody, you may begin.
 2               DR. LIN:  Thank you very much, Mr.
 3   Chairman.  Thank you for your introduction of this
 4   panel.  I wanted to thank Dr. Polan for her leadership
 5   of selecting the three speakers in this panel.  I want
 6   the thank the SACHRP members for identifying
 7   international research as an important issue, and
 8   that's why we have an opportunity here.
 9               My responsibility is the easiest of the
10   three speakers.  I have the responsibility to set a
11   stage for the discussion of the international IRB
12   issue, and I will begin with the perspective of the
13   OHRP and the Department of Health and Human Services.
14               David will follow me, and he will share
15   with you the field's perspective and identify the
16   problems that he encounters as he does the
17   international capacity building.
18               Helen will offer possible solutions, and
19   at the end, you know we don't have -- It's just a
20   possible solution.  We don't have all the solutions. 
21   So we look to SACHRP to give us advice and guidance.
22               So why do we even talk about international
0021
 1   research, and why is it important to talk about
 2   international research, and what are the challenges?
 3               This is NIH budget from 1993 to 2003.  You
 4   can see the trend of NIH budget increase.  Right now,
 5   NIH's budget is -- if I am wrong, please correct -- is
 6   $27.9 billion.  From '90 to 2003, NIH budget really
 7   quadrupled.  
 8               Whenever we talk about NIH budget
 9   increase, if you look at the pie, 85 percent of NIH's
10   budget is for extramural research.  Extramural
11   supporting university all over the United States, and
12   it also includes international research, be it direct
13   support to the international -- other countries or the
14   cooperation with the researcher in this country.
15               This is the NIH international research
16   expenditure.  You can see, each graph is going upward. 
17   It is increasing from 1994 to today.  I have a figure
18   here, 2002, but it was too late to plot these out, and
19   I only got that figure a couple of days ago, but you
20   can see the trend.
21               With the international research
22   expenditure, about 66 percent are for research, and
0022
 1   then other is for training, including bioethics
 2   training.  
 3               This is a map of -- If you see all those
 4   yellow dots, that is where NIH have some research
 5   collaboration, the research site all over the world. 
 6   In our regulations, Department of Health and Human
 7   Services regulations for protection of research
 8   participants involving research, the regulations
 9   require each institution engaged in research, domestic
10   or foreign, require assurance.
11               Assurance is contractual agreement between
12   the institutions receiving money from HHS with OHRP
13   that your institution officials have committed all the
14   investigation and all the research be conducted
15   according to the regulations. 
16               So it is your institution officials
17   commits the researcher to do that, and who approves
18   and negotiates assurance?  OHRP.
19               So this international assurance increased
20   in the past three years, and you can see it is
21   increasing.  The number 1226 may be today's figure,
22   because every day we approve assurance in OHRP.  Just
0023
 1   to give you some idea, about 25 percent of assurance
 2   we approve is international assurance.
 3               So let's look at the industry,
 4   pharmaceutical industry.  I want you to just look at
 5   the lower bar, the bottom of the bar.  From 1991 you
 6   hardly can see clinical trials in other countries.  By
 7   year 2000, more than 1500 of clinical trials were
 8   conducted overseas, which means that research subjects
 9   -- If clinical trial number increased, you need
10   research subjects.  
11               So for the percentage of NDA submissions
12   using foreign data increased three times from 1995 to
13   1999, and the number of foreign human subject
14   participants during that period increased hundredfold. 
15               So we have in September 2001 Department of
16   Human Services, Office of Inspector General report. 
17   The title:  The Globalization of Clinical Trials.
18               Just briefly, give you the -- summarize
19   the findings.  The IG report found a significant
20   increase of drug trials in foreign countries and
21   research sites with limited experience, and FDA has a
22   limitation in assuring protection for the research
0024
 1   conducted at foreign sites.
 2               In 1990 to 1999, investigators -- foreign
 3   investigators conducting drug trials increased
 4   sixteenfold.  However, the inspection increased almost
 5   three times, and the research between 1990 and 1999,
 6   more research sites in countries has limited
 7   experience on ethical review, and I'm sure also other
 8   design issues and monetary issues.  Those are
 9   countries especially in Russia and Eastern Europe and
10   Latin America.
11               FDA has very minimal information on
12   foreign IRBs.  That is the OIG report, and FDA do not
13   have IRB inspections.  I don't think it is true this
14   day that FDA do not have IRB inspections at the
15   foreign sites, but in 2001 that was the report in the
16   IG.
17               IG report make a recommendation for FDA,
18   also for OHRP.  Recommendation for FDA:  FDA should
19   require more information on performance of foreign
20   IRB, and FDA should do capacity building for foreign -
21   - the research conducted overseas.  FDA should require
22   foreign investigators to attest that they know there
0025
 1   are ethical principles and there are regulations and
 2   rules to follow.
 3               Recommendation also requires FDA to
 4   require sponsors to do more monitoring and require FDA
 5   to have a database to track foreign research.
 6               The recommendation for OHRP is quite
 7   stunning, because it went beyond our jurisdiction. 
 8   The recommendation for OHRP to exert leadership in
 9   protection at non-U.S. sites, not only for U.S. funded
10   research, also for New Drug Application research and
11   Federal-wide funded research, and it encourages OHRP
12   to work with other Federal departments to encourage
13   voluntary accreditation for the international sites.
14               So with the IG report, the OHRP
15   established a program, international activity program,
16   March 2002.  Our purpose is to build capacity for
17   ethical review and increase awareness of the
18   requirements, assure compliance to comply to the
19   regulations on ethical principles, ensure that HHS
20   research apply the ethical principles.
21               OHRP international activity, in addition
22   to the IRB registration and the approval of assurance: 
0026
 1   We are in the very beginning as the international
 2   program are very young.  We concentrate in the
 3   capacity building, and we have the collaboration with
 4   different organizations and conduct workshops, and we
 5   also did pilot in quality improvement.
 6               So the collaboration for capacity
 7   building, to begin with, we utilized -- We take
 8   advantage of WHO infrastructure.  So WHO have five
 9   regional offices in the world.  So we have a project
10   with WHO, and the regional fora are Pacific and Asia
11   area and Russia and Confederation of Independent
12   States, in Africa, in Central and South America and
13   North America.
14               What we did was we conducted one workshop
15   in each forum, and we also participate in presentation
16   by invitation in many international conferences and
17   workshops.
18               In June of 2002, three OHRP staff
19   conducted international QI as a pilot.  We visited
20   five institutions, conduct quality assurance and
21   quality improvement programs, and the feedback until
22   this day is very positive.  So we are open -- We open
0027
 1   two additional international QI, if it is justified.
 2               New initiative for OHRP is to identify
 3   institutions with most international research.  We
 4   would conduct with the institution, domestic
 5   institution, research ethics course in those
 6   countries, and we always look to network and find a
 7   collaborator for maximizing the U.S. taxpayer money,
 8   your money and my money.
 9               We have yet to work international
10   accreditation.  However, I know of two countries
11   abroad seeking accreditation.
12               So our challenges are those of
13   infrastructure, because they don't have resources. 
14   They don't even have a IRB staff, and how do you
15   sustain and how long do you support the capacity
16   building, and it is difficult to measure the impact.
17               I will not -- With interest of time, I
18   will not elaborate on this, because Helen and David
19   will do that.  So we conclude that OHRP will continue
20   and seek to build capacity, and we will look for
21   opportunities to cooperate and leverage our resources.
22               I don't know.  It is easy to say, maybe
0028
 1   difficult to achieve.  We would like to maximize the
 2   impact.  Thank you very much, and Mr. Chairman, would
 3   you like to save the questions to the end?
 4               CHAIRMAN PRENTICE:  Yes, with the
 5   indulgence of the Committee, I think it might be best
 6   to hear all the presentations, formulate your
 7   questions, and then we will save some time at the very
 8   end.
 9               DR. BORASKY:  Good morning.  I'll try to
10   make a quick transition.  Melody sort of laid the
11   groundwork from the perspective of OHRP and HHS, and
12   I am going to talk a little bit more now about
13   actually on the ground, in the field, and how the
14   perspectives maybe are a little different and at times
15   complementary, and hopefully this will lead into Helen
16   McGough talking about possible solutions.
17               Not that we all need a history lesson, but
18   just a quick overview to give us a sense of maybe why
19   things are the way they are.  Obviously, in the last
20   50 years in the United States we have seen the
21   development of a research ethics infrastructure,
22   including the building up and refinement of
0029
 1   regulations, various mechanisms for oversight through
 2   groups like OHRP and the BiMo system program.
 3               We have seen the IRB system built up into
 4   a very far reaching and comprehensive system, and most
 5   recently we have seen further professionalization of
 6   that field so that IRB folks like myself can now be
 7   certified IRB professionals.  We see institutions
 8   going for accreditation of human research protection
 9   programs, and groups like PRIM&R and ARENA are
10   facilitating some of that process, but it has really
11   become a thing unto itself; whereas, the last 50 years
12   in developing countries, first of all, it is marked by
13   just the idea of being reborn as a country, this idea
14   of national independence.
15               In the years since that time, many of
16   these countries have been marked with a lack of
17   political stability.  That continues to this day-- we
18   look at the Mugabe regime in Zimbabwe, for instance --
19   and civil war, most recently in countries like the
20   Cote d'lvoire, and these are countries where we are
21   trying to carry out research in this context.
22               At the time of national independence, a
0030
 1   lot of these countries had public health systems that
 2   were left behind by the colonial governments that they
 3   have been charged with maintaining, and that proved
 4   difficult.  
 5               As a result, many of these public health
 6   systems have deteriorated, and the HIV/AIDS pandemic
 7   has only exacerbated that problem, because the few
 8   resources they have are being poured into responding
 9   to that problem.
10               Then building on top of that is the
11   problem of poverty, extreme poverty in a lot of these
12   countries, which leads directly to a lack of education
13   and, again, an inability to support basic public
14   health or health care needs, let alone developing
15   regulations or research ethics infrastructure.
16               So this tends to be a very low priority,
17   and when we are going to go into countries, we find
18   that they haven't spent time building up even basic
19   regulations or an IRB system, let alone an individual
20   IRB.
21               Skip just to the last five years where in
22   the U.S. we have seen increasing regulatory oversight,
0031
 1   thanks in part to our friends at institutions like
 2   Duke University or Johns Hopkins who, through multiple
 3   project assurance suspensions, brought to light the
 4   fact that our well built up programs aren't always
 5   perfect.  
 6               This has led to an emphasis on basic
 7   research ethics training such as the NIH mandate that
 8   all key personnel receive some basic training in
 9   research ethics, and all of this has led to further
10   enhancement of the IRB system.  Again, we've got more
11   work into things like accreditation.  We've got
12   standards being raised, the bar being raised
13   continuously.
14               In developing countries and in resource
15   poor countries, as Melody pointed out, they have been
16   exposed to an upsurge in foreign sponsored research
17   coming in, and this has led to the creation of IRBs
18   just in general, creation of new IRBs, not the
19   development of new IRBs within a well maintained or
20   well regulated system.
21               So while we have spent the last five years
22   sort of beefing up what we already have, they have
0032
 1   spent the last five years giving birth to a whole new
 2   system.
 3               So what are some field perspectives on all
 4   of this?  Well, when we are talking about Health and
 5   Human Service funded research, international sites are
 6   required to form an IRB, if they don't have one, and
 7   obtain a Federal-wide assurance; and most of these
 8   sites are guided through this process not by OHRP
 9   necessarily but by their U.S. based institution that
10   received the funding to go overseas.
11               So we would hope there would be some
12   mentoring and hand holding, but what we often find is
13   that, as one institution told me, we were told to get
14   our FWA done quickly, it was really just a formality 
15   so that we could get the study started.
16               Another institution tells me that they
17   were told that, by checking 45 CFR 46 on that FWA
18   application, it really helped speed up the process. 
19   Nobody wants to go through this notion of negotiating
20   an assurance.
21               There's good reasons that some of the
22   American institutions do this, one being that there is
0033
 1   a lack of clarity on the idea of equivalent
 2   regulations.  U.S. institutions don't really quite
 3   know what that means or how to use those equivalent
 4   regulations.  
 5               There's been very little guidance to IRBs
 6   on what they would do if an institution they are
 7   working with has equivalent regulations, but that
 8   don't have all of sort of the checklists and subparts
 9   that the American regulations do.  So there is a bit
10   of fear about trusting equivalent regulations.
11               Some perspectives on IRB functions:  At a
12   lot of these institutions, when they are told to
13   create an IRB, they sort of pluck their best people to
14   sit on this IRB, and sometimes that's because the core
15   of the best people are the ones who are doing all of
16   the research.  They figure they are in the best
17   position to review these studies.
18               What this leads to is a lack of the
19   unaffiliated or nonscientist voice on the IRB,
20   sometimes a lack of just presence, but even when they
21   are there, sometimes a lack of empowerment by those
22   members.  
0034
 1               Then because these are sort of the best
 2   and brightest people, attendance is poor.  They are
 3   being pulled in 15 directions to take care of the
 4   failing public health system.  They've got their
 5   clinic duties.  They've got private practice duties. 
 6   They've got research duties.
 7               Some local IRBs also suffer -- or some of
 8   the international IRBs also suffer because there's a
 9   lot of uncertainty about the role of the IRB.  The
10   focus of the review is often on the methodology or the
11   science and not the ethics.
12               In fact, in one location we heard that the
13   primary reviewer makes a presentation to the IRB in
14   which he describes the proposal and reviews the
15   methodology.  This is followed by a brief discussion
16   and vote, and the key message being that, you know,
17   this is what we are familiar with, this is what we
18   look at, and we think that's sufficient.  But very
19   little talk of recruitment and about consent forms.
20               There may be some good reasons for that. 
21   I think one of the reasons IRB functions fail is --
22   Well, if you compare it to getting a new car, when you
0035
 1   get a new car, it comes with an owner's manual, and it
 2   tells you how often to change the oil and what to do
 3   to keep it maintaining -- running the way it should
 4   run, and it also includes things like how to set the
 5   radio, sort of the little details that we sort of take
 6   for granted, but they are all there.
 7               Well, when these institutions decide to
 8   become an IRB and get an Assurance, it doesn't come
 9   with an owner's manual.  So they are left to figure a
10   lot of these things out by themselves.  They don't get
11   the OPRR guidebook.  They don't get the FDA
12   information sheets, and they don't necessarily know
13   where to go online to look for these things, and in
14   some cases going to look for them online itself would
15   be quite a challenge.
16               So there's reasons why they are
17   foundering, and this also moves into the management of
18   IRBs, marked again by a lack of policies, standard
19   operating procedures, the sorts of things that IRBs
20   over here in the United States have been building up
21   nonstop specifically for the last five years.
22               When you don't have SOPs, when you don't
0036
 1   have policies, it leads to a lack of consistency that
 2   is not helped by the fact that there's no rules to
 3   follow.
 4               This is further bothered by the lack of
 5   dedicated human resources.  When you've got sort of a
 6   long list of health care priorities, devoting half of
 7   someone's time to maintain records and create IRB
 8   minutes is not a high priority.  So they have a lack
 9   of dedicated human resources that is not helped,
10   because there is no SOPs to guide in their absence.
11               In talking about how IRBs process things,
12   one IRB tells me, when we receive a protocol, we send
13   it to a reviewer sort of for a prescreening.  After 30
14   days, we send a reminder to the reviewer asking for
15   their comments.  We do this again at 60 days and, if
16   necessary, 90 days.  
17               If my IRB held a protocol and pre-review
18   for three months, I would be out of a job awfully
19   fast, but in a place where you don't have policies
20   that guide reviewers in what to do and you don't have
21   SOPs talking about how the committee is going to
22   function as a working committee, this kind of a
0037
 1   problem is not uncommon.
 2               One of the biggest complaints my
 3   researchers have about international IRBs is that a
 4   lot of them are just darn slow, taking six months,
 5   eight months to review and approve a project.
 6               As a result of that, sometimes things go
 7   wrong.  I want to talk a little bit about the National
 8   Council of Science and Technology in Uganda.  This is
 9   a site that has been doing HIV research for years, and
10   in the region they are really an excellent research
11   institution by regional standards.
12               Well, in March of 2002 this Uganda
13   National Council of Science and Technology received
14   the dreaded letter from OHRP, a letter that alleged
15   some noncompliance, specifically a failure to conduct
16   continuing review, a failure to ensure that risks are
17   minimized, a failure to report problems such as
18   serious adverse events or protocol violations and
19   deviations, etcetera, and a failure to maintain
20   adequate documentation, the minutes, the records. 
21   They were all alleged to be in disarray.
22               The Ugandan response at its core was, we
0038
 1   wish to indicate that Uganda, like many developing
 2   countries, generally lacks adequate capacity to ensure
 3   proper documentation, storage, and retrieval of
 4   information. 
 5               Now this is an institution that has a
 6   Federal-wide Assurance and agreed to the terms of this
 7   Federal-wide Assurance, which included doing all of
 8   those things.  Now one would think that, when they
 9   looked at that list of terms, they might have said, we
10   may have trouble meeting some of these, maybe we
11   should talk to OHRP, but instead they went forward
12   with the Assurance, starting doing research, and then
13   problems weren't covered.
14               Over time they ended up coming into
15   agreement with OHRP about how to fix the problems.  So
16   one year later, 18 months later, they are implementing
17   a corrective action plan, including IRB membership
18   being reviewed and trying to figure out how to make
19   sure that non-scientists are included in the process,
20   how they are educating their members about how to be
21   IRB members, something they really hadn't worried
22   about before, because these were the smartest people
0039
 1   in town.  They shouldn't need it.
 2               They are finally developing operational
 3   guidelines that will give their committee a sense of
 4   how do we function as a committee.  They've got
 5   dedicated staff time for documentation and record
 6   keeping, something they didn't have before.
 7               That sounds great, but we have to keep in
 8   mind that this is still a huge strain on their
 9   financial and human resources, and they do continually
10   look sort of outside for help.  In fact, two people
11   from this IRB were at the recent PRIM&R and ARENA
12   meeting with funding from NIH.  So there are some
13   encouraging signs that we are, as a community, trying
14   to turn things around.
15               So what are some lessons learned from all
16   of this?  Well, developing country IRBs definitely
17   have needs, and among those urgent needs are mentoring
18   from U.S. partners.  That's already started to happen
19   a little bit.
20               In fact, a lot of institutions are using
21   their upcoming round of the NIH enhancement grants to
22   reach out to some of their international partners.  I
0040
 1   know my institution will be mentoring IRBs in Zambia
 2   and Malawi, and the Fred Hutchinson Cancer Research
 3   Center is reaching out to other IRBs in the Caribbean
 4   and in Africa.
 5               So some of this is taking place, but it
 6   needs to be ongoing.  It has to be more than just one
 7   year of enhancement grants.
 8               While over here we complain a lot about
 9   oversight and sort of having Big Brother looking at
10   us, developing country IRBs actually, I think, have an
11   urgent need for more oversight and guidance from
12   regulators.  
13               Melody talked about the amount of research
14   over there skyrocketing while the amount of direct
15   oversight through compliance visits is only sort of
16   trickled out, and for a lot of these institutions,
17   getting sort of a hands-on perspective of what the
18   problems are and some hand holding from the regulatory
19   agencies may help to improve the processes.
20               Then training an IRB administration and
21   IRB review:  Over here we've got groups like PRIM&R
22   and ARENA that fill that vacancy quite a bit, and
0041
 1   Melody has talked about the international office of
 2   OHRP doing some outreach, but more needs to take
 3   place.
 4               How are we reaching out to them?  It is
 5   not going to be a long term feasible thing to say we
 6   will just bring over planeloads of IRB administrators
 7   from around the world once a year to a conference. 
 8   How are we reaching out to them?  Are we looking to
 9   build programs of excellence within countries,
10   something to look at there.
11               Then finally, strategies to generate IRB
12   review:  If financial resources are a big part of the
13   problem, can we show them models for building up some
14   revenue through their work?  
15               Talking with an IRB in Kenya last year,
16   they proudly told me that for all sponsored studies,
17   they charge a $100 fee for review, which for them is
18   great, but when you tell them that they could -- could
19   for sponsored studies charge up to ten times that in
20   the United States and be in line with sort of -- with
21   national standards, I mean, they are just
22   flabbergasted, because $1,000 will go a lot farther in
0042
 1   Nairobi than it will go, say, in Washington, D.C.  Yet
 2   they seem often completely unaware that they could
 3   even try to do this.  So again, what are we telling
 4   them in that sense?
 5               Those are sort of some lessons learned
 6   and, hopefully, I haven't stolen a lot of thunder from
 7   Helen McGough, who I am going to turn it over to, to
 8   talk about capacity building and how we might help out
 9   these -- our partners in research some more.
10               CHAIRMAN PRENTICE:  Than you, David.
11               DR. McGOUGH:  Thank you.  Well, I wanted
12   to say thank you very much to all of you SACHRP
13   members.  We just sit here in awe at what you are
14   doing, both the extent of the problems you are taking
15   on and, clearly, the depth with which you are
16   analyzing them, and also really appreciate your being
17   willing to and interested in listening to the issues
18   related to international research.
19               So I am going to -- He did steal my
20   thunder.  That's the way it goes.  So there will be a
21   little repetition, but I may make some different
22   points as well.
0043
 1               I think you have heard, both from Melody
 2   and David, why this is an important issue, but since
 3   my interest is really in how to actually do capacity
 4   building, I did want to go over the basics of the
 5   relationship.
 6               Usually, research, at least that OHRP is
 7   interested in and FDA is interested in, gets funded
 8   through a domestic U.S. institution that receives the
 9   prime award, and then accepts the responsibility for
10   making sure that the appropriate IRB reviewer, ethics
11   committee review, occur at all the sites where
12   research is conducted.
13               Those domestic institutions usually have
14   established IRBs with MPAs or FWAs in place.  I would
15   remind you, however, that there is a wide variety,
16   just as there is overseas, in the ability of domestic
17   IRBs to comply with regulations, the whole gamut from
18   superb IRBs that do a wonderful job to ones that are
19   marginal both in the ethical sense and in the
20   regulatory sense.
21               The nondomestic institution receiving a
22   subcontract usually from a prime award issued to a
0044
 1   domestic institution is required by Federal regulation
 2   to produce an ethical review before the research can
 3   be conducted; and as David has pointed out, they may
 4   or may not have an established or an experienced IRB.
 5               I can only second what David has said
 6   about some times the attitude toward the FWA. 
 7   However, despite the fact that some non-domestic
 8   ethics review committees consider it a mere formality,
 9   it may not be because they just want the money.  It
10   may be because it is another paperwork piece on top of
11   an extensive regulatory structure that they already
12   have in their own country.
13               So some of the problems that David has
14   told you about, we have run into as well:  No ethics
15   review board at all; duplication of reviews that are
16   happening at many sites.  Timeliness of review is
17   certainly one that comes up over and over again,
18   noncompliance, inconsistency among reviewing ethics
19   review boards.
20               A point that I think Mary wanted to make
21   sure that got brought out was that not only are the
22   foreign researchers not aware sometimes of their
0045
 1   requirements, but even the domestic researchers who
 2   are the recipients of the prime awards are not always
 3   fully cognizant of their requirements to get IRB
 4   review for research that they conduct overseas, and
 5   also the prime awardee's responsibility for making
 6   sure that the non-domestic ethics review committee
 7   does its work as well.  
 8               So I've listed some possible sources of
 9   solutions.  Melody described the WHO activities that
10   have been conducted.  This is a wonderful series of
11   global fora that are actually working.  They have
12   gotten off the ground with great support from OHRP and
13   have conducted annual workshops.  Sometimes they are
14   in -- In some places they are in their third year.  
15               Fogarty -- I can't say enough wonderful
16   things.  I wish Maureen Powers was here.  I don't know
17   if there is anyone from Fogarty in the audience or
18   represented here, but they have done just a superb job
19   in enhancing the ability of U.S. institutions to work
20   with foreign sites.
21               CFAR, Center for AIDS Research, also has
22   a great interest, as you know, in making sure that the
0046
 1   non-domestic IRBs ethics review committees do their
 2   job, do it well, and do it in a timely manner.
 3               Public Responsibility in Medicine and
 4   Research -- the acronym PRIM&R has been used over the
 5   past two days.  I wanted to make sure that you knew
 6   exactly what it stood for -- has taken an initial
 7   step, and this year at its last annual meeting in
 8   Washington a couple of days ago held its first ever
 9   international 101.
10               We have a series called 101 that is basic
11   introductory regulatory workshops for IRB
12   administrators, for IRB members.  We do that for
13   responsibility conduct of research in HIPAA and in a
14   wide variety of areas.
15               This year we added to our roster an
16   International 101.  There were over 40 folks who came
17   from -- I think there were about 18 countries, to sit
18   through a day-long workshops and then stayed on for
19   the rest of the PRIM&R and ARENA meetings.
20               The Office of Human Research Protection
21   has clearly done a lot of work, and Melody has already
22   described that.  Certification is available through
0047
 1   ARENA to non-domestic IRB administrators, and I know
 2   at least AAHRPP, the Association for the Accreditation
 3   of Human Research Protection Programs, has an interest
 4   in expanding its accreditation services to non-
 5   domestic IRBs as well.
 6               I wanted to describe what the University
 7   of Washington has done, not because we are better than
 8   anyone else, but I think we were drafted earlier into
 9   the process than anyone else, and I have to honest
10   with you, that the impetus for our involvement really
11   came from complaints from our researchers.  I think
12   David has already pointed this out as well.
13               Our researchers who were the recipients of
14   prime awards, most from NIH, came to us and said, how
15   can we get this moving; those IRBs aren't meeting,
16   those ethics review committees aren't set up; they
17   haven't filed their FWAs; how can we get this process
18   moving?  I've got this money, I want to get the
19   research started.
20               That began our interest at the University
21   of Washington in working very directly with the ethics
22   review committees in the countries in which we had
0048
 1   awards that were going to be used to conduct research.
 2               So what we did was a sort of multi-faceted
 3   approach.  Our office, the Human Subjects Division,
 4   began making directly, person to person contacts with
 5   the people in the IRB offices or ethics review
 6   committees, mostly the chairs and in some cases the
 7   administrators of those committees.
 8               We began developing in-country conferences
 9   with those countries.  We have done five to date in
10   South America, Africa and Asia, and we have two more
11   on the planning board and hope to continue onward.
12               The lessons that we have learned from
13   doing those conferences have been several.  One was
14   clearly to involve in-country researchers and IRB
15   members in curriculum development and conference
16   planning.  It did not work to take a 101 boilerplate
17   workshops and simply take it to a foreign country and
18   do it.
19               The best strategy was to make contact with
20   the faculty at the local university, with the faculty
21   at the local hospitals, with the IRB ethics review
22   committee members and chairs, and ask them to do the
0049
 1   presentations on the regulatory structure, on 45 CFR
 2   46, on Helsinki, on whatever regulatory structure they
 3   had chosen.
 4               One of the most successful was to have in-
 5   country researchers present their own protocols in a
 6   mock IRB or mock ethics review kind of setting.  We
 7   have had some absolutely marvelous discussions about
 8   the ethics of research protocols and had some very
 9   willing investigators lay themselves open to be flayed
10   by this mock ethics committee, and they did an
11   absolutely wonderful job.
12               Including many interactive sessions turned
13   out to be a terrific idea, having people discuss with
14   one another.  Often this was a first opportunity for
15   the ethics committee members from different
16   institutions to actually meet together with one
17   another.  We know that works in the United States.  It
18   works in Africa and South America as well.
19               Then what we have also tried to do is to
20   incorporate with our conferences, our workshops,
21   actual several days of meetings between our
22   representatives and the actual ethics review committee
0050
 1   membership at each of the institutions with which we
 2   have relationships.
 3               We are planning to expand our workshops,
 4   our ethics committee workshops, to include general
 5   issues about the responsible conduct of research. 
 6   This goes a little bit outside the purview of this
 7   committee.  
 8               On the other hand, I think it is essential
 9   to address all of the issues, not just the ethical
10   conduct of research with humans, but all of the
11   collateral responsible conduct elements that really
12   become an integral part of conducting ethical
13   research.
14               So, for example, conflict of interest,
15   issues about data management and ownership become
16   extraordinarily important when you do research
17   overseas, because especially what we have come to call
18   the tissue issue, exportation of tissue from a non-
19   domestic country to the United States, is fraught not
20   only with legal issues but with ethical issues as
21   well.
22               We are looking to providing a more formal
0051
 1   workshop for IRB members and institutional
 2   administrators on infrastructure, resourcing, policies
 3   and procedures, membership recruitment, retention,
 4   voting, FWA and IRB registration, how to get these
 5   done in a meaningful and effective way.
 6               We are expanding our in-country site
 7   visits and allowing time for site visits of IRBs
 8   represented at the workshop, and we are following up
 9   with mentoring programs -- that is, providing
10   fellowships through Fogarty, through our enhancement
11   grant for IRB members and chairs and staff to work
12   directly with U.S. or other registered, experienced
13   IRBs.
14               Specifically, what we are going to do in
15   those two areas has been very effective and low cost
16   for the University of Washington.  We have developed
17   a boilerplate SOP that can be used by a non-domestic
18   institution and tailored to that institution.
19               We have also developed an Access-based,
20   very simple database, so that non-domestic IRBs can
21   keep track of their applications, keep track of their
22   protocols, send out timely reminders for renewals,
0052
 1   keep track of modifications, adverse event reports, do
 2   all the tracking that sometimes we in the U.S. take
 3   for granted.
 4               We have done this on a very basic platform
 5   using Access, and we have provided training for at
 6   least now five IRBs to adapt this Access-based
 7   program, and we are going to assist them in achieving
 8   international accreditation as well.
 9               In the interim, what we have been doing
10   is, again, establishing local connections.  I have to
11   digress a little bit to tell you how important it was
12   for our IRBs to have meetings with the administrators
13   and IRB members and chairs from the non-domestic
14   sites.
15               Our IRB members learned a huge amount from
16   their IRB members.  It was truly an exchange, a
17   collaboration, in which our IRB members felt very
18   grateful, felt blessed that they had been on the
19   receiving end of so much information about how
20   research protocols are received in developing
21   countries or less resourced countries, what are issues
22   related to consent, and so on and so forth.
0053
 1               I think some of the things that we have to
 2   do, in addition to being a resource and some of the
 3   things that we do locally, have to be done on a
 4   national U.S. level, too.  One of those is addressing
 5   the issue of dueling ethical guidelines.  
 6               I'm getting a little distracted here.  I
 7   hope you will bear with me.  I'm almost done.
 8               When an ethics review committee chooses to
 9   tick something other than 45 CFR 46, we have a problem
10   in doing collaborative review, and I would like to
11   suggest just something for thought for this committee
12   is that you can consider the possibility of having a
13   U.S. MPA or FWA assured institution be able to switch
14   its ethical guidelines.
15               So, for example, if the University of
16   Nairobi has chosen to follow Helsinki rather than 45
17   CFR 46, that when the University of Washington and the
18   University of Nairobi have a project in common that
19   the University of Washington be allowed to use
20   Helsinki rather than 45 CFR 46, so that we can have a
21   consistent review.
22               What happens in the current situation,
0054
 1   because most of the prime awards are to American
 2   institutions, is that by default 45 CFR 46 becomes the
 3   regulation of choice, despite what the non-domestic
 4   IRB has chosen, since it is the one, as David pointed
 5   out, with the most checklists and the most specific
 6   kinds of regulations.
 7               I think we have to also at the national
 8   and international level address the major ethical
 9   issues in a collaborative way, provision of care, for
10   example, in treatment trials, how long, to whom, at
11   all.  The issue of placebo controlled trials, I know,
12   is nothing new to the folks in this room.
13               I think, in conclusion, I want to point
14   out not only the importance of education both ways and
15   collaboration in resolving some of these problems, but
16   also to emphasize what David already pointed out. 
17   That is the importance of funding, not only advising
18   non-domestic IRBs of their ability to charge fees for
19   a review, but also reminding them that the -- You
20   know, the University of Washington has about a 50
21   percent overhead charge at facilities, an
22   administration charge.
0055
 1               There is no reason that those institutions
 2   cannot charge an overhead rate to the institution that
 3   is issuing the prime award.  That information is
 4   simply not out there.  It does need to become more
 5   widely known that institutions do have the ability to
 6   resource themselves, that when they take on the
 7   responsibility for conducting research, they have
 8   infrastructure costs of a wide variety.  The most
 9   important one, of course, from my perspective is the
10   IRB support.
11               So again, I appreciate your willingness to
12   listen to these issues, and hope that we have given
13   you at least some food for thought and issues on which
14   you can ask questions.
15               CHAIRMAN PRENTICE:  Thank you, Helen.  I
16   would like to ask the panelists to move up to the
17   table in front.
18               Okay.  We are now open for discussion and
19   questions.  Susan first, then Mark.
20               DR. WEINER:  Yes.  My question is actually
21   for all three presenters.  It has to do with the fact
22   that most of your presentations focused, or almost all
0056
 1   of the presentations focused on questions in
 2   developing countries.
 3               Clearly, the problems that you have
 4   described in developing countries are different from
 5   and not experienced in the same way by developing
 6   countries that have long histories of ethical research
 7   and scientific progress.  
 8               I guess it was Dr. Lin who referred to the
 9   question of the ambiguity of equivalent regulations. 
10   Some of those in the medical community that I deal
11   with, and families as well, wonder why FWAs have to be
12   -- conform to the letter for countries that are not --
13   whose standards really stand on their own, so to
14   speak.
15               DR. LIN:  I did not recall I ever used the
16   word equivalent protection in my presentation.  You
17   did?  You want to take it?
18               DR. BORASKY:  Melody can probably comment
19   on this, but when I was talking about equivalent
20   regulations, I mean, actually we recognize that there
21   is the ability to have equivalent regulations noted on
22   your Assurance.  It's just that the question is, as 
0057
 1   Helen pointed out, do the U.S. institutions know how
 2   to work with institutions that have equivalent
 3   regulations?
 4               Then in my case, when we are talking about
 5   helping start up an IRB in a place that doesn't
 6   already have one built up, is it just easier to get
 7   them to check off 45 CFR 46 rather than try to worry
 8   about equivalent regulations?  I don't know if that
 9   answers your question.  Maybe I misunderstood it.
10               DR. WEINER:  It really refers to the
11   requirement that developed countries have FWAs to
12   participate in U.S. Federally sponsored research.  
13               DR. LIN:  Okay.  In the OHRP FWA we make
14   it flexible for international sites to be able to
15   check -- I believe there are six options that they can
16   check.  But that is within the context of assurance.
17               FWA is not just a few pages form that they
18   have to fill out.  They have to abide the terms of
19   assurance, which is also on the website, and term of
20   assurance has some U.S. requirement in it.
21               The only person that can call other
22   regulations equivalent, provide at least equivalent
0058
 1   protection, is the Department agency head, which is
 2   the Secretary.  You can say the Secretary have
 3   dedicated authority to OHRP.  Indeed, OHRP has
 4   established a HHS working group to look at this issue
 5   of equivalent protection.
 6               The working group submitted a report to
 7   Dr. Schwetz, and the report very carefully identify
 8   where the regulation really afford the protection to
 9   the subject, and it is all there.  The criteria of
10   other international guidelines or international policy
11   that can be called equivalent, the criteria are there.
12               So what we need, the next step we could do
13   is to use the other country's guideline of SOP to
14   compare with ours, and if it is all fit into that
15   criteria from the regulation, we can call it for
16   equivalent protection.  But we haven't got to that
17   yet.
18               CHAIRMAN PRENTICE:  Felix?
19               DR. GYI:  Thank you for a very succinct
20   presentation of a very complex issue, and especially
21   on a topic like this.  I really appreciated your
22   comments about what the host countries' limitations
0059
 1   are.  It really does parallel our experience in the
 2   international work that we have been doing.
 3               A couple of points to just sort of keep in
 4   mind here:  When we talk about experience that we want
 5   to have the host countries demonstrate to us, and you
 6   talk about infrastructure, keeping minutes, many of
 7   these countries are so poor that having paper and
 8   pencil is a luxury.
 9               So when you talk about things like
10   computer infrastructure, I wonder how we sustain
11   something like that without true commitment on
12   multiple levels.
13               Helen, I really like your recommendations
14   as well, because it speaks to the issue of us not
15   imposing what many people have referred to as ethical
16   and regulatory imperialism, but rather trying to find
17   some balance that makes sense for both our side as
18   well as on their side.
19               The confusion that I see, though, in some
20   of the discussion is what, Melody, you presented,
21   which is the crossover between FDA-related activities,
22   FDA regulated research, and the imposition of how OHRP
0060
 1   might assure appropriate conduct.
 2               I wonder if you might comment to the fact
 3   that FDA regulations are different enough from OHRP
 4   that there is a great deal of confusion to be
 5   addressed, and how you see addressing some of those
 6   and how you bridge those concerns.
 7               DR. LIN:  In my presentation, I did say
 8   the HHS OI, Office of Inspector General report
 9   recommendation for OHRP to exert leadership in the
10   research conducting of foreign countries sort of
11   astonishing, surprising to me at least, because the
12   accommodation went beyond our jurisdiction.
13               I think what we have done is that, at
14   least our OHRP-WHO collaborative project, as we
15   develop the agenda and as we go to different parts of
16   the world to do the capacity building, we always
17   include FDA official, and Dr. LePay can confirm that
18   to you.
19               So that we realize that the regulation is
20   very similar, but we do not have authority to speak
21   for FDA.  That's why we always want Dr. LePay or other
22   FDA representative he recommended to be with us.
0061
 1               DR. GYI;  Just one quick follow-up.  Do we
 2   have any data on what the FA regulated research looks
 3   like in comparison to Federally funded research? 
 4   Volume?
 5               DR. LIN:  Volume?  Mr. FDA,. Dr. LePay,
 6   would you answer that?
 7               DR. LePAY:  I'm not sure I can speak for
 8   the volume of Federally funded research, because most
 9   research outside of the United States that ultimately
10   comes back to FDA in the form of new product
11   applications is more often commercially funded, most
12   studies that are conducted abroad.
13               Clearly, there are indications that will
14   be studied, particularly in the anti-infectives area,
15   where the disease condition is relevant and studied
16   within a developing country, less relevant or less of
17   an issue here in the United States.  But in answer to
18   the question, I don't have those kind of matrix, if
19   that is what you specifically asked.
20               CHAIRMAN PRENTICE:  You have been patient,
21   Mark.
22               MR. BARNES:  Yes.  I just want to follow
0062
 1   up on Susan's question, because I just want to make
 2   sure that I understand this.  I think there's some
 3   ambiguity out there and some lack of understanding
 4   about when the FWA needs to kick in and when it
 5   doesn't, the FWA abroad.
 6               If there is a U.S. institution that has an
 7   FWA and it is conducting research abroad that is
 8   Federally funded -- I'm going to put forth a
 9   hypothesis, and you tell me whether this is accurate
10   or not -- and has a research project abroad that is
11   Federally funded, then the institution abroad would
12   have to have its own FWA, and then would have an
13   option of which regulations or set of guidelines it
14   would follow when it fills out the FWA.  Right?  Okay.
15               If the U.S. institution has an FWA but is
16   conducting privately funded research abroad, then
17   there is no requirement that that institution abroad,
18   the University of Nairobi, Harare Hospital, whatever
19   it might be -- there is no requirement that it have an
20   FWA.  Is that correct?  Non-Federally funded research?
21               DR. BORASKY:  I wouldn't even go that far. 
22   Non-HHS funded research -- I mean, they are the ones
0063
 1   that are going to require an FWA, but if it's -- you
 2   know, if Merck is going to do a study or Glaxo or
 3   something, they don't --
 4               DR. McGOUGH:  I think your assumptions are
 5   absolutely correct.  What many institutions like the
 6   University of Washington that conduct large numbers of
 7   such projects that are not HHS funded is that we do
 8   encourage as much as possible local host country IRB
 9   review or ethics committee review.  
10               We don't require it, but we also think,
11   for a wide variety of reasons, it is important for a
12   U.S. researcher to make links with the research
13   institutions in the host country.  That is often a
14   convenient way -- I mean, I'm thinking of Academia
15   Seneca or any of the other research institutions in
16   foreign countries that can provide valuable support to
17   that researcher.      
18               So most institutions operate under an FWA
19   with non-HHS funded research, that there is no FWA in
20   the domestic -- I'm sorry, in the host country
21   required, but we do encourage a relationship.
22               DR. LIN:  Well, Mr. Chairman, can I ask a
0064
 1   question?
 2               CHAIRMAN PRENTICE:  Yes.
 3               DR. LIN:  In follow-up what Helen just
 4   said, described, what if your FWA commit all your
 5   researchers to the assurance, regardless the source of
 6   funding, and what do you do then with your researcher
 7   that conduct research overseas but using private
 8   money?
 9               DR. McGOUGH:  Then the FWA at the
10   University of Washington requires University of
11   Washington review, but it does not require review in
12   the host country.
13               MR. BARNES:  Let me follow up just with a
14   couple of other items targeted about this.
15               So, therefore, in a privately -- say, a
16   Merck funded, just for hypothetical's sake -- a Merck
17   funded project that goes to the University of
18   Washington, not HHS funded at all.  Then, therefore,
19   ultimately if Merck and your researchers wanted to
20   submit the results of that research to support an FDA
21   application, although the institution abroad would not
22   have to have an FWA, the research conducted abroad
0065
 1   would have to have comported either with Subpart A or
 2   with the Declaration of Helsinki and all of the
 3   commentary and guidance on the Declaration, and that
 4   is pursuant to specific FDA regulations.  Right?
 5               DR. LIN:  I think -- Dr. LePay, if I am
 6   not correct, please correct me.  I think that in that
 7   case, for the international research FDA would honor
 8   that the overseas site followed the ICH TCP
 9   guidelines.
10               DR. LePAY:  It might be worthwhile just to
11   interject one point here, because in fact, in most
12   international studies, we have no legal control at all
13   outside of the United States.  Our jurisdiction is
14   largely restricted to applications, and that is, we
15   get jurisdiction at the time an application comes in
16   to us specifying that jurisdiction.
17               The application could be coming in to us
18   long after the study is conducted.  In some cases, the
19   application is at the level of a research permit. 
20   That is, the sponsor decides that they want to come to
21   us before they even begin the study and voluntary put
22   that study under FDA regulation, but until an
0066
 1   application comes in to FDA pertaining to that study,
 2   we have no jurisdiction whatsoever, no legal
 3   jurisdiction.
 4               That is what is most limiting, of course,
 5   to our ability to look at IRBs in real time.  We
 6   cannot go to an IRB and say we are going to inspect
 7   you, where there is no application and there is no
 8   legal authority to look or any relation to an FDA
 9   regulated study at that time.
10               MR. BARNES:  Just a final question, and
11   then I'll be quiet.
12               So you have sort of retrospective
13   jurisdiction, which is a very odd concept indeed.  But
14   in your presentations, all through your presentations,
15   you talked about developing countries, and that is
16   where these issues tend to come up, but I'm interested
17   in the European conducted studies and in your liaisons
18   with or your alliances with European institutions.
19               Of course, European institutions are
20   following national codes or EU codes on research that
21   are at least as protective as what we have here.  But
22   what has your experience been, if any, with the
0067
 1   European Data Directive and your attempts to comply
 2   with the Data Directive for importing data from Europe
 3   to the U.S.?
 4               Have you had experience with that, and
 5   have you had troubles with that?  That's my last
 6   question.
 7               DR. McGOUGH:  We do have some limited
 8   number of studies in Europe with countries that have
 9   signed the EU Data Directive initiatives.  So far we
10   have not had any problems with importing data, but I
11   have to tell you that those studies do not -- happen
12   not to involve tissues, and I don't know what would
13   happen if they did involve importation of tissues.
14               CHAIRMAN PRENTICE:  I guess, Helen, David
15   and Melody, you mentioned that it would be a good idea
16   for your institution to have enough flexibility to be
17   able to accept alternative ethical standards such as
18   Declaration of Helsinki, ICH, E-6 guidelines versus 45
19   CFR 46.
20               Quite frankly, when I compare the two
21   documents or the three documents, I find the
22   Declaration of Helsinki and the ICH guidelines far
0068
 1   more complex, far more comprehensive than this short
 2   little 45 CFR 46 we have been living with for the last
 3   22-23 years.
 4               So I'm kind of curious as to what kind of
 5   documentation you would want to have relative to how
 6   an overseas institution would be complying with those
 7   documents.
 8               DR. McGOUGH:  It was actually more for our
 9   convenience than -- I mean, the local -- The host
10   country IRB has already chosen through the mechanism
11   of the FWA which regulatory set it wants to follow. 
12   So the flexibility would be more on the domestic IRB's
13   part to be able also to switch to that, to make a
14   consistent choice in regulatory guidelines.
15               The burden then for documentation would
16   fall on the U.S. IRB, and I agree with you that,
17   certainly, ICH is more complex than 45 CFR 46.  But
18   since we do so much overseas research already, we are
19   already in compliance with ICH, and we do that
20   additional documentation as well.  So it would not be
21   a burden for an institution like ours.
22               CHAIRMAN PRENTICE:  My second question
0069
 1   deals with possible solutions, and you mentioned
 2   accreditation.  My institution is currently trying to
 3   prepare a cell study for AAHRPP.  Quite frankly, it is
 4   a very labor intensive, complex process.  I suspect
 5   that, if AAHRPP came in right now to try to accredit
 6   me, I might not pass.
 7               So, consequently, the genesis of my
 8   question:  How far away are HRPPs in developing
 9   countries from being able to meet such standards that
10   are put forth by either AAHRPP or PHRP?
11               DR. LIN:  I think, in most cases, very far
12   away, because we are still struggling on capacity
13   building and worrying about infrastructure, they
14   aren't ready for accreditation.  However, having said
15   that, there are a few countries very advanced and very
16   diligent about setting up their human research
17   protection program because they have the incentive.
18               Some believe that their next wave of
19   economy would be research and development of medical
20   devices for FDA approval.  So that not only the health
21   ministry devote effort into the clinical trial human
22   subject protection; even the ministry of economic
0070
 1   affairs are devoting a lot of effort into it.
 2               I can tell you at least two countries, and
 3   you can guess probably, that are quite prosperous. 
 4   The countries are quite prosperous, and they are
 5   putting their effort into the human research
 6   protection program.
 7               We talk a lot about cost for accreditation
 8   yesterday in this country.  For the few countries that
 9   I know in the international setting, cost is not the
10   issue for them.  So they are preparing for
11   accreditation.
12               CHAIRMAN PRENTICE:  Mary Lake?
13               DR. POLAN:  Well, first I would like to
14   thank you all for coming and speaking with us, because
15   my interest in your subject matter derives from the
16   fact that my department now has two international
17   investigation areas, and from that comes two
18   questions.
19               First, I just want to make sure I
20   understood your answer to Mark's question.  If you are
21   working with a country that does not have an IRB
22   structure, then you can use your own home IRB.  You
0071
 1   don't have to develop an IRB in a country that doesn't
 2   have such a structure before you can do an
 3   investigation, as long as it is not HHS sponsored.
 4               DR. McGOUGH:  And not FDA regulated.
 5               DR. POLAN:  And not FDA regulated.  Okay.
 6               The second question is a little bit
 7   different.  This is very interesting and, certainly,
 8   important to develop capacity -- Go ahead.
 9               DR. McGOUGH:  Can I back just a little
10   bit?  I mean, I think what we always say at every
11   PRIM&R meeting and every ARENA meeting is a reminder
12   that the Federal regulations are a minimum standard,
13   above which any institution can rise.  Your
14   institution or mine might set the bar a little higher,
15   and might have that additional requirement, but it
16   would not be a Federal requirement.  It would be a
17   local requirement.
18               DR. POLAN:  That's true, and one would
19   hope that, if an institution made a local requirement,
20   it would be willing, as your institution does, to
21   support development and capacity building in host
22   sites.  But that actually leads to the next question.
0072
 1               This information has all been about host
 2   countries and how to help them build capacity.  I am
 3   also concerned about perhaps not the IRBs in this
 4   country, although there was recently an example in the
 5   newspapers of an IRB head who said, no, we didn't have
 6   to get approval in another country, which was clearly
 7   wrong.  But what kind of information are you all
 8   giving out to investigators, particularly from Melody
 9   and from funding institutions or regulatory
10   institutions; because I don't believe that most
11   investigators understand this in the least?
12               DR. LIN:  I think that, especially since
13   the handful of domestic institutions assurance was
14   suspended by OHRP, I think that the sentiment of
15   having institution-wide education were there for many
16   years, and I believe many, many universities and
17   hospitals are having these educational programs, not
18   only for IRB members or IRB chairs, also for
19   investigators and the institution officials.
20               While OHRP do not have a requirement for
21   education, many institutions have an educational
22   program and spell out what the institutions expect of
0073
 1   each party, investigator, IRB, and institution
 2   official.
 3               Bear in mind also, NIH has a requirement,
 4   if you receive NIH money, the investigator do require
 5   education.  So my answer is I think that institutions
 6   -- I don't like to use the word fail, but institutions
 7   do not tell the investigator what they expected them
 8   to do to be a clinical researcher.
 9               DR. McGOUGH:  Our experience has been that
10   it is all over the board.  I think agency -- or parts
11   of NIH, like NIAID, are right on it.  When they issue
12   an award letter, in the award letter is a reminder to
13   the investigator that they need to make sure that each
14   site is in compliance.  But there are other agencies
15   that simply don't have the familiarity with
16   international requirements and international research
17   in general.  
18               This is a new thing.  Fogarty is clearly
19   right on it.  That information comes out directly to
20   the investigator very early on in the process, but I
21   think you are right, that others may -- that word may
22   not be coming directly out from the funding agency.
0074
 1               DR. BORASKY:  Yes.  I mean, what my office
 2   does is just maintains -- First of all, we've got
 3   offices in about 36 countries.  So in each of those we
 4   try to identify somebody who will sort of be the in-
 5   office leader on IRB issues, just a point person, so
 6   to speak.  
 7               So we try to make sure we keep the lines
 8   of communication open to those -- not just our
 9   domestic staff, but our global staff, and remind them
10   specifically about what our institutional commitments
11   are when it comes to these programs and what my IRB's
12   expectations are, which go hand in hand with the
13   institution's expectations.  But it is mostly just
14   through a communication process.
15               Having said that, I mean, we are an
16   organization that does mostly international research. 
17   So it is not a novel or unique thing for us, where in
18   a lot of bigger domestic institutions, it's students
19   or faculty going abroad for the first time.
20               DR. POLAN:  Could I just ask one more?
21               CHAIRMAN PRENTICE:  No.  No, we got too
22   many questions.  I have a list of five people here. 
0075
 1   If we can get through the five, then you can.  Sorry.
 2               Celia, you are next.
 3               DR. FISHER:  First of all, I was very
 4   impressed with the amount of education that you have
 5   been doing and the efforts that are being made.  I'm
 6   trying to understand the request.  Is this on?  
 7               I'm trying to -- First of all, I was
 8   complimenting them, because I think it is very
 9   impressive, the educational efforts that are being
10   made, and I know they take time and effort and
11   understanding.
12               I'm trying to understand what has been
13   asked of us, and I'm trying to place it within the
14   human subjects protections framework.  So I'm going to
15   make a couple of comments, and then maybe you can
16   respond, in terms of what I'm thinking.
17               It sounded as if what you were requesting
18   was our consideration of whether U.S. investigators
19   could be permitted to switch codes to complement that
20   that was checked by the other country's IRB or
21   whatever they are.
22               So some of the issues that emerge for me
0076
 1   is from a human subjects protection is that it sounds
 2   as if a lot of the focus is on the standard operating
 3   procedures.  It seems to me, human subjects
 4   protections within international and our national
 5   regulations are, one, you protect subjects by having
 6   these good standard operating procedures so that data
 7   isn't lost and there is monitoring that goes on, and
 8   then there is the protection of subjects that has to
 9   do with the regulations that are specific to those
10   protections.
11               I am finding it difficult to separate
12   those two, and I don't want to throw out the baby with
13   the bath water.  So, for example, it seems to me that
14   -- and when Felix -- Let me just say everything and
15   then frame the question.  
16               When we talk about ethical imperialism,
17   there is a difference between ethical imperialism and
18   ethical relativism.  You know, we have our 45 CFR 46,
19   because we believe in the human subjects protections
20   that we deliberated on very carefully, and in fact, we
21   are working on this committee to further
22   operationalize what those are.  So at least as a
0077
 1   nation, we have an investment in the type of ethical
 2   procedures that emerge from those.
 3               So I'm conflicted in that aspect.  I
 4   certainly am not conflicted if we are requiring
 5   individuals to go with whatever code has the higher
 6   standard, because it would mean they would be
 7   fulfilling ours as well as something else, but I get
 8   a little uncomfortable in going toward a lower
 9   standard.
10               The framework which we are ignoring in
11   some sense -- We are talking about capacity building
12   and sustainability.  But we are only talking about it
13   from the IRB side.  We are not talking about it in
14   terms of these countries developing IRBs at the same
15   time they are developing their scientific resources 
16   so, in fact, there is something to sustain if the
17   United States isn't coming in.
18               So I'm a little confused with the way we
19   are throwing around terms.  
20               Then the other issue is that the potential
21   for exploitation, for example, the use of outsourcing
22   and why different technical products are being tested
0078
 1   in developing countries, not specific to that country
 2   but because actually the labor is cheaper.  The
 3   subject costs are cheaper.
 4               So I don't think we can skirt the ethical
 5   issues and the importance of our guidelines, and we
 6   cannot say that we have different ethical values for
 7   our investigators when they are somewhere else with
 8   individuals to exploit. 
 9               So to summarize, how do we maintain human
10   subjects protection and at the same time provide the
11   flexibility that you are asking for, so this kind of
12   research can be done?
13               DR. McGOUGH:  Maybe since I asked for it,
14   I can respond to that.  OHRP has already made the
15   decision about equivalence.  That's not at issue. 
16   OHRP has said Helsinki is equivalent to 45 CFR 46.  So
17   is CIOMS.  So is the Belmont Report.  Am I incorrect? 
18   They are allowed to choose.
19               DR. LIN:  They are allowed to choose one
20   of the six -- or one of the five in the context of
21   terms of assurance.  So they have to follow what is
22   terms of assurance, and terms of assurance have all
0079
 1   the stipulations of what is in this 45 CFR 46,
 2   paraphrasing.  
 3               DR. McGOUGH:  The choices that are given
 4   include?
 5               DR. LIN:  They can choose in the context
 6   of the terms of assurance.
 7               DR. McGOUGH:  Correct.  They can choose
 8   the -- So even if there has not been an explicit
 9   statement, the assumption is that, if they choose
10   Helsinki, that the subjects for whom they are
11   reviewing research are receiving --
12               DR. FISHER:  I'm sorry.  Are you talking
13   about the United States?
14               DR. McGOUGH:  No.  I'm talking about the
15   host country.
16               DR. FISHER:  Just the local.  Okay.
17               DR. McGOUGH;  Just the local, yes -- that
18   the host country is protecting its subjects to a level
19   of regulatory compliance that is acceptable to OHRP
20   that has issued the FWA.  Perhaps I am
21   misinterpreting.  Mike is shaking his head.  So I'm
22   confused.  But my understanding was that they tick off
0080
 1   what they want to follow.  They follow it, and OHRP
 2   accepts the FWA.
 3               DR. CAROME:  There are two choices made in
 4   international FWA.  One is for what ethical standard
 5   you are going to apply, and that is either the Belmont
 6   Report, Declaration of Helsinki or other.  
 7               Then there is the procedural standards you
 8   are going to follow, which is 45 CFR 46, the FDA regs,
 9   CIOMS and three others, but not the Declaration of
10   Helsinki.  That's not a procedural standard.
11               DR. McGOUGH:  I am sorry.  Okay, and I
12   misspoke.  But the problem that leads us to is there
13   can be different structures followed by the host
14   versus the U.S. institution.  I guess what I was
15   asking for was the ability to at least -- have the
16   flexibility to operate under the same structures for
17   the domestic and the host institution, which, I think,
18   is a reasonable issue.
19               As Dr. Prentice pointed out, ICH, for
20   example, and CIOMS are more rigorous in their
21   requirements.  I am not going to say that requirements
22   and protections are the same.  I'm not sure that they
0081
 1   translate across the board, but certainly the
 2   requirements are as or more rigorous in ICH and CIOMS
 3   than they are in 45 CFR 46.
 4               If I can go on to other requests, I think
 5   the requests are for continued allocation of resources
 6   through the Department of Health and Human Services to
 7   support both capacity building and sustainability.  It
 8   is remarkable what institutions can do with surplus
 9   computers, for example.  
10               I mean, this is really a very low cost way
11   of providing both capacity building and
12   sustainability.  Building in funding in Federal HHS
13   grants to allow institutions to buy a computer, to
14   provide the sustainability technology that is
15   necessary to have the ethics review committee or the
16   IRB continue to support American funded research.
17               CHAIRMAN PRENTICE:  Okay.  We have five
18   names on this list.  We've got five minutes.  You can
19   ask a question.  You are going to have to confine it
20   to about 30 seconds.  Otherwise, we are never going to
21   get through.  Fair enough?  Okay, and we may not get
22   through all five names on the list, because I want to
0082
 1   save some time for the panel to tell us how we can
 2   help resolve some of these issues.
 3               In other words, what can SACHRP do and
 4   what can OHRP do to enhance human subject protection
 5   internationally?  So far we have spent all of our time
 6   talking about a lot of the issues, but we haven't got
 7   to any solutions.  So I want to devote some time to
 8   the solutions.
 9               I am going to take one more question from
10   a SACHRP member.  Then I am going to go to one of our
11   ex officio members.  They have an opportunity to ask
12   questions as well.  So, James, you are going to be
13   number two.  Susan, you are up next.
14               MS. KORNETSKY:  This may lead into the
15   discussion.  Helen, how do you fund the activities
16   that you are doing?
17               DR. McGOUGH:  Primarily through Fogarty.
18               MS. KORNETSKY:  And the other thing, which
19   is really just -- and we'll get to this as a
20   recommendation -- is:  Melody, is there a guidance
21   from OHRP for IRBs about some of these ideas for
22   international studies for the local centers on how to
0083
 1   do this?
 2               DR. LIN:  I think we have in-house
 3   guidance not posted yet.  
 4               MS. KORNETSKY:  It's not posted yet? 
 5   Okay.  So I think that might be a recommendation. 
 6   Thanks.
 7               CHAIRMAN PRENTICE:  Okay.  James?
 8               MR. SHELTON:  I guess my mic is on.  I
 9   just want to make a couple of points about local IRBs,
10   because a lot is invested in them.  A couple of
11   significant reservations that I have:  One point built
12   on a point that David made, which is that, you know,
13   very often the composition of these boards is not only
14   biomedical and university and researcher, but there is
15   a huge social distance between the people that are on
16   that review committee, and very often the subjects are
17   the research, even more so, I would argue, oftentimes
18   than in the United States.  So that's just another
19   reservation.
20               The other thing is that the focus of these
21   discussions often ends up being fairly biomedical, but
22   I want to remind people that there is a lot of other
0084
 1   kinds of research, social science research, survey
 2   research, epidemiology and, most importantly to us,
 3   program research.
 4               Within the HHS context, that is growing by
 5   leaps and bounds through CDC in the developing world
 6   but, I assume, to some extent NIH as well.  That also
 7   makes these local IRBs even less qualified in a sense,
 8   because they really don't have much expertise in these
 9   areas, and they tend to be divorced from these kinds
10   of activities in many ways.
11               One of the reasons why AID does not
12   require local IRB approval, though we encourage it, is
13   because very often people that are collaborating in
14   these things, the institutions, are not research
15   institutions.  They don't have the infrastructure, nor
16   is there a lot of value added to try to build that
17   into a local NGO or a local health department.
18               So part of the solution could be some
19   bending, I suppose, on that aspect as well.
20               CHAIRMAN PRENTICE:  Bob?
21               DR. HAUSER:  I found your presentations
22   educational and, I must say, concerning.  I would like
0085
 1   to ask a question, and I hope you take it in the right
 2   way.
 3               In your opinion, are we using U.S. Federal
 4   funds to conduct clinical research outside the U.S. at
 5   sites where adequate human investigation protection is
 6   not in place?
 7               DR. BORASKY:  Probably.  And we talk about
 8   the fact that a lot of the times -- Well, let's take
 9   HIV, for instance.  A lot of the times, the
10   populations that are most affected by it are the most
11   marginalized, the most stigmatized, the populations
12   that are perhaps engaging in behaviors or activities
13   that aren't within the local social norms.
14               So that is going to create some
15   injustices, and certainly it is a question of does the
16   research that we are doing over there add to the
17   injustice?  Hopefully not.  I mean, there should be
18   some beneficence to the research, not making things
19   worse for the people.
20               At the same time, I mean, there is the
21   recognition that we've got to do the research.  These
22   are the folks that need the research done the most
0086
 1   and, unfortunately, the populations that we have to
 2   work in, because they are the most severely affected
 3   by it.
 4               Hopefully, my institution, Helen's
 5   institution, Melody's institution, are doing what they
 6   can to, if not specifically improve the function of
 7   the programs, they are raising the awareness with
 8   their in-country investigators and their host
 9   institutions to take into account these problems and
10   not exacerbating what is already a bad situation.
11               DR. McGOUGH:  I would agree with David's
12   response, but I would also remind the group that this
13   is why most of us have not deferred review, why we do
14   collaborative reviews, so that there at least two
15   institutions conducting the review, and we hope that
16   between us we make up for one another's deficiencies.
17               While there may be deficiencies, being the
18   host country IRB in terms of infrastructure issues,
19   they often have, despite what Dr. Shelton said,
20   insights into the cultural appropriateness of a study
21   that we don't have.  So I argue that the collaboration
22   is what makes the best possible review, even though
0087
 1   each individual IRB may have its own deficiencies.
 2               CHAIRMAN PRENTICE:  Okay.  Nancy?
 3               DR. JONES:  Some of the follow-up of Mary
 4   and, I think, Susan and some of Helen's comments was
 5   on the investigator end.  I know that, Melody, you
 6   pointed out that a lot of people are trained to do --
 7   I mean are accredited by their institutions to do
 8   human subject research, but I would say most of it
 9   doesn't include international.  That is a really
10   special skill.
11               So again, getting investigators to the
12   point that they can understand what it requires,
13   especially in institutions that don't have a long
14   history or an infrastructure already in place, I would
15   say is probably not adequately done, and needs to be
16   done so that the investigator can understand to put in
17   the extra line for the support or the different
18   mechanisms that they can do for the country.
19               So I don't know -- Your comments about
20   would there be a need in this place, if people aren't
21   doing a critical mass of international research, to
22   refer it outside their institution for additional
0088
 1   review or help.
 2               CHAIRMAN PRENTICE:  Response?  Okay.  All
 3   right.  Tom, you have the last word.  No more
 4   questions after this.
 5               DR. ADAMS:  Thank you for an excellent
 6   panel.  I have learned a great deal this morning.
 7               One of the themes that, obviously, ran
 8   through it as it related to developing countries is
 9   the issue of funding.  Helen, you spoke briefly about
10   the fact that you were letting other institutions know
11   that there was possibility of adding administrative
12   fees and that type of thing.  
13               Is there any other -- Are there sources
14   that institutions in developing nations can turn to
15   for funding?  I know that with our organization, which
16   educates individuals, we run into the same problem.
17               DR. McGOUGH:  Are you aware of any others? 
18   Go ahead.
19               DR. BORASKY:  Well, I think it's been
20   tough.  We were talking about this amongst ourselves
21   yesterday evening and saying why aren't folks like the
22   Gates Foundation on board.  To some extent, it's just
0089
 1   not, I guess, a sexy thing.  But there are other
 2   avenues opening up out there.
 3               The Welcome Trust has established a fund
 4   where you specifically can't be from the U.S. or, I
 5   think, the EU and still qualify for this sort of
 6   support funds.  Obviously, there are groups like
 7   Fogarty who are already channeling back dozens of
 8   folks who have been trained specifically in bioethics
 9   who, hopefully, go back and become institutional
10   leaders.  If you want to add to that.
11               DR. McGOUGH:  There are programs at
12   Harvard.  There are programs at Yale that are
13   specifically designed to train ethicists and ethics
14   committee members to go back to their countries. 
15   That's a non-money thing, but I think getting the word
16   out -- and I'm not popular with my investigators when
17   I urge local sites to request a higher overhead,
18   because it all comes out of the prime award.  So they
19   are not thrilled with that idea, but nonetheless I
20   think it is an important word to get out, that host
21   countries can charge an indirect rate to conduct
22   research, and it's a good source of money.
0090
 1               CHAIRMAN PRENTICE:  All right.  I want to
 2   remind everybody of the provisions in the Secretary's
 3   charter, that we will advise the Secretary on matters
 4   concerning the protection of human subjects with
 5   particular emphasis on -- and in that "particular
 6   emphasis on" is international studies.
 7               We brought you here today to have an
 8   opportunity to hear about the issues pertaining to
 9   international research.  We are here to try to fulfill
10   the Secretary's mandate.  Therefore, it is essential
11   that you advise us as to what we can do to help solve
12   some of these problems.
13               I think it is very clear that there is a
14   great deal of activity that is going on in terms of
15   trying to enhance protection of human subjects,
16   international research.  It is also very clear that
17   they are in some countries significantly far behind,
18   which is not surprising, obviously.  As Felix
19   mentioned, paper and pencil is sometimes hard to find
20   in some of these developing countries.
21               So in the next six minutes, because we are
22   pushing lunch ahead 15 minutes -- we are going to take
0091
 1   a break exactly at 10:45.  In the next six minutes,
 2   could you tell us, SACHRP together with our partner,
 3   which is OHRP, can do to help address some of these
 4   issues?
 5               DR. LIN:  I will start.  Knowing that the
 6   pharmaceutical industry are conducting more research
 7   abroad, knowing that NIH, HHS are funding more
 8   international research, either collaborative or direct
 9   funding, we must avoid unethical conduct with our 
10   international research, as Mr. Hauser's concern.
11               Therefore, I think capacity building is
12   very important for now, at least in the very
13   beginning.  The worry is very big, and OHRP is very
14   small.  I think, in order for OHRP on behalf of HHS to
15   do more work, we need to either have more
16   collaboration with others that are doing it, leverage
17   the resources, because the resources is very limited.
18               So I do not have a solution, because I am
19   in it.  I am responsible for international activity
20   for OHRP and HHS, and first my parents teach me to be
21   modest.  Second, as an HHS employee, I should not be
22   doing budget busting.
0092
 1               CHAIRMAN PRENTICE:  So in other words, you
 2   want more money.  That's the bottom line here?  More
 3   resources, more money?
 4               DR. LIN:  I didn't say that.
 5               DR. BORASKY:  Well, one thing --
 6               CHAIRMAN PRENTICE:  Yes, go ahead, Tom.
 7               DR. ADAMS:  More collaborations.
 8               CHAIRMAN PRENTICE:  Yes, more
 9   collaborations.
10               DR. BORASKY:  One thing that I know would 
11   help me and would probably help Helen is if OHRP were
12   to offer clear guidance on what equivalence
13   protections are and how domestic institutions can take
14   advantage of that.  It seems like that would be a
15   simple thing.  
16               In fact, I think in the NBAC report there
17   was a huge table of different international
18   regulations and how they matched up with the U.S.
19   regulations.  But good guidance on what equivalent
20   regulations are and how to use them would be helpful. 
21               DR. McGOUGH:  Absolutely.  I second that. 
22   I am also reminded of the earlier days of NBAC in
0093
 1   which there was an effort by NBAC to collect
 2   information on the knowledge of the agencies, the
 3   funding agencies, about human subjects protection.  
 4               I would like to request that this group
 5   urge or have happen, make it so, that an equivalent
 6   investigation was done of NSF, NIAID, NIH in general,
 7   FDA, on the level of understanding of the protections
 8   of human subjects in the international research.  How
 9   much is being done, who is doing it, where is it being
10   done.
11               My last request would be, again,
12   collaboration.  I think that's the name of the game,
13   making sure that we all know what is going on, so that
14   we don't re-duplicate efforts and are able to work
15   together rather than to work independently.
16               CHAIRMAN PRENTICE:  Okay.  Dr. Schwetz, do
17   you have anything you would like to add on behalf of
18   OHRP?
19               DR. SCHWETZ:  No, I don't, Ernie.
20               CHAIRMAN PRENTICE:  All right.  Quick.
21               MR. SHELTON:  My own observation is to put
22   something on the table that hasn't really been
0094
 1   discussed, which is I think a huge impediment is the
 2   informed consent process.
 3               Everywhere I go, I continue to see people
 4   who equate the consent process with reading the
 5   consent form, when in fact it is not supposed to be
 6   reading the consent form.  When this plays out in the
 7   developing world, it is far worse, in my view, than it
 8   is in our world, because not only do you have the
 9   translation problems, but you have all the colloquial
10   and sort of social status problems.
11               So I think we need a social norm that gets
12   -- and part of it is a legal issue -- that gets people
13   away from the idea that they have to read consent
14   forms and that's the consent process.
15               CHAIRMAN PRENTICE:  Okay.  Thanks, James. 
16   All right.  Mary, you have been very patient, and we
17   have one minute left, and I'm going to allow you to
18   ask one more question.
19               DR. POLAN:  Well, actually, you asked it
20   for me.  I was going to ask the panel what we could do
21   to help you.  So that leads me to the very last
22   question, which is how are we going to respond to
0095
 1   their requests?
 2               I, for one, would volunteer to help write
 3   something that might be brought back to this panel,
 4   this group, to SACHRP, in conjunction with not just
 5   the people who might be interested in contributing to
 6   this.  How do you want to do this, Ernie?
 7               CHAIRMAN PRENTICE:  Actually, you
 8   anticipated my closing comments.  I was going to ask
 9   you whether or not you would be prepared to do that. 
10   I think that we have some ideas here.  Some of them,
11   I would hope, are easier to accomplish than others. 
12   Certainly, there is no reason in the world why OHRP
13   can't offer clear guidance on these issues.  That is
14   something that ought to be able to be put together
15   rather quickly and disseminated out to the IRB and the
16   research community.
17               In terms of collaboration between OHRP and
18   other organizations, obviously, that is up to OHRP and
19   the other organizations to try to make this happen. 
20   SACHRP can't make that happen.  All we can do is
21   encourage that to go forth.
22               In terms of enhancing the level of
0096
 1   understanding on the part of the funding agencies with
 2   regard to requirements and human protection issues,
 3   that is probably something that OHRP and FDA need to
 4   be looking at, as to how we could best accomplish
 5   that.
 6               So I appreciate you volunteering.  Is
 7   there anybody else on SACHRP that is particularly
 8   interested in this issue that wants to work with Mary
 9   Lake?
10               MR. BARNES:  Ernie, I will offer to work
11   with Mary Lake on one targeted issue, which also is a
12   bridge to our next meeting, in regard to the necessity
13   for HIPAA -- according to the current regulations, for
14   HIPAA authorizations gathered in studies abroad, which
15   is a preposterous requirement, although that is what
16   the law says.  I think that we should probably throw
17   that in as one of the complicating issues in regard to
18   human research.  Does the panel --
19               DR. McGOUGH:  Thank you, thank you, thank
20   you.
21               CHAIRMAN PRENTICE:  Yes?
22               DR. FISHER:  Ernie, can I make a request
0097
 1   from our group, that when we talk about collaboration,
 2   that you address a distinction between the SOP and the
 3   standards of human subjects protection, so that we
 4   understand what is being said about collaboration. 
 5   And given the excellent description of the lack of
 6   adequacy of the SOP processes in these other
 7   countries, how do we make sure that we are just not
 8   approving our national folks to settle for a lower
 9   standard of SOP, even though I understand the
10   regulations may be more complex?  But for me, that
11   would be a major issue to have to grapple with.
12               CHAIRMAN PRENTICE:  Okay.  I would like --
13               DR. JONES:  Ernie, I will be glad to help
14   Mary.
15               CHAIRMAN PRENTICE:  Okay.  Let me write
16   this down.  I would like to thank the panel for taking
17   their time.  I know some of you had to fly in a long
18   ways, all the way from the West Coast.  So we really
19   appreciate you coming here and addressing us with
20   these international issues that are so very important.
21               So we are going to now take a break for 15
22   minutes.  Then we are coming back, and we are going to
0098
 1   consider the next area, adverse events.  
 2               (Whereupon, the foregoing matter went off
 3   the record at 10:45 a.m. and went back on the record
 4   at 11:05 a.m.)
 5               CHAIRMAN PRENTICE:  The next panel is
 6   going to deal with adverse events.  We've got,
 7   actually, two panels, one in the morning, one in the
 8   afternoon.  
 9               I am going to briefly introduce each
10   individual.  As a matter of fact, I'm not even going 
11   to take the liberty of going through the bios, as I
12   did last time.  I want to save time.  I hope that they
13   will forgive me for that.  I will simply tell you who
14   they are.
15               We have Michael Carome, who is the
16   Associate Director for Regulatory Affairs at OHRP;
17   David Lepay, Senior Advisor on Clinical Science,
18   Office of Science and Health Coordination with the
19   Food and Drug Administration.  We have John Zaia, and
20   he is at the Beckman Research Institute at City of
21   Hope.  He is a virologist and the Chair of their IRB;
22   and we have Patricia Scannell who is the Director of
0099
 1   the Human Studies Program, Human Studies Committee
 2   rather, at Washington University in St. Louis.
 3               We have 15 minute presentations scheduled. 
 4   So, Mike, are you ready?  As before, we will hold our
 5   questions for the discussion period.  We seem to be
 6   having a bit of a PowerPoint problem here.
 7               DR. CAROME:  We can go from my handout. 
 8   Did that get handed out?  Okay.  
 9               CHAIRMAN PRENTICE:  Are you comfortable
10   with doing that, Mike?
11               DR. CAROME:  Yes.
12               CHAIRMAN PRENTICE:  All right.
13               DR. CAROME:  Well, it is a pleasure to
14   speak to the Committee about what is viewed by many in
15   the IRB community and the human subject protection
16   community as a very important issue.  What I am going
17   to do in opening the panel is simply provide very
18   quickly in six or seven minutes a quick overview of
19   what are the regulatory requirements as they relate to
20   adverse events, so that you have that background of
21   understanding.
22               What I hope you leave with is an
0100
 1   understanding of what needs to be reported with
 2   respect to adverse events, who they need to be
 3   reported to, and when they need to be reported.  The
 4   regulations that I am speaking to are solely the HHS
 5   regulations at 45 CFR Part 46, which are the HHS
 6   regulations for the protection of human subjects.
 7               So the first question you might ask is: 
 8   What adverse event reporting requirements are
 9   stipulated by the HHS regulations for protection of
10   human subjects?  The answer to that is there are none.
11               If you go through the set of regulations
12   I just cited, you will not find the words "adverse
13   events" or "adverse event reporting" in our
14   regulations.  
15               So what I want to do is cite for you four
16   specific provisions that do have relevance with
17   respect to reporting of certain adverse events, and
18   these are in my presentation.
19               One is, first of all, at 45 CFR 46.103(b). 
20   It states the following in part:  "Assurances
21   applicable to Federally supported or conducted
22   research shall at a minimum include the following,"
0101
 1   and one of those following is "written procedures for
 2   ensuring prompt reporting to the IRB, appropriate
 3   institutional officials, and the department or agency
 4   head or their designee any unanticipated problems
 5   involving risk to subjects or others," so any
 6   unanticipated problems involving risk to subjects or
 7   others, and you might expect that some adverse events
 8   would presumably fall under that category of
 9   unanticipated problems, and also any suspension or
10   termination of IRB approval.
11               Sometimes IRBs suspend or terminate
12   approval of research because of certain adverse events
13   that have occurred or a pattern of adverse events that
14   is occurring.  So that's the first provision that
15   relates to adverse events.
16               The next one at 45 CFR 46.103(a) states
17   that -- So I am going back to 103(a), and this is just
18   to point out there is one other "to whom" that must be
19   reported, and it states that "When the existence of an
20   HHS approved assurance is accepted in lieu of
21   requiring submission of a separate assurance to
22   another Federal department or agency head, reports
0102
 1   required by this policy are to be made to OHRP."
 2               So when reports are required under an
 3   assurance that applies that is approved by OHRP, you
 4   must submit those reports to us.
 5               Next 45 CFR 46.113 says the following: 
 6   "An IRB shall have authority to suspend or terminate
 7   approval of research that in part has been associated
 8   with unexpected serious harms to subjects" --
 9   unexpected serious harms to subjects.  Presumably, the
10   only way the IRB could make a judgment to suspend or
11   terminate approval for such events would be if those
12   events were reported to the IRB.
13               "Any suspension or termination of approval
14   shall include a statement of the reasons for the IRB's
15   action and shall be reported promptly to the
16   investigator" -- so there is backward reporting when
17   the IRB takes an action in response to such an event -
18   - "to appropriate institutional officials" again, "and
19   the Department or agency head," and based upon what I
20   last said, if it is done under an OHRP approved
21   assurance, to OHRP.
22               Lastly, with respect to IRB records, 45
0103
 1   CFR 46.115 states in part:  "An institution or, when
 2   appropriate, an IRB shall prepare and maintain
 3   adequate documentation of IRB activities, including,
 4   among other things, reports of injuries to subjects."
 5               This doesn't mean that all injuries to
 6   subjects need to be reported to the IRB.  It just
 7   means that, when an IRB does get a report of a
 8   particular event that involved an injury, that is
 9   among the records that must be maintained by the IRB
10   under our regulations.
11               So having said that, the "what events that
12   need to be reported under the regulations" are:  Any
13   unanticipated problems involving risks to subjects or
14   others or any suspension or termination of IRB
15   approval, which sometimes occurs because of adverse
16   events.
17               Having said all that, so how do adverse
18   events fit into these regulatory requirements that I
19   just quickly went over?  In general, OHRP expects that
20   a minority of adverse events -- a minority --
21   occurring in subjects will be determined by
22   investigators and/or the IRB to represent
0104
 1   unanticipated problems involving risk to subjects or
 2   others, and it is these adverse events, a small subset
 3   of all adverse events, that need to be reported in the
 4   time frame and to the individuals or entities that I
 5   went over.
 6               Now to ensure compliance with these
 7   reporting requirements with respect to adverse events,
 8   investigators should promptly report unanticipated or
 9   unexpected serious adverse events to the IRB.  Those
10   are the adverse events that, obviously, are going to
11   be most pertinent under our regs.
12               In looking at these events, the
13   investigator and the IRB in reviewing them should
14   carefully assess the relationship of the events to the
15   research interventions and interactions.  They should
16   determine whether the adverse event represents an
17   unanticipated problem involving risk to the subjects
18   or others at your institution.  They should follow
19   written procedures for ensuring that reporting of
20   these events is appropriately carried out and, when
21   appropriate, they should determine whether the IRB
22   protocol, the IRB approved protocol, and informed
0105
 1   consent document need to be modified in any way, given
 2   the nature of the event.
 3               Any adverse events or group of adverse
 4   events that result in suspension or termination of IRB
 5   approval of research must be promptly reported.  It is
 6   important to note when thinking about unanticipated
 7   problems and their relationship to adverse events, not
 8   all adverse events -- and as I've said, probably a
 9   minority -- represent unanticipated problems involving
10   risk to subjects.  However, conversely, not all
11   unanticipated problems involving risk to subjects or
12   others are adverse events.
13               Again, to emphasize to whom must be
14   reported, when an adverse event does fall into one of
15   these reportable  categories, they need to be reported
16   to the IRB, appropriate institutional officials, the
17   head of the supporting department or agency or their
18   designee, and OHRP.
19               What is the time frame for reporting?  The
20   only word we have in the regulations is prompt or
21   promptly.  The time frame is otherwise not specified,
22   but prompt generally means, certainly, sooner than
0106
 1   never.
 2               In conclusion, let me just -- The take-
 3   home points I'd like to leave you with is, number one,
 4   the HHS regulations again do not have provisions that
 5   specifically reference adverse events.  The HHS
 6   regulations do reference unanticipated problems
 7   involving risk to subjects or others, and unexpected
 8   serious harm to subjects.
 9               Under our regulations, only a minority of
10   adverse events occurring in subjects must be reported
11   to the IRB, the agency heads, appropriate
12   institutional officials in our office; and from our
13   perspective, ensuring that serious unanticipated or
14   unexpected adverse events are reported is most
15   important to our office.  Thank you.
16               CHAIRMAN PRENTICE:  Thank you, Mike. 
17   David.
18               DR. LEPAY:  Okay, very good.  What I am
19   going to try to do in the next 15 minutes or so is run
20   through FDA's fairly comprehensive series of
21   regulations dealing with -- It's not going to work, is
22   it?  Let's just hold that -- dealing with adverse
0107
 1   event reporting and review.
 2               What I would like to cover -- I need to
 3   make at least brief mention of the concept of good
 4   clinical practice, because that overrides all of our
 5   regulations -- it is a common theme among them; some
 6   of the definitions about what must be collected in
 7   clinical trials, FDA regulated clinical trials; who
 8   reviews what in this scheme; and who reports to whom
 9   and when.
10               As I stated, I think the overarching theme
11   in FDA's regulation of clinical research is the
12   concept of good clinical practice.  Our regulations
13   are rooted in this concept, and what we are talking
14   about here is fundamentally a system of shared
15   responsibilities among all those that we regulate that
16   are participants in the research process.
17               That is clinical investigators.  We have
18   direct authority over clinical investigators,
19   institutions and institutional review boards, as we
20   share that with OHRP.  They are in the area of
21   Federally funded research, ours in the area of FDA
22   regulated research.  
0108
 1               We have direct authority over industry
 2   sponsors and monitors of clinical trials and, as well,
 3   GCP is built on the concept that regulators also have
 4   responsibilities in this scheme.
 5               I think it is important to note that, of
 6   course, good clinical practice standards are becoming
 7   more and more worldwide.  We have began an initial
 8   harmonization process with developed countries, the
 9   European Union, and Japan, but GCP has been embraced
10   very widely, and the WHO has its own GCP guidelines
11   that are currently undergoing revision at this
12   particular time.  We are part of that process.
13               I want to also say a couple of things in
14   using the term shared responsibilities.  Each of these
15   groups under FDA regulations has discrete regulatory
16   responsibilities.  There is some redundancy in the
17   system, and largely that redundancy is built in, in
18   the areas of greatest risk.  That is risk to subjects
19   or risk to FDA's application review process.  Of
20   course, safety reporting does carry with it risks to
21   both.
22               A very brief reminder about FDA and
0109
 1   clinical research.  I think these are concepts well
 2   known to everyone here.  We are regulators of clinical
 3   research.  There is very little research that is
 4   funded or conducted by FDA.  Our approach is not based
 5   on an assurance system, but rather an approach based
 6   on regulation, commitments, including investigator
 7   commitments that must be signed to in a 1572, and a
 8   system of inspections.
 9               For us, the principal point of contact and
10   the principal control point is the study sponsor,
11   although, clearly, we do have direct regulatory
12   authority over clinical investigators and IRBs. 
13   Generally, our point of contact and our control point
14   is not at the institution level, although our
15   regulations are also written to embrace both IRBs and
16   institutions.
17               Now there's a great deal of data that is
18   collected in a clinical trial, and why is this?  Well,
19   in fact, it is to serve two protection purposes.  One
20   is the protection of subjects who are participants in
21   that clinical research.  The other is our broad public
22   protection mission.  
0110
 1               At the end of the day, we have to be able
 2   to use that data, including that safety data, to make
 3   decisions that broadly affect the public about
 4   approvals of products, about their labeling, and in
 5   some cases about their promotion.  
 6               So indeed the information that is being
 7   collected has multiple purposes beyond the protection
 8   of subjects in that individual trial.  
 9               Among the things collected are adverse
10   events, serious adverse experiences, unexpected
11   adverse experiences, a requirement to collect overdose
12   information, information about pregnancy during the
13   trial, as well as information that is relevant to the
14   specific protocol, project-specific data that will
15   help establish -- that is used in developing
16   endpoints, also help to establish the safety and
17   efficacy of that product, vital signs, laboratory
18   data, ECG, special tests, and so forth.
19               Our regulations do not explicitly define
20   the term adverse event, although it is used in most
21   cases where the definition exists.  It is usually
22   prefaced by some qualifier, serious adverse
0111
 1   experience, unexpected adverse experience.  But we do
 2   have a definition within the internationally
 3   recognized guidelines, the ICH E2a guidance which we
 4   are party of.  So this is harmonized between the U.S.,
 5   the European Union, and Japan, and this is the
 6   definition of an adverse event here under FDA's
 7   purview.
 8               In fact, as I say, it includes any
 9   untoward medical occurrence in a patient or subject 
10   administered a pharmaceutical product.  It does not
11   necessarily have to have a causal relationship with
12   the treatment.  It can be any unfavorable and
13   unintended sign, which can include laboratory
14   findings, symptom or disease temporally associated,
15   but again not necessarily related to the medicinal
16   product.  So this is the information that will be
17   collected quite generally within clinical trials.
18               Of note as we start to get into the issue
19   of prompt reporting and IRB reporting in many cases is
20   the serious adverse experience, and that is also
21   fairly well defined in regulation.  Again, this is
22   from regulation.  
0112
 1               It is any adverse experience at any dose
 2   that results in any of the following outcomes, and you
 3   can see the list here.  These are clearly serious
 4   issues:  Death, a life threatening condition,
 5   inpatient hospitalization, disability, incapacity,
 6   congenital anomalies, as well as the ability to
 7   embrace adverse events in the view of the investigator
 8   or others are judged serious by medical standards.
 9               The second regulatory definition we need
10   to go through very quickly is unexpected adverse
11   events.  The definition here from the regulations is
12   any adverse experience, the specificity or severity of
13   which is not consistent with the current investigator