1

          1   Department of Health and Human Services

          2   

          3   

          4               Meeting of the

          5     NATIONAL HUMAN RESEARCH PROTECTIONS

          6         ADVISORY COMMITTEE (NHRPAC)

          7   

          8            Monday, July 30, 2001

          9   

         10   

         11   

         12   

         13   

         14   

         15   

         16            The DoubleTree Hotel

         17             1750 Rockville Pike

         18          Rockville, Maryland 20852

         19   

         20   

         21   

         22   


                                                                        2

          1                            A G E N D A

          2   

          3   Monday, July 31, 2001

          4   

          5   8:30-8:45      Department of Health and Human

          6                  Services & Human Subject Protections

          7                  Arthur Lawrence, Ph.D.

          8                  Acting Principal Deputy Assistant

          9                  Secretary for Health

         10   

         11   8:45-9:15      The Perilous Intersection of

         12                  Protecting Human Research Subjects and

         13                  Conflicts of Interest

         14                  Michael Wood, M.D.

         15                  President and CEO, The Mayo Foundation

         16   

         17   9:15-9:30      WELCOME:  Overview of Meeting

         18                  Mary Faith Marshall, Ph.D.

         19                  Chairperson, NHRPAC

         20   

         21   

         22   


                                                                        3

          1   9:30-10:30     Final Review & Approval of NHRPAC

          2                  Response to Financial Relationships

          3                  Mark Barnes, J.D.

          4                  Chairperson, Working Group

          5   

          6   10:30-12:30    Update:  Children's Workgroup

          7                  Alan Fleischman, M.D.

          8                  Chairperson, Working Group

          9   

         10   10:15-10:30    BREAK

         11   

         12   12:00-1:30     LUNCH (On your own)

         13   

         14   

         15   

         16   

         17   

         18   

         19   

         20   

         21   

         22   


                                                                        4

          1   1:30-3:30      The Office for Human Research

          2                  Protections (OHRP)

          3                  Introduction

          4                       Greg Koski, Ph.D.,M.D.

          5                       Director, OHRP

          6                  Education

          7                       Jeffrey Cohen, Ph.D.

          8                       Director, Division of Education

          9                  Assurance

         10                       George Gasparis, Acting Director

         11                       Division of Assurances and Quality

         12                       Improvement

         13   

         14   

         15   

         16   

         17   

         18   

         19   

         20   

         21   

         22   


                                                                        5

          1                     A G E N D A - (Continued)

          2   

          3   1:30-3:30      OHRP

          4                  Compliance

          5                       Kristina Borror, Ph.D.

          6                       Division of Compliance

          7                  International

          8                       Melody Lin, Ph.D., Deputy Director

          9                       and Director, Office of Policy and

         10                       Planning, and Special Projects

         11                  Policy

         12                       Irene Stith-Coleman, Ph.D.

         13                       Director, Office of Policy, and

         14                       Planning, and Special Projects

         15   

         16   3:30-3:45      Break

         17   

         18   3:45-4:30      Update and Discussion:  Third Parties: 

         19                  Research Subjects?

         20                  Mary Kay Pelias, J.D., Ph.D.

         21                  Chairperson, Working Group

         22   


                                                                        6

          1   4:30-4:45      Closing Comments/Adjourn

          2                  Mary Faith Marshall, Ph.D.

          3   

          4                         ROSTER OF MEMBERS

          5   

          6   MARY FAITH MARSHALL, Ph.D., Chairperson, Director

          7   of Program in Bioethics, University of Kansas

          8   Medical Center 

          9   

         10   GREG KOSKI, Executive Secretary, Ph.D., M.D.,

         11   Director, Office of Human Research Protections,

         12   Office of Public Health and Science, OS

         13   

         14   MARK BARNES, J.D., LL.M., Partner, Proskauer Rose

         15   LLP

         16   

         17   MS. MARGARET BORWHAT, President, Women's Cancer

         18   Advocacy Network 

         19   

         20   SANFORD CHODOSH, M.D.

         21   

         22   


                                                                        7

          1   ELLIOT N. DORFF, Ph.D., Rector, Distinguished

          2   Professor of Philosophy, University of Judaism

          3   

          4   ALAN R. FLEISCHMAN, M.D., Senior Vice President,

          5   The New York Academy of Medicine

          6   

          7   JENNIE R. JOE, Ph.D., M.Ph.H., R.N.

          8   Professor, Family and Community Medicine

          9   Director, Native American Research and Training

         10   Center, University of Arizona

         11   

         12   SUSAN Z. KORNETSKY, M.P.H., C.I.P., Director,

         13   Clinical Research Compliance, Department of

         14   Clinical Investigation 

         15   

         16   FELICE J. LEVINE, Ph.D., Executive Officer,

         17   American Sociological Association

         18   

         19   ROBERT LEVINE, M.D., Professor of Medicine, Yale

         20   University School of Medicine 

         21   

         22   


                                                                        8

          1   ABBEY S. MEYERS, President, National Organization

          2   for Rare Disorders

          3   

          4   JONATHAN D. MORENO, Ph.D., Emily Davie and Joseph

          5   S. Kornfeld Professor of Biomedical Ethics,

          6   Director, Center for Biomedical Ethics, University

          7   of Virginia Health System

          8   

          9   MARY Z. PELIAS, Ph.D., J.D., Professor, Department

         10   of Genetics, Louisiana State University Health

         11   Sciences Center 

         12   

         13   Roster of Members (Continued)

         14   

         15   ROBERT R. RICH, M.D., Executive Associate Dean of

         16   Research, Emory University School of Medicine

         17   

         18   ADIL E. SHAMOO, Ph.D., Professor, Department of

         19   Biochemistry and Molecular Biology, University of

         20   Maryland School of Medicine 

         21   

         22   


                                                                        9

          1   JUDITH L. SIEGEL, Ph.D., Vice President, Head U.S.

          2   Clinical Operations, Hoffman-La Roche, Inc.

          3   

          4   DENYSE THORNLEY-BROWN, M.D., Assistant Professor,

          5   Division of Nephrology, University of Alabama at

          6   Birmingham

          7   

          8   KATE-LOUISE GOTTFRIED, J.D., M.S.P.H., Executive

          9   Director, National Human Research Protections

         10   Advisory Committee

         11   

         12   EX-OFFICIO MEMBERS

         13   

         14   Dr. James Shelton, USAID

         15   Dr. Maryann Danello, CPSC

         16   Dr. Joseph Spence, USDA

         17   Ms. Linda Beth Schilling, USDOC

         18   Mr. Tryn Stimart, Alternate

         19   CDR Douglas Forcino, DOD

         20   Ms. Blanca Rosa Rodriguez, DOED

         21   Dr. Susan L. Rose, DOE

         22   


                                                                       10

          1   Dr. Dixie Snider, DCD, DHHS

          2   Dr. David A. Lepay, FDA, DHHS

          3   Dr. Belinda Seto, NIH

          4   Alan Sandler, D.D.S., NIH

          5   Dr. Francis D. Chelsey, Jr., Healthcare Research

          6   Dr. Paul Gatons, DHUD

          7   Dr. Donald Prosnitz, DOJ

          8   Mr. Thomas G. Raslear, DOT

          9   E. Donald Sussman, Alternate

         10   Dr. John H. Mather, DVA

         11   Joan Porter, D.P.A., MPH, Alternate

         12   Mr. Roger S. Cortesi, EPA

         13   Dr. Richard S. Williams, NASA

         14   Dr. Philip Rubin, NSF

         15   Mr. Howard L. Bradley, SSA

         16   

         17   

         18   

         19   

         20   

         21   

         22   


                                                                       11

          1                       P R O C E E D I N G S

          2                                       [Time noted:  8:40 a.m.]

          3             CHAIRPERSON MARSHALL:  Good morning and

          4   welcome all committee members, our ex-officio

          5   members, our visitors and public members.  I am

          6   Mary Faith Marshall and I chair the National Human

          7   Research Protections Advisory Committee.  Many of

          8   you are friends and acquaintances.

          9             Let me just say to those of you who have

         10   not attended one of our meetings before that, we

         11   will allow during the course of the day and the

         12   course of our meeting ample time for any and for

         13   all to speak.

         14             Our agenda to set up differently perhaps

         15   than another meetings you may have attended in the

         16   past, other FACA meetings, in that we allow the

         17   same amount of time for committee members, ex-

         18   officio members and members of public to speak

         19   about the issues at hand.

         20             I would like to welcome all of you and it

         21   is a special honor and privilege to welcome Dr.

         22   Arthur Lawrence who is the Acting Principal Deputy


                                                                       12

          1   Assistant Secretary for Health at the Department of

          2   Health and Human Services and human subject

          3   protections.

          4             Those of us who sit on the Committee know

          5   him well.  He has appointed each of us to this

          6   Committee and has been instrumental in the founding

          7   of the National Human Research Protections Advisory

          8   Committee and the Office for Human Research

          9   Protections and has been a stalwart -- to me as the

         10   Chair of the Committee and to Kate as the Executive

         11   Director to Greg Koski as the Executive Secretary

         12   of the Committee and also as the Director of the

         13   Office for Human Research Protections.

         14             Art, we thank you so much for all of your

         15   guidance in the past and for your support and we

         16   are honored to have you here with us today.

         17             [Applause.]

         18             DR. LAWRENCE: [Off mic.]  I don't need

         19   microphone   [inaudible] -- will argue --

         20             It is a pleasure to be here -- 

         21             Also the folks who are sitting in the

         22   audience because in fact the greater community will


                                                                       13

          1   not benefit from research in advancing human

          2   medicine and in human knowledge unless we can

          3   assure individuals as they participate in trials

          4   that they are protected to the maximum extent.

          5             This is very, very much an Exdionian

          6   community activity.  The folks in the community may

          7   not understand it, but when I go to places like my

          8   hometown in New Hampshire that probably doesn't

          9   have but maybe one trial going on in a small part

         10   of the town, I try to explain to them the

         11   importance of this sort of -- extend my thanks to

         12   the Committee because they are taking on such tough

         13   issues.

         14             These are issues that need to be discussed

         15   the public which need to be discussed at a high

         16   level and they need to be discussed in the public

         17   interest.  And they are tough.

         18             These are not easy issues.  I once had

         19   somebody tell me that a certain advisory committee

         20   which was set up in the late '80s was going to deal

         21   with all the tough issues up front, but I have yet

         22   to see that committee deal with any issues that


                                                                       14

          1   wasn't tough.  So this takes an awful lot of

          2   people's time, it takes people away from their

          3   children and their family.  And I would extend on a

          4   personal note saying that I give personal thanks

          5   because both my daughter and I at one time or

          6   another have been human subjects.

          7             I appreciate what this committee does and

          8   I appreciate the advice that it is giving us and

          9   the public health service and the department and I

         10   look forward to a bright future for the committee

         11   as it moves forward through human subjects

         12   protection in the United States.

         13             So let me now just slink away and go argue

         14   for some money.  Once again thank you very much and

         15   the best to you all. 

         16             [Applause.]

         17             CHAIRMAN MARSHALL:  We apologize for the

         18   feedback problem.  I think they're trying to work

         19   on it and I know it is irritating.  So I hope that

         20   it would disappear soon.

         21             We do have a very full agenda for the next

         22   two days.  We have been working hard and we have a


                                                                       15

          1   lot work to do.   So I am going to forego my usual

          2   housekeeping remarks unless something comes up

          3   within the context except to remind all of us that

          4   we should be thoughtful in terms of what we have to

          5   say, we should be stewards of our time and others'

          6   time and please do not hold back in terms of things

          7   that are important that need to be put on the table

          8   and that need to be said relative to the protection

          9   of human research subjects and conflicts of

         10   interest.

         11             I'm now very glad to introduce to you Dr.

         12   Michael Wood.  Dr. Wood is the president and CEO of

         13   the Mayo Foundation.  He is going to speak to us

         14   this morning on the perilous intersection of

         15   protecting human research subjects and conflicts of

         16   interest.  And it will be, I think, a beautiful

         17   segue into the work that we have been doing on

         18   financial relationships.

         19             Welcome, Dr. Wood.

         20             [APPLAUSE.]

         21             DR. WOOD:   Thank you, Mary Faith.

         22             Good morning everyone.  I think we will be


                                                                       16

          1   able to get started here right away as soon as we

          2   get our visuals all set up.  It is always a little

          3   bit of the risk with PowerPoint.

          4             You can all gather around the computer

          5   here and we will move on.

          6             Here we go, relief is on the way.

          7             CHAIRPERSON MARSHALL:  These multi-

          8   talented OHR people.  It's a real teacher.

          9             DR. WOOD:  Well, again, good morning.  I

         10   hope everyone got here all right with the rain and

         11   all that.  It seems like a pleasant summer in

         12   Washington.  I also appreciate the opportunity to

         13   be here and spend a few minutes with you talking

         14   about what I think is a very important subject for

         15   the medical profession today.

         16             Medical discoveries and exciting new

         17   advancements are progressing very rapidly; if one

         18   just considers between the bronze age and the

         19   1900s, man's life expectancy increased 27 years. 

         20   And then between 1900 and 2000 yet another 27 years

         21   was an added to the average life expectancy.

         22             Many are expecting predicting frequent,


                                                                       17

          1   perhaps routine, life spans beyond age 100 in the

          2   next generation or two with functionality of middle

          3   age developed by today's standards.  This is not

          4   particularly good news for pension benefits

          5   managers.  But it might be just what the doctor

          6   ordered for our children are grandchildren.

          7             In the last few years especially, advances

          8   in information technology and enacting of the human

          9   genome have opened a portal for advancement in

         10   medicine unrivaled since the discovery of

         11   penicillin and this comparison may in fact be an

         12   underestimation.

         13             All of these advances are creating

         14   unprecedented opportunities for scientists and

         15   inventors who are often funded by public monies. 

         16   They can become highly successful entrepreneurs who

         17   have loyalties, licensings of intellectual property

         18   and actually been founders in start-up companies.

         19             Well, why is this a relatively new subject

         20   of discussion?  Some might argue that is not a new

         21   subject and to support this position let us

         22   consider the position of Dr. Benjamin Waterhouse,


                                                                       18

          1   one of three, full-time professors at Harvard

          2   Medical School in 1799.

          3             Dr. Waterhouse learned of generous

          4   observations about the efficacy of cowpox

          5   vaccinations for smallpox through generous written

          6   reports to the royal college.  Waterhouse proposed

          7   to test the vaccine in Boston by a clinical study

          8   which included his own children and 19 others who

          9   were then exposed to smallpox.

         10             If successful he proposed to develop a

         11   monopoly to inoculate New England children for a

         12   fee.  His clinical trial was successful.  None of

         13   the children, and most especially his own,

         14   contracted smallpox.

         15             I cannot tell you what his wife had to say

         16   about all of this, but his two colleagues at

         17   Harvard Medical School perceived his proposal as

         18   most reckless and self-serving.  As a result, Dr.

         19   Waterhouse was expelled from Harvard in 1812

         20   despite President Thomas Jefferson dubbing

         21   Waterhouse as the founding father of vaccination in

         22   this country.


                                                                       19

          1             And to my knowledge, his vaccine monopoly

          2   never materialized been no fees of any lasting

          3   substance derived to him. 

          4             Beyond this example, perhaps one of the

          5   major reasons why entrepreneurs in medicine was not

          6   a frequent or comfortable mix.  Prior to World War

          7   II most, if not all, medical research funding came

          8   from internal forces.  Universities through

          9   tuitions, some private philanthropic foundations,

         10   and the practice revenues from academic medical

         11   institutions.

         12             Moreover, societal expectations for

         13   academics and medical researchers were different. 

         14   A strong assumption of altruistic motives.

         15             Following World War II, building for the

         16   military infrastructure, public funding became

         17   accepted and perhaps even expected by society as a

         18   source of funding for medical research to benefit

         19   society.

         20             Thus, the National Institutes of Health

         21   became ever more important as a catalyst for

         22   medical research and was supplemented by


                                                                       20

          1   increasingly relevant participation of private

          2   foundations.

          3             If one considers the response by Jonas

          4   Salk when asked, "who owns the right to his polio

          5   vaccine discovery?"  His answer was, "well, the

          6   people I would say."  There is no problem -- this

          7   was clear recognition that public funding supported

          8   his research.

          9             By the 1970s, the ability of tax payers

         10   and philanthropic organizations to keep up with the

         11   appetite for research and the rapid pace of

         12   discovery brought on by Sputnik and the space race

         13   was stretched to the limit.  At this time revenues

         14   from patient care began a downwards trajectory and

         15   American competitiveness was being challenged by

         16   international manufacturers.

         17             In the 1960s and 1970s, there was much

         18   study surrounding federal patent policy.  There

         19   seemed to be a lack of success by the federal

         20   government in promoting the adoption of new

         21   technology by industry.

         22             For many reasons there was very limited


                                                                       21

          1   flow of government funded inventions to the private

          2   sector.  In 1980, the federal government held title

          3   to about 28,000 patents.  Fewer than 5 percent were

          4   licensed to industry for development of commercial

          5   products. 

          6             In 1980, there were approximately only 25

          7   to 30 universities actively engaged in the

          8   patenting and licensing of inventions.

          9             At least in part, this led to the passage

         10   of the Bayh-Dole Act in 1980 which was an overt

         11   effort to stimulate translation of American

         12   scientific discovery to successful commercial

         13   activities.

         14             In a nutshell, the Bayh-Dole Act gave a

         15   grantee and his or her contractor organization,

         16   perhaps, for example, a university or a hospital

         17   title to inventions resulting from federal research

         18   funding.  With that title came the happy prospect

         19   of sharing in any royalties resulting from

         20   patenting the invention.  And, indeed, it appears

         21   that the Bayh-Dole Act has been quite effective in

         22   accomplishing its intended purpose.


                                                                       22

          1             Academic institutions were granted more

          2   than 8,000 U.S. patents between 1993 and 1997. 

          3   More than 2,200 companies had been formed since

          4   1980 based on the licensing of an invention from an

          5   academic institution.

          6             Approximately $30 billion in annual

          7   economic activity supporting 250,000 jobs can be

          8   attributed to the commercialization of new

          9   technologies from academic institutions.  There are

         10   more than 1,000 products currently on the market

         11   based on university licensed discoveries.  It is

         12   estimated that 70 percent of the active licenses

         13   are in the life sciences, yielding products and

         14   processes that diagnose disease, reduce pain and

         15   suffering, and save lives.

         16             The number of university-generated patents

         17   has increased from approximately 250 per year prior

         18   to the Bayh-Dole Act to more than 4,800 and more

         19   than 3,000 licenses in 1998.

         20             Along with this, since 1980, industry

         21   support for medical research has greatly increased. 

         22   And has in many disciplines taken over as a


                                                                       23

          1   dominant funding for clinical research trials.  If

          2   one reduces this to hard dollars, in 1999, clinical

          3   research funding from industries totaled $9

          4   billion.  While that from government was about half

          5   of this or 5 billion.  At this is not because of a

          6   shrinking government support.

          7             Indeed, since 1995, the NIH budget has

          8   gone up 57 percent through generous taxpayer

          9   support and by 2003 is projected to double from its

         10   1995 level to $27 billion.

         11             As far his clinical drug trials, industry

         12   provides an estimated 70 percent of funding.  One

         13   might say, so what is the problem with industry

         14   support?  Isn't all the money green?  It certainly

         15   is not an unreasonable question to raise and in the

         16   same vein some logical questions come forth from

         17   our commercial partners in this somewhat

         18   tempestuous married.

         19             For example, if a commercial firm should

         20   fund a piece of research, is it not reasonable to

         21   expect a return on investment?  What control should

         22   a company have on the research?  Should the company


                                                                       24

          1   have the right to suppress or embargo publication,

          2   or unexpected, or worse yet, adversarial results,

          3   if they funded it?  And if the results are indeed

          4   promising, and particularly if they may have the

          5   major impact on public health, does a commercial

          6   firm, as the funding company, have exclusive rights

          7   to the intellectual property?

          8             And should researchers funded by a company

          9   be expected to endorse the company's products

         10   either directly or indirectly?

         11             All of this leads us to another question

         12   and that is, is entrepreneuralism in medicine

         13   really an issue that can in any way harm society or

         14   the public at large?

         15             One way to get an answer to this question

         16   is to observe what makes the front page of

         17   newspapers.  The Wall Street Journal, January 30th

         18   of this year, in one front-page header, "Adroit

         19   Scientists Aid Biotech Company With Taxpayer

         20   Money."  This article cited examples of multiple

         21   NIH grant awardees owning a substantial stake in a

         22   commercial firm which owned exclusive rights to all


                                                                       25

          1   discovery.  Often these commercial firms were in

          2   the same facility as the research laboratory.  And

          3   a few months ago the front page of the USA Today,

          4   February 26, '01, both physician and university

          5   stand to gain without informed consent.

          6             Another fairly recent example that caught

          7   the attention of the press, Sandoz Pharmaceuticals

          8   now in Novartis signed an agreement with a very

          9   well-known American medical research institute the

         10   right $300 million in funding in return for the

         11   institute giving the company first option to

         12   license the institute's biomedical research,

         13   including that funded by public monies from the

         14   NIH. 

         15             Ultimately, because of public outcry, and

         16   NIH objections, the Institute was forced to

         17   scaleback, but not terminate, the agreement.

         18             Are there, in fact, some examples of

         19   problems or improprieties that have resulted from

         20   scientific misconduct whether related to

         21   entrepreneuralism or not?  There are.  Just to name

         22   a few:  the Tuskegee Syphilis Study, an example of


                                                                       26

          1   scientific misconduct, not entrepreneurial

          2   misconduct.  It started in 1932, half of a group of

          3   men with known syphilis were treated with

          4   penicillin and half were not.  Neither with

          5   informed consent.  By 1947 the efficacy of

          6   penicillin for treatment of syphilis was well

          7   confirmed and was indeed the standard treatment.

          8             Despite this, the natural history of

          9   untreated syphilis, and 399 people was kept under

         10   study without treatment until 1972 when the study

         11   was exposed at terminated.  At no time were the

         12   participants informed of their treatment options or

         13   even whether they were being treated.

         14             Another the Willowbrook Home Study; this

         15   study involved in known exposure of mentally

         16   retarded children in a New York institution to

         17   hepatitis virus to test the efficacy of a newly

         18   developed hepatitis vaccine.  Patients and parents

         19   were neither informed of the study nor offered the

         20   opportunity to decline participation.

         21             There also is objective evidence that

         22   financial incentives can influence medical


                                                                       27

          1   judgment.  A study by Schren and Landafield [ph]

          2   suggested that physicians who requested that

          3   specific drugs be added to the hospital formulary

          4   were more than ten times as likely as their

          5   colleagues to have received financial support from

          6   the pharmaceutical manufacturers.

          7             Votenheimer [ph] reported that industry-

          8   supported drug trials are more likely to favor a

          9   study drug over conventional therapy than is the

         10   case for nonindustry-supported trials.  Quotron and

         11   Barrel, in separate studies, showed that when a

         12   scientist has a financial interest or funding by a

         13   company related to his or her research activity,

         14   the resulting research is lower in quality and more

         15   likely to favor the sponsor's product.

         16             So what are the issues at hand?  Is it

         17   simply a matter that the insulation between medical

         18   discovery commercialization has grown thin?  Or has

         19   this thick asbestos firewall disappeared between

         20   academic science for the sake of science and the

         21   opportunity for individuals to achieve personal

         22   wealth to act as commercialization of their


                                                                       28

          1   intellectual productivity.  And most important how

          2   can public trust in the medical profession be

          3   sustained or in some cases restored?

          4             Without appropriate policies and

          5   procedures, according to Dr. Kathryn DeAngeles, JMA

          6   editor, the academic institutions where most

          7   clinical research is based, and their faculty

          8   members who perform the research, are in grave

          9   danger of losing the support and respect of the

         10   public.  Without this support and respect, trust in

         11   new medical discoveries and their applications will

         12   not be forthcoming.  Without trust medical research

         13   is doomed.

         14             And the trust we are talking about is not

         15   only from patients, but also from regulatory

         16   agencies, legislative bodies, academic partners,

         17   and research sponsors.

         18             To ensure this trust three significant

         19   issues are receiving attention in the medical

         20   scientific community.  The presence or absence of

         21   conflict, either conflict of commitment or conflict

         22   of interest, the ethical mandate of full


                                                                       29

          1   disclosure, and the importance of informed consent

          2   for all human studies.

          3             I would like to comment on all three of

          4   these topics and how these three topics represent

          5   the minimum standards for contemporary ethical,

          6   conduct in medical research.  Let us focus first of

          7   all on conflict of interest in science.  Few topics

          8   may evoke more subjectivity in interpretation but

          9   most interpretations challenge the notion of

         10   objectivity in pure science.

         11             Conflicts may be individual in context,

         12   that related to personal and individual advantage;

         13   or institutional when they favor the objective of a

         14   group.

         15             One might encounter the institutional

         16   conflicts in instances of equity ownership in a

         17   biotech company by a university hospital or

         18   company.  This issue has been in the news in recent

         19   months in regards to a very well-known and

         20   respected university campus center involving the

         21   institution as a whole and a number of their

         22   investigators.


                                                                       30

          1             And as recently as this month the editors

          2   of the Journal of the American Medical Association

          3   announced a more specific and more stringent policy

          4   for reporting offers, financial conflicts of

          5   interest, and a new policy reporting relationships

          6   between investigators and research sponsors.

          7             There is not universal agreement about the

          8   definition of "conflict of interest."  In most

          9   cases it denotes a situation rather than an act or

         10   behavior that is a potential problem rather than a

         11   done deed.

         12             Jordan Cohen, President of the American

         13   Medical Association of Medical Colleges, defined

         14   "conflict of interest" as follows:  a conflict of

         15   interest exists whenever an individual or an

         16   institution has a primary allegiance that requires

         17   certain actions and simultaneously has a secondary

         18   interest that could abrogate the primary allegiance

         19   and the sufficient attempting to raise a reasonable

         20   possibility that it might actually do so.

         21             In other words, a situation where one's

         22   judgment about what is best for an individual


                                                                       31

          1   patient could be hindered.

          2             Conflicts may be real or perceived and may

          3   be financial or non-financial.  Most people and the

          4   public tend to think in terms of financial

          5   conflicts of interest because it is quantifiable

          6   and it is easy for most people to relate to.

          7             Conflicts might also be in appearance

          8   only; and these too can be quite serious.  In fact,

          9   in most cases it is the appearance of conflict that

         10   may inflict a devastating blow on the medical

         11   profession in terms of public trust.  A recent

         12   example of this might be illustrated by the highly

         13   publicized case of Jesse Gelsinker, [ph] the 18-

         14   year-old boy who died in 1999 from complications of

         15   an experimental gene therapy program at one of this

         16   country's leading medical schools.

         17             It was only later that his family and the

         18   public learned that the doctor running the clinical

         19   trial had in equity interest in the biotech company

         20   sponsoring the trial.  Conflicts in some cases can

         21   be avoided but in some cases this is not possible.

         22             Dr. David Korn, Senior Vice President of


                                                                       32

          1   the Association of American Medical Colleges has

          2   written, "that conflicts of interest are ubiquitous

          3   and inevitable in academic life."  Indeed, in all

          4   professional life.  The challenge for academic

          5   medicine is not to eradicate them, but to recognize

          6   and manage them sensibly and effectively.  Thus,

          7   mitigation, rather than avoidance, is often what is

          8   required when dealing with conflicts.

          9             One of the ways to mitigate conflict, and

         10   in many instances to minimize the development of

         11   conflicts, is to require full disclosure of any

         12   secondary interest from anyone in a position of

         13   public or institutional trust.  This, in fact, is a

         14   condition of employment for 55 percent of the major

         15   biomedical research institutions in this country as

         16   of 1999 and is increasingly regarded as a minimum

         17   requirement to safeguard ethical behavior.

         18             Disclosure should be to colleagues,

         19   students, and certainly patients, and should be

         20   included in consent forms, publications, and

         21   presentations regarding specific research. 

         22   Disclosure should also address both individual and


                                                                       33

          1   institutional conflicts.

          2             In most cases, disclosure is required of

          3   any relations or transactions that involve money,

          4   tangibles of value, for example, gifts, equity in a

          5   company, even if of little current value, support

          6   for researcher education, and other perks; for

          7   example, tickets for sporting events, receptions,

          8   et cetera.

          9             At times, depending upon the human risk

         10   level, disclosure alone is insufficient, and other

         11   measures such as subject-by-subject external review

         12   or actual divestiture of interest is more

         13   appropriate.

         14             The final issue that I would like to

         15   discuss that is increasingly challenging public

         16   trust in medical research is the adequacy of

         17   informed consent for his human studies.  This is

         18   something that affects all of us.  It acknowledges

         19   our society's respect for an individual's

         20   prerogative to opt in or to opt out of unproven

         21   treatments.

         22             Let me briefly review some of the history


                                                                       34

          1   leading up to our present informed consent policies

          2   in this country.  In the 1960s the U.S. Food, Drug,

          3   and Cosmetic Act amendment was passed which

          4   mandated that people must consent to participate in

          5   experimental therapy.  This was prompted by some

          6   anecdotal but egregious examples of the use of

          7   experimental and unproven therapies on people

          8   without adequately informing them of the context. 

          9   Probably the most notable among these is the high

         10   incidence of upper limb abnormalities in babies of

         11   pregnant women taking thalidomide.

         12             In 1967, the FDA policy clarified that

         13   informed consent for clinical studies must be in

         14   writing.  In the 1970s, the National Commission for

         15   the Protection of Human Subjects of Biomedical and

         16   Behavioral Research was established.  In part, a

         17   direct result of the Tuskegee study previously

         18   discussed.  The national commission recommended

         19   that all institutions engaged in biomedical

         20   research establish an institutional review board to

         21   review all studies involving human subjects.

         22             This was followed in 1972 by the


                                                                       35

          1   establishment of the Office of Protection from

          2   Research Risks within NIH to monitor the safety of

          3   all clinical studies funded by NIH.  And just in

          4   June of 2000, the Office of Human Research

          5   Protections was established as part of HHS, which,

          6   of course, is related to why we're here this

          7   morning.

          8             Has the mandate for institutional review

          9   boards and the establishment of various offices

         10   within our regulatory agencies taken care of the

         11   problem?  Let me again cite a recent newspaper

         12   article, USA Today, February 26, 2001.  "Great

         13   medical advances have been made but there also have

         14   been costs, increasing scientific misconduct and

         15   patient debts and fully informing human volunteers

         16   of health risks is being eroded in a mad dash for

         17   money and fame."  And just two weeks ago, the

         18   adequacy of informed consent was questioned in the

         19   press relative to the Hexancarnonium induced asthma

         20   study that was associated with the death of a study

         21   participant nearby.  This ultimately led to the

         22   temporary suspension of all federal funding for


                                                                       36

          1   human research at one of the most prestigious

          2   medical universities in this country effective July

          3   19th.

          4             From the regulatory perspective the

          5   mainstay of human studies protection at the present

          6   time must be the Institutional Review Board because

          7   it is the infrastructure in place that can best

          8   accomplish the tests.  There are about 6,000 IRB's

          9   in the U.S.; virtually all medical research

         10   institutions receiving federal funding must have

         11   one or a relationship with one.

         12             The overwhelming majority of these review

         13   boards do an excellent job of protecting patients,

         14   and these fall under the purview of the Office for

         15   Human Research Protections.  However, occasionally,

         16   the decisions and reach of IRB's can fall into a

         17   gray zone which in many cases leads to the dilemma

         18   of unproven research versus offering the latest

         19   potential breakthroughs in clinical care.

         20             In these types of cases it is not an

         21   institutional review board but the treating

         22   physician whose level of honesty and integrity will


                                                                       37

          1   determine if informed consent is required,

          2   appropriate, and fairly presented.

          3             Let me conclude this subject by a quote

          4   from a bioethicist, Dr. Arthur Kaplan of the

          5   University of Pennsylvania.  "Informed consent is

          6   the absolute bedrock of the protection systems."

          7             In summary, we have touched on some of the

          8   issues and challenges that entrepreneurial

          9   opportunities are presenting to the medical

         10   profession.  The balance between professionalism

         11   and blatant capitalism may be hard to titrate,

         12   especially in those fields of great biotechnology

         13   interests.

         14             There are three safeguards that are

         15   presently available and these should be compromised

         16   only with the great caution or concern.  They

         17   include the avoidance or negation of conflicts, the

         18   requirement for full disclosure of secondary

         19   interests, and the uncompromising use of informed

         20   consent for all investigational treatments

         21   presented in an objective and fair manner.  These

         22   are emerging as the minimum standards of ethical


                                                                       38

          1   conduct in the medical profession.

          2             May I finish with a quote from EMJ mail

          3   from 1921.  "Commercialism in medicine never leads

          4   to true satisfaction and maintaining our self-

          5   respect is more precious than gold."

          6             At Mayo Clinic, our primary value

          7   statement is captured in seven words, "the needs of

          8   the patients come first."  If that is the ultimate

          9   goal for all involved, conflicts of related

         10   professional ethical issues can be effectively

         11   managed and the most appropriate choice between

         12   negation or elimination of conflict will likely

         13   become more obvious.

         14             Thank you very much and I will be happy to

         15   answer any questions at this time.

         16             [Applause.]

         17             CHAIRPERSON MARSHALL:  We do, I believe,

         18   have ample time.  So what I would like to do is to

         19   follow our pattern and give the committee some time

         20   for questioning and our ex-officio members and then

         21   our public members.

         22             And first I would like to recognize Dr.


                                                                       39

          1   Fleischman.

          2             DR. FLEISCHMAN:  Dr. Wood, thank you very

          3   much for your presentation.  In a few minutes we're

          4   going to review an interim guidance recommendation

          5   and I wonder if you have had an opportunity to

          6   review that and if you have any wisdom about --

          7   comments about it?

          8             DR. WOOD:  Alan, I have not have the

          9   opportunity review that, but if you want to pick

         10   out any particular hot button items and ask for an

         11   off-the-cuff opinion, I would be happy to do so.

         12             CHAIRPERSON MARSHALL:  Jonathan.

         13             DR. MORENO:  Thank you for that, that was

         14   an excellent summary.  Regarding your three minimum

         15   standard of ethical conduct, I do not think anybody

         16   would disagree with those standards, but putting

         17   them in context of the two incidents that you

         18   mentioned, namely the death at Penn and the recent

         19   death at Hopkins, it's not clear to me that any of

         20   them actually speak to what appears to have

         21   happened in each those cases, let's say what

         22   appears to have happened in the Gelsinger death


                                                                       40

          1   seems to have something to do with inadequate

          2   protection and evaluation of the subject from a

          3   medical point of view.  And in the case of the

          4   Hopkins death, there are allegations that there was

          5   poor preparation on the part of the investigator

          6   with respect to the effect on human subjects of the

          7   drug that was being used in that physiologic study;

          8   whether that is the case or not, I do not know, but

          9   that is what is being said at least.

         10             So what the standards, which are the same

         11   kind of standards that I have urged in my own

         12   talks, are clearly very important with respect to

         13   sustaining public confidence in the system.  Does

         14   it seem to you that there are some perhaps with

         15   respect to these two cases anyway there are some

         16   other problems that might occur that are matters of

         17   human error that are much harder for us to identify

         18   in advance.

         19             DR. WOOD:  Jonathan, I would certainly

         20   agree with the final statement that you made.  I

         21   think the area that is most within our control at

         22   this time really backs up to the issue of public


                                                                       41

          1   trust and I think that although all of us in

          2   dealing with the active treatment of patients

          3   recognize that the potential for pitfalls are

          4   significant in terms of not being able to control

          5   the response in biology, but certainly the

          6   standards by which we move forward and offer

          7   treatment to our patients.  It is something that I

          8   think in recent years has become recognized as more

          9   and more of an issue.  And it is likely that many

         10   of these things will be listed for a long time,

         11   going back to Dr. Waterhouse.

         12             However, with the awareness of the issues

         13   at the present time, it has just ramped up the

         14   standards by which we all must behave and I think

         15   it is clear that we do not do this, and we do not

         16   step up to it, it is going to have devastating

         17   effects on how we interrelate with our patients and

         18   the public.

         19             DR. DORFF:  Are you aware of any other

         20   country that has done this in a way that you think

         21   is better than the way we're doing it?

         22             DR. WOOD:  I think if one turns over all


                                                                       42

          1   the rocks that were -- I would not say that we are

          2   any worse off than any other country.  Indeed, I

          3   think if one really looks into most of our peer

          4   countries, if you will, one might say, aren't we

          5   setting the standards even higher than several?

          6             And I think that unquestionably is going

          7   to be a worldwide issue, but I think this country

          8   has to be the pacesetter in terms of that.  The

          9   rest of the world looks at us, I think, for these

         10   types of protections.  And unfortunately the

         11   converse of that is that the intellectual linkage

         12   that is occurring in this country because of more

         13   liberal standards, if you will, I would not say we

         14   are any worse off than anyone else, but I do think

         15   this country has to be held to a little higher

         16   standard maybe than the rest of the world because

         17   we're looked at for that purpose.

         18             CHAIRPERSON MARSHALL:  Let me just

         19   interject for a moment before I recognize Susan. 

         20   For those of you who are standing in the back,

         21   there are multiple seats on the front row.  So if

         22   you would like to, please come up front.


                                                                       43

          1             DR. KORNETSKY:  Picking up from Alan's

          2   comment that we are now trying to put together a

          3   practical type of guidance for institutions to

          4   think about this and realizing that there are some

          5   institutions that have very sophisticated systems

          6   about thinking about conflicts of interest and

          7   others that don't, from your experience at Mayo,

          8   what works of what does not work?

          9             DR. WOOD:  Well, probably the most

         10   powerful impact of all institutionally is the peer

         11   pressure to do this.  And I think as far as the

         12   actual mechanic stuff, to get to that peer pressure

         13   to be the individual setting the high standards, I

         14   think the most significant advance that we have

         15   done in the last several years in this regard is

         16   actually set up a conflict of interest

         17   subcommittee.  And for many, many years we had a

         18   body known as the Medical Industrial Relations

         19   Committee that has looked at these source of

         20   issues.  But setting up a targeted conflict of

         21   interest subcommittee I think very much puts the

         22   issue right in everyone's face so they can


                                                                       44

          1   understand where conflicts exist.

          2             We started out with this totally as an

          3   internal body and I know many other universities

          4   have done this, but I think even to take it to the

          5   standard that IRBs are at this point, that is

          6   inviting public members -- in fact a committee will

          7   probably the be the next evolution that we will be

          8   undertaking.  But I think this is something that is

          9   well within the control of any university without

         10   establishing a burdensome bureaucracy, if you will,

         11   --

         12             DR. KORNETSKY:  Just a quick follow-up,

         13   your institutional relationship, you are talking a

         14   lot about how this impact IRBs and where

         15   responsibility lies, how does that committee in

         16   interact with the IRB?

         17             DR. WOOD:  Well, it is an independent

         18   committee of the IRB.  And for a couple practical

         19   reasons, I'm not even talk about looking for a huge

         20   amount of detail, but most academic institutions

         21   will have a certain amount of turnover on their IRB

         22   and it is kind of an obligation of faculty members,


                                                                       45

          1   and typically, at least, I find it is not

          2   particularly embraced or welcomed as a diversion to

          3   keep in the UK say have to begin video three nights

          4   before the meetings every week.  But I think what

          5   comes a conflict of interest there are some issues

          6   here that really need some tenure, if you will, and

          7   experience in this.  I think one of the reasons

          8   that we are -- one of the bases and fundamentals at

          9   least in our own subcommittee is to have a group of

         10   people who actually have had for some time to get a

         11   chance to really become wise in their judgments

         12   rather than just knowledgeable.

         13             CHAIRPERSON MARSHALL:  I had Greg Koski

         14   and then Abbey.

         15             DR. KOSKI:  Dr. Wood, since the draft

         16   document that is our interim guidance draft was put

         17   out, we have heard a lot of discussion around the

         18   fact that it breaks new ground in terms of

         19   addressing institutional conflicts of interest and

         20   people repeatedly say, this is a complex area. 

         21   Since you are here before us as someone who leads

         22   one of these big institutions, what is it that is


                                                                       46

          1   so new about institutional conflicts of interest,

          2   that concept, and what do you see as the sort of

          3   major challenges that need to be addressed in terms

          4   of, you know --

          5             DR. WOOD:  Greg, I think one of the major

          6   issues, at least one that we have had some direct

          7   experience with, is the fact that you can have

          8   institutional conflicts coexist without individuals

          9   really recognizing it and the potentiality of

         10   influencing their judgments.  One of the practical

         11   issues that we have been dealing with is how do we

         12   ensure that everybody who is a position to exercise

         13   choice over something actually recognizes the

         14   institutions possible involvement.

         15             I think the other thing is that in the

         16   next decade it is very likely that this becomes

         17   more and more of an issue and I know that you kind

         18   of joined us last March when we had a day of

         19   discussion in this, primarily because I do not know

         20   of any academic institutions that is not trying to

         21   strongly consider what are the acceptable mutual

         22   opportunities between sources of funding and


                                                                       47

          1   creating partnerships with commercial firms to help

          2   have them meet their academic mission.  And at this

          3   point in time, I think just inadequate thought has

          4   been put into how are these actually going to play

          5   out.

          6             And, unfortunately, there are enough

          7   anecdotes out there about how institutions have

          8   become enamored with the source of income and the

          9   potentiality for them to influence their judgment

         10   that the time has clearly come, may be just a few

         11   years late, but better late than never.

         12             So I would like to say on behalf of one of

         13   those academic institutions that we very much

         14   appreciate the work of this committee and your

         15   agents.

         16             CHAIRPERSON MARSHALL:  Abbey.

         17             MS. MEYERS:  One of the issues that we are

         18   wrestling with is whether informed consent

         19   documents should specifically state the dollar

         20   amount -- that an investigator or an institution

         21   should have, or whether there should just be a

         22   generalized statement saying the conflict of


                                                                       48

          1   interest committee has looked into.  At Mayo, in

          2   that informed consent document, does it say -- 

          3             DR. WOOD:  -- informed consent we do not

          4   require the dollar amount between the investigator

          5   and the study participants.  However, we do require

          6   the dollar amount to be revealed through the

          7   conflict of interest subcommittee.  I think we felt

          8   that was a fairly reasonable compromise since the

          9   ability of an individual to get focused on the

         10   dollar amount as opposed to the risks involved, in

         11   fact there is a downside as well as a plus side,

         12   however, the conflict of interest subcommittee I

         13   think they are a body that is used to seeing these

         14   sort of things and are used to weighing that and

         15   understanding, you know, when is that consistent

         16   with, if you will, "the market" for this sort of

         17   intellectual property versus not?

         18             [Sound outage.]

         19             DR. WOOD:  One that is put in language

         20   that the participants can understand, but we have

         21   not gone to the level of detail that you just asked

         22   at that level, rather up the line at the


                                                                       49

          1   institutional review level.

          2             CHAIRPERSON MARSHALL:  I'm going to take

          3   two more questions from committee members.  I have

          4   Sandy and then we will open things up.

          5             DR. CHODOSH:  Dr. Wood, your excellent

          6   presentation really seem to stress the relationship

          7   of academia and industry, and did make one

          8   statement which I think might be in question and

          9   that is pharmaceutical research, I think that there

         10   was more pharmaceutical research now outside of

         11   academia than within academia and I wonder what

         12   your thoughts are about how do we approach those

         13   problems because many more human subjects are being 

         14   involved outside of academia and it seems there's

         15   no control over it and industry has all the

         16   control.

         17             DR. WOOD:  Well, I think you point out

         18   another problem that's right there and I agree,

         19   most of our efforts have been in dealing with how

         20   an institution of a certain size can actually set

         21   its own level of standards, and I do not have the

         22   answer to that.  But I do think that academia needs


                                                                       50

          1   to lead the way.  I think they need to be active

          2   participants in setting the standards and actually

          3   adhering to the standards themselves.  Because I

          4   think the failure to do so will open the

          5   floodgates, if you will, for those more diffuse

          6   areas and particularly for the large clinical

          7   research organizations.

          8             I think if we are successful in getting

          9   strong compliance with our academic community in

         10   this regard, the CROs will certainly feel a

         11   significantly greater degree of pressure to follow

         12   suit.

         13             CHAIRPERSON MARSHALL:  And I hate to ask

         14   you use a microphone, but we are going to

         15   reposition them during the break so they are easier

         16   to access and maneuver towards. 

         17             AUDIENCE PARTICIPANT:  Dr. Wood, I enjoyed

         18   her presentation very much.  I was curious, as a

         19   follow-up to Abbey Meyers' question, you do not

         20   really say very much in your document other than

         21   there is a tangible reward that may accrue to the

         22   physician or the institution, how many people


                                                                       51

          1   actually opt into such as study group -- I'm not

          2   going there.  -- it seems so general that I would

          3   be surprised if anybody dropped out with the kind

          4   of verbiage you mentioned; do they?  Would you join

          5   a study because of that?

          6             DR. WOOD:  I would probably have to give

          7   you a very off-the-cuff type of response to that

          8   that I would admit to you that relatively few

          9   people that I am aware of ever opt out, based on

         10   that.  I think that probably the bigger issue, at

         11   least for us, is how an investigator is viewed by

         12   their peers as they are moving forward here.  It is

         13   certainly my impression that that is the biggest

         14   area of where the standards really are adhered to,

         15   is at the peer interaction.  But I really cannot

         16   give you any information about the actual incidence

         17   of people either not agreeing to participate;

         18   certainly those do exist. 

         19             AUDIENCE PARTICIPANT:  Well, you know,

         20   this thing is true in our institute really, at the

         21   Child Health Institute at NIH, almost no child ever

         22   refuses to join the study no matter what they're


                                                                       52

          1   told.  Because if they do, their brothers go home

          2   and hit them and the next day they come back and

          3   enter the study.

          4             Another question I had, the thing you

          5   ended with, was about the Mayo Clinic and you said

          6   that the patient's needs are primary; that is our

          7   primary goal.  But who in the world determines the

          8   patient's needs?  Is it the patient?  Is it the

          9   family?  Is it the doctor?  Or some researcher that

         10   happens to be passing by the bedside and say, you

         11   need adfixinam, there's no question about it and if

         12   you don't get and join the study, you are in danger

         13   of clotting to death. 

         14             [Laughter.] 

         15             AUDIENCE PARTICIPANT:  So, the point is,

         16   who determines the patient's needs?  If it is so

         17   important, you can't just get away with that

         18   without deciding where these needs are and who does

         19   it.

         20             DR. WOOD:  Well, I think that is the key

         21   issue.  I think the patient's needs really have to

         22   be done in concert with the patient, the family,


                                                                       53

          1   and the physician.  It certainly can be subjective,

          2   at least in our institution, it is considered

          3   absolutely mandatory that the patient be part of

          4   determining what their needs are.  And the needs of

          5   one patient may a turn out to be a little different

          6   than the needs of the next patient in the door. 

          7             AUDIENCE PARTICIPANT:  Absolutely.  Thank

          8   you very much. 

          9             CHAIRPERSON MARSHALL:  Any other questions

         10   from our ex-officio members or from members of the

         11   public?  Please, go to a microphone.

         12             MR. SUSKO:  Hi, my name is Mike Susko, and

         13   I am president of a nonprofit, CRCR, Citizens for

         14   Responsible Care in Research, and the question I

         15   have is, have you encouraged any studies to see how

         16   conflicts of interest actually distort the

         17   scientific data.  I think there have been some

         18   studies done where the researchers who have those

         19   interests tend to find, you know, more favorable

         20   results.  I am just wondering about the actual --

         21   of what is trying to be done.

         22             DR. WOOD:  I'm not aware at Mayo that any


                                                                       54

          1   specific studies have been done in our institution

          2   in regards to that, but I cited about four studies

          3   that have been done that have shown the adverse

          4   effects of having some equity relationship or

          5   potential conflicts in terms of the quality of

          6   study.  I think it is relatively remarkable that I

          7   am aware of almost no study that has not shown some

          8   linkage in this regard.  I think we can almost take

          9   it and fairly well scientifically documented that

         10   the existence of a conflict has a much greater

         11   chance of influencing results in a negative

         12   direction than in a positive direction in a

         13   relationship to the objectivity that we are trying

         14   to reinforce.

         15             MR. SUSKO:  So it is there a more

         16   permanent solution to perhaps remove the degree of

         17   conflict of interest -- 

         18             DR. WOOD:  Well, probably the most

         19   permanent solution is actually removal of

         20   conflicts.  And, as a mentioned, even in our own

         21   institution, sometimes we need to do this.  But I

         22   think in most regards, mitigation is still the area


                                                                       55

          1   where most people are focusing in rather than

          2   complete removal.  And I think there are ways that

          3   the research institutions in this country can do a

          4   much better job at mitigation rather then just jump

          5   to the alternative of complete removal.

          6             I realize that there have been some

          7   statements, no conflict, no interest, but I think

          8   that is the other extreme of the situation as well. 

          9   But at the present time, I do think there is a more

         10   middle ground that can benefit our patients and the

         11   public considerably more than they doing right now.

         12             CHAIRPERSON MARSHALL:  I will give the

         13   last question to Dr. Koski.

         14             DR. KOSKI:  Thank you, Dr. Marshall.  We

         15   seem to enter these discussions frequently with a

         16   sort of bias if you will that money is the root of

         17   all evil.  But I heard consistently and as you

         18   heard very compelling arguments from industry, from

         19   individual entrepreneurs, and so on.  In fact the

         20   risk to a company, for instance, that is investing

         21   in the design of a new product, it is so great that

         22   if there's anything that is done wrong that in fact


                                                                       56

          1   there be no greater guarantee that things will be

          2   done right and will be not only according to the

          3   rules but would never want to harm anyone than

          4   having your money tied up.

          5             So that in fact money can be, you know, if

          6   you are looking at it from the business case, if

          7   you invest, you know, multiple millions of dollars

          8   in development only to find out that data has been

          9   fabricated or individuals have been harmed and so

         10   on, you basically, you lose a lot more that way.

         11             I was recently at a meeting of the medical

         12   technology leadership forum where these issues were

         13   discussed at some length and was impressed by the

         14   fact that I think there is some validity to that

         15   argument and there is another side of this that I

         16   have not heard discussed as fully as it might be

         17   before this group.  And I wondered what your

         18   reaction to that might be.

         19             DR. WOOD:  Greg, I would agree with you. 

         20   In other words, I think that it just comes back to

         21   the Bayh-Dole Act.  I think medicine in this

         22   country has been seriously propelled forward and


                                                                       57

          1   for the benefit of our patients by the fact that we

          2   have opened up a whole level of activity that we

          3   may have been at a more indigent without those

          4   possible pathways.  And I do think it is a mistake

          5   to characterize industry as the great savings in

          6   this sort of thing. 

          7             There are many commercial firms that in

          8   fact realize that their business strategy has to be

          9   based on being absolutely ethically pristine.

         10             You can turn back a few layers and you

         11   certainly can cite examples where there is another

         12   direction.  I've heard many of the representatives

         13   from FARMA also talk about the valuable role that

         14   they are placed in, in terms of educating the

         15   public on possible new therapeutic options and

         16   things of this nature as well, and there probably

         17   is an element of truth to it.  But I think for all

         18   those reasons it is going to be hard to be way to

         19   the right or way to the left on this issue and we

         20   need to try to approach it sensibly but bearing in

         21   mind that we really need to keep the needs of the

         22   patients in front of us.


                                                                       58

          1             MS. MEYERS:  Do you ever look at the

          2   contracts that some of these investigators have

          3   with these companies?  For example, there is a

          4   paragraph in their that says that the company will

          5   have the final say on whether an article should be

          6   published if the study comes out negative, for

          7   example, or that the company has to review any

          8   publication of the journal --

          9             DR. WOOD:  We review -- we do not allow --

         10   I'm talking about Mayo -- we do not allow an

         11   interaction between any of our staff and a

         12   commercial firm in any other format except under a

         13   contract.  And those contracts are all done by a

         14   central body. 

         15             For example, the point you raised, that we

         16   would not sign a contract that requires any

         17   stipulations on publishable ability even a certain

         18   period of bottling it. I know that on the other

         19   side of it I hear from some of our faculty that

         20   that is being excessively fastidious about our

         21   relationship, but I think we feel it is just one of

         22   the standards that we wish to put forward and --


                                                                       59

          1             MS. MEYERS:  The IRB or conflict of

          2   interest community review those contracts?

          3             DR. WOOD:  Well, the committee that I

          4   previously mentioned, the Industrial Relations

          5   Committee reviews all the contracts and we have an

          6   assigned lawyer for those activities.  And its only

          7   those that have a potential for personal or

          8   institutional conflict that backup to the conflict

          9   of interest subcommittee.  The MEDRIL Committee is

         10   the main ship.  That is the mouth of the tunnel for

         11   all these.  But I think it is.  It served us very

         12   well requiring everything to be a contract between

         13   the company and the institution, not between the

         14   individual and so we don't have any interactions

         15   that aren't between Mayo Foundation and the

         16   company; and this is where the standards for it

         17   must be publishable and it's not publishable we're

         18   not in the contract research business for that

         19   purpose.

         20             CHAIRPERSON MARSHALL:  Dr. Wood, thank you

         21   very much for a wonderful presentation and for

         22   entertaining questions.


                                                                       60

          1             DR. WOOD:  Thank you.

          2             [Applause.]

          3             CHAIRPERSON MARSHALL:  I hope that you

          4   might be able to join us for the next hour if you

          5   have time for discussion.  We would love for you to

          6   interact with us during this time as well.

          7             And if someone is here from the hotel to

          8   remove the podium from the front of the desk, that

          9   would be helpful.

         10             [Brief recess.]

         11             CHAIRPERSON MARSHALL:  If we could

         12   reconvened a meeting, if we have quiet in the room,

         13   please.  Our official break is not for an hour.  If

         14   you would like to step out then please do so

         15   quietly.

         16             I'm going to use the lavaliere because it

         17   seems as though my microphone is the culprit.  So

         18   he cannot hear me, then please let me know.  And if

         19   I make any untoward asides, please ignore them.

         20             I have been remiss, oh, he is not here. 

         21   Jim Taggart I will wait until later to introduce

         22   Jim to you.


                                                                       61

          1             I do not, however, need to introduce Mark

          2   Barnes who has chaired our working group on

          3   financial relationships, and as you know, from our

          4   previous meetings has done a stellar job at that. 

          5   His group has been working hard.  We are coming, I

          6   think, close to a conclusion in terms of, at least,

          7   the financial relationship component of conflict of

          8   interest.  As you know, there are many sorts of

          9   conflict of interest.  I would like to turn the

         10   floor over to Mark.

         11             MR. BARNES:  Thank you, Mary Faith.

         12             I'm here today to report on the latest

         13   iteration and hopefully the last iteration to be

         14   approved by the committee of all comments from this

         15   committee to the Secretary, in regard to the draft

         16   and on guidance that was promulgated now quite some

         17   time ago before the present administration in

         18   regards to financial conflict of interest that was

         19   written not only by Stuart Nightingale --

         20             There is a process that we've engaged

         21   since the last meeting.  What has happened is that

         22   based upon the comments made at the last meeting --


                                                                       62

          1   about the basic principles and why and policy and

          2   conflicts of interest.  We went back to the drawing

          3   board and we did another iteration of the draft

          4   letter -- the draft comment letter that was

          5   circulated to the committee I think about a month

          6   after our last meeting.  There were comments on

          7   that draft and the comments of the draft resulted

          8   in the draft that is before you now.

          9             There were comments received from a number

         10   of members of NHRPAC on what will be the

         11   penultimate draft of the comment letter.  And each

         12   comment was considered.  I printed them all out.  I

         13   looked at them together.  I compared and contrasted

         14   what everyone tried to say I tried to include what

         15   everyone wanted me to include as long as it did not

         16   conflict with the underlying message of the

         17   document and as long as two people did not say

         18   different things about the same line, which did

         19   happen sometimes, and I had to use discretion to

         20   choose what I thought would be suggestive of the

         21   spirit of the document.

         22             I want to highlight some of the major


                                                                       63

          1   changes in the document and major issues that we

          2   have yet to look at.  But let me make a couple of

          3   brief comments in terms of things that ought to

          4   focus our attention if Dr. Wood's comments did not

          5   focus us enough on this issue.

          6             One is that I think it would be wise, and

          7   I would suggest, certainly, compliance hospitals

          8   and medical centers and physician group clients

          9   that they read closely the entire findings of OHRP

         10   in regards to the Johns Hopkins studies; because

         11   the findings are not simply about the particular

         12   study.  They are in fact very much about the

         13   process of human subjects research approval at

         14   Johns Hopkins.  There are a couple of things buried

         15   in those findings that bear noting for anyone

         16   concerned about human subjects research.

         17             One is that there was a finding and this

         18   is posted on the OHRP web site that the letter to

         19   Hopkins -- and this is important, not for today's

         20   discussion, but for tomorrow's -- that there was a

         21   the lack of consideration of the privacy and

         22   confidentiality of human subjects in the course of


                                                                       64

          1   the IRB approval process which is certainly

          2   relevant to our discussion at HIPAA tomorrow and

          3   the effect of HIPAA on human subjects research.

          4             But for today's discussion there was also

          5   a finding that there was a failure in some cases

          6   for IRB members who had conflicting interests,

          7   conflicting financial interests to recuse

          8   themselves from the IRB consideration protocol in

          9   which the IRB member's interest was affected. 

         10   There are more than 30 findings in the OHRP

         11   findings in regards to Johns Hopkins.  I encourage

         12   all of us to read those and to use it as a

         13   compliance checklist for what you're doing what

         14   you're not doing in your process, and certainly the

         15   conflict of interest finding ought to come home to

         16   all us and we should take a to heart.

         17             The second thing that has occurred which

         18   we actually referenced in a new paragraph in the --

         19   what I hope will be the final draft of this is the

         20   fact that there also had been, since we last met, a

         21   consideration of the issue of a serious and

         22   significant consideration, the issue of


                                                                       65

          1   institutional conflicts of interest by the

          2   financial services industry.

          3             The National Association of Securities

          4   Dealers has in fact issued draft guidance and I do

          5   not suggest that we try to comment on their draft

          6   guidance -- 

          7             [Laughter.] 

          8             MR. BARNES:  -- as we have enough trouble

          9   with coming to consensus on the HHS guidance.  But

         10   interestingly, the NASD which is the trade

         11   organization, the trade association for securities

         12   firms and research around the country has looked

         13   very carefully on promulgated draft guidance about

         14   the issue of when a research analyst and his or her

         15   firm owned shares of stock, owned financial

         16   interest, have significant financial relationships

         17   to companies, to private companies, whose shares

         18   they are essentially recommending, endorsing, or

         19   peddling.

         20             And although the guidance is interesting,

         21   and I encourage you to look at it on the NASD web

         22   site that in many cases they are struggling, the


                                                                       66

          1   NASD is struggling in their draft guidance with

          2   many of the same issues with which we have been

          3   struggling.  For example, what amount of

          4   disclosure, should they be required, are there

          5   minimum thresholds for disclosure, how do you

          6   divide an institutional interest or not?  And this

          7   is open for comments and comments will close on

          8   August 15 before the NASD.  And I bring that to our

          9   attention only to say that there are institutional

         10   conflicts and the relationship between employees

         11   and their institutions -- between persons

         12   affiliated with the institution and the

         13   institutional interest is an issue that emerges not

         14   simply in the context but it promotes another

         15   context as well where there are, not lives at

         16   stake, but certainly financial interest applied to

         17   individual investors and I should they add that --

         18   grapple with this is that there were some adverse

         19   events especially with the flop in a stock market

         20   and especially in high-tech stocks in which it was

         21   clear or it was alleged that there were firms,

         22   financial services firms that were recommending


                                                                       67

          1   shares and research analyst that were recommending

          2   companies when in fact -- but those research

          3   analysts in investment firms had significant

          4   sharers or stakes in those companies even though by

          5   all rights and indications the time for

          6   recommending those companies had long passed.

          7             And this is referenced again in what I

          8   hope will be the final draft of the letter.

          9             Now, let me just turn for second to review

         10   some of the major features of what we are endorsing

         11   if we do endorse, and decide as a body to send this

         12   letter on to the HHS secretary.

         13             First of all, it is important that we do

         14   recognize institutional conflicts of interest as a

         15   significant issue in regards to the conflict of

         16   interest analysis.  We endorse the focus by Dr.

         17   Nightingale, Dr. Koski and others on the issue of

         18   examining institutional conflicts of interest

         19   within the context of all conflicts of interest.

         20             We endorse the idea of there being a

         21   conflict of interest committee or body that would

         22   be an adjunct to the IRB but independent of the


                                                                       68

          1   IRB, composed of people who are able, who have the

          2   professional background and expertise to evaluate

          3   these conflicts of interest.

          4             We endorse the idea that there ought to be

          5   some kind of minimum threshold put on the

          6   examination of conflicts of interest although that

          7   minimum thresholds is not defined in our letter. 

          8   We do reference in our letter the fact that more

          9   and more institutions are moving towards

         10   calibrating their minimum thresholds and their

         11   disclosure policy to be in line with the public

         12   health service thresholds of $10,000 or 5 percent

         13   investment.

         14             We also endorse the idea which I think

         15   significantly goes further than what Dr. Wood was

         16   talking about and certainly what most institutions,

         17   in fact almost all institutions, that I have ever

         18   counseled or looked at which is to say that part of

         19   compensation that ought to be disclosed not to be

         20   looked at it includes the compensation within the

         21   context of the research contract itself.  So, in

         22   other words, it is not simply the emolument, the


                                                                       69

          1   honoraria, the tryst, the financial patent, it also

          2   is the compensation for the research or any

          3   institution that is embedded in the research

          4   contract itself, particularly when that

          5   compensation exceeds the fair market value of the

          6   research services that are being rendered by the

          7   institution.

          8             I just want to flag that, we have

          9   discussed it before, but we are pushing the

         10   envelope in that regard.  I think it is entirely

         11   appropriate.  I think that most of us think it is

         12   appropriate to look at that but that certainly is

         13   -- and it goes to the issue, by the way, of so-

         14   called "enrollment bonuses" that are paid to some

         15   investigators by some companies, by some other

         16   research sponsors.

         17             I also want to point out some of the

         18   differences between some of the -- or amendments to

         19   this draft as opposed to the draft that we looked

         20   at, at our last meeting.

         21             One thing that we have made clearer in

         22   this draft is the issue of disclosure of the actual


                                                                       70

          1   conflict, of the actual financial interest to the

          2   research subject.  What we have endorsed here is

          3   certainly the idea that the conflict of interest

          4   committee that there should be full disclosure of

          5   the researcher and the institution and the IRB

          6   members to the conflict of interest committee who

          7   would examine and look at those conflicts.

          8             We also have again endorsed the idea of

          9   there being some kind of minimum threshold,

         10   although we do not attach a dollar limit to it. 

         11   Bob Levine would like us to, but he was not bold

         12   enough to offer a suggestion as to what he would

         13   like that threshold to be and I certainly did not

         14   venture one.

         15             We also say that the conflict of interest

         16   committee and the IRB should look at essentially

         17   the degree of risk that that financial conflict,

         18   that particular individualized, case-by-case, on a

         19   case-by-case basis the financial conflict of either

         20   the institution for the researcher or the

         21   researchers proposed and should calibrate

         22   disclosure to the patient to be in line with the


                                                                       71

          1   degree of risk, so in the most risky circumstances,

          2   for example, presumably there would be disclosure

          3   of the actual interest which again goes further

          4   than what Dr. Wood was talking about in terms of

          5   the Mayo model.  But on the other hand where the

          6   financial interests are more tenuated presumably

          7   there could be what we have termed "generic

          8   disclosure."  The fact that there is a process in

          9   the institution that there was a financial interest

         10   that was flagged but that there also were conflict

         11   management strategies in place, or in processes, to

         12   avoid there being any adulteration of either

         13   scientific integrity or of informed consent.

         14             To endorse the idea again that there be --

         15   we have not said that there should be disclosure of

         16   each and every share of stock.  What we have said

         17   is that there should be a case-by-case analysis.

         18             What we have also said, very importantly,

         19   I think, and I do want this to get lost either in

         20   what we say or in what Dr. Wood was talking about,

         21   and that is that disclosure is not enough. 

         22   Disclosure is not enough.  The primary


                                                                       72

          1   responsibility is not to disclose the financial

          2   conflicts of interest.  The primary obligation of

          3   the researcher and of the institution and of the

          4   IRB is to manage the conflict of interest, to

          5   manage it to a level that is below the level of

          6   what would pose as a significant risk to the

          7   research subject.

          8             And we put that management obligation

          9   first, we put disclosure second.  Because, again,

         10   as one of the audience members pointed out, in

         11   fact, as a couple of them pointed out, even when

         12   there are financial interests disclosed, does that

         13   really dilute the willingness of participants to

         14   engage in research?  Usually not, I think in most

         15   of our experiences, and in fact those who know more

         16   bear a greater responsibility and that would be the

         17   conflict of interest committee and the IRB.

         18             In the draft there are a couple of

         19   additional things.  I want to point out that we

         20   received several comments including from Susan

         21   Kornetski from Bob Rich and from others and from

         22   Adil Shamoo, that were respected and I tried to


                                                                       73

          1   include in essence, but the basic comment and there

          2   were enough of us to comment on it, I wanted to

          3   bring to the committee's attention, there were

          4   those of us in the comment period who said that the

          5   IRB should be -- that we should suggest that IRB's

          6   should actually not be able to overrule the

          7   judgment of an internal conflict of interest

          8   committee.  And in fact that IRB's must bow to the

          9   wishes or the suggestions, recommendations, I

         10   should say, of a conflict of interest committee. 

         11   That particular suggestion was not included in this

         12   draft, it was included in a different forum, the

         13   idea was included, and you will see the idea

         14   reflected in the redline version that you have in

         15   your notebook in front of you, but why was it not

         16   included?  It was not included for three reasons.

         17             First of all, as we sit today, IRB's have

         18   full legal responsibility to pass on informed

         19   consent.  Conflict of interest committees have no

         20   legal status.  So we cannot be in the position of

         21   saying that IRB's which are there for the legal

         22   responsibility and moral responsibility for what


                                                                       74

          1   they are passing on that they must bow to someone

          2   else's wishes, they have to be free, both in the

          3   legal or ethical matter to decide themselves what

          4   should be on an informed consent form and what

          5   should not be on the informed consent form.

          6             That is not to say that they should not

          7   take extremely seriously the recommendations of a

          8   conflict of interest committee.  In fact, on any

          9   kind of risk management strategy or administrative

         10   oversight out of the IRB itself one would -- and I

         11   say in the draft that is unthinkable that an IRB

         12   would ignore the recommendations of a conflict of

         13   interest committee, but in fact the IRB cannot

         14   simply advocate its responsibility to a COI

         15   committee at least as the legal responsibilities

         16   are currently configured.

         17             Secondly, as many people said, this

         18   guidance -- this draft interim guidance promulgated

         19   by HHS is meant to be guidance and not regulations

         20   and therefore I hesitate to say particularly when

         21   COIs are not embedded in the law yet other then

         22   they will be, eventually, I hesitate to say that


                                                                       75

          1   somebody must do something since in fact we reserve

          2   in our letter the word "must" for those

          3   circumstances that are currently legally required

          4   and we are careful to do that in our letter.  The

          5   word "must," as Elliot clarified early on for us,

          6   the word "must" means that you really have to do it

          7   because it is required by law; "should" means you

          8   have an ethical duty to do it; and "may" means that

          9   that is a possible way of resolving or fulfilling

         10   either a legal or an ethical responsibility and

         11   those words are carefully used throughout the

         12   draft.

         13             And, the third reason that I did not

         14   include it was really a policy reason, and that is

         15   that we are assuming in making those comments the

         16   COI committee is going to be tougher than the IRB.

         17   But that may not be the case, and the IRB has got

         18   to be free to beat tougher than the COI committee,

         19   in regards to evaluating financial conflicts of

         20   interest and informed consent.

         21             Finally, let me say this, the one set of

         22   comments that I was not fully able to -- and Bob I


                                                                       76

          1   do not want to put you on the spot and I apologize

          2   for this, but the one set of comments that I could

          3   not include completely, although I did try to

          4   respond to, insofar as what is consistent with the

          5   guidance were some of those of Dr. Rich on this

          6   committee.  And I do not what I speak for Dr. Rich,

          7   he is a big boy, he's bigger than I am, and I am

          8   sure he can speak for himself.  But essentially

          9   there was -- and this is something that has been

         10   expressed not only by Dr. Rich but by many others

         11   outside of this committee, there was a feeling --

         12   there has been a feeling from various associations

         13   that we should not -- it is not time to the

         14   government to move, the government should wait in

         15   terms of the draft interim guidance, the government

         16   should wait for the private associations to do

         17   their voluntary work.  And I think that many of his

         18   comments or some of his comments reflected that.

         19             I think it was my sense and I think it was

         20   the sense of most people in NHRPAC that the time

         21   horizon is short, that the integrity of research is

         22   only at stake in regard to the issue of financial


                                                                       77

          1   conflicts of interest and that the time for

          2   government to move and for this committee to act is

          3   really now.  And not to wait, not to save the

          4   private association results should not be respected

          5   and looked at when they are finally issued, but

          6   that we should not really wait for those in order

          7   to issue their own guidance.

          8             What I did do in the draft that tried to

          9   be respectful of what various people -- including

         10   but not only Dr. Rich -- had suggested that it is

         11   more clear, I think, in this draft that we are

         12   asking that HHS really regard this as guidance and

         13   not as regulation.  And that guidance not be

         14   interpreted by OHRP as being regulation and that is

         15   contrary to what other experiences have been in the

         16   health-care industry when guidance comes out and

         17   immediately is interpreted as regulations.

         18             Am with that I think I will turn it back

         19   over to Mary Faith.

         20             CHAIRPERSON MARSHALL:  Thank you, Mark. 

         21   Can you all hear me?  No.

         22             That was a beautiful summary.  Thank you


                                                                       78

          1   for bringing all of us up-to-date from where we

          2   were last time and thank all of you committee

          3   members who responded to the working group draft. 

          4   I am sure that there will be fair amount of

          5   discussion.

          6             Bob, I would like thank you for your very

          7   thoughtful input that you gave to us, beautifully

          8   written, beautifully worded.

          9             What I would like for us to do at the end

         10   of the hour, or after I should say, the half-hour

         11   or the 25 minutes is, I would like to come to

         12   closure of this part of our work and I understand

         13   that we may not achieve consensus, that there may

         14   be dissenting opinions that would be incorporated

         15   into our final product, and that's fine.  But I

         16   would like to bring closure to this within the next

         17   half-hour.  So I will entertain comments and we

         18   will move forward expeditiously.

         19             I have Abbey, Susan, Adil, and I think we

         20   will give Bob the first word.

         21             DR. RICH:  Thank you, Mary Faith. I would

         22   like to begin by saying, for the benefit of those


                                                                       79

          1   of you who did not seen my comments, that I am

          2   deeply respectful of the work of the working group

          3   about this and there was in actual fact very little

          4   of the summary of materials that Mark has just

          5   presented with which I disagreed.  My problem is

          6   really a problem of what guidance from a federal

          7   regulatory agency except that guidance is usually

          8   issued as to an explication of federal regulations. 

          9   So the regulations are put into the law through a

         10   process that is very well-defined and then in order

         11   to interpret those regulations oftentimes guidances

         12   are developed to help institutions understand what

         13   the regulations actually mean.

         14             I think there has been numerous occasions

         15   particularly in recent years where unfortunately

         16   guidance has gotten out in front of regulation and

         17   I think that was a part of the problem that in fact

         18   to be candid OPRR actually had with the scientific

         19   community when there were things that were issued

         20   as guidances or as policy that in actual fact the

         21   statutory authority or the regulatory authority as

         22   promulgated through the Federal Register and


                                                                       80

          1   through the usual process was not at all clear.  I

          2   think if one takes a look at the process by which a

          3   federal agency usually issues regulations and then

          4   develops guidance is it is somewhat different from

          5   what we are seeing here.  And that has been my

          6   major concern.

          7             I think the concern of a large number of

          8   individuals in the community, most of whom endorse

          9   the bulk of the materials in this document and in

         10   actual fact, my major problem with the whole

         11   document was with a simple paragraph, which said,

         12   essentially, NHRPAC rejects the thoughtful comments

         13   that have been received from a large number of

         14   institutions, I think, to its disservice, from my

         15   perspective, dismisses them rather out of hand when

         16   I believe those thoughtful comments are part of the

         17   regulatory process, part of the rulemaking process,

         18   and the process for OHRP is very well spelled out

         19   in administrative law and I do not think it

         20   incorporates guidance in advanced regulation.

         21             At the very least I think there are

         22   improvements in this final draft, since I have been


                                                                       81

          1   on the country I just saw it this morning for the

          2   first time, but I am appreciative of what Mark has

          3   tried to do to improve it.  I do believe that if it

          4   is to be endorsed by the committee at least from my

          5   perspective NHRPAC should not be seen as a

          6   monolithic entity with which there is no dissent.

          7   And it sort of suggests that NHRPAC takes issue

          8   with these points.  Well, maybe some members of

          9   NHRPAC do and maybe even most of the members of

         10   NHRPAC do but not all members of NHRPAC do.  And I

         11   believe that the language needs to be respectful

         12   all of some dissension with the process, not with

         13   points but with the process.

         14             CHAIRPERSON MARSHALL:  Thank you, Bob. 

         15             DR. MORENO:  A point of clarification

         16   perhaps from you or from Greg, or somebody else,

         17   perhaps Kate, is it accurate that the process of

         18   promulgating guidance differs from that which has

         19   taken place with respect to this matter as far as

         20   OHRP is concerned, or DHHS is concerned?

         21             CHAIRPERSON MARSHALL:  I will let Greg

         22   speak for OHRP.


                                                                       82

          1             DR. KOSKI:  No, I do not believe that is

          2   true.  In fact, the process for development of both

          3   guidance and rules, okay, os to generally seek

          4   broad public consultation and incorporate that

          5   feedback into the process.  Ultimately, as Bob has

          6   pointed out, there is a full, legally required

          7   procedure that certainly OHRP is very well aware of

          8   and that is required specifically for issuing any

          9   new rules and so on.  There is some, I think,

         10   ambiguity I guess within government as to what to

         11   call certain things, you know, how you get

         12   information out and of all that. 

         13             Certainly, in this instance I think

         14   there's been some perhaps misunderstanding or

         15   perhaps mischaracterization of the status of the

         16   draft document that was put out in order to

         17   stimulate public discussion which I think has been

         18   very effective in doing.  At no point was there

         19   ever any intent to issue that as a formal

         20   requirement.  So, in fact, it did not deviate at

         21   all from what I would be a normal expected

         22   procedure, but nevertheless, that does not bar from


                                                                       83

          1   being perceived in that way by certain parties

          2   which I think was perhaps the case.

          3             So that, again, what we would expect to

          4   within the department would be to again take the

          5   council that has been provided not only from this

          6   committee but although independently outside of

          7   this committee from the very professional

          8   organizations and the individuals that share

          9   interests and then construct appropriate documents

         10   and issue those through the appropriate processes

         11   in concert or in compliance with the Administrative

         12   Procedures Act and all, so, that's exactly what we

         13   intend to do.

         14             CHAIRPERSON MARSHALL:  I have a question

         15   for Bob and that is the fact that aside from your

         16   critique relative to the specific wording about the

         17   input that NHRPAC received and the fact that we may

         18   take issue and your point being that not all of us

         19   do take issue.  I think that point is well taken.

         20             My question, Bob, it is that the letter I

         21   think does reflect advice to the Secretary through

         22   the Assistant Secretary that other organizations,


                                                                       84

          1   as we know the double AMC, the AAU are working very

          2   hard at coming up with other solutions to this

          3   evolving problem.  And I think that that is well

          4   spoken pay and I think that it is spoken seriously

          5   to in the letter and I wonder whether you feel that

          6   that is adequate in the sense of advising the

          7   government that any process that it has in terms of

          8   developing guidance and issuing guidance, how it

          9   conceives of guidance should be iterative and

         10   responsive to these other initiatives.

         11             DR. RICH:  To the extent that it is simply

         12   understood as a dialogue, I do not have a problem

         13   with it.  But my problem is that what I understand

         14   in this document is that NHRPAC is rejecting the

         15   process of dialogue and saying that it is time for

         16   government action.  And by "action" I usually think

         17   of it in terms of a regulatory process.

         18             I do not know what OHRP or HHS regard as

         19   action short of a regulatory process that did not

         20   involve something -- some "must"s as opposed to

         21   some "should"s and "may"s.  But I take it from this

         22   matter to be a call for must.  To be a call for


                                                                       85

          1   things that the government should insinuate itself

          2   short of the formal regulatory process or in

          3   advance of the formal regulatory process and should

          4   not wait for a formal regulatory process I do not

          5   think that that is wise.

          6             CHAIRPERSON MARSHALL:  Thank you.

          7             I'm not sure that I necessarily agree with

          8   at least my take on what we as a committee are

          9   saying, and if we need to strengthen that, then I

         10   think we should.  Because I think it would be very

         11   unfortunate and I hope it is necessarily spelled

         12   out that we feel as though, you know, again, that

         13   for the government to be silent on this very

         14   important issue sends the wrong message to the

         15   community, the scientific community, to the

         16   research participants of the world, and I think

         17   that, again, maintaining and fostering public trust

         18   is perhaps the larger goal here in addition to

         19   working through a mechanism for dealing with

         20   financial relationships.

         21             Okay.  And, Greg, I will give you the

         22   floor and then I have Bob, Abbey, Susan and Adil.


                                                                       86

          1             Dr. KOSKI:  Just a comment which is

          2   directly on point to Bob's concern where in the

          3   letter it says that there NHRPAC would ask and

          4   expect that HHS not portray or regard the guidance

          5   as a regulatory requirement, a phenomenon that has

          6   occurred in the past in regard to other guidance

          7   documents, even where government officials wouldn't

          8   read that, I think we understand and know exactly

          9   what the intention is there.

         10             PARTICIPANT:   [Off mic.] 

         11             DR. KOSKI:  Right.  So I think we are

         12   certainly having seen -- not only now this comment

         13   from NHRPAC but also from other agencies, we are

         14   certainly sensitive to that.  To go back to your

         15   original point, though, about guidance being an

         16   explication of the regulation; the regulation,

         17   basically the common rule under which we operate,

         18   or the corresponding part of the FDA regulations, I

         19   think make it very clear that we have to consider a

         20   host of issues that have a direct impact on the

         21   well-being and interests of the participants of

         22   research.


                                                                       87

          1             One of the things that we noticed from the

          2   outset from the office conference is that this is

          3   an area under which the regulations clearly defy

          4   that there has been inadequate explication in terms

          5   of providing the kind of guidance that is necessary

          6   to help IRBs, institutions, investigators work in

          7   that area.  So we are very mindful of the ongoing

          8   work of doubling in fee and a host of other groups

          9   that are working on that -- overly concerned about

         10   it.

         11             CHAIRPERSON MARSHALL:  Abbey.

         12             MS. MEYERS:  Yes, I want to reiterate, you

         13   are very lucky to have Mark Barnes on this panel. 

         14   This is just a superb piece that will be relied on,

         15   I think, for many years in the research community. 

         16   But I have only one problem, and that is the Mercy

         17   Hospital paragraph.  And it comes because my family

         18   has been in many studies and in those studies I

         19   know that when I put the life of my children in the

         20   hands of this doctor at university, and completely

         21   trusting him, and I would not daresay because of

         22   that little line in that Mercy Hospital paragraph,


                                                                       88

          1   oh, tell me how much stock you own.  In function, I

          2   would lose my relationship with him, if I am scared

          3   to ask questions.  I would fear that and so the

          4   paragraph itself is intimidating to a parent or to

          5   a patient who really does not want to say, by the

          6   way, are you a member of the Communist Party?

          7             [Laughter.]

          8             MS. MEYERS:  And basically, I guess the

          9   message that it sends really, trust this conflict

         10   of interest committee at the hospital because we

         11   are really smarter than you.  And we're handling it

         12   so you can put the life of your kids in our hands

         13   also.  And so I am really bothered.  I think that

         14   the paragraph should say, it does not have to give

         15   the dollar figure, but it should say, the

         16   investigator owns stocks, the university owns

         17   stocks, that the contract with the company says

         18   that no paper will be published unless the company

         19   reviews the paper and agrees to it.

         20             It should also say that the pediatrician

         21   got paid $5,000 for the referral and that is the

         22   most important thing that can be in this paragraph


                                                                       89

          1   because they trust their pediatricians, and when

          2   they are referred for clinical trial, they think it

          3   is for the sake of their child.  And when they get

          4   to the hospitals they find out that the

          5   pediatrician has been paid off.  It is really an

          6   eye opener.  So I think that paragraph is just too

          7   disturbing to go through the way that it is.

          8             MR. BARNES:  Abbey, I hear what you are

          9   saying, but I just want to point out the framing of

         10   this.  This is different than the context of the

         11   Mercy paragraph in the draft that was presented at

         12   the last meeting and it is different because there

         13   is a paragraph, that precedes the paragraph that

         14   contains the Mercy paragraph, which makes it clear

         15   that in fact the Mercy example is only for those

         16   situations in which the financial interest is so

         17   attenuated that the COI and the conflict of

         18   interest committee and the IRB is not choosing to

         19   mandate the specific disclosures of each and every

         20   share os stock.

         21             So, for example, in the paragraph above,

         22   the new language is that the IRB and the conflict


                                                                       90

          1   of interest committee should be aware -- should

          2   calibrate -- should look at the possible conflict

          3   and the nature of the conflict and the conditions

          4   and extent of disclosure should be calibrated by

          5   the COI committee and the IRB to correspond to the

          6   level of risk that the conflict poses so that there

          7   is, for example, in the application of that

          8   principle if there is, for example, $5,000 received

          9   by a pediatrician as a referral fee, then that is

         10   enough of a direct financial interest that that

         11   certainly would be disclosed and one would not

         12   revert to the Mercy paragraph.  The Mercy paragraph

         13   is only used as an example of what we have called

         14   generic disclosure rather than specific and generic

         15   disclosure is reserved for those situations in

         16   which the financial interest is quite attenuated

         17   and not direct.

         18             Okay.  That is one thing.

         19             The second thing is that also taking into

         20   account some of the commentary and discussion at

         21   the last meeting, there is also a new sentence --

         22   and the reason is not redlined in here is because


                                                                       91

          1   it was redlined in the previous draft you got about

          2   two months ago, and that is that in regard to this

          3   issue of particular disclosure is the researchers

          4   and institutions must recognize that when they have

          5   direct personal investment in a research item or

          6   device, research subjects' safety and independent

          7   decisionmaking must take priority over researchers

          8   and institutions financial privacy.

          9             So I want to just point out that both

         10   before the Mercy paragraph and after the Mercy

         11   paragraph your point of view, I thought, had been

         12   really taken into account here because I really --

         13   the way that I interpreted the letter as it stands

         14   now, is that the Mercy paragraph is really reserved

         15   for those situations in which, for example, the

         16   physician might have shares in a mutual fund or a

         17   blind trust where he or she may have some financial

         18   relationship but it is quite diluted.  And that

         19   would be what the Mercy paragraph would be used

         20   for.

         21             MS. MEYERS:  I am more or less afraid that

         22   that paragraph is there and that it is going to be


                                                                       92

          1   relied on as the example.  I would feel more

          2   comfortable if it were taken out completely.  The

          3   rest of the paper is inadequate.

          4             DR. FLEISCHMAN:  I want to speak to

          5   support Abbey's position here very staunchly.  At a

          6   minimum I think we need an additional paragraph

          7   that describes what the IRB ought to put into the

          8   consent form if there is a specific focused

          9   conflict that they are concerned about.  My concern

         10   in reading this is having spent 25 years rewriting

         11   consent forms on IRB's that this is very confusing

         12   as a paragraph.  To me, as the research subject

         13   potentially, and to me as an IRB member, I would

         14   not be satisfied that the level of understanding of

         15   the subjects would be sufficient to meet the

         16   standards that most IRB's have created for other

         17   parts of the document.

         18             So I think we need two things at a

         19   minimum.  One is an indented paragraph that

         20   describes the kinds of problems that are in that

         21   paragraph above and how we would recommend to an

         22   IRB to deal with those kinds of conflicts and that


                                                                       93

          1   might make Abbey and myself feel more secure on

          2   that.  And the second is, Dr. Wood this morning

          3   talked about the trust issue and we're focusing

          4   much on institutions as well as investigators and I

          5   guess inherent in that is that I'm not certain

          6   about Mercy Hospital and I would like to trust it

          7   more. 

          8             So I would like to really make this

          9   paragraph much more clear, that we are a little

         10   worried here Mercy Hospital about this problem. 

         11   We're doing everything we can to be sure that you

         12   personally and your child who are the subject of

         13   research are being protected and we have this

         14   process in place that is in place to do that.

         15             And if you want to know more about the

         16   process, you know, let us casted.  But it is just

         17   not clear to me.

         18             CHAIRPERSON MARSHALL:  Did you want to

         19   respond to that, Mark, or shall be continue on? 

         20             Okay. I have Susan, Adil. 

         21             DR.  KORNETSKY:  My comment is about

         22   something else.  So if you want to continue to


                                                                       94

          1   discussion and then come back to me, that is fine.

          2             CHAIRPERSON MARSHALL:  Denyse, are you on

          3   point?

          4             DR. THORNLEY-BROWN: I too have had a level

          5   of discomfort about the Mercy Hospital paragraph. 

          6   Part of it is the vagueness.  It is difficult to

          7   understand even for people who are educated and

          8   involved in clinical research.  But the thing that

          9   bothers me more if that sentence, if you would like

         10   more information, blah-blah-blah, please ask the

         11   researchers or the research coordinator.  If there

         12   is an IRB and if there is a conflict of interest

         13   committee that has been assigned to address these

         14   things, why not refer the subject to these

         15   committees rather than a PI or other people

         16   involved -- directly involved.  I think, as Abbey

         17   said, people are very intimidated about asking the

         18   doctor.  If they can ask someone else in another

         19   committee like in the conflict of interest

         20   committee, that might be easier.

         21             CHAIRPERSON MARSHALL:  Susan, Adil and

         22   Felice.


                                                                       95

          1             MR. BARNES:  I hear what Abbey, what Alan,

          2   and what others have said.  And we could certainly

          3   review this paragraph and change it, I mean, if you

          4   have particular suggestions, I like be happy, you

          5   know, to include them, Alan. 

          6             You know what should humble us a little

          7   bit is that if we have trouble as a committee

          8   trying to come up with a paragraph like this or a

          9   paragraph for what we have termed as "specific

         10   disclosure" then this really goes to Bob's point

         11   that it certainly is hard for institutions out

         12   there to try to implement these thing when, again,

         13   we had trouble drafting a paragraph as a model.

         14             You know, what I would suggest, perhaps,

         15   is one of two options.  Either we can -- we can

         16   certainly include what Denyse has referred to as

         17   referring the patient or the central research

         18   subject to the IRB or COI as sources of

         19   information, but we either can simply eliminate the

         20   Mercy paragraph example, we could do that, or we

         21   should really go back and try to write paragraphs

         22   that really captures the specific disclosure


                                                                       96

          1   example and also that references, and we can

          2   certainly do this in very practical ways in which

          3   institutions can in fact manage conflict of

          4   interests which would be, for example, outside

          5   monitors of the informed consent process, outside

          6   data monitors, close IRB attention to the SMB

          7   reports, data tech monitoring board reports,

          8   outside review of interpretation of data and

          9   reports.  I mean, these are all things that we

         10   could certainly put into the document.  So those

         11   are, you know, I just put those open as two

         12   possibilities, but I'm certainly open to any

         13   changes in the language.

         14             CHAIRPERSON MARSHALL:  I would just like

         15   to speak to that and then perhaps we can move on. 

         16   One of the things that we have been committed to as

         17   a committee is providing concrete advice to those

         18   whom we are supposed to advise, including research

         19   subjects and IRB members.  So I think when we can

         20   do something like provide a draft paragraph that

         21   might be a template, that would be helpful.

         22             Perhaps during the course of the day


                                                                       97

          1   today, or at least by the end of the meeting

          2   tomorrow, we might ask Mark, Abbey, perhaps Alan,

          3   other members of the committee who might be

          4   interested in drafting an additional -- working on

          5   the Mercy Hospital paragraph, adding one for an

          6   honest attenuated financial relationship.  And,

          7   Bob, if you had suggestions in terms of tempering

          8   the language, then we could do that and then by the

          9   end of the meeting we can have a document that we

         10   are ready to move forward with.  I would like to

         11   make that concrete suggestion. 

         12             And I have -- Elliot, was that on point,

         13   or -- I do have you on my list.  Okay.  Go ahead.

         14             DR. DORFF:  I just have some suggestive

         15   language along Bob's line.  That paragraph, just

         16   before the sentence before the last.  "The issuance

         17   of non-regulatory suggested best practices guidance

         18   through an interim guidance document does -- that

         19   document's ultimate content inconsistent with the

         20   goal of prudent government action on a rapidly

         21   evolving issue" and then I would just simply add,

         22   "Or with continuing input from individuals and


                                                                       98

          1   professional organizations.  In that spirit NHRPAC

          2   would ask and expect" and so on. 

          3             CHAIRPERSON MARSHALL:  Thank you.  Kate

          4   has duly noted that.  Thanks Elliot.

          5             And I have Susan, Adil, Felice.

          6             DR. KORNETSKY:  Mark, I just wanted to

          7   thank you very much for taking into consideration

          8   my concerns.  I feel a lot more comfortable with

          9   them.  I still do share the concerns of Dr. Rich

         10   that this is not -- regulatory, but also trust Greg

         11   that they hear us.  So, I think I'm fine on that.

         12             The one thing that I did want, you refer

         13   to here a diagram in Exhibit A which we don't have. 

         14   And I remember the initial one, at least in my mind

         15   was problematic.  And I think that I would like to

         16   review that because I, again, am very concerned

         17   about the relationship of what to put on the IRBs. 

         18   And perhaps as we talked about with examples so

         19   that it isn't looked at, you know, a picture speaks

         20   a thousand words sometimes and I'm afraid that this

         21   will be the diagram, this is the way we need to do

         22   it.  That perhaps we may want to have two different


                                                                       99

          1   models, or ways of doing things.  Thank you. 

          2             CHAIRPERSON MARSHALL:  Thank you, Susan. 

          3   Adil and then Felice, and then I would like to open

          4   the floor up. 

          5             DR. SHAMOO:  Thank you.  I want to echo

          6   everybody's compliment to Mark.  It's a brilliant

          7   job in trying to put this document together.  I

          8   would like to see, as Mark knows, a greater

          9   disclosure to patients and there should be really a

         10   threshold amount.  Otherwise, universities and

         11   research institutions will have such a latitude

         12   that it will be ridiculous.

         13             Some institutions, as you know, Harvard

         14   wanted to modify their conflict of interest policy

         15   to move it up to $100,000, and there was an

         16   outbreak in the media and among academic

         17   institutions they backtracked.  So institutions are

         18   already thinking 100,000 is okay, some institutions

         19   would think 100 million is okay.

         20             Having said that, I would like to just

         21   clarify, since you put me in Bob's and Susan's camp

         22   about that conflict of interest relationship to the


                                                                      100

          1   IRB, my comments were very clear, and that is, if

          2   the conflict of interest committee of the

          3   institution being this proposal is coming through

          4   with entangled conflict of interest and they're

          5   rejecting it on that basis, that the IRB should not

          6   be able to overrule it.

          7             Again, I am on very thin ice having to

          8   oppose a brilliant lawyer who is chairing the

          9   committee, Mark, and that is, in my comments I

         10   said, "I don't see administratively how that will

         11   work."  Institutions, the -- OHRP officially deals

         12   with institutions even though IRB is the legally

         13   authorized through the common rule to deal with

         14   issues.  If the institution chooses not to allow a

         15   research proposal to go through, they have multiple

         16   ways of stopping it; the chairman of the

         17   department, the dean, the president, and I cannot

         18   see how an IRB can overrule an institution which

         19   deems this is full of conflict of interest and says

         20   the IRB should go because the institution doesn't

         21   want to apply for that grant proposal.  So I'm

         22   saying, that sentence is really flawed by logic, by


                                                                      101

          1   precedence, by experience, and the legal

          2   relationship that NIH has with institutions, the

          3   grants are given to the institutions.  Thank you.

          4             MR. BARNES:  Adil, I thought that I had

          5   really included that point.  Because I think you're

          6   absolutely right.  Just because an IRB approved

          7   anything, does not -- or a COI committee approved

          8   anything, does not mean that the administration

          9   anywhere needs to let that study go forward.  And

         10   administration can certainly decide that they don't

         11   want this study.  And they don't want to take the

         12   money and they don't want to take the

         13   responsibility.

         14             And that was why I said in one of the

         15   sentences that was added here in the section -- I

         16   don't know exactly what page it's on, but the

         17   section that is subtitled "Financial Disclosure

         18   Process COI Committees and Designated Officials" I

         19   added the sentence, "that it would be nearly

         20   unthinkable as a matter of risk management and

         21   ethical behavior that an IRB would ignore COI

         22   committee's recommendation on these issues or that


                                                                      102

          1   a health care facility's administration would allow

          2   research to proceed if it's IRB had significantly

          3   relaxed the recommendation of a COI committee." 

          4   And I thought that the presumption of that sentence

          5   was that the institution always has the -- not only

          6   the authority, but really the responsibility to

          7   stop a study if the institution's directors or

          8   administration really believes that the study is

          9   substantially flawed.

         10             DR. SHAMOO:  But at least to me, for

         11   someone who has an accent, I still understand IRB

         12   can't ignore the COI committee.  And I'm saying

         13   there is no way it can ignore the institution's

         14   decision. 

         15             MR. BARNES:  And I would agree with that. 

         16   I think that the institution can certainly

         17   overrule, you know, it's own IRB To say -- not to

         18   say that the study can go forward, but to say that

         19   the study must be aborted. 

         20             CHAIRPERSON MARSHALL:  Okay.  Bob has a

         21   very quick point and I still have Felice and Greg

         22   and then we have about ten minutes left because Dr.


                                                                      103

          1   Fleischman has graciously allocated us 15 minutes

          2   of his time.  But I want to move on to our ex-

          3   officio and our public members.  So, please make

          4   your points. 

          5             DR. RICH:  I'll make this very quick, and

          6   I want to speak directly to Adil's comment about a

          7   minimum threshold which I think -- notion.  One of

          8   the things that we only skirted around is the whole

          9   issue of conflicts of interest outside of academia

         10   and particularly when one is dealing with things

         11   like enrollment bonuses where a -- and where

         12   payments and contracts are per patient as opposed

         13   to a global contract.  One could very easily see,

         14   for example, a $500 or $1,000 payment per patient

         15   falling below any threshold and actually being a

         16   way of completely getting around the problem of

         17   disclosure of those kinds of bonuses.

         18             So I think setting a minimum threshold has

         19   a real danger to it in the sense of them being able

         20   to skirt under it by contracts that are on a per

         21   patient basis.  And I believe we're better served

         22   by not being too specific about that, at least in


                                                                      104

          1   this document. 

          2             CHAIRPERSON MARSHALL:  Felice.

          3             DR. F. LEVINE:  Let me address first the

          4   conflict of interest.  I think I was in the COI

          5   group, being the group of last resort.  And I felt

          6   comfortable with your explanation.  So when Adil

          7   and others have reraised the point, I think that

          8   role of the institution really make -- the final

          9   determination.  I think our concern was really in

         10   the context in which a CIOS that work really should

         11   not go forward or that the conflicts are so

         12   substantial that an IRB -- rethink that in such a

         13   way that makes the conflict less substantial.  So I

         14   think that somehow that ultimate judgment for the

         15   institution to make that reconciliation might help

         16   in that crossing of words.

         17             I also think that the Mercy paragraph -- I

         18   think we should seek to follow what Mary Faith

         19   said.  I think we should try to revise it and

         20   operationalize it, so we put some real skin on the

         21   bones.  Because of the emphasis we are putting on

         22   conflict management, not just on the determination


                                                                      105

          1   -- not just on disclosure and I think having more

          2   sense of how that management process will unfold

          3   and the ways that you just really -- Mark, would be

          4   extremely helpful.

          5             And in that regard I would like us to use

          6   the language that Bob Levine would of course

          7   emphasize that we should use and that is that it's

          8   not just in the consent form.  It's a consent

          9   process. 

         10             And, frankly, in the past year and

         11   especially since joining NHRPAC, I am struck with

         12   how many forms I sign all the time and I'm reading

         13   them and I'm seeing what I'm reading, and I'm

         14   thinking, but I've got to move on because I've got

         15   to navigate this process.  And I think I agree to

         16   all kinds of things that I wouldn't otherwise agree

         17   to because it's time to accept the process.  And I

         18   assume that many persons in these situations will

         19   find the information -- but really want to

         20   understand what do you do now if you find out and

         21   you're learning this thing as, in a sense, not the

         22   11th hour, but the ninth hour, and -- 


                                                                      106

          1             PARTICIPANT:  You agreed to that? 

          2             [Laughter.] 

          3             DR. F. LEVINE:  Well, the third thing I

          4   just wanted to address, let me just do it briefly,

          5   is the issuance of letter.  And I'm appreciative of

          6   what Bob said.  I didn't read the letter.  I would

          7   always be concerned about guidance stepping ahead

          8   of regulation, but I thought we had nearly worked

          9   that through on the -- exceptionally well. 

         10             I read the letter and it was extremely

         11   measured, almost a model, in my view, and that is

         12   that NHRPAC, we're a body, and we do have a voice. 

         13   There was lots of use of the words "majority" and

         14   "minority" "consensus" it's not unanimity that we

         15   are a body, we also have individual acts and

         16   expressed in various ways.  And I thought this

         17   letter really captured the nuance quite well.  I

         18   think to go on at any greater length about all the

         19   differences of our individual perceptions, even my

         20   own on COI, I think would really kind of undercut

         21   commonality of our voice, but I thought this was

         22   really -- I would like to -- 


                                                                      107

          1             CHAIRPERSON MARSHALL:  Thank you, Felice. 

          2   Greg very quickly, and then we'll open the floor. 

          3             DR. KOSKI:  Very quickly.  In this whole

          4   discussion of guidance versus regulation, I've

          5   emphasized many times that regulations are

          6   basically promulgated in order to either get people

          7   to do things that they wouldn't otherwise do that

          8   they should do, or to keep people from doing things

          9   that they otherwise would do that they shouldn't

         10   do.  So it's very clear where we need regulation,

         11   okay, and that general context.

         12             I think as this discussion goes forward,

         13   and particularly as we get more input, for

         14   instance, from the AANC process, in other words,

         15   there will be certain areas where certain processes

         16   are identified.  And we've heard some of them

         17   talked about here, bounties to individuals and all

         18   are just so egregious and carry such a difficult --

         19   there may be a requirement for regulations to

         20   prevent those in order to make sure that there is a

         21   level playing field across the board.

         22             In fact, the conference that Mike Wood


                                                                      108

          1   hosted back at Mayo earlier in the spring, this was

          2   one of the surprising conclusions from about 80

          3   institutions from across the country that in fact

          4   when it came to certain points they would rather

          5   see regulations because it means everybody is going

          6   to play by the same rule. 

          7             So I think we, at this point, our sense of

          8   the fact, that we ought to, you know, go forward in

          9   a deliberative manner, get all the input, I don't

         10   want anyone to misinterpret my comments, meaning

         11   that there will be no federal regulations coming

         12   out of HHS with regard to financial relationships

         13   and conflicts of interest in human research, but I

         14   think we know that there is a process and a time

         15   for that.  

         16             CHAIRPERSON MARSHALL:  Thank you, Greg. 

         17   I'm sorry, committee, I'm going to move forward and

         18   ask if there are ex-officio members who would like

         19   to ask questions of Mark Barnes or any anyone else

         20   in the audience? 

         21             [No response.] 

         22             CHAIRPERSON MARSHALL:  Then I will


                                                                      109

          1   entertain Alan's question. 

          2             DR. FLEISCHMAN:  Actually, it's not a

          3   question, but I rise to Mark's challenge.  And as I

          4   understand it, Mark, there are three possible

          5   scenarios.  One is that the conflict of interest

          6   committee and the IRB have found that there is a

          7   conflict of interest which warrants the research

          8   not going forward. 

          9             The second is, there's a conflict of

         10   interest of a level of significance which warrants

         11   mitigation, the mitigation having been done and the

         12   research should go forward with disclosure.

         13             And the third is that there is some

         14   potential conflicts of interest, but not at such a

         15   level as to warrant disclosure, but to warrant

         16   reassuring that the research subjects that the

         17   committees have dealt with the problem.  Is that --

         18             MR. BARNES:  And in the last example

         19   providing the research subject with the opportunity

         20   to get more information if they really have a

         21   particular concern about it. 

         22             DR. FLEISCHMAN:  Well, my understanding is


                                                                      110

          1   that in both the second and the third, we would

          2   want the research subjects to have the opportunity

          3   to ask further questions anyway.  So I would

          4   suggest something like this.  Every research

          5   scientist and physician at Mercy Hospital must

          6   disclose significant financial interest in private

          7   companies or institutions that may be related to

          8   this research study.

          9             Our hospital committees have reviewed this

         10   information and have concluded that there are some

         11   financial relationships between the investigator or

         12   the institution with the company that funds this

         13   research project. 

         14             At this point, if it was in the category

         15   of significant, we would disclose what that is.  If

         16   it's not in the category of significance, we would

         17   not disclose it.  But in both circumstances we

         18   would then continue with, however, the committee

         19   believes that there are no conflicts of interest

         20   which will influence the way you are treated in

         21   this study, or in the way the research study will

         22   be conducted.


                                                                      111

          1             If you wish to have more information

          2   concerning the process of review or these conflicts

          3   of interest, please contact whatever.

          4             CHAIRPERSON MARSHALL:  Thank you, Alan. 

          5   Stewart, would you like to make any remarks?

          6             Dr. NIGHTINGALE:  [Off mic.] 

          7             CHAIRPERSON MARSHALL:  Thank you. 

          8             DR. KOSKI:  If I could just introduce, for

          9   those of you who don't know Dr. Steward

         10   Nightingale, he actually has been instrumental in

         11   helping us move all of this forward, and in fact,

         12   chairs the working group of the Human Subjects

         13   Research Subcommittee that will be working on the

         14   recommendations to come forward from this group and

         15   other public comments to promulgate whatever. 

         16             [Laughter.] 

         17             CHAIRPERSON MARSHALL:  Mark, let me ask

         18   how you would like to proceed in terms of time?  We

         19   have closing time at the end today, or would you

         20   prefer for us to make time in the schedule tomorrow

         21   for a revisit of a new paragraph for us to come to

         22   closure on the document with?


                                                                      112

          1             MR. BARNES:  I'll tell you what I would

          2   prefer if NHRPAC would indulge me on this.  What I

          3   would prefer to do is basically to suggest the

          4   following.  That we include Alan's language in

          5   place of the Mercy paragraph with appropriate

          6   framing.  That we include reference to the

          7   financial management strategy, the conflict of

          8   interest management strategy that I alluded to,

          9   that we include the language that Elliot had to

         10   meet Bob's point, and, finally that we come up with

         11   a diagram that satisfies Susan. 

         12             [Laughter.] 

         13             MR. BARNES:  And that accurately reflects

         14   the content of the letter.  And with those, and

         15   with the committee basically trusting, I guess, me

         16   and Kate, and you as chairperson to make sure that

         17   those are included and with those -- to ask for

         18   approval of the letter and that we will try to get

         19   this out as quickly as possible and probably by

         20   some point next week, you know, to everyone in case

         21   there are any kind of final objections.  But I

         22   think that -- I mean, I would prefer that we do it


                                                                      113

          1   that way because we've already been through a

          2   lengthy process.  I think that we trust each other,

          3   you know, in terms of implementing the suggestions

          4   of the committee and I would ask for that approval.

          5             CHAIRPERSON MARSHALL:  Let me just ask,

          6   I'm seeing a lot of heads nodding around the table,

          7   but I want to ask anyone, including Bob, if you

          8   have objections to that way of proceeding?

          9             DR. RICH:  I'll be happy to accede to

         10   Mark's judgment provided that in the one paragraph

         11   to which I have particular objection, I think

         12   Elliot has contributed something important, but the

         13   one other thing which is to say, most members of

         14   NHRPAC in a couple of places to make it clear that

         15   there was at least -- I don't think that we --

         16   argument very much, but it does make it clear that

         17   not every member of NHRPAC saw it exactly the same

         18   way.

         19             CHAIRPERSON MARSHALL:  Thank you. 

         20             So I think that we have achieved consensus

         21   yet again.  Thank all of you.  Mark and the members

         22   of your working group, thank you especially for an


                                                                      114

          1   absolutely fabulous job. 

          2             [Applause.] 

          3             MR. BARNES:  Mary Faith, can I thank --

          4   there's a University of Chicago law student in the

          5   audience, Dan Powell, who dug up the National

          6   Association of Security Dealers information for me. 

          7   So I want to thank Dan. 

          8             CHAIRPERSON MARSHALL:  Please stand up,

          9   Dan. 

         10             [Applause.] 

         11             CHAIRPERSON MARSHALL:  And we are going to

         12   take a 15-minute break.  We will begin at exactly

         13   five minutes after 11.  Thank you. 

         14             [Brief recess taken at 10:50 a.m.]

         15             CHAIRPERSON MARSHALL:   Before I turn the

         16   floor over to Dr. Alan Fleischman who chairs the

         17   working group on children as research subjects, I

         18   would like to introduce someone to you, and he is

         19   James Taggart.  Jim, would you mind standing?

         20             Jim is a Greenwald Fellow at Johns Hopkins

         21   University at their center for Bioethics, I

         22   believe, and he's helping us with work on the


                                                                      115

          1   social sciences and non-biomedical research working

          2   groups.  And, Jim, we are so glad that you are on

          3   board and thank you very much for your wonderful

          4   help.

          5             Now, I will turn this portion of the

          6   agenda over to Dr. Fleischman.

          7             DR. FLEISCHMAN:  Madam Chairperson, I have

          8   a question to ask of you before we get to the

          9   substance of the conversation because it is

         10   relevant to the substance and the process of the

         11   working group.  And that has to do with the

         12   question of dissenting opinions.  I took the

         13   opportunity recently to reread a book by Jonathan

         14   Moreno in which he describes the distinction

         15   between consensus and compromise.  And I would

         16   suggest that we may wish professor Moreno to share

         17   that distinction with us. 

         18             My understanding is, in consensus people

         19   may dissent, but the majority or a good solid

         20   majority has agreed to a certain direction.

         21             This morning you suggested that dissenting

         22   opinions will be incorporated into our products. 


                                                                      116

          1   Professor Rich asked that we modify some language

          2   which says the majority of NHRPAC believes or some

          3   of NHRPAC believes, or one or two people, but it --

          4             [Laughter.]

          5             DR. FLEISCHMAN:  -- but he made the point

          6   that we should be respectful of dissenting views

          7   and allow members of NHRPAC or working groups or

          8   others to have dissenting views and to be respected

          9   by not suggesting that it is unanimity in our

         10   language.  But I do wonder whether it is your

         11   intention that as we bring forward documents out of

         12   NHRPAC that you will take the opportunity to share

         13   all the dissenting views with everybody we're

         14   sending our opinions about issues, or will you just

         15   share the consensus?

         16             CHAIRPERSON MARSHALL:  Thank you, Alan.

         17             If I can be heard.  I guess this is my

         18   bias at the moment, and that is, I hope that in the

         19   future we will achieve consensus and I do

         20   understand that consensus is not unanimity.  I

         21   think if we did achieve unanimity on everything

         22   that there would be a problem in terms of how this


                                                                      117

          1   committee is constituted. 

          2             [Laughter.] 

          3             CHAIRPERSON MARSHALL:  I guess my sense is

          4   that, if there are strong dissenting opinions, that

          5   they should be acknowledged within a document. 

          6   That does not mean that we have to attach a

          7   separate document that is a formal dissent, but as

          8   we have been working drafts in the past, I think

          9   that we can incorporate the idea that those who

         10   dissent may be trying to convey or simply the

         11   disagreement with a certain point.  But I think

         12   that we need to be respectful of the breadth of

         13   opinion that we have in the room and that when

         14   there are great differences that they should be

         15   acknowledged.

         16             Otherwise, I think it is sufficient to say

         17   that we have achieved consensus and I hope the

         18   majority of the world understands that that does

         19   not mean unanimity.

         20             And, Jonathan, can you enlighten us in

         21   anyway?  Or do you have anything further that you

         22   might want to add?


                                                                      118

          1             DR. MORENO:  Well, I want to encourage

          2   everybody to buy the book now that Alan has

          3   mentioned it.

          4             [Laughter.]

          5             DR. MORENO:  Since I might finally sell

          6   it.  There is no conflict of interest here.

          7             [Laughter.]

          8             DR. MORENO:  I finally might sell a couple

          9   though.  I think even descriptively consensus -- 

         10   and there is data on this -- is not always

         11   understood as unanimity.  And without venturing to

         12   the distinctions that one reviewer said led him

         13   into alpha state when reading the book, there is

         14   one that I think we reflected in our activity this

         15   morning, namely that while we might not have been

         16   able to achieve substantive consensus or unanimity

         17   on everything in the financial conflict of interest

         18   report we did achieve procedural consent with

         19   respect to, as you put it, Mary Faith, the language

         20   that was to be used in characterizing our

         21   deliberations and our conclusions.

         22             And that I think is often what -- all that


                                                                      119

          1   is needed, I do not think we necessarily need to

          2   reach beyond that.

          3             DR. FLEISCHMAN:  Thank you very much.

          4             Let me then put in context our first part

          5   of the conversation from the children's working

          6   group and that is a draft document which the

          7   committee has in front of it.  And this morning, I

          8   believe, the committee also got a dissenting view

          9   from one of the working group members and we will

         10   probably, I think, be able to talk more about that

         11   as we go on in our conversations, but in your

         12   packet today, at the table, there was the

         13   dissenting comment.

         14             Let me put in context what -- I want

         15   everyone to understand, I do not believe it is the

         16   most important issue that the working group on

         17   children's regulation will deal with in its tenure,

         18   but it is a timely issue.  It is a timely issue

         19   because in April the FDA in its review of whether

         20   its regulations were consistent and congruent with

         21   the HHS/NIH regulations came to the conclusion that

         22   one part of the children's regulations 408(c) was


                                                                      120

          1   not consistent with the FDA regulations; and they

          2   could not support that regulation.  And let me

          3   remind you what that very small part of the

          4   children's regulation states.  And it is in the

          5   document.

          6             It states that "if the IRB" -- I am

          7   quoting, "if the IRB determines that a research

          8   protocol was designed for conditions or for a

          9   subject population, for which parental or guardian

         10   permission is not a reasonable requirement, to

         11   protect the subjects, for example, neglected or

         12   abused children, it may waive the consent

         13   requirement in subpart (a) of this part and

         14   paragraph (b) of this section provided an

         15   appropriate mechanism for protecting the children

         16   who will participate as subjects in the research is

         17   substituted and provided further that this waiver

         18   is not inconsistent with federal, state, or local

         19   laws. 

         20             The choice of an appropriate mechanism

         21   would depend upon the nature and purpose of the

         22   activities described in the protocol, the risk in


                                                                      121

          1   anticipated benefits of the research subjects and

          2   their age, maturity status and condition."

          3             The rejected this section, in my opinion,

          4   not because they believed it was wrong, but because

          5   they believed that the law that empowered them did

          6   not allow it.  That's my understanding of the FDA's

          7   statement.

          8             The working group reviewed that question

          9   and using the following example, were concerned for

         10   future mature adolescents.  In the late 1980s and

         11   early 1990s, when HIV and AIDS drugs were being

         12   found to be effective in adults, the physicians

         13   caring for adolescents came forward and wished to

         14   enroll adolescents in clinical trials with what

         15   were drugs that were under FDA regulation, but the

         16   research would be funded through NIH clinical

         17   trials.  IRBs around the country, some opted to use

         18   408(c) because some mature adolescents had come

         19   forward to be treated clinically for this disease,

         20   requesting of their doctors to not inform their

         21   parents. 

         22             Those youngsters would not have allowed


                                                                      122

          1   the clinicians to inform their parents about the

          2   behaviors or the diagnosis for which they were

          3   being treated.  It was perfectly legal for those

          4   clinicians to treat those youngsters.

          5             However, they could only be enrolled in a

          6   clinical trial if there was a process for waiving

          7   parental permission and assuring that the

          8   adolescents would have a procedure to protect their

          9   interests.

         10             IRBs interpreted this to mean, in general,

         11   that there ought to be some capacity determination

         12   of those adolescents to assure that they had the

         13   ability to make judgments.  They also interpreted

         14   these in general to mean that there ought to be

         15   some procedural safeguards like ombudspersons,

         16   nurses, or social workers, separate from the

         17   research enterprise which the adolescents could go

         18   to for counsel.  Not in lieu of parental authority,

         19   but for counsel, so the adolescents would have

         20   someone else to chat with that was not part of the

         21   research project.  And the IRBs were, in general,

         22   had to assure that this process went on in a robust


                                                                      123

          1   and rigorous way.  And, indeed, IRBs did that.

          2             And I believe that IRBs did that without

          3   any knowledge that the FDA might have thought that

          4   this wasn't the right thing to do.  In fact, they

          5   were doing it based on the NIH clinical trials and

          6   believing that 408(c) was consistent with what they

          7   were doing.  At least the IRBs I sat on believed

          8   that.

          9             So the working group rose to this concern,

         10   writes this document to share with the FDA our hope

         11   that they would reconsider their conclusions and

         12   harmonize their structures with the NIH guidelines

         13   for a specific small group of mature adolescents

         14   for specific circumstances and with specific

         15   procedural safeguards which are implied and now I

         16   think ought to be specifically argued in a guidance

         17   from OHRP as to what 408(c) might imply for such

         18   youngsters.

         19             And we attempted to write this in this

         20   letter and we raised it to the level of NRHPAC's

         21   discussion.  And as Kate has shared with the

         22   committee, the FDA is awaiting our letter.  The


                                                                      124

          1   time frame for having given comments has passed. 

          2   But they have said that they will accept our

          3   letter, I assume, as long as we get it in, in a

          4   timely manner which means very soon.  But that

          5   doesn't mean we can't revise it or change it.

          6             Now, may I just comment on the specific

          7   dissent from one working group member?

          8             I think that, and I expect that Ms. Sharav

          9   is here and will speak to her dissent.  But I think

         10   it really is a concern about the protection of

         11   children and the role of parents in that regard. 

         12   And I think it is an honest concern, and I think

         13   that I would only caution that the working group,

         14   and I believe NHRPAC wishes this to be about a

         15   specific group of mature adolescents which we have

         16   tried to explain.  And if we have not explained it

         17   sufficiently, then we ought to explain it

         18   sufficiently.

         19             It is not an intention to go around

         20   parental permission.  It is not an intention to say

         21   to clinicians that there isn't a role for parents

         22   even in those adolescents who come forward and say


                                                                      125

          1   they don't wish their parents involved, clinicians

          2   in general ought to consider that serially with

          3   adolescents.  The American Academy of Pediatrics

          4   has said that and most pediatricians would argue

          5   for the value of parental involvement in chronic

          6   diseases in youngsters.  But there does come a

          7   point in time where the interests of those

          8   adolescents may outweigh involvement of parents in

          9   specific circumstances.

         10             DR. DORFF:  I agree with the substance of

         11   the letter, I just have three suggestions.  One is,

         12   on the bottom of the first page where you are

         13   identifying what group of adolescents you're

         14   talking about, it's unclear because the regulation

         15   addresses, I'm reading at the bottom of the first

         16   page, "protecting children specifically neglected

         17   or abused children, however, it would be the

         18   exceptional situation, if ever, that would involve

         19   attending -- from youngsters 10, 11, or 12 years of

         20   age.  A committee focused, per se, is not in

         21   chronological age alone, but rather places greater

         22   emphasis on the youngster's level of maturity,


                                                                      126

          1   condition, or status.  But the problem is that then

          2   the question is, well, you don't need 10, 11 or 12,

          3   what do you mean, 13?

          4             You know, and what I would suggest to you

          5   is that the LA County -- there's a joint commission

          6   of the LA County Environmental Association that

          7   deals with biological stuff and they have a

          8   guideline foregoing life-sustaining treatment for

          9   minor patients.  And their language, I think, is

         10   just much clearer.  The principal is that the minor

         11   should be part of a decisionmaking process to

         12   whatever extent his or her abilities allow. 

         13             And her comment is:  California court

         14   opinions and statutes suggest that mature

         15   quote/unquote minors will typically include at

         16   least minors 14 years of age or older.  Other

         17   minors may also be considered mature based upon the

         18   evaluation of a parent and the physician.  The more

         19   mature the individual, the greater the weight to be

         20   given to his or her opinion.   So that basically

         21   what you're trying to do, and I think rightly so,

         22   is to balance the chronological age with


                                                                      127

          1   psychological age.  But I think you need to -- I

          2   think it's not helpful in a letter like this to

          3   just leave it as vague as it will depend upon the

          4   maturity of the individual as evaluated by whom. 

          5             All right.  So, I mean, I think if you had

          6   some kind of benchmark age, chronological age, that

          7   could be -- I mean, you could have somebody who is

          8   14 who is a seven-year-old in terms of abilities;

          9   right?  But, I mean, I think what you want to have

         10   is a sort of a benchmark age like 14, you know, a

         11   14-year-old was just convicted of murder; right? 

         12   And sentenced to 28 years; right?  So the thing is,

         13   I mean, I think that there is -- and you might want

         14   to have a benchmark age and then also say, with the

         15   proviso that, you know, younger children might be

         16   mature enough and children of 14 or above might not

         17   be mature enough.  Something like that.

         18             DR. FLEISCHMAN:  May I clarify.  You know,

         19   based on that California statement which tracks the

         20   New York State law somewhat, you're not suggesting

         21   that parental -- that we talk to parents about

         22   whether they think in this case --


                                                                      128

          1             DR. DORFF:  No.  No. 

          2             DR. FLEISCHMAN:  -- the child is mature?

          3             DR. DORFF:  No.  This was -- I'm sorry,

          4   that's right, this is only in regard to withdrawal

          5   -- 

          6             [Simultaneous conversation.] 

          7             DR. FLEISCHMAN:  Okay.  But we're not --

          8   so there needs to be a process of determining the

          9   maturity or capacity of the youngster, but it

         10   doesn't involve a parent in that regard?

         11             DR. DORFF:  That's correct.  That's

         12   exactly right.

         13             The second suggestion that I have is this,

         14   toward the end you have in bold print, on the last

         15   page, I think, finally, NHRPAC strongly urges the

         16   development of a guidance for dissemination of IRB

         17   that will explain the use of this section to

         18   provide examples of procedural safeguards to

         19   implement the part of the Section 408 -- do you see

         20   that -- that requires appropriate mechanisms for

         21   protecting the children.  But you give such

         22   safeguards.


                                                                      129

          1             Two pages earlier the last paragraph is in

          2   bold.  "In addition IRBs" -- but the sentence just

          3   before that says, "Such safeguards might include an

          4   individual, independent, or research team available

          5   to counsel.  They had a lesson to monitor the

          6   consent process and provide ongoing independent

          7   monitoring as appropriate."  So why be bashful at

          8   the end?  Right?  

          9             In other words, it seems to me that what

         10   we should be saying is there are such -- you know,

         11   that we should have such procedural safeguards. 

         12   For example, this would be one way to do it.  Not

         13   the only way, probably, but at least here are some

         14   -- just to show that it certainly is possible, you

         15   know, and that here is a concrete suggestion as to

         16   how it might be done.

         17             And then my last point is just that you

         18   mentioned earlier on in the document, before you

         19   get to the conclusion that one of the things that

         20   you want to do is to reconcile the FDA and HHS

         21   requirements.  I would make two points to that. 

         22   One is that you should include that point in a


                                                                      130

          1   conclusion just so that people don't lose sight of

          2   the fact that that's another thing that is

          3   motivating.  And the other point that I would make

          4   is that in the Federal Register materials that were

          5   given to us and they come right after your document

          6   in the book, the register itself -- the Government

          7   itself wants to do that.  I'm on page 20591.  Under

          8   "II. Highlights of the Interim Rule," second

          9   paragraph, second sentence, the paragraph begins

         10   "FDA is adopting HHS subpart D as directed by

         11   Congress with only those changes necessary do to

         12   the differences in FDA -- authority, the agency is

         13   aware that dissimilar or inconsistent federal

         14   requirements governing pediatric protection could

         15   be burdensome to institutions, IRBs, in the process

         16   of clinical investigation." 

         17             So the government itself is on record that

         18   this is a concern of the government.  And so what

         19   you are trying to do is to say, well, if it's a

         20   concern, then do something about it.

         21             CHAIRPERSON MARSHALL:  Thank you very

         22   much, Elliot.  I have Adil, Jonathan, Judy.


                                                                      131

          1             DR. SHAMOO:  Alan, I'm troubled by this. 

          2   And the reason is as follows:  These children

          3   mostly likely will not be the children of this

          4   committee or even the audience.  They will be

          5   children of the poor, the drug addicts, the

          6   uneducated, and therefore we are establishing a

          7   mechanism by which we could constrict their

          8   children for research purpose not necessarily for

          9   health care, it's research purpose.  And that's how

         10   it is going to be seen by the outside people. 

         11             Having said that, there is a point by

         12   which government interests or the state interests

         13   overtakes the family's interest in health care. 

         14   That's much more understandable.  But this is for

         15   research.  And all the safeguards you have done,

         16   and the safeguards that's been used previously are

         17   based on the same research institution who has an

         18   interest in increasing the number of their human

         19   subject.  As we have said before, prior to this

         20   discussion on conflict of interest, there is an

         21   inherent conflict of interest in the institution

         22   that is the investigator wants 50 to 100 children. 


                                                                      132

          1   The institution wants this money for this research,

          2   there is a built in.  And in your guidance it says

          3   such safeguards might include that individual. 

          4   That disturbs me, "might include that individual"

          5   why it should not be "should include an individual

          6   who is outside the institution which provides an

          7   independent objective judgment on whether this

          8   drastic step of taking over those children for

          9   research purposes for the general interest of the

         10   public at large and the child her or himself.

         11             DR. FLEISCHMAN:  I think using "should"

         12   rather than "might" if Professor Dorff agrees -- 

         13             [Laughter.] 

         14             DR. FLEISCHMAN:  -- would be a -- you

         15   know, I think would be totally appropriate. 

         16             We were soft here because we really were

         17   holding out language toward the guidance.  You

         18   know, this letter is to the FDA, it is the working

         19   group's hope that we will develop a guidance, we'll

         20   get to that shortly.  And that is where we were

         21   going to be a bit more assertive in our language,

         22   but I'm perfectly comfortable with "should" rather


                                                                      133

          1   than "might" in this language because I believe

          2   that they should.

          3             CHAIRPERSON MARSHALL:  Jonathan and then

          4   Judy.

          5             DR. MORENO:  First I want to subscribe to

          6   Adil's suggestion.  I do think we are potentially

          7   on the horns of the classic double-agent dilemma

          8   here.  I am thinking though in the context of this

          9   discussion I'm remembering a presentation I made to

         10   a group a few years ago in New York that included a

         11   number of advocates for homeless adolescents in

         12   which I and our friend Jeff Bluestein argued that

         13   there should be a high level of protection, a

         14   greater level of protection for these young people

         15   in research than might be required of the kinds of

         16   kids who are parented by many of us in this room.

         17             And one of the advocates, more than one,

         18   actually, stood up after my presentation and said,

         19   "you've got it exactly backwards.  These young

         20   people are very often much more" -- to use the

         21   language that she used -- "street smart, much more

         22   skeptical, much more careful about what they get


                                                                      134

          1   into than your kids would likely to be who have had

          2   a good experience with authority figures."  So I

          3   simply put that on the table as kind of an

          4   interesting -- it changed my perception of what

          5   many of these kids are about. 

          6             My question that I have for anyone who can

          7   tell me, since I also have only recently been

          8   enlightened as a former IRB member about the FDA --

          9   the difference between the FDA and the common rule

         10   on this is whether there is in parts 50 and 56 any

         11   exception for adolescents whose parents are not

         12   reasonably available, for example, and whether

         13   authority for those adolescents to participate in

         14   research can be achieved, for example, through

         15   permission by a legal guardian.  Or is that

         16   unexceptional.

         17             DR. FLEISCHMAN:  Legal and authorized

         18   guardians, I don't think there's a problem here. 

         19   Their problem, as I understand it and if our FDA

         20   person is here who would like to comment -- she's

         21   not.  Okay. 

         22             Or one of the attorneys in the room more


                                                                      135

          1   knowledgeable than I on this, but my understanding

          2   is their belief that not reasonably available -- 

          3             DR. MORENO:  Would not cut it. 

          4             DR. FLEISCHMAN:  -- would not cut it.  If

          5   they were a legal guardian, that's perfectly fine. 

          6   And they come to this based on the issue -- the

          7   general issue of whether the law respects the

          8   mature minor doctrine.  And I think that's open to

          9   interpretation.  And I think they interpreted it

         10   one way and we're asking them to change their mind.

         11             DR. MORENO:  May I just add one thing that

         12   if it's not already obvious, some of the kids in

         13   this population may suffer from conditions that

         14   would not be prevalent in other kids.  And

         15   therefore, there may be special reason to attempt

         16   to get them to be part of a research project,

         17   understanding always the dilemma that Adil has

         18   identified. 

         19             CHAIRPERSON MARSHALL:  Thank you,

         20   Jonathan.  I have Judy and then Greg. 

         21             DR. SIEGEL:  Both of my comments have to

         22   do with being clear in this document and I think


                                                                      136

          1   we've talked about a definition of "mature" which

          2   clearly I have no way to assess from this document

          3   what our thoughts on the definition of "mature"

          4   would be.  So I agree, we need that.  I also think

          5   we need, in the part of this bolded statement that

          6   deals with when the conflict between HHS and FDA

          7   would occur, to be clear on the example given.  I

          8   don't actually think the example given is in itself

          9   correct.  You can do trials that include drugs that

         10   would not be subject to FDA rules.  And so -- I'm

         11   saying you can.  There are examples.

         12             And so I think in the piece here where we

         13   are actually comparing the trial where at that

         14   moment you would have a conflict within the trial,

         15   we just need to be a little bit more clear and also

         16   be clear on where we would always have to invoke

         17   the FDA ruling on this. 

         18             DR. MORENO:  You're thinking about a non-

         19   phase trial? 

         20             DR. SIEGEL:  Yes.  Sure.  A drug that's

         21   been approved that someone is using and looking at

         22   a different indication.  Anything that is not,


                                                                      137

          1   quote, going to be used for a regulatory approval

          2   of some sort would fall out of this.

          3             DR. FLEISCHMAN:  Or a technique or a drug

          4   --

          5             DR. SIEGEL:  Yes.  So for this, if we're

          6   going to include it, I think we should have an

          7   example of where HHS would be the only rule to

          8   invoke or FDA would be the only rule to invoke and

          9   when you have the conflict, which is where we

         10   actually want to deal.  But further, the question

         11   is, do we actually now say, under HHS, if you do an

         12   HHS rule study you have this decision to make and

         13   if you do an FDA, you have this decision to make,

         14   which we will discuss at several points today.  We

         15   have conflicting rulings and at one point are we

         16   going to at least suggest that they are going to be

         17   brought together somewhere.

         18             CHAIRPERSON MARSHALL:  Thank you.  Greg.

         19             DR. KOSKI:  Just one comment and then I

         20   would ask the committee to sort of opine on

         21   something.  I wanted to just sort of respond

         22   briefly to a comment that Adil was making with


                                                                      138

          1   respect to conflicts of interest among

          2   institutional review boards in an institution.  I

          3   think we've come to realize that while there are

          4   certainly instances where an institutionally

          5   appointed board may be in a position whereby they

          6   may not be serving the best interests.  There could

          7   be pressure to somehow influence by the interests

          8   of the institution that does occur and it's

          9   unacceptable, so that needs to be fixed. 

         10             But on the other hand, I don't think we

         11   should lose sight of the fact that there are many

         12   institutions that have made a very real and serious

         13   commitment to protection of human subjects and

         14   indeed the interests of the institution are best

         15   served by having an institutional review board that

         16   takes that seriously as well. 

         17             So it's kind of like the whole conflicts

         18   of interest thing, you know, it depends upon where

         19   you happen to be standing.  I don't think we want

         20   to indict all institutional review boards based at

         21   institutions as somehow being, you know, corrupt. 

         22   I think what we need to do is make sure that all


                                                                      139

          1   institutional review boards are appropriately

          2   constituted and positioned so that they are free to

          3   exercise autonomous decisionmaking to protect human

          4   subjects.  It's just an aside remark to get that

          5   out.

          6             The point that I wanted though to ask the

          7   committee about, we started out with Alan saying,

          8   "might" and then Adil said, "should"; well, what

          9   about "must"?  I mean, is this -- 

         10             [Laughter.] 

         11             DR. KOSKI:  And, you know, I just would

         12   sort of push the envelope, as long as we are

         13   exploring all of this, as I said, if this is an

         14   area in which there is sufficient concern, and it's

         15   sufficiently complicated that we, again, need to

         16   make sure that everyone is doing it the same way. 

         17   Again, if we were to change either what's in the

         18   current, you know, FDA regulation or in the -- it

         19   is going to be a regulatory change.  We are going

         20   to do something we might as well do it right the

         21   first time and not have to go back.  So I just ask

         22   you to explore that.


                                                                      140

          1             DR. FLEISCHMAN:  The working group I don't

          2   think would have any problem with "must," but what

          3   I learned this morning was that "must" is based in

          4   regulation so we could recommend that a new

          5   regulation be created with a "must" but even before

          6   that occurs, we would recommend a "should".

          7             DR. KORNETSKY:  I would also be concerned

          8   if we do recommend it as a "must" then we are

          9   developing something that's different than HHS. 

         10   So, if we're saying "must" for FDA, that we must

         11   have an advocate, that's not something that is

         12   embedded in HHS regulations, so it may be

         13   incongruous there.

         14             DR. FLEISCHMAN:  408(c) has been used in

         15   far less onerous research processes than drug

         16   trials.  It has been used with populations who have

         17   been allowed to get clinical care and have minimal

         18   risk questionnaires around sexually transmitted

         19   diseases, other kinds of behaviors and in that

         20   regard the level of protection and the procedural

         21   safeguards need to be titrated to the level of risk

         22   to the individual subjects.  So we would certainly


                                                                      141

          1   -- I think the working group would agree on a

          2   "must" for anything that was FDA-related clinical

          3   trials of drugs that were still in the regulatory

          4   structure.  On the other hand, the beauty of the

          5   language of 408(c) now allows the IRB to be

          6   flexible enough to develop protocol specific

          7   procedural safeguards and we referenced the Journal

          8   of Adolescent Medicine work of their -- of the

          9   Society for Adolescent Medicine group a few years

         10   back that reviewed this question and tried hard to

         11   get this concept across of the level of protection

         12   and the procedural safeguards being consistent with

         13   the level of risk to the subjects when parental

         14   permission is being waived.

         15             So we need to clarify all of that.  If we

         16   were going to put a "must" in, we would have to be

         17   very clear that we were suggesting that in the most

         18   serious concern studies.

         19             CHAIRPERSON MARSHALL:  Greg, I think,

         20   would like to, while we're talking about hortatory

         21   language would like to weigh in. 

         22             DR. KOSKI:  Actually, Alan just made the


                                                                      142

          1   point that I was going to make that, you know, if

          2   there is a "must" a "must" can be appropriately

          3   framed with respect to -- and we see this in the

          4   way Sections 4, 5, 6, and 7 are already put in

          5   there, that there's a graduated consideration of

          6   risk and benefit and that certain things are only

          7   required when a determination has been made that,

          8   and in that case there's a specific requirement to

          9   go above and beyond and it matches the level of

         10   risks with the level of protection and all.  So I

         11   think we're saying the same thing. 

         12             MR. BARNES:  It seems to me just as a

         13   formal matter, Alan, that really what we should be

         14   saying to the FDA in these regards is we are asking

         15   or recommending that they take an aggressive

         16   interpretation of their own authority under their

         17   existing regulation to achieve the objective that

         18   we want, or if they don't want to do that, we're

         19   suggesting that they change their regulations in

         20   50.20 to be consistent with the common rule.  And

         21   so that is really the -- you know, in terms of the

         22   formal recommendation, I think that's what we're


                                                                      143

          1   making to the FDA.

          2             CHAIRPERSON MARSHALL:  Let me -- I haven't

          3   seen hands come up from the committee and in

          4   thinking about time, what I would like to do is

          5   maybe continue this discussion until noon and then

          6   give Alan time to move on to discuss other working

          7   group matters, if he so chooses.  I know that Dr.

          8   Lepay is here.  David, if you would, at any point,

          9   like to have the floor, it is yours. 

         10             DR. LEPAY:  Let me make a clarification

         11   here.  I think several sections of this rule were

         12   pointed out in its preamble.  Certainly we do

         13   recognize some of the differences that exist.  Our

         14   goal was, of course, to eliminate these differences

         15   to the extent possible.  Now, what we are talking

         16   about -- here, again, I'm not a lawyer, and I don't

         17   know if I have any representation here behind me

         18   from FDA's legal end.  So I would want to be very

         19   careful how I phrase this.

         20             MR. BARNES:  You want to say nothing.

         21             [Laughter.]  

         22             DR. LEPAY:  Our understanding of the


                                                                      144

          1   reason the language was proposed as it was, was not

          2   based on current FDA regulations, but rather an

          3   interpretation of the Food, Drug and Cosmetic Act

          4   which underlies FDA's regulations.  So, FDA alone

          5   is not in a position necessarily to be able to make

          6   the kind of changes that would support complete

          7   identity of these two regulations in these areas. 

          8   Ultimately, again, unless we are interpreting this

          9   incorrectly, the changes would have to be made at

         10   the level of the FD&C Act and legislation to that

         11   effect.  Again, speaking as a non-lawyer here.

         12             I think as we start to talk down that

         13   line, one of the considerations here, and

         14   particularly if we go the route or at least the

         15   recommendation is to go the route toward changes in

         16   legislative language.  We have to be very careful

         17   how we go about doing that because basically the

         18   read of FDA's current -- the FD&C Act in these

         19   areas is in fact one that FDA is not able to

         20   provide IRBs with the authority to waive informed

         21   consent.

         22             So, indeed, if we are starting to move


                                                                      145

          1   down this route, what it can effectively do in

          2   changing the law that governs these particular

          3   provisions, we have to make sure that we are not in

          4   fact opening up a whole situation where the

          5   informed consent requirements under the law are

          6   lessened to be much broader than what we are

          7   talking about here in one provision of one

          8   regulation.

          9             So I think this is really what the

         10   committee does need to take into account and to

         11   deliberate on if the recommendation is indeed that

         12   this is an important point and needs to move

         13   forward toward legislative changes to accommodate

         14   it.  I think it's going to be a multi-step system

         15   where we are going to have to see where that

         16   legislation will go and how to prevent it from

         17   otherwise reducing the protections that currently

         18   exist in the law for human subject protection.

         19             CHAIRPERSON MARSHALL:  Thank you very much

         20   for clarifying that.  And I would also like to

         21   thank you and the FDA for allowing us to make these

         22   comments after the fact in terms of your time


                                                                      146

          1   frame.  We are very much appreciative of that. 

          2   Alan.

          3             DR. FLEISCHMAN:  And I do appreciate your

          4   clarifying that.  The working group would argue,

          5   again, with no lawyers behind me either, that we

          6   are not waiving informed consent.  And that is the

          7   substance of our argument as to why we believe the

          8   FDA might be able to interpret and I loved Mark's

          9   language, and we will try to use that language, but

         10   we believe that the adolescent, him or herself who

         11   is mature and who has the capacity, is giving

         12   informed consent, not assent, and that we are not

         13   waiving informed consent in this regard.  That's an

         14   important part of the ethical underpinning of this

         15   section.  It isn't that no one is giving informed

         16   consent, it's that we are respecting the young

         17   person as a person who has the capacity and

         18   therefore we give him the authority to give the

         19   informed consent.

         20             Now, that may have no legal standing

         21   whatsoever in the Food, Drug and Cosmetic Act, but

         22   we hope it would.


                                                                      147

          1             CHAIRPERSON MARSHALL:  Thank you.  And now

          2   let me ask if there are ex-officio members of the

          3   committee who would like -- any ex-officio? 

          4             [No response.] 

          5             CHAIRPERSON MARSHALL:  Then let me just

          6   open the floor, and I would like to recognize Vera

          7   who is a member of the working group and has given

          8   us a written dissent that we should put on the

          9   table and discuss.  Thank you, Vera.

         10             DR. SHARAV:  Thank you.  Even from the

         11   discussion just now, it has become apparent that

         12   terms have no real definitions.  For example,

         13   informed consent according to the law as Dr. Lepay

         14   again reminded us, is very specific.  Only

         15   competent adults, under the law, can give informed

         16   consent. 

         17             The law also speaks of children.  There is

         18   no division right now between children and

         19   adolescents.  And all children can only give

         20   assent, legally.

         21             The definition or the supposition that

         22   abused and neglected children would be better


                                                                      148

          1   served by assuming the responsibility -- the adult

          2   responsibility on their shoulders by waiving the

          3   parental involvement.

          4             Now, I would like to know what evidence

          5   there is that that is so.  First of all, who

          6   decides who is an abused and a neglected child? 

          7   Again, there are legal stipulations and someone

          8   else will talk about it; Howard Fishman is an

          9   expert on this.  But just to lay the ground, there

         10   are definitions and the committee is really either

         11   unaware of those very specific requirements before

         12   a child is adjudicated as an abused child and

         13   someone else is assigned to make decisions on their

         14   behalf.  That is very different from what is

         15   happening here.

         16             The other area that I would like to

         17   mention that was mentioned before about "should,"

         18   "must," "might; there are some assumptions being

         19   made about the current level of safeguards in human

         20   subject research, both adult and children.

         21             And those assumptions in light of the real

         22   world, and should I list all these scandals that


                                                                      149

          1   we've had in the last three years, I think everyone

          2   knows it, but the big elephant is not in the room. 

          3   The question I have, why is there such a rush to

          4   accommodate research by diminishing the protections

          5   that children now have?  Those protections restrict

          6   access to them.  That's the one safety that they've

          7   had until now, that there had to be very strong

          8   justification for using children in experimental

          9   research. 

         10             It was, again, affirmed by the Radiation

         11   Advisory Commission that has a very strong chapter

         12   about why children need particular protections, and

         13   I really do find it almost offensive to call it

         14   "added protection" when in fact we are reducing

         15   them by assuming a whole lot of things which have

         16   not been proven.

         17             I think that for the government to enter

         18   into the family -- the parent/child relationship

         19   and in some manner diminish it without having very

         20   strong justification, that the child first of all

         21   needs that, or that he will better off after. 

         22   There are victims in research.  We all know that


                                                                      150

          1   research involves risks.  What happens when a child

          2   is harmed, one that the parent was not involved? 

          3   Do you bring back the parent?  Who will take care

          4   of that child?  Who will worry about him once he's

          5   finished with research and he's harmed?  Or, just

          6   the fact that he's now on his own.  There has been

          7   a breach in that parent/child relationship which

          8   was initiated by the government.  I think that's a

          9   very heavy load for this panel.  I really do.

         10             CHAIRPERSON MARSHALL:  Thank you, Vera.  I

         11   sit on this working group as well.  And I would

         12   like to respond to your comments by saying that the

         13   very sorts of research that we're talking about and

         14   that I think have been very clearly articulated are

         15   the sorts of research that would aim to prevent

         16   harm to children to include children who are in a

         17   certain situation who may not have access to

         18   research, but whose situations need to be

         19   understood and learned about so that we can care

         20   for those children in a better way.

         21             So, I understand your sense of outrage and

         22   I think all of us have it.  In particular


                                                                      151

          1   situations it does our consciences credit, but it

          2   is not always a service in terms of what we are

          3   trying to achieve professionally as a committee.

          4             So, I can't agree with you.  I think

          5   there's a little bit of disingenuity in your

          6   remarks.  And I'll stop there and maybe ask if

          7   anyone else has comments that they would like to

          8   make.  Felice.

          9             DR. F. LEVINE:  I think as a member of the

         10   working group, I think, Mary Faith, at least as I

         11   would see it and heard it and feel it as a

         12   contributor, better captures the spirit of the

         13   working group, and that is to -- for a particular

         14   -- I'll say somewhat narrow class of adolescents to

         15   provide than the opportunity to be subjects where

         16   they otherwise would not have that opportunity and

         17   where we cannot, therefore, help them absent their

         18   having the capacity to participate.  And this is

         19   not so classed-based. 

         20             As I said on the phone, if anyone would

         21   like to take a field trip, I can take you to some

         22   of the best neighborhoods in town than we might


                                                                      152

          1   like to think.  I think there's a lot of

          2   sociological stereotyping about this as if we are

          3   talking about person who couldn't possibly be the

          4   adolescents of people around this table and were

          5   not, as we know.

          6             CHAIRPERSON MARSHALL:  Thank you.  Mark. 

          7             MR. BARNES:  I'm not a member of the

          8   working group, but I wanted to offer one example

          9   which may actually refine the controversy.  Alan

         10   had used the example, I think, in his draft report

         11   or draft letter and also here during his remarks of

         12   the adolescent who might want to be enrolled in an

         13   AIDS/HIV drug trial because those trials in fact

         14   have been -- many of them have been -- especially

         15   with the proteus inhibitors have been enormously

         16   successful.  And the trials were even aborted in

         17   the middle of them because they were thought that

         18   the prospect of success was huge and in fact the

         19   success was huge.  In some cases leading people to

         20   say or to regard the effect of the proteus

         21   inhibitors as what's called the "Lazarus Syndrome." 

         22   So, in fact, it was not even a marginal gain in


                                                                      153

          1   health, it was a huge gain in health for those

          2   people that participated in the trial at an early

          3   stage. 

          4             But I think there may be an even better

          5   example, Alan, which is -- it's an earlier example

          6   in AIDS/HIV of NIH trial O76 which involved the

          7   administration of AZT as adavudine to pregnant

          8   women in various dosages in order to prevent

          9   infection of the fetus of the child when he or she

         10   was born.

         11             And in regard to maternity services, it's

         12   quite clear in the law that adolescents who are

         13   mature have the right to consent to their own care

         14   regardless of what their parents may or may not

         15   say.  They have the right to seek reproductive

         16   counseling, they have the right to seek abortion

         17   services if they so desire.  This is a principal

         18   that's enshrined in most of the either state

         19   statutory laws or respected by state courts when

         20   they've interpreted state constitutions.  And, in

         21   fact, the O76 trial was really about maternal care. 

         22   It was not about care necessarily of the mom,


                                                                      154

          1   although that was important too, but it was also

          2   about her decisionmaking about the safety of her

          3   child or child to be.

          4             So, in fact, the O76 trial itself was

          5   aborted because the early results of the trial were

          6   so positive in terms of making it clear that the

          7   administration of AZT, at least in limited dosages

          8   during pregnancy was, in fact, going to protect

          9   these children -- the children to be born. 

         10             So, in fact, I like that example perhaps

         11   better than simply the proteus inhibitor example

         12   because it relies on an underlying category of

         13   girls, of females, women, young women -- who knows

         14   what to say these days -- 

         15             [Laughter.] 

         16             MR. BARNES:  -- whatever.  

         17             [Laughter.] 

         18             MR. BARNES:  But I like that example

         19   because it is a category of decisionmaking which is

         20   historically reserved to the less than 18-year-old. 

         21   And yet it was a situation in which the enrollment

         22   in the trial led very directly to positive health


                                                                      155

          1   consequences.

          2             DR. FLEISCHMAN:  Mark, I would strongly

          3   urge us not to use that example.  I know that trial

          4   extremely well.  Those young women who were less

          5   than 18 and who were pregnant and who were

          6   enrolled, were enrolled as emancipated minors which

          7   is a different category than we are talking about. 

          8   Because of their pregnancy, they were felt to have

          9   the same rights and legal standing as adults.  And

         10   this is a different group.  I wouldn't want to base

         11   our argument on what I think are a legally adult

         12   standing -- that the young women in O76 had.  I

         13   don't think any IRB used 408(c) in that regard.

         14             I think there were other issues about O76

         15   concerning paternal consent and other things that

         16   we could perhaps talk about at some time, but that

         17   -- and with all due respect, I think that example

         18   is not the one that I would share with the FDA

         19   because I think they would then blow away all the

         20   other mature minor issues.  And I think we need to

         21   define what we mean by "mature minor" very

         22   carefully, distinguish it from the emancipated


                                                                      156

          1   minor which are those youngsters who are less than

          2   18, independently contributing to our society

          3   through work or having been parents or are pregnant

          4   which is my understanding of that distinction.  And

          5   I would just respectfully suggest we not go down

          6   that road.

          7             CHAIRPERSON MARSHALL:  Abbey.

          8             MS. MEYERS:  Well, I just want to say that

          9   part of the whole bioethics discussion is respect

         10   for persons, and we need to respect the wishes of

         11   an adolescent not to tell their parents something,

         12   just as no parent has the right to have access to

         13   the psychiatric records of their child.  There are

         14   other issues that children don't want to talk to

         15   their parents about and they should have that

         16   right.  So I don't think that we should eliminate

         17   this whole class of people just because they don't

         18   want their parents to know something.

         19             CHAIRPERSON MARSHALL:  Please, if you

         20   could use the mike and identify yourself. 

         21             DR. FISHMAN:  Hi.  My name is Howard

         22   Fishman.  For the past seven years, and it goes


                                                                      157

          1   back much longer, I have been consulting on and

          2   acting as an expert witness in child abuse cases. 

          3   I've been qualified as an expert in 13

          4   jurisdictions.  There are some fundamental kinds of

          5   issues that are raised when people say that someone

          6   has been disingenuous.  That's problematic for me. 

          7   Because what has been utterly and totally ignored

          8   are the rights of parents, and what I have referred

          9   to as this concept of in loco parentis running

         10   amok. 

         11             People who propose to replace parents with

         12   their infinite wisdom perhaps ought to be called

         13   upon to replace the so-called "research subjects"

         14   with their own children.  It's very easy to talk

         15   about what should happen to someone else's kids.

         16             We were reassured a few minutes ago that

         17   this is across the spectrum of socioeconomics, et

         18   cetera.  Wrong.  There are 600,000 children in

         19   state care in the United States.  A larger

         20   proportion than any other nation in the world.  The

         21   preponderant majority of those children have never

         22   been physically harmed or sexually abused by their


                                                                      158

          1   parents. 

          2             Furthermore, nowhere in this document do I

          3   see a definition of an abused or neglected child. 

          4   And I've heard five or six times, well, you know,

          5   we really have to look at better definition.  I

          6   can't imagine how a position could have been

          7   arrived at without those definitions.  Legally

          8   there is a definition.  An abused or neglected

          9   child is an individual who has been adjudicated as

         10   abused or neglected in a court of law. 

         11             I hate to tell you, maybe FDA should be

         12   aware, that even when a child has been adjudicated,

         13   abused, or neglected, the state, the custodian,

         14   does not have permission, may not proceed to

         15   provide medical treatment to that child without

         16   parental permission.  Such a status is achieved

         17   only when parental rights are terminated.

         18             These are niceties that are somehow

         19   ignored in all of this.  But the fundamental issue

         20   is the undermining and sabotaging of the American

         21   family and of the American parent.  And, again,

         22   this issue of across the broad spectrum of


                                                                      159

          1   sociopolitical statuses, nonsense. 

          2             The vast majority of children in state

          3   care are minorities.  They are of the

          4   socioeconomically marginalized populations.  So,

          5   I'll conclude with where I started.  To the extent

          6   that folks here would like to volunteer their own

          7   children, they should feel free to just ignore the

          8   parents of these other children who are far more

          9   vulnerable, far more susceptible to coercion, to

         10   manipulation, and to bribery.

         11             When we find that the most prestigious

         12   research institution in this country has been

         13   assessed and found to evidence fundamental flaws in

         14   its research protocols and ethics, and then we want

         15   to blithely suggest, well, most IRBs are doing a

         16   fine job.  Please, folks, that's disingenuous.

         17             CHAIRPERSON MARSHALL:  I see a few hands

         18   go up.  I don't think that anyone on this committee

         19   has made any blithe suggestions this morning.  And

         20   I won't speak for -- I am not a parent myself, so I

         21   can't speak to that.  But I would ask any other

         22   committee member who may wish to do so.


                                                                      160

          1             But I also would like to remind us, and I

          2   generally start the meeting this way, and I didn't

          3   this morning for time purposes, and that is that

          4   our remarks should be made in the spirit of

          5   respect, they should be made in the most accurate

          6   way possible, without sweeping generalizations,

          7   without anecdote, and so I would hope to keep the

          8   level of discourse -- I will keep the level of

          9   discourse of this meeting at a high one in terms of

         10   respectful interactions between individuals.

         11             And when I sense that members of the

         12   committee or members of audience are not treating

         13   one another with that respect, then I will say so. 

         14   Dr. Koski, I see two hands -- Dr. Koski, Alan, and

         15   then the two folks there on the front row.

         16             DR. KOSKI:  Thank you, Mary Faith.  Just

         17   very quickly, I found myself several times today in

         18   sort of the position of shifting perspective a

         19   little bit for the sake of fostering greater

         20   communication.  I find myself there once again.

         21             I think there is a great deal of truth to

         22   what Vera pointed out that there is a certain


                                                                      161

          1   presumption that, you know, there is, will be, I

          2   would say, must be, an effective system for

          3   protection of human subjects overall if we're going

          4   to make what we do meaningful.  And, so, clearly,

          5   that's an area that, you know, we shall continue to

          6   work in.

          7              But, nevertheless, the perspective that

          8   one brings to these discussions, okay, can in a

          9   very substantive way sort of color what you see. 

         10   And if one starts with the presumption that all

         11   research is being done by, you know, evil

         12   entrepreneurial self-serving malevolent individuals

         13   that want to harm people, then you come down sort

         14   of on one side.  I'm speaking now as an extreme,

         15   whereas, if you, on the other hand were to believe

         16   that none of those things were true, you might come

         17   down on the other.  The truth is, we have to

         18   operate sort of in this -- more in the middle

         19   region.  Okay.  And that's complicated.

         20             I think that in my reading of what the

         21   working group has done here, there is a genuine

         22   belief that there's a need to address the concern


                                                                      162

          1   that some adolescents might be prevented

          2   unnecessarily from participating in research and

          3   thereby deprive them of what might be real benefits

          4   toward understanding the conditions that affect

          5   them and providing ways to help them.  So I believe

          6   it was in that spirit that many of these

          7   recommendations were made. 

          8             At the same time, I think we can't lose

          9   sight of the fact that there is a need for real

         10   protections because there may be instances where,

         11   again, people step out of that bound and begin to

         12   try to be, you know, exploitative from what they

         13   are doing.  And so it's -- I think we've got to

         14   consider, you know, both of these sort of views as

         15   we go forward to make sure that any policy

         16   recommendations or regulatory changes that might be

         17   made will reflect that appropriate balance.

         18             By the way, I have enrolled my own

         19   children in research trials. 

         20             CHAIRPERSON MARSHALL:  Elliot.

         21             DR. DORFF:  I think it's important to

         22   understand that the background behind all of this


                                                                      163

          1   is a problem that we have in our own society in

          2   understanding teenagers.  

          3             [Laughter.] 

          4             DR. DORFF:  My kids are in their late

          5   twenties and early thirties already, so I'm well

          6   beyond that.  I really understand it.  No, I don't.

          7             [Laughter.] 

          8             DR. DORFF:  What I am recalling is a

          9   lecture I once heard by an anthropologist who

         10   compared what happens in America to what happened

         11   in a particular South Sea Island where people are

         12   children until age 15.  At age 15 they have a

         13   particular right, one for women and one for men. 

         14   And at the end of that right they are adults for

         15   all intents and purposes.  And they compared that

         16   to what happened in the United States where you

         17   become an adult for admission prices to movies and

         18   for airlines at 12.  You become an adult for

         19   driving at 16.  You become an adult for voting at

         20   18, for alcohol at 21, and if you're a male, you're

         21   not an adult for car insurance until you're 25. 

         22   Right?


                                                                      164

          1             So from 12 to 25 we have this gray area

          2   where we don't really know, you know, what we're

          3   supposed to say about people in that age group and

          4   what responsibilities they can take on themselves,

          5   and what kinds of decisions they should be able to

          6   make for themselves.  And, we as a society, are

          7   facing this kind of thing in these cases recently

          8   in a variety of different states having to do with

          9   how you treat teenagers, do you put them into adult

         10   courts, or do you put them into juvenile courts? 

         11   And for what purposes?

         12             I mean, this kind of problem that we have

         13   is a problem in law as well as a problem in terms

         14   of how to treat these people.  And I think that --

         15   well, in my own tradition it starts at 13 where you

         16   have the right to make these kinds of decisions and

         17   also the responsibility.

         18             Now, that comes from a period long past

         19   when life expectancy was less and all kinds of

         20   other things were true.  But you didn't go to

         21   school until your mid-20s.  But the thing is that

         22   -- I mean, I think we have to understand that the


                                                                      165

          1   underlying reality to these problems that we're

          2   having has to do with how we understand

          3   adolescents.

          4             My own feeling is that when you're talking

          5   about what we're talking about, namely that, you

          6   know, these kinds of trials, and I think Dr. Koski

          7   -- Greg, is exactly right.  I mean, we have to

          8   presume the middle ground.  We have to presume that

          9   everybody involved in drug trials and conducting

         10   them is not on the one hand a saint, but on the

         11   other hand not necessarily a sinner either; but is

         12   rather a normal human being with propensities for

         13   both ends of the spectrum.

         14             And what we want to do is make -- I mean,

         15   what this letter wants to do and the reason why I

         16   support it is because it enables people roughly 14

         17   to 18 to become part of trials that may ultimately

         18   be for their own benefit, and certainly will be for

         19   benefit of others that are of that age.  And to

         20   recognize the fact that some people in that age

         21   group certainly have the ability, and the

         22   responsibility, to make these kinds of mature


                                                                      166

          1   decisions.

          2             If they can drive a car at 16 and endanger

          3   all the rest of us that way, and we have good

          4   evidence of that, then on this kind of thing, I

          5   mean, it seems to me that this is at least opening

          6   the door for some of these people who choose to do

          7   this, to do this recognizing that they've achieved

          8   at least a certain level -- a necessary level of

          9   maturity to be able to make that decision.

         10             CHAIRPERSON MARSHALL:  I'm sorry.  Please

         11   go ahead and then I have Gail and then I have

         12   Jonathan. 

         13             MR. SUSKO:  Hi.  I'm Mike Susko, the

         14   president of CRCR, Citizens for Responsible Care in

         15   Research.  I agree with the principle of dialogue

         16   that we are really talking about tension between,

         17   in some sense, too noble a cause as one is, can we

         18   do some research that really benefits people? 

         19             I was talking to the head of the Pain

         20   Clinic at Hopkins and there is a nobility in trying

         21   to stop pain and trying different things with that

         22   problem that's not fully solved.  On the other hand


                                                                      167

          1   there is the issue of the protection of the

          2   research subject and truly informed consent about

          3   the risks and there's nobility in people who tried

          4   to defend that cause.  So there really is attention

          5   here.

          6             I think, though, my view would be we might

          7   tend to err on the side of protection.  And the

          8   Nuremberg Code sort of said, informed consent was

          9   the bottom line.  That's got to be the bedrock

         10   principle.  We can't gain, you know, other advances

         11   at that risk because then you run into, you know, a

         12   lot of problems.  And so the difficulty of informed

         13   consent intrigues me.

         14             I was talking to a pathologist and she

         15   said, "well, I would never enter into a new drug

         16   study because I know there's a percentage with

         17   adverse effects and some might die."  Nor would she

         18   put her children in.  So here is a mature woman who

         19   knows the field, who just wouldn't do a certain

         20   type of study.  And then we are going to say, well,

         21   a mature adolescent, you know, who doesn't know a

         22   lot of the hard science and so forth, is able to


                                                                      168

          1   make some sort of decision.

          2             And I reflect back on the recent death in

          3   my home town of the Baltimore woman.  And I looked

          4   at the consent form about the asthma inducing agent

          5   there and the title of the study was "Relaxation"

          6   it had the word "relaxation" in it.  They said you

          7   might get drowsy if you try to stand up.  Just when

          8   you read that whole consent form, I mean, you had

          9   to be somewhat expert to figure out what was really

         10   going on that there might be a high risk.  And I

         11   just think of a mature adolescent trying to grapple

         12   with some consent form and then make, you know,

         13   really informed consent decision.  It seems like

         14   there should be a type of advocate for the child if

         15   you're going to have any type of waiver.  A devil's

         16   advocate or maybe a children's advocate, we would

         17   call it.  Somebody who would help the child make

         18   sense of what is going on in here and not just the

         19   people who have a vested interest in the research,

         20   a neutral party would be a suggestion.  Thanks.

         21             CHAIRPERSON MARSHALL:  Thank you very

         22   much, Mike.  And I think, you know, as we were --


                                                                      169

          1   as Alan mentioned, we feel as those procedural

          2   safeguards, not only up front in terms of consent,

          3   and support there, but ongoing monitoring is

          4   something that we will include in our letter in the

          5   "should" category and that we may exorge the FDA or

          6   others, that should they change the regulations in

          7   the future that then the "must" category would be

          8   entered in terms of continued oversight.

          9             MR. SUSKO:  When we are talking about

         10   ethical principles, there's a principle of

         11   distributive justice here too.  In the American

         12   Academy of Pediatrics in 1995, I had a committee on

         13   drugs combined with a committee on bioethics who

         14   published an article in pediatrics saying that it's

         15   actually unethical not to do studies in children. 

         16   And this is a very special group of children that

         17   Alan is pointing out that need also to benefit from

         18   that principle of distributed justice.  It's wrong

         19   to leave them out.

         20             You're trying to craft a way within all

         21   legal bounds to include them in research because

         22   they can get permission for themselves to be


                                                                      170

          1   treated as children.  There may be a very important

          2   drug that they need that it would be ironic that

          3   they could not receive and it would be in

          4   contravention to these beautiful ethical principles

          5   espoused by the American Academy of Pediatrics.  So

          6   I do feel strongly about that.

          7             I would also like to add that a child -- a

          8   male child between 21 and 25 cannot rent a car. 

          9   That's very interesting too.  So there are these

         10   ethical principles that are definitely in

         11   contravention with one another. 

         12             But I would say that Vera has a good point

         13   and also Dr. Fishbein, I believe, because we do

         14   have to pay attention to the legalities.  And maybe

         15   there are not enough lawyers in this group. 

         16   Because there are definitions in law that we have

         17   to pay attention to.  I think that was a good

         18   point.  But another point was about the distant

         19   ingenuity that is going on around here. 

         20             On page 4 of your rebuttal, you mention

         21   the "child abuse industry."  And I don't know if

         22   anybody would classify themselves as working in the


                                                                      171

          1   "child abuse industry".  I'm not sure that's a good

          2   term.

          3             MR. BARNES:  Could I say, that's the only

          4   time I've ever heard a doctor say that there aren't

          5   enough lawyers in the room. 

          6             [Laughter.] 

          7             CHAIRPERSON MARSHALL:  I have Jonathan,

          8   Roger, Adil, and Greg. 

          9             DR. MORENO:  Thank you.  I guess I must be

         10   a lot younger than Elliot because my kids are 15

         11   and 11 and a half.  And at the risk of committing

         12   what I'm sure Felice would observe is the fallacy

         13   of assertion by hypothesis because I'm not in this

         14   situation, if either of my kids were in the

         15   situation described on page 2 of Alan's report,

         16   then I would hope that they would -- and if they

         17   didn't feel they could confide in me or my wife, I

         18   would certainly hope that they could feel able to

         19   enter a clinical trial that could be beneficial to

         20   them.

         21             But that leads me to a concern that I do

         22   have that we are all familiar with, with respect to


                                                                      172

          1   the current regulations, namely the meaning and

          2   interpretation of beneficial.  And I do think,

          3   Alan, that we need to flesh that out a bit more,

          4   particularly with respect to this population.  At

          5   least we need, I think, to have some more

          6   procedural understanding about how benefit is going

          7   to be understood, how those conclusions would be

          8   reached, and perhaps even some guidance about what

          9   would not be considered to be beneficial. 

         10             For example, would a placebo controlled

         11   study be considered -- I hear Bob Levine shouting

         12   in my ear.  So I think that perhaps that phrase

         13   carries the greatest burden in this set of

         14   recommendations.  I do think we need to perhaps

         15   give more attention to how that conclusion is going

         16   to be reached.  I'm not sure I would want either of

         17   my kids to be in a study that was not potentially

         18   beneficial if they were in the circumstances

         19   described.

         20             And I'm not sure I would have utter

         21   confidence in just anyone making that determination

         22   without a little more public guidance about what


                                                                      173

          1   the criteria might be.

          2             CHAIRPERSON MARSHALL:  Alan.

          3             DR. FLEISCHMAN:  I'm jumping the queue to

          4   respond to Jonathan and perhaps I'll respond to Dr.

          5   Fishman as well.  I think this letter can't carry

          6   too much freight here.  I'm quite in favor of our

          7   trying to clarify through guidance the concepts of

          8   beneficial.  And if we have the opportunity and the

          9   working group will report its intention to do that. 

         10   It is extremely difficult for this simple letter to

         11   carry too much freight. 

         12             I would argue that IRBs ought to make this

         13   determination very carefully.  This is not

         14   something that IRBs ought to suggest they embark

         15   upon wholesale.  These are very specific kinds of

         16   protocols.  The reason we gave the example was

         17   because these were protocols that had tremendously

         18   promising results in adults, but still hadn't yet

         19   been completed and the investigators wished to

         20   enroll the youngsters because this was another

         21   cohort who could directly potentially benefit.

         22             So, how we would frame that without


                                                                      174

          1   knowing the case-by-case basis what kind of

          2   language we could put into something like this,

          3   except to exhort the IRBs, to be very careful, to

          4   be very circumspect about what kinds of protocols

          5   they would allow this to be in, I'm not certain and

          6   that's what could be troubling.  I could consider a

          7   placebo controlled trial.  I could.  You know, I

          8   could hypothesize, a placebo controlled trial in a

          9   disease for which there was no therapeutic

         10   intervention that had a one-year life expectancy

         11   with some suggested hope in adults before we had

         12   any therapies that were standard.  I might consider

         13   an adolescent placebo control trial under these

         14   circumstances.  So, you know, I don't want to get

         15   into that level of detail, but I don't know how to

         16   use this document to do that work.  That would be

         17   my response to Jonathan.  Although, I would exhort

         18   IRBs to be very careful, thoughtful and give the

         19   idea that there was some hoped-for benefit knowing

         20   full well, as Adil points out, that even in the

         21   best of intended studies, there may be toxicities,

         22   there may be risks, there may be unknown problems. 


                                                                      175

          1   That's why we're doing the research. 

          2             DR. MORENO:  Could I just have a quick

          3   follow-up.  One, I acknowledge the difficulty of

          4   loading the document with answers that we may not

          5   be able to articulate at this point, but one

          6   example of something we might want to consider as

          7   part of the guidance would be that IRB should do

          8   what they have the authority to do, mainly to bring

          9   in consultants who are expert in the condition that

         10   applies to these kids, which might not otherwise be

         11   the case. 

         12             MR. BARNES:  May I go back to Dr.

         13   Fishman's comment, which I did appreciate, and I do

         14   think that Dr. Fishman's definitions are clear and

         15   I think correct.  But let me remind the committee

         16   that we're not talking about children primarily

         17   here in this case who have been determined to be

         18   abused and neglected, nor are we talking about

         19   children or their parents who have gone through the

         20   process of termination of parental rights.  What we

         21   are talking about are a group of youngsters for

         22   whom abuse might occur.


                                                                      176

          1             We don't have absolute certainty.  But

          2   they have suggested that their families might

          3   respond to the truth telling with responses that

          4   would be very hurtful to them.  And I've had the

          5   consequences speaking to such youngsters who have

          6   convinced me, certainly, that they would be thrown

          7   out of their homes where they're going every night

          8   now and getting good meals and getting housing,

          9   that they might be abused or worse, in revealing

         10   their diagnoses to their families, and they are not

         11   neglected or abused, they haven't been adjudicated

         12   as neglected and abused, their parents' rights

         13   haven't been terminated, nor does this approach

         14   attempt to do any of that work.  And in those cases

         15   in which children are abused and neglected, then

         16   the pediatricians have the responsibility to go

         17   down that path.  But that is not what we are

         18   talking about here and I think it's important that

         19   the committee understand that we're not speaking

         20   merely about -- I use the word "merely" in quotes,

         21   "merely" about abused and neglected children, but

         22   we are speaking about specific adolescents who are


                                                                      177

          1   mature and who have serious illnesses for whom they

          2   don't wish, as Abbey has pointed out, the

          3   appearance to be informed.

          4             CHAIRPERSON MARSHALL:  I have Roger, Adil,

          5   Vera, and then Greg, and I'm going to stop there

          6   procedurally so that we can come to closure on

          7   this. 

          8             MR. CORTESI:  My only question is, how

          9   often is it necessary to use as subjects, children

         10   who will or adolescents who will not get their

         11   parents' permission.  I mean, are we talking about

         12   a widespread problem or are we talking about

         13   something that comes up once in a blue moon?

         14             DR. FLEISCHMAN:  I don't know about blue

         15   moons, but it's not a widespread problem, it's a

         16   very unusual problem.  But it is an important

         17   problem.  Because there is good reason to believe

         18   that if you exclude these youngsters you will not

         19   be getting the population that you need often to

         20   answer the questions you're asking.  And that's

         21   very important to all youngsters to have the

         22   appropriate population for whom the therapeutic


                                                                      178

          1   intervention will likely be used.  And, once it is

          2   standard treatment, then it can be used for

          3   youngsters without parental permission in clinical

          4   use based on the youngsters coming forward and

          5   asking clinician to treat them and we allow in each

          6   of our states for that to happen.  But we would

          7   never have done the research to assure that those

          8   children were safe.

          9             So, it is rare, and that's why I prefaced

         10   this whole discussion by saying this is not the

         11   most important issue.  The working group will

         12   discuss in its tenure, but it is an important

         13   timely issue.

         14             CHAIRPERSON MARSHALL:  I have Adil then

         15   Vera.

         16             DR. SHAMOO:  This is specifically in

         17   answer to Dr. Koski's comment because it's been

         18   twice made.  And that is whether the IRB members or

         19   IRBs whether they're 100 percent evil or 100

         20   percent good or zero percent evil, however you say

         21   it.  I for one have stated publicly and orally that

         22   I think the overwhelming majority of researchers


                                                                      179

          1   and IRB members are noble people.  That's really

          2   not the question.

          3             The question is, what percent?  We know

          4   it's not zero because of the cases you have shut

          5   down.  There has been now 23, 24 in the past ten

          6   years.  And is it 5, 10, 15 percent?  I'm saying if

          7   it is 5 percent or 10 percent of those who are in

          8   the gray zone or even evil, maybe .1 percent, we

          9   are trying to reduce that number.  And that's

         10   really our purpose.  That's the whole purpose of

         11   regulatory agencies and your office is one of them.

         12   So that is the -- I understand you want to build a

         13   associate so you could illustrate your point of

         14   view.  But I don't think I have ever sat in any

         15   place that all IRBs or all researcher are not even

         16   close to that number, that they are really not

         17   noble. 

         18             I think the overwhelming majority, maybe

         19   we'll put this to rest -- the overwhelming majority

         20   are nobel, wonderful, and well meaning.  However,

         21   still we have problems.  And these problems, I

         22   think are serious and we need to address them.


                                                                      180

          1             CHAIRPERSON MARSHALL:  Thank you, Adil.  I

          2   couldn't agree more.  And we need research.  We

          3   know some numerators, but we don't have a

          4   denominator and I think that we're all agreed on

          5   that.  Well said.

          6             Vera.

          7             DR. SHARAV:  I want to say to answer -- I

          8   don't know who you are, but part of the issue, I

          9   think, here is in fact broadening the use of

         10   children in research.  Until now this clause may

         11   not have been used very often if at all.  But, the

         12   push to incorporate it into FDA regulation and the

         13   really accelerated aggressive pace of recruitment

         14   of children in the United States into clinical drug

         15   trials is part of the reason that I am so very

         16   concerned about this.  Because the safeguard are

         17   not there.  We speak about them, if, maybe, must,

         18   should.  They're not there.  They are not reliable.

         19             Children -- younger and younger children

         20   are being recruited; under this little waiver they

         21   will be  recruited without even parental consent

         22   and Alan in a sense made real what I said in my


                                                                      181

          1   dissent which is that a broad number of children,

          2   not those who have been adjudicated, not those who

          3   there's even any proof of abuse would be

          4   designatable by a researcher in search of children. 

          5   The fact is that there is great problems getting

          6   children from responsible parents into clinical

          7   trials.  That's why we've got money on their head. 

          8   Parents are being bribed.

          9             Now, again, which parents, from what level

         10   of society are going to volunteer their children

         11   for $645 for three-year-old children into clinical

         12   trials.  That's the reality.  There's a protocol

         13   out there that is recruiting three- to five-year-

         14   old children and offering parents a bounty of $645

         15   in addition to traveling expenses.  So I am

         16   concerned that this is a back door to get at

         17   children and circumvent parental consent.

         18             CHAIRPERSON MARSHALL:  Vera, let me just

         19   ask you, if we're talking about a very narrow

         20   circumstance in which Alan identified, and, you

         21   know, during the course of our working group

         22   meetings we're talking about a situation in which


                                                                      182

          1   notifying parents or asking parental permission for

          2   a child to enter the study may not be in the

          3   child's best interest, whereas participating in the

          4   study in terms of a risk benefit analysis could be

          5   beneficial to the child, to other children

          6   similarly situated if we build in, as we are

          7   saying, these safeguards that are required that

          8   don't necessarily pertain to other research that is

          9   going on with children, what are your thoughts

         10   about that?

         11             DR. SHARAV:  Is it life threatening to the

         12   child?

         13             CHAIRPERSON MARSHALL:  Well, do you mean

         14   the research or the problem? 

         15             DR. SHARAV:  The problem. 

         16             CHAIRPERSON MARSHALL:  The problem.  I

         17   think we would be talking about an array of -- 

         18             DR. SHARAV:  You asked for my bottom line

         19   in a sense? 

         20             CHAIRPERSON MARSHALL:  Right. 

         21             DR. SHARAV:  If it's life threatening,

         22   then I will entertain it and wondering who decides


                                                                      183

          1   which child goes into which arm there are problems. 

          2   I mean, that's one thing.

          3             The other thing is, in the working

          4   committee we did discuss a bit, and it was kind of

          5   rejected, I asked, well, if it's so very specific

          6   as you have just outlined it, then it would have to

          7   be -- that language would have to be in the

          8   regulation, but it's not.  The regulation is broad-

          9   based, it's children, it does not -- regardless of

         10   the recommendation in the letter, it is not

         11   restricted to a specific age group or maturity or

         12   anything else; right? 

         13             Nor -- and this is a big concern, an adult

         14   -- a waiver of informed consent for an adult is

         15   only for minimal risk research.  Children though

         16   with waiver you're talking about any level of risk. 

         17   There's no restriction there.  You're talking risk

         18   benefit analysis, what level of risk?  Slightly

         19   more than minimal risk?  It can be any risk. 

         20   Nothing is restrictive in the language of 508(c).

         21             CHAIRPERSON MARSHALL:  Yes, but I think

         22   we're disagreeing on the point of whether what


                                                                      184

          1   we're talking about constitutes a waiver or not.

          2             And Greg has asked for the final word and

          3   then I want to come to closure and we need to go to

          4   lunch.

          5             DR. KOSKI:  The final word.  Mary Faith

          6   always gets the final word.  Lest there be any

          7   doubt whatsoever, I just want to reiterate that

          8   Adil and I share completely the goal.  There is no

          9   controversy about that.

         10             MR. BARNES:  Could I make a suggestion

         11   about sort of concritizing this and perhaps moving

         12   on as a person who is not a member of the working

         13   group?  I mean, I heard a few things said today,

         14   you know, in this discussion.  One was -- and,

         15   again, not to load up the letter with too many

         16   other problems, but a better definition of

         17   beneficial or some definition -- a better

         18   definition or some definition of mature and a

         19   clarification that that is what we are talking

         20   about as opposed to either emancipated minors or

         21   other categories.  The idea of very careful case-

         22   by-case consideration by the IRB of circumstances


                                                                      185

          1   in which they would allow a mature minor to consent

          2   in the situation.

          3             The suggestion that one of the mechanisms

          4   that might be used by the IRB was the use of an

          5   independent child advocate, as one not an exclusive

          6   possibility, but one possibility of dealing with

          7   that with a case-by-case discrimination, the idea

          8   perhaps not life threatening, but what we would

          9   probably be talking about here when an IRB would be

         10   talking about would be medical conditions that have

         11   significant mortality or morbidity, not marginal

         12   gains in mortality or morbidity in most cases.  And

         13   finally, the idea that what we are encouraging as a

         14   procedural matter for the FDA to do is either to

         15   take an aggressive interpretation of its underlying

         16   authorizing legislation or regulation or if

         17   necessary change its regulation in this regard.

         18             And what I would suggest that we do is

         19   that -- I mean, if people can agree that those were

         20   the major points -- I think they were the major

         21   points that were made, then let Alan, you know, go

         22   back, use his incredible skill and background


                                                                      186

          1   knowledge of this particular issue more than any of

          2   us, I think, perhaps who knows about this issue to

          3   include these comments in the letter.  And then

          4   since there is a real time pressure to get it out,

          5   what I would suggest is that, you know, we have two

          6   and three people who might volunteer either from

          7   the working group or from the committee simply that

          8   Alan could share it with and then they could give

          9   him the sign-off to go ahead and do it and delegate

         10   the authority of NHRPAC that way in order to speed

         11   the process.

         12             CHAIRPERSON MARSHALL:  Thank you.  That

         13   was the exact sort of closure that I was looking

         14   for.  Committee members are you comfortable with

         15   this?  Alan.

         16             DR. FLEISCHMAN:  I am more than

         17   comfortable.

         18             CHAIRPERSON MARSHALL:  Volunteers to

         19   assist Alan to review the letter?  Volunteers to

         20   review the letter? 

         21             Okay.  Thank you very much.  Thank you for

         22   a good morning.  We will adjourn for lunch and we


                                                                      187

          1   are back at 1:30.  Thank you all.

          2   [Whereupon, at 12:35 p.m., the meeting was recessed

          3   to be reconvened this same day at 1:30 p.m.]

          4   

          5   

          6   

          7   

          8   

          9   

         10   

         11   

         12   

         13   

         14   

         15   

         16   

         17   

         18   

         19   

         20   

         21   

         22   


                                                                      188

          1                 A F T E R N O O N   S E S S I O N

          2                                       [Time noted:  1:35 p.m.]

          3             CHAIRPERSON MARSHALL:  Welcome back.

          4             We have asked the staff of the Office for

          5   Human Research Protections to brief us as a

          6   committee on their current organization, perhaps

          7   speak to plans for the future.  But we thought,

          8   Kate and I and Greg, that as a working group that

          9   it was important for us to know as we moved along

         10   with our work what was happening with a relatively

         11   newly formed Office for Human Research Protections

         12   and what each of its old and new offices or

         13   subcompartments was all about.  So we've asked Dr.

         14   Koski, Greg Koski to give us an overview and

         15   introduction.

         16             Then we are going to hear from various

         17   staff members at the Office from Jeffery Cohen who

         18   is the Director of the Division of Education;

         19   George Gasparis, who is the Acting Director of

         20   Division of Assurances and Quality Improvement;

         21   then we hear from Kristina Borror, Division of

         22   Compliance. 


                                                                      189

          1             Well, Greg, I don't believe Melody is here

          2   today, but Dr. Koski, you are going to make that

          3   presentation as well.  And Irene Stith-Coleman is

          4   with us who is director of the Office of Policy,

          5   Planning, and Special Projects.  So, those of you

          6   from OHRP, thank you very much for giving us your

          7   afternoon and to tell us about you and what you are

          8   all about.

          9             DR. KOSKI:  Thank you, Mary Faith, and

         10   welcome back everybody.

         11             Now, we often talk about OHRP in these

         12   meetings and, you know, I often feel kind of like

         13   that thing out there on the bow spright sometimes,

         14   you know, sort of the waves coming up and splashing

         15   me in the face from time-to-time.  But there is

         16   really a huge sort of ship and a great crew that

         17   are behind this sort of figurehead and we thought

         18   that it would be very valuable to have an

         19   opportunity for you all to meet some of them to

         20   hear some of the stuff that's going on.

         21             I just wanted to very, very briefly sort

         22   of give you an overview of how the office is


                                                                      190

          1   constructed and talk very briefly about some

          2   upcoming initiatives, and then introduce the

          3   members of our team who are the ones that are

          4   really making things happen.  And so we will get

          5   right onto that.

          6             As you know from our previous discussions

          7   here, OHRP was actually created last June. 

          8   Actually, it was created in April and I think it

          9   became official in June and was basically

         10   established within the Office of the Secretary at

         11   HHS in order to provide an appropriate platform for

         12   both leadership and exercise of responsibilities. 

         13   And the Office, as it is currently constructed, was

         14   basically established to serve not only the need to

         15   sort of reach up and out, but also, you know,

         16   within organizations it has a very broad kind of

         17   role with some key functional activities,

         18   operational activities; and I think the structure

         19   of the office reflects that.

         20             We have the Office of the Director in

         21   which I spend, you know, my professional life. 

         22   It's basically the office where we provide the


                                                                      191

          1   central coordination for all that goes on.  And our

          2   administrative officer, Gary Rice, who is, I don't

          3   think, here today.  And Tony Goodwin who runs the

          4   Executive Secretariat function within our office. 

          5   They play critically important roles.  Tony, I

          6   think, is outside at the table, again, sort of

          7   keeping things going. 

          8             But we also have sort of branching off of

          9   the Office of the Director two component offices. 

         10   One of those is the Office for Planning Policy and

         11   Special Projects that Dr. Irene Stith-Coleman heads

         12   up for us and she'll be talking to you.  That's an

         13   office that has to deal with just a vast array of

         14   things that come up that don't fit into the

         15   otherwise sort of ongoing operational activities of

         16   the office.

         17             We also, last year, created the Office for

         18   International Activities to serve a focal point, a

         19   coordinating center, kind of the one-stop shopping

         20   process to tap into the functional or operational

         21   details of the office in a way to address the

         22   growing need for coordination of, again, a host of


                                                                      192

          1   activities in international conduct of human

          2   research.

          3             Dr. Melody Lin, our Deputy Director has

          4   also agreed to serve in the capacity as the

          5   Director of that Office for International

          6   Activities and I'll talk to you about that in a

          7   minute.

          8             But the real meat of the office's

          9   activities are carried on by the three operating

         10   divisions there.  One of those, the Education

         11   Division, headed up by Jeff Cohen, I think you all

         12   know Jeff.  The Compliance Oversight Division which

         13   is headed up by Mike Carom, and then the new

         14   division for assurances and quality improvement

         15   that currently George Gasparis serves as the Acting

         16   Director for that.  And I think one of the key

         17   steps in moving our office from what had been a

         18   compliance-based sort of focus to one that is truly

         19   looking forward toward outreach interaction,

         20   prevention of harms, which is what we all really

         21   want to do, focusing on performance of the whole

         22   human research protection system in a


                                                                      193

          1   forwardlooking manner rather than looking back to

          2   see where there have been failures.

          3             The extent to which we can prevent

          4   failures to where we can really focus on our true

          5   goal of protecting human subjects and actually

          6   promoting the responsible conduct of research is

          7   something that will serve all of our interests.

          8             Now, last September we laid out our sort

          9   of plan for remodeling in the testimony that I gave

         10   before the House Committee on Oversight of Veterans

         11   Affairs.  We described a host of activities there

         12   and I'm very happy to say that we have moved ahead

         13   with each and every one of them and basically

         14   accomplished, or at least have initiated pretty

         15   much all of them.  These studies are on time and

         16   under budget which is a good place to be in

         17   government and we'll talk more about some of those

         18   things.

         19             We have, of course, had to deal with, you

         20   know, certain things that pop up in government

         21   administratively that have made it challenging at

         22   times, but I'm very happy to report to everyone


                                                                      194

          1   that in fact all of the positions that had been

          2   authorized for our office, we had been given

          3   approval to go ahead and fill all of those

          4   positions and we have outstanding people who will

          5   be joining our office soon which will bring our

          6   compliment of full-time personnel from the current

          7   level of 24 which is actually lower than what we

          8   started with, up to the 47 that it's supposed to

          9   be.  So, I think that's a very, very positive sign

         10   and we're very excited about that.

         11             The things that I'm sort of, in terms of

         12   new initiatives that are out there, that are coming

         13   that people should be aware of, and, again, you may

         14   get more detail on this as you hear the individual

         15   presentations, one of them is the implementation of

         16   our new quality improvement program that we are

         17   extremely excited about.  We will actually --

         18   currently it's in pilot testing.  We hope that as

         19   early as right after Labor Day we will begin to

         20   scale it up to full scale.

         21             When it's in place it will be a voluntary

         22   program that George is going to describe, but we


                                                                      195

          1   will actually be reaching out and interacting with

          2   some 60 sites every month which is a new sort of

          3   trend.  It's a program that is voluntary in nature,

          4   but, again, focused on achieving real performance

          5   in the system.

          6             So you will hear more about that from

          7   George.  We also have upcoming what we have

          8   referred to as our SUEE task force.  The "SUEE" is

          9   an acronym that stands for Simplification

         10   Uniformity Efficiency and Effectiveness, which

         11   clearly, I think you would all agree is something

         12   that within government would serve everyone's needs

         13   well.

         14             We would like to find ways to make the

         15   whole process simpler, to find those things that

         16   are actually working to protect the interests of

         17   human subjects, emphasize those, find the ones that

         18   we're asking people to go through that are really

         19   not serving that need in the most effective way and

         20   get rid of those.  We want to try to clearly

         21   revolutionize some of this and we are very happy

         22   that Susan Zulo who is seated back here and who


                                                                      196

          1   operates out of Irene Stith-Coleman's offices

          2   taking on the challenge of doing this under the

          3   auspices of the Human Subjects Research

          4   Subcommittee where all of the federal agencies are

          5   going to be working together to achieve some of

          6   these goals.

          7             Another project that that group is working

          8   on is a federal-wide handbook for human research

          9   that would sort of pull all of the common ground of

         10   human research subject protection together and to

         11   what would be a valuable resource to everyone

         12   engaged in the process.  And, actually, Susan Rose

         13   from the Department of Energy and Alyse Summers

         14   from our office are working on that.  Jeff may

         15   mention it more.

         16             Finally, I think one of the issues that

         17   remains to be sort of untackled as yet is the whole

         18   issue of what happens after the IRB says okay. 

         19   We've reviewed, approved a project, people are

         20   going to be enrolled, but there is still not a

         21   consistent approach to how we deal with the actual

         22   people engaged in the research and the occurrence


                                                                      197

          1   of adverse events, the appropriate roles for

          2   medical monitors and data monitoring committee,

          3   safety monitoring committees, patient advocates and

          4   so on.  Continuing review, all of this activity

          5   fits together in what has been pretty much a gray

          6   zone and sort of a free style activity where done a

          7   lot of different ways, a lot of different places

          8   under a lot of different sort of authorities.

          9             We want to pull together a governmentwide

         10   task force to really focus on how we could be doing

         11   that right.  And we hope to do that soon because

         12   it's certainly something that we need to be doing

         13   well.  So those are, I think, three things that are

         14   coming while the rest of our activities are

         15   ongoing.

         16             Since what the other folks here have to

         17   say is far more important than what I have to say,

         18   I'm going to be quiet and turn it over overtime

         19   them.  I'm not sure of the order, but I believe to

         20   start off -- Jeff. 

         21             Jeff Cohen is going to talk to us a bit

         22   about the activities of our Division of Education. 


                                                                      198

          1   Jeff. 

          2             DR. COHEN:  First of all I want to thank

          3   the committee for the opportunity to share with you

          4   what we're doing in the Education Division at OHRP. 

          5   And our mission -- our overall mission is as the

          6   name of our division says, is education.  But more

          7   in a broader sense of the term of education and

          8   more appropriately it would be outreach,

          9   communication, and really our aim goes back to what

         10   Greg had said before about prevention.  And we

         11   believe very sincerely that the best prevention

         12   method in this field is education.  That most

         13   people, most researchers, most institutions want to

         14   do the right thing, they just don't know what the

         15   right thing is, or how to do it.  And so it's our

         16   aim to make sure that at least is not the case. 

         17   And everyone, as much as we possibly can knows what

         18   the right thing to do is, and how to do it.  And so

         19   we're working very hard in that effort. 

         20             We focus basically in three main areas. 

         21   Presentations and training programs, workshops and

         22   town meetings, and then finally educational


                                                                      199

          1   materials.  And let me go through those three and

          2   tell you what we are doing and what we plan to do

          3   in the future.  Hold on one second. 

          4             [Pause.] 

          5             DR. COHEN:  Okay.  Just double checking on

          6   what the current thinking is. 

          7             [Laughter.] 

          8             DR. COHEN:  That's about as current as it

          9   gets. 

         10             [Laughter.] 

         11             PARTICIPANT:  At least he understands how

         12   it works. 

         13             [Laughter.] 

         14             DR. COHEN:  Let me start with the

         15   presentations and training programs.  We do a great

         16   deal of outreach.  We try to make ourselves

         17   available for giving presentations.  We give

         18   presentations at professional society meetings.  We

         19   give presentations at universities, medical

         20   centers, government agencies, IRBs, groups of

         21   researchers, we gather people on the street corner,

         22   we grab them walking down the street.  Any


                                                                      200

          1   opportunity to get the word out we will take and

          2   we've got a standing offer and we try to fulfill

          3   all of the requests that we possibly can fulfill.

          4             Just this year alone we've given well

          5   upwards of 60 presentations in different

          6   organizations and settings.  We've also done some

          7   more focused training programs at institutions for

          8   IRBs, for institutions that have come to us and

          9   asked us to do training for their investigators. 

         10   We tend to try and avoid, because it's

         11   impracticable -- using a famous word --

         12   "impracticable" -- I don't even know if there is

         13   really such a word.

         14             There is no way we could fulfill all of

         15   the requests.  If we were to get -- the demand is

         16   infinite.  We could have 100 people on the road all

         17   of the time, seven days a week, and not fulfill the

         18   demand.  And so what our focus is on the

         19   presentations and training programs, is to try and

         20   get groups of people together.  So we try to avoid

         21   going to a single institution and doing a training

         22   program for that institution just because it's


                                                                      201

          1   impracticable.  And so what we encourage people to

          2   do and wherever is to bring together groups of

          3   institutions, IRBs from various institutions,

          4   various research centers, faculty together and do

          5   them as groups.  And that's our focus in that

          6   respect.

          7             We also have a series, a sort of a formal

          8   series of workshops and town meetings.  Let me

          9   explain the difference between a workshop and a

         10   town meeting as we use the terms.  A workshop is a

         11   general program.  It's sort of the traditional

         12   program, presentations, breakout sessions and

         13   discussion groups, for large groups.  We hold these

         14   around the country, and they are open to enrollment

         15   to anyone. 

         16             The town meetings are more like day-long

         17   question and answer sessions.  Because the feedback

         18   that we get from our workshops is that there is not

         19   enough time for questions and answers.  And so we

         20   came up with the concept of a town meeting where we

         21   provide -- there is very little in terms of

         22   presentations or didactic material and it's almost


                                                                      202

          1   totally question and answer.  Sometimes focused,

          2   sometimes broad, but plenty of opportunity for

          3   questions and answers.

          4             This year we did -- we have already done

          5   five workshops and we have one other one planned in

          6   September.  We did workshops in Washington, D.C.,

          7   Honolulu, Newark, Charleston, and Los Angeles and

          8   our upcoming workshop in September, a little plug,

          9   September 20th and 21st in Minneapolis at the

         10   University of Minnesota.

         11             One of the main features, and I think one

         12   of the most exciting features of these workshops is

         13   that it's not just an OHRP workshop.  These are

         14   joint workshops which we are doing with the

         15   Veterans Affairs, ORCA, the Office of Research

         16   Compliance and Assurance form Veterans Affairs, the

         17   Food and Drug and Administration, the National

         18   Institutes of Health. 

         19             At our last workshop in Los Angeles, last

         20   month, not only did we have those three agencies,

         21   but we had representation for the National Science

         22   Foundation, Department of Education and Department


                                                                      203

          1   of Energy.  So it really is an opportunity, and one

          2   of the great feedbacks that we get on these is it's

          3   a great way to see the feds.  They actually see us

          4   that we're real people, we don't bite, you know,

          5   and give them an opportunity to pigeonhole us and

          6   talk to us.  And so we're very proud of the fact

          7   that these are joint workshops from many federal

          8   agencies. 

          9             And we also encourage the other federal

         10   agencies who are represented in the room to join in

         11   with us in future workshops.  And we are in the

         12   process of planning next year a series of workshops

         13   and we are again planning about five or six

         14   workshops for the upcoming year.

         15             Our town meetings, we did three town

         16   meetings this year, one in Dallas, one in Boston,

         17   and one in St. Louis.  Our Boston workshop was an

         18   experiment, we got informed consent, I guess,

         19   verbally, apparently.  We did that.  That was our

         20   first video town meeting.  And we did that as a

         21   two-way interactive video town meeting, except the

         22   fact that Greg was at the site, we were here.  All


                                                                      204

          1   of the representatives from the federal agencies

          2   were here in Washington.  The audience was in

          3   Boston, and we got very good feedback.  It went

          4   very well.  Susan Kornetsky was in the audience and

          5   I think it went very well.  And it went so well

          6   that we are planning future video town meetings. 

          7   The town meeting format lends itself to the video

          8   -- interactive video method.

          9             Finally, with the education materials and

         10   this is an area where we haven't devoted as much

         11   attention as we would have liked to just because

         12   we've been focusing on the other two areas,

         13   primarily.  The educational materials that we offer

         14   right now are our IRB guidebook and our videotape

         15   series.  Unfortunately, our videotape series dates

         16   back to 1986.  The guidebook dates back to 1993. 

         17   So we have planned this year -- fully staffed and

         18   resourced, we will be updating both of those.

         19             And the guidebook, as Greg mentioned, our

         20   efforts with updating the guidebook is federalwide. 

         21   We are going to be working with other federal

         22   agencies who have already begun and Susan Rose has


                                                                      205

          1   already begun the effort.  So it will be a

          2   federalwide guidebook and not just an OHRP

          3   guidebook. 

          4             Finally, we have in terms of new

          5   initiatives, we began this year what we call our

          6   OHRP mailbox.  And we see this as part of our

          7   education effort.  And this is a question and

          8   answer mailbox.  We have an e-mail address,

          9   ohrp@osophs.dhhs.gov.  You know, I say that a lot. 

         10   And we see that as our question and answer mailbox. 

         11   Anyone can send any question they want about human

         12   subjects research, anything about ethics,

         13   regulations, what OHRP is doing, anything at all,

         14   and we assign staff to review that mailbox on a

         15   daily basis and get back to people as quickly as

         16   possible with an answer.  And so we are going to be

         17   beefing that up and trying to provide as much

         18   feedback to people as we can and answer their

         19   questions.

         20             Finally, one more new initiative which we

         21   began this year and is going to be continuing which

         22   we are really only a part of, but we helped get


                                                                      206

          1   started, is what we called in the initial phases

          2   our education summit.  We brought together along

          3   with the Office of Research Integrity people

          4   involved from the private sector, from

          5   institutions, from industry, from federal agencies,

          6   everyone involved in education and responsible

          7   conduct of research in the broadest sense of the

          8   term, not just human subjects research, but all

          9   responsibility conductive research.  And to discuss

         10   how we could best coordinate, facilitate, make it

         11   easier for institutions to do the kind of training

         12   that is necessary for their faculty, for their

         13   researchers.

         14             Our first meeting was back in February. 

         15   It was very exciting and one of the main

         16   conclusions of that meeting was that there needed

         17   to be a body, an independent body, not a government

         18   body, but an independent body to somehow perform

         19   this function.  And so where the group is meeting

         20   again this August to actually kick off and create a

         21   body which right now we would be calling the

         22   Education Council.  And it's goal will be to


                                                                      207

          1   coordinate education efforts to be a clearinghouse

          2   of educational materials, educational programs, and

          3   to really try -- the goal is to make it as easy as

          4   possible for institutions to do the kind of

          5   training and education of their researchers that

          6   they need to do.  And so we are very excited about

          7   that.  Especially since we are not doing it.  It's

          8   a public/private partnership which is really the

          9   best way to go.  So all of these things will come

         10   out of the research community with our involvement.

         11             So we are very excited about our education

         12   programs.  We are going to be doing even more. 

         13   Like I tend to say to people, you are going to be

         14   sick of us by the time we are done, you are going

         15   to hear so much from us.

         16             So thank you for this opportunity.  If

         17   anybody has any questions. 

         18             DR. MORENO:  Thanks Jeff.  I have two

         19   questions.  Actually, first I want to acknowledge

         20   that you've agreed to come to Charlottesville for a

         21   workshop and remind you of that. 

         22             DR. COHEN:  Yes.


                                                                      208

          1             DR. MORENO:  And thank you for that. 

          2   Granted that we don't have 100 people to do these

          3   things.  How many FTEs do you have to do education? 

          4   And the second question is, the mailbox idea sounds

          5   like a great idea.  It also scares the hell out of

          6   me from your point of view because I could imagine

          7   that you could be inundated with questions that are

          8   quite technical in nature and how are you -- I'm

          9   sure you've thought about this, but how are you

         10   going to assure that the responses that you get

         11   have some consistency, that you give have some

         12   consistency. 

         13             DR. COHEN:  Right.  Let me start with the

         14   mailbox question first.  And that is that the way

         15   we've been working it and we've had a lot, but not

         16   inundated at this point.  But the way we've been

         17   working it is we have someone assigned to review

         18   the mailbox.  That person, from our staff, is an

         19   experienced person, so the simple questions she can

         20   answer herself.  And then the questions that she

         21   doesn't feel that she can answer, we tend to

         22   circulate amongst the staff at OHRP to get a


                                                                      209

          1   consensus answer and whoever is best suited to

          2   provide that information.

          3             I'm sure there will be a point, a volume

          4   point where we are going to have to try to come up

          5   with a better procedure, but we are committed, I

          6   think this is a very important effort.  Because one

          7   of the things that we get -- comments we get all of

          8   the time is, we don't know what to do, we don't

          9   know what the answer is and we can't wait for a

         10   conference or we can't wait, you know, we need some

         11   feedback fairly quickly.  And so I think it's a

         12   very important effort and we are committed to

         13   trying to make it work.  And we do always tell

         14   everyone, we're always willing to entertain

         15   hypothetical questions.  We have -- I know of this

         16   institution who is doing this -- 

         17             [Laughter.] 

         18             DR. COHEN:  -- is that okay, you know.  

         19             [Laughter.] 

         20             DR. COHEN:  As far as the FTEs are

         21   concerned, I believe we currently have -- there are

         22   three of us in the education division.  At this


                                                                      210

          1   point in time we lost some ground.  We have plans

          2   for adding, I believe, four or five people to that. 

          3   Those are still under development as we've now been

          4   able to move into a new effort.  And I should

          5   mention also, very importantly that it's not

          6   limited to the education division that we call on

          7   the entire staff of OHRP in our education effort

          8   and whenever people are available and are

          9   appropriate, we call them in and bring them into

         10   the education effort.  So the whole office is

         11   committed to the education effort.

         12             DR. DORFF:  I know you're not looking for

         13   more work, but one of the things that you may want

         14   to think about is creating a unit for college and

         15   graduate students to prepare them -- who are going

         16   to be going into research of one sort of another,

         17   just to give them a heads up while they're in

         18   training about the importance of this stuff. 

         19             DR. COHEN:  Yes, that's a very good idea. 

         20   We are looking for more work.  We are looking for

         21   new, particularly in terms of materials, brochures,

         22   guidebooks, we do want to do more of that.  And so


                                                                      211

          1   we will be actually looking for new ideas.

          2             AUDIENCE PARTICIPANT:  [Off mic.] 

          3             DR. COHEN:  Many medical schools do.  And

          4   I think it's a growing number that do.  And, of

          5   course, the NIH training grant requires such a

          6   course.  And so any institution that has an NIH

          7   training grant has to have a course like that.  So

          8   there is a growing number of courses.  Bob, maybe

          9   you would know a little more about that.

         10             DR. R. LEVINE:  I wanted to bring up a

         11   different topic.  Given your limitations in

         12   resources, there is an organization that has been

         13   out there trying to educate people on IRBs and IF

         14   --  for getting on to 30 years now, the Primer

         15   Organization.  There are three members of the board

         16   here at this table and they can assure you that I'm

         17   not speaking for them or the organization.  But I

         18   would like to know in what way you think your

         19   educational program compliments or supplements what

         20   Primer has been doing all along? 

         21             DR. COHEN:  Oh, absolutely.  I don't think

         22   anyone can doubt my allegiance to Primer.  But,


                                                                      212

          1   yes, we see that as a supplement and we also work

          2   very closely with Primer at their conferences and

          3   provide speakers and resources.  We see it as

          4   complimentary. 

          5             DR. R. LEVINE:  I didn't ask my question

          6   well.  Is there something in the efforts of Primer

          7   that left a gap that you felt impelled to fill? 

          8             DR. COHEN:  I think the main -- and,

          9   again, it's why we tended to focus on the group

         10   presentations because that was an area that --

         11   Primer was particularly with its IRB 101 program,

         12   it does an excellent job going to individual

         13   institutions and helping them educate their

         14   faculty.  And that's why we moved away from that

         15   focus.  And there was a need to do it in a larger

         16   group setting.  And the Primer meetings are

         17   wonderful, but only so many people can attend

         18   Primer meetings. 

         19             DR. R. LEVINE:  Let me say that 101 is one

         20   of the things that Primer has been doing in the

         21   last few years.  But their large scale meetings

         22   which were held as national meetings, I don't know


                                                                      213

          1   how many people applied to go to them, but at our

          2   last meeting we started turning people away when

          3   the registration hit 1400. 

          4             DR. KOSKI:  If I could just -- you asked

          5   about gaps.  I think that we do have, in fact,

          6   three serious gaps in education that we need to

          7   fill.  One of those is the investigative community. 

          8   Okay.  The people that tend to come to the primer

          9   community are the people that are already committed

         10   to doing this particular thing.  Not that

         11   investigators are not, but it's not something that

         12   fits into the regular daily life many time of the

         13   investigators.  And that's, in my mind, a problem.

         14             Increasingly though, we are seeing

         15   investigators taking advantage of opportunities for

         16   education, and, indeed, the investigator

         17   certification program that the Association of

         18   Clinical Research Professionals has now launched is

         19   taking off, you know, great guns so that people are

         20   going there.  But I think everyone recognizes the

         21   need to educate all the way up and down the chain

         22   here, the chain of command, and that points to


                                                                      214

          1   another gap.

          2             I think that oftentimes the people at the

          3   very top of our institutions and companies and all

          4   are people who could benefit from having a greater

          5   interaction with this particular segment of the

          6   human research community.  And so we are, again,

          7   looking for ways to do that.

          8             But, finally, I think the most serious gap

          9   in the whole thing is the lack of understanding

         10   that the public has about the nature of the

         11   research process.  The expectation that research is

         12   risk free is a problem.  And the lack of awareness

         13   of the entire IRB process is a problem.

         14             The lack, of understanding of what the

         15   informed consent process is all about is a problem. 

         16   And I think as we go forward we have to focus on

         17   not just educating IRB members and chairs and

         18   investigators and all, but really get the message

         19   out there to the American public about what

         20   research is really all about.  Because that's the

         21   single best way to improve the informed consent

         22   process, have people who are coming in who might be


                                                                      215

          1   interested in participating in the research to

          2   better understand the process and what's involved

          3   early on.

          4             MS. BORWHAT:  Related to what you just

          5   said, public outreach, do you have any plans to do

          6   the workshop or the video on the web as well?  And

          7   are any of the materials presented at the workshops

          8   or the educational presentations available on the

          9   web? 

         10             DR. COHEN:  Not currently, but that is in

         11   our plans.  We are looking at how we can best both

         12   the actual presentations themselves and the slides. 

         13   We are working with -- our last workshop was with

         14   the University of Southern California and they

         15   video taped the workshop and we are working with

         16   them to explore digitizing that workshop and

         17   putting it on the web.  So we are looking at ways

         18   to do that to get that accomplished.

         19             And let me mention, because Margaret, I

         20   already had a conversation about this earlier, the

         21   role of community members on IRBs, and we are

         22   looking at focusing some training on those


                                                                      216

          1   individuals because they have a special need and a

          2   special role to play.  And that's one of the areas

          3   that we've already talked about.

          4             DR. KORNETSKY:  As a member of the IRB

          5   community that uses the educational services of

          6   your office, I think it's important for this board

          7   to understand that there's really been great

          8   improvement over the past year and that they really

          9   are very receptive and I think whatever we can do

         10   to get the word out to people not to be afraid to

         11   call and use the educational services and have

         12   their questions answered is worthwhile.  Thank you.

         13             DR. COHEN:  One of the things that I say

         14   whenever I give a talk is no one ever has and I

         15   don't think anyone ever will be investigated based

         16   on a question.  And so people don't have to worry

         17   about asking questions. 

         18             CHAIRPERSON MARSHALL:  Jeff, maybe I'll

         19   just make one final remark and that is to commend

         20   you on your wonderful work in the education area. 

         21   And it truly is the most important thing, I think,

         22   in terms of prevention.  One other thought aside


                                                                      217

          1   from the tremendously important top down and bottom

          2   up idea of educating institutional CEOs and deans,

          3   and perhaps chairs of promotion committees and so

          4   forth, as well as research participants themselves

          5   and the public, might be a focus on science

          6   journalists and science writers.  Because I think

          7   they play -- as we know, if we look back at the

          8   history of research ethics and sort of crisis and

          9   response, that many of the stories that we first

         10   heard about are the cases such as Tuskegee and

         11   others, we heard about through science journalists. 

         12   And I think responsibility reporting is something

         13   that will go a great way towards educating the

         14   public as well and perhaps focusing on science

         15   writers would be a good thing.

         16             Thank you very much.

         17             MR. BARNES:  Could I ask one final

         18   question, please, if you don't mind.  Just quickly. 

         19   You know, do you have any relationship to -- have

         20   you ever done any public education with HCFA --

         21   with CMS?  And I'm particularly wondering because

         22   one of the issues that IRBs are grappling with


                                                                      218

          1   right now is -- because it's required by the common

          2   rule, instead of determining the informed consent

          3   process, what do patients have to pay for and what

          4   don't they have to pay for?  Which in turn is

          5   governed by the guidance that was put out by HCFA

          6   which is quite opaque in its interpretations.

          7             And I say that, you know, HCFA has its own

          8   web site, and I'm glad that you can answer all your

          9   questions, because clinical trials at HCFA.gov

         10   doesn't answer all of the questions posed to it, I

         11   can assure you.  And, I mean, this is a real

         12   practical question that IRBs are really grappling

         13   with it.  If you have reached out to CMS, I would

         14   really encourage you to try to do some joint

         15   presentations with the staff of CMS. 

         16             DR. COHEN:  I think that's an excellent

         17   idea.  We have interacted with them and in part to

         18   help bring them up to speed in terms of their

         19   developing their policies.  But I think that's an

         20   excellent idea to do some joint programs with them

         21   to focus on that issue would be -- you know, we

         22   would be happy to do that.


                                                                      219

          1             DR. R. LEVINE:  If I could comment on

          2   that.  I think that HCFA has been concentrating

          3   recently on the sort of clinical trial, the

          4   prototype for which was the National Emphysema

          5   Treatment Trial where HCFA took the position that

          6   it would not pay for services that were going to be

          7   evaluated in the National Emphysema Treatment

          8   Trial, in particular, it wouldn't pay for the lung

          9   reduction surgery unless the patients agreed to be

         10   randomized in the NETT trial.  And since that model

         11   was introduced there have been other things having

         12   to do with cardiovascular devices and so on.  But I

         13   don't think HCFA has addressed generally what would

         14   be called for by way of payment for various types

         15   of therapies that are being evaluated.

         16             MR. BARNES:  It actually has, Bob, because

         17   it put out a guidance document in September of last

         18   year which it is now trying to interpret it own

         19   guidance document.  But there is a general guidance

         20   document that was issued which has many gaps and

         21   that sort of thing.  

         22             CHAIRPERSON MARSHALL:  Is it Mike?


                                                                      220

          1             MR. SUSKO:  [Off mic.] 

          2             CHAIRPERSON MARSHALL:  Could you please

          3   use the mike.  I'm sorry, we need to tape our

          4   proceedings.

          5             MR. SUSKO:  Yes, my name is Michael Susko

          6   from CIRCARE.  Just one group that I don't think

          7   should be omitted in the whole general rubric of

          8   education would be the people who are likely to be

          9   enrolled in these projects.  And like at the

         10   various drop-in centers and soup kitchens, they're

         11   getting phone calls, the institutions are calling

         12   and asking about their research subjects.  So maybe

         13   that would be a place you could leave literature

         14   around so that people might be able to aware of

         15   their rights, the people who can read that are in

         16   that group.  But just don't forget that group. 

         17             DR. COHEN:  I think as Greg mentioned, the

         18   whole area of public education and education of

         19   potential subjects, wherever they are is high on

         20   our list.  We haven't had the resources to get to

         21   that yet.  But we are very committed.  That's a

         22   very, very, very important issue.


                                                                      221

          1             Like they say with used cars, the best

          2   protection is an informed consumer.  And so we

          3   really are -- that's on our list and we really do

          4   want to approach that at all levels.

          5             CHAIRPERSON MARSHALL:  Thank you, Jeff,

          6   very much.

          7             Next we have George Gasparis who is the

          8   Acting Director of the Division of Assurances and

          9   Quality Improvement. 

         10             MR. GASPARIS:  Good afternoon.  It's a

         11   great pleasure to be with you this afternoon to

         12   share the workings of our division and our new

         13   initiatives.  And I also would like to express a

         14   sincere thank you to NHRPAC for inviting me here.

         15             Our division used to be called the

         16   Division of Policy and Assurances, and under the

         17   restructuring has been moved to the new title,

         18   Division of Assurances and Quality Improvement. 

         19             I would like to take a moment to recognize

         20   our rather small division, or I would call it a

         21   small division considering the enormous workload

         22   that we have facing us.  Roslyn Edson, Dr. Kamal


                                                                      222

          1   Mital, Frieda Yoder, Janice Walden who joined us

          2   recently, and we have been fortunate to also have

          3   help from outside the division with a Dr. Sharkey

          4   and Dr. Nasbatin who is in the audience today,

          5   helping in with the division, and we have one

          6   support staff Denise Dejarne.

          7             Real quickly, I think there's only one

          8   person of the division here business of other

          9   obligations.  Dr. Batins, if you could stand.  And

         10   was Frieda able to make it this afternoon?  I guess

         11   not.

         12             Kamal is attending a conference and Cliff

         13   is out of town and the others are holding up the

         14   fort while I'm here this afternoon.

         15             Actually, I do prefer to probably stand up

         16   -- since I'm using PowerPoint -- if you can hear me

         17   clearly; otherwise, I'll sit back down closer to

         18   the microphone.

         19             Real quickly, I want to go over our old

         20   system of assurances of compliance so you can

         21   understand why we felt the need to revamp a system

         22   and move to a new system. 


                                                                      223

          1             We have three general types of assurances

          2   in the past:  a multiple project assurance,

          3   cooperative project assurance, a single project

          4   assurance.  And the later two we adopted through

          5   international sites.  And that adaptation was that

          6   they could reference other standards -- procedural

          7   standards, for example, C-owns and other ethical

          8   principles, the Declaration of Helsinki rather than

          9   the Belmont Report and our regulations.

         10             Real quickly, just to share with you the

         11   fundamental aspect with each of these assurances,

         12   and assurance is simply a written commitment from

         13   an institution engaged in human subject research

         14   supported by the Department or the federal

         15   government under the common rule that they provide

         16   to us a commitment that they understand the

         17   regulations and will comply with them.

         18             Starting with the lowest level of

         19   assurances, single project assurance, we internally

         20   reviewed the individual brain application and

         21   proposed informed consent form because we felt that

         22   these were smaller institutions that did not have


                                                                      224

          1   an experienced IRB to review that research.  Under

          2   the cooperative project assurance, what we reviewed

          3   was the infrastructure in place with the design of

          4   the protocol and the informed consent, and we felt

          5   competent that these multi-center trial were

          6   managed properly and with sufficient expertise that

          7   we could approve institutions over a CPA for a

          8   five-year period for any research under a

          9   cooperative protocol which falls under this

         10   program.  And these are the famous oncology trials,

         11   AIDS clinical trials group which put out pretty

         12   polished products.

         13             And under the highest level of assurance,

         14   also for a five-year period, we approved the major

         15   institutions and academic medical centers under a

         16   multiple project assurance because they had proven

         17   to us in the past that the IRB had sufficient

         18   expertise that we could rely upon that institution

         19   to conduct their own review, and we didn't have to

         20   review that project internally.

         21             Well, what we found happening in our

         22   office was a significant increase in volume


                                                                      225

          1   especially since 1995, and just from 1999 alone to

          2   2000, we had a 48 percent increase in workload

          3   under the single project assurances.  This was a

          4   tremendous workload that made it almost impossible

          5   for us to review each individual project.  And

          6   toward the latter part of 2000, we had to turn away

          7   the individual reviews of those protocols and put a

          8   disclaimer on our approval letters that we did not

          9   review the informed consent for that document.

         10             So, we felt the need to move to a new

         11   assurance system in which we would treat every

         12   pretty much equally even though every institution

         13   wouldn't be at the same starting place, and include

         14   in this assurance more education and then approach

         15   each institution down the road and work more

         16   closely with the IRBs to strengthen the overall IRB

         17   system. 

         18             So, under Greg's leadership towards the

         19   end of last year, we did release the federal-wide

         20   assurance, the new assurance mechanism under a

         21   pilot program thereby eliminating all the

         22   permutations of the old system making it a much


                                                                      226

          1   simpler system which there is one assurance

          2   document per institution and we still manage to

          3   keep the flexibility for international

          4   institutions.  All institutions are eligible for a

          5   federal-wide assurance which has great significance

          6   which it means that an institution no longer has to

          7   wait for a grant to be awarded to apply for an

          8   assurance, i.e., a single project assurance. 

          9   Therefore, we are removing the hold up with a

         10   regulatory burden in which research is being

         11   delayed for our review.

         12             Eventually the federal-wide assurance will

         13   be entirely web-based, meaning that an institution

         14   can submit to us electronically and receive an

         15   electronic approval, but by no means are we

         16   limiting or eliminating any institution that

         17   doesn't have access to the internet they could

         18   still submit the federal-wide assurance under a

         19   paper submission and this is of most concern

         20   perhaps to some international organizations that do

         21   not have the same technological capabilities that

         22   we have.


                                                                      227

          1             For the federal-wide assurance we broke it

          2   down into a two-step process where the IRB, whether

          3   it's the own institutions IRB or another outside

          4   IRB would have to register in our database and we

          5   worked closely with FDA to develop our IRB

          6   registration which was jointly released with the

          7   federal-wide assurance.  Under the IRB registration

          8   system, any IRB can submit to us for registration. 

          9   There is no requirement that they review federally

         10   funded research.

         11             The IRB submission process is very simple. 

         12   It's downloading a three-page form which could be

         13   completed in a matter of a half hour or less.  And

         14   one advantage for an IRB to register with us is

         15   that we can notify them of any upcoming new

         16   guidance, new policies being released by our

         17   office, or any new information which we think would

         18   be helpful to them.

         19             Anyone can track any approval of an

         20   assurance or any IRB that's been registered on our

         21   web site.

         22             I mentioned how we handle the assurances


                                                                      228

          1   because with the single project assurances,

          2   remember, we are no longer going to review these

          3   individual protocols.  So, we felt that we had to

          4   strengthen the federal-wide assurance mechanism by

          5   emphasizing the need for education.

          6             One aspect of the federal-wide assurance

          7   that we did not handle properly or as well as we

          8   should have when we released it was to clarify the

          9   difference between our assurance training modules

         10   which we produced three assurance training modules

         11   for the signatory official, human protections

         12   administrator, and IRB chair to complete for

         13   submission of a federal-wide assurance versus

         14   educational training. 

         15             First of all, the assurance treatment

         16   modules we do not consider to be educational

         17   training, but rather training towards the essential

         18   requirements of the responsibilities under an

         19   assurance. 

         20             Education training, on the other hand, we

         21   feel is essential for the IRB, its chair, members

         22   and staff, and for investigators and we do


                                                                      229

          1   articulate the need for educational training by the

          2   institution under the federal-wide assurance.

          3             Such training should cover ethical

          4   principals, the regs, state law and institutional

          5   policy.

          6             Well, what is our experience so far under

          7   federal-wide assurance?  Well, to date, "to date"

          8   being Friday afternoon with any approval entered in

          9   our database, we've approved 789 federal-wide

         10   assurances and we've approved 804 single project

         11   assurances.  For seven months, it may not seem like

         12   there was much difference here with a pretty much

         13   50/50 split. 

         14             I don't want to bore you with numbers, but

         15   I took a look at just the past three months and

         16   there's an almost seven-fold approval of FWAs

         17   versus a single project assurance.  What this

         18   suggests to us is that our office, our division is

         19   going to gain tremendous efficiency in that we are

         20   going to have to spend less time on review and

         21   approval of assurances and we could turn to our new

         22   initiative which I'll explain in a moment.


                                                                      230

          1             Recall that federal-wide assurance is

          2   approved for a three-year period.  A single project

          3   assurance is approved for only that individual

          4   grant.  So once an institution has a federal wide

          5   assurance we will gain tremendous efficiencies by

          6   the diminishing need of review of assurances in the

          7   future.

          8             We have received many comments from other

          9   federal agencies, the public, IRBs, on our federal-

         10   wide assurance, on confusion about how to apply it

         11   for certain institutions.  Again, by going to a

         12   one-model-fits-all, we tried to fit all the

         13   necessary responsibilities of an assurance under

         14   one document.  That's difficult to do when you

         15   apply it to a large institution conducting research

         16   versus a nursing home with just a school that is

         17   engaged in one or two projects.

         18             So, we gained from all the comments

         19   submitted, we drafted new versions of the federal-

         20   wide assurance, it's terms and the IRB registration

         21   form which we think will serve just or answer to

         22   the criticisms and the comments that we have


                                                                      231

          1   received so far and we do feel that the final

          2   products will be very useful in application to all

          3   types of institutions. 

          4             Once we finalized these versions, we will

          5   submit in the very near future to OMB for clearance

          6   of these final documents and we will release them

          7   on our web.

          8             Under Dr. Koski's leadership, we have

          9   implemented our new initiative which we feel is

         10   necessary, especially for those smaller

         11   institutions which under the single project

         12   assurance we didn't have confidence that the IRB

         13   could review as well as an MPA institution.  But we

         14   feel that all IRBs, because of the amount of burden

         15   facing them, do need some assistance and we need to

         16   ensure that they are doing the best job possible. 

         17             Therefore, under our new program we have

         18   objectives to improve the performance, quality, and

         19   effectiveness of IRBs, and secondarily to help them

         20   ensure compliance with the regulations. 

         21             As Dr. Koski mentioned, it's a voluntary

         22   program for institutions and we will approach this


                                                                      232

          1   new program under a three-pronged approach with

          2   site visits, videoconferencing, and self evaluation

          3   through a self-assessment tool.

          4             We developed our QA self assessment tool

          5   and released it just this past month to nine

          6   institutions for review and comment.  And as Dr.

          7   Koski mentioned, we are now beginning our pilot

          8   testing of the QA tool.

          9             And during the questions and answers if we

         10   have time, I'll leave my e-mail for any of you who

         11   wish to forward any comments. 

         12             CHAIRPERSON MARSHALL:  Adil. 

         13             DR. SHAMOO:  Thank you.  The Office of

         14   Research Integrity, ORI, does not have the system

         15   of assurance which is really a contractual

         16   agreement between the institution and OHRP.  But

         17   what they do have -- and they have evolved into

         18   this -- a model institutional policy regarding

         19   scientific misconduct.  They have published that in

         20   the web, they give copies of it, they describe how

         21   the inquiry stage, the investigation stage, the

         22   membership, et cetera, et cetera. 


                                                                      233

          1             Institutions are developing now

          2   institutional policies parallel to scientific

          3   conduct issue, how to deal with it, how to deal

          4   with human research protections. 

          5             Now, those institutional policies varies

          6   literally from A to Z.  And I was wondering whether

          7   one way to mainstream those fallacies is for OHRP

          8   to develop a model institutional policy dealing

          9   with Human Research Protections as well as, and I

         10   know this will give you more work, as well as ORI

         11   does it, the institution before final approval by

         12   their board of trustees, or the president of their

         13   institution of these policies they are giving a

         14   copy to your office, for example, equivalent to

         15   ORI, they review it, they send back comments, you

         16   missed your -- you have all non-tenured professors,

         17   or you don't have enough tenured professors, or you

         18   didn't wait 30 days or 60 days, et cetera, and they

         19   send it back, the institution go over it, of course

         20   the institution all the time make their policy

         21   slightly tougher than the federal requirements, so

         22   they will be safe.  And I'm saying is, could you


                                                                      234

          1   move in that direction and lessen the confusion

          2   among institutions in developing their own

          3   institutional policies regarding human research

          4   protections. 

          5             MR. GASPARIS:  I'll let Greg chime in

          6   after I make some comments, because I'm sure he has

          7   some thoughts on this as well.  We've toyed with

          8   the thought of developing standard operating

          9   procedures.  Your latter comments addresses our

         10   difficulty with releasing such a document because

         11   from our perspective our sample policies would be

         12   applicable to the regulations which we govern.  But

         13   when an institution drafts and writes operating

         14   procedures they must also consider the FDA regs,

         15   they must consider state law, experiences within

         16   that institution.  So, therefore, there could be

         17   quite a variance in the actual SOPs that each

         18   institution has. 

         19             Under our QA program we will look at the

         20   operating procedures of each institution and we do

         21   have already guidance which an institution can use

         22   to draft their own written policies if they


                                                                      235

          1   haven't.  Hopefully most institutions already have

          2   operating procedures for their IRBs in human

          3   subject protection system because they're required

          4   by the regulations.  But the guidance that we

          5   already have on our web site available now to

          6   institutions is from the compliance division issues

          7   of revolving concern.  I don't think I've mentioned

          8   the title, as you will see it on the web site, but

          9   if you look under "compliance division" you'll

         10   easily find this document.  And it goes point-by-

         11   point with many of the procedural concerns that an

         12   institution should address in their operating

         13   procedures.

         14             Our self-assessment tool will also be a

         15   document which an institution can use to verify

         16   that their operating procedures are comprehensive

         17   with respect to at least our regulations. 

         18             DR. KOSKI:  If I could just quickly add in

         19   there.  Obviously we need to have a level playing

         20   field across the board for all entities engaged in

         21   human research, we can't have the level of

         22   disparity in regional practice or local practices


                                                                      236

          1   that we have now.  So that we are really fostering

          2   efforts to get there.  Again, George mentioned some

          3   of the tools that are available within government. 

          4   Already organizations like CIOMS have prepared a

          5   guideline for operating procedure for institutional

          6   -- it's a work around the world.  And those tools

          7   are already available.  So I'm not sure that we

          8   would gain a lot by doing that.

          9             Instead, we are trying to emphasize what

         10   both the research community and the Office of the

         11   Inspector General have called for, and that's

         12   flexibility with accountability.  We recognize that

         13   institutions vary enormously in size, the way they

         14   operate, and it's not just institutions also.

         15             So as we move to a level playing field, we

         16   have to consider that there's all the research, in

         17   fact, more research done in the private sector

         18   that's non-institutionally based.  And so, again,

         19   the key thing here is for everyone to understand

         20   their responsibilities and take the actions

         21   necessary through their own initiatives to meet

         22   those responsibilities and expect to be held


                                                                      237

          1   accountable for doing so.

          2             CHAIRPERSON MARSHALL:  Sandy.

          3             DR. CHODOSH:  I'm a little bit dense as I

          4   get older, but it's a little unclear to me how

          5   avoiding looking at SPs and replacing it with

          6   federal-wide assurances is going to help with the

          7   problem for which SPs were designed, namely, the

          8   institutions that do not do very much work, do not

          9   have the kind of depth of staff and how does the

         10   FWA improve that? 

         11             MR. GASPARIS:  Good question, Sandy. 

         12   Actually, to give this overview in 15 minutes, I

         13   couldn't go into detail with some of our thought

         14   processes along the way.  We feel comfortable

         15   moving ahead because most of the research covered

         16   by SPAs tends to be lower-risk research that's to

         17   small business enterprise or innovative research

         18   grants.  And when most of this research involves

         19   higher risk research, it involves a medical center

         20   where the research is actually conducted.  So,

         21   there is some safety net already in the system

         22   moving forward in that that research would be


                                                                      238

          1   reviewed by a more experienced IRB.

          2             We found though in our past experience

          3   that some of the research that we reviewed that was

          4   minimal risk, however, these IRBs just don't get

          5   it, or don't do as well of a job and we need to

          6   reach out quickly to them to strengthen that IRB

          7   system.

          8             So I'm going to try to invite all former

          9   SPA institutions to join rather quickly in our QA

         10   initiative.  We've already received many requests

         11   for a QA program once it's released.  But that's

         12   the part that we want to attack pretty aggressively

         13   and reach out to these smaller IRBs that don't have

         14   as much experience to strengthen their operation.

         15             We had to move forward in this direction,

         16   however, because we were falling behind.  We

         17   couldn't keep up with the workload.  It was just

         18   too much to do.  We had to overhaul our review

         19   system to a more effective review system.

         20             DR. KOSKI:  I think also that we need to

         21   recognize that spot approvals, kind of like spot

         22   zoning, if you will, means that things may be okay


                                                                      239

          1   on the corner of Fifth and Vine, but, you know,

          2   there's a lot of different corner operations that

          3   need to be addressed.  The focus in our efforts are

          4   toward building a real system instead.  And, using

          5   the combined approach of systemwide education with

          6   systemwide quality improvement efforts coupled

          7   with, in the private/public partnership

          8   accreditation as a means to establish that level

          9   playing field, I think is the way to get to where

         10   we need to be to have really a uniform safety net

         11   that's tightly knit across the board.

         12             So we are trying to put our resources into

         13   that and, of course, to get there, we need to turn

         14   to the private sector to really rely on and

         15   collaborate with organizations such as Primer and

         16   ACRP and a host of others that sort of crossed the

         17   entire domain in order to begin to knit this

         18   together.  So that is where we are going.

         19             DR. CHODOSH:  I understand what you're

         20   saying.  I guess I have some concerns about how

         21   long it's going to take to get that net up in place

         22   -- the safety net.  And, you know, I would hate to


                                                                      240

          1   see a lot of things falling through the cracks. 

          2   That's all. 

          3             CHAIRPERSON MARSHALL:  Denyse, did I see

          4   your hand up?  No.  Okay. 

          5             Jonathan.

          6             DR. MORENO:  In the spirit of Sandy's

          7   comment, will we have the opportunity to see the

          8   draft version of the FWA? 

          9             MR. GASPARIS:  Yes

         10             DR. MORENO:  Will we have the opportunity

         11   to see it before the next meeting, I guess is the

         12   force of my question since -- 

         13             MR. GASPARIS:  Yes.  A little better than

         14   that.  In your book right now you do have the FWA,

         15   its terms of assurance and IRB registration which

         16   is currently in practice.  You also have the draft

         17   QA tool which was developed and released last month

         18   -- released last month, developed over the past few

         19   months.  Either this evening or after this meeting

         20   we will give you a copy of the draft. 

         21             DR. MORENO:  Thank you. 

         22             DR. KOSKI:  If I could just throw in one


                                                                      241

          1   more comment on this also.  The way the new

          2   assurance process is developed, by the way, allows

          3   for smaller institutions, okay, that may not be

          4   able to truly afford the really enormous costs of

          5   running an effective human research protection

          6   program to actually rely upon another organization

          7   to serve the central part of that while they

          8   maintain their own local implementation component

          9   of that.  So it's still respectful of the

         10   individual site where it's being done.  I believe

         11   that as we go forward, as we see the system evolve,

         12   okay, people will come to recognize that this

         13   assurance is more than just a contract.  It is a

         14   promise.  An assurance is a promise.  And when you

         15   promise the federal government that you're going to

         16   do it according to a specific set of regulations

         17   and realize that there are enormous consequences

         18   for not keeping your promise to the federal

         19   government, I think we'll begin to see a movement

         20   toward reliance upon programs that can provide that

         21   function in the most robust way with greater

         22   efficiency and effectiveness.  So this is something


                                                                      242

          1   that has to evolve.

          2             However, under our new -- you'll hear also

          3   about our expansion of compliance oversight

          4   activities on a not-for-cause basis in a moment. 

          5   We will be reaching out to probably 70 or more

          6   programs engaged in human research per month. 

          7   Okay.  That's not four per year, or, you know,

          8   whatever.  It's 70 per month which is a very, very

          9   different spectrum.  And merely the fact that

         10   people know that not only are they making a

         11   promise, but that someone is going to be looking at

         12   what they're doing to fulfill that promise in a

         13   very active way provides a powerful incentive for

         14   making sure you're doing it right.

         15             CHAIRPERSON MARSHALL:  Mark. 

         16             MR. BARNES:  George, I wanted to ask you

         17   about the QA process.  It seems to me that based on

         18   the form that you have here that what you're

         19   calling QA is actually a form that's submitted by

         20   the IRB to your office to determine the compliance

         21   with a series of standards.  And I wonder a couple

         22   of things.  One is, what's the line going to be


                                                                      243

          1   between sort of enforcement and QA since

          2   institutions are voluntarily submitting this stuff

          3   to you, and especially if some of their answers to

          4   this are that they are not doing what they ought to

          5   do, then how will that, or will that not be used by

          6   the people on the compliance side?

          7             And the second question is, this is an

          8   observation for whatever good it's worth, the QA

          9   traditionally in health care is done under a cloak

         10   of confidentiality and that confidentiality is not

         11   federal law, it's state-by-state law.  And state

         12   laws basically insulate the quality assurance

         13   process from discovery during malpractice suits and

         14   other kinds of suits.

         15             With the specter of liability hanging over

         16   IRBs and IRB members now because of the many -- the

         17   multiple lawsuits that have been filed against them

         18   in various of the controversies that have been

         19   talked about today, it seems to me that there is --

         20   aside from what you are doing here, that if one

         21   wants the -- if you guys want appropriately IRBs to

         22   really have an internal quality assurance process,


                                                                      244

          1   then have you thought about what kinds of

          2   protections would attach and about whether there's

          3   maybe some room for some federal regulation here? 

          4             MR. GASPARIS:  Excellent questions and I

          5   didn't expand on our QA program to inform you of

          6   our thinking because it's tough to do that in 15

          7   minutes and I may not have time to -- 

          8             [Laughter.] 

          9             MR. GASPARIS:  -- do it now.  But we've

         10   thought through all of these questions which you

         11   pose right now and we are coming up with, I think,

         12   answers that will allow an institution to trust us

         13   they volunteer under the QA program to improve

         14   their system without causing damage.  So we are

         15   going in to an institution to work in a very

         16   collegial manner in which we will discover

         17   deficiencies and point the IRB and the overall

         18   institution of human subject protection system in a

         19   right direction; point them to the regulation, show

         20   them that they need to improve in this area and

         21   share the positive experiences from other human

         22   subject protection systems, other IRBs in which the


                                                                      245

          1   IRB under scrutiny can improve their operation.

          2             So, if we see an effective system, we'll

          3   share that with the IRB as a suggestion.

          4             With regards to your question about

          5   confidentiality, what we are looking towards is

          6   having an exemption under FOIA where any

          7   information collected under the QA program would

          8   not be released.  And we've made some significant

          9   positive steps that we can gain an exemption under

         10   FOIA so that we could keep the promise that we will

         11   not release information collected under QA.  We are

         12   very sensitive that whatever information we collect

         13   we're going to collect it in a manner in which we

         14   could do our work, but would not be released to an

         15   outside group.

         16             CHAIRPERSON MARSHALL:  Bob.

         17             DR. R. LEVINE:  I wanted to make a general

         18   comment.  What we are starting to do now is what I

         19   thought the purpose of NHRPAC was when I agreed to

         20   join it, whenever I agreed to join it.  We are now

         21   actually looking at the policies and practices of

         22   OHRP.  And I think that's the most important thing


                                                                      246

          1   that this committee can do.

          2             I'm sorry that this is taken out of

          3   George's 15 minutes, but -- 

          4             [Laughter.] 

          5             DR. R. LEVINE:  -- but as we've heard from

          6   our speakers so far, there's been any number of

          7   issues that I would have brought up if we had

          8   enough time to deal with them in detail.  I think

          9   Mark's question highlights the need for this.  The

         10   time to explore confidentiality of quality

         11   assurance is not after you've got the program up

         12   and running.  And this is why I think NHRPAC

         13   probably ought to be kept aware of what your plans

         14   are with regard to the future.  I think it would

         15   have been helpful before you decided to recognize

         16   CIOMS and Helsinki as good alternatives to Belmont

         17   to have talked with this committee and you would

         18   have heard some stories about Helsinki in

         19   particular and CIOMS to a lesser extent is flatly

         20   inconsistent with federal -- U.S. federal policies

         21   and practices.  And, you know, perhaps you might

         22   have come to a different conclusion.


                                                                      247

          1             But what I want to put in a plea for is

          2   for this committee to serve, as I thought it was

          3   going to, as in a relationship to OHRP is say the

          4   Advisory Council of NIMH serves to the program

          5   staff at NIMH to discuss policy decisions and

          6   strategies before they actually get out there. 

          7             One of my big concerns is that the recent

          8   activities of OHRP have been interpreted variously

          9   in the newspapers and by members of IRBs.  When you

         10   say you want your educational program to reach

         11   people who serve on appointments and promotions

         12   committees, and Mary Faith says, well, we're glad

         13   you're reaching out to them, I'd be astonished if

         14   any of them come to your educational program. 

         15   Investigators want to do, at this point they're

         16   happy to take their one hour on the Internet and

         17   get their certificate so they can submit their

         18   grant.

         19             These are things that I think could be

         20   discussed at this committee which is made up of a

         21   lot of people who have a lot of experience of a

         22   type -- of various types that people at OHRP don't


                                                                      248

          1   have.  I think we could help enhance not only the

          2   activities of your office, but also the public's

          3   response to it. 

          4             DR. MATHER:  Could I just make a comment? 

          5   John Mather with the VA.  Because I'd like to go

          6   back to the FWA and we've been working with George

          7   and OHRP to eliminate duplicate effort that

          8   happened in the VA where we had our own assurance

          9   and then there was the OPRR and the OHRP

         10   assurances.  I think over the last year our

         11   experience in working with this pilot has been it

         12   has in fact strengthened and simplified and made

         13   more efficient.  There was probably one downside

         14   and that is, if you don't run your own IRB under

         15   your own FWA, it will probably spawn another set of

         16   guidances that you're going to need in a government

         17   structure.

         18             So if you use somebody else's IRB, you're

         19   going to have to have some kind of agreement, MOU,

         20   or whatever you want to call it, and certainly in

         21   the accreditation program that the VA is sponsoring

         22   through NAQUA, there's a requirement there that if


                                                                      249

          1   one uses somebody else's IRB that there is these

          2   understanding in a government structure.

          3             But it's gone one step beyond that and

          4   very clearly there is no free lunch.  And this

          5   costs money.  And so if you don't use your own IRB

          6   in all likelihood, just like with commercial IRBs,

          7   it's going to cost money.  And I think somewhere in

          8   this and Greg and I have talked a little bit about

          9   this.  Although it's not our responsibility in a

         10   way to worry about the money, this is still a high

         11   cost endeavor.  And if you more into the other

         12   areas George and I have taught about, the QA and we

         13   are doing something similar in the VA, again, this

         14   is no free lunch.

         15             And the concern I have in some of this is,

         16   the underlying issue that yet has got to be

         17   addressed and that is issues like NIH indirects and

         18   the other kinds of money that support this kind of

         19   enterprise.  It's terribly important the direction

         20   we're going in, but I want to raise the issue that

         21   this is no free lunch.

         22             CHAIRPERSON MARSHALL:  Thank you very


                                                                      250

          1   much.  I think Bob wanted to respond to that, then

          2   I have Elliot. 

          3             DR. R. LEVINE:  Not respond to that, but

          4   one thing that Mark's comment, one memory it

          5   recalled for me that I wanted to make as part of

          6   what I said earlier is that OHRP and its

          7   predecessor OPRR have been perhaps unknowingly

          8   exploited by people out there.  One favorite trick

          9   of plaintiff's attorneys is to file an anonymous

         10   complaint against an institution and then have OPRR

         11   or OHRP more recently go in there, conduct a full-

         12   scale investigation and then they get access to all

         13   of the records of this under Freedom of

         14   Information.  They're getting about $30 to 50,000

         15   worth of free discovery, and then this is used to

         16   form the basis of litigation against the

         17   institution that was targeted with an anonymous

         18   complaint which OHRP frequently finds is

         19   groundless.

         20             CHAIRPERSON MARSHALL:  Elliot -- or, Greg,

         21   were you going to respond to that?

         22             DR. KOSKI:  I just wanted to quickly


                                                                      251

          1   comment with respect to Dr. Mather's comment, that

          2   certainly the issue of resources for human research

          3   protection programs have not gone unnoticed nor

          4   have some of the other issues that Bob brought up.

          5             Indeed, we're working actively with both

          6   NIH and with the budget office to find appropriate

          7   ways to make sure that resources are directed

          8   toward doing this job right.  There are a number of

          9   issues that we won't go into now in the interest of

         10   time about how you categorize them as either

         11   allocable, direct costs, direct costs, indirect

         12   costs, administrative costs, special costs, it

         13   doesn't matter.  What we need to do is to make sure

         14   whatever mechanism is used, and it may be a

         15   creative mechanism, is such that it provides, you

         16   know, the resources necessary to do the job,

         17   recognizing that protection of human subjects, as

         18   I've said many, many times is part of the research

         19   endeavor.  It's not just an administrative add-on

         20   to that and we've got to look at it in that

         21   context. 

         22             Dr. Baldwin at NIH has been instrumental


                                                                      252

          1   in trying to move this forward and I don't see

          2   Wendy or Belinda here today, Belinda Seto, but they

          3   are working actively on that.  And I believe that

          4   everyone recognizes that need.  So we'll continue

          5   to move forward with it.  Thanks.

          6             DR. DORFF:  I'm a novice to all of this. 

          7   So forgive me if what I'm about to say is way off

          8   base.  Right.  But two things.  One is, there are

          9   an awful lot of abbreviations that you've been

         10   using -- 

         11             [Laughter.] 

         12             DR. DORFF:  That -- 

         13             AUDIENCE PARTICIPANT:  [Off mic.]

         14             DR. DORFF:  But you're creating a self

         15   assessment tool for people who are not part of the

         16   government.  Right.  And I think, you know, you

         17   have to ask yourself -- I mean, there are two

         18   places in here which you use an abbreviation that

         19   you actually spell out the meaning of.  That's

         20   great.  Do that.  Okay.  If you're going to do

         21   that.

         22             But, I mean, like in your presentation you


                                                                      253

          1   have one line in here, MPA, CPAs, SPAs, CAs, 2A,

          2   A2s, NIAs eliminated.  I'm glad for that.  

          3             [Laughter.] 

          4             AUDIENCE PARTICIPANT:  [Off mic.]  That's

          5   all you need to know.

          6             DR. DORFF:  That's right.  But the other

          7   thing -- and then, also, in the form you refer to

          8   -- I'm on questions 97, 98 -- for research

          9   involving prisoners of the -- document IRB findings

         10   is required under 45 CFR 46.305,306.  I mean, I

         11   think minimally you at least have to provide a copy

         12   of that to any institution that is going to be

         13   doing it, all right. 

         14             DR. KOSKI:  Let me just say -- 

         15             DR. DORFF:  And then the other thing --

         16   the other thing is, you have 128 questions here. 

         17   Right?  I mean, more is less, to be very honest.  A

         18   good principle in education.  It seems to me that

         19   if you could pare this down to what you really need

         20   to know for an IRB to be able to figure out, to

         21   evaluate itself and to figure out what is -- you

         22   know, what's going on, and only the very last part


                                                                      254

          1   of this deals with human subject protections.   So,

          2   I mean, if this is a quality assurance thing, I

          3   take it for everything about the IRB and not just

          4   human subject research -- right -- protections. 

          5             So, I mean, first of all, okay.  But, I

          6   mean, they should at least know what they're

          7   getting into if they're doing this.  That this is

          8   not only for human subject protection, that this is

          9   for other things as well.

         10             But even for these other things, I mean,

         11   if you had 20 questions rather than 128, it would

         12   go much further. 

         13             DR. KOSKI:  Well, I was just going to

         14   point out that if there's anyone running an IRB

         15   that doesn't know what 45 CFR 46 is, they shouldn't

         16   be running an IRB. 

         17             CHAIRPERSON MARSHALL:  Susan.

         18             DR. KORNETSKY:  Yes, Elliot, I just want

         19   to say, you are a novice to it.  I mean, I've had

         20   an opportunity to look through this and for someone

         21   who works in the IRB profession, a lot of it does

         22   make sense.  There may be some areas that it can be


                                                                      255

          1   shortened and, you know, they are obviously looking

          2   for input, but it's a pretty complicated thing. 

          3             MR. GASPARIS:  Elliot, I would like to

          4   thank you for your comments.  First of all, our

          5   ears have grown a lot over the past eight months

          6   and are continuing to grow.  And perhaps the

          7   biggest skill we are trying to improve on is

          8   listening.  So any comments you have about the

          9   draft, please submit them to us and we'll consider

         10   them very objectively and especially about

         11   abbreviations.

         12             The reason I did not explain in a

         13   presentation what all those abbreviations were, it

         14   was intention because I want to show that we're

         15   moving from this complicated system to a much

         16   simpler system.  So, that accomplished my goal in

         17   that you were confused. 

         18             [Laughter.] 

         19             MR. GASPARIS:  That's what I wanted you to

         20   experience. 

         21             DR. CHODOSH:  Could I suggest that you

         22   actually have an excellent quality assurance model


                                                                      256

          1   here.  You have 128 questions if you'll only add to

          2   it, yes, no, I don't understand the question.  And

          3   if you can reduce that latter category, you'll have

          4   an excellent quality assurance model. 

          5             MR. GASPARIS:  Thank you, Sandy.  That's a

          6   great suggestion. 

          7             With regards to the size of the tool,

          8   we're soliciting feedback, we're trying to balance

          9   two objectives here; to be as comprehensive as

         10   possible, but because IRBs are so burdened, I don't

         11   want to take up a tremendous amount of time site

         12   visiting them and distracting them from their task

         13   at hand in protecting human subjects.  So we need

         14   to balance the amount of comprehension that we can

         15   gain of the system versus least amount of time that

         16   we can do to assess them. 

         17             DR. KOSKI:  I would just quickly comment

         18   that the real purpose here, again, is quality

         19   improvement.  Not so much quality assurance. 

         20   Quality assurance is an auditing tool.  Quality

         21   improvement means you get a better product out of

         22   it.  And, of course, you have to make an assessment


                                                                      257

          1   before you can find where there are strengths and

          2   weaknesses in order to fix the process, in order to

          3   make it work better.

          4             But the real emphasis here is on quality

          5   improvement.  And there are two needs basically. 

          6   One is to make sure that you're satisfying your

          7   requirements under your assurance which means the

          8   regulatory requirements, although we didn't want

          9   that to be the focus, the rest of it is to actually

         10   go beyond the minimal regulatory requirements to

         11   try to help build a program.

         12             And in setting up this kind of tool, it

         13   focuses on a number of areas that may not be

         14   immediately required under regulation, but it would

         15   help prepare programs for achieving accreditation

         16   within the private voluntary sector.  So there

         17   actually is a logic to it.

         18             In fact, there are probably more than 128

         19   specific points that you need to meet under the

         20   regulations, but we don't need to go into all of

         21   those right now.

         22             CHAIRPERSON MARSHALL:  Any questions from


                                                                      258

          1   our ex-officio or our public members and folks in

          2   the audience?  Any others for George? 

          3             DR. F. LEVINE:  That sort of picks up on a

          4   number of themes and something great that you just

          5   made reference to when this is this at-the-moment

          6   voluntary accreditation process in the private

          7   sector, that is -- is likely to evolve and how much

          8   and how are you thinking about kind of the

          9   alignment between your ends of the process and what

         10   will be this additional tier which each are under

         11   resourced and somewhat partial. 

         12             DR. KOSKI:  Well, the beauty of the

         13   quality or, I'm sorry, of at accreditation process,

         14   okay, is that it is something that is nonregulatory

         15   in nature that actually allows sites to demonstrate

         16   their commitment to achieving a standard of

         17   excellence in their performance that can actually

         18   serve as a plus in the marketplace, if I may use

         19   that term loosely.  Indeed, the pharmaceutical

         20   industry has already stepped up and said, we

         21   recognize the value of this. 

         22             In fact, if we only place our research at


                                                                      259

          1   institutions that have achieve accreditation for

          2   their human research protection program, we are

          3   going to be better off because we will have fewer

          4   studies that are being thrown out because they

          5   haven't been done right with respect to protections

          6   of human subjects.  So it actually, the whole

          7   process works better that way.

          8             We see the private voluntary accreditation

          9   as an extremely powerful complement to the

         10   government's regulatory activities.  Because if we

         11   have a database for instance that covers all

         12   registered programs and we can cross-reference that

         13   to a database of all accredited programs, well, if

         14   you've got 80 percent that are accreditation and 20

         15   percent that aren't, where would we most

         16   productively devote our efforts toward further

         17   improvements in the program? 

         18             I think you can see, in fact, there's a

         19   logic to the way it all fits together.  And, yes,

         20   it will take some time to get there.  It has to

         21   grow.  But that's the very reason why the very

         22   first step that we tried to foster was to work with


                                                                      260

          1   the private sector in order to develop systems for

          2   accreditation of human research protection

          3   programs, again, focusing on the programmatic

          4   systems issues rather than just on accreditation of

          5   IRBs.

          6             CHAIRPERSON MARSHALL:  George, thank you

          7   very much. 

          8             Kristina, Division of Compliance, welcome.

          9             DR. BORROR:  Well, thank you very much for

         10   this opportunity to come talk to you today about

         11   OHRP's compliance oversight procedures in general. 

         12   It's a great pleasure to be here.

         13             Generally, I am going to talk to you today

         14   about the activities in the Compliance Division and

         15   some of the common areas of noncompliance that OHRP

         16   identifies during investigations and some of the

         17   underlying causes of noncompliance.  Actually, I

         18   don't know if I'm going to get to that last one.

         19             OHRP's jurisdiction includes research that

         20   is conducted or supported by the Department of

         21   Health and Human Services and also research that is

         22   conducted at an institution that has an applicable


                                                                      261

          1   assurance of compliance.  And George told you a lot

          2   about the assurance process.

          3             Our compliance oversight activities

          4   include compliance oversight investigations.  This

          5   is probably a lot of the bulk of the work that our

          6   division does.  We receive allegations of

          7   noncompliance from a variety of sources including

          8   people who have been subjects in research and

          9   believe that they have been harmed or mistreated;

         10   from investigators themselves; or people who are at

         11   institutions who believe that there is

         12   noncompliance going on; or from the public, and

         13   even sometimes in reading the literature our own

         14   staff sometimes identifies problems or potential

         15   problems that we see in research.  And then we

         16   determine whether or not we have jurisdiction and

         17   write a written inquiry to the appropriate

         18   institute and those officials.

         19             We receive from them a report from the

         20   institution and relevant IRB documents and review

         21   them very carefully.  And this can take a long time

         22   as some of you who have been on the receiving end


                                                                      262

          1   of an allegation may know.  That we have additional

          2   correspondence back and forth with the institution

          3   often first telling them about questions or

          4   concerns that we may have that arose from our

          5   review of the material.  We will sometimes talk to

          6   them on the phone because sometimes that's a lot

          7   quicker than going back and forth with letters. 

          8   And, very occasionally a site visit may be

          9   warranted.  And after all of this is done we

         10   usually issue final determinations.

         11             There are many possible determinations or

         12   outcomes that can result from an investigation. 

         13   The one that everybody would like to see is

         14   protections under that institution's assurance are

         15   in compliance.

         16             Another one that is very common is

         17   protections under their assurance are in

         18   compliance, but OHRP can recommend additional

         19   improvements that the institution can make.  And

         20   another outcome is that we identify areas of

         21   noncompliance and require particular corrective

         22   actions.  Also, we may identify noncompliance and


                                                                      263

          1   restrict the assurance pending corrective action. 

          2   Additional and more severe outcome is that

          3   noncompliance is identified and the assurance is

          4   withdrawn from the institution by OHRP.

          5             In addition, even more strong outcome is

          6   that we can recommend to appropriate department

          7   officials or agency heads that either an

          8   institution or an investigator can be temporarily

          9   suspended or permanently removed from participation

         10   in a specific project or that peer review groups be

         11   notified of noncompliance prior to review of new

         12   projects. 

         13             And this last one has never been done, but

         14   that's that OHRP may also recommend that

         15   institutions or investigators be declared

         16   ineligible to participate in HHS research.  This is

         17   known as debarment.

         18             I believe in the packet that you got are

         19   some of the common findings that are made by our

         20   office and these are common areas of noncompliance

         21   that we identified.  This can also be found on our

         22   web site and I think that you'll find that it's


                                                                      264

          1   very helpful.  These areas include all the areas

          2   that IRBs are involved in and that researchers

          3   interact with IRBs regarding initial and continuing

          4   review, expedited review, unanticipated problems

          5   reporting, changes to protocols, informed consent,

          6   et cetera.  I'm going to go into this in a little

          7   bit more detail.

          8             Some of the common findings that we make

          9   regarding initial and continuing IRB review are

         10   that the IRB receives insufficient information from

         11   the investigator in order to make the

         12   determinations that whether or not the research is

         13   really in compliance.  Also we sometimes find that

         14   there is inadequate review, or that continuing

         15   review is not substantive.  There is also a very

         16   common failure to conduct continuing review at

         17   least annually.  There is sometimes a lack of a

         18   quorum, there is not enough people at the IRB in

         19   order to actually vote on protocols, or a very

         20   serious problem.  Sometimes research is actually

         21   conducted without ever being brought to the IRB for

         22   review.


                                                                      265

          1             Some other findings regarding expedited

          2   review are inappropriate use of expedited review

          3   both for initial and continuing review, and also

          4   for the review of changes to protocols or the

          5   failure to advise the full IRB of expedited

          6   approvals that were done by either a chair or an

          7   IRB member.

          8             We often see problems with informed

          9   consent, both with the process and with the form. 

         10   The elements that are required under 45 CFR 46.116

         11   are not often all there.  Or it's sometimes

         12   appropriate to include the additional elements at

         13   116(b) and informed consent documents will

         14   sometimes either underestimate the risks that a

         15   subject may be exposed to or overestimate their

         16   potential benefits which is a problem.

         17             The language sometimes is very complex. 

         18   It has a lot of medical jargon that the average

         19   subject wouldn't understand.  And it sometimes

         20   contains exculpatory language in which a subject

         21   may appear to waive rights.  There are also

         22   findings that we make regarding IRB membership,


                                                                      266

          1   expertise and support, including lack of diversity

          2   of the membership, lack of expertise for research

          3   regarding children and a lack of a prisoner,

          4   representative, or just insufficient understanding

          5   of the regulations and a big one, a major one, is

          6   inadequate resources for the IRB.

          7             Common findings regarding their policies

          8   and procedures and the findings they make include

          9   inadequate IRB records and minutes, failure of the

         10   IRB to consider what additional protections may be

         11   needed for research involving vulnerable subjects

         12   or to make required findings regarding research

         13   involving children.  Also, making required findings

         14   regarding waiver of informed consent or

         15   documentation of informed consent.  And a very,

         16   very common finding is just lack of appropriate

         17   written policies.  They may be doing the right

         18   things, but they just don't have them written down

         19   sometimes.

         20             What are some of the underlying clauses of

         21   noncompliance?  Some of these are no-brainers, but

         22   they are very common.  One was addressed by Dr.


                                                                      267

          1   Cohen and that is inadequate education of IRB

          2   members, the staff, and also the investigators. 

          3   It's also sometimes inadequate staff and resources

          4   for the IRB and tied to that, just overburdened

          5   IRBs.  The IRBs, either one or a few, are just

          6   reviewing too much research in too little time. 

          7             I think that's the end, and I'll take any

          8   questions. 

          9             CHAIRPERSON MARSHALL:  I'm sure that there

         10   will be some.  I have Bob, Sandy, Adil, and Abbey.

         11             DR. RICH:  I serve as the editor of a

         12   major scientific journal.  We have four categories

         13   of responses that we get with submitted

         14   manuscripts.  The largest majority of manuscripts,

         15   about 60 percent get a rejection letter; about 25

         16   percent get a letter that says, "not acceptable in

         17   its present form"; a small percentage get an

         18   acceptable with minor revisions; and almost nobody

         19   gets a clean bill of health.

         20             I am trying to put that same kind of

         21   notion into the context of your possible outcomes

         22   of review and I'm wondering whether anybody ever


                                                                      268

          1   gets a clean bill of health as one outcome and the

          2   one we hear about in the newspaper, of course, are

          3   the ones that come, maybe not all the way to the

          4   death sentence, but come as close to that as one

          5   might come without having any -- and I'm wondering

          6   if you can give me a sense of how that breaks down.

          7             DR. BORROR:  You're correct in that there

          8   is always room for improvement.  I certainly -- you

          9   know, I haven't been in this office as long as some

         10   others who are talking to you today, but I have

         11   always been able to find problems.  Sometimes we

         12   just make recommendations.  The most common problem

         13   as I maybe mentioned is just the written procedures

         14   and policies are just not there.  And as I said,

         15   they may be doing it.  They just haven't written it

         16   down in a way that gives enough details that you

         17   understand what it is that they're doing and that's

         18   probably the most common.  And I can find it almost

         19   every time. 

         20             You know, the more serious allegations

         21   that we are very concerned about, you know, happen

         22   less often.  And it's not unusual to, you know, at


                                                                      269

          1   the end of the day, make some findings, but in

          2   overall to say that the main allegation was not

          3   substantiated.  But very often they are and we can

          4   always find room for improvement.

          5             DR. RICH:  If I can just follow-up on that

          6   then.  Provided that you're responding to a

          7   specific allegation, I'm wondering how often your

          8   finding of being in noncompliance relate to human

          9   subject protections that are relevant to the

         10   allegation of a problem as oppose to filling off a

         11   long list of things that you might be able to check

         12   off, did they do this, did they, did they -- you

         13   know, whether a quorum and everything.  Were all

         14   the minutes properly recorded and -- 

         15             DR. BORROR:  We try to get enough

         16   information to be able to certainly address the

         17   allegation.  You know, we also do get information

         18   -- we usually will ask for the policies and

         19   procedures so that we can -- even though that might

         20   not be part of the allegations and we do sort of

         21   have -- I mean, it's not really a sort of a mental

         22   checklist to be able to do that.  But we


                                                                      270

          1   concentrate -- we do a lot of look to see that the

          2   allegations themselves, but we also try to look and

          3   see if the whole entire system for the protection

          4   of human subjects is in place and appears to be

          5   working.

          6             CHAIRPERSON MARSHALL:  Sandy. 

          7             DR. KOSKI:  If I could just quickly

          8   comment to that also.  For too long, you know, the

          9   whole human research protection process has been

         10   viewed really as sort of an administrative burden.

         11   in many instances rather than its real purpose. 

         12   And that's often reflected, but it's been

         13   dramatically changing.  Okay.  We see it every

         14   place we go, all kinds of places are really working

         15   to, you know, make effective systems.  Realizing

         16   that this is -- it's critically important as part

         17   of the foundation for doing the research

         18   responsibly.

         19             In most instances noncompliance is

         20   symptomatic.  It's a symptom of either a lack of

         21   understanding, a lack of resources, you know,

         22   sometimes a lack of commitment.  Our office,


                                                                      271

          1   remember, our motto is "doing it right together"

          2   and the emphasis on doing it right together, that

          3   means we have a certain role and so do the

          4   institutions that have to fill their

          5   responsibilities, investigators and others.  So I

          6   think that we clearly work very, very hard to use

          7   the tools of our office to try and get people to

          8   fulfill their responsibilities appropriately.  But

          9   we also have to recognize that there are instances

         10   where people are unwilling to do that, for one

         11   reason or another and we try to make sure that

         12   whatever actions our office takes are appropriately

         13   measured and responsive to the concerns and the

         14   risks that the situation might pose.

         15             So it's something where the goal, again,

         16   is one that is not focused on punishment, but

         17   rather on working toward making the system operate

         18   as it's supposed to for the protection of human

         19   subjects.

         20             DR. RICH:  I would just say that it's

         21   surprising to me that nobody seems to be doing it

         22   right though.  If what I'm hearing is -- you know


                                                                      272

          1   --  

          2             DR. BORROR:  I think that I would like to

          3   emphasize here is there's always room for

          4   improvement.  And part of my job is to give

          5   recommendation and guidance to help IRBs and the

          6   human subject protections systems improve.

          7             CHAIRPERSON MARSHALL:  Sandy.

          8             DR. CHODOSH:  This is along the same line. 

          9   And I'm not really quite sure if I heard the

         10   answer.  If I were a member of the press sitting

         11   here right now, and I walked away with this

         12   document, I could write a tremendous indictment of

         13   the whole system.  And I don't think that that is

         14   entirely true.  I think that just as we're talking

         15   about definitions of other things such as minimal

         16   risks et cetera, we need to talk about what is

         17   common.  Now, you put common on all of those things

         18   and I think that common significant, common

         19   administrative, I think that we need to put some

         20   definition on this of else it looks like no one is

         21   doing the job right.  And I concur with Bob is

         22   saying.  And I can't believe that.  You know, I


                                                                      273

          1   know that there is no one who is perfect, and I

          2   know that you're right.  Everyone can improve. 

          3   That's life.  But to put it in the tone of you an

          4   always find something wrong is not really the

          5   message that we should be hearing.  We should be

          6   hearing, most people are doing things right, I

          7   would hope, but there are areas and these are the

          8   kinds of areas and these are the kinds of

          9   percentages, et cetera.  Otherwise, I think we're

         10   sending the wrong message. 

         11             DR. BORROR:  I agree that there's no

         12   numerator or denominator here.  And I think that

         13   the reason why this document was made public is to

         14   be more of a guidance document to institutions so

         15   that they can look and learn from the mistakes of

         16   other institutions and to really look hard, you

         17   know, at this whole quality assurance and quality

         18   improvement process is taking that a step further,

         19   but to see where other institutions have made

         20   mistakes and look at their own institute and say,

         21   ah, well, are we doing that too? 

         22             DR. KOSKI:  Sandy, one thing that I think


                                                                      274

          1   is important to recognize is that for 30 years the

          2   side of human research protections that's been

          3   overseen within HHS and the others has been

          4   basically a kind of a free-running process where no

          5   one has really been looking, except for those

          6   instances where something would pop up where there

          7   was a complaint or something.  It was a system that

          8   was based primarily on trust.  And it's very

          9   interesting because if you contrast this

         10   environment with what the corporate sponsors, you

         11   know, have been faced with over the years which has

         12   been a very strict regulatory structure with

         13   auditing and everything else to enforce that,

         14   there's a difference in the cultural approach.

         15             And, of course, what's happened over the

         16   last several years it that in the face of

         17   increasing concerns about how well the system is

         18   working, all of a sudden the eyes of the

         19   regulators, okay, are being in a sense turned on a

         20   system that has simply had a different cultural

         21   orientation.

         22             And I think that there are some


                                                                      275

          1   adaptations, you know, that's still going on and

          2   some have certainly argued that there's been too

          3   much focus on, again, regulatory compliance as the

          4   goal which I for one have stated that many times so

          5   that, again, I think that as we see a pendulum

          6   swing back and forth, we'll begin to see, as we are

          7   now doing across the board everyone, I think,

          8   rising to the challenge to do things as best they

          9   can.  And our efforts are to support that. 

         10             It's very interesting to note that in

         11   recent analyses done by FDA from their field

         12   auditors, the numbers or the percentage of studies

         13   that they audit now that have, you know, serious

         14   deficiencies in critical elements of the kind of

         15   research has actually fallen by more than 30 some

         16   percent over the last year.  So, again, that

         17   heightened awareness and everything is there.  But

         18   I think your points are well taken.

         19             You know, Adil and others have pointed out

         20   today, you know, by and large a lot of committed

         21   people who are really making the effort to do

         22   things right and that's what we clearly want to


                                                                      276

          1   support.

          2             CHAIRPERSON MARSHALL:  I have Adil, I have

          3   Abbey, I have Alan and then Elliot.  Adil, and then

          4   we need to move along. 

          5             DR. SHAMOO:  You said invariably you found

          6   that even the institutional policies just doesn't

          7   have it in it to do certain things.  And that

          8   brings me to my question an hour ago.  Why don't we

          9   do this process prior to there is a complaint. 

         10   That is, OHRP review those institutional policies

         11   and ensure that they are at least the minimal

         12   existence of those requirement are in their

         13   institutional policy rather than later on, you

         14   know, hit them with a hammer.  And I know for a

         15   moment I'm sounding like Bob and Sandy, but forgive

         16   me. 

         17             [Laughter.] 

         18             DR. KOSKI:  Adil, again, to emphasize the

         19   point that we've been saying many, many times, when

         20   you make a promise that you're going to protect

         21   human subjects and have an effective program to do

         22   that, you make the promise.  You know, if people


                                                                      277

          1   would like to see government regulators come in and

          2   review everything, okay, that's an approach that

          3   can be taken.  And many have suggest that that's

          4   the approach that should be taken. 

          5             We, in fact, believe that a different

          6   approach, one that allows institutions to

          7   demonstrate their responsibility and their

          8   initiative to do it on their own, okay, is a more

          9   productive approach.  The key thing about the

         10   quality improvement program, all right, is that it

         11   fosters that kind of self evaluation.  You can look

         12   and see yourself.  If there's anyplace in the

         13   country doing human research and has a human

         14   subjects protection program that hasn't done that

         15   already, I can only ask, why not?  Why not?  What

         16   are you waiting for?  Okay.  Because if you've made

         17   the promise, it's time to act on that.  Okay.  So I

         18   think it's the initiative that they have to bring

         19   forward. 

         20             DR. SHAMOO:  Can I give you their

         21   perspective since I served with one of those

         22   institutions more that an one, as a matter of fact.


                                                                      278

          1   And I quote/unquote, help them once in a while. 

          2   They do not know sometimes what you are thinking,

          3   what you want.  They do not know.  I see Sandy

          4   shaking his head.  We don't know exactly how you

          5   are interpreting these things.  Sometimes they are

          6   -- and you know me.  I'm not on their side, but

          7   really I feel for them sometimes.  

          8             [Laughter.] 

          9             CHAIRPERSON MARSHALL:  We're making lots

         10   of history here today, Adil. 

         11             [Laughter.] 

         12             CHAIRPERSON MARSHALL:  Those of you who

         13   are standing there are a lot of seats up here on

         14   the side.  If you would like to sit, please feel

         15   free. 

         16             Abbey, Alan and Elliot and then we need to

         17   move along. 

         18             MS. MEYERS:  I'm wondering whether you

         19   think that the penalties that are available to you

         20   are adequate?  It seems to me that sometimes you

         21   use a cannon to kill a mosquito and you have to,

         22   you know, so many times shut down a whole


                                                                      279

          1   university rather than -- if you had, for example,

          2   the ability for civil monetary penalties or

          3   whatever, would that be better?  Something.  We

          4   could target the investigator rather than the whole

          5   institution. 

          6             DR. KOSKI:  We would never use a cannon to

          7   swat a mosquito.  As I said earlier, the actions

          8   taken in the compliance mode by our office are

          9   actions that are specifically directed to be

         10   appropriate to the situation encountered.  We have

         11   enormous flexibility as Christine already mentioned

         12   to target activities toward a specific

         13   investigator, a specific project, or a specific

         14   component of the IRB process.  To a section of

         15   research, to the entire institution.  I think there

         16   are a number of tools there.  And so certainly what

         17   our office has been trying to do again is to -- if

         18   an action is required, to try and make sure that

         19   that action is appropriately measured to the

         20   situation to avoid what you might call collateral

         21   damage and to avoid exactly this problem.  So, you

         22   know, I can make it very clear to everyone that


                                                                      280

          1   that's the way our office works.

          2             With respect to the civil monetary

          3   penalties, this was an idea that was actually

          4   floated a year or more ago when Secretary Shalala

          5   talked about various initiatives.  It was an

          6   initiative that I think recognized that in a

          7   situation where monetary incentives may lead to

          8   misconduct that monetary penalties may be an

          9   appropriate remedy for that.  While many still hold

         10   to that, I think that the reception that the notion

         11   received in Congress, the first go around was such

         12   that no one has continued to maintain a high level

         13   of enthusiasm for that particular approach.  I

         14   think we may hear more about that, though, when the

         15   General Accounting Office speaks to us tomorrow

         16   afternoon.

         17             CHAIRPERSON MARSHALL:  Alan and then

         18   Elliot.

         19             DR. FLEISCHMAN:  I guess I have two

         20   questions, one easy and one perhaps impertinent. 

         21   The easy one is really to ask how you and George

         22   get along?  That is to say -- 


                                                                      281

          1             [Laughter.] 

          2             DR. FLEISCHMAN:  -- you know, how close

          3   are those two offices?  I mean, we talked about

          4   trust this morning and the academic community,

          5   you've gotten the academic community aware of the

          6   Office of Human Research Protections and the public

          7   aware of the office.  And you are now asking the

          8   academic community to voluntarily get involved in

          9   quality improvement which I happen to think is a

         10   marvelous thing to do.  And yet you've got this

         11   other arm called compliance that does have multiple

         12   potential negative consequences for the academic

         13   community.  And in looking at that quality

         14   improvement form, it's not a lot different than

         15   your review of an organization.

         16             So, what should I tell the dean?  That's

         17   the first question. 

         18             And the second question is, we are really

         19   -- we're discussing all of this in the abstract and

         20   it strikes me that we have a very concrete example

         21   in our midst with lots of public information

         22   available about that example.  That is the Hopkins


                                                                      282

          1   example.  And I wonder if you could share with us

          2   the process by which the Division of Compliance

          3   went through in making the determination that it

          4   made about its ultimate response to the university.

          5             DR. BORROR:  Well, I can't really -- I'll

          6   take your first question.  There is a lot of

          7   interaction between the divisions within OHRP.  As

          8   I said, there is always room for improvement.  As

          9   far as the quality improvement part of this, and

         10   Greg may correct me if I'm wrong here, but we want

         11   to set a sort of a firewall in those -- you know,

         12   the question about whether or not this information

         13   is obtainable under the Freedom of Information Act,

         14   and so forth, that institutions can feel free to,

         15   you know, sort of air their dirty laundry so that

         16   they can get improvement.  That said, I think that

         17   if we found like really serious problems and, you

         18   know, there was concern that human subjects were at

         19   risk at a particular institution we would have to

         20   ask, I believe.  Do you agree with that? 

         21             DR. KOSKI:  Sure.  Again, since George

         22   isn't up here, I'll speak sort of on your behalf. 


                                                                      283

          1   The goal here is to conduct the quality improvement

          2   activities in what we call safe mode, okay.  Fully

          3   collaborative, open, exchange of information with

          4   the understanding just as if you were in the

          5   emergency room taking care of, you know, kids.  You

          6   know, when you have a kid come in who has obviously

          7   been potentially abused, you have a certain

          8   responsibility to act.  I think that within the

          9   quality improvement mode the expectation would be

         10   that if a situation of such severity was

         11   discovered, which I think in fact is unlikely, that

         12   the institution would voluntarily sort of take that

         13   sort of action. 

         14             The whole quality improvement program is

         15   one that's voluntarily based.  But people have to

         16   understand that while that's going on in a

         17   voluntary mode, there is running in the background

         18   a separate subroutine called "compliance oversight"

         19   that will include not only for-cause site visits,

         20   but also an expanded array of not-for-cause

         21   surveillance visits.  So that if people are

         22   unwilling to do what they need to do in a voluntary


                                                                      284

          1   fashion in order to make the program effective,

          2   then it may become necessary to resort to a

          3   compliance initiative.  But I would hope that that

          4   would not be the case.  I can tell you that we

          5   already have a waiting list of people volunteering

          6   to have our teams come and conduct quality -- you

          7   know, improvement visits with them.  And similarly

          8   they are already -- there's a waiting list for

          9   people saying that they want to get in line for

         10   accreditation as well.  So I think it demonstrates

         11   again the commitment from most places to really try

         12   and do this in a very responsible manner.  What we

         13   want to do is support those efforts and basically

         14   reserve compliance enforcement activities for those

         15   who are unwilling or unable to do so.

         16             CHAIRPERSON MARSHALL:  Elliot.

         17             DR. DORFF:  Greg, that was a very good

         18   lead in to the point that I was about to make which

         19   is that I'm not used to the process of accrediting

         20   IRBs.  But I am used to the process for accrediting

         21   universities because I have been a provost and on

         22   and all of that and have gone through accreditation


                                                                      285

          1   of our university a number of times.  And it's a

          2   very long process and all of that, but it's a very

          3   important process, truthfully, for universities. 

          4   And there, first of all, it doesn't happen on the

          5   basis of allegations which, frankly bothers me,

          6   because you could sort of get the sense that

          7   somebody is, you know, relaying a secret whether

          8   that person is identified or not, and, you know,

          9   questions of rights of defense and all of that.

         10             And I think -- I mean, you are probably --

         11   from what you've just said, you're overwhelmed

         12   already.  But what you may want to look toward the

         13   accreditation of universities model as a different

         14   way to do it.  That is, where either your office or

         15   an association of IRBs of some sort or another,

         16   does this on a regular basis, every whatever, every

         17   three years or something, there is a visitation

         18   from this association to review the processes that

         19   are going on in this particular IRB with the

         20   intention of identifying those things which the IRB

         21   is doing terrifically well and those places where

         22   there might be room for improvement.  In the cases


                                                                      286

          1   of universities, they have the ultimate, you know,

          2   ability to either put the accreditation -- well, to

          3   discredit them altogether or to say that your

          4   accreditation is not going to be for six years,

          5   it's going to be for three, and it will be

          6   conditional on certain kinds of things and so on. 

          7   And even though that's not a government agency, it

          8   has real power because if you're not accredited,

          9   you're not going to get students, you're not going

         10   to get grants, you are not going to get a whole

         11   variety of other things.

         12             And when I think that, you know, if it

         13   were independent of your office, then you wouldn't

         14   be overwhelmed to the extent that you are, in doing

         15   this kind of thing, but even if you were to do

         16   this, in other words, if you were to have -- you

         17   know, get more people than the 47 and do this not

         18   on the basis of allegations, but on the basis of a

         19   regular kind of review process, I think people

         20   would be -- well, first of all, they would be

         21   helped by it as universities are helped by it. 

         22   And, aside from that, it would be everybody's in


                                                                      287

          1   the same boat.  It would literally be doing it

          2   together.

          3             DR. KOSKI:  Elliot, I refer you to the

          4   report issued by the Institute of Medicine that we

          5   had commissioned, it was issued last April called

          6   preserving the public trust, accreditation of human

          7   research protection participant programs where

          8   those issues have been developed in really

          9   elaborate detail.  And, indeed, what you are

         10   suggesting is exactly the program that is already

         11   moving forward.  There are two organizations that

         12   are currently engaged in, or at least getting ready

         13   for actually conducting the accreditation in the

         14   private sector.  One of those is the National

         15   Council of Quality Assurance which has a contract

         16   with the Veterans Administration to conduct

         17   accreditation of all of the VA's human research

         18   programs.

         19             The second is a group called the

         20   Association for the Accreditation of Human Research

         21   Protection Programs which is now a private, not-

         22   for-profit independent corporation entity that was


                                                                      288

          1   established with seed money from a number of

          2   professional organizations through an effort that

          3   was spearheaded in part by both Primer and the

          4   Association of American Medical Colleges, but with

          5   buy in from the CASA, a whole host of organizations

          6   and FARMA with exactly this notion in mind:

          7             You can establish a level playing field of

          8   excellence rather than one based on minimal

          9   regulatory requirements that actually provides a

         10   positive recognition of the accomplishments that

         11   can be rewarded rather than punished.  It is

         12   totally unrelated in any way to the compliance

         13   oversight activities of our office.  It's a private

         14   complement to the processes that go on within

         15   government. 

         16             CHAIRPERSON MARSHALL:  I'm sorry.  Thank

         17   you.  We need to move on, we're behind.  But I want

         18   to second that remark that Greg just made and say,

         19   for committee members, probably reading at least

         20   the executive summary of that report should be

         21   required reading for all of you.  This should be

         22   part of your background knowledge as members of


                                                                      289

          1   this committee.  It's superb work.  So I commend it

          2   to you highly, and it's available from the

          3   Institute of Medicine on their web site.

          4             I will ask Kate, we will get them for you. 

          5   We will have a copy for all of you because it's

          6   tremendous work. 

          7             Thank you very much, Kristina.  

          8             And Greg is not suffering from an identity

          9   crisis, but he will be Melody Lin for the next few

         10   minutes. 

         11             DR. KOSKI:  I will be very quick on this. 

         12   Melody couldn't be here today.  She's back holding

         13   down the fort as any good deputy would under these

         14   circumstances.  And so I actually offered to sort

         15   of fill in for her on just a very quick sort of

         16   update on where things stand with the new office

         17   for international activities.  Clearly, human

         18   research is increasingly global in its scope and

         19   conduct.  And it's brought a number of issues to

         20   the fore.  Many of those, by the way will be sort

         21   of addressed in an upcoming report from the Office

         22   of the Inspector General of HHS.  They were also


                                                                      290

          1   addressed in the recent NBAC report on

          2   international clinical trials.  I should point out

          3   though that while those deal primarily with

          4   clinical trials, there's a whole issue of non-

          5   biomedical research that also goes on, on a global

          6   basis that we need to keep in mind also.  But we

          7   are now seeing around the world, organizations such

          8   as the global forum on bioethics, the European

          9   forum on good clinical practices, the World Health

         10   Association, the World Medical Association, the

         11   CIOMS which is the Council of International

         12   Organizations of Medical Societies, I believe --

         13   Medical Sciences.  Yes, thank you. -- and others.

         14             There are also organizations within many

         15   countries such as Canada, India, Peru, the European

         16   Union, China, Japan, a whole host.  We are

         17   beginning to see a nucleus of people who are

         18   committed toward working toward a more harmonized

         19   world with respect to the review and the conduct of

         20   human research.  I think there is a sense that

         21   where standardization is possible and appropriate,

         22   that might be a good thing to achieve, but


                                                                      291

          1   recognize that this is a very complex world we live

          2   in.  So that harmonization is sort of one of the

          3   buzz words.

          4             And we've seen that very effectively done

          5   in the International Committee on Harmonization's

          6   Good Clinical Practice Standards that now allow

          7   data that's collected in clinical trials from

          8   various countries to actually be used in support of

          9   the drug approval process in multiple countries.

         10             One of the other key words is building

         11   capacity so that we -- some countries have more of

         12   a system in place than others.  Occasionally though

         13   we have research that is intended to be done in a

         14   culture or a country where there basically is no

         15   infrastructure or system in place for either

         16   overseeing or conducting the research.  And where

         17   there are instances of exploitation where people

         18   who are serving their own interest rather than

         19   those of research subjects, sort of, those are the

         20   kinds of things that have caught some of the

         21   attention, fortunately they are few and far

         22   between.  But, nevertheless, it's an area that has


                                                                      292

          1   raised concerns so we see this going forward.

          2             Our Office of International Activities is

          3   working very closely with the Fogarty International

          4   Center at NIH, the FDA, our Office for

          5   International Refugee Health as well as the various

          6   federal agencies such as USAID and others that

          7   actually are engaged in the global community.  CDC

          8   has been instrumental in that is.  So that our

          9   office is not so much to create a new federal

         10   bureaucracy for the oversight of international

         11   research activities, but rather to serve as a

         12   coordinating center; a focal point for bringing

         13   together and fostering activities that will

         14   actually help to ensure that any research that is

         15   done in the global community is done in an

         16   appropriate manner with the highest scientific and

         17   ethical standards.

         18             We previously discussed some of the issues

         19   around the Declaration of Helsinki.  Again, that 's

         20   an ongoing debate, but the World Medical

         21   Association has established a committee to actually

         22   look into some of the various issues that have been


                                                                      293

          1   raised, not only by our department, by this

          2   committee, but also by other organizations and

          3   groups around the world.  I think this is going to

          4   be something that's going to be on the front burner

          5   now for this next decade as the world again comes

          6   closer and closer together and gets smaller and

          7   smaller. 

          8             I'm sorry that Melody couldn't be here

          9   today, but if I can answer any questions on her

         10   behalf, I would be happy to do so.

         11             CHAIRPERSON MARSHALL:  Any questions? 

         12   Abbey?

         13             MS. MEYERS:  All this attention on these

         14   foreign studies.  It seems to me that they didn't

         15   get any attention at all until the Washington Post

         16   did its expose.  I'm wondering why no attention has

         17   been paid to this? 

         18             DR. KOSKI:  Abbey, I respectfully would

         19   say I don't think that's true.  I think that just

         20   was one of those things that because it happened to

         21   be a five part series or six part in the Washington

         22   Post, it did capture a lot of attention that might


                                                                      294

          1   not otherwise have been there.  But the concerns

          2   have clearly been sort of rising within the

          3   scientific community then the international

          4   community and it's just eventually you get enough

          5   critical mass that you begin to tackle some of

          6   these things head on.  So it's been there.  It's

          7   not going to go away.  And we'll continue to work

          8   on it.

          9             CHAIRPERSON MARSHALL:  Bob.  

         10             DR. R. LEVINE:  I wanted to say that

         11   there's been a lot of attention given to

         12   international research since 1953 when the World

         13   Medical Association first formed its ethics

         14   committee and charged it with the responsibility to

         15   develop what we now call the Declaration of

         16   Helsinki.

         17             CIOMS wrote its first international

         18   ethical guideline in 1982.  There has been a frenzy

         19   of activity or a frenzy of attention of journalists

         20   to the international matters ever since there was a

         21   publication in the New England Journal accusing

         22   people who ran the placebo control trials the short


                                                                      295

          1   duration of AZT having done something unethical on

          2   the grounds that it violated the Declaration of

          3   Helsinki.  So there's been a lot of activity there.

          4             I wanted to respond to something Alan

          5   Fleischman raised earlier and that is that our

          6   discussions in general have been at a level of

          7   abstract generalities.  I think many of us sitting

          8   around this table could easily provide you with

          9   concrete examples of specific issues that have been

         10   problematic. 

         11             I can think of -- I mean, as we've been

         12   talking, I can think of several dozen, but I've

         13   held back on mentioning them because many of them

         14   are attached to specific people and there's no need

         15   to create public embarrassment, so I'll just

         16   mention one that came up that was already mentioned

         17   in the public forum at the meeting Greg and I went

         18   to at the University of Illinois in Chicago where

         19   somebody reported from the Veterans Administration

         20   that they had been through an experience with this

         21   accreditation group, the NCAQ.

         22             And they had been advised that the


                                                                      296

          1   regulations require that the minutes of the meeting

          2   show that who was in the room from minute-to-minute

          3   and any time somebody left the room, you had to

          4   record what time they left and when they came back,

          5   you had to record what time they came back.  And

          6   this was explained as being required by regulations

          7   because there was no other way to be sure that any

          8   particular protocol was discussed when somebody

          9   whose primary interests were in some area other

         10   than science was in the room.

         11             That's the sort of excess -- that's the

         12   sort of thing that's creating great alienation

         13   between the IRB world and the people who seem to be

         14   acting on behalf of the federal government in the

         15   educational and accreditation arena.  These others,

         16   you know, like the show used to say, there's 8

         17   million stories in the naked city, this is just one

         18   of them.

         19             DR. KOSKI:  Bob, I would just like to sort

         20   of note -- go on record as someone who actually

         21   chaired an IRB for a long time, as did you, that I

         22   am personally painfully aware of a number of the


                                                                      297

          1   burdens that are imposed by the process.  That's

          2   one of the reasons why as part of sort of our

          3   promise and our remodeling effort in going forward

          4   we focused on things such as the SUEE task force

          5   that I mentioned earlier where we realize that

          6   there are probably real opportunities to move away

          7   from these kinds of detailed procedural

          8   requirements that may not be serving our best

          9   interests.

         10             But, again, one of the points, I mean, to

         11   the extent that we can identify those and find ways

         12   to basically get to the things that really serve

         13   the purpose of protecting human subjects and then

         14   implement those, we would be -- I think that would

         15   be a good thing to do.  I would also say though

         16   that it's very difficult to do things that may be

         17   perceived as in some way weakening the protections

         18   process from a position of skepticism as to whether

         19   or not the system is working in the first place.

         20             So we need to help shore up a foundation

         21   of trust and all that.  As we go forward the SUEE

         22   task force will be starting this fall and my hope


                                                                      298

          1   is that we'll have not only your several dozen, but

          2   even more suggestions that we can identify as

          3   opportunities to move forward to improve the

          4   process.

          5             CHAIRPERSON MARSHALL:  A final question

          6   from the committee for Adil.

          7             DR. SHAMOO:  Yes, could we just have a

          8   copy of the slides of Dr. Borror?  Because they're

          9   not in package and will be very helpful for our own

         10   education. 

         11             CHAIRPERSON MARSHALL:  Anyone in the

         12   audience who would -- 

         13             [No response.] 

         14             CHAIRPERSON MARSHALL:  All right.  Then

         15   let me introduce Irene Stith-Coleman who is

         16   director of the Office of Policy, Planning and

         17   Special Projects.  It sounds to me as though that

         18   means she is head of everything and up there

         19   somewhere in the pantheon with the first lady of

         20   the admiralty.  Welcome, Irene. 

         21             Dr. STITH-COLEMAN:  Good afternoon.  I

         22   would like to also say that I appreciate being


                                                                      299

          1   invited to speak to you this afternoon.  I'll be

          2   brief, I promise.

          3             Greg mentioned that there is an Office of

          4   Policy, Planning, and Special Projects.  We have a

          5   total of three people including myself.  In

          6   addition to me there is Susan Zulo.  Susan would

          7   you stand?

          8             And Cliff Sharkey who is not here.  In

          9   addition, Ana Beton, stand, has been very helpful

         10   on a number of things that we're working on as

         11   well.

         12             Susan has been leading the effort with

         13   respect to the SUEE task force.  And in additional

         14   to the SUEE task force, we are also involved in a

         15   range of other issues including special panels that

         16   are being created for special areas of research

         17   including research involving prisoners and

         18   children.  And I won't go into that today.

         19             I thought that what I might do for about

         20   the next five minutes is talk to you about a

         21   proposed final rule dealing with Subpart B because

         22   that is, in fact, one of the key things that the


                                                                      300

          1   Department has actually published.  And the

          2   important thing about that is that there is still

          3   time for public comment.  And in light of this

          4   morning's session in which there was discussion

          5   about parental informed consent with respect to

          6   adolescents, I thought that one of the

          7   modifications that's being proposed in Subpart B is

          8   quite relevant to that discussion.

          9             You do have a copy of the proposed rule

         10   that was published on July 6.  And what I thought I

         11   would briefly do is talk about the three

         12   modifications that are being proposed.  And just

         13   add some context to that proposed rule, what is

         14   doing is proposing to make some changes in the rule

         15   that was published on January 17th, 2001.  That

         16   effective date of the January rule was supposed to

         17   be March 17th of 2001.  

         18             Oh, I see some degree of confusion.  The

         19   rule published in January of 2001 had an effective

         20   date of March 17th.  However, the new

         21   administration on February -- I think it was

         22   February -- published a notice indicating that


                                                                      301

          1   there would be a delay.  And this was part of the

          2   Administration's assessment going back, I believe

          3   it was 90 days to look at the regulations that then

          4   had come into effect with the prior administration.

          5             On May 18, the effective date of the

          6   January rule was further delayed for 180 days.  And

          7   at that time it was indicated that several

          8   modifications, three, would be made.  And in the

          9   July 6th proposed rule that you have in your

         10   packet, those are the details of -- it contains the

         11   details of the three modifications.

         12             And without going into detail.  The first

         13   modification has to do with the definition of

         14   fetus.  What it is proposing to do is to modify the

         15   definition of fetus so that it describes only the

         16   stage prior to delivery.  The Department believes

         17   that using the term "fetus" only for those fetuses

         18   that have not been delivered is more in keeping

         19   with the ordinary meaning of what that word means. 

         20   That's the first modification.

         21             The second in line with that, there is

         22   also a proposal to add a new term "neonate" to


                                                                      302

          1   describe an infant that has been delivered but has

          2   not yet been determined to be viable.  The

          3   modification would not change the regulatory

          4   framework.

          5             The second modification that's being

          6   proposed in the July 6th proposed rule is to

          7   require parental consent when the father is readily

          8   available in federally funded research that's

          9   directed solely at the fetus.  In the case of

         10   research that's directed at the mother or mother

         11   and fetus, the mother still retains the right to

         12   provide informed consent.

         13             The third modification is a clarification

         14   that fetuses of uncertain viability may be

         15   subjected to greater than minimum risk only if the

         16   research is intended to enhance the probability of

         17   survival of that particular fetus.  So those are

         18   the three sets of modifications.

         19             In terms of the process, the public

         20   comment period goes from July 6th up until

         21   September 4th.  I encourage each of you to the

         22   degree that you can express your rights as public


                                                                      303

          1   citizens to provide public comments.  And the

          2   public comments should be sent to me.  The

          3   specifics are in the proposed rule in terms of the

          4   address a well as the e-mail, as well as my phone

          5   number.

          6             With that, I'll stop and take questions if

          7   there are any.

          8             CHAIRPERSON MARSHALL:  Do we have

          9   questions?  Jonathan's hand is up.

         10             DR. MORENO:  Could you go over that

         11   parental consent modification again?  I'm afraid I

         12   missed that. 

         13             Dr. STITH-COLEMAN:  The parental consent

         14   modification proposes that in cases in which the

         15   research is directed solely at the fetus, parental

         16   consent would have to come from both the mother and

         17   the father, unless the father was not readily

         18   available. 

         19             The difference with respect to how this

         20   modification differs from the January 17th rule is

         21   that within the January 17th final rule, the

         22   parental consent need only come from the mother.


                                                                      304

          1             DR. MORENO:  Alan, maybe you can help me

          2   out.  A long time ago, when we were talking about

          3   076, we stumbled -- as you mentioned this morning

          4   -- on the paternal consent requirement.  How does

          5   -- I believe there already is a paternal consent

          6   requirement; isn't there?  For -- 

          7             Dr. STITH-COLEMAN:  There is.  There is. 

          8   Yeah.  One of the issues, my understanding, that

          9   led to the January 17th rule was lack of clarity in

         10   terms of practice on the part of a lot of IRBs in

         11   terms of how the current regulations were

         12   interpreted. 

         13             DR. R. LEVINE:  But that was not an

         14   example of lack of clarity.  They were quite clear

         15   on the point that you required the consent of both

         16   the father and the mother.  And when the specific

         17   complaint during the 076 trial was that many people

         18   -- and I was one of them -- thought that it would

         19   have been appropriate to give the mother the sole

         20   authority to decide whether or not she would enroll

         21   in a placebo controlled trial of something designed

         22   to protect or prevent transmission of the virus


                                                                      305

          1   from her to the fetus.

          2             What you are doing now, it seems to me, is

          3   taking the side against the protestors including

          4   all the women.  It sounds that way.

          5             DR. KOSKI:  Actually, no, I don't think

          6   so.  Because in the instance of the 076 trial where

          7   there was the potential for benefit for both the

          8   mother an the fetus, under those conditions there

          9   would still be under the newly proposed rule it

         10   would permit the mother to be the sole

         11   decisionmaker in that instance. 

         12             Under the current administration's

         13   policies, there is an expressed interest in

         14   promoting the role of the father in a family unit

         15   and it's in the context of promoting that that, you

         16   know, the integrity of the sort of the family

         17   process that they felt that this particular

         18   revision to the proposed rule would be more

         19   appropriate.

         20             DR. R. LEVINE:  Let me respond.  This is

         21   not the proper place to debate that subtlety.  But

         22   I don't think that anyone in the field of dealing


                                                                      306

          1   with HIV would attempt to pretend that the purpose

          2   of the O76 regimen was to provide a therapeutic

          3   benefit for the mother.  In fact, some people

          4   protested that pregnant women were the only adults

          5   in the United States who would get a single anti-

          6   retro viral that everyone else got combinations and

          7   because of this it appeared that the woman was

          8   being treated, and I forgive the infelicity of this

          9   term, as mere fetus containers.  Because they were

         10   not being attentive to her needs.  If they were,

         11   they would have given combination therapy.

         12             Well, I can only say that there's an open

         13   period for public comment and we would urge anyone

         14   who chooses to comment on the provisions of the

         15   proposed final rule to do so.

         16             DR. KOSKI:  I'm trying to make the point

         17   that the time to consult this committee is before

         18   you made a commitment in writing in the public

         19   forum to perhaps profit from some of the advice the

         20   people on this committee with its various types of

         21   expertise could offer. 

         22             CHAIRPERSON MARSHALL:  Mark.


                                                                      307

          1             MR. BARNES:  Since this is open for public

          2   comment, could this be something that's referred to

          3   the children's subcommittee for Alan and others to

          4   comment on?   That's one comment.

          5             The other comment is on a lighter note

          6   since this is a very weighty topic.  I do want to

          7   tell you that you can get away with calling this

          8   group your task force SUEE like in New York and Los

          9   Angeles, but I want to tell you where I'm from -- 

         10             [Laughter.] 

         11             MR. BARNES:  -- I live down a little dirt

         12   road in Alabama, that's the way that my great

         13   grandmother called her pigs. 

         14             [Laughter.] 

         15             MR. BARNES:  So just be careful. 

         16             DR. KOSKI:  Mark.  Thank you.  I've

         17   actually raised that point.  Where I grew up in

         18   Ohio that was also the way we called pigs.  And,

         19   you know, the greater caution, I think, was

         20   expressed to me shortly after President Bush and

         21   his team, you know, got here.  Because SUEE is also

         22   the call of the Arkansas Razorbacks -- 


                                                                      308

          1             [Laughter.] 

          2             DR. KOSKI:  Nevertheless, I think the

          3   goals are laudable and I hope that the acronym

          4   doesn't stand in the way of progress.  It's our

          5   intent to take the recommendations from the SUEE

          6   task force which will be a brainstorming session

          7   that will broadly consult with the research

          8   community every stakeholder as well -- I mean, you

          9   know, across the board and bring those

         10   recommendations to this committee for their input

         11   so that we get a real sense of, you know, an

         12   okayness as we go forward to try to implement those

         13   suggestions.

         14             The last comment I might make around this

         15   issue.  We've heard Irene say that her office has

         16   three people and we've heard Jeff say his office

         17   has five people and so on, I think it's important

         18   to recognize that the overall system for protection

         19   of human subjects is one that is broadly

         20   distributed.  Our office is essentially one office

         21   that serves a very important coordinating role in

         22   terms of implementing the government's regulatory


                                                                      309

          1   authorities and so on.  But, indeed, the whole

          2   system is one that involves some 4 to 6,000

          3   institutional review boards with -- if you multiply

          4   that out, it's probably somewhere on the order of

          5   40 to 60,000, you know, IRB members and other

          6   people participating in this.  And, it's, you know,

          7   as I said, a distributed system where much like the

          8   Air Transportation Safety System, you have people

          9   working in role all over the country, around the

         10   world that are all trying to make things safe for a

         11   good reason.  I think that's the concept that we

         12   are trying to bring toward human research

         13   protections as well, which is why we've placed so

         14   much emphasis on working together.  So I would

         15   suggest that we not see human research protections

         16   as simply, you know, 47 designated FTEs within the

         17   Office for Human Research Protections, but

         18   recognize that there are people both throughout

         19   government and out there in the real world who

         20   share in these goals and responsibilities. 

         21             CHAIRPERSON MARSHALL:  I'm going to take

         22   that prerogative, the chair and ask a question of


                                                                      310

          1   Irene and maybe perhaps have it be the last

          2   question since we are behind time now.

          3             Irene, what do you see?  I think Bob's

          4   remark does beg the question of the relationship

          5   between the SUEE task force and this committee, and

          6   how do you see that relationship playing out? 

          7             Dr. STITH-COLEMAN:  Greg, do you want to

          8   answer that? 

          9             [Laughter.] 

         10             DR. KOSKI:  Well, we look to this

         11   committee as, again, a source of advice.  When that

         12   advice comes to us, then it's our responsibility

         13   within, you know, government to use it, in our best

         14   judgment to develop appropriate guidance, rules,

         15   regulations, legislation, whatever is necessary to

         16   accomplish the goals so that, again, this committee 

         17   is a critically important advisory committee.  To

         18   the fullest extent possible, we would like to get

         19   that advice ahead of time.  I think given the

         20   intricacies or complexities of government, or the

         21   realities also, that that's not always possible,

         22   but to the extent possible, we hope to do that.


                                                                      311

          1             CHAIRPERSON MARSHALL:  One last question

          2   of Alan and then we'll move on into our break.

          3             DR. FLEISCHMAN:  I think this would be a

          4   question for information.  I was wondering if Dr.

          5   Stith-Coleman, you or someone in your office, has a

          6   grid which would share with us the regulations as

          7   they were extant before January, the regulations

          8   that were in fact proposed in January and these and

          9   how they are different.

         10             It's my understanding that these are quite

         11   different than January's regulations and have

         12   implications that are far different from those. 

         13   And I just wondered if you had those arrayed and if

         14   you could share those with us. 

         15             Dr. STITH-COLEMAN:  I know I have the last

         16   two.  And I would think that someone in OHRP would

         17   have the first one.  So, probably yes.

         18             CHAIRPERSON MARSHALL:  Thank you very

         19   much, Irene.

         20             And Kate has one last word and then we

         21   will take a ten-minute break.

         22             MS. GOTTFRIED:  I just want to mention to


                                                                      312

          1   the committee that some of you may not have

          2   complete Children's Report to Congress, and if so,

          3   just let Tony know outside, and if she's not there,

          4   let me know.  Because some of the books seem to be

          5   complete and for some reason some of them aren't. 

          6   And it's hard for us to figure out which ones are

          7   which.  So just let us know if anything in your

          8   briefing book is incomplete and we'll make sure you

          9   get a full copy.

         10             CHAIRPERSON MARSHALL:  And those of you

         11   from OHRP, thank you very much for bringing us up

         12   to speed this afternoon. 

         13             [Applause.] 

         14             CHAIRPERSON MARSHALL:  We will reconvene

         15   at ten after four.

         16             [Brief recess taken at 4:00 p.m.]

         17             CHAIRPERSON MARSHALL:  Actually, before we

         18   begin with our agenda, we have an announcement that

         19   may be of interest to those of you in the audience

         20   who are researchers. 

         21             MS. WARNER:  Hi, I'm Ellen Warner from the

         22   National Heart, Lung and Blood Institute and I


                                                                      313

          1   would like to suggest that early in August, you

          2   look at the NIH training web site, we are going to

          3   be releasing two new program announcements.  One is

          4   a T-15 institutional training grant in bioethics,

          5   the other is a KO1 mentored scientist research

          6   award in bioethics training.  And I think they

          7   would be of great interest to you all.

          8             CHAIRPERSON MARSHALL:  Thank you very

          9   much.  

         10             Mary Kay is on the agenda next.  We have

         11   an update and a discussion from a working group

         12   that is a relatively new working group.  It as

         13   formed at our last meeting.  Mary Kay is the

         14   chairperson, Mary Kay Pelias.  If you want to give

         15   us an update.  And I know that this discussion is

         16   actually going to sort of segue into tomorrow's

         17   work as well.

         18             DR. PELIAS:  Thank you, Mary Faith.  As

         19   the members of the Committee know, we were

         20   constituted at our last meeting and it started out

         21   with discussion of perhaps we were going to go

         22   directly into questions of genetics.  And then we


                                                                      314

          1   sort of backtracked and said, well, maybe before we

          2   do genetics, perhaps we ought to get into the issue

          3   of human subjects and discuss whether or not the

          4   definition in the federal regs, the definition of

          5   human subjects is appropriate and then maybe we

          6   would take this discussion down to the issue of

          7   third parties.  And someday perhaps in the future

          8   we'll get on to the issue of genetics.

          9             Today I would like to give you a rundown

         10   of what we've been up to for the last couple of

         11   months and I would invite you to follow along in

         12   the materials that you have because some of it I'm

         13   going to skip over rather quickly.  And then I'll

         14   give you a little bit more details about questions

         15   that have come up for our workgroup.

         16             Whenever I get into a discussion like

         17   this, I always believe that it's important to look

         18   for a little while at the historical perspective

         19   because I don't believe that we can go forward

         20   without knowing where we have come from.  So part

         21   of our attention for the last couple of months has

         22   been devoted to the historical perspective


                                                                      315

          1   beginning with the Nuremberg Code and some of the

          2   language that we draw from the Nuremberg Code about

          3   human subjects including language and phrases that

          4   go to voluntary consent and legal capacity,

          5   knowledge, comprehension, free power of choice and

          6   without constraint or coercion.  These are very

          7   important phrases.   And I think with respect to

          8   the Nuremberg Code they address the interests of

          9   the individual subject.

         10             Quite a while after the Nuremberg Code was

         11   promulgated in 1946, we had the advent of the

         12   Declaration of Helsinki and I would summarize that

         13   very quickly by saying that first of all it

         14   stresses international questions, but also I

         15   believe that it's written from the perspective of

         16   the investigators, the researchers, the

         17   professionals.  It calls on investigators and so-

         18   called clinically competent medical persons to

         19   conduct themselves in ways that are appropriate

         20   protections for the people that participate as

         21   subjects in human research.  So we have from the

         22   Declaration of Helsinki language like "freely given


                                                                      316

          1   informed consent"; "dependant relationship";

          2   "protector of the life and health of the subject";

          3   and ideas about discontinuing things if they seem

          4   to become harmful.

          5             We heard this morning from Dr. Wood more

          6   information about experimentation with human

          7   subjects that went on into the 1970s including

          8   mention of Tuskeegee and Willowbrook.  In addition

          9   to those two travesties, we also have history in

         10   Jewish Chronic Disease Hospital about whether or

         11   not cancer is infectious.  And we have a very long

         12   history of radiation exposure both in civilian and

         13   military arenas.

         14             We move on up a little bit further and we

         15   have the Belmont Report and then eventually the

         16   regulations that bring us all here together today. 

         17   Specifically we have the establishment of our

         18   Institutional Review Boards, and that famous

         19   Subpart A of 45 CFR 46.  I should not have

         20   included, by the way, in my write-up the topics of

         21   Subparts B, C, and D, as part of the common rule,

         22   but that was my error when I was writing this up


                                                                      317

          1   very quickly.

          2             With regard to what we've been up to for

          3   the last couple of months, we met briefly at the

          4   end of our last meeting here in Washington.  A

          5   short time after that I circulated a document

          6   called, "Defining Human Subjects" which included

          7   the current definition in the Federal Regulations

          8   as well as the historical perspective and questions

          9   about language in the current definition.  I also

         10   submitted a new and extremely unrefined definition,

         11   almost intentionally to try to generate some

         12   discussion and that certainly worked.  And we

         13   considered possible pathways for further

         14   deliberation.

         15             We had a conference call, then we put

         16   together all the information from the conference

         17   call and send out a second document and had yet

         18   another conference call.  And we came at the end of

         19   the second discussion on the telephone, we came to

         20   a few conclusions that I can share with you now. 

         21             I had considered the possibility of

         22   reading into this record the current definition of


                                                                      318

          1   a human subject because we spent a lot of time

          2   talking about the language.  But I think I will not

          3   do that.  I will rather skip on down to a critique

          4   of the current definition beginning with questions

          5   of language.  We went over and over phrases.  We

          6   agreed that the parentheticals, three of them

          7   anyway, the first three in the current definition

          8   are really not necessary.  We agreed, for example,

          9   that the definition of "investigator" would be

         10   perhaps better if it said that an investigator is

         11   any person who conducts a research investigation or

         12   who participates as a member of a research

         13   investigation team.

         14             The most troublesome part of our

         15   deliberations over the last couple of months

         16   continues to be what constitutes private

         17   information?  Some of our members suggest that

         18   private information should be defined according to

         19   the kind of information that is collected.  Is it

         20   sensitive?  Is it potentially harmful?  Is it

         21   embarrassing if it's improperly disclosed?

         22             The next question is, can we really define


                                                                      319

          1   any of those words, sensitive, or potentially

          2   harmful or embarrassing, and if so, from whose

          3   point of view?

          4             There was some discussion about whether we

          5   should distinguish between collecting personal

          6   information about people and how personal

          7   information might be distinguished from private

          8   information.  And is it private information if it

          9   can't be linked to an identifiable individual? 

         10             There are a number of other questions

         11   about whether or not, for example, we can define

         12   private information as privileged and confidential;

         13   is private information the kind of information we

         14   can collect from a subject or does it necessarily

         15   include information that is gathered from a subject

         16   about a third party?  These are all questions that

         17   we are wrestling with right now.

         18             One member of our working group went back

         19   to the question of what is research and noted that

         20   the definition of research is the systematic

         21   collection of data with the intent of advancing

         22   scientific knowledge.  And it was this observation


                                                                      320

          1   that brought us into the problem of defining

          2   parties.

          3             We've heard a lot about parties, first

          4   parties, second parties and third parties, and for

          5   the sake of clarity and conciseness right now, we

          6   can say that first parties are investigators,

          7   second parties are those subjects that have direct

          8   contact with the investigator, they may also

          9   include those who are studied directly by the

         10   investigator either through direct intervention or

         11   use of pre-existing data or tissue. 

         12             And third parties which are generating so

         13   much trouble now are perhaps persons about whom the

         14   investigator gathers information from second

         15   parties.  Now, we haven't come to conclusions about

         16   this yet, but this sort of outlines the directions

         17   that we are headed.

         18             There was considerable discussion in our

         19   group about the question of changing or amending

         20   federal regulations and my feeling at the end of

         21   our second conference call was that people threw up

         22   their hands and said, we can't change the federal


                                                                      321

          1   regulations, they're essentially written in stone. 

          2   We have an acute problem here that we have to

          3   address and perhaps the way to address this is to

          4   formulate guidelines within the current federal

          5   regulations to give IRBs some sort of a handle on

          6   how to deal with this difficult question of third

          7   parties.

          8             So we went on then to this idea of

          9   crafting guidelines that would help IRBs number

         10   one, identify human subjects and third parties in

         11   biomedical research.  And number two, questions of

         12   considering waivers for informed consent from the

         13   third parties.

         14             We had a long discussion of our ideas

         15   about how we would include certain individuals in

         16   the category of human subjects.  And I think

         17   without reading all of these various comments I

         18   think I've generally summarized that already. 

         19   Human subjects will be those individuals with whom

         20   an investigator has direct contact and third

         21   parties will continue, at least for the time being

         22   to be those individuals that do not have direct


                                                                      322

          1   contact with the investigator, but about whom the

          2   investigator gets information from the research

          3   subjects, the real persons that are in contact with

          4   each other.

          5             We also would consider standards for

          6   handling private information and this is going to

          7   continue to be a very difficult area for us.  Some

          8   of the comments that came in to us came in from the

          9   various members of the working group were these: 

         10   private sensitive, identifiable information whether

         11   about a research subject or a third party must be

         12   protected.  Investigators should secure data at all

         13   stages of research.  When data identifying research

         14   participants are no longer necessary to the

         15   progress of the research investigators should take

         16   steps to deidentify research records.

         17             So we've got a lot of ideas just in this

         18   one opinion from one member of our group.  But I

         19   will say that the feeling I have over all the

         20   comments of the members of our group is this.  We

         21   feel very, very strongly that any data that are

         22   collected or any information that is collected in


                                                                      323

          1   the context of a research project should be very,

          2   very carefully protected and guarded.  How we are

          3   going to do this, I don't know.  We talk about

          4   stiff fines and sanctions according to the HIPAA

          5   regulations, or whatever, but I think the consensus

          6   of our group at this time is that we must establish

          7   safeguards for this information and make violations

          8   of the safeguards subject to severe strong

          9   sanctions.

         10             So we have a few other questions to get

         11   into, we need a working definition, for example, of

         12   identifiable information with regard to the

         13   language of the current definition of human

         14   subjects.  We really don't quite know what it means 

         15   to make information public, we need a definition

         16   there.  We need to certainly formulate our

         17   guidelines for our IRBs, so that IRBs will have a

         18   handle on how to approach individual investigators

         19   and how to judge research proposals so that any

         20   information that is collected will be very, very

         21   carefully guarded.

         22             I think this pretty much summarizes what


                                                                      324

          1   we've been up to.  We are concerned about who the

          2   research subjects are and defining third parties. 

          3   We are very concerned safeguarding information, and

          4   we have a couple of other issues that are going to

          5   enter into these discussions as we continue.

          6             First of all, does a third party become a

          7   research subject as soon as an investigator obtains

          8   identifiable information about him or her?  This

          9   raises a question of what do we mean by

         10   identifiable?  Sometimes, for example, we might be

         11   collecting a family history and have a full name

         12   and birth date, but we have no idea how to get in

         13   touch with that individual. 

         14             On the other hand, we might have

         15   information about an individual that would let us

         16   find this person, this third party, and contact

         17   this thirds party.  But then we raise the question

         18   of, if we contact a third party without an

         19   introduction by the person who talked about this

         20   person to begin with, are we going to be invading

         21   that individual's privacy.  So we've got a real,

         22   real problem here.


                                                                      325

          1             And another question that was raised, this

          2   is the last one that we will have to deal with, the

          3   last question that we raised is, what kind of

          4   information are we going to be collecting about our

          5   subjects and our third parties?  Whether we should

          6   collect data and ask questions that are only

          7   immediately relevant to the study that we're doing,

          8   or whether or not we're going to deal with the

          9   question of very broad questionnaires that are sent

         10   out to people and all sorts of information that is

         11   collected that doesn't necessarily have direct

         12   relevance to a particular study.  A few members of

         13   our group have suggested that we should try to

         14   avoid expansive and far-reaching questionnaires and

         15   that we should limit what we are allowing -- the

         16   kind of information that we are allowing people to

         17   collect to information that is reasonably relevant

         18   to the study that we're doing.

         19             So that's where we are at this stage of

         20   the game.  I understand that we're going to have

         21   considerably more discussion after this with the

         22   two working groups meeting together right after


                                                                      326

          1   this assembly.  And we'll more public discussion of

          2   these issues tomorrow evening.  So that explains

          3   why we're running a little late, but that's it for

          4   right now.

          5             CHAIRPERSON MARSHALL:  Mary Kay, thank you

          6   very much.  I'm reading Mark Barnes' mind and he's

          7   saying, thank God I'm not chairing that working

          8   group. 

          9             [Laughter.] 

         10             CHAIRPERSON MARSHALL:  You all have taken

         11   on some very difficult, core conceptual work.  And

         12   it sounds as though you're making beautiful

         13   progress.  And I an tell you, having served on a

         14   recent 407 panel and trying to parse out the

         15   meaning of the word "serious" just how difficult

         16   this very basic work is.  So, I commend you and

         17   your fellow working group members.

         18             Let me open the floor up to other

         19   committee members, but the framework that you've

         20   provided and the steps that you've taken in this

         21   direction look wonderful.  So thank you very much. 

         22             Elliot.


                                                                      327

          1             DR. DORFF:  First of all I want to echo

          2   that.  I mean, what you're talking about is

          3   absolutely critical and very messy.  Okay.  And so

          4   -- I mean, so if there are difficulties along these

          5   lines, both in the articulation of what the issues

          6   are and what to do about them, that's to be

          7   expected and whatever headway you can make is

          8   applauded.  And my comments here are in that

          9   spirit.  Right.  I'm just going to try to tell you

         10   how we reacted to some of the things that were in

         11   this.

         12             First of all, matters of language.  The

         13   first thing that you raise is the issue of living. 

         14   A human subject means a living individual about

         15   whom an investigator or professional student

         16   conducting research obtains one or two, right?  And

         17   somebody raised the question of living.  Well, of

         18   course, that then, you know, in the bioethical

         19   literature raises the whole issue of when does life

         20   begin.  Right.  You know, the old -- you know, the

         21   Catholics think it's when sperm and egg come

         22   together.  There are those who think that it's when


                                                                      328

          1   quickening happens, the Supreme Court said, that

          2   when the fetus was viable, there are those who

          3   think that when it -- you know, the fetus is born. 

          4   And then Jews think it's when your child gets into

          5   medical school. 

          6             [Laughter.] 

          7             DR. DORFF:  But the point -- I'm sorry, I

          8   couldn't resist.  

          9             AUDIENCE PARTICIPANT:  [Off mic.] 

         10             [Laughter.] 

         11             DR. DORFF:  That's right.  But anyway, the

         12   point that I'm after here is that when we're

         13   talking about a living individual, one of -- you

         14   should be aware of the fact that there are some

         15   critical philosophical and also frankly political

         16   issues involved in what's the status of the fetus. 

         17   For that matter, at this moment, what's the status

         18   of a sperm and an egg in a petri dish?  You know,

         19   is that in terms of the debate about stem cell

         20   research, I mean, all of that is really critical

         21   stuff which I would suggest that you try to punt

         22   on.  Okay. 


                                                                      329

          1             What I mean by that is, if you were to

          2   talk about saying a human subject is a person,

          3   about whom an investigator and just leave the word

          4   "person" there to basically avoid everything that

          5   happens in regard to what goes on in utero unless

          6   you want to apply all of this to that.  And what we

          7   were just hearing before the break is that where

          8   there were definitions of "fetus" and what could

          9   happen with the fetus, I mean, you may want to

         10   include that in your definition as something that's

         11   going to be -- you know, to which you are going to

         12   be applying these regulations.  But you should at

         13   least be aware of that issue.

         14             And on the other end of things, I think

         15   that research on dead people is a very different

         16   sort, but even the dead require a certain amount of

         17   respect on our part.  And so you may want -- you

         18   know, there may be -- I mean, I think the

         19   regulations would be far less stringent, but

         20   nevertheless you want to have at least something to

         21   say about the sacredness of the human body even in

         22   death.


                                                                      330

          1             The second thing is, investigator.  I'm on

          2   page 3.  "Investigator" would be better defined as

          3   any person who conducts a research investigation or

          4   participates as a member of a research

          5   investigation team.  The immediate problem with

          6   that is you cannot use the word that you're

          7   defining in the definition.  So what I would do is

          8   just simply cut out "investigation" -- both uses of

          9   "investigation" in the definition and then you're

         10   all right.  Investigator would be better defined as

         11   any person who conducts research or who

         12   participates as a member of a research team.

         13             Then, the third thing is, what is

         14   "research"?  I'm on page 4.  The current definition

         15   of "research" is the systematic collection of data

         16   with the intent of advancing scientific knowledge. 

         17   I think that's fine, but I wanted you the be aware

         18   of the fact that part of the real problems in human

         19   subject protection, I'm thinking about the Nazi

         20   experiments, for example, had to do with

         21   manipulating data, manipulating circumstances in

         22   order to be able to create the data as to what


                                                                      331

          1   would happen when you froze bodies, for example. 

          2   Right.  So, if you understand the systematic

          3   collection of data very broadly to mean not just

          4   simply collecting what is there, but also

          5   manipulating what's there to find out certain facts

          6   about what happens to people when something happens

          7   to them, then that's fine.  I mean, the definition

          8   can stand.  But I think you need to understand it

          9   broadly.

         10             The fourth one that I wanted to make was

         11   that on page 5, where you go through guidelines for

         12   inclusion as a human subject, the part that was not

         13   clear to me throughout all of that is what is the

         14   purpose of the definition of sometimes it seems to

         15   be b for consent requirements.  In other words,

         16   when do we have a human subject such as you need

         17   consent in order to be able to do the research

         18   morally?  And sometimes that had to do with privacy

         19   issues.  And it may not be -- those two things may

         20   not be the same. 

         21             In other words, what is a human subject --

         22   when we were talking this morning, where are the


                                                                      332

          1   children, for example, right?  Children are

          2   certainly human subjects, but they may not be able

          3   to give consent.  At the moment they give assent. 

          4   And we're talking about teenagers and whether they

          5   can give consent.  So, I mean, I think you need to

          6   be -- in that section, Section V.  You need to be

          7   very clear as to what the purpose is that you have

          8   in mind and then ask the question about what seems

          9   reasonable when you're trying to figure out what

         10   the rules should be in regard to consent, and what

         11   the rules should be in regard to privacy.  But

         12   understand that those are the two issues at least

         13   that you've identified here that you are after and

         14   you should think about in terms of those things.

         15             And the last thing that I wanted to say

         16   was on page 6 where you're talking about privacy. 

         17   It reminded me frankly of a discussion in the

         18   Talmud in regard to embarrassment.  When according

         19   to the Talmud, when I -- if I strike you, if I

         20   assault you, then I am responsible for five

         21   different types of damages.  And one of them is for

         22   the embarrassment that I caused you.  So then the


                                                                      333

          1   Talmud then asks, well, how do you define

          2   "embarrassment"?  Is it that the victim had to

          3   actually fee the embarrassment and be aware of it,

          4   or what would happen if I insulted you when you

          5   were sleeping and so you weren't even aware of it? 

          6   Is that still embarrassment?  And what would happen

          7   even if I was awake and I wasn't embarrassed myself

          8   but everybody else knew that I had just been

          9   dissed?  And that's a technical term. 

         10             [Laughter.] 

         11             DR. DORFF:  Now, the thing is, I think

         12   that's a similar kind of discussion here in terms

         13   of what is private.  One way to go with it is that

         14   what is private is whatever I want -- whatever

         15   information I want to retain about myself so that

         16   nobody else knows about, in which case the

         17   definition is dependent upon the individual. 

         18             Another way to go with it is that it

         19   depends upon the community, what the community as a

         20   whole thinks ought to be private, whether the

         21   person thinks so or not.  The person may have --

         22   may choose to divulge those things, if that person


                                                                      334

          1   wants to, but that the community retains as private

          2   certain types of information which get defined as

          3   being inherently private; right.

          4             A third way to go to it has to do with

          5   results.  In other words, that is private which

          6   could be damaging to a person if it were known, and

          7   that which is not private, if it's not going to be

          8   damaging -- first you have to ask what "damaging"

          9   means, but the point is that those are at least

         10   three different ways of attacking the problem of

         11   what constitutes private.

         12             CHAIRPERSON MARSHALL:  I have Susan, then

         13   Bob, then Abbey.

         14             DR. KORNETSKY:  Mary Kay, I think you did

         15   a wonderful job outlining the issues.  And I'm not

         16   on the working group, but sort of trying to read

         17   through sort of end results, I think there's one

         18   particular area that isn't on your list and I'm

         19   just bringing it up.  I think regardless of whether

         20   you consider a third party a human subject or not,

         21   you're going to probably boil down to the issue of

         22   informed consent.  Regardless of what you call


                                                                      335

          1   them, when you need to think about obtaining that

          2   or not.  And if you look to the common rule about

          3   informed consent and waivers of informed consent,

          4   and I think about this on a daily basis with human

          5   subjects, one of the things that probably you will

          6   need to think about is one of the categories if you

          7   want to waive it is that it is impracticable to get

          8   informed consent.  And I think from having spent

          9   probably two or three months thinking about that

         10   and trying to give our investigators guidance, I

         11   don't see a way that you're going to be able to

         12   avoid that in the situation.

         13             CHAIRPERSON MARSHALL:  Bob.

         14             DR. R. LEVINE:  I want to second the

         15   congratulations to the working group and to Mary

         16   Kay.  I'm very glad you began with the discussion

         17   of the relevant histories.  I want to just add a

         18   couple of points to that. 

         19             The first is that the National Commission

         20   which gave the recommendations that formed the

         21   framework for the current regulatory system never

         22   defined human subject.  The reason the regulation


                                                                      336

          1   writers felt it necessary to define the human

          2   subject is that they wanted to extend the reach of

          3   the regulatory standards to medical records review

          4   which many people were arguing did not entail

          5   interaction with the person, but you were getting

          6   information about living persons.  No one ever

          7   imagined that it would be applied to the walking

          8   around relatives of people that you were actually

          9   interviewing.  And that definition stood there

         10   without having been interpreted as applying to

         11   living relatives until the Virginia Commonwealth

         12   case about, what, one or two years ago.

         13             In the current regulations we find a lot

         14   of the requirements for informed consent are

         15   compared with what goes on in medical practice.  It

         16   says, for example, that you don't have to get

         17   written documentation of consent if the procedure

         18   you are doing for research purposes is one that is

         19   ordinarily not -- consent to do this procedure is

         20   ordinarily not documented in a written form in the

         21   practice of medicine.

         22             This brings me into considering analogies


                                                                      337

          1   with medicine.  In medicine a routine medical

          2   history involves asking whoever the identified

          3   patient is all sorts of questions about their

          4   personal history and their relatives' history.  It

          5   goes into greater detail than almost any

          6   interviewer survey instrument that would be

          7   employed by a geneticist or by a sociologist or by

          8   a psychologist.

          9             To be consistent, we would have to say

         10   that before a doctor could get a family history

         11   that the doctor would have to get permission from

         12   all of the patient's relatives to get this.  That's

         13   what Susan just reminded us, that it would violate

         14   the impracticability standard.

         15             The other thing is that in research the

         16   confidentiality safeguards are very, very much more

         17   secure than they are in medical practice.  I had a

         18   patient who was a medical records librarian who

         19   refused to talk to me as long as I had a pen in my

         20   hand.  But now what happens routinely when you go

         21   into the hospital, you waive your rights to

         22   privacy.  You sign a document saying that the


                                                                      338

          1   hospital has the authority to turn your entire

          2   medical record over to your insurance company.  It

          3   doesn't say just that part that has to do with

          4   determining what should be billed in this

          5   admission, but everything in your medical record

          6   which is a very much plenary violation of privacy

          7   standards than anything that goes on in the

          8   research context.

          9             The other thing is, what about the problem

         10   about people like the father at Virginia

         11   Commonwealth who was offended because they asked

         12   his daughter to comment on his genitals.  I think

         13   the way we usually protect ourselves against such

         14   disclosures is that we don't tell our children such

         15   things.  They shouldn't know it in the first place. 

         16   But if it comes up in the course of conducting

         17   social or genetic research, the odds that it will

         18   be further disclosed are very much less in a social

         19   science or genetics context than they would be in

         20   medical practice.

         21             All of this is just various little points

         22   that I would use to support my argument that in


                                                                      339

          1   almost all research of the type we're talking

          2   about, the only person who should be called upon to

          3   consent is the person they're actually talking to

          4   with the exception of when you're talking to little

          5   children.  That's why we have limitations of the

          6   exemptions from the federal regulations.  They say

          7   these apply to everything except when you're

          8   talking to children.  And that's because we don't

          9   think children age six, seven, eight, ten know

         10   enough about what the family would like to keep

         11   private to be proper guardians of this information. 

         12   So we then say, well, at least they have to submit

         13   their plan to an IRB not exempt from coverage by

         14   the regulations.

         15             CHAIRPERSON MARSHALL:  Thank you, Bob.  I

         16   have Abbey and then Bob.

         17             MS. MEYERS:  Well, one of the issues here

         18   is that when we look at this third-party question,

         19   which is a new question, I don't think it's been

         20   really raised before, before the Virginia twin

         21   study took place, that we can't change the laws,

         22   and we can't change the regulations.  But even if


                                                                      340

          1   we could, we're advisory to the HHS Secretary and

          2   research isn't just part of HHS.  So if we said

          3   that the law has to be changed or the regulations

          4   have to be changed, the interpretation of human

          5   subject in the common rule has to be changed, it

          6   would take 100 years and have to go through what,

          7   17 federal agencies; right? 

          8             Do you want to answer that? 

          9             DR. KOSKI:  Yeah, if I could just address

         10   it.  We frequently hear that kind of talk thrown

         11   around.  I think it's time to stop that.  I think

         12   that in fact where there is thoughtful change

         13   required in regulations that you would find all of

         14   the federal agencies that subscribe to the common

         15   rule stepping up to the plate to engage in that. 

         16   In fact most of them are represented here.  And I

         17   don't think that continuing -- and I'm not picking

         18   on you with this, Abbey, I'm just getting it out

         19   there for everybody else, I just don't think that

         20   continuing that sort of mythology is serving our

         21   interests.

         22             I think it's time to say that where we


                                                                      341

          1   need to change, we should look at it and we should

          2   change it and we can do that.  So, you know, but

          3   again, the emphasis has to be on thoughtful

          4   delivery things that will serve the purposes of

          5   responsibly conducting research.  But let's get

          6   that off the table now.

          7             MS. MEYERS:  The most we could do is

          8   recommend that they be changed.  Right?  Because

          9   we're advisory to the HHS Secretary. 

         10             Okay. So the issues then in the Virginia

         11   twins study was that -- from my perspective anyway,

         12   the questions that were asked were not relevant at

         13   all to this young girl being a twin, you know,

         14   whether her father had deformed organs or whatever

         15   had absolutely nothing to do with it.

         16             So I think that the definition that we're

         17   talking about the research has to be relevant to

         18   the questions  is really important.  But the

         19   primary thing is, no matter what, whether you're

         20   talking about your dead grandmother or, you know,

         21   your uncle who never threw anything away and they

         22   needed a backhoe to clean out his house because he


                                                                      342

          1   was an obsessive/compulsive, or whatever, those

          2   kinds of things need to be private without even

          3   guessing whether it would be embarrassing to him or

          4   not.  I think that the primary aim here is a

          5   guarantee on confidentiality for -- and not

          6   identifying a human being with the data.

          7             And if we could just de-identify the data,

          8   then you could collect all the information you want

          9   without having to worry about stepping on anybody's

         10   rights whether they're dead or alive.  I think that

         11   it's wrong to expect somebody to get a waiver for a

         12   relative who they may not have talked to for 20

         13   years, but we need the information for research

         14   purposes and there's no way to tell a person you

         15   shouldn't be talking about your uncle that way

         16   because your uncle has rights and you have to be

         17   confidential.  I think the information is okay.  It

         18   has to be collected, but it has to be de-

         19   identified, that's the main thing.

         20             DR. PELIAS:  I have one more comment about

         21   language and that's the word "de-identify"; it

         22   seems to me that it sound awfully close to


                                                                      343

          1   "anonymize" and the question there is who has the

          2   right to make those decisions to take identifiers

          3   off of data.  We'll have to deal with that sometime

          4   down the line.  But that's just another question to

          5   throw into the hopper at this time.

          6             CHAIRPERSON MARSHALL:  I'm just going to

          7   make a procedural remark here and that is that we

          8   are actually running overtime and we do have two

          9   working groups that are going to continue to work

         10   after the meeting.  So I am going to close the

         11   questioning at 5:00 knowing that we will have time

         12   tomorrow to revisit the issue that's on the table. 

         13   So if your question or your remarks aren't made

         14   this afternoon, there will be time for them

         15   tomorrow.

         16             I have Bob and Adil, Mark and Judy as the

         17   order depending on how the time goes. 

         18             DR. RICH:  I would like to just continue

         19   the question of de-identification for just a moment

         20   with the concern that is in at least one of the

         21   points here that a research project can be

         22   identified as a discrete entity and then at the


                                                                      344

          1   conclusion of the project, the data are de-

          2   identified.

          3             And as you know better than anyone here as

          4   a geneticist, Mary Faith, I think increasingly as

          5   we move into areas where data are in the form of

          6   archived tissues, where the questions haven't been

          7   considered yet, that we may be needing those

          8   tissues for research purposes a decade from now,

          9   the issue of de-identification becomes very

         10   problematic.  And that's not to say that I disagree

         11   at all with the idea that there needs to be a sharp

         12   separation between individuals who have access to

         13   the medical records and who could re-identify them

         14   and the investigators who don't need a specific

         15   identifier identifiable information.  But I think

         16   there are very problematic issues if we are to

         17   actually be able to exploit the incredible power

         18   that we will be gaining by these archived tissues

         19   and archived data samples that we need to somehow

         20   be able to get back and ask the questions ten years

         21   from now that we don't even understand about right

         22   now.


                                                                      345

          1             CHAIRPERSON MARSHALL:  Adil.

          2             DR. SHAMOO:  I think this working group

          3   brings the general question which I have brought to

          4   your attention through e-mails and every meeting

          5   and Bob Levine was kind enough to bring that up all

          6   over again and that is the general issue.  What

          7   human research protection, what are we covering? 

          8   There is research done with human subjects which is

          9   not covered now as we all know.  Definition of

         10   issue, minimal risk, direct medical benefits.  The

         11   whole definition of what research -- these are the

         12   kind of general issues and back final reports have

         13   at -- the global issue.  And we're really, we're

         14   sort of again and again avoiding the amount.  I

         15   plead with Mary Faith and Dr. Koski, maybe we

         16   should address them at the next meeting as an

         17   agenda item because they are going to come up all

         18   the time.  And then doing them within each work

         19   group may not serve the overall purpose.  That's

         20   one comment.

         21             And then I have a point of information

         22   from Kate.  I did ask what portion of proceedings,


                                                                      346

          1   work groups, e-mails, become an official part of

          2   the record of this committee for the public to see

          3   in the web site or other documents.  Thank you. 

          4             MS. GOTTFRIED:  Wait and just in a quick

          5   response.  I definitely have looked into that. 

          6   Unfortunately the people who were here earlier

          7   today are the FACA -- some FACA experts who would

          8   have been able to opine for you specifically on

          9   that.  But in light of that I will get their

         10   official response and distribute it to the

         11   committee.  

         12             CHAIRPERSON MARSHALL:  And, Adil, actually

         13   I wanted to thank you.  You and I have talked about

         14   this general issue and the fact that in light of

         15   our different workgroups we may be looking at the

         16   trees, but not necessarily the forest.  And I think

         17   that tomorrow beginning with Congresswoman DeGette

         18   we're going to be taking -- we're going to be

         19   looking at taking that broad overview.  And

         20   certainly the folks from the NBAC and so forth.  So

         21   I think that the whole point of tomorrow morning's

         22   session is for us as a committee to begin to get a


                                                                      347

          1   sense of the landscape to help us start to form a

          2   larger picture in our own mind collectively as a

          3   committee of where we want to go and how we want to

          4   frame issues that aren't necessarily being

          5   addressed more concretely or in a more narrow

          6   fashion.

          7             So I would hope that the session beginning

          8   with our first speaker tomorrow morning will head

          9   us in that direction and that we may also wind up

         10   the end of the day with some plans for moving

         11   forward in those directions.

         12             And I'll take one more question.  Mark.

         13             MR. BARNES:  A general comment, perhaps to

         14   set the stage for the fact that we're going to hear

         15   from Julie Kaneshiro tomorrow about the

         16   relationship between HIPAA and clinical research.

         17             I just wanted to point out the following

         18   in terms of the workgroup, the charge of the third-

         19   party workgroup here.  We do have these new federal

         20   regulations that goes to what Bob Levine was

         21   talking about too.  We did these new federal

         22   regulations that govern medical privacy and


                                                                      348

          1   confidentiality that essentially have done the

          2   following.  They basically have, one could say, for

          3   the research process, they have unbundled the

          4   privacy rights, the right to the use and disclosure

          5   of one's medical information.  They have unbundled

          6   that from the informed consent process, although

          7   one could say it's still part of the informed

          8   consent process.  And there are a separate set of

          9   rights and obligations that adhere to an

         10   institutions or a researcher's use and disclosure

         11   of medical information.

         12             One thing that we are talking about the in

         13   the third-party work group is in fact the

         14   definition of who is a research subject and at what

         15   point does the collection of data cross the line --

         16   become so intrusive or so comprehensive that it

         17   really crosses the line and another person who has

         18   not had contact with the research subject does

         19   become the subject of research.  But there's

         20   another thing that the third-party workgroup really

         21   needs to grapple with too which is that under HIPAA

         22   that person -- information that is collected about


                                                                      349

          1   that third party may become at some point,

          2   depending on HHS's interpretation of the HIPAA

          3   regulations, that person, that third party, that

          4   may become protected help information of that third

          5   party in which case the third party may not need to

          6   consent to the research for informed consent

          7   purposes, but may need to consent for the

          8   additional uses and disclosures of the information.

          9             That isn't -- it's an unintended

         10   consequence of the way in which the HIPAA regs were

         11   -- and perhaps statue, but really more the regs

         12   were written.  But the point is that the HHS

         13   Secretary who is the one who ultimately has

         14   authority over -- or at least part of the authority

         15   over the common rule is also the one whose general

         16   counsel is writing interpretations every day of the

         17   HIPAA regulations.  So one of the things that we

         18   need to be cognizant of, I think in the third-party

         19   workgroup, is not simply that we're coming on

         20   informed consent standards, but also that we are

         21   advising the -- through Greg, through Dr. Koski and

         22   his staff -- the Secretary of HHS about what ought


                                                                      350

          1   to be the permissible uses and disclosures and when

          2   or under what circumstances the HIPAA regulations

          3   ought to be read to require or not to require the

          4   gaining of that consent or authorization under

          5   HIPAA for the additional uses and disclosures.

          6             CHAIRPERSON MARSHALL:  Let us end here.  I

          7   would like to thank the Committee as a whole for

          8   all of your hard work prior to today's meeting,

          9   those of you who are on working groups.  Some of

         10   the folks out in the audience have participated in

         11   the working groups and thank you for being here. 

         12             Mark and Alan, thank you for your

         13   wonderful work.  We have come to some closure today

         14   on some of our very early projects and I think it

         15   felt good.  The process felt good.  We arrived at

         16   consensus.  We are moving forward well. And I look

         17   forward to an excellent meeting tomorrow.

         18             I want to thank Kate for all of her hard

         19   work in pulling this meeting together.  I want to

         20   thank Greg for his continued support and most

         21   excellent advice.  Those of you on the committee

         22   who might want to discuss food could -- we've taken


                                                                      351

          1   care of food.  Okay.  

          2             The two workgroups will meet then here in

          3   this room in just a few moment.  So -- yes? 

          4             AUDIENCE PARTICIPANT:  [Off mic.] 

          5             CHAIRPERSON MARSHALL:  Kate is going to

          6   pass that information out to all.

          7             DR. F. LEVINE:  Can I just say, I think

          8   it's less clear to the social and behavioral

          9   science working group that since the social and

         10   behavioral science working group is also addressing

         11   the issue of third parties that those of us who are

         12   present or have become present will join the third

         13   party working group after the conclusion of this to

         14   continue that conversation.  But not everyone in

         15   the room knew that.  Some people are looking

         16   around.  Who is coming where?

         17             CHAIRPERSON MARSHALL:  Thank you very

         18   much, Felice, for clarifying that.  So thank you

         19   all very much for a very successful day and we'll

         20   see you tomorrow.

         21             [Whereupon, at 5:00 p.m., the meeting was

         22   recessed to be reconvened on Tuesday, July 31,


                                                                      352

          1   2001, at 8:30 a.m.]

          2   

          3   

          4   

          5   

          6   

          7   

          8   

          9   

         10   

         11   

         12   

         13   

         14   

         15   

         16   

         17   

         18   

         19   

         20   

         21   

         22   


                                                                      353

          1             CERTIFICATE OF OFFICIAL REPORTER

          2             This is to certify that the attached

          3   proceedings before the National Human Research

          4   Protections Advisory Committee held Monday, July

          5   30, 2001, was held as herein appears, and that this

          6   is the original verbatim transcript thereof, and is

          7   a full correct transcription of the proceedings.

          8   

          9   

         10   

         11                                                       

         12                                 Gerald T. Brooks, Sr.

         13                                 Official Reporter

         14   

         15   

         16   

         17   

         18   

         19   

         20   

         21   

         22