1

          

          1   

          2   Department of Health and Human Services

          3   

          4   

          5     NATIONAL HUMAN RESEARCH PROTECTIONS

          6     ADVISORY COMMITTEE (NHRPAC) MEETING

          7   

          8            Monday, April 9, 2001

          9   

         10   

         11   

         12   

         13   

         14   

         15   

         16             POOKS HILL MARRIOTT

         17            5151 Pooks Hill Road

         18             Bethesda, Maryland

         19   

         20   

         21   

         22   


                                                                        2

          1                            A G E N D A

          2   Monday, April 9, 2001

          3   8:30-9:15      Welcome:

          4                  Introduction of New Members (brief

          5                  comments about yourself; areas of

          6                  particular concern)

          7                  Mary Faith Marshall, Ph.D.

          8                  Chairperson NHRPAC

          9   

         10                  Office of Human Research Protection

         11                  Updates

         12                  Greg Koski, Ph.D., M.D., Director

         13                  OHRP, Executive Secretary, NHRPAC

         14                   Chairman, HSRS

         15   

         16                  Clarification of NHRPAC Roles

         17                  Mary Faith Marshall, Ph.D.

         18   9:15-9:30      The Department's Commitment to

         19                  Protection of Human Subjects

         20                  The Honorable David Satcher, M.D.,

         21                  Ph.D., Surgeon General

         22                  Committee Discussion 


                                                                        3

          1   10:30-10:45    BREAK

          2   

          3   11:00-11:45    Update Declaration of Helsinki

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

          5   

          6   11:45-12:15    Public Comment

          7   

          8   12:00-1:30     LUNCH (On your own)

          9   

         10   1:30-4:30      Panel Discussion

         11                  Moderator

         12                  Francis Collins, M.D., Ph.D.

         13   

         14                  Family Members/Third Parties:  Should

         15                  Family Members/Third Parties of Survey

         16                  Subjects, Themselves become Subjects

         17                  of a Protocol -- if so, Must Informed

         18                  Consent be Obtained for Investigator

         19                  to Retain Private Information on These

         20                  Individuals?

         21   

         22   


                                                                        4

          1   2:15-3:15      Guest Panel

          2                  Jeff Botkin, M.D., M.P.H.

          3                  Department of Pediatrics

          4                  The University of Utah Medical Center

          5                  Terri Arledge, Ph.D.

          6                  GalaxoSmithKline

          7                  Sharon Terry

          8                  Vice President for Consumers

          9                  Genetic Alliance and

         10                  President of PXE International

         11                  Terri Seargent

         12                  Consumer Advocate Alpah1 Association

         13   

         14   3:15-3:30      BREAK

         15   

         16   3:30-4:30      Discussion 

         17   

         18   4:30-5:15      Public Comment

         19   

         20   5:15-5:30      Closing Comments/Adjourn

         21   

         22   


                                                                        5

          1   PARTICIPANTS:

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

          3   of Program in Bioethics, University of Kansas

          4   Medical Center 

          5   

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

          7   Director, Office of Human Research Protections,

          8   Office of Public Health and Science, OS

          9   

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

         11   LLP

         12   

         13   SANFORD CHODOSH, M.D.

         14   

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

         16   Professor of Philosophy

         17   

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

         19   The New York Academy of Medicine

         20   

         21   

         22   


                                                                        6

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

          2   Clinical Research Compliance, Department of

          3   Clinical Investigation 

          4   

          5   FELICE J. LEVINE, Phase.D., Executive Officer,

          6   American Sociological Association

          7   

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

          9   University School of Medicine 

         10   

         11   ABBEY S. MEYERS, President, National Organization

         12   for Rare Disorders

         13   

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

         15   S. Kornfeld Professor of Biomedical Ethics,

         16   Director, Center for Biomedical Ethics, University

         17   of Virginia Health System

         18   

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

         20   of Genetics, Louisiana State University Health

         21   Sciences Center 

         22   


                                                                        7

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

          2   Research, Emory University School of Medicine

          3   

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

          5   Biochemistry and Molecular Biology, University of

          6   Maryland School of Medicine 

          7   

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

          9   Clinical Operations, Hoffman-La Roche, Inc.

         10   

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

         12   Division of Nephrology, University of Alabama at

         13   Birmingham

         14   

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

         16   Director, National Human Research Protections

         17   Advisory Committee

         18   

         19   

         20   

         21   

         22   


                                                                        8

          1   EX-OFFICIO MEMBERS

          2   

          3   Dr. James Shelton, USAID

          4   

          5   Maryann Danello, Ph.D., CPSC

          6   

          7   Dr. Joseph Spence, USDA-ARS

          8   

          9   Ms. Linda Beth Shilling, Commerce

         10   

         11   CDR Douglas Forcino, USDOD

         12   

         13   Ms. Blanca Rosa Rodriguez, Education

         14   

         15   Dr. Susan Rose, Energy

         16   

         17   Dr. Dixie Snider, DHHS

         18   

         19   Dr. David A. Lepay, FDA

         20   

         21   Dr. Belinda Seto, NIH

         22   


                                                                        9

          1   Alan Sandler, D.D.S, NIH

          2   

          3   Francis D. Chelsey, Jr., M.D., AHRQ

          4   

          5   Dr. Paul Gatons, DHHS

          6   

          7   Donald Prosnitz, Ph.D., DOJ

          8   

          9   Mr. Thomas G. Raslear, DOT

         10   

         11   John H. Mather, M.D., VA

         12   

         13   Mr. Roger S. Cortesi, EPA

         14   

         15   Richard S. Williams, M.D., F.A.C.S, NASA

         16   

         17   Dr. Philip Rubin, NASA

         18   

         19   Mr. Howard L. Bradley, SSA

         20   

         21   

         22   


                                                                       10

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

          2                               [Time noted:  8:35 a.m.]

          3             CHAIRPERSON MARSHALL:  Good morning. 

          4             Welcome to the second meeting of the

          5   National Human Research Protections Advisory

          6   Committee.  I perceive that we have more people at

          7   the table than we did last time.

          8             Committee members you haven't been out

          9   there cloning yourselves in the interim have you? 

         10             [Laughter.] 

         11             CHAIRPERSON MARSHALL:  We would get into

         12   real trouble with the Surgeon General if that was

         13   the case.   But, no, I perceive we have new members

         14   and we will introduce you and give you a chance to

         15   tell us about yourselves in just a moment.

         16             But I am foremost honored to introduce to

         17   you the Honorable David Satcher who is the Surgeon

         18   General.  And he is going to welcome all of us and

         19   tell us where human subjects protections fit within

         20   the Department of Health and Human Services's

         21   priorities and we are delighted that you are with

         22   us and honored.   Thank you so much, sir, for being


                                                                       11

          1   with us.

          2             DR. SATCHER:  Well, thank you.  I am

          3   delighted to be able to join in welcoming you to

          4   the staff.  Now that your sworn in, I want to help

          5   to tell you what you ve gotten yourselves into.  I

          6   think most and you know.

          7             But I think it is fair to say that the

          8   work that you are doing is really critical to the

          9   future of the nation, because research is so

         10   critical, and you know that.  But in case you have

         11   not reflected on it, when you think back to the

         12   last century and the major developments and see CDC

         13   took the time to try to define the major

         14   achievements of 20th-century, you know, in addition

         15   to the fact that we've gained 30 years of life

         16   expectancy.  They pointed out major developments in

         17   areas like immunizations, development of new

         18   vaccine, especially the polio vaccine.  They

         19   pointed out the eradication of smallpox using a

         20   vaccine that was developed much earlier.

         21             But all of the achievements that we've

         22   made in the 20th-century are based on immunization


                                                                       12

          1   programs and the development of antibiotics and

          2   antivirals and other drugs that made such a

          3   difference in the lives of people.  All because of

          4   a research enterprise that was able to really

          5   function and to gain the cooperation and trust of

          6   people throughout this country and the world.

          7             We gained save food and safe water; we've

          8   gained fluoridated water that made such a

          9   difference in tooth decay in children.  And

         10   certainly we've gained enhanced diagnostic tools,

         11   including things like the CAT scan all because of

         12   research.

         13             And looking at all of that as I certainly

         14   did when I became Surgeon General and had

         15   responsibility of planning healthy people 2010 and

         16   noting the dramatic decline in deaths in

         17   cardiovascular disease in the last 30 to 40 years

         18   and in the last decade of course the declining

         19   mortality from cancer.  So when you think about

         20   what research has produced and what we have gained

         21   from research, I think it's really critical that we

         22   protect this enterprise, and we protect the trust


                                                                       13

          1   that people have had in it over the years.

          2             But I think it is also fair to say that

          3   the 20th-century have produced some burdens for us

          4   too as it relates to research.  And, of course,

          5   some of them stand out such as the Tuskegee Study. 

          6   And that burden is very much with us because there

          7   are just so many people who when they think of

          8   research unfortunately they think of Tuskegee when

          9   people were taken advantage of.  So issues like

         10   informed consent and beneficence in research and

         11   justice sort of are in bold perspective as a result

         12   of some of our experiences in the 20th-century.

         13             The Tuskegee study sort of standing out

         14   among them, but certainly not alone.  So we have

         15   some major challenges as we enter the 21st-century;

         16   and we enter the 21st-century with tremendous

         17   opportunities in research.  We know more then we ve

         18   ever known before, including our understanding of

         19   the brain which we talked about a lot in the

         20   Surgeon General's Report on Mental Health and the

         21   difference that's making an treating mental

         22   illness; our knowledge of the human genome and all


                                                                       14

          1   of the accomplishments that we have made as a

          2   result of that.

          3             The technology, the sophistication of our

          4   technology, especially our ability to manage

          5   information.  All of those things are going to have

          6   a tremendous impact on research in the 21st

          7   century.

          8             We have so much more in terms of money and

          9   resources to support research and I think we have

         10   so many more well-trained people.  However, I think

         11   the critical questions that we face, are do we

         12   really have the trust, do we have the ethical

         13   standards, the moral values to protect people in

         14   the research enterprise.

         15             Can we really trust researchers and

         16   institutions to put people first and to protect

         17   human subjects and volunteers?

         18             Is the environment in which we live

         19   conducive to that?

         20             And when you think about it, there are

         21   some major environmental challenges in every area

         22   of our lives, in entertainment.  In the youth


                                                                       15

          1   Violence Prevention Report we talked about the role

          2   of violence, money, and drugs in entertainment and

          3   what impact does that have on children who develop

          4   in that environment.  We don't know the answer

          5   fully, but it is a very appropriate question in

          6   terms of what is shaping us as human beings.

          7             And most important, I think, for you is

          8   the system in place to really protect human

          9   subjects and that system includes not only the

         10   researchers and their ethical standards and the

         11   knowledge of responsibility of the subjects,

         12   themselves, the communities in which they live, the

         13   institutions, industry; is the system in place to

         14   put all these things together to work for people?

         15             While having raised all those questions,

         16   let me say that I think going into the 21st Century

         17   we have the right goals.  I think we have the right

         18   commitments.  And I am going to tell you why I say

         19   that, because healthy people 2010 is the nation's

         20   health plan for the next decade.

         21             And we really struggle with what should be

         22   the goals of healthy people 2010; this is our


                                                                       16

          1   national nation's plan.  We came up with two very

          2   important goals.  The first goal was a goal which

          3   sort of developed out of our knowledge and concern

          4   for the fact that as a nation we are aging, if you

          5   will, in the sense that there are 35 million people

          6   over 65 years of age that grows by 6,000 a day.  

          7   There are 50,000 people over 100 years of age and

          8   the fastest growing group of people in this country

          9   are people over 85 years of age. 

         10             So it was in great part due to that, that

         11   we decided that one goal should be not just to

         12   continue to increase the span of life, but to add

         13   to that the quality of life.  We are really

         14   concerned about the experience that older people

         15   are having in this country in terms of the quality

         16   of their lives.

         17             That concern led us to the concern about

         18   disabilities and a concerned about children,

         19   because some of the greatest threats to the quality

         20   of life occur in children.  If you think about a

         21   child with asthma and a child born with a

         22   disability.   So that goal encompasses not only our


                                                                       17

          1   concern for older people, but for people who have

          2   threats to the quality of life -- of their lives at

          3   every age. 

          4             There are some key research questions in

          5   this area having to do with aging, having to do

          6   with the brain, et cetera, having to do with the

          7   management of disabilities, the rights of people

          8   with disabilities. 

          9             The second goal, I think, is also a very

         10   worthy goal for this nation, and it is the goal of

         11   eliminating disparities in health among different

         12   racial and ethnic groups.  It's a really critical

         13   goal for this nation, not just because of Tuskegee,

         14   but because we have always believed in public

         15   health.  That to the extent that we respond to the

         16   health needs of the most vulnerable among us, we

         17   actually do most to promote the health of the

         18   nation.  So this goal to eliminate disparities in

         19   health, I think, is a really critical.  I think its

         20   right, a think it is reasonable. 

         21             It raises a lot of challenges though for

         22   us.  Major challenges about access to quality


                                                                       18

          1   health care that have not been adequately dealt

          2   with.  Major challenges having to do with human

          3   behavior lifestyles; do we really have in place the

          4   knowledge and the programs to help people modify

          5   their behaviors?

          6             Last week I released the Surgeon General's

          7   Report on Women and Smoking.  And I can't tell you

          8   the number of people who have said to me, "I never

          9   thought that more women died from lung cancer than

         10   breast cancer."  But the fact of the matter is that

         11   in the year 2000, 27,000 more women died from lung

         12   cancer than from breast cancer, and that continues

         13   to go up. 

         14             So this role, this issue of human

         15   behavior, physical activity, nutrition, smoking,

         16   drugs, sexual behavior, do we have a balanced

         17   research agenda?  A research agenda that balances

         18   research in human behavior and basic biomedical

         19   health services research, community-based

         20   prevention research?  Do we have a balanced

         21   research agenda to achieve that goal?

         22             That s the major question and challenges. 


                                                                       19

          1   The environment, what do we know about the

          2   environment in which people live and what role is

          3   the environment playing on healthy people?  CDC

          4   just came out with a very interesting report based

          5   on a very sophisticated laboratory looking at the

          6   different toxins that are found in the blood of

          7   different people.  And showing again that

          8   minorities are more likely to have elevated levels

          9   of many of these toxins because we know that

         10   African-Americans and Hispanics are much more

         11   likely to live within two miles of hazardous waste

         12   sites.  So in all these areas we have the

         13   challenges.

         14             But I think the question for today is:  as

         15   we work to improve the quality of life of all

         16   people and to eliminate disparities in health, what

         17   kind of system is it going to take to protect

         18   people and to gain the trust of communities in the

         19   research enterprise?  

         20             We have the apology for the Tuskegee study

         21   which, I think many of you know, grew out of a

         22   background study down at CDC when I was director. 


                                                                       20

          1   We tried to make the point that it was not enough

          2   to apologize, we really needed to define some

          3   strategies for the future that would be ensure that

          4   nothing like this happened again.  So we focused on

          5   the need to emphasize ethics and to better train

          6   researchers in bioethics.  So we created the

          7   Bioethics Center at Tuskegee University, and now we

          8   have programs where people do fellowships there,

          9   and, hopefully in time, everybody entering research

         10   will be required to have a background in the ethics

         11   of research; and I think we are moving in that

         12   direction.

         13             But it is the system that I think you're

         14   responsible for advising us on.  What kind of

         15   system will pull all these pieces together in such

         16   a way that it works?  Even when there is failure in

         17   one aspect of it, the system still works because it

         18   has the right checks and balances.

         19             How do we involve the young, the elderly

         20   people with disabilities in this research

         21   enterprise?  How do we involve more effectively

         22   racial and ethnic minorities in women and the


                                                                       21

          1   young?  How can we establish communities of trust?

          2             I think this is all very challenging, very

          3   difficult, but one of my favorite quotes, of

          4   course, is from John Gardner who was Secretary of

          5   Health Education and Welfare in the '60s.  John

          6   Gardner liked to say that, "life is full of golden

          7   opportunities carefully disguised as irresolvable

          8   problems"; and I think that's what you have.

          9             Thank you.

         10             [Applause.]

         11             CHAIRPERSON MARSHALL:  Dr. Satcher, thank

         12   you so much for being with us this morning and for

         13   sharing with us your sense of the priorities that

         14   we face and the challenges that we face.  And I can

         15   tell you from my heart, that as a committee, we are

         16   committed to working towards creating and

         17   supporting a system that affords all research

         18   subjects the same protections regardless of their

         19   age or their background, or the source of funding

         20   for the studies in which they participate.

         21             So we thank you for honoring us this

         22   morning.


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          1   

          2             [Applause.]

          3             CHAIRPERSON MARSHALL:  We have some wiggle

          4   room in our schedule this morning, so I'm not

          5   concerned about time.  But let us get down to

          6   business.

          7             At our first meeting each of us who sits

          8   on the committee had somewhere in the neighborhood

          9   of five minutes to introduce herself or himself to

         10   the committee, and the ex officio members, and to

         11   our public members and we would like for those of

         12   you who are new members to please tell us a little

         13   about yourselves; what you background is; and what

         14   you think in terms of your priorities are the

         15   important reasons for you to be here and to sit at

         16   this table and perhaps where we should go as a

         17   committee.

         18             So, Felice, could we start at your end of

         19   the table and perhaps work around?

         20             DR. F. LEVINE:  I had the privilege -- let

         21   me start, I'm the Felice Levine and I am the

         22   executive officer of the American Sociological


                                                                       23

          1   Association.  I am a social psychologist by

          2   training with background both in sociology and my

          3   Ph.D. in psychology.

          4             I consider myself broadly into the

          5   disciplinary, not only across the social and

          6   behavioral sciences, but having spent 12 years at

          7   the National Science Foundation, I like to see

          8   myself as broadly collaborative across all fields

          9   of research and science.

         10             I had the privilege of addressing this

         11   group in December so I have also the liability of

         12   perhaps being redundant of what I ve already said

         13   about myself.  Prior to going to the National

         14   Science Foundation in essentially 1980, as my

         15   detailed statement about my biography and conflict

         16   enumerating everything that I did said it was

         17   really December 1979, but prior to that I was full-

         18   time as I consider myself a bench scientist at a

         19   research Institute in Chicago that was dedicated to

         20   doing empirical research on various aspects of law

         21   and human behavior, the American Bar Foundation,

         22   and I think my initial interest in research and the


                                                                       24

          1   regulation of research, as I said to this group in

          2   December, really stemmed from that interest in law

          3   and in human behavior and in regulation of science

          4   of course not being inattentive to some of the

          5   troubles spots and issues that were very dominant

          6   during the '70s, that brought the Belmont Report to

          7   the fore and subsequently.

          8             While my own research has been on children

          9   and youth largely, including work on violence and

         10   at-risk youth.  My broader interest in law and

         11   human behavior led me, at the National Science

         12   Foundation also, to develop a broader interest in

         13   human subjects, protections, the regulation of

         14   science, conflicts of interest, data access, data

         15   sharing, and other issues, I think, that very

         16   centrally pertain to the agenda of this group.

         17             So it really was with a great deal of

         18   enthusiasm and passion that I was very excited

         19   about the opportunity to serve because it reflects

         20   both a nice convergence between my strong and long-

         21   standing interest in research and research policy

         22   particularly with respect to human subjects issues


                                                                       25

          1   and human subjects protection, and how much that

          2   was at issue and is at issue, in some of my own

          3   agendas of research, particularly in the areas of

          4   children and youth and at-risk populations.

          5             I probably could not have better

          6   summarized what I would have said had the Surgeon

          7   General not had said it before me.  I think that he

          8   really sets forth the kind of agenda that I know

          9   all of you and all of us share and I really welcome

         10   participating with you and collaborating with you

         11   on that agenda. 

         12             I guess I should say just in conclusion

         13   that, in part, in my being one of the expansion

         14   persons to this group, it was to include more of an

         15   interest in or an awareness expertise in the social

         16   and behavioral sciences.  And I will try not to be,

         17   because I don't perceive of myself as a one-issue

         18   seat around the table.  So I hope that all of us

         19   together will really learn from each other and that

         20   I will be able to contribute some of that level of

         21   attentiveness; but I don't see myself as only

         22   promoting those interests any more than I see each


                                                                       26

          1   of you only promoting your own backgrounds and

          2   fields. 

          3             So I really welcome the collaboration.  I

          4   welcome bringing that expertise to the table.  My

          5   own research has spanned from the laboratory

          6   experiment to the large-scale surveys and to the

          7   analysis of secondary and extant databases and

          8   while one cannot assume that one brings expertise

          9   in each of these areas, I guess the breadth of my

         10   eclecticism I hope will bring me in good stead to

         11   this group to raise the kind of issues or to even

         12   signal the kinds of expertise that we might need to

         13   bring around the table to do our job as a

         14   sensitively and sensibly as we can.

         15             CHAIRPERSON MARSHALL:  Thank you Felice.

         16   Welcome, that was beautifully said.

         17             Jonathan.

         18             DR. MORENO:  Good morning.  My name is

         19   Jonathan Moreno.  I direct the Center for

         20   Biomedical Ethics at the University of Virginia. 

         21   I'm a philosopher by trainer.

         22             Among the things that we do at UVA is


                                                                       27

          1   educate bright people in bioethics, and, of course,

          2   Mary Faith Marshall is our favorite daughter.  

          3             [Laughter.] 

          4             DR. MORENO:  I suppose that my career took

          5   a turn toward a special interest in the ethics of

          6   human subjects research seven years ago this month

          7   when I had the opportunity to work for the Advisory

          8   Committee on Human Radiation Experiments.  And one

          9   theme that Dr. Satcher mentioned which has

         10   fascinated me ever since is, the problem of trust

         11   in government.  Trying to sell a book on the

         12   history of the use of human subjects in national

         13   security experiments has given me the opportunity

         14   to speak with callers on AM radio in drive time,

         15   all around the country.  And I can tell you that

         16   our subject matter, human experimentation, a

         17   somewhat pejorative expression these days, it

         18   seems, has excited among many people out there, a

         19   grave concern about the extent to which they can

         20   trust government and its organizations and other

         21   structures of authority like academic medical

         22   centers.


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          1             So a trust in government is certainly a

          2   theme that I find to be one that continues to

          3   occupy me. 

          4             I'm also happy to note that although the

          5   CDC did yeomen service in making the Tuskegee

          6   Syphilis study apology possible, the University or

          7   Virginia, I think, was where the conference was

          8   held where my predecessor John Fletcher made the

          9   original suggestion. 

         10             In historical fairness and balance, the

         11   University of Virginia Medical School also trained

         12   the public health service doctors who designed the

         13   Tuskegee Syphilis study.  So here we come full

         14   circle.

         15             I'm also interested in as a result of

         16   particularly my work for the National Bioethics

         17   Advisory Commission where I had the opportunity to

         18   help draft a report on the use of persons with

         19   decisional impairments in research.

         20             I'm also very interested in -- and I know

         21   Greg is also interested in an acute paradox.  As a

         22   philosopher, I probably enjoy ambiguity more than


                                                                       29

          1   the scientists at the table, and certainly more

          2   than the lawyers.  But I have to say that I do take

          3   a perverse fascination in the inherent ambiguity an

          4   the moral paradox of human subjects research as one

          5   of the great expressions of what it is to be a

          6   human being and the expression of our talents and

          7   our excellence and our compassion, and at the same

          8   time, the hazard, the moral hazard that the

          9   involvement of persons in research creates, and

         10   similarly, I'm very interested as Greg is, in the

         11   relationship between the delicate balance between

         12   continuing to ensure that investigators feel that

         13   they can disabuse themselves of their personal

         14   moral responsibility for the involvement of their

         15   subjects.  And at the same time, a widely perceived

         16   need for more external regulation of their

         17   activities.

         18             And I worry about the point at which we

         19   reached the tipping point between the sense that

         20   investigators can take a moral holiday and let the

         21   IRB worry about it, or some government agency worry

         22   about it, or people at this table worry about it,


                                                                       30

          1   or the lawyers for the university worry about it,

          2   and that they don't have to worry about it.  I am

          3   very concerned about that.

          4             So I look forward to exploring these

          5   issues with you in the next coming months and I am

          6   really very honored to be here.  Thank you.

          7             CHAIRPERSON MARSHALL:  Thank you,

          8   Jonathan.

          9             We're certainly not on a moral holiday

         10   today or tomorrow.  We are going to be working very

         11   hard and we are so very glad to have you at the

         12   table.

         13             Margaret.

         14             DR. BORWHAT:  My name is Margaret Borwhat. 

         15   I serve as president of the Women's Cancer Advocacy

         16   Network.   And I've been a patient advocate for the

         17   last 10 years working at local, state, and national

         18   level.  I serve currently as a patient advocate on

         19   one of the cancer clinical trials cooperative

         20   groups, on several of their committees including

         21   patient issues and ethics committee.

         22             I also serve on the Cancer Genetics


                                                                       31

          1   Network.  I'm frequently asked to review protocols

          2   and informed consent on both publicly and privately

          3   funded cancer research.  And I served on the State

          4   of Virginia's panel on informed consent.  I'm

          5   particularly interested in the informed consent

          6   process of as opposed to just looking at the

          7   document in itself.

          8             And as Dr. Satcher mentioned, and I would

          9   concur with, I'm particularly interested in access

         10   to research and clinical trials and the increase in

         11   which that is occurring at the community setting

         12   and within physician's offices.  And feel that this

         13   will increase access but on the other hand, we have

         14   to provide and balance that what ethical

         15   considerations through education and guidelines.

         16             CHAIRPERSON MARSHALL:  Thank you very

         17   much.  And we are very glad to have you.  You bring

         18   a balance to our group that we didn't have before

         19   and it is a critical balance.   So thank you so

         20   much for being here.

         21             Susan.

         22             MS. KORNETSKY:  Good morning.  I m Susan


                                                                       32

          1   Kornetsky, the Director of Clinical Research

          2   Compliance at Children's Hospital.  And I've been

          3   at Children's Hospital and working with IRB s for

          4   the past 18 years.  I'm the immediate past

          5   president of ARENA, Applied Research Ethics

          6   National Association, which is an association of

          7   professionals that are dedicated to IRB s and

          8   IOCOCS.

          9             I'm also involved in Primer, performance

         10   standards committee, developing standards for the

         11   accreditation for IRBs.  I know there's been a lot

         12   of discussion about that.  And I'm on the Council

         13   of Certification of IRB Professionals and during

         14   the past year we developed a program to certify IRB

         15   professionals like myself based on a test of

         16   knowledge.

         17             To date we have 160 people who have been

         18   certified based on two test dates and we continue

         19   to offer the examination.  I also serve on the

         20   primers IRB 101 faculty that provides education to

         21   institutions and investigators and had served on

         22   about 12 different institutions to do that type of


                                                                       33

          1   training.

          2             I think my role on the committee is really

          3   to represent the IRB professional.  Eighteen years

          4   ago there was no such thing.   Now it's been

          5   recognized that way.  During the past years the

          6   emphasis on institutional -- there's been an

          7   emphasis on the institutional role on protecting

          8   human subjects, but the reality is, in order to do

          9   this there's usually an office or individual who

         10   has to pull the pieces and the policies and help

         11   with the interpretation and that's usually someone

         12   like myself in the institution.

         13             I devote 100 percent of my time to working

         14   with IRBs.  I consider myself on this committee

         15   sort of the voice of practicality.  In other words

         16   we can debate the issues and set the policies, but

         17   the implementation is the real challenge and that's

         18   where I'm going to speak out on how and what seems

         19   reasonable to implement within different

         20   institutional cultures.

         21             As an IRB professional I consider myself

         22   really in the trenches doing this work.  I d like


                                                                       34

          1   to think Dr. Koski and the committee for

          2   recognizing the need for this role this committee I

          3   think it's very important.

          4             Obviously, my own interest within

          5   pediatrics I look forward to those discussions. 

          6   I've also done a lot of thinking about genetics,

          7   biological specimens; I mean I've really had to

          8   think about because of my role with the

          9   Institutional Review Board everything I look

         10   forward to collaborating with everyone.

         11             CHAIRPERSON MARSHALL:  Thank you very

         12   much.  And I think we second your goal for

         13   professionalization in IRB activities for IRBs to

         14   have the resources and the strengths and the

         15   institutional commitment that they need in over for

         16   them to do their job and recognize that all of

         17   those needs are not currently being met.  And that

         18   we hope that our work will rectify that situation.

         19             I d I'd like now for the members -- our ex

         20   officio members to introduce themselves.  I don't

         21   recall whether we did this last time or not.  But

         22   you are very important members of our committee and


                                                                       35

          1   we would like to hear you.  If you could just stand

          2   up to tell us which agency you represent and if you

          3   have any other comment you would like, to make we'd

          4   be glad to hear it.

          5             Introductions off mic.

          6             DR. RUBIN:  Phil Rubin, National Science

          7   Foundation. 

          8             CHAIRPERSON MARSHALL:  Thank you all for

          9   being here and we hope to hear from you.

         10             Our standard that we set at our last

         11   meeting is to allow an equal amount of time in

         12   discussion for our committee members, our ex

         13   officio committee members and our public members. 

         14   So, so I hope that you all will be an active part

         15   of the discussion today and at every meeting. 

         16             We have one new member -- Dr. Alan

         17   Fleischman -- who is a pediatrician who is not with

         18   us yet, but he will be here and we will ask him to

         19   tell us about himself when he arrives.  Those of

         20   you who were at our first meeting know Alan and

         21   have heard from him.  And Alan has been chairing

         22   our working group on children and working very hard


                                                                       36

          1   since our last meeting.

          2             A couple of remarks that I would like to

          3   make before I ask Dr. Koski to give us an update on

          4   human research protections and -- 

          5             I want to make some comments about

          6   something that's not really an issue but a concern

          7   that I have had.  And as a bioethicist my job has

          8   always been not to ignore the hippopotamus, if

          9   there's a hippopotamus in the middle of the room,

         10   but to direct attention to it.  And I have had a

         11   concern about the relationship or the role of

         12   having an executive director and a an executive

         13   secretary for this committee; especially given the

         14   history of how this committee came about and how

         15   the Office of Human Research Protections came

         16   about.

         17             That it was formerly the Office of

         18   Protection From Research Risk and lived at the NIH

         19   and there was a perceived, if not real, conflict of

         20   interest in having the OPRR live at the NIH when

         21   the NIH was funding much of the human subjects

         22   research that is done in the country.  And then


                                                                       37

          1   having the agency that regulates that research be a

          2   part of the same institution.  So that was that

          3   perceived or real conflict of interest was a reason

          4   for the restructuring and the reshaping of that

          5   office and moving it into the office of the

          6   Department of Health and Human Services and the

          7   Office of Public Health and Science.  Thank you,

          8   Kate.

          9             I just want to say that Greg and Kate and

         10   I have discussed the issue of having our executive

         11   director, Kate Gottfried, sort of live and work out

         12   of the OHRPR office and having the executive

         13   secretary function and the designated federal

         14   official function for our committee be Dr. Koski.

         15             Dr. Koski is also the head of the Office

         16   of Human Research Protections and is someone who by

         17   our charter we advise.  So, we have acknowledged

         18   the fact that that could be a concern.  We are

         19   talking among ourselves about professional roles

         20   and responsibilities and we don't think this is an

         21   issue that can't be managed in terms of perceived

         22   or real conflicts.


                                                                       38

          1             But I just wanted to put that out on the

          2   table to let you know that we certainly had

          3   discussed it and that to also say to that in an

          4   area that could have been politically or personally

          5   challenging that Dr. Koski has been nothing but

          6   open and forthright and that we certainly all share

          7   the very same goal, human research protections. 

          8             So I don't have concerns but I wanted to

          9   let you all know that we had talked about that

         10   issue.  

         11             And then just a couple of words in

         12   general.  These are primarily for our new members

         13   about our task and how we work as a group.  Our

         14   guiding principle was articulated by secretary --

         15   former secretary Donna Shalala in her sounding

         16   board article in the New England Journal of

         17   Medicine, September 14th of last year.  And it's

         18   very simple, and it's something that I want us to

         19   bear in mind.

         20             Felice, you made a wonderful remark about

         21   your professional qualifications and the fact that

         22   you brought them to the table but they did narrowly


                                                                       39

          1   confine what you construed as your role at the

          2   table.  And that's correct.

          3             Each of us at the table, each of us in the

          4   room, has a responsibility to follow former

          5   Secretary Shalala s dictum, and that is that no

          6   priority in research is more important in the

          7   protection of subjects and that our system of

          8   protections must be exemplary.  And that is our

          9   goal and our charge.

         10             We have an extraordinary opportunity as a

         11   committee.  Victor Hugo has said that an invasion

         12   of armies can be resisted, but not an idea whose

         13   time has come.  And we are very much an idea whose

         14   time has come.  And because we face significant

         15   opportunities and significant challenges our

         16   response as a committee must be and will be

         17   exemplary.

         18             I'm mindful to that end of the social

         19   contract that we have between the scientific

         20   enterprise and public, and that exceptional

         21   outcomes of us as a committee depend on the

         22   integrity of our process as a committee.


                                                                       40

          1             So the proposed by words that our earlier

          2   committee members will be familiar with are the

          3   following:  integrity of our process, fairness,

          4   that all who are at the table and should be at the

          5   table are there and that their voices are heard.

          6             And I hope you will recognize the

          7   additional members of our committee as our

          8   sensitivity to the concerns that were expressed by

          9   the public and by members of the professions that

         10   we didn't have all the voices at the table that

         11   should be at the table and that we have, I hope,

         12   rectified that problem.  That we are creative. 

         13   That we are flexible in our thinking.  That we

         14   think outside of the box.  That we show respect for

         15   our guests and our fellow committee members.  That

         16   we engage in civility in terms of our

         17   deliberations.  And perhaps most importantly, that

         18   we engage in critical thinking.  The essence of

         19   which is suspended judgment.

         20             In our meetings, in our work, we should

         21   aim for clarity, for focus on our task, for open-

         22   mindedness and flexibility, respect for our staff


                                                                       41

          1   and we shouldn't be reticent in raising

          2   controversial or sensitive issues.

          3             So if I perceive that we are ignoring a

          4   hippopotamus in the middle of the room as a

          5   committee, then I will direct our attention to the

          6   hippopotamus.

          7             And finally, I hope that we will, as a

          8   group, feel ownership and pride in our work.  We

          9   have a wonderful agenda today.  We have working

         10   committees that have been working very hard in the

         11   interim since our last meeting.  We will hear from

         12   them today and tomorrow.  So I want to thank all of

         13   you all for being here and I look forward to two

         14   very productive days in moving our work forward in

         15   a positive and concrete way.  Thank you.

         16             Dr. Koski.

         17             DR. KOSKI:  Mary Faith, thank you very

         18   much.   Good morning, everyone.

         19             I really appreciate the opportunity to

         20   actually update the committee as well as the rest

         21   of the folks who are attending today on basically

         22   what's going on with respect to the Office for


                                                                       42

          1   Human Research Protections, and in particular this

          2   important task of remodeling the system for

          3   protection of human subjects in research.

          4             Last September, as you know, we launched

          5   this effort.  It's basically a three-phase program

          6   to try and remodel the entire system for human

          7   research protections.  A remodeling that is based

          8   largely on the architect's recommendations within

          9   the Office of the Inspector General Report that was

         10   originally issued in 1998 and subsequently

         11   reemphasized in 1999.

         12             The system that we are working to build is

         13   one that clearly is based on performance, not just

         14   process and paperwork.  It's a system that will

         15   focus not just on compliance and as a goal in

         16   itself but rather on true protection of human

         17   subjects and prevention of harms.  We are working

         18   to build a system that is more flexible certainly,

         19   but at the same time will be more accountable.

         20             We are currently completing phase one of

         21   our efforts.  This effort began with the creation

         22   of our new office which Mary Faith already


                                                                       43

          1   described and its placement within the Office of

          2   Secretary and the Office of Public Health and

          3   Science, a position which provides it with a

          4   platform from which it can not only exercise its

          5   responsibilities, but also provide leadership

          6   broadly in this area, both within and outside the

          7   government.

          8             Part of this was initially a

          9   reorganization of the office into three operating

         10   divisions:  education, compliance oversight, and

         11   insurance and policy, an office of the director

         12   which includes not only our administrative

         13   functions but also a new office for policy and

         14   planning and special projects, and, of course, a

         15   new office for international activities that we may

         16   talk about later today.

         17             We are in the process of hiring new staff. 

         18   I will tell you honestly that we've been impeded

         19   somewhat in these efforts to some of the

         20   complexities of government both in the delays and

         21   approving the new budget for this fiscal year and

         22   then also by the hiring freeze that always happens


                                                                       44

          1   when a new administration comes in.  But these are

          2   certainly not insurmountable goals and we will

          3   continue there.  I think we are making great

          4   progress.  We've been undeterred and I think that

          5   much of the progress that we've made is clearly

          6   attributable to the enormous efforts of the people

          7   who are working together towards these goals.

          8             We have implemented revisions to our web

          9   site.  It's a first stage.  You can stay tuned,

         10   there will be dramatic revisions to our web site

         11   coming in the future.  We implemented an e-mail

         12   hotline for advice, a new list serve for reaching

         13   out and providing information to the entire

         14   research community.   Soon we expect our 800 line

         15   for immediate advice and assistance to be put into

         16   place, all these being part of our orientation on

         17   service, and outreach to the community that we

         18   serve.

         19             We implemented a simplified -- I'm sorry,

         20   a unified federal registration process for all

         21   institutional review boards regardless of whether

         22   they're constructed under the federal funding


                                                                       45

          1   mechanisms or private funding mechanisms.

          2             We introduced a simplified federal-wide

          3   assurance process that greatly simplifies the

          4   rather complex process of obtaining or making

          5   assurances, a system that fosters collaboration as

          6   well as flexibility.  And, again, we're reaching --

          7   we've been in a pilot phase of this for the first

          8   few months.  We except to have this finalized as we

          9   move into the end of this month and look forward to

         10   the enormous opportunities that this will provide

         11   for institutions to work together and in much more

         12   effective and efficient ways.

         13             We've dramatically expanded education

         14   programs.  We ve held an educational summit.  We ve

         15   been having conferences that are now held jointly

         16   with the Veterans Administration, the FDA.  We have

         17   reached out to the research committee by having a

         18   series of ambassadorial visits at institutions

         19   across the country.  As I was recently quoted in

         20   the Washington Fax, I think we estimated that I

         21   personally address somewhere around 8,000 people

         22   now over the last six months; which is a lot of hot


                                                                       46

          1   air, believe me.

          2             So we also, as we will be following up on

          3   the educational summit that Jeff Cowen put together

          4   so expertly in terms of developing new resources

          5   and tools for the entire research community.  We

          6   have created this committee, empaneled it, had its

          7   first meeting; thanks again to the enormously

          8   expert work of Kate Louise Gottfried and all of the

          9   members who ve contributed to that.

         10             And clearly as Mary Faith said, there is

         11   no conflict of interest here.  That in fact there

         12   is an absolute critical synergy between this

         13   committee and our office and the Department.  As we

         14   work together to tackle these challenges, we look

         15   to this committee for the advise that is so

         16   essential to what we do.  

         17             Importantly, we have revitalized the human

         18   subjects research subcommittee, the ex officio

         19   members from the other federal agency and offices

         20   who are here today are part of that group.  This is

         21   a group that is a subcommittee of a Committee on

         22   Science operating out of White House.  It pulls


                                                                       47

          1   together representatives from all the federal

          2   agencies, offices, and departments that share

          3   responsibilities in this area.  We are working

          4   together to develop a integrated approach to human

          5   research oversight across the entire government to

          6   achieve greater simplification, uniformity,

          7   efficiency and effectiveness across the board.

          8             At the same time that we are pursuing

          9   these activities within government we are

         10   encouraging the development within the private

         11   sector of credentialing and training programs for

         12   IRB professionals, research coordinators, principal

         13   investigators.

         14             We also, as you know, have engaged the

         15   Institute of Medicine at the National Academy of

         16   Sciences to issue forth a first set of uniform

         17   standards for accreditation of human research

         18   protection programs that will be issued probably at

         19   the middle of this month.  And that's some very

         20   important items to stay tuned for.

         21             We're winding down phase one now after

         22   having achieved these important changes in the


                                                                       48

          1   foundation and setting us on a new course.  As we

          2   enter phase two, we look toward the full-scale

          3   implementation of a support and quality improvement

          4   program within our office.  A program that will

          5   utilize both site visits, videoconferencing, as

          6   well as directed self-evaluations tools to not

          7   focus on empty assurances up front, but rather work

          8   with institutions making assurances to ensure that

          9   they are up to the task so that they can do their

         10   jobs.

         11             We will be clearing away the back log of

         12   compliance oversight investigations that had

         13   accumulated within our office over the last couple

         14   of years; made great progress there and as we do

         15   that we will begin to focus compliance oversight

         16   activities in a new way.  One that focuses, again,

         17   on surveillance not for-cause visits to further

         18   increase the accountability within the system.

         19             We look forward to the pilot testing and

         20   implementation of the accreditation process; a

         21   private voluntary accreditation process within the

         22   private sector which will provide an enormously


                                                                       49

          1   important complement to the government's efforts

          2   for regulation.  Again, establishing a level

          3   playing field on that high plateau of excellence

          4   that's so essential to build the public trust that

          5   Dr. Satcher spoke about in his opening remarks this

          6   morning.

          7             We, again, at the same time recognize the

          8   need to expand activities in the international

          9   arena.  We have created and are looking forward to

         10   actual implementation of the functions of our new

         11   office for international activities that will serve

         12   as a focal point for pulling together the many

         13   offices within the government that share interests

         14   and responsibilities in this area as we work toward

         15   developing a more harmonized approach toward human

         16   research conduct across the world.

         17             We expect to wrap up phase two toward the

         18   end of this year.  As we do that, we will enter a

         19   phase three period that basically involves

         20   evaluation; assessment of where we are.  We will

         21   make midcourse corrections as necessary to be sure

         22   that were on the right track.  We, again, will be


                                                                       50

          1   looking to the Institute of Medicines, working

          2   group on human subjects protection for guidance in

          3   this area as they develop standards for -- or

          4   measures, I should say, for actually accessing the

          5   effectiveness of the system for human subjects

          6   protection.

          7             In every one of the activities that we

          8   undertake, we will, of course, be working in the

          9   same collaborative spirit that we have applied in

         10   these first six, seven months with all of the

         11   members of the other federal agencies so that we

         12   basically achieve common goals through working

         13   together.

         14             We work not only with the NIH and the FDA

         15   and the CDC and AHRQ and all the other agencies

         16   within HHS, but, again, all of the agencies across

         17   government through the human subjects research

         18   subcommittee.  And as we undertake that work, we

         19   will do it with the advise of NHRPAC very much in

         20   our minds.

         21             As I said, we've made a great deal of

         22   progress so far, but we still have a great deal


                                                                       51

          1   that lies ahead.  Our motto is  doing it right

          2   together," and that's exactly what we are doing.

          3             I would like to acknowledge the fact that

          4   the only way that we are really able to do much of

          5   what we're doing is through the support of some

          6   truly extraordinary people who certainly assist me

          7   in my efforts.  Among them are my deputy director,

          8   Melody Lynn, who -- Melody, if you would just stand

          9   up so that people know who you are. 

         10             Melody carried the ball through the

         11   summer, certainly until I got there in September

         12   and has been an enormous asset all along.  And I

         13   think in the back there somewhere is, Mike Perome,

         14   our assistant director who is wearing a couple of

         15   hats.   Again, two pillars that keep our office

         16   going.   And my senior policy advisor, Irene

         17   Stiffcolman, who, Irene, if you could stand too. 

         18             I just want to thank all of you here and

         19   the other members of the office who are present as

         20   well as the ex officio members who have come today

         21   to participate in these activities.  This is a team

         22   effort and I'm very grateful.  Thank you.


                                                                       52

          1             CHAIRPERSON MARSHALL:  Thank you, Greg,

          2   very much.

          3             I told Greg over Christmas that I thought

          4   he probably logged more miles in December than

          5   Santa Claus did.  Now he's making me think of a

          6   South Carolinian that we all know and I hope love,

          7   James Brown, who is the hardest-working man in show

          8   business and I m thinking perhaps that Dr. Koski is

          9   the hardest-working man in bioethics.  But we ll

         10   forgo giving him the title of the James Brown of

         11   bioethics.

         12             [Laughter.]

         13             MS. MEYERS:  Dr. Fleischman has just

         14   arrived.  Alan, we have -- the new members have

         15   each introduced themselves.  And I know you are not

         16   especially a newcomer to this group having worked

         17   hard at our first meeting without being a member.

         18   But we would like to give you five minutes or so if

         19   you don t mind just to tell us about yourself and

         20   why you re here; besides the fact that you were

         21   asked.

         22             DR. FLEISCHMAN:  First let me apologize


                                                                       53

          1   for being late.  I had a taxi driver who could not

          2   find this place even though I thought I could.

          3             I am a physician; I am a pediatrician

          4   neonatologist and have done bioethics over the last

          5   30 years.  I am presently the senior vice president

          6   at that the New York Academy of Medicine which is a

          7   research-intensive than tank in New York advocating

          8   for the health of public for over 150 years.

          9             I also -- for 20 years -- spent some time

         10   at the Albert Einstein College of Medicine and the

         11   Montefure Medical Center in the Bronx, where I had

         12   the pleasure of being on two IRBs and create the

         13   clinical bioethics program there.  Have published a

         14   bid in the neonatal and perinatal issues both in

         15   ethics and in physiology, and have an enduring

         16   interest in all of the issues around bioethics

         17   including research.

         18             CHAIRPERSON MARSHALL:  Thank you so much

         19   for being here and welcome to the group as a member

         20   of our committee.

         21             Well, let us get down to business.  That

         22   wasn t a pun, but I guess one could be implied.


                                                                       54

          1             [Laughter.] 

          2             CHAIRPERSON MARSHALL:  Mark Barnes has

          3   been working very hard with members of the working

          4   group on financial relationships and has prepared

          5   for a response and update on financial

          6   relationships.  And just to remind you we were

          7   charged with commenting on the draft interim

          8   guidance financial relationships and clinical

          9   research.  Issues for institutions' clinical

         10   investigators and IRB to consider when dealing with

         11   the issues of financial interests and human

         12   subjects protections.   And Mark is going to give

         13   us an overview of the work that his working group

         14   has done and then we will have committee discussion

         15   about that work.

         16             I want to just say we received a lot of

         17   public commentary on this issue certainly the

         18   academic medical community weighed in heavily and I

         19   think the themes from the academic medical

         20   community were somewhat consistent.  That there

         21   were concerns about the guidance perhaps being

         22   premature, burdensome, and overreaching that the


                                                                       55

          1   department was perhaps setting new policy through

          2   ad hoc procedures such as guidance rather than

          3   formal rulemaking, and a plea to work together with

          4   the AAU and the Association of American Medical

          5   Colleges on the issue of financial conflicts of

          6   interest.

          7             Other concerns that were raised, perhaps

          8   at the other in a spectrum, were by members of the

          9   public such as Paul Galsinger, Jesse Galsinger s

         10   father who urged the committee strongly to look

         11   closely and hard at the issue of financial

         12   conflicts of interest as related especially to

         13   public trust.  So there is, I think, a balance that

         14   we must look for and seek somewhere between those

         15   two.  And we'll hear from Mark about how his

         16   committee came out on that issue.

         17             Thank you, Mark.

         18             MR. BARNES:  Thank you, Mary Faith.  First

         19   let me introduced the members of the working group

         20   who participated in these deliberations and whose

         21   commentary and participation really yielded the

         22   draft letter -- the draft commentary letter that we


                                                                       56

          1   have before us.  It is Adil Shamoo, Sandy Chodosh,

          2   Judy Seigel and unfortunately Elliot Dorff, I

          3   assume, is traveling today and therefore is not

          4   here.  

          5             They were all extremely patient with each

          6   other with the complexity of the issues involved. 

          7   Elliot wins the forbearance award for actually

          8   staying on a conference call for about six hours

          9   with us from Los Angeles because he couldn't be

         10   here during the day that we had our face-to-face

         11   meeting on March 21st.

         12             For members of the public there are some

         13   copies here of the draft letter and there also are

         14   some copies up here of a redline version for the

         15   interest that I provide an interest of transparency

         16   so that you can actually understand the

         17   evolutionary process or the archeology of this

         18   particular draft.

         19             There was an earlier version of this draft

         20   commentary which was provided to the members of the

         21   committee and actually to members of the working

         22   group and also the entire committee.  And then


                                                                       57

          1   there were comments over the past week and these

          2   were incorporated into the new draft which is the

          3   draft that you have in front of you.

          4             So I direct the committee's attention -- 

          5   NHRPAC s attention, not to be draft that is in the

          6   materials provided to you by Kate Gottfried, but

          7   rather to the draft that's in front of you.

          8             What I propose to do this morning is

          9   basically to go through a number of issues

         10   regarding this draft, regarding the draft intern

         11   guidance, and basically I want to the -- I'm going

         12   to give a presentation hopefully not too lengthy to

         13   leave adequate time for discussion among NHRPAC

         14   members that will have basically addressed three

         15   issues.

         16             One issue is to give the members of the

         17   committee and overview as to exactly what the

         18   actual legal requirements are now for the

         19   disclosure and management of financial

         20   relationships in human research so that we have a

         21   background for exactly what we are all commenting

         22   on; and we'll get a baseline understanding of that. 


                                                                       58

          1   That will be, hopefully, a brief presentation and I

          2   have in the course of preparing this presentation I

          3   tried to simplify a number of things so some of the

          4   complexities have fallen away.  So please forgive

          5   me for that, but in the interest of time I was

          6   trying to really give the -- and I will try to give

          7   the bottom lines.

          8             Second part is to review briefly the draft

          9   interim guidance that was put together by the

         10   Department which is the document on which NHRPAC is

         11   commenting on and to summarize some of the major

         12   public comments that were received during the

         13   comment period about that draft interim guidance.

         14             And thirdly, the third part of our

         15   presentation this morning will be to review the

         16   major features of the draft that we have in front

         17   of us that is the draft of our comments on the

         18   Department's draft interim guidance on financial

         19   relationships in human subjects research.  So with

         20   that, let's get started.

         21             Basically in terms of background for what

         22   is required for the basic requirements, legal


                                                                       59

          1   requirements, regulatory requirements, the way the

          2   world exists now in terms of things that must be

          3   complied with by researchers, by research sponsors

          4   and by academic institutions and other places where

          5   research takes place there are multiple federal

          6   regulations and state regulations that dictate

          7   policies and procedures in this area.  Not all

          8   states have such regulations, but some of the

          9   states in fact do have particular state

         10   regulations. 

         11             There are obviously -- one of the goals

         12   here, or there are multiple goals in these statues

         13   and regulations and one could even say that there

         14   are competing goals and one of things that we try

         15   to articulate in our committee deliberations were

         16   in fact to try to tease out exactly what the goals

         17   are in financial disclosure in human subject

         18   research and in the management of these conflicts

         19   that are identified.  Yes, Bob?

         20             DR. R. LEVINE:  Mark, do you want us to

         21   comment as you go a long or should we hold it off

         22   until the end?


                                                                       60

          1             DR. BARNES:  I think that if you have

          2   something burning -- a burning issue that you just

          3   can t hold off on, you ought to interrupt me and

          4   say it.  That s what I think.

          5             [Laughter.]

          6             DR. R. LEVINE:  Well, one man s burning

          7   issue you know -- 

          8             DR. BARNES:  Well, go ahead.

          9             DR. R. LEVINE:  This one doesn t burn.

         10             [Laughter.]

         11             DR. R. LEVINE:  But I ll say it anyway.

         12             [Laughter.]

         13             MR. BARNES:  Go ahead.

         14             DR. R. LEVINE:  You have in the text of

         15   your draft report -- what I find a persuasive

         16   statement that we should be referring to financial

         17   interests rather than conflicts of interests.  And

         18   one slide ago -- I'm just think that was a very

         19   good idea and I'd like to get on with it.

         20             DR. BARNES:   Okay.  Well, I assure you

         21   that actually in our deliberations we have tried to

         22   very carefully distinguish between financial


                                                                       61

          1   relationships, complicating financial relationships

          2   that are relevant to the research and actual

          3   conflicts of interest.  Okay.  It's a part of the

          4   conceptional clarity that we would urge the

          5   Department to adopt in it interim guidance.

          6             Okay.  Under the way that the federal regs

          7   read now certain financial conflicts of interest

          8   must actually be disclosed to the institution where

          9   researchers conduct their study or to the sponsors

         10   who are sponsoring the research sponsors who are

         11   conducting the actual research.  And then under

         12   federal requirements a subset of those financial

         13   relationships that have been identified as

         14   conflicts must in turn be identified either to the

         15   governmental agencies that are funding the research

         16   or that are reviewing the research that is

         17   conducted by these researchers.

         18             In addition to that, and we will talk

         19   about those federal requirements, in additional to

         20   that though, I want to give you the background idea

         21   that there are state regulations governing the

         22   professional practices of medicine and the practice


                                                                       62

          1   of any licensed professional, whether it's a

          2   clinical psychologist conducting the research or

          3   any person who is granted a license -- professional

          4   license by a state -- and all of this is state law

          5   and not federal law when you talk about licensure

          6   and regulations of professionals.

          7             And under those rules there are in almost

          8   all states particular provisions which basically

          9   prohibit a licensed professional from exercising

         10   what's called "undue influence" over a particular

         11   patient or converting the treatment relationship

         12   with that patient, that fiduciary relationship,

         13   into a relationship that benefits the practitioner

         14   rather than the patient.  And I think that we need

         15   to understand that as the background professional

         16   obligation, the plenary professional obligation of

         17   every licensed professional, particularly every

         18   physician who engages in or participates in human

         19   subject research.

         20             There also are specific state and federal

         21   requirements governing conflicts of interest in

         22   financial relationships held by IRB members


                                                                       63

          1   themselves who are considering the proposals to

          2   approve human subjects research. 

          3             Now, one of questions is, what's the risk

          4   and all this?  Why a do federal regulations address

          5   this that all?  Clearly we have seen a number of

          6   particular anecdotal reports in the media attention

          7   and in the professional literature about instances

          8   in which individuals have, professionals have, or

          9   institutions have conducted research when they in

         10   fact have particular financial interests or

         11   relationships that might be expected or assumed or

         12   feared would contaminate or adulterate the conduct

         13   of the research, the gaining of informed consent

         14   and/or the interpretation and analysis of

         15   presentation of data.

         16             There are -- and I give you only a few

         17   examples here, and not to single out any one

         18   particular institution or group of professionals,

         19   but there clearly have been a number of media

         20   reports that have really called into question

         21   fundamentally public trust in terms of these

         22   underlying financial relationships in clinical


                                                                       64

          1   research.

          2             In January of 2000 there was also a META

          3   analysis that was published in JAMA which I think

          4   was entitled, "Is a Pharmaceutical Company Gift

          5   Ever Just a Gift?   And not to single out

          6   pharmaceutical companies because one could apply

          7   the same thing to medical device manufacturers and

          8   biotechnology companies and others who are for

          9   profit and not-for-profit entities of funding

         10   research.

         11             But essentially what this study found --

         12   it was, again, a meta-analysis of 29 studies -- is

         13   that physicians receipts, receipt of financial

         14   remuneration, really does influence in a

         15   significant way prescription patterns or

         16   decisionmaking by those clinicians in regard to

         17   their patients.  Which really gets to the core of

         18   what we fear, I think, and I speak for the working

         19   group although if someone disagrees then I

         20   encourage them on the working group to speak out. 

         21             What we fear really is the foundation of a

         22   fear in regard to the conduct of research when


                                                                       65

          1   there are financial relationships that are

          2   implicated in the research.  Clearly the Jesse

          3   Galsinger case was one of the exciting causes of

          4   the attention of the national research community to

          5   these issues.

          6             There were in fact in that case -- they

          7   were called into question some significant

          8   financial ties that the co-PI had to the sponsor. 

          9   And this led directly to the adoption by the

         10   American Society of Gene Therapy to a general

         11   probation in its guidelines -- it's institutional

         12   guidelines, its associational guidelines that those

         13   members of the society not in fact own, at all,

         14   equity stock options or other ownership interests

         15   in the companies who products they were engaged in

         16   testing. 

         17             This could be paraphrased and was by

         18   Marsha and Joe at the August 2000 conference held

         19   at NIH on this issue that physicians and others and

         20   institutions should be free to invest in race

         21   horses, rubies, and real estate but should leave in

         22   fact all medical suppliers and vendors and


                                                                       66

          1   pharmaceutical companies and research sponsors

          2   alone in terms of their personal and institutional

          3   investments.

          4             There also have been multiple articles

          5   published.  Yes, Abbey.

          6             MS. MEYERS:  In that case the university

          7   also had a stake in the ownership of the company,

          8   was anything done about that?

          9             DR. BARNES:  Was anything about the

         10   Galsinger case?

         11             DR. MEYERS:  Yeah, is there any

         12   prohibition?  There is no legal prohibition against

         13   universities owning a share in a company.

         14             DR. BARNES:  That is correct, and we ll

         15   get to that.  But there is no actual legal

         16   prohibition on institutional conflicts of interest

         17   or institutional financial relationships involved

         18   in research.  Although some institutions have

         19   clearly adopted their own policies that are more

         20   aggressive than the existing federal regulations on

         21   the issue.  Okay. 

         22             There was this conference hosted in August


                                                                       67

          1   of 2000 at NIH on this particular issue which

          2   resulted in the draft interim guidance that was

          3   authored by a member of people, but I think that

          4   it's fair to say that the effort was led by Stuart

          5   Nightingale in the Office of the Assistant

          6   Secretary.  I think that is where Stuart is.  I'm

          7   sorry, planning and evaluation.

          8             There are essentially three -- and, again,

          9   this is the actual regulations of what must be done

         10   as opposed to what should be done, or what could be

         11   done, or what might be done, and it's important to

         12   keep those distinctions in mind as we proceed

         13   through that this issue. 

         14             There are regulations of public health

         15   service regarding funding, PHS-funded research

         16   studies, the regulations of the NSF, the National

         17   Science Foundation, regarding studies funded by

         18   NSF.  And there also are specific regulations of

         19   the FDA that apply to research sponsors who are or

         20   that are submitting applications for approval of

         21   drugs or devices. 

         22             Now to take the PHS first, PHS regulations


                                                                       68

          1   importantly do not apply to privately funded

          2   research, okay.  They apply only to research funded

          3   by the PHS agencies or that are proposed for

          4   funding by PHS.

          5             The basic requirement is that the

          6   investigators, the researchers, who participate in

          7   the studies, they are supposed to submit review to

          8   an official at their institution that is applying

          9   -- that is submitting the application -- a listing

         10   of their own, what are called significant financial

         11   interests and then they fall into categories.  But

         12   basically significant financial interest that would

         13   reasonably appear to be affected by the research.

         14   Okay. 

         15             The financial disclosure has got to be

         16   made prospectively at the time that the

         17   investigators -- that the institution submits the

         18   grant application.  Then go further into the

         19   regulations, what is a significant financial

         20   interest that could reasonably appear to be

         21   affected by the research?  Well, there is a

         22   definition, a threshold definition in the PHS


                                                                       69

          1   regulations that basically is cash remuneration on

          2   an are of stocks other ownership interests that

          3   exceeds $10,000 or that constitutes more than a 5

          4   percent ownership in a single organization.

          5             What it does not include is salary and

          6   other compensation from the research institution,

          7   including the compensation that is flowing from the

          8   research study itself.  It also does not include

          9   other kinds of income from seminars, et cetera,

         10   that are sponsored by public or not-for-profit

         11   entities.

         12             Now, importantly in the regulation,

         13   however, there is no definition as what significant

         14   financial interest would appear to be reasonably

         15   affected by the research.  So that is a great gap

         16   in the existing definitional structure of

         17   regulations.

         18             The institution -- once the disclosure is

         19   made by the investigator to the institution the

         20   institution is not required -- is not required --

         21   to re-disclose that to the federal government

         22   unless the institution actually thinks that there


                                                                       70

          1   is an actual risk that the significant financial

          2   interest could directly and significantly affect

          3   the design conduct or reporting of the PHS funded

          4   research.  Which means the bottom line in this is

          5   that the category of conflicts or potential

          6   conflicts that must be reported by the institution

          7   to the public health service is narrower than the

          8   range of financial interests that must be reported

          9   by the researcher to his or her own institution.

         10             The PHS regulations also require that

         11   financial relationships that are complicating, that

         12   rise to the level of conflicts of interest, that an

         13   institution must have guidelines, internal

         14   guidelines to manage those conflicts of interest

         15   appropriately or to reduce them or eliminate them.

         16             Now, it does not decree what those

         17   guidelines must be, but it just says that the

         18   institution must have internal guidelines to do so.

         19             Now, one question that Elliot has often

         20   asked and I think quite appropriately is  once a

         21   conflict of interest is actually identified as

         22   being a significant financial interest that could


                                                                       71

          1   reasonably appear to be affected by the research,

          2   how would that be managed?"  And there are some

          3   suggestions that are not exclusive remedies, but

          4   that are suggestions in the regulations and they

          5   range from publicly disclosing the financial

          6   interest that is complicating to actually requiring

          7   that the investigator if he or she wants to proceed

          8   with the study actually sever their financial

          9   relationship or divest themselves of the financial

         10   relationship.  But there are a number of

         11   intermediate steps that could also be kind of

         12   intermediate sanctions, as it were, that could be

         13   applied in order to manage the conflict.

         14             NSF itself has a conflict of interest or

         15   financial disclosure rules that largely track the

         16   PHS standards, but they only apply to NSF-funded

         17   research.  I won t go into the complications here,

         18   they are arcane and quite obscure and actually, in

         19   the end, probably not to important because the NSF

         20   requirements are largely the same, although not

         21   entirely, as the PHS requirements.

         22             On the FDA requirements, however, are the


                                                                       72

          1   other large source of background regulations on

          2   these issues and they apply to a pharmaceutical

          3   company, a device manufacturer, or any other party

          4   that has submitted a marketing application and is

          5   therefore an applicant to the FDA for approval. 

          6   Because the financial relationships that are

          7   required to be reported by the FDA are submitted --

          8   are collected by the sponsor during the course of

          9   the research, but submitted at the time of

         10   application, they are largely retrospected in

         11   nature rather than the prospective application of

         12   the PHS, NIH, and NSF guidelines.

         13             Clinical investigators under the FDA

         14   regulations do not report their financial

         15   relationship directly to the FDA.  They report them

         16   to the sponsor who in turn is responsible for

         17   collecting the information and then redisclosing it

         18   to the FDA. 

         19             For every clinical investigator in a

         20   covered clinical study, there are definitions in

         21   the FDA relations as to what must be reported and

         22   those are not consistent, they are not consistent


                                                                       73

          1   with the PHS and NSF requirements in terms of the

          2   definition of the financial relationship.

          3             In fact, they basically would -- like the

          4   PHS requirements that definition of a financial

          5   relationship that must be disclosed actually

          6   excludes the compensation to the researcher that

          7   flows from the research itself that is in question,

          8   but it includes in the other compensation from the

          9   sponsor that is worth more than essentially $25,000

         10   per year.  It also includes any ownership or other

         11   financial interest in the sponsor held by the

         12   clinical investigator that exceeds an approximately

         13   $50,000 during the time that the investigator is

         14   conducting the study or within a year after the

         15   completion of the study.  Okay.

         16             And, again, it is the sponsor the

         17   applicant, the FDA of applicant that submits this

         18   information to the FDA, not the clinical researcher

         19   or himself or herself.

         20             Now, what are the differences, the basic

         21   differences between the PHS and the FDA

         22   requirements?  Note that the dollar thresholds are


                                                                       74

          1   higher in the FDA regulations.  That PHS

          2   requirements focus on conflicts that reasonably

          3   appear to affect the research.  Or, actually that s

          4   not accurate.  They reasonably appear to be

          5   affected by the research.  Whereas FDA requirements

          6   focus on conflicts essentially relating between the

          7   relationship between the investigator and the

          8   research sponsor.  And one gets then to the issue

          9   of the goals.

         10             It looks as though one of the primary

         11   goals, and perhaps the primary goal, of the FDA

         12   regulations is essentially to assure that there is

         13   not undo financial relationship or inappropriate

         14   financial relationship between the researcher and

         15   the sponsor leaving the sponsor and/or the

         16   researcher to misinterpret data or aggressively

         17   interpret data in favor of the approval of the

         18   application.  Also note that disclosure to the FDA

         19   is retrospective at the time of application, but

         20   PHS requirements are prospective.

         21             And, finally, another thing that's

         22   embedded in here is that PHS requirements only


                                                                       75

          1   apply again to PHS-funded research whereas FDA

          2   regulations apply to all research that is submitted

          3   as part of an FDA application and therefore to

          4   privately funded research.  But that means in the

          5   end that there is a range of activity that is not

          6   funded by PHS, not funded by NSF, and that is not

          7   submitted as part of an application to the FDA

          8   witch is privately funded research that is subject

          9   to none of these requirements.  Okay.

         10             In additional there is law that governs

         11   the financial relationships or conflicts of

         12   interest held by IRB members themselves.  There are

         13   some state laws that are applicable here.  I won t

         14   go into them but they, in many cases, are either

         15   consistent with or can even be more restrictive

         16   than the FDA and PHS regulations.

         17             There is obviously and the common rule is

         18   one of the primary sources of law for IRBs

         19   including on this particular issue as are FDA

         20   regulations.

         21             Basically the HHS and the FDA regulations

         22   prohibit the participation of a IRB member when the


                                                                       76

          1   IRB member's review of the project is reviewing a

          2   project in which the IRB member has a conflicting

          3   interest.  Although importantly there is absolutely

          4   no definition in any of the state rules that I know

          5   of, or the federal rules regarding what is a

          6   conflicting interest.  There is no threshold amount

          7   as at least we have in the PHS and the NSF and the

          8   FDA regulations.

          9             Now, since there is no definition of what

         10   is a conflict and what s not what s a conflicting

         11   financial relationship or a troubling financial

         12   relationship, how ever one describes it, then

         13   institutions are free to develop their own

         14   definitions.  But they clearly, according to the

         15   regulations, need to document and enforce the

         16   policies that they adopt.  And the recommendation

         17   or actually more than recommendation, the

         18   requirement in the regulations that there be an

         19   institutional official who is given the

         20   responsibility for monitoring this, or that there

         21   is a system for monitoring this.

         22             There are clearly some conflicting roles


                                                                       77

          1   here in terms of duties, because especially if an

          2   IRB member is actually a PI in a study then

          3   obviously a dual role can also cause a nonfinancial

          4   conflict, or even a financial conflict, which is

          5   also apparently prohibited by the various federal

          6   IRB requirements.

          7             This needs to be considered obviously by

          8   institutions in selecting IRB members when they

          9   frequently have conflicts.  In other words they are

         10   often PI's in studies and this is obviously

         11   something that should be avoided.  And it's a

         12   problem that's even more severe if the IRBs chair

         13   is in fact a PI himself or herself. 

         14             There is some guidance from OHRP on this

         15   issue which basically is a strong recommendation

         16   that when an IRB member has a conflicting interest,

         17   which the inn is not defined, that they leave the

         18   room when they IRB votes, that the departure from

         19   the room is noted in the IRB minutes and then there

         20   are a few others as well.  But the important point

         21   here is that there is no definition in these regs

         22   as to what is a conflicting interest of an IRB


                                                                       78

          1   member and what isn't.

          2             So, basically, I'll tell you what most

          3   institutions actually do, at least in my experience

          4   and perhaps members of the committee could add to

          5   this, but actually most institutions because there

          6   is no particular definition of conflicting

          7   interest, most institutions that have strict

          8   research policies actually have a zero tolerance

          9   for conflicting interests when it comes to IRB

         10   members and say that if there is any financial

         11   relationship to the study or even non-financial

         12   relationship to the study at issue the IRB member

         13   should recuse himself or herself.  Okay.

         14             So that in the end is the background that

         15   we have here.  We have PHS requirements.  We have

         16   NSF requirements close to the PHS and then we have

         17   FDA requirements.  They deal with the conflicting

         18   relationships both of the researchers and of the

         19   IRB members but they do not -- there are gaps in

         20   the coverage and obviously there is no definition

         21   here in the restriction on what has been termed an

         22   institutional financial relationship to the


                                                                       79

          1   research or rising perhaps to the level depending

          2   on the case of an institutional conflict of

          3   interest.

          4             Now, because of that, or perhaps as a

          5   result of that, there have been these concerns

          6   raised which led to in fact to the conference to

          7   the various publications on these issues, the

          8   conference in August of 2000 at NIH, to the various

          9   publications on these issues, to the attention from

         10   the New England Journal, and in its amassed

         11   editorials on this issue and related issues, and,

         12   finally, the draft interim guidance was issued late

         13   last year I believe it was issued and the comments

         14   were received through March; although hopefully

         15   they will accept our comments that would be late

         16   filed as not to untimely how. 

         17             This draft interim guidance basically is

         18   an attempt -- appears to be an attempt by the

         19   Department to really craft some guidelines that

         20   would try to fill some of these gaps and try to

         21   develop a best practices -- a series of best

         22   practices recommendations for how these conflicts


                                                                       80

          1   can be identified, managed, financial relationships

          2   can be identified and classed either as a troubling

          3   financial relationship or as an actual conflict of

          4   interest.

          5             I am not going to go through all of the

          6   draft interim guidance that are available on the

          7   web, and I know that many of you have already read

          8   it, but let me just go through a few of the

          9   highlights of the draft interim guidance.

         10             The draft interim guidance basically

         11   endorses the idea that there would be a conflict of

         12   interest process or an actual conflict of interest

         13   committee or designated official that would be

         14   essentially an adjunct to the operation to the IRB

         15   itself.  So that the IRB itself is not faced with

         16   the task of not only protecting human subjects in

         17   terms of assuring their informed consent, but also

         18   indulging in -- I shouldn t say indulging in --

         19   engaging in -- because I don't think it's much of

         20   an indulgence -- engaging in the -- maybe a plenary

         21   indulging or something, but in the religious sense

         22   -- 


                                                                       81

          1             [Laughter.] 

          2             MR. BARNES:  -- but it s clearly a task

          3   but so that the IRB would not be faced with the

          4   very onerous task for which it is not -- it members

          5   are really not particularly well-qualified and

          6   don't really have the expertise of deciding what is

          7   a conflict, what is not conflict, what is a

          8   financial interest, what is not a financial

          9   interest, or what exactly a stock ownership or

         10   future springing right in a patent would or would

         11   not be in terms of a conflict of interest in the

         12   research.

         13             The guidance also importantly identifies

         14   and contemplates the policies for the disclosure of

         15   and the management of institutional conflicts of

         16   interest in which the actual research institution

         17   -- the place at which the research is conducted

         18   would have an interest, a financial relationship to

         19   the product or device on being tested or the

         20   company that owns that product or device. 

         21             There are suggestions for education and

         22   training of IRB staff members and investigators on


                                                                       82

          1   these issues.  And also importantly the draft

          2   introduces the idea which was oft expressed in the

          3   August 2000 conference that in fact when financial

          4   relationships are identified that are relevant to

          5   the research that there should be some level of

          6   disclosure to patients, or financial research

          7   subjects, in the conformed consent process.

          8             So I would in the end probably -- and

          9   others may have different interpretations of these

         10   draft interim guidance but there essentially are

         11   three features of the draft interim guidance that

         12   have perhaps been most troubling to some on both

         13   sides of the issue; those who think that the draft

         14   guidance goes too far, and those who think that the

         15   draft guidance doesn't nearly go far enough.  And

         16   that would be the identification of a conflict of

         17   interest process that was separate from the IRB,

         18   but an adjunct to the IRB number one.

         19             Number two would be the idea of there

         20   being institutional conflicts of interest that

         21   would have to be revealed or financial

         22   relationships that would have to be revealed and


                                                                       83

          1   actively managed when they rise to the level of a

          2   possible conflict of interest.  And number three

          3   would be the idea of disclosure of these financial

          4   relationships to research subjects to potential and

          5   actual research subjects.

          6             Now, there were comments received -- many

          7   comments received by the Department through the

          8   period and I believe all of these are posted on the

          9   web so that anyone can see the various comments

         10   that were received.  I tried to, in a sense of a

         11   religious cosmology, to limit my bullet points to

         12   12, but my best efforts at this were in fact

         13   thwarted by my colleagues who insisted that other

         14   things be added. 

         15             So in fact we have for the 12 disciples. 

         16   We have Mathias and Paul and perhaps Timothy added

         17   on, but anyway, let me go through the basic

         18   comments that were received on these issues.

         19             The one basic comment is that the draft

         20   guidance is to directive and is not compliant with

         21   the Administrative Procedure Act, that it would

         22   essentially, once issued, have the effect of


                                                                       84

          1   regulation, but would not have been issued through

          2   the regulatory process.  

          3             Another set of comments said, please wait

          4   until the private associations have acted on these

          5   issues.  And in fact the AAMC has appointed a

          6   committee recently and has essentially a two-year

          7   process for developing policies and procedures for

          8   it s own members on these issues. 

          9             There were requests for additional

         10   consultation with stakeholders.  There was the

         11   general comment that the roles of the IRB and the

         12   COI committee or entity or not clear in the

         13   guidance and that related set of comments were that

         14   IRBs are already over burden and perhaps they

         15   should not even be an adjunct to the IRB process. 

         16   They should simply be a separate conflict of

         17   interest process.  There were other comments that

         18   the COI function should not be vested in the

         19   committee, but should be vested in an institutional

         20   official like a Dean, Provost or Administrator.

         21             There were particularly a series of

         22   comments that criticized the idea of identification


                                                                       85

          1   and on disclosure requirements for institutional

          2   conflicts of interest.  The basic comment from the

          3   different commenters was that the draft interim

          4   guidance was going too far into uncharted territory

          5   on this issue.

          6             There were other comments that research-

          7   related compensation, that is compensation that

          8   flows either to the institution and/or to the

          9   researcher in as part of the actual research study

         10   should itself be subject to financial disclosure

         11   and to analysis in the conflict of interest process

         12   which is a radical departure from the existing

         13   requirements of FDA, PHS and NSF.

         14             Other comments received that the

         15   disclosure of these identified financial interests

         16   to subjects is undefined; there's no practical

         17   experience that we have a and little data in the

         18   area; that much attention is needed to a conflict

         19   of interest process in the so-called "independent

         20   IRBs" and also the contract research organizations

         21   that are not particularly -- that may work with

         22   institutions but are, in fact, not subject to


                                                                       86

          1   institutional oversight and regulation.

          2             There was a general comment that was

          3   received or a few general comments that the draft

          4   guidance was too complicated, that it promoted

          5   bureaucracy and ran the risk of actually stifling

          6   human subjects research.  That's perhaps the

          7   tipping point that Jonathan was referring to

          8   earlier.

          9             There were also comments that in fact

         10   there was no need for draft interim guidance in

         11   this area.  That there were only a few bad apples

         12   that have been identified in the media that

         13   anecdotes should not drive -- anecdotes of bad

         14   research practice should not drive policy in the

         15   area.

         16             Other comments that I think would be

         17   obvious from our presentation so far is that the

         18   PHS, FDA and NSF disclosure requirements should

         19   definitely be standardize, and by regulation if

         20   necessary, and she'd be extended, I should point

         21   out, to all research regardless of source of

         22   funding.


                                                                       87

          1             Another set up comments that conflict of

          2   interest is not simply financial, but also

          3   implicates issues of personal procedure, academic

          4   advancement, et cetera.  The other comments that

          5   the draft guidance in fact had unclear goals or

          6   even possibly conflicting goals is the goal to

          7   avoid COI or to manage COI and is in fact the

          8   government putting forward the position that there

          9   is and ought to be a zero tolerance for identified

         10   conflict of interest.

         11             And, finally, what is the goal of the COI

         12   process itself?  Is it to ensure research

         13   integrity?  That is, integrity in the

         14   interpretation analysis and presentation of the

         15   data, or is it to protect subjects from

         16   unscrupulous researchers, or even for those

         17   researchers who motivations may very well be mixed

         18   and whose subconscious motivations may enter into

         19   the equation because of their conflicting duties.

         20             These are the -- in general, the comments

         21   that were received in the process.  So we got

         22   together the working group of this committee and we


                                                                       88

          1   developed a process by which we thought we could

          2   try to come up with a consensus which certainly

          3   does not reflect the individual opinions of the

          4   members of the working group, but is proposed only;

          5   but does represent, I think, a kind of nipping and

          6   tucking and pushing and pulling in very polite ways

          7   during the process among the members of this

          8   working group.

          9             The working group was charged at our last

         10   meeting of this committee.  We reviewed the draft

         11   interim guidance and we also reviewed all of the

         12   comments that were received in the process of the

         13   draft interim guidance by the Department.  We had a

         14   couple of conference calls with roundtable

         15   discussions to identify issues and map out some

         16   strategy proceedings and to share some of our

         17   insights and reflections on this.

         18             There was a day-long face-to-face meeting

         19   in Washington at the Department on March 21st in

         20   which the members of the working group really

         21   engaged in a full-day discussion, not only of the

         22   draft guidance, but also of an agenda for conflicts


                                                                       89

          1   of interest for the committee that may actually --

          2   although embedded in our proposed comments, would

          3   actually go beyond the draft interim guidance and

          4   go into the future on these issues.

          5             We put together a draft which was

          6   circulated last week and then there were comments

          7   that were delivered during the week last week by e-

          8   mail.  The draft was revised and what you have in

          9   front of you is the revised draft and the redline

         10   version so that you can compare the previous draft,

         11   the penultimate draft, to the ultimate draft

         12   hopefully preceding this committee's ratification

         13   of the draft so that we can actually make it or

         14   something resembling it into a committee comment --

         15   a formal comment to the Department.

         16             Now, let me go through the third part, and

         17   the final part of this presentation, which is, to

         18   kind of outline and review the basic highlights of

         19   the proposed commentary put together by the working

         20   group.

         21             We were called to task by Elliot who is a

         22   philosopher and a theologian who basically required


                                                                       90

          1   that we identify our goals and that identification

          2   of goals and objectives be front and center in all

          3   of our duties and he really kept us honest in this

          4   process, and we identified a few goals and

          5   objectives which are hopefully complementary but in

          6   fact they are different goals.

          7             One is to ensure the integrity of the

          8   informed consent process to make sure that

          9   researchers are not compromising the research of

         10   the informed consent process because of their

         11   possibly conflicting duties or conflicting

         12   relationships to research sponsors or to government

         13   funding agencies.

         14             The second goal is to promote research by

         15   assuring research integrity.  That is, to make sure

         16   that financial relationships that researchers or

         17   institutions have to the research sponsors or to

         18   products or investments that may reasonably be

         19   expected to be affected by the research, that that

         20   does not influence the interpretation, the

         21   analysis, the presentation of data.

         22             And then a kind of subheading under that


                                                                       91

          1   is to make sure that data is not actively or even

          2   passively misinterpreted and to make sure that

          3   there is a rigorous adherence, no misprision of

          4   research and  professional duties of researchers

          5   and of institutions. 

          6             In general, what the -- and please if the

          7   working group members have different opinions about

          8   this, then please jump in.  We basically thought in

          9   response to especially to the comments that we

         10   received, we thought that OHRP and the department

         11   should actually proceed with these guidelines --

         12   should not hold back from them, but should proceed

         13   in a careful and stepwise manner.

         14             We thought that there was a continual need

         15   once the draft interim guidance was finalized as in

         16   fact guidance rather then draft interim guidance,

         17   that those guidelines be periodically and perhaps

         18   frequently, especially at the beginning, revisited,

         19   reviewed and their effects evaluated.

         20             We also thought that as the private

         21   associations had develop their guidelines over next

         22   couple of years that the best features that emerge


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          1   from that development should in fact be folded

          2   into, be adopted selectively by the department in

          3   additional iterations of the interim guidance.

          4             In terms of -- then I will go to the

          5   subheadings here -- in terms of defining conflicts

          6   of interest, we did make it clear, I think, in our

          7   draft, and it is clear especially in the revised

          8   draft that you have before you, that financial

          9   disclosure is not the same and financial

         10   relationships are not the same as conflicting

         11   financial relationships.  And that a financial

         12   disclosure process does not mean that there are

         13   actual conflicts of interest that are identified

         14   and that different categories have to be kept

         15   separate.  And basically what emerged from the -- I

         16   think, by a kind of group thing among the working

         17   group members, was the idea that there should be a

         18   financial disclosure process, that financial

         19   relationships that emerge that really are related

         20   to the research, that those should be identified as

         21   some category, whether they are called relevant

         22   financial relationships, complicating financial


                                                                       93

          1   relationships, or troubling financial relationships

          2   depends very much for your perspective on those

          3   financial relationships, but in fact there is that

          4   category and then a subset of those relevant

          5   troubling or complicating financial relationships

          6   would actually rise to the level of being

          7   identified actively as an actual conflict of

          8   interest in the research or even as a possible

          9   conflict of interest in the research.

         10             We also thought that it was important in a

         11   financial disclosure process that confidential

         12   reality for researchers was definitely needed.  And

         13   we thought that there had not been enough attention

         14   really paid to that issue.  Confidentiality in that

         15   if researchers do not feel comparable that the

         16   process is going to be a confidential process

         17   especially in these interim beginning stages before

         18   a troubling financial relationship or an actual

         19   conflict is even identified that they would not be

         20   willing perhaps to fully disclose, it would act as

         21   a business to fully disclose, and it would also be

         22   in the end, if there is not confidentiality


                                                                       94

          1   actually be a deterrent for researchers who have

          2   financial investments of any kind to participate in

          3   research in close cases.

          4             We also thought that even where there is a

          5   financial relationship that is -- and this is a

          6   departure, I will tell you, from the draft interim

          7   guidance that where there is a financial

          8   relationship that is disclosed that is even related

          9   to the research, that there ought to be some

         10   threshold levels that there are some levels beneath

         11   which one share of stock or ten shares of stock in

         12   a company that is also sponsoring a research simply

         13   is so trivial, that for issues of convenience, of

         14   effectiveness of regulation, and for identification

         15   of actual or possible conflicts that things falling

         16   below those thresholds should not, in fact, be

         17   identified as complicating, troubling, or relevant

         18   financial relationships.  So we did believe that

         19   there should be de minimus exceptions in the

         20   process of financial disclosure.

         21             We preferred the PHS standards if we had

         22   to about standards that were in place now.  We


                                                                       95

          1   thought that those were obviously more restrictive

          2   than the FDA standards, and we would encourage the

          3   Department on either through the draft interim

          4   guidance in terms of suggested best practices or in

          5   the end in terms of actual regulations to

          6   standardize these requirements and let the PHS

          7   standards prevail; the $10,000 and/or 5 percent

          8   ownership interest standard prevail as opposed to

          9   the FDA standard.

         10             We also thought, and this went further

         11   than the draft interim guidance that this ought to

         12   be applied to all research not simply to that

         13   research that falls under the PHS, NSF, and FDA

         14   regulations.

         15             We thought that research compensation

         16   should be analyzed itself as part of the conflict

         17   of interest process to make sure that the money

         18   that is changing hands in the research endeavor

         19   would in that particular study itself in terms of

         20   the researchers and also the institution should be

         21   transparent in the conflict of interest process. 

         22   And that the conflict of interest analysis should


                                                                       96

          1   not just apply to honoraria and trips and

          2   investments and that sort of thing.

          3             We also recognized that in certain

          4   illnesses that there was a reason even for

          5   financial relationships that exceeded the PHS

          6   standards that there was a reason to have an

          7   exception or a series of exceptions for compelling

          8   in necessary circumstances in which individuals,

          9   physicians and others, but especially physicians,

         10   who -- and if I don't say this right, please tell

         11   me, who in fact are the primary individuals who

         12   treat particular diseases when they develop these

         13   devices or interventions or therapies themselves

         14   and they may be in fact, especially in the early

         15   stages of research, in the very best position to

         16   test those devices and to test those product so

         17   that the highest degree of safety for patients is

         18   assured.  And that was strictly thought in the

         19   early stages of research and there were thoughts

         20   that there should be some exceptions, actually to

         21   allow such research to proceed, but obviously with

         22   conflict management safeguards.  And we can talk


                                                                       97

          1   about what those might be.

          2             In terms of the conflict of interest

          3   process, we thought that IRBs clearly were already

          4   over burdened with what they already have to do

          5   simply in terms of the analysis of protection of

          6   human subjects research and particular with the

          7   inundation of IRBs by adverse events reports that

          8   have phenomenon that has occurred especially in the

          9   last couple of years.

         10             We endorse the idea of the creation of an

         11   adjunct conflict of interest financial disclosure

         12   process with a conflict of interest committee

         13   reporting to the IRB existing to receive and

         14   analyze financial disclosure and then identify

         15   those discloses financial interests that would rise

         16   to the level of relevant, troubling, complicating

         17   financial interests or a possible conflict of

         18   interest, or even actual conflicts of interest.

         19             We thought that the COI analyses should

         20   precede the IRB review and should in fact be

         21   required, that the participation of the researcher

         22   and the institution in that conflict of interest


                                                                       98

          1   analysis process should be required as a precedent,

          2   as a condition precedent to the submission of the

          3   research application to the IRB so that when the

          4   IRB receives the research application it has

          5   digested information about these issues;

          6   information that has been digested with firm

          7   recommendations by the conflict of interest entity

          8   or committee.

          9             We thought that this should be integrated

         10   at appropriate with existing conflict of interest

         11   mechanisms and the financial disclose the process

         12   that are ready should exist as a general compliance

         13   mechanism in most institutions that are connected

         14   with research and that exists as a background issue

         15   -- as a background compliance issue not for

         16   research particularly, but for all of the other

         17   compliance reasons for conflict of interest process

         18   in all of our hospitals, et cetera. 

         19             Now, unfortunately, I'm not sure that you

         20   can see this, but I am going to try and walk you

         21   through this what this handy pointer.

         22             This was one iteration and if it looks


                                                                       99

          1   like a mess, I apologize for that, but it was the

          2   best that a poor lawyer could do in regard to an

          3   organization chart.  This is the basic idea and

          4   this is only one possible iteration of what a

          5   conflict of interest process might look like. 

          6   Okay.

          7             Basically, you have a PI, you have the

          8   institution, and you have the IRB members reporting

          9   their disclosure forms to a COI committee or a

         10   designated official of the institution, or the

         11   independent IRB or of the CRO who is responsible

         12   for receiving this information and analyzing it.

         13             Please note that IRB members if there is a

         14   conflict then although they should obviously

         15   participate in the conflict of interest disclosure

         16   process they are generally expected to recuse

         17   themselves from the process with the idea being

         18   that IRB members themselves should be like Caesar's

         19   wife, above suspicion.  Okay.

         20             Now, once financial interests are

         21   disclosed their basically or two and if one adopts

         22   the idea or embraces the idea that we had that


                                                                      100

          1   there should be some thresholds for financial

          2   interests, that would once disclosed would rise to

          3   be level of troubling, complicating, or a possible

          4   conflict, then one would adopt a two-part analysis. 

          5   One is that those for financial interest that fall

          6   under the threshold or in fact that just simply

          7   don't exist at all because they don t -- they are

          8   not in fact a relevant financial relationship, as

          9   opposed to those that come in that are disclosed

         10   that are relevant to the research and that are over

         11   the threshold. 

         12             Let's follow the simple case first which

         13   is, for those that under the threshold or financial

         14   interests that are disclosed that really aren't a

         15   conflict, then one would go to -- the COI would in

         16   fact consider the  -- what does that even say?  I

         17   can t even read it from up here?  Can you see what

         18   it says Judy?

         19             Exactly the COI committee -- thank you --

         20   would make recommendations and would consider the

         21   issues and obviously would make the recommendations

         22   but it would be under the threshold -- unless there


                                                                      101

          1   were compelling circumstances in which a financial

          2   interest that fell even under the threshold would

          3   rise to the level of being a possible or troubling

          4   financial relationship.

          5             This will be reported to the IRB which

          6   either would approve the research in its normal

          7   course of business or disapprove the research; and

          8   if it approved the research, then there would be no

          9   disclosure because there would be no troubling

         10   financial relationship that had been disclosed.

         11             If in fact the financial relationship

         12   disclosed were over the threshold amount or even

         13   under the threshold but were identified as being

         14   particularly complicating or troubling, then the

         15   COI process or committee would consider this, it

         16   would make its recommendations.

         17             If it thought that something disclosed

         18   over the threshold was in fact not a conflict, and

         19   one can imagine some situations in which that might

         20   be the case, then it would go over to this process. 

         21   If there were a conflict that were identified, then

         22   it could discuss that conflict or that troubling


                                                                      102

          1   financial relationship and can make its

          2   recommendations about management or control of the

          3   conflict to the IRB.

          4             It may decide, however, that a financial

          5   relationship is so troubling that the conflict in

          6   fact should really mean that is the conflict is not

          7   divested or pruned away by the research or

          8   institution that the research actually should be

          9   aborted; that the research should not proceed.

         10   Okay. 

         11             If, in fact, however, there were conflict

         12   management strategies that were identified that

         13   were regarded as appropriate, then the

         14   recommendation would flow to the IRB which would

         15   either consider the issue and either approve the

         16   research or disapprove research and then, if it

         17   approved the research, it could order a couple of

         18   different things.  It could order various conflict

         19   management strategies, and those were outlined as

         20   examples in the existing PHS regulations, for

         21   example, to have outside parties be the external

         22   data monitors, have outside parties actually


                                                                      103

          1   observe the informed consent process, make the

          2   researcher place his or her investments in the

          3   blind trusts.  There are many different things they

          4   could be done to manage a conflict.

          5             And then there also would be in the IRB's

          6   consideration of the informed consent process and

          7   the informed consent form, there would be a

          8   generic, what we would call a generic disclosure

          9   made to patients.  I will get back to that.

         10             But the generic disclosure would not, in

         11   fact, contain under this scenario, the actual

         12   amount of the investment, the identity of the stock

         13   interest, the identity of the patent, but would be

         14   a generic disclosure that would say to patients  we

         15   have a conflict of interest process, the conflict

         16   of interest process has worked in this process,

         17   there have been complicating financial

         18   relationships identified.  There have been steps

         19   taken and recommendations made that it must be

         20   followed by the researcher and the institution to

         21   manage and control those conflicts, and if you want

         22   more information, please go to be research


                                                                      104

          1   administrator or the physician who is in charge of

          2   the research and they are required to give you

          3   additional specific information about these issues.

          4             And we'll get in a minute to why we

          5   adopted the issue of generic disclosures as opposed

          6   to specific and complete detailed disclosure in

          7   this case.

          8             These disclosures and these financial

          9   relationships would then go to the research subject

         10   or the patient.  The patient, if he or she chose to

         11   ask additional questions, then those questions must

         12   be answered, under our recommendation, truthfully

         13   and completely by the institution and/or the

         14   research administrator and/or the clinical

         15   researcher.

         16             And the disclosure could consist of a

         17   disclosure of the actual financial relationship,

         18   depending on what the patient asked about, a

         19   disclosure of the particular financial relationship

         20   and all of its particulars, a discussion of what in

         21   fact, the general COI guidelines and practices are

         22   of the institution and/or the researcher and the


                                                                      105

          1   IRB, and might consist of a detailed discussion of

          2   the conflict management strategies that were

          3   adopted as apart of the research approval process,

          4   which takes us up there.  Okay.

          5             So this is only one scenario, not

          6   exclusive, but one scenario that we tried to

          7   identify, and, I think, I hope it captures the

          8   general thought of the working group.

          9             Institutional conflict of interest.  We

         10   supported the draft interim guidance response to

         11   this.  We thought that it was essential especially

         12   given the troubling financial relationships that

         13   have been reported, albeit in anecdotal cases, that

         14   there be attention finally to the issue of

         15   institutional investments or financial

         16   relationships in the process of research, and not

         17   just to private sponsors, but also to public

         18   agencies, or not-for-profit agencies that fund

         19   research.

         20             We noted the increased incidence of these

         21   institutional investments in, or financial

         22   relationships in research, and particularly given


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          1   that, for example, you know, several of the

          2   hospitals, particularly in the Boston area had even

          3   entered into plenary agreements with pharmaceutical

          4   companies that pharmaceutical companies have

          5   intimate relationships with the clinical research

          6   in these medical centers in Boston.  The last one

          7   reported was the Beth Israel Deacons in Boston

          8   which has recently entered into such an arrangement

          9   with a particular pharmaceutical company.  I point

         10   that out by way of example, not because I know or

         11   would say anything about on Deacons .

         12             We noted the attenuated influence -- or

         13   the pharmaceutical company -- on IRB members who

         14   are affiliated with the research, this could take

         15   the form of people who sit on IRB who themselves

         16   may have complicating or complicated relationships

         17   and duties because they may in fact be responsible

         18   for the financial integrity of the institution

         19   itself.  So if they sit on the IRB, then there are

         20   some issues perhaps with the way in which they make

         21   decisions when research compensation is flowing to

         22   the institution itself.


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          1             We noted the NBAC recommendation with

          2   regard to the 50/50 split recommendation between

          3   the affiliated and unaffiliated members of the IRB. 

          4   We had doubt about the efficacy of that and the

          5   practicality of doing that given the difficulty and

          6   even getting anybody to be an unaffiliated member

          7   to sit through IRB meeting these days.  But we

          8   understood and appreciated the goals and we

          9   supported the idea of having additional

         10   unaffiliated members if that's possible.

         11             Finally disclosing conflict of interest to

         12   research subjects.  We noted that there is little

         13   data on best practices.  That what was needed here

         14   was real information for patients, not information

         15   that is simply thrown at patients or research

         16   subjects willy-nilly with lots of facts and details

         17   but in and undigested form.  Because we did not

         18   think that that contributed to a meaningful

         19   informed consent process for patients.

         20             And we certainly did not think -- and I

         21   bring this up because I think there were many

         22   people at the August 2000 conference who did think


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          1   that we did not think that simply disclosing

          2   financial relationships to patients substituted for

          3   an effective conflict management process by the

          4   institution and by the researcher himself or

          5   herself.

          6             We thought that those duties existed

          7   independent of, and had to be really respected and

          8   enforced by institutions independent of simple

          9   disclosure to patients, as tough that's the only

         10   answer to this problem.

         11             The goal here was that if a real conflict

         12   exists, their information should be reasonably

         13   available to be subject or potential subjects.  We

         14   thought that patients should be given things,

         15   information that is understandable to them.

         16             It was generally thought that generic

         17   disclosure, once there have been a troubling

         18   financial relationship identified, would give the

         19   patient enough information to let them know that

         20   there were financial relationships identified that

         21   were relevant, that there was a conflict management

         22   process in place, that there were processes and


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          1   systems within the institution or the research to

          2   manage those conflicts, and then to allow the

          3   subject as the subject is interested to pursue and

          4   to get full disclosure of whatever relevant

          5   information on these issues he or she wants.

          6             Here is one example of a generic

          7   disclosure to patients that is floated in the --

          8   and I have no idea what Mercy Hospital is, it just

          9   sounded like a good name in line with my

         10   theological approach.  I guess I was trained too

         11   well as a child.  So here is Mercy Hospital

         12   disclosing to a patient or a potential research

         13   subject that there was a financial relationship

         14   disclosed, that it was a relevant or troubling

         15   financial relationship, that there is a conflict

         16   management process in place, and if the subject

         17   wants additional information then the research

         18   subject may ask about it and will receive it.

         19             And obviously this means that there is a

         20   duty on the part of the researcher and the

         21   institution to the answer these questions

         22   truthfully and fully.


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          1             Education and compliance.  We obviously

          2   said that once the policies are adopted that

          3   compliance mechanisms that are in place either

          4   research compliance mechanisms, or general

          5   compliance mechanisms at institutions, really need

          6   or medical staffs or whoever or whatever body has a

          7   compliance process in place needs to audit whatever

          8   process that is adopted by the institution to make

          9   sure that it's respected enforced.  And obviously

         10   compliance cannot occur without education of key

         11   staff, and that's in line with many of the

         12   initiatives that Dr. Koski talked about earlier, to

         13   require education of staff in a number of areas

         14   regarding research compliance.

         15             So in conclusion, the working group

         16   generally supported the concept of an interim

         17   guidance document carefully crafted and subject to

         18   periodic review, evaluation, and revision.  We did

         19   not think that the Department should hold off on

         20   this issue, but we do think there is reason to

         21   proceed in a careful and step-wise fashion with

         22   evaluation at appropriate points and with


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          1   integration of private association guidelines as

          2   those guidelines issued.

          3             We also thought that one of the really

          4   animating reasons for proceeding with the draft

          5   interim guidance is for the pressing need to

          6   bolster public confidence in the integrity of the

          7   research enterprise itself.

          8             And, with that, I will conclude and I

          9   apologize for running a little over on time. 

         10             [Pause.]

         11             CHAIRPERSON MARSHALL:  We are doing well

         12   on time because of Dr. Koski is not going to need

         13   45 minutes for his declaration of Helsinki update,

         14   so I just wanted to let you all know that and

         15   reassure you that we will have time for discussion.

         16             Mark, thank you very much.  That was a

         17   stellar report.  You and your committee just did a

         18   fabulous job.

         19             What I would like to do in terms of

         20   sequence is to give Adil -- who is a member of the

         21   committee, and has its own comment that he would

         22   like to make -- time to do that then I would like


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          1   for us to take a 15-minute break and come back for

          2   discussion.

          3             So, Adil.

          4             DR. SHAMOO:  Thank you, Mary Faith.

          5             I have a written statement I want to

          6   distribute copies of it.  I have enough for

          7   everybody.

          8             I concur, as you know, during the

          9   discussion with a great deal of what -- and I think

         10   Mark has done a great job.  However, I do have a

         11   different spin on it.

         12             I would like to express my own views

         13   regarding the discussions on conflict of interest

         14   policy.  The draft NHRPAC policy on conflict of

         15   interest rests solely on IRBs and their

         16   institutions.  The proposed policy is well

         17   intentioned but not workable within the current

         18   system.  The structure of IRBs and its relationship

         19   to their institution makes these policies

         20   ineffective.

         21             In order to restore public trust in our

         22   research institutions, it is vital that an


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          1   effective and viable conflict of interest policy be

          2   put in place.  The campaign waged by universities,

          3   their lobbying organizations, their apologists, and

          4   supporters is shameless, self-serving, and

          5   arrogant.  It is shameless because they do not want

          6   anyone to produce an effective and viable policy on

          7   conflict of interest.  It is arrogant because they

          8   demand that a federal agency withdraw the weak and

          9   mild draft proposed guidance.

         10              These are the same research institutions

         11   and their supporters who claim that there is only

         12   anecdotal evidence with regard to the issue of

         13   human subjects that requires new reforms. To my

         14   knowledge, these institutions have never called for

         15   a study to find out the data on violations of

         16   federal rules.

         17              These are the same research institutions

         18   in ten years of research with nearly seventy

         19   million Americans as human subjects reported only

         20   eight deaths to the former OPRR.  When more surely

         21   occurred.  This is in violation of the federal

         22   reporting requirements and can in no way be


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          1   construed as anecdotal evidence.  No one with any

          2   common sense believes that such a number is

          3   correct.  On the contrary, the estimates would

          4   indicate that hundreds if not thousands of

          5   reportable deaths go unreported.

          6             These are the same research institutions

          7   in the same ten years reported a mere 300-400

          8   adverse events.  And these are not, again,

          9   anecdotal evidence. 

         10             On the contrary, the same type of

         11   statistical estimates would indicate that tens of

         12   thousands of adverse events go unreported.  These

         13   are the same research institutions that were

         14   investigated on site 41 times by OPRR resulting in:

         15   51 percent suspensions/terminations; 34 percent

         16   violations in informed consent; and 27 percent

         17   requiring re-review.

         18             These data are from official records of

         19   the federal government.  These startling data were

         20   obtained by OPRR without ever looking at the

         21   medical records of human subjects.  Could we

         22   imagine what the results would have been if medical


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          1   records were audited?  This is in addition to

          2   countless reports in the media regarding

          3   allegations of flagrant violations of ethical

          4   standards including issues of conflict of interest.

          5             These same institutions also keep most of

          6   their IRB membership and their minutes closed from

          7   public scrutiny.  These research institutions and

          8   their supporters or their lobbying organizations

          9   want the public to trust them.  They tell us that: 

         10   they will not engage in research where their

         11   researchers and universities will make millions of

         12   dollars of profit and their stocks or equity value

         13   goes up or down depending on positive outcome from

         14   clinical trials conducted in their institutions.

         15             Human subjects and the public are supposed

         16   to put their trust in these same institutions

         17   without any checks and balances. 

         18             More specifically, my recommendations are:

         19             1.  The conflict of interest policy should

         20   be made within the context of the overall system

         21   and oversight of human research protections.

         22             As I have stated at the first meeting, we


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          1   need to start addressing the overall problem rather

          2   than piecemeal enacting a policy on conflict of

          3   interest policy without reworking the overall

          4   system avoids the issue and may result in

          5   unintended loopholes.   This approach was

          6   recommended by NBAC.

          7             2.  IRBs are the gatekeepers for the

          8   protection of all human subjects.  Unfortunately,

          9   IRBs as currently constituted are structurally and

         10   functionally flawed.  They are riddled with

         11   conflict of interest simply because they are

         12   employees of the same research institutions.  These

         13   are the same IRBs that approve the projects leading

         14   to the negative events I cited earlier.

         15             Moreover, research institutions can change

         16   the composition of IRBs at any moment.  They can

         17   fire and hire the administrator at will.  And they

         18   can eliminate an inconvenient IRB.  So also has

         19   NBAC recommended that 50 percent of IRB membership

         20   should come from the community.  I think we should

         21   follow the NBAC s recommendation.

         22             3.  Conflict of interest should be


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          1   disclosed to human subjects.  Human subjects carry

          2   the ultimate burden of risk for drug testing.  It

          3   is not sufficient for the so-called institutional

          4   conflict of interest committee to just simply state

          5   that they looked at and it has been managed.  And

          6   we are told that if the patient asks then the

          7   investigator should inform the subject of the

          8   nature of the conflict orally.

          9             This is unacceptable because it lacks

         10   specificity and accountability.  All significant

         11   conflicts of interest whether for the investigator

         12   or the institution should be disclosed in writing

         13   to the patient and/or patient s ombudsman. 

         14   Concerns for the privacy of the investigator or the

         15   institution are secondary to the evaluation of

         16   safety of the study by the subject.

         17             4.  Severe sanctions should be levied for

         18   infractions on requirement for conflict of

         19   interests  disclosures such as:  cause for firing,

         20   rescinding of IRB approval for the implicated

         21   research and other lesser sanctions.

         22             5.  Once the conflict of interest


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          1   committee has determined that a study should not go

          2   forward, the IRB should never be able to overrule

          3   the decision of the COI committee.

          4             Finally, at the last meeting of this

          5   committee, I was challenged on my statement that

          6   some physicians are paid up to $20,000 per patient

          7   as a bonus.  I was wrong on the upper limit. 

          8   During the deliberation of the conflict of interest

          9   workgroup a colleague with first-hand knowledge in

         10   this area informed us that the upper limit is even

         11   higher.  A I quote: 

         12             "Investigators have received stipends in

         13             the range of $5-30,0O0 per subject for

         14             participating in clinical research trials. 

         15             These stipends may be offered on top of

         16             reimbursement for the hospital charges for

         17             the procedure, blood chemistries, nursing

         18             support and technical assistance charges.

         19             Thank you, Madam Chairman.

         20             CHAIRPERSON MARSHALL:  Thank you, Adil.

         21             I would like for us to break now for 15

         22   minutes.   And we will restart promptly. 


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          1             Let me ask Greg, I would perhaps like to

          2   have our comment period on the financial

          3   relationships paper and then make sure we give you

          4   adequate time at the end for your Declaration of

          5   Helsinki update.

          6             DR. KOSKI:  Yes, Madam Chair, I would say

          7   just looking at the schedule, my report, the update

          8   on the Declaration of Helsinki, probably would not

          9   take more than 15 minute and I would encourage that

         10   the time that we have available before lunch be

         11   directed primarily toward discussion of the

         12   financial relationships issues.

         13             Thank you. 

         14             CHAIRPERSON MARSHALL:  Thank you.  So we

         15   plan then on 12 to 12:15 for the Declaration of

         16   Helsinki update.  And let me just ask those of you

         17   -- everyone in the room, committee members, ex

         18   officio members, public members to think about your

         19   comments that he would like to make now.  We want

         20   to be fair we want everyone to have a chance to

         21   speak who would like to speak.  So I would like for

         22   them to be concise  and on point.  And I will hold


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          1   you to that.

          2             We will see you back here promptly at 11,

          3   thank you.

          4             [At 10:50 a.m., a recess was taken.]

          5             CHAIRPERSON MARSHALL:  A little less than

          6   an hour before Dr. Koski has the floor for his

          7   update on the Declaration of Helsinki.  What I

          8   would like to do first is give the members of the

          9   committee an opportunity to ask Mark and other

         10   members of the working group about questions of

         11   fact or interpretation relative to the presentation

         12   and then move into the discussion.

         13             I also do want to make one observation and

         14   that is about Adil s statement.  That this is not a

         15   NHRPAC policy, NHRPAC does not set policy, NHRPAC

         16   gives advice to those who by our charge ask for it. 

         17   So I just want to clarify that.  And I am sure you

         18   understand that and didn't mean that, Adil, I just

         19   wanted to make that observation.

         20             We will give the floor first to Mark as

         21   the workgroup leader and then please just raise

         22   your hands and I will take your name.


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          1             MR. BARNES:  Just a brief comment on

          2   Adil s statement which we appreciated very much and

          3   it certainly is consistent with many of the

          4   positions that Adil articulated very eloquently

          5   during our discussions of the workgroup in the

          6   workgroup deliberations.  But I do want to point

          7   out really the following:  that there were other

          8   people on the committee who felt strongly in other

          9   directions from Adil and the committee -- I should

         10   say working group process really tried to reach a

         11   basic consensus about these issues, to try to in a

         12   concerted way, in a way that kind of respected all

         13   points of view to move the ball forward in

         14   significant ways.

         15             And, in fact, I mean, if one looks at what

         16   the proposed commentary of NHRPAC would be under

         17   the working group proposal as opposed to the world

         18   as it is now there really are some very significant

         19   departures that we re recommending.  We're

         20   recommending that all research be covered, you

         21   know, either through this draft interim guidance

         22   although it could only be in the form of suggested


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          1   practices instead of regulation; that's a different

          2   story. 

          3             We're recommending that institutional

          4   conflicts of interest be identified and disclosed. 

          5   We're recommending disclosure that it, we're

          6   recommending generic disclosure to patients of

          7   troubling financial interest, and that if patients

          8   have questions they can get all the information. 

          9   So these are really significant although obviously,

         10   you know, Adil's points of view are very strongly

         11   felt.  In fact, I do want to just for the committee

         12   to know and the public to know that his point of

         13   view really did push this process forward and many

         14   of his points or the general thrust of his points

         15   and of other people's points are included in the

         16   document as it is.

         17             CHAIRPERSON MARSHALL:  Thank you, Mark.  I

         18   have Abbey, Alan, Bob, Denise, Greg and Susan.

         19             MS. MEYERS:  First of all, it's just a

         20   wonderful job you've done, and as I was reading it

         21   I was saying, I know that you had to make a lot of

         22   compromises and you did a wonderful job in finding


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          1   those compromises.  So I have, I think, just three

          2   comments.

          3             First, it's wonderful that you put in the

          4   paragraph on page 6 about compelling and necessary

          5   exceptions.  Because for scientists who are

          6   studying rare diseases, for example, rare genetic

          7   diseases that might affect 300 or 600 people in the

          8   whole country, once they publish, they become known

          9   as the United States expert on the disease.  And so

         10   if they're going to try to develop something and

         11   always in the beginning at least, it's without a

         12   commercial sponsor, they get the IND and then every

         13   child in the country is treated under their IND.

         14             So there could be conflict of interest

         15   there that can t be eliminated.  So it is important

         16   that in those cases that they be managed.  But it

         17   seemed to me in the last sentence you talk about

         18   consulting with cardiac surgeons, and orthopaedic

         19   surgery groups, but there are also others like the

         20   inborn areas of metabolism those types of

         21   professional groups.

         22             The next thing is page 10 on the paragraph


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          1   that you've drafted up about Mercy Hospital.  You

          2   know in a normal informed consent document it says

          3   that at any point you can decide not to continue in

          4   the study.  And if you decide to drop out it will

          5   not be held against you and your future care at

          6   this hospital won't be put in jeopardy.  That needs

          7   to be added to this sentence.  Because, first of

          8   all, if there is a sentence about conflict of

          9   interest and a patient wants to ask, they're going

         10   to be number one embarrassed, because it is their

         11   doctor and, of course, they trust him. 

         12             But number two, they're going to wonder if

         13   they ask if it'll be held against them.  So they

         14   have to be assured that there is not going to be

         15   any punishment for asking.

         16             And the third thing is that I want to

         17   reiterate my unwaiving support for 50 percent

         18   membership of IRBs coming from the community.  I

         19   don't think that there is an institution in this

         20   country who could possibly say they can't get

         21   volunteers from the community.

         22             I run a charity and I have to get people


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          1   come up to be on committees, to decide, for

          2   example, which patient deserves to get free drugs

          3   because they have no insurance and they can't

          4   afford it.  And I have a waiting list of people

          5   trying to get on those committee not only from the

          6   retired community, but from young mothers, who if I

          7   do something to help them with their daycare,

          8   they'd love to come up there and just do it.  And

          9   they love it and they wouldn't miss a meeting.

         10             So I think that its just an excuse saying

         11   it's impossible, we can't do it.  If you find a way

         12   to do it you can do it and it should be done

         13   because IRB should not be composed of employees of

         14   the institution.

         15             CHAIRPERSON MARSHALL:  Thank you, Abbey.

         16   Greg has a quick comment on point and then I have

         17   Alan.

         18             DR. KOSKI:  Thank you.

         19             I think it is important as we enter into

         20   the discussion to mention that as part of our

         21   overall remodeling of the system that I described

         22   earlier which is very much underway already, Adil,


                                                                      126

          1   we emphasized the need to, what I call, "get the I

          2   out of the IRB."  Okay.  Which doesn't mean to take

          3   the IRBs out of institutions necessarily, but

          4   rather to defuse the institutional interest in the

          5   outcome of the human research review and protection

          6   process which can be accomplished in many ways.

          7             And in many instances we are already

          8   beginning to see individual institutions join

          9   together with broader community groups or through

         10   private foundations a host of different

         11   organizational structures that actually move us

         12   from the current model in which it's often very

         13   difficult, as has been pointed out, to separate the

         14   institutional interest from the IRB process. 

         15             So I think as we look forward toward the

         16   future let's think a little beyond the current

         17   structure.  Because we need to think out of the box

         18   in order to accommodate the changes that are

         19   coming, and, in fact, in many places they are

         20   already instituted.

         21             CHAIRPERSON MARSHALL:  Thank you, Greg.  I

         22   second that. 


                                                                      127

          1             I think that the National Breast Cancer

          2   Coalition and their work and training their members

          3   to serve on IRBs is a wonderful model and that we

          4   should be moving in that direction.

          5             I have been remiss in not making some

          6   procedural and organizational statements in terms

          7   of how we might proceed as a committee and we are

          8   setting some precedence for ourselves here.  I

          9   don't want us to feel rushed or constrained by

         10   other people's time, agenda and need.  I want the

         11   committee to have its time to do good work and to

         12   put out a good product.  So, I would propose that

         13   in terms of moving forward with the working group's

         14   draft report to us, that we have a conversation

         15   today.  Obviously we we will not finish that

         16   conversation today.  Mark's presentation will be

         17   put on the web.  The draft document will be put on

         18   the web.  He will take comments from the public and

         19   others about it.

         20             We will continue the conversation among

         21   ourselves as a committee and look forward to our

         22   July meeting where we might as a committee put


                                                                      128

          1   forward a document that we have achieved consensus

          2   on.  So, I just wanted you to frame your remarks

          3   knowing that there will be ample opportunity in the

          4   future to weigh in if you don t get a chance today.

          5             Alan.

          6             DR. FLEISCHMAN:  Mark, I had two questions

          7   which would help me understand some of the, I

          8   think, major thrusts of this report.  One is, and

          9   this is kind of half a question, half a comment

         10   about the process of the evaluation of the

         11   financial relationships and the potential conflicts

         12   of interest.

         13             It seems to me that that process should be

         14   independent of any research initiated and that it

         15   ought to be a general process in the institution in

         16   which all physicians and research scientists are

         17   asked by such financial relationships having

         18   nothing to do with their independent assessments as

         19   to whether there are potential or real conflicts. 

         20   At which point then, when an investigator comes

         21   forward with a proposal, he would not need or she

         22   will not need at that moment in time to add in more


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          1   information about their financial relationships to

          2   industry, because that would already be on record.

          3   And the conflict of interest process would be

          4   evaluating what is on record in the institution;

          5   making a recommendation about either management or

          6   lack of any kind of conflict. 

          7             For me that s an important safeguard in

          8   this process which allows for the conflict of

          9   interest officer or committee to make judgments far

         10   more broadly than relative to just this research

         11   project.  And I wonder whether that's imbedded in

         12   here, intended in here or not intended.  That's one

         13   question.  Should I give the second one or go with

         14   that?

         15             CHAIRPERSON MARSHALL:  Yes.   And please

         16   be mindful that I have a list of about five other

         17   people who need to speak as well.

         18             DR. FLEISCHMAN:  So I should give my

         19   second one?

         20             CHAIRPERSON MARSHALL:  Please do.

         21             DR. FLEISCHMAN:  Okay.  I think Mercy

         22   Hospital is well intended in its paragraph, but I'm


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          1   not convinced of this approach and I'd like you to

          2   share with us more of the thinking, of the working

          3   group, as to why we ought not disclose something

          4   about this conflict which has been determined

          5   rather than just kind of a flag that says,  we did

          6   it, we fixed it, if you're interested call us."

          7             DR. BARNES:  Let me try to answer these

          8   two questions and if other members of the working

          9   group have different opinions or views then, please

         10   voice them.

         11             Most institutions that receive -- whether

         12   they are private institutions, private corporations

         13   not-for-profits, or hospitals, academic

         14   institutions have a conflict of interest process

         15   which usually requires, which is an annual form

         16   that is filled out by all employee and medical

         17   staff members.  The problem is that in that form

         18   there are certain generic or particular disclosures

         19   that have to be made.  But very few hospitals, very

         20   few institutions, in my experience, you know, in

         21   counseling hospitals on compliance processes and

         22   medical schools actually have a requirement that


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          1   for example every single financial interest be

          2   disclosed. 

          3             They do not require that all investment

          4   interest be disclosed.  They are not his nearly as

          5   vigorous as, for example, the federal employment

          6   guidelines in requiring that we all had to fill out

          7   for what passes for us as federal employment as --

          8             [Laughter.]

          9             DR. BARNES: -- which I think falls more on

         10   the issue on the realm of good works, but I guess

         11   that is employment too.

         12             It s not nearly that detailed and so, in

         13   fact, I agree with you and I think the working

         14   group contemplated that the conflict of interest

         15   process for research would operate in relation to

         16   and informed by the general conflict of interest

         17   process within institutions.  But that conflict of

         18   interest process in most institutions does not

         19   actually require, for example, that every financial

         20   relationship be disclosed and therefore what we

         21   would be searching for and seeking that the

         22   researchers and the institutions disclose and the


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          1   institutions and the IRB members disclose in the

          2   conflict of interest disclosure process would be

          3   those financial relationships that in particular

          4   could be reasonably expected to be affected by the

          5   research under the PHS as thresholds.

          6             So certainly one could develop a COI

          7   process for research and one ought to with the

          8   background of the general COI process and informed

          9   by all of the disclosures that are made in the

         10   general COI process, but I think that's not --

         11   that's still not going to be enough under most

         12   institutional compliance programs to vindicate the

         13   goal here.  So that is the answer perhaps to your

         14   first question.  Okay.  Fair?

         15             DR. FLEISCHMAN:  I don't agree with the

         16   approach, but I think that's a fair answer.

         17             [Laughter.] 

         18             DR. BARNES:  Okay.  On the second issue, I

         19   call your attention to the paragraph in terms of

         20   the thinking, in my attempt to sort of encapsulate

         21   the thinking, I call your attention to the

         22   penultimate paragraph of the section that is


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          1   marked, "disclosing relevant financial

          2   relationships and conflict of interest to research

          3   subjects."  And this is in regard to the so-called

          4   "Mercy Hospital disclosure."

          5             CHAIRPERSON MARSHALL:  Can you tell us

          6   what page you're on, Mark? 

          7             DR. BARNES:  Actually it is page 11 at the

          8   bottom, okay.

          9             Basically there was one minority view

         10   which was certainly articulated well by Adil which

         11   is there should be complete transparency of all the

         12   information.  On the other hand there were other --

         13             DR. SHAMOO:  All significant -- 

         14             DR. BARNES:  All significant, yes.  That s

         15   right.  All relationships that rose to the level of

         16   troubling or significant. 

         17             Number one, if a financial interest is

         18   identified and is relevant and is over the

         19   threshold and is relevant and is troubling or a

         20   possible conflict, then the goal of the conflicts

         21   management process must be to reduce the level of

         22   risk or influence of the conflict to a level that


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          1   is underneath that is below the level of

          2   significant risk or material risk to the patient.

          3             So that is the goal of the conflict

          4   management process.  So there is already that

          5   process in place and that process cannot be, we

          6   thought could not be substituted for by simple

          7   disclosure to patients.  And what that means is,

          8   that if that process is operating whereby the

          9   conflict once identified is reduced by the

         10   management strategy to something that is less than

         11   a significant risk to the research subject, then

         12   one must use a comparative analysis in

         13   understanding that if something -- that if any

         14   risk, for example, an adverse effect is below the

         15   level of significant that too is not disclosed to

         16   research subjects in the standard informed consent

         17   process.

         18             Only significant risks material risks are

         19   disclosed.  So, in fact, we're using a comparative

         20   analysis about risks and what risks are disclosed

         21   that already the conflict of interest process has

         22   reduced that below the level at which the regular


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          1   sets of risk are disclosed.  But we're not

          2   satisfying ourselves with that because we're going

          3   beyond that in this situation, largely because the

          4   quantification of risk in this area is a new

          5   process.  So we're saying that where the patient

          6   has questions, the research subject or potential

          7   research subject has questions, then they deserve

          8   to be able to -- to know that they can ask those

          9   questions, to ask those questions, and to get full

         10   disclosure once they asked those questions.  

         11             Number two.  We fear, and at least I speak

         12   for myself, I don't know what everybody else fears,

         13   but I fear that if we have simple disclosure that

         14   that will be to patients of anything that is in the

         15   level of significance.  That will be a default

         16   position that will rapidly kick in by IRBs and by

         17   COI committees or entities so that they will simply

         18   default and say, it's being disclosed so why

         19   operationally should we engage in this tight

         20   attention to the conflict of interest management

         21   process.

         22             Number three, informed consent forms float


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          1   all over the hospital.  They are readily available

          2   to almost anybody.  They're looked at by the IRB

          3   they're approved by everybody.  Is ita fair to

          4   researchers, is it the kind of incentive we want to

          5   set up so that their individual financial interests

          6   -- forget about the institution for a second,

          7   because I have less concern about the institution's

          8   financial disclosures.  Do we want to impose the

          9   burden on them that their personal financial

         10   information is actually printed and distributed

         11   willy-nilly around a medical center?  I don't think

         12   so.

         13             And so those were the things that would

         14   deter people from engaging in research.  It's not

         15   going to mean that all research is going to stop,

         16   it's going to mean in close cases that there could

         17   be some self deferrals from engaging in the

         18   research process because of financial disclosure. 

         19   So those were the, I think, the animating reasons

         20   for our reasoning on that point.  I don't know if

         21   you all have different opinions.

         22             CHAIRPERSON MARSHALL:  Thank you, Mark.  


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          1             I have Bob, Denyse, Greg, Susan, Felice,

          2   Jonathan and Margaret.  Bob.

          3             DR. R. LEVINE:  I would like to first say

          4   something about the proposition of having half of

          5   the members of the institutional review board be

          6   unaffiliated with the institution.  As I followed

          7   the debate on this, I find it curious that the most

          8   forceful advocates for that are the most forceful

          9   opponents for having all of the members not

         10   affiliated.  There have been proposals about

         11   turning everything over to private corporations

         12   like Western IRB or Philadelphia Area Clinical

         13   Trials.  And the concern has been that they are too

         14   far removed from the daily realities of the

         15   institution.

         16             I also want to say that when Greg says

         17   that we've got to get the  I  out of the IRB, I

         18   think that has to be considered very carefully.

         19             Right now I think the discussion is

         20   dominated by an  I  called interest and interest in

         21   the sense of financial.  It is very important to

         22   keep in mind that these institutions have very


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          1   powerful interest in not being exposed publicly as

          2   being evil or exploitative.  and they are making

          3   enormous investments in that.  I think it's very

          4   important to have members of the institution who

          5   experience that institutional commitment to not be

          6   added to the hit list along with Rush and Duke and

          7   so on.  That let's try not to dilute that too much.

          8             A couple of other brief comments.  First,

          9   I m concerned, I think it's okay to express an

         10   awareness of the fact that the desire for fame,

         11   prestige, and academic advancement maybe for the

         12   typical academic a much more powerful incentive

         13   than any amount of money that any corporation might

         14   pay.

         15             However, I don't think we can go much

         16   further than to acknowledge that.  It would get a

         17   little silly if we started putting on consent forms

         18   that if this all goes well here I might get tenure,

         19   you know.

         20             A third comment is on the proposal to have

         21   the conflict of interest determination made before

         22   the IRB reviews the protocol.  You did, Mark, call


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          1   attention to all the other things that are done by

          2   committees other then the IRB, ranging from bio-

          3   safety, radiation, DSMP s and so on.  I think it is

          4   important not to create an inflexible requirement

          5   about what comes first.  In general, many of these

          6   things occur in parallel.  And any requirement that

          7   something must be accomplished before the next

          8   step, imposes some delays in the project that would

          9   probably be unwelcome and probably in many cases

         10   would act to the detriment of the research

         11   subjects.

         12             And finally, Adil Shamoo was asked at the

         13   last meeting to provide documentation for the upper

         14   level he estimated for payments to doctors for

         15   individual research subjects.  He gave us

         16   documents.  He said it was in the Medical College

         17   of Georgia case, a statement that was corrected by

         18   Sidney Wolfe later in the day.

         19             Now, he s coming in with different

         20   documentation.  We are told that a colleague with

         21   first-hand knowledge in this area informed us,

         22   blah, blah, blah.  Some of us don t consider that


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          1   documentation.  I can tell that a colleague who

          2   knows all about such matters has told me that Greg

          3   is a bad guy.  You probably want something more

          4   substantial than that.  Thank you.

          5             CHAIRPERSON MARSHALL:  Denyse.

          6             DR. THORNLEY-BROWN:  I just have two

          7   questions.  First of all, did the working committee

          8   make any recommendations about the composition of

          9   the conflict of interest committee?  So, for

         10   example, by analogy to the IRB having members of

         11   the community in the committee would this be

         12   something that they would address?  And the second

         13   thing is, any recommendations or comments regarding

         14   monitoring conflicts of interest that develop

         15   during the course of research.  So, for example, if

         16   a study is having problems with recruitment, the

         17   sponsor may want to put in some incentives to try

         18   to increase recruitment.  What would be done to

         19   evaluate that?

         20             DR. BARNES:  Brief responses to that. 

         21   First of all, I think that we actually did not or

         22   perhaps we should have gotten more deeply into the


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          1   issue of the composition of the COI committee or

          2   the identity of the institutional official.  I

          3   think it was our general feeling that those who sit

          4   on the conflict of interest committee should be

          5   removed enough from the situation so that there is

          6   a fiduciary duty that can be meaningfully exercised

          7   so that they are not, for example, they don't have

          8   conflicting interests themselves in judging

          9   conflict of interest, but, in fact, I think that we

         10   did not spend really any significant amount of time

         11   in discussing those issues.  Do you all agree with

         12   that?

         13             DR. CHODOSH:  I think that what we were

         14   talking about is that it is not clear that there is

         15   one ideal way to approach this, and that we were

         16   looking at the possibilities of having people

         17   develop workable situations in which indeed the

         18   conflict of interest committee can't have

         19   conflicts.  Now, how that is going to work out in

         20   institutions or independent situations is really

         21   not clear at this point, and for us to specify that

         22   at this point would have really been pushing the


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          1   situation and that's not what we intended.

          2             What we intended was that there be a

          3   mechanism developed within any one who s doing

          4   research of this kind to do this job appropriately. 

          5   Now, appropriately has a lot of leeway to it but we

          6   are talking about, you can't have a conflict of

          7   interest committee that has a conflict of interest. 

          8   And if you think of it that way we have a better

          9   chance of developing something worthwhile.

         10             DR. BARNES:  In answer to the second

         11   question that you had, in fact I think that we can

         12   -- it certainly is our intention and it is required

         13   under the existing guidelines that do exist that

         14   information be updated.  That as new financial

         15   interests emerge that would implicate the research

         16   that those in fact that there is an affirmative

         17   duty of the researcher and the institution to

         18   disclose those to the conflict of interest in the

         19   conflict of interest process which would then

         20   proceed along the lines that we set forth.  But we

         21   can clarify that in the final draft.

         22             CHAIRPERSON MARSHALL:  Thank you.  Susan.


                                                                      143

          1             DR. KORNETSKY:  I promised to bring up the

          2   practical and I think that's what I'm going to do. 

          3   First of all, I definitely want to support the

          4   separation of the conflict of interest committee

          5   from the IRB and I think that that's a large change

          6   -- a big change from the first one.  I think that

          7   is very, very important to want to totally support

          8   that.

          9             Having said that just a couple of issues. 

         10   First of all, I think that one of my questions is

         11   the top of your chart you had that the IRB member's

         12   disclosures to conflict of interest committee and I

         13   will ask the practical question of whether you are

         14   thinking about that for every individual protocol,

         15   every individual time, because I think that will

         16   also add a blockage or a time commitment to that. 

         17             Bob took the words out of my mouth about

         18   the idea of having this go before the committee. 

         19   In actuality some of the committees that you've

         20   listed there, there is a parallel process.  It is

         21   important that all of that get accomplished before

         22   any human subject is enrolled and it's probably up


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          1   to the institution to decide how that all can get

          2   done.

          3             I do want to support Adil's comment that

          4   -- his last comment that once the conflict of

          5   interest committee has determined that a study

          6   should not go forward, the IRB should never be able

          7   to overrule that.  I think that that is mixing the

          8   message of keeping the IRB sort of process

          9   separate.  

         10             The other comment about membership from

         11   the community in Abbey s comments, I do believe and

         12   support that there should be more community

         13   representation on the committee.  I am definitely

         14   for that.  But I think it's also important to

         15   remember that we don't want to water down the sort

         16   of the expertise of the committee.  And so although

         17   there may be and perhaps I m unaware, a waiting

         18   list or individuals who want to serve on the

         19   committee you also want professionals and those are

         20   much more difficult to find to serve on committees.

         21             So I want to support community involvement

         22   but I think your definition of "community" and sort


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          1   of  taking the "I" out of institutional, there s a

          2   practical problem there. 

          3             I do support a more general type of

          4   statement for the informed consent, I think having

          5   dealt with informed consents and subjects, I think

          6   that it is very important that they have the

          7   opportunity to ask questions and generally in

          8   support.  I think that is a compromise. 

          9             I'm also to recognize and to support the

         10   institutions can go further than this.  I think

         11   this is, you know, again has to be a minimum

         12   standard and I know there are institutions that may

         13   and will want to go further than this.  Thank you.

         14             CHAIRPERSON MARSHALL:  Thank you.  Robert.

         15             DR. RICH:  I'd like to say that by and

         16   large I congratulate the working group on a fine

         17   product.  As a signatory one of the letters that

         18   you received from one of the associations that

         19   dissented from the draft interim guidance, however,

         20   I want to respond with the comment that I think

         21   that I can endorse everything that's basically in

         22   this letter with the exception of the last


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          1   paragraph on page 3 which suggests -- with maybe

          2   the central paragraph suggesting going forward with

          3   the issuance of formal guidance.

          4             I think it's really important to

          5   understand how seriously the professional

          6   associations that have been engaged in this process

          7   have taken it.  And that the letters that you

          8   received from such organizations as the AAU and

          9   Koger and AAMC, and FASSUP, among others were also

         10   the results of a deliberative process; and I can

         11   assure you are the result of a lot of thinking

         12   about whether or not a formal draft interim

         13   guidance regardless of just how one frames it is

         14   really appropriate at that time these organizations

         15   are trying very hard to wrestle with most difficult

         16   and important issues.

         17             I think that if the draft interim guidance

         18   had been issued from other than a government

         19   regulatory agency that perhaps would not be the

         20   same sensitivity to the word guidance as there is

         21   when organizations that have been so frequently

         22   found guidance translating to -- translating to


                                                                      147

          1   regulation literally in the twinkling an eye, and

          2   with very little in the way of informed discussion.

          3             I would say that OHRP is enjoying a

          4   remarkably collegial relationship with these

          5   organizations and I think that it's a very

          6   productive relationship at the present time.  It is

          7   to be advantaged, I believe, by a process of

          8   discourse and deliberation and not by a process

          9   that jumps ahead of what is a very active engaged

         10   process going on particularly by the AAMC and the

         11   AAU for which I don't speak.  I speak for FASSUP.

         12             Having said that, a couple of other

         13   specific comments --

         14             CHAIRPERSON MARSHALL:  Can I interject

         15   here?  I do want to say that I am troubled by your

         16   use of the word "the letters that you received." 

         17   Those other letters that we received --

         18             DR. RICH:  I'm sorry I should clarify --

         19             CHAIRPERSON MARSHALL:  And you sit on this

         20   committee, yes, wearing a FASSUP hat.  But you also

         21   where a committee hat, and I want us to be mindful,

         22   all of us, of our responsibilities as members of


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          1   this committee and of our responsibilities in

          2   protecting the interest of human subjects.  That is

          3   our primary responsibility.  So I am just throwing

          4   that out there and then we do need to move alone

          5   quickly.  So each of the next people who speak

          6   please be concise.

          7             DR. RICH:  I have no confusion about those

          8   issues.  I thank you for making the clarification.

          9   But I truly am not confused about them, I can

         10   assure you.

         11             I would like to point out that I think

         12   there are important problems that the issue of

         13   thresholds raised and I am particularly glad that

         14   the working group brought up the problem of

         15   researcher compensation into something that Adil is

         16   obviously very much concerned about.  But I think

         17   that even a few hundreds of dollars to a young

         18   physician sometimes in direct compensation to a

         19   researcher is very different from even tens of

         20   thousands of dollars in research support to an

         21   established investigator.

         22             So dollars in an investigator's pocket,


                                                                      149

          1   and I would point out, as most of you know, that

          2   the vast majority of clinical trials are done

          3   outside of academic medical centers and are really

          4   in a sense becoming a business or becoming a part

          5   of the way in which practitioners actually support

          6   themselves.  And so the issue -- I think we cannot

          7   turn away from the issue of researcher

          8   compensation.

          9             I'd like to also echo the comment that

         10   Abbey made about the importance of exceptions with

         11   regard to the involvement of investigators and

         12   extend it from rare diseases to simply the

         13   recognition that in many cases the inventor of new

         14   technologies and the inventor of new devices is the

         15   world's expert and at least at the very earliest

         16   phases of translation into practice, it is

         17   unworkable to prohibit that individual from

         18   actually participating in it.  Because otherwise

         19   the discovery or the invention or the devise will

         20   not be translated into practice.

         21             CHAIRPERSON MARSHALL:  Thank you.

         22             DR. RICH:  And finally, one last very


                                                                      150

          1   brief point.  On community representation I think

          2   that Susan made an important point.  I would simply

          3   say that the most important thing that the IRB does

          4   is protect human subjects and that involves risk

          5   assessment and that certainly involves the

          6   professional expertise of a substantial number of

          7   members of the committee.

          8             CHAIRPERSON MARSHALL:  Thank you.  Felice.

          9             DR. F. LEVINE:  Thank you.  I think what I

         10   will do is just bullet a number of topics that I

         11   hope we discuss more over the months ahead as

         12   opposed to --

         13             CHAIRPERSON MARSHALL:  Let's be specific

         14   to this paper, okay.

         15             DR. F. LEVINE:  Yeah, I will.  I will.

         16             CHAIRPERSON MARSHALL:  Okay.  Thank you. 

         17             DR. F. LEVINE:  No, on this issue, I mean,

         18   as opposed to explicating what might be additional

         19   questions under each.  I thought one of the best

         20   and most elegant parts of this is coming to terms

         21   with the difference between financial relationships

         22   and bias in conflicts or conflicts of interest. 


                                                                      151

          1   Which raised for me the larger issue of when I

          2   first read this, I saw this as focusing on

          3   financial interest and clinical trials.  And so it

          4   raise for me the broader issue of the relationship

          5   between financial interests or financial

          6   relationships of potential conflicts and other

          7   forms of bias in conflicts of interest and how

          8   narrow or how broad we want to go in thinking about

          9   the general conflicts of interest issue.

         10             Also I read this as focusing specifically

         11   on clinical trials and clinical interventions

         12   although you had said on all the reports, as in a

         13   number of spots, that this should meaningfully

         14   reach to all research.  And the nature of the

         15   compensation that we have to have about the

         16   differences between different forms of research is

         17   one of my bullets.

         18             I think that this issue that's come up in

         19   a number of questions and in a number of statements

         20   and in your own presentation about the separation

         21   of the conflict of interest review and the IRB

         22   review is extraordinarily important, and I am


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          1   concerned about the integration of the two. 

          2   Whether they are indeed two separate parts of very

          3   reasonable processes.

          4             One it speaks, of course, to our primary

          5   role with respect to human subjects protection and

          6   another which speaks to larger questions with

          7   respect to the integrity of research that may or

          8   may not raise issues of human subjects

          9   protection's.  So I am not sure the two need to

         10   converge.  I think there are some issues of

         11   cumbersomeness if they do.

         12             I have some concerns about -- and I think

         13   I'd like us to have fuller discussion about the

         14   issue of public disclosure.  There's kind of the

         15   micro issue of how it affects individual patients

         16   or subjects and then there's the macro issue of how

         17   it affects that ratcheting up issue of both

         18   research, research integrity, and the broader

         19   community of research subjects.  And I think short

         20   of publishing everybody's tax returns there are

         21   ways of publicly disclosing what might be conflicts

         22   or potential relational issues that are informative


                                                                      153

          1   about the research and are formative about the

          2   research or without necessarily raising a flag. 

          3   And I think we need further discussion about that.

          4             Which I guess brings me to a broader

          5   issue, I hope, over the next months that we have

          6   additional discussion with other of the federal

          7   agencies that have developed their statements about

          8   how the fit would -- especially if we go broader

          9   than clinical, how the fit between those conflicts

         10   of interest rules and any alterations that might be

         11   recommended with fit.  And especially the Office of

         12   Research Integrity that has played a very primary

         13   role in this issue.

         14             In that regard, I also think a broad

         15   number of scientific societies have developed

         16   statements with respect to conflicts of interest,

         17   less than I would see happen, and it might be

         18   useful to collect those, assess those, and see the

         19   fit between some of the guidance to researchers and

         20   scientists in this area and how that fits with also

         21   their guidance with respect to human subjects

         22   protection.


                                                                      154

          1             CHAIRPERSON MARSHALL:  Thank you, Felice.

          2             Jonathan.

          3             DR. MORENO:  First a question for Mark or

          4   any of the lawyers who happen to be at the table. 

          5   And actually Alan's previous question helped me a

          6   lot and saved me a couple of minutes.  This is with

          7   respect to the status of an OHRP guidance I think I

          8   understand what that means, but just for the

          9   record, in the first instance a guidance from any

         10   federal regulatory agency.  A guidance is

         11   exhoratory; is that correct?  That is to say short

         12   of articulated and recorded as regulation and

         13   policy?

         14             DR. BARNES:  Two answers to your question,

         15   one in general answer and one is a specific answer

         16   about what we're recommending in this proposed

         17   letter.  In general, the federal guidance that does

         18   not have the status of actual regulation and has

         19   not gone through the process of the Administrative

         20   Procedure Act is basically information that is

         21   provided to regulated persons or entities in order

         22   to give them examples of the best practices in the


                                                                      155

          1   area.

          2             The legal effect of that adherence of the

          3   institution's or person's adherence, a covered

          4   person's adherence to those best practices would be

          5   a essentially to provide that person with the kind

          6   of safe harbor so that if they engage in those

          7   practices that are recommended, then they would not

          8   be subject to sanction for having done so okay.

          9             It does not me, however, that they can do

         10   something other than the guidance and they could

         11   still not be subject to regulatory sanctions but if

         12   they did adhere it would be a kind of safe harbor.

         13             In regard to what we recommend, I call

         14   your attention to -- and this was Elliot's

         15   insistence and it really was appropriate and I

         16   think everybody on the working group appreciated

         17   it.  On page four, the third full paragraph, Elliot

         18   was very careful that we recommend to the

         19   Department in the draft interim guidance that there

         20   be a very clear distinction between those things

         21   that must be done which are actual legal duties

         22   under the existing regulations, those things they


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          1   should be done, in which there is a moral duty to

          2   do them, and those things which might be done or

          3   could be done as examples of the fulfillment of

          4   either the moral and/or the ethical duties.

          5             And we really -- I think that the rhetoric

          6   of the guidance is not clear in the use of the

          7   conditionals and the operatives and all that, but

          8   it needs to be, and that was our recommendation.

          9             DR. MORENO:  Very good.

         10             The non to valued logic comes in handy

         11   when you're doing this kind of thing.

         12             That having been said, and I gather this

         13   goes to Dr. Rich's comment as well, under certain

         14   circumstances an enterprising plaintiff's attorney

         15   could, with respect to a grievance against a

         16   noncovered party, identify a guidance as what an

         17   element in a standard of care?  Would you say?

         18             DR. BARNES:  Yes, Jonathan, that's right. 

         19   I mean, that would be.  And the tighter the degree

         20   the more that the should use or must use in the

         21   guidance then the more persuasive that will be as

         22   the articulation of the standard of care.


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          1             DR. MORENO:  Thank you.

          2             Finally, one last point.  Or really a kind

          3   of rhetorical question or maybe a wishful thinking. 

          4   I thought I heard, a few minutes ago, Adil and Mark

          5   and perhaps as well the other members of the

          6   working group agree that what we are talking about

          7   here is significant conflicts of interest, not all

          8   prima facie troubling conflicts of interest, is

          9   that right?

         10             That being the case and without being too

         11   hopeful about this depending on how we filled out

         12   the content of a troubling conflict of interest,

         13   where we set the bar, and perhaps what levels

         14   financial levels were set and so for there might be

         15   room here for some consensus.  I'm not sure I'm

         16   right about that but clearly that's an area we need

         17   to look at, it seems to me, based on what I heard

         18   before that that seems to be an area we need to

         19   look at more closely.

         20             DR. BARNES:  I think that I speak for the

         21   working group when I say that the -- that we felt

         22   there should be thresholds and that where the


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          1   financial relationship that is reported is directly

          2   relevant to the research, but exceeds the

          3   threshold, there is a presumption that that is a

          4   troubling financial relationship.  One could adjust

          5   the thresholds either downward of upward depending

          6   on, you know, as a point of consensus or

          7   negotiation or whatever but that I think was the

          8   general feeling.

          9             DR. MORENO:   So the issue here might not

         10   be disclosure, that is to say, the full hangout

         11   route advocated by Adil or the partial hangout

         12   route advocated by others.  But it might rather be

         13   how we understand what we mean by the term

         14   "significant."

         15             Let me say one last thing.  I think that

         16   anything that we say about how any modification of

         17   the rules or introduction of the new rules could

         18   affect the conduct of research both from the point

         19   of view of the potential subjects, the

         20   investigators themselves, or the institutions is

         21   wholly speculative.  We have no idea how a change

         22   in the rules would affect what happens.


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          1             And I, for example, believe that it would

          2   have relatively little effect on the potential pool

          3   of subjects to have even a very detailed

          4   disclosure, but might cause my colleagues in the

          5   medical community a lot of cirrus in the beginning

          6   depending on how it actually worked out.

          7             DR. BARNES:  One brief response to that

          8   is, that not only the disclosure point, but on the

          9   other points about adopting the PHS guidelines

         10   across the board and disclosing institutional

         11   conflicts of interest over financial relationships

         12   as part as of the process, I can tell you that my

         13   personal experience in advising clients who are

         14   medical institutions is that adhering to those

         15   self-imposed guidelines has not created mass

         16   confusion on anxiety.  In fact, the use of

         17   thresholds across the board to all research is

         18   actually a late anxiety because at least it is

         19   introduced regularity you know and predictability

         20   into the process.

         21             CHAIRPERSON MARSHALL:  Margaret, you have

         22   the last question before we open the floor to our


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          1   ex-officio members.

          2   

          3             DR. BORWHAT:  I just wanted to concur with

          4   Abbey and her statements that advocates and

          5   community representatives are readily available to

          6   work on IRBs and I'm not sure that much of an

          7   outreach has been made to gain community

          8   membership.

          9             I also had a comment on the generic

         10   financial disclosure.  I think we're definitely,

         11   with this type of disclosure, shifting the burden

         12   to the patient and I'm not sure that that's where

         13   it should be.  And I think the essential elements

         14   similar to the informed consent as it relates to

         15   risk in the medical procedures, we ve comprised

         16   essential elements that are a part of the informed

         17   consent.  And I'm not sure that we can't come to

         18   some sort of working document with the same type of

         19   essential elements for financial disclosure.

         20             And at the very least with all the changes

         21   in the health care system and the different and

         22   very complicated financial arrangements that are


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          1   taking place, it at least would be an exercise of

          2   what is going on out there and how it appears to

          3   the public and to the potential participants.

          4             CHAIRPERSON MARSHALL:  Thank you,

          5   Margaret.

          6             I was remiss, I had Greg last on my list

          7   and then we open the floor to our ex officio

          8   members.

          9             DR. KOSKI:  Thank you, Mary Faith.  Just a

         10   couple of points.  The working group noted that of

         11   those regulations that are currently out there, the

         12   FDA has a set of retrospective regulations that

         13   really address only the validity of the data,

         14   that's their intent.  The PHS and the NSF

         15   regulations are prospective, but they are intended

         16   to protect the objectivity of science.  What's

         17   lacking is a set of specific guidelines or

         18   regulations for the protection of human subjects.

         19             The draft interim guidance that was posted

         20   on the web site to stimulate public discussion is

         21   crafted specifically in the context of the common

         22   rule for the protection of human subjects, the


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          1   purpose being to stimulate the discussion leading

          2   to a broad federal government policy for dealing

          3   with these issues in the context of protection of

          4   human subjects. 

          5             I think it is very important to not lose

          6   sight of that.  And I would say that with respect

          7   to the recommendation that we need to watch the

          8   confidentiality of the investigators as well, I

          9   would agree with that in broad terms, however, when

         10   it comes down to human research I think that an

         11   investigator who is going to engage in research

         12   while maintaining a financial relationship that

         13   poses a problem has an obligation to subjugate

         14   one's own claims to confidentiality to the

         15   protection of the individual subjects in that

         16   instance.  So I think that would need to be

         17   qualified.

         18             Having said that, I think it's critically

         19   important in this concept of managing the conflict

         20   of interest that we don't send anything to an IRB

         21   that isn't a problem.  There is enough that goes

         22   there anyway, so in your flowchart that would


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          1   direct certain items that basically have been

          2   deemed through a robust process for analyzing and

          3   managing conflicts of interest, you come up with

          4   something that's not a problem.  Well, that s not

          5   something that an IRB needs to know about.  The

          6   only thing, it seems to me, that an IRB should be

          7   dealing with are those issues that pertain to

          8   specific research projects in which there is an

          9   interest that could compromise the rights, the

         10   interest, the well-being of the research subjects,

         11   that's the only thing they need to know about and

         12   that's what their role should be.

         13             Finally, I would just like to address the

         14   issue that Bob brought up about FASSUP an AAU and

         15   Koger, I would say not only do we enjoy a

         16   collaborative relationship with those

         17   organizations, we relish that, and indeed have

         18   worked closely with them.  I regret, actually, that

         19   in the letters that came from those organizations

         20   there was a characterization of what was put up to

         21   stimulate public discussion as a guidance.  Because

         22   I think it unnecessarily sort of stimulates angst


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          1   because indeed this was a draft document that came

          2   from a public process that was put their only to

          3   stimulate discussion.  And indeed I think anyone

          4   who has been the following this recognizes that

          5   there is no rush in this instance to do something

          6   prematurely, but there is a need to move

          7   expeditiously toward addressing this issue.

          8             And I want to acknowledge openly the fact

          9   that all of these organizations are doing what

         10   they're supposed to be doing.  We have the AAU

         11   effort been made by Bill Danforth, FASSUP has

         12   issued policy statements on this.  The work that

         13   already many of the academic institutions, the one

         14   group that was headed up by Joe Martin at Harvard,

         15   another group that's being headed up by Mayo

         16   Clinic, Bill Wood.  I think this is all wonderful. 

         17   It's a demonstration of the commitment that they

         18   have toward resolving these issues.

         19             And as I said in the beginning of -- or at

         20   the end of my opening remarks this morning, we are

         21   destined to do this right together and that means 

         22   we are going to continue the process.  But make no


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          1   mistake about it, it must move forward and it must

          2   move forward in a timely fashion, because it is not

          3   something that we have time to waste.

          4             Every time there is another incident in

          5   the papers that puts another slam to the body of

          6   science we all suffer from that.  So let's keep it

          7   moving, that's all I ask.

          8             CHAIRPERSON MARSHALL:  Yes, very nice. 

          9   Thank you, Greg.

         10             Let me open the floor to our ex officio

         11   members.  If you could tell us when you ask your

         12   question or make your remarks who you are and what

         13   agency you represent.

         14             DR. RUBIN:  Philip Rubin, from the

         15   National Science Foundation and I really appreciate

         16   particularly Greg s comments at the end.  And I

         17   would like to respectfully disagree in part with a

         18   portion of them and get back to the issue of

         19   practice.  What we've been seeing recently, I agree

         20   that things need to move ahead and I agree with

         21   pretty much almost everything Greg said, but we

         22   have been saying that guidelines are being


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          1   interpreted as regulations, inappropriately

          2   interpreted as regulations and we need to somehow

          3   counter that, that that's not how they are

          4   intended.  So that's the practiced effect and we're

          5   seeing it coming up more and more and more.  And on

          6   that issue I would also suggest that if you're

          7   going to harmonize the PHS with NSF we're real

          8   happy about the way things are working; you're

          9   apparently not so you're going to bring us

         10   potentially aboard.

         11             We have a very good conflict of interest

         12   policy and we strongly support it.  It's the

         13   guiding principle of everything the protection of

         14   participants in research that's our guiding

         15   principle and I think you should consult with our

         16   general counsel Paul Rudolph and Anita Eisenberg

         17   and engage them in the process a little bit more

         18   actively to make sure that any potential

         19   harmonization doesn't adversely pull our

         20   nonclinical research into that domain, and then get

         21   more stuff bogged down, adversely, I think,

         22   affecting the clinical stuff.  Because what's going


                                                                      167

          1   to happen is that the IRBs are going to start

          2   seeing COI's from a whole bunch of stuff that they

          3   should not see, dealing the processes which we

          4   don't want to do.

          5             We are really looking at trying to protect

          6   the participants not bogging down the process so

          7   that it gets so crippled that the larger goal is

          8   missed.  Thank you.

          9             CHAIRPERSON MARSHALL:  Thank you.

         10             MR. MATHER:  John Mather, with the VA. 

         11   I'm not sure if I'm not going to be just a bit

         12   redundant here given what Philip said and Jonathan

         13   was asking.  I do think that it's an important

         14   thing to be clear on the word "guidance."  I'm

         15   reminded of Humpty Dumpty, who was asked by Alice,

         16   you know, what do you mean a word and he says,  I

         17   mean it what it means to mean" in essence.  And I

         18   think it's very important, there's a difference

         19   between a set of ethical principles and the Belmont

         20   Report which just about everybody uses, but that's

         21   far from being a regulation or put in sort of a

         22   mandated guidance and the other end of it being


                                                                      168

          1   taking a set of principles which maybe the FDA may

          2   have to do given the way their construct is to put

          3   it in fact into regulation.

          4             For us in the VA where approximately 20 to

          5   25 percent of our money comes from the NIH meaning

          6   PHS it will certainly be a driving force whatever

          7   is written into this guidance.  I don't know where

          8   I have a solution to it.  I think there is a need

          9   to push ahead.  I think there is a need to push it

         10   out there, but I think there is a very clear need

         11   to be very clear on what this word "guidance"

         12   means.

         13             CHAIRPERSON MARSHALL:  Thank you.  And I

         14   think Greg would like to respond to that.  And I do

         15   just want to say that we acknowledge and I have

         16   certainly heard this overwhelming message regarding

         17   what guidance means and what the implications of it

         18   are.  So thank you very much for saying that.  We

         19   hear you.

         20             DR. KOSKI:  Indeed I will reiterate that. 

         21   I want to also point out that the working group, it

         22   was an HHS working group by and large that crafted


                                                                      169

          1   the draft interim guidance, struggled with what to

          2   call this kind of thing in the context of the

          3   Secretary's announcement that the Department would

          4   issue guidance, but that it seemed pretty immature

          5   to issue guidance that would be precluding of the

          6   broader discussion, particularly of some of the

          7   longer term issues.  And around institutional

          8   relationships in particular because that is new

          9   territory.  And we actually considered using the

         10   words, "points to consider."  As an alternative we

         11   ultimately didn't use that because it had been used

         12   in a specific sort of context of by FDA.  And it

         13   turned out to be the easiest way to get a draft

         14   there was to call it this interim guidance that we

         15   felt was an appropriate thing, and, of course, it

         16   was just a draft document.

         17             Going forward I think, you know, clearly

         18   it is something that we want to be very sensitive

         19   to.  I'm proud to say we have not issued a new

         20   guidance since I've been in my position, but we

         21   want to, again, keep it moving forward.

         22             It may well be that crafting it in some


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          1   way as a points-to-consider document or other

          2   terminology that would be useful to the community. 

          3   That's what we want to do is to have something that

          4   is useful to the community that helps us move

          5   towards the shared goals that we have.  And I think

          6   those comments were very helpful from the

          7   organizations that sent them in, and we look

          8   forward to that.  We also endorse the notion of

          9   having another follow-up conference to, again bring

         10   together the stakeholders to further this

         11   discussion.  So we look forward to all of that and

         12   I know that all was intended it in a most

         13   constructive fashion.

         14             CHAIRPERSON MARSHALL:  Robert.

         15             DR. RICH:  A very brief comment.  I think

         16   if we simply called it "framing the issues" instead

         17   of "draft interim guidance" there would not have

         18   been this controversy.  I think that's what in

         19   actual fact most of the content is simply framing

         20   the issues.  And certainly the content of Mark's

         21   working group was framing the issues and not

         22   presuming the answers.   And I think that that's


                                                                      171

          1   where we are right now is framing the issues.

          2             CHAIRPERSON MARSHALL:  Let me ask whether

          3   there are ex officio members or members of the

          4   public who have comments?  Okay. 

          5             I am going to give Greg and Abbey briefly,

          6   briefly a response to that and then please go ahead

          7   and stand in line because the floor is yours.

          8             DR. KOSKI:  Bob, I would just say we don't

          9   consider it a controversy we consider it a

         10   dialogue.

         11             DR. MEYERS: I don't think you should be

         12   framing the issues.  You know, I spent ten years on

         13   the recombinant DNA Advisory Committee and the Gene

         14   Therapy Subcommittee where everybody had to conform

         15   to points to consider, and they didn't conform and

         16   we ended up a tragedy out of all that.

         17             I think we need something here that says

         18   here are the rules.  If you don't obey the rules,

         19   you're not going to be able to do research.  And I

         20   think that the opposition of the societies makes

         21   institutions look very bad, makes IRBs look like

         22   institutional protection committees instead of


                                                                      172

          1   patient protection committees.

          2             CHAIRPERSON MARSHALL:  Thank you.

          3   

          4             MS. LEE:  I m Bonnie Lee from the Food and

          5   Drug Administration.  Without applying the

          6   financial disclosure guidance to IRB staff, that is

          7   completely missing from yours.  And I m not

          8   advocating that it be added, but I think there

          9   needs to be some conscious consideration as to

         10   whether you would want this to apply to IRB staff,

         11   if it were to apply to IRB staff, how, for example

         12   would you want similar disclosures in the informed

         13   consent form if IRB staff had some significant

         14   financial interest, or would you want them to

         15   somehow not be involved in some way in those

         16   meetings at which it was reviewed.  That would be

         17   very helpful.

         18             Also from FDA's perspective we tend to be

         19   very clear as to when we require something it s a

         20   regulation.  We follow good guidance practices when

         21   we issue guidance to solicit public comment and

         22   perhaps that's another thing you need to consider


                                                                      173

          1   as well if you really want is to apply in all

          2   cases.  As a requirement, at least from our

          3   perspective that would require some regulatory

          4   change.

          5             If this is intended, however, for good

          6   practices and advice then that becomes some form of

          7   a guidance document, and that's another judgment

          8   that clearly I think you need to consider.  Thank

          9   you.

         10             CHAIRPERSON MARSHALL:  Abbey has a

         11   question for you.

         12             DR. MEYERS:  FDA's requirement on conflict

         13   of interest it's like -- it's the most amazing

         14   thing I've ever seen.  It basically says that the

         15   scientist who is being paid by the company has to

         16   reveal to the company whether he has a financial

         17   interest in this product or owns stock in the

         18   company or whatever.  And then they put it in the

         19   file and they keep it in that file until they

         20   submit the new drug application. 

         21             So the conflict of interest is hidden from

         22   view until the whole process is finished.  And


                                                                      174

          1   after all the research is done they still keep it

          2   in the file.  They don't give FDA the file unless

          3   you ask for the file.

          4             So a person could have a tremendous

          5   conflict of interest and it never sees daylight. 

          6   Now how did this come about, why is it this, this

          7   way?

          8             MS. LEE:  I'm not an expert on that rule,

          9   but my understanding is that the whole purpose

         10   behind it is that when the financial interests

         11   reach a certain threshold amount that is reported

         12   to us along in the marketing application.  We can

         13   look at that significant interest if there is one

         14   disclosed, look at the data associated with that

         15   interest and make a determination as to whether we

         16   need to look at the conduct of the particular

         17   study, for example, more carefully, to see if in

         18   fact it honestly reflects the research that took

         19   place.

         20             It's a very different purpose in our

         21   regulations than what you're trying to accomplish

         22   here.  And so I think to look at those regulations


                                                                      175

          1   as a way of protecting subjects wold probably be

          2   inappropriate.  That was not their intent.  It's

          3   done retrospectively as you say.

          4   

          5             CHAIRPERSON MARSHALL:  Bob and then Susan.

          6             DR. R. LEVINE:  The discussion this

          7   morning on the subtle nuances and the distinctions

          8   between guidance and regulations doesn't address

          9   one major problem and that is that there is a

         10   perception out there that OHRP might act very

         11   forcefully on things that are not even guidance. 

         12   Things that were never articulated until an

         13   institution was suspended.

         14             One case in point is the Virginia

         15   Commonwealth incident where everyone out there

         16   thinks that the reason that research was suspended

         17   there was enforcement of a policy that no one had

         18   ever heard of before, the secondary research.  What

         19   I think one problem is that OHRP and its

         20   predecessor never get clear about what were simply

         21   observations and what was the reason they suspended

         22   an institution.


                                                                      176

          1             But another thing is that you have to be

          2   aware of the fact that there is extreme sensitivity

          3   out their that anything that's posted as a even a

          4   solicitation of comment that OHRP is likely to fan

          5   the flames of paranoia that exists out their. 

          6   Thank you.

          7             DR. KOSKI:  Having been an IRB chair for a

          8   decade, I'm sensitive to that.  Thank you very

          9   much.

         10             MR. MATHER:  I just want to come back on

         11   one thing that has been troubling me since it's

         12   been said and that's that this has been an exercise

         13   in framing the issues.  To me it's more than that

         14   that's been going on here.  I think we're trying to

         15   frame some organizational principles that will have

         16   a little bit of teeth in them than just say, well,

         17   let's frame the issues folks, and let's have a nice

         18   little chitchat about them.  

         19             To me I sense as a need to move this thing

         20   a little bit further and whether you call it best

         21   practices or quasi-regs or something, maybe the

         22   term "organizing principles" or "organizational


                                                                      177

          1   principles" gets away from sort of going one way or

          2   the other.  I think we need some best practices. 

          3   We need some frameworks that can be put out there

          4   and say, you know, folks, take them or leave them,

          5   but these are some organizing principles and the

          6   ways in which you can do this.  And, in fact, you

          7   know, it will be helpful to you.

          8             CHAIRPERSON MARSHALL:  Anyone from the

          9   public or I know Susan s hand is up, but I want to

         10   make sure the folks from the public have a chance

         11   to speak.

         12             MS. CHAMBERS:  Hello.  My name is Cheryl

         13   Chambers and I live in Richmond, Virginia.  Three

         14   weeks ago I got the Seattle Times and on the front

         15   cover is a picture of my sister.  I was a donor for

         16   her for two bone marrow transplants and she's

         17   holding my new baby girl that I had to go out there

         18   for the second transplant with the new baby.

         19             We were not informed about the fatalities

         20   of the consent on the consent forms.  My sister

         21   chose the T-cell depletion.  We had undue

         22   influence, as you all said, to do this.  I remember


                                                                      178

          1   sitting in the protocol meetings and saying, if you

          2   had cancer, which transplant would you use?  And

          3   they all assured us that the T-cell transplants had

          4   the highest success rate.

          5             We could have gone anywhere in the country

          6   and we went to the Fred Hutchinson Center because

          7   it had the highest success rate in the world at

          8   that time.  My sister lived in Alabama and I lived

          9   in Virginia.  I left two teenagers and a husband

         10   and went there for four months both times a total

         11   of eight months.  When she signed this T-cell

         12   depletion thing it was a fatal thing because at the

         13   time they already had nine patients in the program

         14   all nine relapsed due to the T-cell depletion.  She

         15   signed her life away.

         16             It was not stopped then.  The doctors

         17   doing the T-cell depletion had stock in a biotech

         18   company.  This company was sold for $294 million. 

         19   These doctors became multimillionaires because of

         20   my sister.  It wasn't stopped in 1985 and '86 after

         21   she died and '87.  It continued on and 10 more

         22   patients were given this protocol even though other


                                                                      179

          1   doctors in the hospital said, "please stop this,

          2   please stop this," and all 20 patients died.

          3             I want something to be done about this. 

          4   As a sibling I cannot sue in the state of

          5   Washington, so I m here to plead my case.  These

          6   are real people I had to photo albums of both

          7   transplants and other patients there that died

          8   because of this.

          9             Also the financial investment, I think

         10   when you show this little form that you had on the

         11   chart, if you leave it down to the patients to make

         12   the final questions.  When you get patients there,

         13   all of us had education; I have a master's in math,

         14   it doesn't help trying to digest all of these

         15   abbreviations you all use up here sometimes.  But I

         16   feel I was educated my sister Becky Wright's

         17   husband owned the only drug store in the little

         18   country town in Alabama.

         19             His brother was a pharmacist and his dad

         20   was a doctor there in the town for 62 years.  We

         21   felt like we were educated, we knew what we were

         22   doing, but when someone is sick you can't sit there


                                                                      180

          1   and say, do you have any financial investment in

          2   this?  If you do let us know; ask any questions

          3   about it; your mind is not in that framework to do.

          4             What I would like to see done is all have

          5   financial disclosure immediately.  In the world

          6   today and the federal workers that we have here,

          7   you have to give your financial disclosures in

          8   everything that you do.  My husband is a minister

          9   and we get audited just about every single year and

         10   we have to put down everything that we own.  Why

         11   can't these hospital's doctors have to do that and

         12   the hospital institutions have to do the same

         13   thing.

         14             The Fred Hutchison Center get $143 million

         15   for federal dollars every single year.  Why can't

         16   they have this disclosure written up?  I appreciate

         17   all the work that you've done and thank you for

         18   having me here today.

         19             [Applause.] 

         20             CHAIRPERSON MARSHALL:  We appreciate you

         21   very much.  Thank you for coming. 

         22             Do you have any specific questions that


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          1   you would like to ask besides making your comments?

          2             Ma am in the back.  

          3             AUDIENCE PARTICIPANT:  [Off mic.]  No,

          4   just work as hard as you are right now.  I would

          5   like to see some regulations and not just

          6   guidelines and not just issues.

          7             CHAIRPERSON MARSHALL:  Come up to the

          8   microphone so that we can record your comments

          9   please.

         10             AUDIENCE PARTICIPANT:  Would you have her

         11   repeat her name.

         12             CHAIRPERSON MARSHALL:  Yes.  Could you

         13   repeat your name?

         14             MS. CHAMBERS:  My name is Cheryl Chambers,

         15   I'm there in Richmond, Virginia.

         16             I would like to see not only guidelines or

         17   issues, I would like to see some regulations. 

         18   There are some review boards out there at all the

         19   hospitals advisory review boards, almost all the

         20   hospitals we've investigated since this, do not

         21   allow their doctors to own stock in the companies. 

         22   At the Fred Hutchison Center nothing has been said


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          1   about this.  They continue to become

          2   multimillionaires.  They won't even admit to how

          3   much stock they own.

          4             One of the Nobel Prize winners that did

          5   this project donated his money from the Nobel Prize

          6   to the hospital, but he won't admit how much stock

          7   he still owns.

          8             For these 20 patients to die once you

          9   start a program you cannot get out of it because

         10   they start a total body chemotherapy and radiation

         11   and once you start that, you have to have the

         12   transplants or you will die.

         13             My sister went through agony, I went

         14   through agony.  I had both kinds of transplants. 

         15   They never brought this up where you're doing

         16   direct medical research.  They said, oh, a

         17   transplant you're going to have two or three holes

         18   in your hip.  The second transplant was like that I

         19   had very few bruising and very little pain.  The T-

         20   cell depletion, and I would like someone to

         21   investigate this, I had 22 holes placed in my back,

         22   I had pressure bandages and tied to the bed when I


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          1   first woke up.  I couldn't sit down for over a

          2   month and I don't know whether they took out more

          3   bone marrow than necessary to do their testing or

          4   procedures or whatever they were doing with this

          5   DNA biotech company.

          6             Once it got done we didn't mind dealing

          7   with it because I knew my sister would probably

          8   have a good chance of living.  She did and all this

          9   time we bragged on the Fred Hutchison Center, the

         10   Swedish hospital there, we sent patients out there

         11   because the work out there is extraordinary.  It

         12   was just for these few doctors and other doctors

         13   tried their best to get it stopped and it took year

         14   after year after year to get it stopped.  And I

         15   want to thank the investigators for finding this

         16   all out for us.  Thank you.

         17             CHAIRPERSON MARSHALL:  Thank you very

         18   much.

         19             Abbey and then Greg has asked to speak. 

         20   Any other members of the public or our ex officio

         21   membership who would like to say something before

         22   we close for lunch?


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          1             DR. MEYERS:  It's just that this is

          2   another body slam to research.  These kinds of

          3   revelations I think that the institutional

          4   community doesn't understand that if it wouldn't

          5   look good on 60 Minutes it shouldn't be done.  And

          6   that should be the measurement that you've got. 

          7   And something like this Fred Hutchison Center, this

          8   series of newspaper articles, its been

          9   extraordinary.  But it just comes from the heels of

         10   how many other institutions with their revelations. 

         11   That's why we can't wait, we have to put something

         12   in place as soon as possible.

         13             CHAIRPERSON MARSHALL:  Judy.

         14             DR. SEIGEL:  I would just like to comment

         15   on a couple of things.  I think within the workings

         16   of the committee one of the primary things that our

         17   working group that we discussed was really not

         18   necessarily only the financial relationships but to

         19   focus back on the protection of human subject.  And

         20   I think probably what's happened over years and

         21   years is maybe that has not been the focus of the

         22   primary deliberations.


                                                                      185

          1             And so I think as we really came through

          2   our deliberations, what I think this guidance may

          3   do is focus people back on what the issue is.  It's

          4   not necessarily how much stock you have someplace,

          5   it's does the existence of that relationship in any

          6   way compromise the protection of this patient?  I

          7   think that's really what we were trying to focus on

          8   in bringing everything back to what is the

          9   question, and the question is what is the

         10   protection of human subjects.

         11             I think to a point earlier, actually I

         12   think Margaret you expressed the focusing on the

         13   informed consent process not to document.  I think

         14   that was another very large discussion that we had

         15   which is:  what is the process?  Do we really know

         16   what the process is?  Is the process really

         17   executed with the attempt to protect the human

         18   subjects or to dump information?  And you're right,

         19   there are elements of informed consent.  If you try

         20   actually to find them in most informed consents

         21   even those of us who actually are involved in

         22   writing them, it becomes very difficult.


                                                                      186

          1             And so as we were discussing this the

          2   issue is, again, I think one of the points that

          3   Mark brought up, is it to eliminate conflict of

          4   interest, to manage conflict of interest, and what

          5   is it that a patient subject needs to know that

          6   will help them make that decision as they are

          7   trying to digest all of the rest.  So I think that

          8   was really the other main thing which is, how do

          9   you tell someone what exists so it can help them

         10   make their decision and protect themselves.

         11             DR. MEYERS:  Do you think the Mercy

         12   Hospital paragraph is the right way to do it?

         13             DR. SEIGEL:  I think what we try to do is

         14   give a stab at it, because, again, I think we get

         15   to that part actually quite late in the day.  I

         16   think it was the intent to basically tell the

         17   patient or subject that in fact there is a process

         18   going on that is intended to protect your rights.

         19              Now, maybe that paragraph is not the be

         20   all and the end all, but the intent of that

         21   paragraph is to tell the patient to synthesize what

         22   is going on in the background a little bit.  It was


                                                                      187

          1   an intent really to give a little bit of hopefully

          2   information about what's going on in the

          3   background.

          4             Now, again the discussion that I think is

          5   still up is, what is the end of that and are their

          6   other ways to actually give some more detail?  But

          7   mostly it was to frame for the patient the fact

          8   that there is this whole thing going on in the

          9   background.

         10             CHAIRPERSON MARSHALL:  This is your lunch

         11   time that your cutting into.  But it is an

         12   important discussion so I don't want to preclude it

         13   will cut short.  Sandy.

         14             DR. CHODOSH:  I think a major issue that

         15   we have to face at some point by this committee or

         16   somewhere is, what is the informed consent form? 

         17   And, finally, we have to decide if we intended to

         18   be a contract or whether we intended to be informed

         19   consent, and we have not decided that.  And if you

         20   read most informed consent forms they are so full

         21   of junk legalese, et cetera, that even the

         22   investigators don't understand that I think that


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          1   that is just a wrong way for us to have gone and in

          2   trying to put something more into this, we were

          3   trying to put something into it which would allow

          4   the subject to understand what is going on and what

          5   is being done, but not overwhelm them again with

          6   all this junk.

          7             Frankly, most of it is not to their

          8   interest at all and we have to get away from the

          9   informed consent form and back to the process and

         10   then we would resolved some of these issues.

         11             CHAIRPERSON MARSHALL:  Thank you, Sandy,

         12   well said.  Alan.

         13             DR. FLEISCHMAN:  I think a response to

         14   both the comments that have been made and some of

         15   the concerns around the table, unpacking with some

         16   examples, examples that may even have some bases in

         17   reality, how this process that we're proposing my

         18   actually prevent harm to research subjects if it

         19   worked well.  That might be very compelling in the

         20   argument.  Because I think some of the concern

         21   that's been voiced is that the subjects are not

         22   going to be knowledgeable enough, based on the


                                                                      189

          1   Mercy Hospital paragraph, to ask the right

          2   questions.  And then, of course, there's also the

          3   concern about who they're asking and whether

          4   they'll get the right answers.

          5             So I think if we could be reassured

          6   through specific example, exploration, at least for

          7   this observer it would be a much more compelling

          8   case.

          9             CHAIRPERSON MARSHALL:  And, Alan, I do

         10   believe that you made room for that and actually

         11   proposed that the academic societies and others

         12   helped flesh those out.

         13             DR. R. LEVINE:  Alan  Fleischman has made

         14   a very interesting and important proposal.  I want

         15   to suggest that it might be a useful exercise for

         16   us to have a long consent form put on the table in

         17   front of us and to have people around the table say

         18   what they want to take out.  Because that's the way

         19   you're going to flesh out the positions of those

         20   people who insist, no, it's got to stay in.  But if

         21   we can find a way to take out all of what Sandy

         22   quite properly calls "junk," we would have done a


                                                                      190

          1   great service to the community.

          2             CHAIRPERSON MARSHALL: Greg.

          3             DR. KOSKI:  Thank you.  Bob, that's an

          4   interesting suggestion.  I will sort of give you

          5   some previews that in fact we were anticipating

          6   putting a discussion of the consent process on the

          7   agenda for the next meeting so we might get a

          8   chance to go through that exercise.  Yes.

          9             DR. R. LEVINE:  I'm not talking about the

         10   process, I'm talking about the form.  The form is

         11   not informed consent.

         12             DR. KOSKI:  I understand that, certainly. 

         13   However, the form is part of the consent process

         14   and I think the exercise that you suggest is one

         15   that would be very interesting.  But let me go back

         16   to that main topic here.

         17             Alan, you asked for examples.  I can think

         18   of few examples that could be more compelling than

         19   the story then we just heard from Ms. Chambers.  I

         20   think that it gives an example of where the process

         21   can clearly go awry.

         22             Now whether or not in such a situation


                                                                      191

          1   anyone ever does anything wrong is almost

          2   irrelevant in some respects, because, you know, the

          3   perception, the damage that can be done to the

          4   scientific process and the public trust in that

          5   process results regardless of whether or not.  So

          6   the harms a very real.  So we need to be sensitive

          7   to that. 

          8             In the draft interim guidance that's up,

          9   there are some specific examples that are given of

         10   where in a human research study an individual

         11   investigator, okay, is most likely perhaps to --

         12   not inclusive -- but most likely to do harm or at

         13   least be in a position to do harm.  Such as in the

         14   identification, recruitment, and enrollment of

         15   patients in the trial as part of the consent

         16   process, such as actually adjudicating an adverse

         17   event to make a determination as to whether or not

         18   that event was in some way related to the actual

         19   test article.

         20             Participation in a safety monitoring board

         21   would similarly be inappropriate.  We can easily

         22   identify certain areas where if an individual has a


                                                                      192

          1   conflict of interest, they probably should not do

          2   those things, because they could still participate

          3   perhaps in other ways without doing damage to

          4   either an individual themselves or the process.

          5             I want to go very much on record as saying

          6   I don't think there's anything wrong at all with

          7   our research institutions or with companies making

          8   money as a result of their discoveries.  I don't

          9   think there's anything wrong with an investigator

         10   getting lots of grants or other kinds of financial

         11   compensation for the work that they do.  That's all

         12   fine, but we can't do those things at the cost to

         13   the individual research subjects.

         14             Now, many institutions in this country

         15   have already adopted policies, many of them have

         16   been in place for decades, hey, that simply say we

         17   recognized this is a problem so we're not going to

         18   do it.  Okay.

         19             And I can tell you some of those are among

         20   the most successful research organizations in this

         21   country.  It's not as though it impairs the

         22   research process.  In fact, I would say quite the


                                                                      193

          1   contrary, I think it promotes the research process

          2   because you don't end up in a position of having to

          3   apologize for a perception or for for actual harms

          4   that are done in the long run.

          5             I've already personally gone on record, at

          6   least twice, publicly, saying that I simply don't

          7   believe that an investigator in a study should hold

          8   equity interest in a company that they are doing

          9   the research for.  That's one of the instances. 

         10   And you talked about 5 percent, well, if you can do

         11   the math.  Let's say your 5 percent in a start-up

         12   company, okay, is 10,000 shares worth 50 cents a

         13   share.  Well you've got $5,000 up there. 

         14             If it works and that turns into 10,000

         15   shares valued at $80 a share, which is not an

         16   unrealistic prospect, you're looking at nearly a

         17   million dollars.  Okay.  

         18             So in those instances the stakes are so

         19   great, okay, that it seems to me that we simply

         20   can't allow that.  But, of course, that's a

         21   personal opinion and I've stated it very clearly.

         22             As I said though, that does not mean that


                                                                      194

          1   the individual investigator need give up the

          2   financial rewards that can come with discovery. 

          3   Indeed investigators may spend 10, 15 years

          4   developing something that ultimately goes on to

          5   become a successful product.  Should they be not

          6   denied the benefits of having created and carry

          7   that work forward?  No, I don't think so.  But,

          8   they can enjoy that without participating in those

          9   roles that could lead -- put them in a conflicted

         10   position and indeed could ultimately, whether

         11   anything goes wrong or not, undermine the trust and

         12   the integrity in the research that ultimately leads

         13   to the success of the product.

         14             And, again, we see many institutions

         15   simply say now, and investigators, we're going to

         16   have someone else do this research because if it

         17   works we don't want there to be any question about

         18   the fact that it worked because it was done by

         19   people who didn't care whether or not it worked. 

         20   And I think that's an important place to end up in

         21   all of this discussion, which is going to go on for

         22   a time.


                                                                      195

          1             Let me reassure everyone that neither

          2   OHRP, this is not an OHRP initiative, of course,

          3   but neither OHRP nor the Department, nor, would I

          4   say, the federal government in general, has any

          5   interest in rushing this to forego foregone

          6   conclusions.  We want this to be a constructive

          7   dialogue, and as I said before, we will all benefit

          8   from the outcome.  Thank you. 

          9             CHAIRPERSON MARSHALL:  Thank you, Greg.

         10             Kate.

         11             MS. GOTTFRIED:  Well, we are just about

         12   ready to wrap up and I just wanted to say one

         13   thing, first of all of to the group overall, that I

         14   think that the workgroup did a phenomenal job.  I

         15   am so impressed with the work that has been

         16   accomplished.

         17             [Applause.]

         18             MS. GOTTFRIED:  And I want to especially

         19   thank Mark Barnes for reflecting what was said

         20   during the day the 21st and all the work up until

         21   that point.  Because I think we re all overly

         22   impressed with the presentation.


                                                                      196

          1             Having said that, I want to say one other

          2   comment based on what was described to us with

          3   respect to the scenario at the Fred Hutchinson

          4   Center.  And that is, we did talk at the workgroup

          5   committee meeting about where the onus is with

          6   respect to disclosure.  That issue did come up, we

          7   thought about it, and I want to reinforce for my

          8   own prospective and my own work in a variety of

          9   capacities that the onus cannot be simply put on

         10   the patient.  That we have to come up with the

         11   system that's mindful and considerate of the fact

         12   that patients can be compromised because of the

         13   situation that they're in; the ordinary patient can

         14   certainly be compromised; the above average patient

         15   can easily be compromised and that to insist that

         16   the patient consider and deliberate based on an

         17   informed consent and then ask the appropriate

         18   questions is in fact a very large burden and

         19   responsibility that I think we have to come to some

         20   sort of understanding as to how to reconcile the

         21   issue.

         22             CHAIRPERSON MARSHALL:  Thank you, Kate. 


                                                                      197

          1   Those were wonderful last words for us to wind up

          2   this session.  And we will be back promptly at 1:30

          3   to begin the discussion on genetics.  Thank you

          4   all.

          5             [Whereupon, at 12:35 p.m., the meeting was

          6   recessed to be reconvened this same day at 1:30

          7   p.m.]

          8   

          9   

         10   

         11   

         12   

         13   

         14   

         15   

         16   

         17   

         18   

         19   

         20   

         21   

         22   


                                                                      198

          1                 A F T E R N O O N   S E S S I O N

          2                               [Time noted:  1:45 p.m.]

          3             CHAIRPERSON MARSHALL:  It is time to

          4   reconvene.

          5             Welcome all of you who have joined us who

          6   weren't here for our very productive morning.

          7             Greg is reminding me to let you know that

          8   we have not foregone to Helsinki discussion, we

          9   will have it later on this afternoon.  There will

         10   be ample time for it.  And thank you, Greg, for

         11   being so gracious as to allow us to be flexible

         12   with the schedule.

         13             It's my distinct pleasure to have Francis

         14   Collins join us today.  And he is going to do a

         15   yeoman's duty, I think we're putting him to work.

         16             Dr. Collins, as you know, is the director

         17   of the Human Genome Research Institute at the NIH. 

         18   He is going to begin our discussion by laying out

         19   for us a framework of current issues in genetics

         20   research that he thinks bear the committee's

         21   attention.  And then he is graciously going to

         22   moderate our panel discussion that will follow on


                                                                      199

          1   the question of whether family members or third

          2   parties should themselves be subjects of a

          3   protocol, and if so, whether informed consent can

          4   be -- should be obtained by an investigator to

          5   retain private information about family members or

          6   third parties.

          7             So we look forward to as fruitful an

          8   afternoon as we had a morning.  And, Dr. Collins,

          9   the floor is yours.

         10             DR. COLLINS:  Thank you very much.  I am

         11   really pleased to have a chance to come and meet

         12   with this committee because I have great hopes for

         13   what you're going to accomplish in the coming

         14   months.

         15             My point, to cut the chase of this

         16   presentation, is to say to you that I believe there

         17   are a number of areas of pressing importance in

         18   genetics research where there is considerable

         19   uncertainty on the part of IRBs researchers and

         20   members of the public about exactly how we ought to

         21   proceed.  And that while those things have been

         22   getting discussed and various conclusions have been


                                                                      200

          1   drawn in an ad hoc bases, there really has not been

          2   the kind of gathering that we have here this

          3   afternoon, to consider those issues by a group that

          4   has been charged to take them on and to make

          5   recommendations that will have a profound

          6   consequence for the future of the way that research

          7   is carried out.

          8             And so if you read USA Today and you

          9   noticed that I said today was a very important

         10   meeting.  I meant it.  This is a very important

         11   meeting.  I will not come to you with a lot of

         12   answers.  I have, like most people, some opinions,

         13   but I think most of the issues that I want to raise

         14   with you are not those for which easy answers can

         15   be obtained.  Just the same, I believe that

         16   together we can find our way through this pathway

         17   in a fashion that encourages research but protects

         18   the interests of those who participate in research

         19   which is, of course, our most important charge.

         20             What I want to do in this presentation is

         21   to give you a quick snapshot of the rate at which

         22   genetics and genomic research has progressed over


                                                                      201

          1   the course of the last two or three years,

          2   especially, and to point out a number of ways in

          3   which research involving genetics has changed its

          4   character as a consequence of the ability to do

          5   things that previously we just didn't know how to

          6   do.

          7             And then I want to pose for you five areas

          8   of where I believe there is considerable need for

          9   clarity and clarification, all of which I hope our

         10   areas that this committee might be able to make

         11   some useful contributions to.  One of them will, in

         12   fact, be this issue of obtaining consent from

         13   family members in pedigree research, but I'm not

         14   going to dwell too heavily on that because that

         15   will be the subject for the panel which follows

         16   after my presentation.  And you have a number of

         17   distinguished folks prepared to talk explicitly

         18   about the issues and then we'll have a chance for

         19   discussion amongst the committee and after that

         20   public members from what I understand from your

         21   chairperson. 

         22             So I don't want to preempt that by going


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          1   too heavily into that topic, but I will touch upon

          2   it.  So without further adieu certainly genomic and

          3   genetics is getting more into the public

          4   consciousness than it used to be.  There are so

          5   many cartoons out there that you could do a whole

          6   talk just based on them, and I think that's good. 

          7   Because it used to be pretty hard to find these.

          8             [Laughter.] 

          9             DR. COLLINS:  And now we're overwhelmed

         10   and here's one from a couple of months ago.  Well,

         11   why are we doing the genome project anyway?  It's

         12   important to remember the reasons that have led us

         13   to this particular juncture.  And while my computer

         14   is trying to find the next image -- there it is. 

         15             We are after all engaged in this effort to

         16   try to understand medical conditions.   Genomic may

         17   tell us a lot about other things but the major

         18   motivation for the genome project was a medical

         19   one, and, in fact, we are making considerable

         20   headway in many directions in that regard.  For

         21   single gene disorders like cystic fibrosis where

         22   the genetics component is very powerful we have


                                                                      203

          1   essentially identified most of the disorders that

          2   are inherited in that fashion to the gene level

          3   albeit, of course, that's just the beginning of the

          4   effort to try to use that information for

          5   therapeutic purposes.

          6             And we are making headway in the middle

          7   category here of conditions like adult onset

          8   diabetes that are partly environmental and partly

          9   hereditary and where the hereditary influence are

         10   much messier than they are for something like CF. 

         11   And even for infectious diseases, we are certainly

         12   learning that hereditary factors can help us a lot

         13   in understanding what happens after an exposure and

         14   using the information to develop new ideas about

         15   therapies is one of the more exciting developments

         16   in the treatment of infectious disease.

         17             So genetics is about all disorders, but to

         18   have this come true, to have those yellow

         19   components of these pie charts and the red

         20   components understood, we're going to need a lot

         21   more research than we currently have had, and hence

         22   the importance of considering how that research


                                                                      204

          1   ought to be done.

          2             The genome project has been underway now

          3   for 11 years in the U.S.  The NIH is the agency but

          4   this is an interimational effort involving many

          5   countries and many laboratories that I have had the

          6   privilege to lead.  And over the course of the last

          7   couple of years, a great deal of progress has been. 

          8   But it didn't just start a couple of years ago. 

          9   The projects focused its first five or six years on

         10   developing maps of chromosomes, genetic and

         11   physical maps, which were themselves of enormous

         12   utility in terms of mapping disease genes to their

         13   appropriate location on chromosomes.  And then we

         14   were able thanks to advances in technology and

         15   particularly to the creative juices of a host of

         16   genome center directors to move forward this

         17   timetable for sequencing the genome which

         18   originally had been targeted for 2005.

         19             In fact, in March of '99 when the largest

         20   genome centers got together to discuss the

         21   possibilities, we had finished about 15 percent of

         22   the genome, as you can see here in this cartoon of


                                                                      205

          1   the various human chromosomes most of the territory

          2   you'll note here was untouched at that point.  But

          3   thanks to a very significant ramp up that was

          4   organized at that point, and a lot of investment

          5   from the NIH and the DOE and our partners

          6   interimationally, it was possible in the space of

          7   15 months to go from that to that.  And if you just

          8   notice the differences there, that's an awful lot

          9   of territory that got covered, sequencing a

         10   thousand base pairs a second, seven days a week, 24

         11   hours a day to get to that point.

         12             So there was a big announcement last

         13   summer about that, and we were all pretty excited. 

         14   But the really interesting parts of this

         15   scientifically were not just to derive the letters

         16   of the code but to try to understand with they

         17   mean.  And in that regard just a month ago in this

         18   issue of Nature we published not only the methods

         19   that were used to sequence 95 percent or so of the

         20   human genome but also an initial analysis of what

         21   could be learned from the sequence itself.

         22             The cover was carefully chosen by the


                                                                      206

          1   international sequencing consortium to depict what

          2   this was really all about.  Which is it's about

          3   DNA, but in fact if you look carefully this cover

          4   is made up of a mosaic of the faces of individuals

          5   from all over the world.  This is the genome of all

          6   of us.  With this is our shared inheritance.  We

          7   are 99.9 percent the same at the DNA level and the

          8   cover is supposed to convey that.  And I think

          9   perhaps for today's discussion it's an appropriate

         10   symbol of the future in that we want to understand

         11   this molecule DNA, we want to understand its role

         12   in health and disease, but to do so will involve

         13   the participation of folks from all over the world

         14   as our full partners in that effort and we need to

         15   be very thoughtful about how we are setting up that

         16   partnership.

         17             Just for fun in this mosaic of individuals

         18   most of whom come from various places and are not

         19   people whose faces you would recognize, we did hide

         20   in here a picture of Watson and Kirk [ph] -- 

         21             [Laughter.] 

         22             DR. COLLINS:  -- just to make it a little


                                                                      207

          1   more interesting.  And having encountered a number

          2   of people who have wasted a lot of time trying to

          3   find this, I will reveal the secret for those of

          4   you in the room so you don't have to do this.  It's

          5   right down there, and if you look very carefully in

          6   that little part of the double helix sure enough

          7   there is the famous photograph from 1953 of Watson

          8   and Creek standing on either side of their model of

          9   the double helix.

         10             So we did learn a lot from this analysis. 

         11   I could go on, and I have on occasion, about the

         12   number of surprises that came out of this discovery

         13   process of looking at the sequence.  Here are just

         14   a few of the cool things we learned about the

         15   genome that we really didn't expect; the number of

         16   genes in the genome coming in at only about 31,000

         17   give or take 10 percent or so.  It's certainly a

         18   lot less than what had been expected, making you

         19   wonder, are we as complicated as we thought?

         20             Well, we certainly are.  And so clearly

         21   our degree of complexity must have some other

         22   basis, one of which seems to be that our genes can


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          1   make more proteins per gene than other critters. 

          2   We can make about three different proteins from

          3   each gene on the average.  There also turns out to

          4   be the case that our proteins are more complex in

          5   what they can do than what you might find in the

          6   similar proteins from worms or flies.

          7             So we seemed to have recovered our sense

          8   of pride here, although this gene count was an

          9   affront to many people, I think we've overcome the

         10   initial hit.

         11             We also discovered that we had genes in

         12   our genome that seemed to have crossed over all

         13   sorts of the boundaries that weren't supposedly

         14   crossable.  That it came from bacteria without

         15   going to the usual evolutionary steps.  This didn't

         16   happen last week, these are genes that arrived

         17   there tens or even 100 million years ago.  But it's

         18   surprising to find that they are there and they're

         19   actually quite beneficial, they're doing us some

         20   good.

         21             We learned the male mutation rate is twice

         22   that of females by a very careful analysis of the


                                                                      209

          1   genome sequence, which if you are a male might be

          2   bad news because here now responsible for two-

          3   thirds of genetic disease.  On the other hand, if

          4   you want to look at it the other way, you're

          5   responsible for two-thirds of evolutionary

          6   progress.  So you can decide.

          7             [Laughter.] 

          8             DR. COLLINS:  And we also studied the

          9   junk, or so its been called, and maybe we should

         10   stop calling it that, and discovered that we can

         11   learn a prodigious amount about where our genome

         12   came from my looking at the repetitive sequences,

         13   which is roughly 50 percent of the genome, and we

         14   learned that at least one large class of such

         15   repetitive elements must, in fact, have a function

         16   after all by the way in which it has been

         17   selectively retained in various parts of the

         18   genome.  And that was a big surprise.

         19             So I could go on and on about this but we

         20   learned a heck of a lot about this.  But not only

         21   do we study the genome sequence that's 99.9 percent

         22   the same, another paper in the same issue described


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          1   the discovery of 1 1/2-million places of the genome

          2   where there are common variations between

          3   individuals.  That catalog of human variations is

          4   going to be an absolutely critical resource for

          5   trying to nail down the hereditary contributions,

          6   the common polygenic conditions, things like

          7   diabetes, heart disease, Alzheimer's disease,

          8   schizophrenia, the common cancers, as multiple

          9   sclerosis, virtually anything you can think of that

         10   runs in families, and that's most diseases, but

         11   doesn't have a nice clean mendelian inheritance

         12   pattern.  Those things are going to be now much

         13   more approachable because of having this catalogue.

         14             So the way in which we hope this would

         15   turn its attention now from a basic science

         16   enterprise into one which has increasing clinical

         17   applications might be diagramed as you see here,

         18   starting at the left and moving to the right, this

         19   is what one would expect to see happening for

         20   disease gene after disease gene in the course of

         21   the next 10 or 20 years.

         22             We have the tools, we believe, to identify


                                                                      211

          1   the genes that are contributing to virtually any

          2   disease that has a hereditary component using what

          3   the human genome project has produced but it will

          4   require a great deal of careful pedigree research

          5   to do so, because you don't know the significance

          6   of a particular variant until you've studied it in

          7   individuals with a condition and people who don't

          8   have that condition.  Otherwise it's just a

          9   candidate change in the DNA.

         10             Human research really will not go very far

         11   without that very big risk clinical effort which

         12   will involve lots and lots of families and

         13   individuals and lots of clinical researchers.  And

         14   that is one of the things really need to talk about

         15   today in terms of how to catalogue that.  Otherwise

         16   the arrow that you see here will not progress very

         17   rapidly.

         18             Once you've identified a variant that

         19   plays a role as a risk factor in disease and then

         20   following that central arrow there, you have a

         21   diagnostic that might allow you to make a

         22   prediction about who else is at-risk but not yet


                                                                      212

          1   affected by the disorder.  If that's all you're

          2   doing is providing a risk estimate without an

          3   intervention that may not be of great interest to a

          4   lie of people, although some will still want to

          5   know.  It would be more impressive, of course, if

          6   you had a preventive option to offer.

          7             Now, already in some circumstances we are

          8   at that point.  For colon cancer, for instance, if

          9   you're in a family that has lots and lots of colon

         10   cancer we have identified a number of the genes

         11   that are involved in those fairly strongly

         12   hereditary forms.  You could find out if you decide

         13   you wish to be tested and go through the

         14   appropriate protocol whether you're at risk or not. 

         15   Then, if you are, then begin a program of

         16   colonoscopy starting at an early age in order to

         17   pick up that polyp while it's still easily removed

         18   and perhaps spare you from a terrible outcome of

         19   metastatic disease down the road.

         20             That kind of preventive strategy is

         21   currently available only for a small number of

         22   conditions.  Which is why we are not yet in the


                                                                      213

          1   circumstance of offering this kind of diagnostic

          2   genetic testing to lots and lots of people for lots

          3   and lots of conditions.  But it will be coming

          4   along with the increasing recognition both of what

          5   the hereditary factors are and of what

          6   interventions might have value.

          7             Pharmacogenomics which I'm sure we'll hear

          8   about a little later on from the panel is also on

          9   this list.  It's a particular kind of diagnostic

         10   where in this instance you're not predicting the

         11   risk of future illness, you're predicting the risk

         12   of responsiveness to a drug that's being given for

         13   a particular condition.  And there is strong

         14   evidence in many conditions that that is at least

         15   in part influenced by heredity.  And if you knew

         16   ahead of time that this is the person who isn't

         17   going to respond well to that drug, or who might

         18   even have an unfortunate side effect, you could

         19   spare them the experience of being treated

         20   ineffectively for a condition where some other

         21   treatment is already available.

         22             So the field of pharmacogenomics has grown


                                                                      214

          1   very rapidly out of essentially of nonexistence

          2   three or four years ago to a very, very important

          3   topic both in academia and in the pharmaceutical

          4   industry with many people predicting that this

          5   approach will come into fruition for drugs that are

          6   already on the market in perhaps the next five to

          7   seven years.

          8             Of course the ultimate outcome that one

          9   hopes to see from all this as far as consequences

         10   is the therapeutic one and that might be a

         11   circumstance where they gene is used as the drug;

         12   that's what gene therapy essentially is.  Or that

         13   you use the understanding of the gene to develop a

         14   sufficiently precise molecular analysis of the

         15   problem to allow you to design a drug that goes

         16   right to the heart of the problem.

         17             If you read in the press last week

         18   accompanying a number of reports in the New England

         19   Journal about this drug called Glivax which was

         20   previously call STI571.  It's a very good early

         21   example of a drug designed specifically based on

         22   molecular understanding of a problem.  In that case


                                                                      215

          1   adult leukemia which appears to be enormously

          2   promising in terms of its success rate in providing

          3   benefit to affected patients.

          4             So this is the pathway that we'd like to

          5   travel, but at every one of these branches we will

          6   not make progress without vigorous clinical

          7   research involving large numbers of individuals,

          8   and hence, the critical importance of getting that

          9   part right and all the more reason why we should be

         10   talking about it today.

         11             Not only will we be studying a lot of

         12   individuals, we will be studying lots of genes in

         13   those individuals and methodologies for studying

         14   how gene expression, getting turned on or off gets

         15   affected by health or disease, has been moving very

         16   rapidly with things like microarrays and you see an

         17   example of that.  So the whole approach to try and

         18   understand illness has taken a turn in the

         19   direction of high throughput methods that we could

         20   not have anticipated a few years ago.

         21             Again, my hope would be that if this moves

         22   forward the way it should, that the use of


                                                                      216

          1   information about genes to develop truly effective

          2   drug will be considerably accelerated.  And this

          3   particular issue of Time magazine from a couple

          4   months ago is a whole special issue on that topic

          5   where the DNA you see here in the bottle is not

          6   really the drug, it's the information that used to

          7   develop the drug.  And I think the field is

          8   extremely promising there and that's why every

          9   pharmaceutical company is basically targeting this

         10   as the way in which they hope to develop the next

         11   generation of pharmaceuticals.

         12             Well, how is this all going to come to

         13   pass?  Let s sort of look at the contrast between

         14   the way genetic research might have been done by

         15   many of us perhaps 15 years ago and the way in

         16   which it is starting to be done now.

         17             Fifteen years ago most genetic research

         18   was done on conditions that were fairly, highly

         19   heritable, because they were the ones you had some

         20   hopes of making progress on so the pedigree over

         21   here would likely be a dominant or a recessive

         22   condition.


                                                                      217

          1             The investigator who is doing the research

          2   might very well be the same person who is examining

          3   those individuals in the clinic and in some

          4   instances even be their physician.  Although we all

          5   recognize there are problems with that the

          6   particular equivalence.

          7             That investigator would be generating

          8   clinical records and would be carrying out DNA

          9   testing and perhaps analyzing tissue.  But it would

         10   all be connected in this fairly small sphere of

         11   activity.

         12             This is all changing with the challenge

         13   now to be to try to understand the genetics of

         14   complex disorders where the genes play a weaker

         15   role individually your only way of success is to

         16   study much larger numbers of individuals.

         17             And so increasing repositories are coming

         18   into the fore.  That means much larger numbers of

         19   subjects, larger numbers of tissues perhaps,

         20   clinical records, DNA test results frequently

         21   finding their way into some central data

         22   repository, and the possibility then of many


                                                                      218

          1   investigators tapping into that to try to answer

          2   important research questions.  A very different

          3   kind of scenario than the rather circumscribed one

          4   that was more familiar fifteen years ago.

          5             And yet much of what we have been

          6   following as far as guidelines that IRBs attempt to

          7   adhere to, is really more focused on the old way

          8   than on the new way.  And most of the issues that I

          9   want to put in front of you relate to what happens

         10   when we make this transition and are we ready for

         11   it.

         12             So we want research to improve human

         13   health.   We all agree based on the principles

         14   established and remarkable that they were and how

         15   well they've stood up in the Belmont report that

         16   respect and beneficients and justice are the goals

         17   of all of these various efforts to try to implement

         18   responsible clinical research involving human

         19   participants.

         20             How do we do that?  Well, I think our

         21   language is important and this is probably a topic

         22   that's come up to this group before.  The whole


                                                                      219

          1   issue of human subject is becoming a bit

          2   controversial.  And the more some of us have talked

          3   about that and discussed it, particularly with

          4   members of the public, I think that more were

          5   coming to a conclusion that this term is probably

          6   conveying a significance that is unfortunate. 

          7   Subjects in general in sort of the classic sense

          8   are those who are subjects to somebody.  They are

          9   the subjects and somebody else is the king or the

         10   queen.  Is that the relationship that we really

         11   want to put forward by our language as we talk

         12   about people participating in research?

         13             I think many of us would argue that really

         14   isn't the very good fit and this is not a specific

         15   opinion of mine.  And this is not an attempt to be

         16   politically correct.  I think it's an attempt to

         17   try to convey with our language what we really mean

         18   about the role of participants in research.

         19             And so recognizing that I'll probably make

         20   the mistake all afternoon and continue to use this

         21   term, I'm going to advocate that we shouldn't and

         22   that instead it would be appropriate to begin to


                                                                      220

          1   move into a language that utilizes an alternative

          2   term of research participant to convey the fact

          3   that both the clinician and the individual being

          4   who is being involved in the research are both co-

          5   participants in the enterprise, and that there is

          6   more of a horizontal relationship than a vertical

          7   one.  Okay.

          8             Having to put particular plug in, let me

          9   go on to point out a couple of the things that are

         10   shifting in their emphasis in research as a

         11   consequence of moving from the so-called old way to

         12   the so-called new way.  Research protocols perhaps

         13   in the time gone past had a clear goal at the

         14   outset.   We're trying to identify the gene for a

         15   particular mendelian disorder.  Whereas

         16   increasingly now we're contemplating large genetic

         17   epidemiological studies where one may not know what

         18   studies you might want to on those materials in

         19   five or ten years.  And that raises the question of

         20   what is the ethical way to obtain consent for such

         21   studies, one of the issues which I'll come back to.

         22             This is one form of shifting emphasis. 


                                                                      221

          1   Another is that I think in the past, much of the

          2   IRB oversight and certainly much of the informed

          3   consent process related to physical risks. 

          4   Genetics have certainly presented relatively little

          5   in the way of physical risk when you're talking

          6   about pedigree studies.  Obviously that's not true

          7   in circumstances such as gene therapy where we've

          8   all been awakened to the great risk there of

          9   potential consequences of that sort of

         10   intervention.

         11             But for pedigree studies where you're

         12   trying to map gene disease susceptibility to

         13   physical risks tend to be quite minor.  But the

         14   psychosocial risks which aren't as well, in

         15   general, covered in previous versions of the

         16   informed consent discussion process loom much

         17   larger.  And that's another part of the shift here

         18   that I think we're seeing over the last 15 years.

         19             A the third shift, perhaps not to be over

         20   emphasized but it's certainly there, is that when

         21   it comes to genetics research much of this was

         22   considered to be rather academic and was carried


                                                                      222

          1   out in academic centers.  And that's certainly not

          2   the case anymore and we have a vast amount of

          3   genetic research now going on in the private sector

          4   with legitimate concerns about whether the

          5   appropriate protections for participants are

          6   equivalently there in those settings as they might

          7   be in academic settings, and, hence, the importance

          8   of facing up to that issue.

          9             So those are three areas of shifting

         10   emphasis.  Now, I want to sort of spend the rest of

         11   my time talking about five issues.  And I could

         12   have chosen, I suppose, a different set of five.

         13             I had interesting discussions leading up

         14   to this meeting with a number of folks and

         15   particularly with my own staff members Kathy Hudson

         16   and Elizabeth Thompson, both of whom are here about

         17   where we thought the highest priority ought to be

         18   paid amongst a long list of possible topics with

         19   regards to trying to beef up the understanding and

         20   the implementation of appropriate oversight of

         21   participation in research by human individuals. 

         22   And we came up with these five.  And, again, I


                                                                      223

          1   could easily be talked into the notion that we left

          2   something off or that maybe one of these isn't as a

          3   important as the rest.

          4             Let's begin though with the first one

          5   which is the topic of the panel discussion that

          6   will follow, and which has been very much, I think,

          7   on the minds of many folks involved in genetic

          8   research studies.  Since this first came to a great

          9   deal of attention as a consequence of a particular

         10   instance where Mr. Richard Curtain who is here with

         11   us today in the process of uncovering something

         12   that was going on with a research study carried out

         13   on his twin son and daughter became quite concerned

         14   that his privacy was being invaded by the

         15   investigator, an investigator at VCU, without his

         16   having been asked for his consent.

         17             And I need to give Mr. Curtain a great

         18   deal of credit for raising this issue to the

         19   consciousness of a lot of folks who I think

         20   intended to discount this as been worthy of serious

         21   consideration.  It is certainly now a topic of

         22   great serious consideration and we will spend much


                                                                      224

          1   of this afternoon on it.  But I must say, it's a

          2   very thorny one because we have a collusion here,

          3   as often is the case in ethical dilemmas, between

          4   two things that are good. 

          5             It is good to do research to try to

          6   uncover the causes of disease and to try to come up

          7   with better methods of understanding and treating

          8   those conditions.  But, it is also good to protect

          9   the privacy of individuals and not to carry out

         10   research on their identifiable private information

         11   without their consent.  And there are certainly

         12   folks in this room, I suspect, who are deeply

         13   concerned about how we could achieve both of those

         14   goods simultaneously.  Recognizing that pedigree

         15   research has depended, for a long time, on the

         16   ability to collect information about the family

         17   history of the proband and we have traditionally

         18   not gone to the extent of looking to see whether

         19   other family members are willing to be consented

         20   for this purpose or not.

         21             I think now we have to face that issue

         22   square on and I hope this committee will do so in


                                                                      225

          1   the follow-up deliberations after today.

          2             I think Mr. Curtain is right that we have

          3   made an assumption in the past that's not really

          4   consistent with other ethical principles and that's

          5   why this is such an important issue to consider.

          6             So a couple of background points and maybe

          7   this will help illuminate a bit the panel

          8   discussion.  Again, although I've said "human

          9   subject" may not be a good term, it is a term that

         10   is certainly written in the regs.   And so in the

         11   definition of a human subject, it means a living

         12   individual about whom an investigator conducting

         13   research obtains:  (1) data through intervention or

         14   interaction with the individual or identifiable

         15   private information.

         16             So you can certainly say in the

         17   circumstance where the proband reports information

         18   about their sibling or their parent which is

         19   identifiable in that they are giving you in the

         20   most extreme case that person's name and address or

         21   phone number, and it's information that that

         22   individual would consider private and would not


                                                                      226

          1   feel would be appropriate to be shared outside of a

          2   very small group of family members, then you could

          3   make the case that that converts that individual to

          4   a human subject by the nature of this definition.

          5             I'm sure we will debate that a bit in the

          6   panel, but that certainly is a case that has been

          7   made.

          8             Now, if that is in fact the case then the

          9   regs would say that consent either has to be

         10   exempted -- and I'm not going to go into the

         11   exemption because I think it's fairly difficult to

         12   make a case that exemption fits in that sort of

         13   circumstance, although perhaps some of the panel

         14   members would like to raise that.  But perhaps more

         15   feasibly one might consider the IRB in a position

         16   to waive consent for those family members.  But

         17   there are very clear statements in the regs about

         18   what is required for such a waiver.  And there are

         19   the four criteria probably familiar to most of you

         20   who have read the regs reread the regs, and reread

         21   t regs, they are these four criteria.

         22             That research is no more than minimal


                                                                      227

          1   risk; that waiver does not adversely affect rights

          2   and welfare; that the research is not practicable

          3   without the waiver; and that whenever appropriate

          4   -- and that's an interesting clause -- subjects are

          5   provided with information after participation.

          6             So one of the things we should talk about

          7   in the panel is whether in fact family members

          8   about whom information is being obtained from a

          9   proband fit the circumstance of this waiver.

         10             Just one observation, certainly the great

         11   concern here, or much of the concern relates to

         12   whether private identifiable information obtained

         13   as part of this research might end up doing damage

         14   to that individual.  And the damage could certainly

         15   occur if that information leaked out into the hands

         16   of other third parties particularly those involved

         17   in employment decisions or other areas where that

         18   individual might be discriminated or injured as a

         19   consequence of that information becoming available

         20   through the researcher's work.

         21             It seems at a minimum that if one were to

         22   consider a waiver of this sort it would require


                                                                      228

          1   very strong confidentiality and privacy protections

          2   provided by the researcher.  And then if IRBs were

          3   to take tis route in trying to decide whether

          4   family members needed to provide consent at a

          5   minimum, they would have to be assured that

          6   researcher has paid close attention to putting up

          7   appropriate firewalls to prevent the leakage of

          8   information of this sort and breaching the

          9   confidentiality and privacy of participants.

         10             Now, whether, in fact, if that kind of

         11   firewall is there that would be sufficient to say

         12   that this is a possible pathway out of the dilemma

         13   is something this committee which I think this

         14   committee will have to wrestle with.  It is

         15   certainly one possible way to look at the issues

         16   but not the only one. 

         17             Now, in trying to delivering about what

         18   kind of pathway out of this dilemma might be

         19   identified there are a number of considerations or

         20   questions that might be asked.  First of all, this

         21   is a process, pedigree research, which is been

         22   going on for some time.  I think it could be argued


                                                                      229

          1   without appropriate consideration of the possible

          2   risks to family members who have not given consent. 

          3   I must say, I think our whole thinking process

          4   about carrying out research on human participants

          5   has been maturing over quite a long period of time.

          6   And this is another example of a circumstance where

          7   I suspect 20 years ago most people would not have

          8   thought that this was a legitimate cause for

          9   concern, and now I think with our consciousness

         10   raised by a variety of issues, it is very much

         11   appropriate to consider it.

         12             But we ought to ask the question, is there

         13   evidence that there have been harms carried out in

         14   the past?  Mr. Curtain may feel that his

         15   circumstance was one of those.  Are there others

         16   that we have not heard about?  Is there a way of

         17   collecting this information?  Is there a research

         18   opportunity here?  They're probably is.

         19             Clearly we need a greater opportunity then

         20   has happened in the last year or so for public

         21   input about this issue in terms of what the level

         22   of public concern is.


                                                                      230

          1             A second point that I would like to raise

          2   to your attention because I think it hasn't

          3   received much attention so far, is that ironically

          4   in certain instances, insisting that there be

          5   consent from family members, might actually create

          6   harms for the proband.  In circumstances, for

          7   instance, where the Proband does not wish other

          8   family members to know they're participating in

          9   research.

         10             In Huntington's disease, for instance,

         11   individuals who participated in the phase of

         12   carrying out presymptomatic testing once there was

         13   actually a gene and you didn't need to have family

         14   members available for linkage purposes, that

         15   individual could find out their risk.  And, of

         16   course, we didn't want to do that as part of

         17   clinical practice of medicine until it had been

         18   carefully studied in research.  Many of the

         19   individuals participating in that kind of genetic

         20   testing protocol for Huntington's disease were

         21   quite adamant that they did not want their family

         22   members to know that they were undergoing such


                                                                      231

          1   research, because they felt that they would in some

          2   ways upset the dynamics of the family by revealing

          3   that they were interested in this information and

          4   they would be probably quizzed fairly strongly by

          5   other family members about the results which they

          6   would not want to necessarily disclose.  For their

          7   purposes their privacy was very important that the

          8   information not be made available to other family

          9   members.  So that creates a certain dilemma.

         10             This dilemma becomes even more acute I

         11   suppose in circumstances where you're talking about

         12   not necessarily genetic research but for perhaps

         13   situations of domestic violence, for instance,

         14   where the mere fact that the individual is

         15   participating in a research project on that topic,

         16   if revealed to other close family or household

         17   members, might in fact place them at some risk of

         18   retaliation.

         19             So one cannot assume that this is simply a

         20   matter of saying oh, heck, we had better just put

         21   the resources into it and go out and find all the

         22   family members and get their consent even though


                                                                      232

          1   it's going to be onerous it's the right thing to

          2   do.  In some instances it may not be the right

          3   thing to do.  It may actually, in the scheme of

          4   things, create a greater harm rather than a lesser

          5   one.  And that needs to be thought about.

          6             In terms of consistency, it's certainly

          7   true now that when you carry out pedigree studies

          8   where you do have consent of a number of the

          9   individuals in the pedigree.  There may be

         10   instances in which you reveal the genotype of

         11   someone who has not given their consent simply by

         12   where they're positioned in the pedigree.

         13             If you know that the grandfather and the

         14   grandchild are carrying a Huntington's disease

         15   mutation, you have revealed that the individual in

         16   between them must also, even if that person was

         17   opposed to the research, and not willing to

         18   participate, it is a natural consequence of the way

         19   that genetics works.  And so one can't be

         20   unrealistic about the fact that even if every

         21   effort was made to get consent from all the family

         22   members who would like to give it, by carrying out


                                                                      233

          1   the research you may still reveal genotypic

          2   information on individuals who did not want to

          3   participate, but, who, because of their family

          4   relationships had their genotypes revealed.

          5             And, of course, there is the question

          6   about how far in the pedigree do you go?  Are we

          7   talking first-degree relative, second-degree, third

          8   degree?  In many pedigree studies you would like to

          9   have information about cousins sometimes distant

         10   cousins if you're trying to track down a particular

         11   inheritance pattern.  How far do you go in that

         12   process?

         13             I know in the panel discussion we'll deal

         14   with these issues and a number of other ones, but I

         15   thought he would be good to put these in front of

         16   you.

         17             Again, I am not here today to propose a

         18   solution to this.  I am here to advocate as SACGT

         19   has already done in their letter to the Surgeon

         20   General that it is really important for NHRPAC to

         21   take this particular task on and to try to come up

         22   with a well-thought-through set of recommendations. 


                                                                      234

          1   Because IRBs are understandably left in the lurch

          2   at the moment with a very unclear situation where

          3   none of the current guidelines seem to be all that

          4   well-written for the circumstance, and they are

          5   seeking guidance and need it and need it soon.

          6             Okay.  The next issue I want you to think

          7   about is this community consultational question. 

          8   And this is a bit of an expansion question about do

          9   you need consent from family members?  Well, if

         10   you're studying an identified population or

         11   identifiable population, you could consider that

         12   that entire population becomes your family members

         13   and do they also need to be involved in the process

         14   of designing and implementing the research?

         15             This has been discussed considerably over

         16   the last three or four years in a number of

         17   gatherings.  And I think we've made some

         18   substantial headway, but I would not stay there is

         19   a consensus about exactly what ought to be

         20   considered by IRBs that are reviewing such

         21   protocols.  After all, research involving

         22   identifiable population's may potentially create a


                                                                      235

          1   risk of stigma that extends beyond the individual

          2   to the whole group.

          3             There is a research study going on in

          4   Baltimore looking at schizophrenia where they have

          5   specifically decided to look at Ashkenazi Jewish

          6   individuals because of the fact that that's a

          7   founder population, where, in general, genetic

          8   research studies have a somewhat greater chance of

          9   success because of a limited number of alleles that

         10   would be expected to be found at a susceptibility

         11   loca.

         12             This is not to say that schizophrenia is

         13   more common in Ashkenazi Jews.  There is no

         14   evidence that it is.  But only to say that a

         15   research study might be more likely to succeed

         16   there.  And for the same reason researchers are

         17   frequently going out and looking at Mennonites or

         18   Amish of people who live in Iceland or other places

         19   where you'd expect there to be a limited founder

         20   pool.  But there is a great potential for

         21   misunderstanding, as there already has been, for

         22   the BRCA1 gene, for instance, which is referred to


                                                                      236

          1   in some press reports as the Jewish breast cancer

          2   gene which is completely turning it on its head

          3   misunderstanding of what's actually happened.  But

          4   there is a risk there.

          5             So should the community be involved in

          6   research, design an implementation is a question

          7   that many people have been asking and many people

          8   do feel the answer is yes.  But it's very difficult

          9   to see how to exactly how to codify this.  And I'm

         10   not sure how much we should try to codify it too

         11   explicitly; after all in many communities it's not

         12   clear who to consult with.  In other communities it

         13   is somewhat more clear but in many it's not so

         14   obvious and how do you do this in a fashion that is

         15   genuinely respectful of the fact that communities

         16   themselves have a lot of diverse opinions.

         17             An example of an early study in which this

         18   what a major issue was the study done here in the

         19   Washington area about three or four years ago

         20   looking at the risks associated with BRCA1 BRCA2

         21   mutations in ashkenazi individuals by collecting

         22   DNA samples and family histories from over 5,000


                                                                      237

          1   such individuals in this area.

          2             In order to set that study up and do it

          3   responsibly, the investigators conferred

          4   extensively with members -- leaders of the Jewish

          5   community before setting up the study and designing

          6   its follow-up.  And I think that was a very useful

          7   learning experience, not to say we got it perfectly

          8   right, but I think it was a good example of a

          9   genuine involvement by the community in the

         10   process.  And yet, one could argue that that was a

         11   community that was particularly well motivated and

         12   perhaps the leadership was easier to identify than

         13   it would be in many other kinds of studies focused

         14   on different populations.

         15             Again, I think IRBs are left somewhat in

         16   the lurch here without clear guidelines about this

         17   kind of community involvement and what is expected

         18   of an investigator who is studying an identified

         19   population, and it would be very timely to give

         20   this matter some consideration. 

         21             Stored tissue research.  Well, goodness,

         22   there has certainly been a lot of discussion, many


                                                                      238

          1   conferences, many articles written, many speeches

          2   given, a few arguments that came almost two blows,

          3   and I wouldn't say that at this point we've

          4   completely reached the consensus.  Although I think

          5   we've come a long way.  In that regard, the old

          6   days of tissue collection might have looked a bit

          7   like this here, another good cartoon from the

          8   recent transition of cartoonist into scientific

          9   topics.

         10             But you probably have noticed that tissue

         11   collection is also becoming big business.  There

         12   are a number of for-profit organizations and

         13   perhaps another not-for-profit that are getting

         14   going now to collect very large numbers of tissue

         15   samples in order to make them available to both

         16   academics and private companies to try to draw

         17   correlations between phenotypes and genotypes and

         18   how does that all fit together here?

         19             Many groups have made recommendations on

         20   the topic of tissue samples, but I would say it's

         21   still the case that researchers and IRBs are

         22   somewhat confused.  NBAC, of course, weighed in, in


                                                                      239

          1   a very definitive and extensive way on this, but

          2   those recommendations had not sort of gotten thrown

          3   over the transom to the IRBs in a fashion that I

          4   think they are fully ready to implement and

          5   incorporate.  That would be very useful thing for

          6   this committee to consider.

          7             A fourth issue, blanket consent; is it

          8   ethical to ask individuals to give open-ended

          9   consent for use of their biological specimens for

         10   all possible purposes for an indefinite period of

         11   time? 

         12             There are many instances where that could

         13   be quite useful for research.  If you're simply

         14   concerned about facilitating research having such

         15   repositories where you have a very large amount of

         16   clinical information, perhaps the possibility of

         17   longitudinal data and following up the individuals

         18   in such studies and carte blanche to do whatever

         19   kind of genotyping you'd like to try to correlate a

         20   particular clinical situation with a particular DNA

         21   spelling would be in many people's view a wonderful

         22   circumstance for getting a lot of important


                                                                      240

          1   conclusions drawn quickly.  And you could argue

          2   that as long as the participant had the chance to

          3   understand all of those things and decided to give

          4   their consent to such open-ended use of there

          5   biological specimens, who are we to say that they

          6   shouldn't do so.

          7             On the other hand I think there are many

          8   people who feel that that kind of open-ended

          9   consent really doesn't meet the standard that we

         10   expect when we use the words "informed consent."

         11              How could you be informed about a host of

         12   possible future uses that the investigator doesn't

         13   really have the ability to enumerate.  And in that

         14   circumstance, maybe we need to do better.

         15             So the alternatives for consent for such

         16   large genetic epidemiological studies, and there

         17   are many of them getting underway, and I think they

         18   are going to be extremely important for the future

         19   of genomic and genetics and the medical

         20   applications thereof.  One can, of course,

         21   anonymize the specimens.  But in the process you

         22   undoubtedly run the risk of losing clinical


                                                                      241

          1   information because if you're truly anonymizing the

          2   specimens you may have to strip off enough clinical

          3   information that nobody could actually track that

          4   back to the individual, and, of course, in the

          5   process, it makes it very difficult although not

          6   quite impossible to incorporate ongoing

          7   longitudinal information about clinical follow-up. 

          8             There is the middle ground here were you

          9   obtain a relatively narrow individual consent for

         10   initial uses.  And then maintain contact with the

         11   participant and recontact them for future uses that

         12   did not fall within the original consent.  And then

         13   there is the blankets consent that I've already

         14   mentioned.

         15             I think many folks would like to see this

         16   migrate in the direction of the middle option here

         17   without being quite sure how to set that up.  And

         18   it would be very useful to have a statement -- 

         19   recommendation from this committee about whether,

         20   in fact, blanket consent is considered ethical in

         21   some circumstances and if so what would they look

         22   like?  Because investigators I think are truly


                                                                      242

          1   interested in trying to have some guidance here and

          2   IRBs are as well.

          3             This is going to come up a lot.  I've

          4   talked in the last three or four months to at least

          5   four different groups that are proposing to carry

          6   out very large genetic epidemiological studies

          7   where they basically want to test every hypothesis.

          8   And it would be most convenient for them to carry

          9   out blanket consent that they want to know.  Is

         10   that something that is legitimate?  Their IRBs want

         11   to know too, is that something that can be done

         12   without violating basic principles of what informed

         13   consent is all about?

         14             Finally, disclosure of research results. 

         15   This is an issue also that I think is somewhat

         16   controversial.  Under what circumstances should

         17   research results that may have very little meaning

         18   at the sort of immediate stage of carrying out the

         19   project be disclosed to patients or to

         20   participants, rather, and under what circumstances

         21   is it legitimate not to do so, providing that, of

         22   course, the investigator has informed the


                                                                      243

          1   participant up front that that information is not

          2   going to be made available.

          3             There is a bit of the controversy, NBAC

          4   coming in on this says that disclosure of research

          5   results to subjects represents an exceptional

          6   circumstance.  If you look at the currently under

          7   review regulations provided by the Secretary in

          8   response to the mandate from HPPA to have such

          9   privacy regulations, and these are currently under

         10   review, it suggests that the individual does have

         11   rights of access to inspect protected health

         12   information which would include a lot of research

         13   information, except when access would violate CLIA,

         14   that is that the results were carried out in a non-

         15   CLIA-approved lab or research that includes

         16   treatment in progress as in a double-blind study,

         17   for instance, where it would perhaps invalidate the

         18   study.

         19             So there's a bit of a discordance here

         20   between these views.  A number of folks have

         21   weighed in on this without passing judgment on

         22   whether these particular criteria are the right


                                                                      244

          1   ones.  Here are certainly five that have been put

          2   forward that it is reasonable to disclose research

          3   results:  first, if the finding is scientifically

          4   valid and confirmed, and that will often not be the

          5   case of course.

          6             If you're carrying out a linkage study and

          7   you have a lot of genotypes who knows at the moment

          8   when you do those first genotype's what they mean?

          9             It takes a lot of follow-up before you

         10   have anything that you could say has validity and

         11   has been confirmed.  Clearly based on other parts

         12   of the law, if you're giving results that are going

         13   to in anyway influence clinical decisionmaking they

         14   should be obtained in a CLIA-approved lab, and so

         15   since most research labs are not CLIA-approved then

         16   you have a bit of a collision here.

         17             The findings have significant implications

         18   for the subject's health that would certainly

         19   increase your sense of responsibility and

         20   disclosure.  A course of action readily available,

         21   that is, it is not only clinical valid but

         22   clinically useful would greatly increase the


                                                                      245

          1   mandate to disclose and, of course, the ability to

          2   provide caring counseling so you're just dumping

          3   valid information into people's laps.

          4             But this is an area also that needs

          5   considerable attention and I think at the moment

          6   many IRBs are not clear.  When they get an informed

          7   consent form that says, "the results obtained in

          8   this research study are not going to be made

          9   available to you the participant."  Is it okay to

         10   go along with that, or is that in violation of some

         11   other principles as have been recently enunciated

         12   in the Secretary's regs.

         13             A fifth issue then on your already very

         14   full plate, finally, I would say, for all of these

         15   the IRB guidebook, which is what IRBs are currently

         16   trying to work with, was last updated in 1993. 

         17   Going through and glancing over it we encountered a

         18   number of howlers that really give you pause about

         19   whether anyone could find appropriate answers to

         20   the kinds of question that are being asked today.

         21             There's virtually nothing in there, for

         22   instance, about studies on genetic alterations that


                                                                      246

          1   might confer a predictive risk of future illness. 

          2   It just sort of wasn't much talked about in 1993. 

          3   So immediately I would suggest there is a need to

          4   take the guidebook and update it, but, of course,

          5   the most effective updating would be predicated

          6   upon some consensus for the five problems that I've

          7   posed in front of you, and probably a few others as

          8   well, and that is going to be a difficult and time-

          9   consuming enterprise.

         10             I must say, finally, in conclusion here,

         11   we have a problem in front of us here about privacy

         12   and particularly public concern about genetics.  I

         13   am personally delighted that this committee has

         14   come into being; personally delighted that Greg

         15   Koski has come here to oversee this effort with a

         16   very approach he has taken; and counting on all of

         17   you to help us see our way out of this thicket and

         18   offering myself and my staff in anyway that we can

         19   be of use to you in helping you come up with some

         20   consensus ideas about how to do these two good

         21   things:  do wonderful research that's going to

         22   advantage human health as quickly as possible but


                                                                      247

          1   also protect the interests of the human

          2   participants without whom none of this will happen. 

          3   Thank you very much.

          4             [Applause.] 

          5             CHAIRPERSON MARSHALL:  Bob, did you have a

          6   comment or -- Bob Levine?

          7             DR. R. LEVINE:  Yes. Thank you.  A very

          8   good, comprehensive look at the field given the

          9   time constraints.  I just what to make a couple of

         10   short comments.  First, the word "subject" as in

         11   research subject is under attack I think

         12   unnecessarily.  People who are attacking it says

         13   that it is used because it talks about subjects

         14   like subjected is to the king.

         15             Actually, the first use of this word in

         16   medical matters was it was used to introduce a

         17   person who was going to be discussed at teaching

         18   rounds.  And the word "subject" is in the sense of

         19   the topic for conversation.

         20             If we shift to participant as many people

         21   are arguing for, you're still going to have to

         22   invent new language to figure out whit could have


                                                                      248

          1   been participants have to file financial

          2   disclosures.  Which ones will become co-authors? 

          3   Which ones are responsible for informed consent? 

          4   And you're going to end up back where you started

          5   anyway.

          6             Another comment I want to make is an

          7   attempt to make current policy conform to the

          8   regulations definition of human subject.  That was

          9   a faulty definition the day it was written.  Many

         10   of the definitions in the regulations are based on

         11   the recommendations of the National Commission for

         12   the Protection of Human Research Subjects.  That

         13   one was not.  And I think instead of changing

         14   policy to conform to this faulty definition, we

         15   ought to write a definition that's valid. 

         16             One final point.  Francis, you're very

         17   concerned about forcing everything to fit under the

         18   rubric of informed consent.  And you rightly ask,

         19   how could one be informed of all possible future

         20   contingencies?

         21             Historically tbe requirement for consent

         22   that was introduced into the field of research


                                                                      249

          1   ethics is in the first sentence of the Nuremberg

          2   code and it calls for voluntary consent.  And while

          3   you might not be fully informed about everything

          4   that will happen in the future, you could say, I've

          5   thought about it and it's my judgment that I'm

          6   willing to have my tissue used for various purposes

          7   into the foreseeable or even unforeseeable future.

          8             Curiously that term "informed consent" was

          9   introduced into our lexicon in an Amicus brief

         10   filed by the American College of Surgeons, and they

         11   were actually opposing the concept.  But the judge

         12   was interested in it and since that time "voluntary

         13   consent" has been called "informed consent."

         14             Thank you.

         15             CHAIRPERSON MARSHALL:  Thank you, Bob.

         16             DR. MORENO:  Can I get one word in

         17   edgewise, Mary Faith?

         18             CHAIRPERSON MARSHALL:  Yes, please do,

         19   while we're -- 

         20             DR.  MORENO:  Actually, as Bob knows from

         21   hearing me talk about this before, the term

         22   "informed consent" was actually introduced in the


                                                                      250

          1   context of an Atomic Energy Commission letter that

          2   was written in a classified conversation in 1947 in

          3   a research context that had to do with the use of

          4   radioisotopes.  So, in fact, the term "informed

          5   consent" does come up in a research context, not in

          6   the clinical context so far as we know.  And the

          7   first documented instance, I think that's

          8   historically important.

          9             Nonetheless, I too was thinking, when

         10   Francis was talking, about the fact that we do have

         11   this rich history of the use of the concept or the

         12   notion of voluntary consent.  And I think that's

         13   one we ought not to forget perhaps in future

         14   discussions.

         15             DR. R. LEVINE:  Jonathan, I ll concede the

         16   point. 

         17             [Laughter.] 

         18             DR. R. LEVINE:  However, I said,

         19   "introduced into the general lexicon."  One of the

         20   problems with the conversation that you're

         21   reporting on now is that it was classified as top-

         22   secret. 


                                                                      251

          1             [Laughter.] 

          2             DR. MORENO:  Actually, it wasn't

          3   classified as top-secret but it was classified.

          4             [Laughter.]

          5             DR. MORENO:  Do you want to split another

          6   hair? 

          7             [Laughter.] 

          8             CHAIRPERSON MARSHALL:  Abbey.

          9             Oh, I'm sorry.  Mary Kay. 

         10             DR. PELIAS:  I think we're going to spend

         11   a lot of time talking about language as we try to

         12   get to the bottom of these genetics problems.  And

         13   while we're quibbling about subjects and

         14   participants I'd like to remind everybody that we

         15   have a few words in the world of genetics research

         16   including "ProBand."  Also we use the word

         17   "informant" who is the individual who gives us

         18   information and who may be the mother of the

         19   ProBand who first came to clinical attention and we

         20   have family members usually with people that we

         21   talk about in terms of the immediate family of the

         22   ProBand, and we have collateral relatives.  So we


                                                                      252

          1   have a lot of language already floating around that

          2   means a lot in the world of genetics research and

          3   may be appropriately applied to ideas of subjects

          4   and participants.

          5             CHAIRPERSON MARSHALL:  Thank you.  I

          6   really don t want to get into a discussion because

          7   we need to move along.  Abbey, just a brief

          8   comment.

          9             DR.  MEYERS:  If it looks like a duck and

         10   it walks like a duck, it s a duck.  And once you

         11   start using those kinds of words, you're going --

         12   ordinary people will not understand it.  They are

         13   not genetic professionals.  So if we just talk

         14   about people and persons, I think we ll keep it on

         15   a level that I think people understand.

         16             But in this one question, this burning

         17   question that s in front of us, I m absolutely at a

         18   loss.  It s gone through my mind, you know, for

         19   several weeks.  When I go into see a new doctor he

         20   takes a medical history, hands me a piece of paper

         21   and he wants to know what all of my relatives had

         22   kidney, liver, you name it, it's there.  If we say


                                                                      253

          1   that this issue of the secondary consent is

          2   important, then we will stop local doctors even

          3   from asking you what your relatives have and that's

          4   just totally unacceptable.

          5             Now, I really want to know from Francis

          6   what do you recommend?

          7             CHAIRPERSON MARSHALL:  I think that this

          8   discussion is a little bit premature.  I would like

          9   to hold off until we have heard from our panel and

         10   then we will open the floor up for discussion.

         11             So, in terms of speaking to and of

         12   persons, I would like to introduce to you Jeff

         13   Botkins, from the Department of Pediatrics at the

         14   University of Utah.  He is going to make a

         15   presentation using the computer.  But we also have

         16   other members of the panel, and perhaps once Jeff

         17   is through the entire panel could convene here and

         18   Dr. Collins is going to moderate it. 

         19             Terri Arledge with GalaxoSmithKlein. 

         20   Sharon Terry who is vice president for Consumers of

         21   Genetic Alliance and president of PXE

         22   International, and Terri Seargent who is a consumer


                                                                      254

          1   advocate with the Alpha One Association.

          2             So, Jeff, when you're done, if all of you

          3   could then convene up here and Francis will

          4   moderate the panel and I d ask each panel member to

          5   please remember that you have 15 minutes.  We are

          6   already slightly over time and we want to have

          7   enough time for a fruitful discussion later.  So

          8   please do not go over time.

          9             DR. BOTKINS:  Good.  Thank you, Mary

         10   Faith.

         11             It's a privilege to be here.  I come to

         12   this discussion as somebody who has been involved

         13   in pedigree research for about the last five or six

         14   years also an IRB member and somebody who's been

         15   interested in the ethical, legal, and social issues

         16   for a number of years as well.

         17             And as you'll see from my analysis of the

         18   issues that I'll present to you, I think for the

         19   most part IRBs can make reasonable judgments on

         20   these issues largely within the framework of

         21   contemporary regulations.  I think that there may

         22   be a little bitter shoe-horning necessary but, for


                                                                      255

          1   the most part, I think the regulations have served

          2   us well for the last 20 years and from my

          3   perspective there doesn't need to be a fundamental

          4   change in order to address these new issues.

          5             As Dr. Collins had outlined, the issues

          6   are pretty straightforward.  And I think that many

          7   of you may have seen an article I had published a

          8   number months ago that was in the packet.  And what

          9   I'm going to do is just touch on the analysis that

         10   I outlined in the article pretty quickly and then

         11   move on to additional concerns and some

         12   clarifications that have arisen since that

         13   publication.

         14             So really the issues are when do family

         15   members and social contact become subjects

         16   themselves?  And then the second level analysis, if

         17   you determine that they are subjects, when is it

         18   necessary to obtain consent?  And I think the key

         19   issue from the investigative standpoint really is

         20   the consent issue.  Do we really have to go out and

         21   get consent to enroll these folks in our projects?

         22             And of course this issue tends to come up


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          1   primarily in the genetics context but it's relevant

          2   to any other context in which were asking one

          3   individual about potentially private information

          4   about others, whether that's students or faculty or

          5   employees et cetera.

          6             Definition of human subjects I think it's

          7   been touched on a couple times today already,

          8   identifiable private information readily

          9   ascertained by the investigator and those are the

         10   key concepts that my comments are going to hinge

         11   on. 

         12             So an individual is a human subject for

         13   the purpose of the regulations when individuals are

         14   readily identifiable, again, to the investigator

         15   and the information required constitutes private

         16   information.

         17             When are family members not readily

         18   identifiable?  I think at least a couple of

         19   circumstances.  Obviously anonymous primary subject

         20   and no unique identifiers on family members.  A

         21   second situation where you may have an identifiable

         22   source, but the family data has been unlinked in


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          1   some fashion perhaps an epidemiologic study.  And

          2   then, thirdly, family members are identified by

          3   family relationship alone to an identifiable

          4   subject.  And I think this may be an issue for some

          5   discussion in controversy.  Does Jeff Botkin sister

          6   constitute a unique identifier for my sister or

          7   does it not?  My claim is that in fact it does not

          8   without additional information about the specific

          9   identity of my sister.

         10             When are family members readily

         11   identifiable straightforward when unique

         12   identifiers are obtained such as full names and

         13   addresses and I think there may be ambiguous

         14   circumstances like initials or first initials and

         15   birth dates, et cetera, that may be t subject of

         16   some discussion.  But I think from my perspective

         17   this aspect is straightforward.

         18             So the implications are detailed health

         19   information can be acquired on family members as

         20   long as the information is not linked with unique

         21   identifiers.

         22             Now, what constitutes private information? 


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          1   This really has been the focus of considerable

          2   discussion in this arena.  My claim here is only

          3   slightly more specific than what is within the

          4   regulations themselves.  And my claim being that

          5   information over which individuals usually want and

          6   can maintain control.  And I think that does

          7   include health information and things like

          8   reproductive history and legal history.

          9             I would make the distinction between types

         10   of personal information that are readily accessible

         11   by casual social contacts, age, employment, family

         12   structure.  Now these are issues that of course

         13   sometime people are sensitive about, but I would

         14   still draw a distinction between private

         15   information and information that is generally

         16   available within our normal social interactions.

         17             So the implications, again, family members

         18   are not human subjects if they identifiable, but no

         19   private information is retained.  Family members

         20   are human subjects if there are unique identifiers

         21   and private information is retained.

         22             So once one has made a determination of


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          1   whether the secondary subjects or family members

          2   social context, et cetera, are human subjects then

          3   the second level of analysis is relevant and that

          4   is, do we have to get consent from these folks and

          5   can we waive it?  Dr. Collins had already talked

          6   about or outlined these four criteria that are part

          7   of the regulations.  And I'm going to focus on

          8   number one and number 3, specifically.

          9             You folks here are probably well aware of

         10   the definition of "minimal risk."  So here's the

         11   key question:  does the recording of health

         12   information on secondary subjects pose more than

         13   minimal risk?  And you need to consider both the

         14   probability of a breach of privacy and the

         15   magnitude of harm should that breach occur.

         16             So I would say there's a couple factors in

         17   the magnitude of harm.  One is whether the health

         18   information is existing or not.  And much of the

         19   discussion around genetic information has focused

         20   on research protocols in which new information is

         21   generated about the future health risks of an

         22   individual, say BRCA1, testing protocol, for


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          1   example, heritor colon cancer risk, et cetera, in

          2   which new health information is being generated by

          3   the protocol.

          4             That's clearly not the circumstance here

          5   in that we're dealing with existing health

          6   information.  You're already relating information

          7   that is obviously known to the family members about

          8   that individual.  I would make a distinction,

          9   however, about whether the information is what I've

         10   termed "highly sensitive" or perhaps not exactly

         11   merely sensitive but at a somewhat lower level of

         12   sensitivity in suggesting that there are few

         13   aspects of research that may be focusing on sets of

         14   information that individuals might consider more

         15   problematic because they are elements of social

         16   stigma involved should there be a breach in

         17   privacy.  And I've listed the mental health

         18   conditions and I would say that that should not be

         19   taken as an all-inclusive or absolute condition but

         20   certainly some mental health conditions I think

         21   still are associated with significant stigma and

         22   discrimination. 


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          1             Issues like sexual orientation, criminal

          2   records, substance abuse records, et cetera, are

          3   the kinds of things that I think may constitute

          4   more than minimal risk in the  conduct of this kind

          5   of research. 

          6             So those are the recording of information

          7   on secondary subjects more then minimal risk --

          8   issue and I think the second aspect the magnitude

          9   is the probability.  And the IRB needs obviously to

         10   look at the data management protocol for the

         11   proposal in front of it.  What's the protocol

         12   that's being developed for the management of this

         13   kind of information?  How well have interviewer and

         14   data management personnel been trained?  And data

         15   security measures.

         16             And I think from a perspective in my

         17   experience the risk posed to privacy is at a

         18   personal level rather than at a database level. 

         19   And I think the risk of people hacking into

         20   databases or getting into locked cabins is

         21   relatively remote.  The possibility of individuals

         22   who are the interviewers coming across a juicy


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          1   tidbit of information that is shared among

          2   colleagues, I think is where the real risk arises.

          3             And this was illustrated with some of our

          4   research protocols in which a member of the kindred

          5   we were working with was a graduate student at the

          6   university as it turned out.  Our interviewers were

          7   graduate students at the university.

          8             The second project we were looking at

          9   genetic testing and the local Ashkenazi jewish

         10   community and many of those individuals are faculty

         11   members at the university.  So I think it's those

         12   sort of personal contacts that may end up being a

         13   greater risk to privacy in this context than data

         14   security measures, per se.

         15             So my conclusion is recording of health

         16   information on family members poses minimal risk if

         17   health information is not highly sensitive and if

         18   there are careful protocols and strong data

         19   security measures in place.

         20             The practicability of research without the

         21   waiver, I think a lot of folks are reasonably

         22   concerned that significant additional burdens of


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          1   informed consent will not make research projects

          2   feasible.  I think the question in this context is

          3   not, can this research project be carried out

          4   without a waiver if the project has not been

          5   adequately developed to address these issues. 

          6             But rather, I think the appropriate

          7   question is, could this line of research not be

          8   pursued if consent was a requirement.

          9             And I think along with this investigators

         10   and funding agencies clearly need to plan for

         11   appropriate support for consent where necessary. 

         12   And I think this is a new trend in the last five to

         13   ten years that funding agencies need to be aware of

         14   and need to evaluate protocols appropriately for

         15   data management.

         16             So conclusions, from my perspective, are

         17   family members human subjects?  Yes, if unique

         18   identifiers are associated with individual data and

         19   information consists of the kinds of things that

         20   we're typically interested in, health status,

         21   health history, et cetera.

         22             If family members are human subjects, can


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          1   consent be waived?  Yes.  It's minimal risk and

          2   which I would consider not highly sensitive data. 

          3   And you have strong data security measures in

          4   place.  And then the other three criteria would

          5   have to be addressed as well.

          6             Now clarification that's emerged in this

          7   debate the I've heard.  First of all, the analysis

          8   that I presented would require consent from only

          9   selected family members.  So only those individuals

         10   on whom you are retaining private information that

         11   are relevant.  Those family members who you haven't

         12   obtained any particularly interesting information,

         13   they're healthy, then it's not clear to me that

         14   consent needs to be obtained from those

         15   individuals.

         16             Secondly, this analysis is not relevant to

         17   take a family history in clinical medicine.  I

         18   think there are privacy concerns with taking a

         19   family history in clinical medicine, but these are

         20   not -- this is not the place to debate or be

         21   concerned about those.  I think a justification for

         22   family history in that context is quite different


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          1   and I don't see any reason why that should be

          2   impinged by this current debate.

          3             Thirdly, and this is something that Dr.

          4   Collins had already mentioned, some family history

          5   data can be extremely sensitive.  Have to find some

          6   better terms here -- history of child sexual abuse,

          7   for example.  How would one do research on that in

          8   pursuing the alleged abuser for consent is not an

          9   appropriate way to proceed.  And so however the

         10   guidelines are developed, there would have to be

         11   obvious attention to this kind of circumstance.

         12             Additional problems.  Temporary retention

         13   of private information on subjects before consent

         14   is obtained.  Now, I think very important to

         15   emphasize that the way that I've approached this

         16   argument is to identify subjects only after you've

         17   obtained the private information.  So, in a sense,

         18   it's backwards from our traditional approach which

         19   is to obtain consent before you pose the risk to

         20   the individuals.

         21             Now, the alternative here is to get

         22   consent on everybody before you even start to ask


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          1   questions about family history.  Now, I find that

          2   to be entirely impracticable, and that wouldn't be

          3   shut down research.  And so this, from my

          4   perspective, is indeed a compromise, but one that

          5   has to be directly addressed.

          6             Secondly, next ask the family members. 

          7   That can be ascertained indirectly from testing the

          8   family members and Dr. Collins already noted this

          9   difficulty.  You test one individual and you know

         10   the parent from the affected kindred is affected

         11   also.  Does the fact that you know that information

         12   and know the identify of that individual all of a

         13   sudden make them a subject?  And this is really a

         14   tough nut to crack if you try to think about the

         15   consent implications in that circumstance.

         16             And then, thirdly, deletion of data when

         17   subjects decline participation.  A smaller point,

         18   but still one that needs to be addressed.  You've

         19   identified a subject.  You think consent is

         20   required.  They don't consent to participate with

         21   you.  What is necessary from your perspective at

         22   that point.  Simply remove the identifiers from


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          1   that individual or does all the data and

          2   identifiers need to be expunged from the database,

          3   et cetera.

          4             A smaller point, but I think one that's

          5   been floating in genetics for a while about what

          6   constitutes withdrawal from research in pedigree

          7   studies.

          8             This was raised by Dr. Walter Nance and

          9   also our research group at Utah with this debate. 

         10   And the question is:  Can we ask family members to

         11   assume some responsibility for guarding the privacy

         12   of family members?  And I think folks have

         13   appropriately pointed out that people can refuse to

         14   participate at any time they would like and can

         15   refuse to answer questions about their family

         16   members.  It may add some additional layer of

         17   protection to reinforce to those individuals, but

         18   they probably shouldn't be telling you things that

         19   they think the family member might object to.

         20             Now, I don't think that's a solution to

         21   this problem, but it's worth considering as

         22   potentially an additional layer of protection. 


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          1             And then lastly, just some research

          2   strategies to consider.  Obviously development of

          3   careful protocols anticipate this problem from the

          4   beginning.  And I think for those genetic studies

          5   that are involved in identifying so-called

          6   interesting families are then subsequent more

          7   detailed analysis.  It's not clear to me, at least,

          8   that many of those initial projects need to be done

          9   with identifier.

         10             As you interview a large number of

         11   individuals and you've now identified a kindred or

         12   two or three that you think may be valuable for

         13   research, then you can focus your resources, obtain

         14   consent from those individuals within the family,

         15   and obtain their medical history.  And I think

         16   obviously a significant advantage of this approach

         17   is that you're going to get a much better history. 

         18   As folks have noted, the accuracy of secondhand

         19   information on health status is poor.  And so as

         20   you talk only to primary subjects about the health

         21   status of their family members, that can only be an

         22   initial stage of research because the quality of


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          1   that information in many circumstances is not very

          2   good.

          3             So by talking to the secondary subjects

          4   directly, not only do you address the consent

          5   issues, but obviously you get first-hand higher

          6   quality health data than you would otherwise.

          7             And then lastly, the broad survey is

          8   designed to create a database resource for research

          9   which is in part how this whole issue arose.  You

         10   should seriously consider avoiding highly sensitive

         11   questions of the kind that I've outlined and that

         12   may make the database less valuable for the conduct

         13   of research, but may help get around some of these

         14   difficult issues by not including data items that

         15   would be considered greater than minimal risk.

         16             So in a whole, I think from my

         17   perspective, these are legitimate issues that raise

         18   a number of complex questions, but I think it

         19   really does offer an opportunity to think through

         20   these issues and potentially to significantly

         21   enhance the quality of research in this arena

         22   without really creating significant roadblocks to


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          1   the conduct of this work.

          2             So thank you.

          3             DR. COLLINS:  Thanks, Jeff, for staying

          4   precisely on time.  That's much appreciated.

          5             I think we should hold the discussion

          6   until all the panel has presented because I think

          7   we'll see a number of these issues raised from

          8   different perspectives by all four.  And we do have

          9   time then for considerable opportunity for

         10   discussion.

         11             The next presentation is Terri Arledge. 

         12   Clearly the private sector is increasingly involved

         13   in genetic research, both in pharmacogenetics and

         14   the effort to identify susceptibility risks that

         15   will lead you to new ideas about therapies and so

         16   it's highly appropriate to have one of our

         17   presenters, in this case, Terri, who comes from

         18   GalaxoSmithKline.  All of us are still trying to

         19   figure out how to say that since it's a fairly

         20   recent merger between Galaxo Wellcome and

         21   SmithKline Beecham to come and give a perspective

         22   from the private sector about that is important


                                                                      271

          1   issue.

          2             It looks like we're ready to go.  Terri.

          3             DR. ARLEDGE:  Good afternoon.  My name is

          4   Terri Arledge.  I'm the U.S. department head of

          5   drug development genetics at GalaxoSmithKline.

          6             Today I want to talk to you about the

          7   pursuit of better medicines through genetic

          8   research and I want to thank you for inviting me.

          9             The overview of the presentation that I'm

         10   going to be giving today in the next 15 minutes,

         11   what I want to do is talk about the genetic

         12   research goals and initiatives at GSK.  I'm also

         13   going to touch on a multi-industry group,

         14   pharmacogenetics working group that's addressing,

         15   ethical, legal and regulatory issues with genetic

         16   research and to drug response.  We call that

         17   pharmacogenetics.

         18             And I will present GSK's perspective on

         19   family consent and suggested points to be

         20   considered.

         21             What are the key genetic research goals at

         22   GSK?  First we want to identify susceptibility


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          1   genes for common diseases.  These would be common

          2   diseases with large unmet needs.  The objective is,

          3   once we identify the susceptibility gene is to

          4   better understand the disease, hopefully identify

          5   new targets, and come up with better therapies.

          6             We want to use the results of the genetic

          7   research to discover new medicines.  We want to

          8   improve the safety and efficacy of medicines by

          9   understanding the genetic basis for both positive

         10   and negative drug response in individuals.

         11             Now, this is on both our marketed

         12   compounds and drugs that are in development at this

         13   point.  And we want to promote education and

         14   informed discussion about genetic research.

         15             Now, we have a genetics counselor on staff

         16   who acts as an interface with our patient groups

         17   and health care providers.  We also have personnel

         18   who are involved in the ethical, legal, and social

         19   issues discussions involving our genetic research.

         20             Now, there are really two key initiatives

         21   in genetic research at Galaxo Wellcome.

         22             First we've got understanding drug


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          1   response which is the area that I work in.  Where

          2   the objective is to correlate genetic markers with

          3   safety and efficacy outcomes and target treatments

          4   appropriately for the right patients.  We get the

          5   right medicine to the right patient. 

          6             The other initiative is to better

          7   understand the disease.  And this is the area where

          8   we're looking at disease susceptibility genes in

          9   order to build or better understand the disease,

         10   come up with new targets, and develop new

         11   therapies. 

         12             Our clinical genetics networks have been

         13   set up to look for disease susceptibility genes. 

         14   These are large, interimational studies among

         15   academic institutions, genome screening centers,

         16   and genetic epidemiology centers. 

         17             The clinicians and the genetic

         18   epidemiologists have come together to develop

         19   protocols with well-characterized, standardized

         20   patient assessment criteria.

         21             The investigator collects a detailed

         22   family history, clinical information, and DNA from


                                                                      274

          1   affected and unaffected siblings and parents. 

          2   Informed consent is gathered from all study

          3   participants and the information, the data and the

          4   blood sample, or DNA sample are coated with a

          5   patient code number prior to leaving the

          6   investigational site.

          7             Again, what we want to do is identify

          8   susceptibility genes, look for new targets, look

          9   for better therapies.

         10             Examples of some of the common diseases

         11   that we're looking at right now include asthma,

         12   depression, COPD, early onset heart disease, and

         13   osteoarthritis.

         14             Now, pharmacogenetic research is the type

         15   of research that I'm involved in.  What we are

         16   looking at is how genetic differences among

         17   patients influence your response to medications. 

         18   In some of our drug development trials, GSK has

         19   included pharmacogenetic research.  Participation

         20   in the pharmacogenetic research portion of the

         21   trial is voluntary.

         22             Patients who are in the main clinical


                                                                      275

          1   protocol do not have to participate in

          2   pharmacogenetics.  If they choose to, they sign a

          3   separate informed consent, they give us a DNA

          4   sample, that's coded with the subject trial

          5   identification number, only the investigator, the

          6   physician at the site, can actually link a number

          7   to a patient name.  And that information is used --

          8   we use that information to correlate drug response

          9   with genetific information.  And that's from pooled

         10   data, either pooled across the study or pooled

         11   across multiple studies.

         12             Now, the SNP map is also offering us a new

         13   avenue of research in pharmacogenetics.  Basically

         14   what we think will happen is because the SNPs are

         15   fairly frequently and evenly distributed along the

         16   genome, they make for good landmarks for what we're

         17   looking for.

         18             What we are anticipating is that we'll end

         19   up with a section of the SNP profile in which we've

         20   got patients without a side effect and patients

         21   with a side effect.  And they end up with a SNP

         22   print that is predictive of the specific side


                                                                      276

          1   effect.

          2             Now, we would use this information to

          3   build the medicine response test so that health

          4   care providers are able to choose the right

          5   medication for their patients using this further

          6   information that we can provide.

          7             I also want to touch on the

          8   pharmacogenetic working group.  This is a multi-

          9   industry group.  It involves 12 pharmaceutical

         10   companies that have gotten together to advance the

         11   understanding and development of pharmacogenetics

         12   by openly addressing and disseminating information

         13   on noncompetitive topics such as ethical, legal,

         14   and regulatory issues.

         15             The first output, the first example of

         16   what they've been doing is that they define the

         17   terminology we use in pharmacogenetic research.  So

         18   they came up with standard definitions for coded,

         19   de-identified, anonymized, and anonymous.  If we

         20   are all using the same terminology, it makes it

         21   much easier for ethics committees, IRBs,

         22   regulators, sponsors, investigators, and patients


                                                                      277

          1   to understand what it is we want to do with the

          2   samples and the data.

          3             Now, these standard terminology have been

          4   accepted by the NIH pharmacogenetic working group. 

          5             Their follow-up activities include

          6   sponsoring symposia, preparing publications,

          7   interfacing with U.S. and European regulators, and

          8   addressing elements of pharmacogenetic research

          9   protocols and consents.

         10             Now, I do want to -- now that you have

         11   background on what we're doing and why, I did want

         12   to try and go through a few things that I would

         13   like the committee and others to consider when they

         14   are discussing this issue.  One is, is there a

         15   distinction among different types of research?  Are

         16   there different social, ethical issues associated

         17   with genetic testing or genetic research on a

         18   monogenic disease versus looking for disease

         19   susceptibility genes for common illnesses or

         20   looking at pharmacogenetics.

         21             Additionally, as has been mentioned

         22   before, there are implications for study


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          1   participants.  Requiring family consent might

          2   impede study participation.  And we also want to

          3   look at the implications for the feasibility

          4   research.  And while it's inappropriate to say that

          5   costs are inconvenience, it's at all a justifiable

          6   reason for trampling on anyone's rights.  We do

          7   need to make certain that when we implement family

          8   consent that it's done in a way that doesn't

          9   completely shut off important research.

         10             Some of the points that we would like to

         11   be considered during the discussion and debate is

         12   the scientific rationale for collecting family

         13   history.  Is there strong scientific rationale?

         14             Is there justification for the degree of

         15   detail that's been collected?  Is there some degree

         16   of confidence that the subject is a credible source

         17   of family history?  Has the researcher implemented

         18   safeguards in data collection environment, data

         19   access, and release of data and results?

         20             Now, we think that informed consent is

         21   critical to ensuring that patient's rights and

         22   welfare are protected.  And we think it's the


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          1   responsibility of sponsors, ethics committees,

          2   investigators, everyone involved in clinical

          3   research and in all types of research to ensure the

          4   integrity of the consent process. 

          5             We would, however, make a few

          6   recommendations to be considered during the

          7   discussions.  We think that responsibility for

          8   assessing family consent issues should remain with

          9   local investigators, ethics committees, and

         10   research sponsors.  And that what is valuable would

         11   be educational and guidance materials developed for

         12   use by researchers, ethics committees and sponsors.

         13             Thank you. 

         14             [Applause.] 

         15             DR. COLLINS:  Thank you very much, Terri.

         16             We now have the opportunity to listen to a

         17   couple of perspectives from notable consumers.  And

         18   I think that's highly appropriate for this

         19   particular discussion.  For some reason three-

         20   quarters of the people on this panel have Terri as

         21   their first or last name which may lead to some

         22   confusion -- 


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          1             [Laughter.] 

          2             DR. COLLINS:  -- but I'll try not to fall

          3   into that trap. 

          4             The next presenter is Sharon Terry who --

          5   as the co-founder of the pseudoxanthoma elasticum

          6   interimational effort which is a consumer group

          7   studying this disorder called PXE -- has played a

          8   significant role for that disorder, but in a much

          9   larger way with the genetic alliance has been one

         10   of the true leaders in the enterprise to try to

         11   raise consciousness about the issues that surround

         12   families that are struggling with genetic disease

         13   and at the same time trying to encourage research. 

         14   And so Sharon brings a great deal of experience to

         15   this issue.  And as soon as we get the computer to

         16   work we will get to hear about that.

         17             While we're waiting, I meant to say in my

         18   presentation, there is a trans-NIH group that has

         19   recently formed to look at this question about

         20   obtaining consent from family members in pedigree

         21   research because it is of great interest to the NIH

         22   to see how this plays out.  That group is being co-


                                                                      281

          1   chaired by Jim Hanson and Sarah Carr who are both

          2   here today and I'm sure would be glad to say more

          3   about what the goals of the group are.  It's

          4   relatively early in its existence, but it is

          5   another entry into this area that hopefully will be

          6   collecting useful data to inform the discussion.

          7             How are we coming.  It's a big file. 

          8             Sharon Terry.

          9             MS. TERRY:  Thank you.  Today I'm going to

         10   give you briefly a consumer perspective on informed

         11   consent and third-party issues.  I'm going to begin

         12   by speaking about my perspective which is informed

         13   by my experience.  I'm the parent of two affected

         14   children.  As Francis mentioned, my husband and I

         15   learned about five years ago that our kids had a

         16   rare genetic disorder and learned some rather

         17   devastating things a couple days before Christmas

         18   and so went through all the typical things that

         19   parents do in this situation.

         20             I'm also a participant in research.  Two

         21   days after our kids were diagnosed, our blood was

         22   drawn without informed consent.


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          1             I'm also a researcher.  I've done a great

          2   deal of research on this disorder leading to back-

          3   to-back papers in nature genetics last year and

          4   also filing an application for a patent on the PXE

          5   gene.

          6             I have a masters degree in religious

          7   studies.  I am truly a consumer and come to this

          8   entirely as a consumer and not as a scientist. 

          9             I'm the administrator for PXE

         10   Interimational, we have 2,000 affected individuals

         11   registered, 50 offices worldwide.  I run a 17-lab

         12   research consortium.  And I'm a board member for

         13   the genetic alliance which is a coalition of over

         14   300 lay advocacy groups working to promote healthy

         15   lives for people with genetic diseases.

         16             In 1995 Elizabeth and Terry were diagnosed

         17   with PXE.  I do have informed consent to use this

         18   picture. 

         19             [Laughter.] 

         20             MS. TERRY:  And they do charge me a

         21   royalty every time I use it. 

         22             [Laughter.] 


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          1             MS. TERRY:  We went through all the

          2   typical things that parents do being overwhelmed

          3   with what this disease meant to us and our family

          4   and our children.  But then decided to face this

          5   head on and look at what we could do to advance

          6   research on the disorder.

          7             We realized quickly that there was a

          8   scientific and political reality and that is that

          9   gene discovery and genome sequencing have no

         10   meaning unless correlated with real people.  So all

         11   the wonderful hype and excitement around sequencing

         12   the genome is important, but until we get the

         13   correlations we need, they won't be as useful as we

         14   need them to be.

         15             Talk a little bit about informed consent. 

         16   I see that really as a seesaw balancing on ethical,

         17   legal, and social issues.  And a number of

         18   continuums being really critical in considering the

         19   risks.  And those continuums we have talked a

         20   little bit about earlier, the type of research, the

         21   length of research, common versus rare diseases,

         22   the morbidity of the disease, the mortality, the


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          1   perceived stigma, familial awareness about the

          2   disease and the community climate.

          3             And until we really start to look at the

          4   nuances of those balances and those risks and

          5   benefits, I don't think we can make any kinds of

          6   assumptions in general about informed consent.

          7             When our parents deliver genetic

          8   information to us as offspring that all of our

          9   information comes from our parents, and we don't

         10   ask our parents if we can give that information to

         11   our offspring.  And so in some sense genetics and

         12   genetic information presents a whole new scenario

         13   and new understanding of family.

         14             I didn't ask my parents if I could give

         15   their genes.  I assume that that, of course, would

         16   be fine.  And so I believe also inherent in that is

         17   something of their medical history and my medical

         18   histories being passed to our children.  And I

         19   think it redefines family in a new way for us as

         20   people and as something that we need to discuss as

         21   a society.

         22             Informed decisionmaking we think begins


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          1   with the individual and we've heard a little today

          2   about some other pieces of that and I propose to

          3   make that fairly concrete and say that the

          4   individual resides within a family and there isn't

          5   anyway to divorce informed decisionmaking for an

          6   individual from the family.  Even if the person is

          7   alienated from the family, genetics ties them to

          8   the family.

          9             I further would recommend that we always

         10   look at that within the context of community.  I

         11   think informed decisionmaking is very different for

         12   different communities.  I think marginalized

         13   communities and disenfranchised communities have a

         14   very different experience of research.  I think the

         15   community context is critical for understanding

         16   what is appropriate and what is not.

         17             And within that community sometimes

         18   resides the research enterprise and sometimes

         19   outside that community and the same goes for the

         20   health care enterprise.  And I think we need to

         21   look at where do those circles overlap, acknowledge

         22   where they overlap, acknowledge where they don't


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          1   overlap, and accept that we need to work within

          2   those parameters.

          3             I don't think there's anything wrong with

          4   pushing the envelope, pushing the edges, but I

          5   think that we at least in the genetic alliance, the

          6   300 or more groups that we speak with regularly

          7   have worked really well with researchers when we've

          8   said, "here is our agenda, and there is your

          9   agenda, and here is where they overlap and here's

         10   where we can live together and really acknowledging

         11   that quite honestly."

         12             I brought an epidemiological study in

         13   which in some sense has been used as a model for a

         14   number of other groups.  The study is looking at

         15   600 individuals with PXE both for natural history

         16   and also for characterization of the phenotype now

         17   that we have the genotype.  It's an IRB-approved

         18   questionnaire even though we are not federally

         19   funded, so we didn't need to do that.  We felt it

         20   was very important.  We have a consent and assent

         21   process for adolescents.  Again, I underline the

         22   word "process" it's a fairly lengthy process.  It's


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          1   really critical that it's a process and not just a

          2   form.  And it does have a form at the end.  But it

          3   has been really well established in terms of being

          4   a process.

          5             Information about relatives is obtained

          6   without identifiers.  And informants contact

          7   relatives.  So if individuals identify -- say to me

          8   that they have relatives who have PXE, I ask them

          9   to go and speak to the relatives.  I don't contact

         10   the relatives myself.

         11             I think there's a number of myths that we

         12   need to consider when we're talking about informed

         13   consent for third parties and those myths, I think,

         14   are that privacy is possible.

         15             In this world now, I don't think privacy

         16   is possible.  I think the critical issue is

         17   confidentiality.  I think misuse of information is

         18   a much more critical issue than actually keeping

         19   information private.  I think you will hear, after

         20   me, Terri Seargent's story and see that misuse of

         21   information is a much more critical issue.  Those

         22   people who work in IT will tell us privacy is not


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          1   something we can be too concerned about anymore in

          2   the sense of retaining it.  What I want to see is

          3   legislation that helps us to know that our

          4   information will not be misused.  That would be the

          5   critical piece for this.

          6             It's a myth that samples can be stripped

          7   of identifiers, even totally anonymized samples are

          8   still samples of DNA and DNA is probably the

          9   ultimate identifier.  So in another age, ten years

         10   from now, we'll be laughing at ourselves for having

         11   this discussion and using these words.

         12             Humans are subjects.  I also take a great

         13   deal of issue with the word "subjects" nd I'd go a

         14   little farther than Francis even and not only using

         15   the king and queen analogy, but maybe to address

         16   yours, you Bob, if you had been invited to be a

         17   part of this committee as a subject of the

         18   committee, you would not feel as good as being a

         19   participant of the committee.  So for those of us

         20   who are people involved in research, we much prefer

         21   to be called participants in research and to work

         22   with the researchers.


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          1             It's a myth that voluntary informed

          2   consent is attainable.  And to a greater or lesser

          3   degree, again, all those scales and continuums come

          4   into play when you're being faced with a research

          5   issue as a family, as a person, you are not really

          6   making voluntary informed consent.  I liken it to

          7   having a rope hung out and you're falling, do you

          8   grab the rope or not?  That's an easy answer.  And

          9   it isn't really making a voluntary decision.

         10             Now, I also do agree that even, for

         11   example, when my blood was taken without my

         12   informed consent, was there a great deal of risk to

         13   me?  No.  But I think we need to continually look

         14   at what does it mean to consent somebody especially

         15   when they're vulnerable and not just vulnerable

         16   according to the kind of end back sorts of

         17   parameters of vulnerable populations, pregnant

         18   women, children, that sort of thing, but also

         19   what's the degree of morbidity and mortality in

         20   their disease, what is the chronic effect on the

         21   family, that sort of thing.

         22             Genetics is about the individual -- have


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          1   talked a little about that.  I think genetics is

          2   really about the family and the community and it

          3   makes it a much more complex issue for us than a

          4   simple visit to the doctor.

          5             It's a myth that research is altruistic

          6   and you discussed that at length this morning.  I

          7   don't mind that research costs something, that

          8   drugs cost money to develop; but, again, I like it

          9   when we say, quite honestly, this is my agenda and

         10   that's your agenda and here's where they overlap

         11   and we live quite well within that overlap.  So I

         12   think it's a myth to continually say though that

         13   it's an altruistic endeavor.

         14             And it's also a myth that the public is

         15   going to learn truths about genetic research via

         16   the media. 

         17             [Laughter.] 

         18             MS. TERRY:  The media is going to teach us

         19   a lot of things and most of it won't be the truth

         20   about genetics.  So I think that we have a lot of

         21   work to do to make sure the real information is out

         22   there and informed consent can be truly had in


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          1   terms of the whole population.

          2             I would propose a number of guidelines

          3   that we have culturally sensitive research.  That

          4   research has to be done in a context and that

          5   includes all kinds of communities everywhere, not

          6   just middle-class white Americans.  So I think it's

          7   a critical issue that we should look at.

          8             That we convey non-coercive hope and not

          9   hype.  I think that also we can go on about that

         10   that a lot of times research conveys a great deal

         11   of hype and that's not a fair way to even look at

         12   consenting anyone.

         13             I think we should contact the informant

         14   only.  The informant, again, being like Mary Kay

         15   said, perhaps the mother of a child who comes to

         16   clinic or perhaps the person themselves.  The

         17   contact should remain with the informant only.

         18             The informant can extend that contact if

         19   they so desire.  Informed consent process should

         20   occur for all who are contacted.  So once a person

         21   is contacted, they are now a participant in

         22   research and there should be informed consent.  And


                                                                      292

          1   we should have state-of-the-art data protections

          2   and our IT people are certainly working on that,

          3   but they should continually be addressed and

          4   improved.

          5             I think the bottom line is that together

          6   we can balance the requirements, the research, and

          7   the needs of the individuals in the context of the

          8   family.

          9             Thank you. 

         10             [Applause.] 

         11             DR. COLLINS:  Thank you, Sharon, that was

         12   great and all said very clear.

         13             The final presentation of the panel is

         14   from Terri Seargent who represents a somewhat

         15   different consumer perspective having gone through

         16   the experience of learning that genetic information

         17   can in fact be used against you and Terri has been

         18   very willing to share that experience in other

         19   settings.  We are fortunate she is willing to do so

         20   today.

         21             Terri. 

         22             MS. SEARGENT:  Good afternoon.  You'll


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          1   have to look at me, let me make a presentation. 

          2   Sorry.

          3             I would like to take a moment to than the

          4   committee for addressing this very important

          5   subject and seriously considering all the issues

          6   involved and for inviting me here today to tell my

          7   story.

          8             Although I have never taken part in a

          9   research study, my story is an example of the

         10   devastation which did happen due to the misuse of

         11   personal medical information. 

         12             I was introduced to the implications of a

         13   genetic disorder twice in my life.  The first time

         14   was when my 37-year-old brother died of a genetic

         15   disease called Alpha1.  The second time was ten

         16   years later when I was diagnosed with the same

         17   disease, Alpha1; and fired from my job because of

         18   it.

         19             Alpha1 is a hereditary, chronic, usually

         20   fatal, recessive disorder in which a low

         21   concentration of Alpha1 antitrypsin is associated

         22   with slowly, progressive, severe lung disease that


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          1   manifests itself in the third to fourth decade of

          2   life.  Twenty million people carry the Alpha1 gene.

          3             In April 1999, I went to the doctor for

          4   what I believed was allergy problems.  In

          5   disclosing my family history I told the doctor that

          6   my brother had died from Alpha1 at age 37.  A test

          7   was immediately ordered to see if I too might have

          8   the disorder.

          9             When the test came back showing that I do

         10   have the defective gene my doctor told me about the

         11   replacement therapy that would keep my symptoms at

         12   bay and protect my lungs against infections.  He

         13   also told me that the treatment would allow me to

         14   continue to live a productive life and not

         15   drastically deteriorate the way my brother did.

         16             After watching my brother die a horrible

         17   death from Alpha1, I opted for the treatment.  To

         18   me there was no alternative.  It was a way to keep

         19   from dying.  That decision cost me my job and my

         20   family our middle-class lifestyle.

         21             I was employed for three and a quarter

         22   years where my annual salary reviews were excellent


                                                                      295

          1   and I had salary increases of 60 percent.  The

          2   company was partially self-insured.

          3             In September 1999, the in-house plant

          4   administrator, who is also the human resource

          5   director, and accounting manager had requested and

          6   received a letter of necessity from my doctor

          7   stating the diagnosis, treatment, and longevity of

          8   treatment.

          9             She did the initial investigation into the

         10   prescribed treatment and found out that the cost of

         11   the drug alone would be approximately $48,000 a

         12   year.

         13             In November 1999, she disclosed to the

         14   president of the company that I had a, quote,

         15   "blood disorder and was facing expensive

         16   treatments." end quote, as reported by her in her

         17   EEOC affidavit.

         18             After another great review and salary

         19   increase in November, by the president and vice

         20   president, I was unexpectedly told my services were

         21   no longer needed, five days before Christmas.

         22             After I was identified as someone with


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          1   Alpha1 a genetic disease, I realized the

          2   seriousness of my disorder.  Not only could it take

          3   a life, it could, and did take my job and ability

          4   to make a living.  And now I'm uninsurable.

          5             When I lost my job, I lost all my life

          6   insurance and disability insurance.  The only way I

          7   will ever get them back is if I get a job in a

          8   company large enough where health questions are not

          9   asked on insurance forms.

         10             My family and I have been devastated by

         11   the loss of my job.  In less than ten minutes we

         12   went from being a secure middle-class family to

         13   financially scraping by and not knowing whether or

         14   not I could afford to continue my life-sustaining

         15   treatments. 

         16             Fortunately, in October 2000, I secured

         17   employment with Alphanet Incorporated and have

         18   health insurance benefits that I pay a partial

         19   premium.  My salary is considerably less than what

         20   I was making, the health insurance coverage is not

         21   as good, and I have to pay twice the amount of out-

         22   of-pocket expenses.


                                                                      297

          1             We have exhausted all of our savings and

          2   retirement trying to keep our family afloat during

          3   this time and to adjust to a minimal lifestyle.

          4             In March 2000, I filed a claim with the

          5   Equal Employment Opportunity Commission charging my

          6   employer with genetic discrimination.  I had to

          7   file under one of the three prongs of the Americans

          8   with Disabilities Act.  I filed under the second

          9   prong that is regarded as disabled.

         10             Even though I do not consider myself

         11   disabled, nor am I considered disabled by the

         12   government, and have not developed any disabling

         13   symptoms, the only way to be able to file with the

         14   EEOC was to declare my genetic condition a

         15   disability. 

         16             On November 20, 2000, the EEOC rendered a

         17   decision that I was discriminated against due to

         18   the cost of my treatment under the guidelines of

         19   the Americans with Disabilities Act.

         20             My hope is that that decision will give

         21   direction to those who have been unjustly

         22   discharged or harassed due to information obtained


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          1   about their genetic disorder.

          2             Our government is spending millions of

          3   dollars funding scientists to map human genes to

          4   find ways to cure disorders and disease so that we

          5   can have a long, quality life.  But what good is

          6   all this money and effort if no one is willing to

          7   take part in research, get tested, or receive

          8   treatment for the fix out of fear that the

          9   information may get into the wrong hands causing

         10   them to lose their job or not be able to obtain

         11   health, life, or disability insurance.

         12             Medical privacy in genetic discrimination

         13   is a real threat to real people.  The Council for

         14   Responsible Genetics a national bioethics advocacy

         15   organization has documented more than 200 reports

         16   of genetic discrimination.

         17             A 1995 Georgetown University study found

         18   that three out of 332 families belonging to genetic

         19   disease support groups, 22 percent said they had

         20   been refused health insurance.  And 13 percent said

         21   that they had been fired from their jobs because of

         22   perceived risks attributed to their genetic status.


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          1             In the Alpha1 community alone, there are

          2   several reports of misuse of private medical

          3   information.  A young, single mother was identified

          4   accidentally when she had a pre-op X-ray for foot

          5   surgery.  She was harassed at work until she left

          6   and took an other job. 

          7             An infant that was born with an unrelated

          8   problem had to have corrective surgery.  His liver

          9   became very slightly enlarged after the surgery

         10   because of the medications he was taking. 

         11   Consequently the orders were read wrong and an AAT

         12   deficiency test was done and surprisingly he was a

         13   ZZ.  He is now a toddler with no symptoms.  His

         14   diagnosis will haunt him and his ability to obtain

         15   health insurance in the future if protections are

         16   not put in place.

         17             An asymptomatic Alpha was identified

         18   through family members that were also ZZ.  This

         19   Alpha is in her mid-50s with normal lung function

         20   and has been denied life insurance over and over.

         21             This is a very typical and reoccurring

         22   problem in the Alpha1 community.  Due to Alpha1


                                                                      300

          1   being a genetic condition, family members are too

          2   quick, out of caring, to give names and relations

          3   to doctors and researchers.

          4             A 28-year-old daughter of an Alpha

          5   personally told me she refused to get tested and

          6   will not discuss it because she is afraid she will

          7   lose her job and her insurance.

          8             A family of four siblings, three of which

          9   had tested positive as ZZ Alphas could not talk

         10   their older sister into getting tested.  In fact,

         11   the fear of anyone thinking that she too could have

         12   this deadly genetic disorder caused her not to have

         13   any contact with her siblings for years to protect

         14   her privacy.

         15             When symptoms began to show at age 62, she

         16   finally agreed to be tested.  The damage to her

         17   lungs is so significant that she needs a lung

         18   transplant.  If she would have gotten tested

         19   earlier and started a replacement therapy, she may

         20   have averted the need for the transplant. 

         21             It is because of this same fear that more

         22   people are not coming forward to tell their story. 


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          1   To protect their privacy and their standard of

          2   living, people are making choices based on fear and

          3   knowledge that at this time there is no protection

          4   to safeguard them against devastating consequences. 

          5   My story epitomizes that devastation.

          6             I think what concerns me most with what

          7   happened to me is that I lost control over my

          8   private medical information.  And because of this,

          9   it was used against me.  I no longer have the

         10   freedom to make personal choices.  I felt violated

         11   and stripped of all security.  Not from something I

         12   had done wrong, but because I have a genetic

         13   disorder, a chance at birth, and I wanted to choose

         14   to live.  But since it costs a lot of money,

         15   someone else whom apparently has no concern for my

         16   life chose for me.

         17             This is all anyone is asking for, respect

         18   each person's right to privacy and allow them to

         19   make their own choices on how their private

         20   information is given and used.

         21             I'm here today because I want research to

         22   flourish and personally understand the benefits of


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          1   genetic testing.  So we must go the distance to

          2   eliminate the fears so that participation in the

          3   research and the testing can be the life-giving

          4   benefit that you so desperately want and I so

          5   desperately need.

          6             Thank you for allowing me to share my

          7   story and my concerns, and Godspeed in research. 

          8             [Applause.] 

          9             DR. COLLINS:  Thank you, Terri, for a very

         10   powerful statement.  And a reminder of just how

         11   critical it is that we do protect this kind of

         12   information from breaches of confidentiality that

         13   can have very real risks.  That's a very important

         14   part of our conversation. 

         15             Mary Faith, should we take a break?

         16             CHAIRPERSON MARSHALL:  About ten minutes. 

         17             DR. COLLINS:  Okay.  It's suggested that

         18   we take a ten-minute break and then we will

         19   reconvene and get into the discussion. 

         20             [Brief recess taken at 3:30 p.m.]

         21             CHAIRPERSON MARSHALL:  What we would like

         22   to do during out discussion period is to ask --


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          1   we're going to designate until 4:30 as time for the

          2   committee and our ex officio members to interact

          3   with the panel and then open the time up at 4:30 --

          4   between 4:30 and 5:15 p.m. for public comment.

          5             There are two people who specifically are

          6   here to make public comments.  So when the public

          7   commentary period begins, perhaps we could hear

          8   first from Mr. Levinson and then secondly from Mr.

          9   Curtain.  That would be great.

         10             So let us move back to perhaps -- I'm

         11   going to ask Francis if he will moderate this

         12   session.  But just remind everyone who has

         13   something to say to remember that there's always

         14   and also someone else who has something to say. 

         15   Please don't repeat what someone else has said, and

         16   please don't be long-winded in the sense of asking

         17   questions that go on forever.  Thank you.

         18             DR. MORENO:  The first question is for

         19   Francis and it's a scientific question, and the

         20   second one is for anybody. 

         21             I attended a meeting of the Howard Hughes

         22   a few weeks ago which you also attended on the


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          1   structural biology.  And I was impressed that what

          2   the smartest people in the world are working on is

          3   what is now being called proteonomics.  That is to

          4   say, rather than genomic, it visualizing and

          5   mapping the protein.

          6             Where does proteonomics fit in your four

          7   pathways of genetic medicine?  That's my first

          8   question and I reserve the right to ask a second. 

          9             DR. COLLINS:  Well, sure.  In fact, there

         10   seems to be a great deal of press attention to

         11   proteomyces right now perhaps because people feel

         12   that genomic is now passe.  Boy that happened

         13   quickly, didn't it. 

         14             [Laughter.] 

         15             DR. COLLINS:  Never mind that we still

         16   have to finish the job of getting the sequence in

         17   finished form; never mind that there are all these

         18   other genomes to be sequenced; never mind that we

         19   don't understand how genes turn on and off very

         20   well.  Proteomyces is basically to study the

         21   protein products of the genes recognizing that

         22   they're the ones that do the work and certainly


                                                                      305

          1   we've been doing that for a long time, one protein

          2   at a time. But what is new here is the idea of

          3   doing this at large scale. 

          4             It is much more difficult to define a

          5   protium project in the same precise terms that we

          6   did a genome project.  It's much more open-ended. 

          7   You want to understand how many proteins there are,

          8   what kind of modifications they have, what other

          9   proteins they touch, where they live in the cell,

         10   all of this.  And while there is undoubtedly going

         11   to be a good deal of focus on this in both the

         12   private and the public domain, it seems unlikely at

         13   the moment that there will be the same kind of very

         14   goal-driven, milestone-driven effort that

         15   characterized the genome.

         16             I would say in my diagram proteomyces

         17   falls into that step of understanding the biology

         18   of the disease after you have pinpointed the

         19   variants that contribute to hereditary risk, how

         20   does that work, usually means you've got to get

         21   into proteins.  And to the degree that we can do

         22   that rapidly and in a global high throughput way,


                                                                      306

          1   we'll get there quicker.  But I don't think it is a

          2   brand-new arrow on the diagram. 

          3             DR. MORENO:  My second question is for

          4   anybody on the panel or in the room.  You mentioned

          5   the community consultation, shall I say, model?  We

          6   have one other experience with community

          7   consultation in human subjects research in this

          8   country, namely in the emergency room.  Not very

          9   much experience, perhaps.  Do we have any

         10   information about how that's gone, how that's

         11   worked, when it's been used, and do we have any

         12   better understanding about what community

         13   consultation means now than we did five years ago?

         14             DR. KOSKI:  No. 

         15             [Laughter.] 

         16             DR. COLLINS:  If I can without it being

         17   inappropriate -- oh, Greg, go ahead. 

         18             DR. KOSKI:  Yeah.  Just to respond a

         19   little split way.  It's very interesting that

         20   actually I can't remember now whether it was the

         21   genome institute or NCI, they held a have I think

         22   it was the first public consultation conference


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          1   here at this very center -- 

          2             DR. COLLINS:  NIGMS.

          3             DR. KOSKI:  Oh, is that where it was. 

          4             DR. COLLINS:  In collaboration with

          5   genome; yes. 

          6             DR. KOSKI:  One of those places.  And it

          7   was very interesting.  I think the take-home

          8   message from it was that the public in fact has an

          9   awful lot more interest in a lot of this stuff and

         10   an interest in being involved in it than we may

         11   have actually given them credit for.  There was an

         12   enormous amount of interest and so that's a good

         13   thing.  I think the experience though from the

         14   emergency waiver of informed consent and the

         15   community consultation there that we really have

         16   very little experience.

         17             I'm only aware of, I think, two projects

         18   that have been approved under that provision in the

         19   last three or four years since it was initially

         20   approved.  And everyone has struggled with, what is

         21   the definition of community?  So we are still -- we

         22   have a long way to go there and I think that that


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          1   may be something worth further discussion in the

          2   future. 

          3             DR. COLLINS:  Could I take the moderator's

          4   prerogative here and ask that we try to focus as

          5   much as possible the discussion on the issue of

          6   family member consent since I think that was the

          7   intention of the organizers of this afternoon's

          8   conversation is to try to dig a little more deeply

          9   into that topic and not try to cover all of the

         10   issues that relate to genetic. 

         11             So, Abbey, is that where you're going? 

         12             MS. MEYERS:  Yes. 

         13             DR. COLLINS:  Okay.  Go. 

         14             MS. MEYERS:  Well, from everything that we

         15   heard this afternoon, what we heard about was

         16   discrimination.  But I'm sure that, for example,

         17   your boss didn't know what Alpha1 antitrypsin

         18   deficiency was and that it was a genetic disease. 

         19   They only knew that they had a $40,000 bill in

         20   front of them.  That's what they care about.

         21             So I'm trying to think whether, you know,

         22   to solve this problem do we need a genetic


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          1   discrimination law or do we need a medical

          2   confidentiality law?  If we had national health

          3   insurance it would solve the whole thing and nobody

          4   would get fired for having expensive diseases. 

          5   But, you know, what do you see as a way to solve

          6   this problem? 

          7             MS. SEARGENT:  In my situation, if he had

          8   not received that information, he would never have

          9   known the costs.  That's the point. 

         10             DR. COLLINS:  Mary Kay.

         11             DR. PELIAS:  I'd like to raise a question

         12   about what actually constitutes private information

         13   under the definitions in the federal regulations. 

         14   Jeff and I have been around about this a couple of

         15   times already and I have been unable to satisfy

         16   myself with the definition of private information

         17   with regard to genetics as private information as

         18   defined in the regulations.

         19             I find myself thinking that if we're going

         20   to allow the individual to define what is private

         21   and what is not, then perhaps we should say that

         22   all information generated from individuals that are


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          1   given to us in genetic studies by individuals

          2   should be regarded as private and be protected in

          3   that way.

          4             To make the point a little bit clearer, I

          5   think when we gather family history information in

          6   genetics, we find that some families are very open

          7   in discussing whatever malady that is in the family

          8   with regard to genetics and they don't feel

          9   stigmatized by discussing, for example, severe

         10   mental illness.  Other families on the other hand,

         11   are very close and very guarded about discussing

         12   the same disease that is in their family.

         13             So, as I've been talking about this, I

         14   think that maybe we have a sliding scale that goes

         15   everywhere from personal information to very, very

         16   private information and that depends on who is

         17   defining it.  So, if we're going to continue to

         18   collect information -- genetic information -- from

         19   families, should we operate from the premise that

         20   all information that we collect is private and

         21   should we then focus on establishing standards for

         22   maintaining confidentiality, very stiff standards


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          1   for maintaining confidentiality of all genetic

          2   information so that we can continue to do our jobs,

          3   and at the same time protect the individuals who

          4   are the foundations of all of our genetic studies.

          5             DR. COLLINS:  I think that's an

          6   interesting suggestion.  And maybe, Jeff, since you

          7   particularly addressed that a bit in your

          8   presentation, I'll just add a query to Mary Kay's. 

          9   In your presentation you talked about both the

         10   magnitude of the risk and the likelihood of the

         11   risk as though the real issue is the product of

         12   those two.  Maybe what Mary Kay is saying is that

         13   if the likelihood can be made very low, likelihood

         14   of disclosure, that even if the magnitude could be

         15   quite high if it happened, the product of the two

         16   is still a small enough number that you might call

         17   that minimal. 

         18             I hope I'm not overdoing the mathematics

         19   here.

         20             How does this play out in your mind

         21   because you thought about this a lot? 

         22             DR. BOTKIN:  Well, I think from my


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          1   perspective we're working with very little research

          2   in this arena to actually document what the risks

          3   may be.  And so a lot of it ends up being intuitive

          4   level, ad hoc, sort of arguments about what

          5   constitutes privacy and what constitutes minimal

          6   risk, et cetera.  You know, from my perspective I

          7   would be willing to concede that if in fact the

          8   risks were extremely low and documented to be such,

          9   then it would be minimal risk irrespective of the

         10   degree of harm that might accrue from a breach of

         11   that -- from a breach of confidentiality.  But I

         12   think getting to any firm conclusion that in fact

         13   documented risk was that low will be quite

         14   difficult.

         15             The other thing that I think has to be

         16   part of the public policy debate is simply people's

         17   sensitivity about that.  And if you ask members of

         18   the public about acquiring these kinds of -- this

         19   kind of information and retain that within a

         20   research enterprise, folks may not be willing to

         21   accept that as appropriate conduct of research

         22   whether or not there's a risk of further disclosure


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          1   and harm.  And I think it gets to the issue of what

          2   do we care about with breaches of privacy?  Is it

          3   the secondary harms that may result from that, or

          4   are there wrongs as part of the simple sharing of

          5   information whether or not it's disclosed further? 

          6   I think that needs to be a significant part of the

          7   public policy debate here.  Do we really care about

          8   secondary effects or is it simply acquiring the

          9   information to begin with that people are

         10   understandably concerned about.

         11             And I think the second aspect of that gets

         12   to the issue of privacy and minimal risk and how

         13   one defines those.  And I think with the conduct of

         14   any kind of research, if you were to ask each

         15   subject what they would consider minimal risk, you

         16   will get a wide range of answers.

         17             And so I think the approach has been for

         18   the IRB to make a determination based presumably on

         19   some sort of reasonable person standard about what

         20   for the population ought to constitute the

         21   definition of these terms rather than make it a

         22   subjective term that has to be addressed in the


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          1   context of each subject that may be enrolled.

          2             So I'm willing to accept a public policy

          3   process that makes that determination based on some

          4   reasonable person standard for those reasons.

          5             DR. COLLINS:  Mark Barnes and then Bob

          6   Levine.

          7             MR. BARNES:  A couple of brief points. 

          8   One is that this issue of the family member medical

          9   information that's embedded in the research record

         10   is not only a research issue, it is also an issue

         11   of those people who are undergoing genetic

         12   counseling and testing right now for together

         13   purposes.  And, you know, the hospitals every day

         14   and physicians face the issue of when a person who

         15   is the patient signs a release for their medical

         16   records and copy is made of the medical records is

         17   all of the information about their family members

         18   included in the record that is sent out to the

         19   third party.

         20             So I just want to make it clear that, you

         21   know, this is not just a research issue.  This is a

         22   medical records and medical privacy and


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          1   confidentiality issue generically.

          2             Second point is that there are precedents

          3   to this.  Because, for example, in the case of

          4   newborn screening for HIV disease, in fact, it is

          5   not the newborn's HIV status that is revealed in

          6   the newborn's record, it is the mother's HIV status

          7   that's revealed in the record.  And, so, there

          8   certainly are differences between HIV infection on

          9   the one hand and many different types of genetic

         10   testing on the other, but there are ways in which

         11   we have dealt with those issues before, largely by

         12   deciding on a case-by-case basis to redact medical

         13   records to redact those portions of medical records

         14   before we send the records out to a third party,

         15   again, on a case-by-case basis really trying to

         16   understand exactly who the party is to whom we're

         17   sending the information.

         18             Finally, on the issue of sort of a related

         19   point, but different, on the issue of health

         20   insurance.  I understand the point that in your

         21   case that the sort of exciting clause was the

         22   release of your genetic information, but in fact


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          1   whether you had a -- your employer had a self-

          2   insured ERISA plan or whether your employer had an

          3   actual group health insurance plan that he or she

          4   purchased from an insurance company.  The fact is,

          5   even if they had not received that information

          6   about you, about the genetic information, then they

          7   would have, at the end of the year, when the time

          8   came to renew their premium and they had a risk-

          9   rated premium, they would definitely have been

         10   given the information that they had one employee,

         11   and the employee probably would have been

         12   identified by name, who had a medical expense that

         13   exceeded by -- you know, by a factor of ten what

         14   the average medical claim history was for the

         15   average employee in that employment situation.

         16             So that they would have probably, if they

         17   were motivated by cost considerations, then I

         18   venture to say as a hypothesis that you would have

         19   been singled out anyway, simply through cost, and

         20   that's regardless of whether you had a genetic

         21   condition of a metastatic breast cancer or AIDS or

         22   HIV or anything else. 


                                                                      317

          1             MS. SEARGENT:  What you're talking about,

          2   Mark, that has been discussed a lot over the last

          3   year and a half.  And two points.  First of all, it

          4   is against the law for an insurance company to put

          5   a name to any of that situation.  So it's a small

          6   company, they could have figured it out.  But it

          7   could not be a name that was passed.  I did want to

          8   make that point.

          9             Secondly, in this case scenario, in mine,

         10   there were other people that had very large costs

         11   through that one year.  The point was, he knew the

         12   longevity and that was another situation.  I mean,

         13   his own father-in-law had cancer.  They removed him

         14   from the policy a year before and just took him on

         15   his own.  So there is -- things happen, but he knew

         16   the longevity of it and that is a major point. 

         17             DR. COLLINS:  Yes, Bob. 

         18             DR. R. LEVINE:  Thank you.  I just wanted

         19   to make a point about the use of risk probability

         20   and magnitude language in the definition of "risk". 

         21   I'm the one that wrote that definition, of risk,

         22   not of minimal risk.  And I just want to say


                                                                      318

          1   something about what was intended when the National

          2   Commission recommended this.  It was not intended

          3   to be a mathematical algorithm that if you

          4   multiplied the probability by the magnitude, if you

          5   came out with a low number you're okay.  What it

          6   really was, was an exhortation to the IRB to keep

          7   in mind that they had to consider both probability

          8   and magnitude.

          9             The third component that I put in that

         10   made it into the commission's recommendations, but

         11   did not make the cut in the regulations was that

         12   one should also consider the nature of the risks. 

         13   And you've given us a good illustration of one

         14   subset of the issue of nature when you identified

         15   sensitive information such as information that

         16   could expose you to prosecution or serious

         17   prejudicial behavior.  I think that's an extremely

         18   important one.

         19             There are some things that don't make you

         20   die often, but can create enormous problems in your

         21   life as we've heard from Terri Seargent. 

         22             On minimal risk my argument to the


                                                                      319

          1   National Commission was that this was a stupid

          2   idea.  And, you know, they were really distorting a

          3   lot of concepts there and this has been adequately

          4   addressed by many of my colleagues, most notably

          5   Loretta Kobelman. 

          6             I do want to say though that one of the

          7   problems with the definition of minimal risk is

          8   that it's not only measured in terms of what would

          9   occur in the daily life of the subjects, but also

         10   what would be -- what would happen in a routine

         11   medical examination.  And as Abbey Meyers has

         12   pointed out so clearly, in a routine history in a

         13   doctor's office they ask a lot of questions that

         14   are far more sensitive than any geneticist would

         15   ask.  And you've also heard about how available

         16   that is to insurance companies and so on.  So one

         17   might say in effect that if we can really take in

         18   account what happens in a routine medical

         19   examination very nearly all epidemiology and

         20   genetics pedigree work is minimal risk.  And I

         21   don't think that's what you want to say.

         22             Finally, Mark Barnes talked about


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          1   redaction of records.  People who create medical

          2   records know that that is very nearly impossible. 

          3   And in the cases where the court has required that

          4   you turn over research records to someone who

          5   appeals for them, they have usually made as part of

          6   their decision that it's the obligation of the one

          7   who requires the records to pay for the redaction.

          8             Thank you. 

          9             DR. COLLINS:  Thanks.  Moving to this side

         10   of the table, we have Felice and then Adil and then

         11   Denise.  Felice.

         12             DR. F. LEVINE:  Thank you.  This was a

         13   riveting panel from everyone.  The Terri's,

         14   Francis, Jeff.  It was just terrific.

         15             I want to focus and ask a question in the

         16   context of human participant protection and

         17   research.  Although other issues have come up that

         18   I think are important about privacy and protection

         19   of health related records and information.

         20             And that is, the hardest issue that I

         21   think among the many hard issues, the hardest that

         22   I think we face is the notion of human participants


                                                                      321

          1   other than those engaged in the research to be

          2   classified as human participants, secondary

          3   parties, tertiary parties, and each of you

          4   struggled with that issue in a way.  And this is --

          5   although it pertains to the particular context of

          6   the gene research we're talking about, this really

          7   has much broader implications for many other forms

          8   of research that I think Jeff outlined in his

          9   presentation.

         10             And I guess I'm wondering and want to ask,

         11   given the liabilities of defining, as human

         12   participants, secondary and tertiary parties not

         13   engaged in the research and communities, were the

         14   investment put in innovative protection of these

         15   data, methods not only of confidentiality, but also

         16   of not just redacting, which I recognize has

         17   problems, but even separation of files with ways of

         18   running analytic procedures from a research point

         19   of view that never even physically has the link and

         20   other methodologies that I think in the social and

         21   behavioral sciences I won't say are everyday

         22   commonplace methods, but certainly exist in our


                                                                      322

          1   scientific capacity to do.  Would that go a long

          2   way to keeping the best of ethical practices and

          3   the protection of human participants without the

          4   downsides of defining such a range of individuals

          5   as human participants? 

          6             DR. COLLINS:  Who wants to respond? 

          7   Terri. 

          8             DR. ARLEDGE:  Well, let me respond from an

          9   industry perspective.  We already have a number of

         10   those firewalls and data safety provisions in place

         11   to ensure that we -- but, keep in mind, it doesn't

         12   come without a cost.  Because everything that we

         13   design has to be GLP, GCP appropriate and if we've

         14   not identified samples, we can no longer make any

         15   kind of regulatory claims.  So even if we find

         16   something, it's not clear that we could go to the

         17   FDA, we could go to the EMEA and make a regulatory

         18   claim. 

         19             So it's possible.  We certainly have it in

         20   place.  It is not inexpensive.  But it is what

         21   we're doing.  It has certain costs associated with

         22   it.  We certainly have it in place, it is not


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          1   inexpensive, but it is what we're doing.  It has

          2   certain costs associated with it, both resource,

          3   monetary, and what we loose the ability to -- like

          4   I said, to make a regulatory claim.

          5             DR. F. LEVINE:  If I could just clarify. 

          6   That it isn't that I was necessarily suggesting

          7   that extreme was at all levels of risk necessary or

          8   appropriate, but what I was postulating is the

          9   spectrum of strategies that could be used short of

         10   defining individuals that are not human

         11   participants in any realistic way, human

         12   participants, in order to ensure that private

         13   information about them isn't vulnerable. 

         14             MS. TERRY:  I think I totally agree with

         15   that and see that the continuum that I named plus

         16   now the continuum trying to define who is a

         17   participant and who is not do lend us to say, let's

         18   put our resources elsewhere.  And the issue of

         19   protecting information is going to be much more

         20   critical.

         21             I think the other thing I tried to say too

         22   was that we are not going to be able to make


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          1   blanket statements for all of the U.S., for all

          2   families, for all communities.  We have said that

          3   over and over in many ways.  And that if we could

          4   start to look in communities and this is where I

          5   think a community IRB with community members on the

          6   IRB makes a real difference in terms of assessing

          7   for those individuals.

          8             Sometimes people ask me, how many people

          9   have refused to be part of my epidemiological

         10   study.  It's 900 fields that people fill out. 

         11   People told me, no one will fill this out.  Well, I

         12   got back 600 out of 1,000.  That's pretty good. 

         13   And not one person refused.  Because it's done in

         14   the context of a community.  And it's all over the

         15   world, but we have a community of persons who

         16   understand the values that we're espousing, and the

         17   protections.  It's a double-blinded thing, the

         18   codes are removed and only I have the key to

         19   anything. 

         20             DR. BOTKIN:  And I do think this is a

         21   wonderful opportunity to rethink research

         22   methodology with families and try to come up with


                                                                      325

          1   some new creative ways that may limit the risk.

          2             Along with that, I would say, that one of

          3   the risks we run in this whole enterprise is

          4   creating an aura around genetic information that

          5   isn't justified.  And to the extent that genetic

          6   information becomes exceptional, then, in fact, we

          7   may create the sort of shame and stigma and

          8   discrimination that we are trying to protect people

          9   against, but fostering that social attitude in the

         10   process.  I do see that as a problem.

         11                                 Medical information in

         12   general, but I think it probably goes along with,

         13   the more secretive we are about things, then the

         14   more people may feel ashamed by events that they

         15   can't control when disclosed.

         16             DR. SHAMOO:  I have a quick comment and a

         17   question for Mark.  Medical records are protected

         18   by state and federal law, a little bit federal law,

         19   but mostly state.  But research records is the

         20   property of the principal investigator in most

         21   cases, that's my understanding.  So the research

         22   records you can do whatever you want with it, so


                                                                      326

          1   far.

          2             The question is, we talked about an

          3   anonymization or delinking, and my question is, is

          4   it temporary or permanent and whether it is

          5   permanent or temporary, are we talking about

          6   destroying the fingerprint, the DNA fingerprint

          7   itself, so that it cannot identify the person or

          8   even destroying the tissue or just destroying it --

          9   there is still a file cabinet there, somebody --

         10   and it has happened to me.  I was in a research

         11   committee was trying to appoint me to something,

         12   and I got the job, they were supposed to, and I had

         13   access to the search committee's minutes so I saw

         14   all the pros and cons of what they said about me. 

         15             [Laughter.] 

         16             DR. SHAMOO:  So they have ways of -- and I

         17   went to the guy who said the negative comments, of

         18   course, he wasn't very happy. 

         19             [Laughter.] 

         20             DR. SHAMOO:  Did you really say that?  But

         21   anyway, if I didn't get the job, of course, I would

         22   have never seen those records.  So, what's your


                                                                      327

          1   answer?  Is it temporary; permanent; and what type?

          2             DR. COLLINS:  Well, I would be interested

          3   in Terri Arledge's response because I gather there

          4   has been a discussion in this working group about

          5   these definitions.  Certainly the numerous

          6   conversations about stored tissue disagreed to some

          7   degree about the definitions.  But I think most

          8   came to the general consensus that if you're saying

          9   "anonymized" you mean that it is irreversibly

         10   delinked, that that tissue cannot be connected with

         11   any individual by anybody who currently lives on

         12   the planet.

         13             Now, I will take the point that was made

         14   by one of the earlier speakers that that is perhaps

         15   a bit of a fiction in that DNA itself is capable of

         16   identification.  If you have something to compare

         17   it to and you're seeking a match, we do that in

         18   forensics all the time.

         19             A current assumption is that that would be

         20   impractical to do in most situations because we

         21   don't have databases about everybody's DNA to make

         22   that comparison and to be able to draw the


                                                                      328

          1   identities.  But that may be only a matter of time

          2   before that opportunity looms ever larger.  In

          3   which case, to call something truly anonymized may

          4   no longer be possible.  At least at this moment in

          5   time "anonymized" means irreversibly delinked in

          6   most people's parlance.  Is that how you did it as

          7   well? 

          8             DR. ARLEDGE:  Yes.  That is how the

          9   pharmacogenetics working group has defined this. 

         10   And to give you an example, we bring in samples,

         11   for example, undercoded.  And that would mean that

         12   they're coded with the individual subject

         13   participation number.  Only the investigator at the

         14   site can link a number with a name.

         15             We do some limited research, very

         16   restricted research while it's coded, and then we

         17   make them deidentified or, excuse me, anonymized

         18   which means we renumber the samples and the data

         19   and we destroy the mapping file.  That means

         20   they're anonymized.

         21             If we had a third party retain the mapping

         22   file that linked the two numbers, that would be de-


                                                                      329

          1   identified.  Sort of subtle, but we do not destroy

          2   the actual forensic results.  So it could be

          3   tracked back to someone if you had another DNA

          4   sample to compare it against.

          5             DR. THORNLEY-BROWN:  I just wanted to get

          6   the panel's opinion about recruiting the secondary

          7   subjects.  I mean, one of -- can you hear me?

          8             One of the reasons why get pedigree data

          9   is in order to study some of the relatives of these

         10   people. 

         11             I know, Sharon Terry, you mentioned that

         12   you believe that only the informant should be

         13   contacted.  Did other people on the -- that seemed

         14   a little bit impractical.  Do other people on the

         15   panel have comments? 

         16             MS. TERRY:  I can make a further comment. 

         17   Because of the shortness of the talk, I couldn't go

         18   into some nuances which are that, again, because

         19   it's a real community, I keep all the identifiers. 

         20   No researcher ever sees any data on anyone except

         21   what I give them in terms of DNA samples and

         22   phenotype information that's coded.


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          1             In various instances it is much more

          2   practical for Uncle John to call me and say:  could

          3   you call my sister, she really would love to hear

          4   from you.  And I do.  So within the context of what

          5   I see as a community within the values of that

          6   community, I think it works very well for me to

          7   approach other people.  If we're going to make

          8   absolutely blanket statements about protecting

          9   people, then I think we have to say the informant

         10   is the person we'll work with and we'll try to go

         11   through the informant to get to other subjects. 

         12             But I think in community contexts, and I'm

         13   working now with an African-American community with

         14   a native American community and it's working for

         15   them to come to the researchers as they need to

         16   rather than just going through the informant.  But

         17   I don't think we can make blanket statements about

         18   these things.

         19             DR. THORNLEY-BROWN:  You're talking about

         20   a very specifically defined community.  I'm

         21   thinking of other diseases, people with

         22   hypertension and kidney disease, with diabetes,


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          1   diseases that maybe subclinical, et cetera.  The

          2   community isn't as well defined. 

          3             DR. ARLEDGE:  If I can give you some

          4   experience that we've gone through because we are

          5   looking at these common diseases.  We're looking at

          6   cardiovascular disease and asthma and COPD and OA. 

          7   And the community is not well-defined.  We are

          8   still making preliminary contact with the families

          9   through the proband or through the informant.  And

         10   unless they tell the investigator it's okay for

         11   them to go ahead, the proband is the one that goes

         12   back to the family and asks them to participate or

         13   asks them to contact the investigator. 

         14             DR. COLLINS:  I'm involved in a study

         15   that's looking at prostate cancer in African-

         16   Americans and this is a challenging effort to try

         17   to enlist the participation of the families that

         18   are affected because of a number of issues. 

         19   Prostate cancer is still, in many of those

         20   families, a subject that's not talked about.  It is

         21   certainly a community that has considerable

         22   concerns about research in general for which


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          1   Tuskegee is still very much on their minds.

          2             And in that instance, in general the

          3   proband who is seen by a urologist is asked about

          4   family history.  If the family history appears

          5   fairly dramatic with multiple affected males, then

          6   that proband is asked to be the messenger to the

          7   rest of the family about an interest in

          8   participating.  But then you do end up with the

          9   investigator which in this case is the community-

         10   based -- often a urologist, often who is part of

         11   the same community contacting the other affected

         12   males directly after gaining permission to do so

         13   from the proband; and developing a relationship

         14   with them that is also associated with their

         15   specific informed consent.

         16             What you don't end up doing in general is

         17   having consent from everybody in the family, either

         18   because of geographic lack of availability, or

         19   because they're not affected, or because they're

         20   not interested.

         21             That's, I think, a fairly typical kind of

         22   scenario for the way a lot of this research goes. 


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          1   You start with an involved proband and then you see

          2   where it takes you.

          3                                 Mary Kay.

          4             DR. PELIAS:  I've been intrigued for quite

          5   a while now about this verb "to anonymize."  And I

          6   would like to put a question to the committee and

          7   to the panel about where the ultimate authority

          8   lies for stripping identifiers from samples,

          9   especially samples that we are collecting now and

         10   prospectively for future studies.

         11             Retrospective sample collection, that's

         12   one thing altogether.  But I have contended that

         13   it's important to recognize that the person who

         14   donates the samples may have some interest and

         15   should therefore at least retain or elect not to

         16   retain identifiers attached to those samples with

         17   the option for future feedback.  And I think this

         18   is something that we need to address as we're going

         19   through this business about consent, exactly how

         20   far can consent go and can it be a blanket consent

         21   and so on and so forth? 

         22             DR. COLLINS:  Now, those are very good


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          1   questions and it touches on the issue of under what

          2   circumstances does an investigator carrying out a

          3   genetic research protocol actually find themselves

          4   carrying the responsibility to recontact research

          5   participants because the finding is of such

          6   importance clinically that not to do so is to place

          7   those individuals at-risk.

          8             I didn't put that on my list of areas to

          9   look at.  But it is clearly one of the ones that's

         10   on some people's minds and pretty soon I'll

         11   probably need some additional guidance because I

         12   don't think there's any real consensus there. 

         13   Susan.

         14             MS. KORNETSKY:  Thank you.  This is more

         15   just a comment than a question and perhaps for Greg

         16   and the OHRP office to direct it to.

         17             I appreciate your article and actually as

         18   someone sitting on an IRB trying to instruct an IRB

         19   what to do when we actually get involved with these

         20   issues, I appreciate your article and your

         21   presentation.

         22             Two of the things that you mention, I


                                                                      335

          1   think we all recognize now where we haven't in the

          2   past that involving secondary family members can be

          3   research subjects.  And then we move on to the

          4   discussion about waiver of informed consent which

          5   you point out in your article.

          6             You correctly point out that the first and

          7   the third, the minimal risk and the practicability

          8   are the difficult ones to get over.  My question --

          9   my issue about minimal risk, we have often heard or

         10   IRBs have been told that genetic research should

         11   not be considered minimal risk.

         12             And I guess the issue is, does this mean

         13   that the research prior to steps being taken is

         14   minimal risk?  Or does this mean that there can be

         15   steps taken so an IRB can consider it minimal risk? 

         16   And this comes up not only with genetics, but with

         17   other types of questionnaires.  And there's been

         18   some inconsistency and perhaps when we do come up

         19   with some guidelines OHRP can help us understand

         20   how to interpret that minimal risk. 

         21             The third thing is the practicability. 

         22   And you had made a statement that it's not


                                                                      336

          1   necessarily the particular research project, but

          2   can any research project be done?  And both of

          3   these things have been a little bit inconsistent

          4   with at least the way IRBs have been operating.  So

          5   I guess my plea is that given this discussion, that

          6   there also be some interpretation of the

          7   regulations and that also that this applies to

          8   other research as well, not only genetic research,

          9   it has implications for that. 

         10             DR. BOTKIN:  Excellent question and I

         11   guess I would just make a couple of brief comments. 

         12   I wouldn't accept the distinction between genetic

         13   and nongenetic conditions in terms of minimal risk. 

         14   I think it hinges on other aspects of the

         15   information and how sensitive is it, how is it

         16   regarded within society, et cetera.  And it so

         17   happens that some genetic conditions fit that bill

         18   pretty well, but a lot of nongenetic conditions do

         19   as well.  So I wouldn't be so concerned about that

         20   aspect.

         21             I think the general question for debate is

         22   whether information, per se, and Dr. Collins had


                                                                      337

          1   pointed out, we're moving into the sort of

          2   psychosocial realm rather than physical risks.  Are

          3   there distinctions to be made between different

          4   kinds of information that will confer substantially

          5   greater risks for some types of information versus

          6   others, or is that entirely a subjective call.

          7             I think that kind of line drawing is

          8   something, of course that I attempted to do and

          9   folks have disagreed with where those lines are

         10   drawn.  But I think the general task is an

         11   important one.  And I think the practicability one,

         12   I would just echo a welcome for further discussion

         13   of that particular problem.

         14             And my presentation here may have been a

         15   little starker than what I actually believe.  I

         16   think the question is, can nobody do research

         17   without the waiver?  But, you know, does it create

         18   such a substantial barrier that it is unreasonable

         19   in balancing that with the potential benefits of

         20   the projects.

         21             MS. KORNETSKY:  I agree with your

         22   interpretations.  The point I want to bring up is


                                                                      338

          1   that this hasn't always been the IRB's

          2   understanding of those interpretations. 

          3             DR. COLLINS:  Sandy. 

          4             DR. CHODOSH:  I'm having some trouble,

          5   Terri -- this Terri, with what she is doing. 

          6   Because this is a little bit different than some of

          7   the other situations.  This is FDA-related research

          8   in which you are tagging a separate consent form

          9   onto a regular consent form that has to do with the

         10   actual drug trial.  That information of the regular

         11   drug trial obviously must be linked to what you're

         12   doing in terms of the other work or else what

         13   you're trying to do can't be done.

         14             That linkage to FDA-related information

         15   which goes to the FDA and which the FDA can now

         16   review and research on site and subpoena records

         17   that although confidentiality is always relative, I

         18   wonder about whether that linkage is really

         19   described very well.

         20             I had a problem actually with your folks

         21   in England when you were Glaxo discussing this in

         22   that they couldn't give me a good answer.  I said,


                                                                      339

          1   well, you can't just use the specimen of the DNA

          2   without the history and what happens with the

          3   study.  So why are you telling me this is a

          4   separate consent form?  It's not.  So we didn't do

          5   that part follow-on the study.  And I wonder what

          6   you're thinking is.  This is not a simple -- it's

          7   more complicated than usual genetic research. 

          8             DR. ARLEDGE:  Well, I agree with you, it's

          9   very complex and we periodically go back and review

         10   our processes, work with outside ethicists to try

         11   and ensure that what we're doing is the best that

         12   we can do to protect confidentiality.  So I'll

         13   start with that general thought and then I'll go

         14   down tot specifics.  Basically when we're doing

         15   what we call "coded research" which is

         16   pharmacogenetic research where the DNA sample and

         17   the results are coded with the subject number, and,

         18   again, only the investigator can relate that to a

         19   patient.  We restrict ourselves to looking

         20   specifically at candidate genes involved in the

         21   drug target or drug metabolism.

         22             Now, we don't return these results.  So


                                                                      340

          1   the results do not end up back in the patient's

          2   medical record.  We ask that the site ensure that

          3   they don't even write down that the patient was in

          4   the pharmacogenetic research in their medical

          5   record.  That information is kept just in the study

          6   file and they signed an informed consent document. 

          7             Now, when we produce tables it is just

          8   aggregate data. 

          9             DR. CHODOSH:  What you're describing would

         10   be illegal in the VA.  I don't know about the rest

         11   of the world.  But consent forms must be part of

         12   the medical record. 

         13             DR. ARLEDGE:  When IRBs have raised that

         14   issue, and that's actually been fairly infrequent. 

         15   There have only been two or three that have raised

         16   that issue.  We have told them that they need to

         17   follow the process that they have established, but

         18   it needs to be clear in the consent form what it is

         19   that they're doing and that the information will be

         20   in the patient's medical record.

         21             Now, we have argued that this is purely

         22   research.  It has nothing to do with medical


                                                                      341

          1   treatment or diagnosis.  We do not look at

          2   candidate genes that have clinical relevance.  And,

          3   therefore, this information does not need to be in

          4   somebody's medical record.  But it's up to the IRB.

          5             DR. CHODOSH:  I'm sorry, this is double-

          6   talk.  Because you're looking for things that have

          7   clinical relevance and therefore to say it doesn't

          8   happen, you know, is a little disturbing to me, you

          9   know.  How far back -- if this were not FDA-

         10   related, I would say that you probably have a much

         11   better chance at ensuring a higher level of

         12   confidentiality than you could in this situation. 

         13   I really am concerned about this. 

         14             DR. ARLEDGE:  When I say "clinical

         15   relevance" I do mean that we're not looking at

         16   specific genes that are associated with disease,

         17   Huntington's, BRCA, those kinds of things.  So if

         18   that will help you any with the clinical relevance.

         19   

         20             The other thing is, a lot of this

         21   information is so new that we are just in the

         22   hypothesis generation phase and we need to confirm


                                                                      342

          1   it, replicate these findings in order for it to

          2   truly be clinically relevant.  But even if we

          3   replicate it, remember, we're not a CLEO associate

          4   and not a CLEO-approved lab.  This is all research

          5   results.

          6             DR. KOSKI:  Thank you.  While this has

          7   been a very interesting discussion of a number of

          8   different points, I'm a little concerned that we

          9   still seem to be talking around the central issue

         10   here.  With medical records we have well-

         11   established procedures that we've used for years

         12   that determine when and how it's appropriate to

         13   allow access to medical records for research

         14   purposes with waiver of consent, what appropriate

         15   safeguards are and so on. 

         16             The real question that we are here to talk

         17   about right now is how do we apply that in a

         18   situation where we have one individual who has

         19   volunteered to participate in research who has

         20   access to information that would not otherwise be

         21   available that is of some concern to other

         22   individuals with whom they have relationships where


                                                                      343

          1   that information may have been obtained under

          2   certain expectations of privacy.  Okay.

          3             When is it permissible, okay, to have that

          4   individual disclose that information that has been

          5   given to them under some expectation of privacy for

          6   use in research, and when is it permissible for us

          7   to allow a waiver of the informed consent for those

          8   individuals about whom that information is being

          9   disclosed.  These are the real questions that we

         10   have to get to.  And at the risk of sounding like

         11   some kind of a slave driver here, I think it's

         12   important that we try to focus the discussion on

         13   this central issue.  Because if we -- the

         14   complexity of how do we deal with archive samples,

         15   how do we deal with, you know, this and that, we're

         16   going to miss the real meaty matter that we have to

         17   deal with right now.

         18             So I would ask you, please, if you could,

         19   try to focus a little bit on that.

         20             MS. MEYERS:  Well, I'm going to try again,

         21   but I think it's hard to get people to understand.

         22             A few months ago we had medical


                                                                      344

          1   confidentiality regulations were published and the

          2   Secretary has suspended them.  If we had guaranteed

          3   legal confidentiality of medical records that

          4   anything that we say about ourselves or our

          5   relatives would be confidential and nobody -- it

          6   wouldn't hurt anybody.  If I told you that my uncle

          7   had schizophrenia, my mother had -- you know, it

          8   doesn't matter if nobody can get into my medical

          9   records.  Even if I give that away for research, if

         10   you're showing a family three that is not

         11   personally identifiable to me, then it wouldn't

         12   matter what my relatives have.  All you would have

         13   is data on a family tree.

         14             DR. F. LEVINE:  Perhaps I was oblique, but

         15   I thought that was exactly what I was saying or

         16   suggesting or implying with my question and that is

         17   that unless a human participant is engaged in that

         18   research all of those secondary, tertiary, and

         19   community parties are not human participants and

         20   thus are not necessarily fall under any framework

         21   of consent.  That the human participants is that

         22   individual who has consented to be in that


                                                                      345

          1   research.

          2             If that person is sitting with a medical

          3   record in their drawer of their mother and chooses

          4   to hand it over, then that person perhaps is

          5   engaged in a criminal act himself or herself or

          6   something by turning over something that, you know,

          7   some private information.  But to respond to a

          8   series of questions doesn't -- about parties that

          9   one is connected to whether familial based or other

         10   forms of networks, I think leads us down a slippery

         11   slope.  Or I guess I was asking the panel, and I

         12   thought I got a pretty good response from the

         13   panel, it's potentially leading us down a slippery

         14   slope to anthropomorphize those individuals as

         15   human participants and I thought the responses were

         16   reasonably clear.  I say as a devil's advocate. 

         17             DR. KOSKI:  Well, I think we've seen the

         18   definition, it's the legal definition if you are

         19   within the regulations of human subject which is,

         20   of course, what the regulations talk about.  As

         21   being an individual about whom an investigator

         22   obtains private, identifiable information.  And,


                                                                      346

          1   so, you know, I think that this has been the

          2   interpretation that way it's been applied.

          3             Bob, I know, you may have again some

          4   further insight on this.  But I guess what I'm

          5   striving for in my comments is to try to get some

          6   real clarity here that can be used in a pragmatic

          7   way as to development of sensible policy guidance

          8   on this issue. 

          9             DR. COLLINS:  Well, it seems as if a

         10   number of the panelists have been trying to respond

         11   to that in the sense that it does seem that there

         12   may be considerable opportunity to utilize the

         13   waiver guidelines to fit this situation.  But that

         14   the real challenge is to figure out when do they

         15   fit and when do they not?  When are you in a

         16   circumstance where that family member is being

         17   exposed to a greater than minimal risk as however

         18   we now decide we want to define that.  But I think

         19   there has been some sense that the waiver pathway

         20   might be the most appropriate way to deal with the

         21   issue in that it does require the IRB to think

         22   about it, to look at the details of the situation,


                                                                      347

          1   to consider what is the information that's being

          2   collected from family members, and how much of a

          3   risk does it pose to them, and what kind of

          4   confidentiality practices are being applied to this

          5   particular circumstance.  So, not to overstate what

          6   may not be a consensus at all, but I think I heard

          7   a little bit of that in some of the responses.

          8             Bob seems anxious to respond, and then we

          9   have Mark, and then we should go to the public

         10   testimony. 

         11             DR. R. LEVINE:  I want to say that I do

         12   not think the waiver is the way to go. 

         13             [Laughter.] 

         14             DR. R. LEVINE:  I think that it's a bad

         15   definition.  It's a definition that was written

         16   without skill.  And it has create a category of

         17   secondary research subjects that is not part of the

         18   ethics or e-thoughts of any research group.  And

         19   now what we are trying to do is to make up for this

         20   poorly crafted definition by trying to squeeze it

         21   in under a waiver.  And what we ought to just say

         22   is, research subjects are people that we actually


                                                                      348

          1   engage personally.  And, also, part two of that

          2   definition was not intended to pick up people --

          3   relatives that you ask about their relatives.  It

          4   was intended to pick up such things as use of data

          5   sets, secondary use of data sets for research

          6   purposes. 

          7             I think what we really need is to rewrite

          8   that definition so that it's coherent. 

          9             DR. SIEGEL:  I think I'm struggling with

         10   the same thing.  I'm reading 21 C.F.R. Parts 50 and

         11   56 which define a human subject differently than

         12   4546.  21.50 and 56 define a human subject means an

         13   individual who is or who becomes a participant in

         14   research either as a recipient of the test article

         15   or as a control.  And where I guess I've been

         16   having a problem during this whole conversation is,

         17   much of the research that I've been involved with

         18   for the past 20 years has actually involved the

         19   collection of information from our research

         20   participants on family issues.  And depending on

         21   the type of research. 

         22             So, for instance, my own specialty was


                                                                      349

          1   psychiatric research, we collected a lot of

          2   information.  Because, again, along with looking at

          3   drug response, you're also looking at predictors,

          4   you're also looking at a lot of things. 

          5             Now, I guess where I'm having -- this

          6   discussion has never made its way onto that side of

          7   the fence.  It's always on the genetic side and I

          8   guess that's been my -- if it's an issue, shouldn't

          9   it be an issue or not.  And, again, we get into a

         10   regulatory definitional difference that sort of

         11   gets us all confused again; or me anyway.

         12             DR. KOSKI:  Yeah, I think it's very

         13   important to recognize that the definition under

         14   Title 21 is specifically crafted to deal with the

         15   type of research that FDA regulates, and, indeed,

         16   much of the research that we're talking about here,

         17   particularly that which would involve social and

         18   behavioral sciences, there is no test article.  And

         19   so we need to think differently about that

         20   definition.  But, I think the important point here

         21   is that if in fact there is a consensus that the

         22   regulatory definition was poorly written


                                                                      350

          1   misunderstood, or whatever, in the first place,

          2   then we ought to get down to the hard business of

          3   saying what it ought to be instead.  And this

          4   sounds like real progress.

          5             MR. BARNES:  Just a brief comment.  There

          6   actually are a host of other duties here which are

          7   not addressed in law at all, which is that for

          8   research participants or subjects who actually

          9   acquire genetic information on their relatives and

         10   their family members, they have no legal duty in

         11   regard to disclosure or maintenance of the

         12   confidentiality of that information in the way that

         13   all laws are drafted now.

         14             For everybody else there are at least kind

         15   of plenary ethical, legal, professional duties to

         16   keep information private.  But for those who -- but

         17   for recent participants who are actually given

         18   information by researchers about their family

         19   members, there is no duty to keep that information

         20   confidential because they're not a licensed

         21   professional, they haven't signed a contract or

         22   anything else, which raises a host of issues about


                                                                      351

          1   whether in fact research participants should

          2   themselves have duties of confidentiality.

          3             DR. KOSKI:  If I may just quickly respond

          4   to that.  While there may be no legal duty, okay,

          5   many would argue that the very nature of privacy

          6   and confidentiality and intimate relationships

          7   would mean that there is a moral duty to preserve

          8   the sanctity, if you will, of the relationship in

          9   which private information is disclosed to another

         10   person.

         11             After all, the only way that we can

         12   interact with people and get to know them is to

         13   share some information about ourselves in one way

         14   or another, and we do that within the context of a

         15   relationship that sets the bounds around how that

         16   information is going to be used.

         17             So that while there is no legal

         18   responsibility, I think that we would be remiss not

         19   to recognize the important moral responsibility and

         20   make sure that as we go forward we're respectful of

         21   that with how we interpret and apply these things.

         22             MR. BARNES:  And just one thing to that,


                                                                      352

          1   you -- more intact family than I do in regard to

          2   people protecting one another.

          3             [Laughter.] 

          4             CHAIRPERSON MARSHALL:  Was that a howler,

          5   Dr. Collins?  Have we achieved the level of howler

          6   yet?

          7             [Laughter.] 

          8             CHAIRPERSON MARSHALL:  Can we open the

          9   floor up to the public.  Mr. Levinson. 

         10             You need to use the microphone please,

         11   because we are recording. 

         12             DR. LEVINSON:  -- for the United States

         13   for the Interimational Society of Psychiatric

         14   Genetics.  My name and e-mail address are listed

         15   there for anyone who needs them.

         16             I represent a group of investigators --

         17   senior investigators in one of the fields which is

         18   most heavily involved in genetic research and in

         19   complex disorders, and one of the fields which has

         20   the most critical need to use family history

         21   information in the course of the research.  It's

         22   difficult to explain in the course of a few minutes


                                                                      353

          1   that are available today why that need is present. 

          2   I would be happy to do that at another time and our

          3   task force would be happy to work with or assist

          4   this committee in any way that would be helpful.

          5             We have been working on this issue for

          6   nine months and we have developed a certain

          7   understanding of it, although we feel that more

          8   data are needed.

          9             Let me just briefly discuss some of our

         10   concerns about these issues and I hope to have more

         11   opportunities to work with some of you later.

         12             This started with the, quote, "VCU" case. 

         13   I would like to point out that from the perspective

         14   of those of us who work everyday in this field,

         15   that was an unusual protocol in a number of ways. 

         16   It involved the research registry of twins,

         17   something that most studies do not involve.  It

         18   collected a highly diverse set of personal and

         19   family history data, not focused on a particular

         20   health problem of each subject.  Very different

         21   from what we do everyday.

         22             As some OHRP staff have pointed out, there


                                                                      354

          1   was a wide variety of potentially identifying

          2   information about relative in that database which

          3   created special problems and risks with which I

          4   tend to agree, although I haven't investigated it

          5   in detail.  And there were serious questions,

          6   apparently, of an adequate IRB oversight of the

          7   rationale for the protocol and its procedures. 

          8             In most human subjects, in most human

          9   genetics protocols, by contrast, the subject

         10   suffers from a serious disorder, whether its a

         11   common disorder or a rare disorder, psychiatric, or

         12   other, or non-psychiatric, the subject has a

         13   compelling interest in research on that specific

         14   disorder; very limited family history information

         15   is typically collected in the protocols I know

         16   about. 

         17             The information is about only directly

         18   relevant disorders, it's limited in scope, it's

         19   known by the subject from many shared family

         20   experiences over a long period of time, and is

         21   really part of the subject's own health history

         22   because the disorder is at least probably genetic.


                                                                      355

          1             This creates very serious questions about

          2   whether this is information that is truly the

          3   relative's private information, or whether it's

          4   experience that in a sense both the subject and the

          5   relative have some control over.  And I think that

          6   that's one reason why, for the past 20 years, very

          7   few IRBs have considered family history procedures

          8   when appropriately limited and appropriately

          9   focused to be a violation of the relative's rights

         10   or to be something that the relative has to consent

         11   to.  These are the real circumstances we deal with. 

         12   The regulation defines "private information" in

         13   terms of a, quote, "reasonable person's

         14   expectations."  And the fact is that most adults

         15   accept that their adult relatives have some

         16   autonomy in making decisions about disclosing very

         17   limited family history which has a direct relevance

         18   to their own personal health risks.  Whether that's

         19   to a doctor, or with far greater confidentiality

         20   protections, to a researcher.

         21             On the other hand, this is clearly a

         22   controversial issue.  Reasonable people have


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          1   different feelings about it.  Health information

          2   seems intuitively private.  And it may be difficult

          3   to achieve a total consensus at any point about the

          4   definition of private information.

          5             Nevertheless, IRB practice, since 1981,

          6   since these regulations were promulgated, has

          7   recognized the scientific need for family and for

          8   history information for certain types of studies. 

          9   Researchers have generally been permitted to record

         10   family history information on a very confidential

         11   basis or in some cases information has been

         12   considered private and waiver of consent has been

         13   considered justified.  It's buried usually the

         14   first, sometimes the second.

         15             It seems to me from experience as a

         16   researcher and an IRB member in the past that IRBs

         17   have considered the risks to be minimal.  Members

         18   of my task force who have collected tens of

         19   thousands of subjects don't know of a case or

         20   breach of confidentiality in family history

         21   information by researchers.  No such breach

         22   occurred even in the VCU case whose procedures we


                                                                      357

          1   questioned; and none of the participants in the

          2   recent forum on third-party risks that was held at

          3   VCU knew of such a case.

          4             So although there may be such cases -- and

          5   I'd be prepared to admit there may be ones we don't

          6   know about -- they must be rare.  And if they're

          7   rare, researchers are apparently doing a far better

          8   job in protecting confidentiality than the health

          9   industry is.  And that's one reason why IRBs tend

         10   to feel that what we're doing is not unreasonable.

         11             Although I'm not saying that every

         12   researcher has been reasonable or that every IRB

         13   has been reasonable, in general we've done a pretty

         14   good job.

         15             A few other points, that I think are of

         16   historical relevance, it's very difficult to

         17   predict the harm that would befall a specific human

         18   being if their information were violated.  We

         19   really disagree seriously with Dr. Botkin's lines. 

         20   You know, you may think that a heart attack is not

         21   a very sensitive condition.  But if you're an

         22   airline pilot, you're going to lose your job.  If


                                                                      358

          1   you're an associate professor at Penn, you're not. 

          2             If you have depression you have no problem

          3   telling your Chairman at the University of

          4   Pennsylvania that you have depression.  If you're

          5   an airline pilot, you can be on an antidepressant,

          6   but you better not have a heart attack.  It's very

          7   difficult to predict.  What we need to do is

          8   protect all information.  Not to claim that IRB

          9   members can sit and decide who would be hurt by

         10   breaches.  We have to prevent breaches of

         11   confidentiality.  We've done a good job, perhaps we

         12   can do a better job.  And I think the discussion is

         13   well worth it.

         14             We were disturbed by some of the

         15   statements that were made the OHRP representative

         16   who spoke at the VCU third-party risks forum.  Some

         17   examples were that a relative may expect that

         18   information that is given to perhaps the subject

         19   will not be repeated.  The example that was given

         20   was, what if a husband tells his wife that he has

         21   HIV infection or perhaps a genetic disorder in

         22   order that they can discuss health decisions or


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          1   childbearing decisions together.

          2             And the statement was made that the

          3   subject may be violating the relatives -- the

          4   husband may be -- the wife may be violating his

          5   wife's privacy rights if she discloses that

          6   information to a researcher.

          7             Well, you know, I think that really

          8   depends on the situation.  I think that's a very

          9   dangerous position to take and a somewhat

         10   ideological one in my view.  What if that wife

         11   decides to enroll in a prospective study of what

         12   happens to women who perhaps have had risk factors

         13   for HIV and she wants to be in that study?  In

         14   order to be in it, she has to describe what her

         15   risk was.  Well, I'm married to someone who tells

         16   me he has HIV and I had sex with him.  Does she

         17   need her husband's permission to enter that study

         18   about her own health risks or to tell the study why

         19   she is at risk? 

         20             What if they divorce and she has medical

         21   decision authority over their child?  Their child

         22   develops that genetic disorder, she wants to enroll


                                                                      360

          1   him in a genetic study, the researcher says, tell

          2   us a bit about him and his history?  The father's

          3   diagnosis is part of that child's health history. 

          4   Does the wife have to have her ex-husband's

          5   permission to tell a researcher, we have a family

          6   history of that disease, we would like to be in

          7   your study.

          8             I'm not sure, but I don't think so, but I

          9   think that we should take seriously whether all of

         10   this family history information in focused,

         11   directly relevant studies to the subject's health

         12   risks is really private to the relative, or may, in

         13   fact, be the subject's own health information.

         14             By the approach that's just been

         15   described, that was ascribed to the conference, no

         16   family history inquiry would be possible about

         17   identifiable relatives by the position that this

         18   representative took.  Because virtually all health

         19   information will be defined as private, so all the

         20   relatives would be subjects and because the wife's

         21   action is being interpreted as a violation of the

         22   husband's rights, you can't waive consent because


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          1   there's a violation of rights involved which

          2   invalidates that part of the regulations.

          3             So we would be totally invalidating

          4   something that IRBs have been routinely allowing

          5   for 20 years, since the regulations were

          6   promulgated.  That is a major change.  But it was

          7   asserted at the conference that this was not a

          8   change.  

          9             I respectfully submit that this

         10   interpretation of the regulations by some OHRP

         11   staff represents a substantial change in

         12   interpretation of the regulations.  And, in fact,

         13   could be defined as a change in the regulation. 

         14             What are the alternatives to that

         15   approach?  Well, Dr. Botkin has pointed out that in

         16   many studies identifiability of relatives can be

         17   reduced or the definition of identifiability may be

         18   such that many studies are not really identifying

         19   the relatives in a unique way.

         20             I would mention, though, it's very

         21   difficult to pick a reasonable change in these

         22   regulations based on one's information about a few


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          1   types of research because there's always another

          2   type that would be totally paralyzed by that exact

          3   same approach.

          4             What if you're using genealogical

          5   information? You have to identify people.  At some

          6   point the scientific and public community have to

          7   decide whether researchers can be trusted to

          8   maintain certain information confidential when they

          9   really need it, and IRBs have to decide when we

         10   really need it and when we don't.

         11             We could define some family history

         12   information as the subject's health history, not as

         13   the relative's private information which I believe

         14   is reasonable in certain kinds of studies, perhaps

         15   not in others.  Or we could define it as private,

         16   but say that the people's rights -- the relatives'

         17   rights are not being violated depending on the

         18   nature of the information and its real relevance to

         19   the subject; not a blanket permission to collect

         20   whatever we want from subjects about the relatives

         21   who -- I don't think any of us believe is

         22   justified.


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          1             The interpretations that were presented by

          2   OHRP staff at VCU are really inconsistent with the

          3   regulation's original intent, with their actual

          4   wording, and with 20 years of IRB decisions.  The

          5   basic principal of the Belmont report is

          6   "magnificence," maximized benefits/minimized risks. 

          7    Are we reducing the potential benefits of research

          8   without reducing risks?  And the reason I'm raising

          9   this question today is that we are already

         10   beginning to see IRBs change their behavior based

         11   on the following. 

         12             I think there's a serious question of

         13   whether in this issue I think in a sincere way and

         14   in the interest of addressing a serious issue OHRP

         15   staff may in fact be overstepping their authority

         16   in the short term.

         17             IRBs alone have the authority to interpret

         18   federal regs.  It's a very fundamental principal of

         19   our system based on the Neuremburg codes and based

         20   on 45 C.F.R. 46.  Centralized authority was held to

         21   be dangerous and undesirable.  There is not

         22   supposed to be a centralized agency telling IRBs


                                                                      364

          1   exactly how to interpret regulations other than

          2   procedural issues and gross negligence.

          3             Is OHRP in its current approach of this

          4   issue in effect imposing new interpretations on

          5   IRBs?  I think there's some evidence that this may

          6   be happening, but I don't have enough data about it

          7   right now to give chapter and verse.  NIMH staff

          8   are trying to look into this and find out exactly

          9   what's happened in different cases.  But what I do

         10   know is that IRBs are starting to fear OHRP

         11   intervention around this issue.  After all, VCU

         12   lost its multiple project assurance and it cost

         13   them millions of dollars and a delay of one year of

         14   many research projects.

         15             While those actions may have been

         16   justified at VCU, I mean, I wasn't there, I didn't

         17   investigate it.  IRBs now feel from a variety of

         18   stories they've heard about other cases that if

         19   they don't vote on family history issues the way

         20   OHRP wants, they may get the university in trouble. 

         21   That is exactly what our regulations were written

         22   to prevent.  A central agency is not supposed to


                                                                      365

          1   dictate to IRBs, nor this committee, exactly how to

          2   interpret regs.  IRBs must accept that

          3   responsibility.

          4             What we can do is try to develop more

          5   information, more consensus, more discussion.  If

          6   we really need a change, we should change the regs

          7   in a public and, you know, legitimate legal way so

          8   that there is some consensus. 

          9             Our recommendations to this advisory

         10   committee is that in the short run we do believe

         11   that OHRP should issue clarifying guidelines to

         12   IRBs to remind them what their formal obligation is

         13   on other regulations which apparently the VCU IRB,

         14   for one, did not follow, and maybe many IRBs are

         15   not following.

         16             They have to determine in any protocol

         17   that obtains information about third parties what

         18   is being collected from whom, about whom, by what

         19   procedure, with what kind of identifying

         20   information, and very critically, what's the

         21   rationale.  There's a real question in the VCU

         22   case, was there a good scientific rationale for


                                                                      366

          1   what was done?  There may not have been.  And

          2   that's an IRB responsibility.

          3             Part of the relatives really human

          4   subjects based on what regulations, and if so, was

          5   waiver of consent justified?  I have 30 more

          6   seconds.

          7             Secondly, we believe that IRBs should be

          8   informed in the short run that the regulations have

          9   not changed.  They should be reminded in writing. 

         10   There has been no change in 45 C.F.R. 46. They

         11   alone retain the authority to interpret these

         12   regulations.  And I would hope that OHRP staff

         13   would decide to refrain from any actions that have

         14   been interpreted as imposing interpretations of the

         15   regulations, on IRBs in areas where there is a long

         16   established interpretation in place and where there

         17   is no compelling reason to force a change.

         18             There is no evidence of great harm to

         19   subjects.  There is no evidence of any breach of

         20   confidentiality.  So we could obstruct very

         21   important research without helping relatives or

         22   subjects.  We have time for a deliberate and broad


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          1   discussion involving diverse groups and individuals

          2   about what really needs to be done and what doesn't

          3   need to be done in this area.

          4             We also would like scientific groups, our

          5   own, American Society of Human Genetics, advocacy

          6   groups and others to begin work and we urge to

          7   begin work on their own standards and curricula for

          8   what would be reasonable procedures and training

          9   for staff in this area, both when there's family

         10   history information needed, how should it be

         11   collected, and how do you train staff to maintain

         12   our high standard of protection of privacy of that

         13   information.

         14             I believe that if those kinds of

         15   guidelines and standards are developed and put in

         16   writing, they can serve as a gold standard for IRBs

         17   to compare to protocols and to help them make

         18   decisions in their own local and community

         19   contexts.  I think in the long run it will not be

         20   necessary to dictate those interpretations

         21   centrally.  I think a reasonable consensus will

         22   develop.  It may  involve clarification of


                                                                      368

          1   regulations in the future.  It may involve

          2   producing some new regulations.  But I think that

          3   consensus will be helpful.  Thank you.

          4             CHAIRPERSON MARSHALL:  I would like the

          5   panel members to come back if they could.  We are

          6   engaging the panel.  And the panel is going to have

          7   the first opportunity to respond to Mr. Levinson.

          8             I'm asking the panel members, anyone on

          9   the panel, would you like to respond to Mr.

         10   Levinson?  Dr. Levinson.  Thank you. 

         11             Abbey.

         12             MS. MEYERS:  I'm not sure if he was right. 

         13   Some expert here will be able to say whether he's

         14   right that local people -- it's more or less like

         15   the State of Kansas passed a law that evolution

         16   won't be taught in Kansas because local people have

         17   the right to make local laws.

         18             Is it true that the federal government

         19   doesn't have the right to tell IRBs what to do?

         20             CHAIRPERSON MARSHALL:  I'm moderating this

         21   panel.  Thank you.  I have Bob, I have Adil, I have

         22   Greg.  And I want to say that I want this


                                                                      369

          1   discussion to be limited and to remember what our

          2   focus is this afternoon.  And I do not want this to

          3   degenerate into a discussion about what happened at

          4   VCU and parsing out the federal regulations.  So

          5   let's try and keep it focused on protecting human

          6   subjects and on the secondary or the family

          7   secondary subject issue.  Thank you. 

          8             Bob would like to respond to that on

          9   point.  Greg would like to respond to that on point

         10   and then I have Adil.

         11             DR. R. LEVINE:  As much as I agree with

         12   Dr. Levinson, I have to say that there's nothing in

         13   the regulations that says that only the IRB can

         14   make these decisions.  I will say though that in

         15   the background to the regulations, particularly in

         16   the introductory chapter of the National

         17   Commission's report on IRBs, it presented a very

         18   strong argument for why the centerpiece of

         19   decisionmaking about a particular research project

         20   should be made by an IRB that is in the locale in

         21   which the -- or preferably in the institution -- in

         22   which the research is going to be carried out.


                                                                      370

          1             It had a lot to do not only with

          2   interpreting local standards, and it was assumed

          3   that there could be important differences across

          4   different communities, but it also had to do with

          5   the capacity to educate and also to be aware of the

          6   players that do this work within the institution. 

          7   You would hate to say this in regulations, but the

          8   National Commission reflected its awareness that

          9   some people are more inclined to be respectful of

         10   human subjects' rights and welfare than others. 

         11   And the colleagues of the individuals within the

         12   institution were most likely to be aware of which. 

         13   Thank you.

         14             CHAIRPERSON MARSHALL:  Thank you.  Greg.

         15             DR. KOSKI:  I would just say that with

         16   respect to the local issue, there certainly may be

         17   instances in which a local IRB simply abrogates its

         18   responsibility to effectively protect the

         19   participants in the research.  And in an instance

         20   such as that, and we could all come up with

         21   examples, I believe it's important to recognize

         22   that there is a responsibility to make sure that


                                                                      371

          1   they're doing what they're supposed to be doing in

          2   a faithful manner.  And to a certain extent, I

          3   think it falls to -- in some instances -- what may

          4   be application of a prevailing community standard

          5   of decency and appropriateness and those are

          6   difficult issues.

          7             But I can assure you that in the event

          8   that a local IRB failed to exercise in a

          9   responsible manner it's responsibility to protect

         10   human subjects our office would do what was

         11   necessary to correct the action of that local IRB.

         12             CHAIRPERSON MARSHALL:  Adil and then Mr.

         13   Curtain.

         14             DR. SHAMOO:  [Off mic.] -- for someone --

         15   for advocacy -- Dr. Levinson.  I hope I did not

         16   understand you that medical psychiatric information

         17   did not contribute.  You had a few cutsie examples

         18   of how discrimination occurred, heart attack, about

         19   the airline pilot, or at your own university if it

         20   is depression, the chairman wouldn't mind.  But as

         21   you well know there is a wholesale discrimination

         22   toward the mentally ill in health care, in jobs, in


                                                                      372

          1   all aspects of life, and I have a son who has

          2   schizophrenia, he's 30 years old.  He is the last

          3   one to be hired, and the first one to be fired.

          4             And furthermore somehow you have neither

          5   heard us nor listened to us and to all the

          6   newspaper reports and other that there are

          7   wholesale violations of 45 C.F.R. 46 and that's why

          8   you see there has been in ten years 21 suspension/

          9   terminations, 12 of them or at least ten of them

         10   entire institutions were suspended.  You probably

         11   will not hear until in the morning that we have

         12   eight deaths reported in ten years to OPRR.  You

         13   could tell me with 70 million Americans we have

         14   eight deaths only.  So there are wholesale

         15   violations and every regulatory agency has the

         16   right to insure compliance by the local, whatever

         17   system is in place.  And in this case it's the IRB.

         18             CHAIRPERSON MARSHALL:  Thank you.  And I

         19   would like to close the discussion on that narrow

         20   construal of what we are about this afternoon and

         21   refocus us on the issue of family members and

         22   others and the privacy of their information and


                                                                      373

          1   adequate protection of human subject.  Mr. Curtain.

          2             MR. CURTAIN:  No, VCU, right, Dr.

          3   Marshall?

          4             In his opening remarks Dr. Collins listed

          5   five issue areas. And one common theme that I saw

          6   discussed through all five of those areas was, and

          7   this is almost a quote, the IRBs are confused.

          8             This is just unacceptable.  The IRBs are

          9   the advocate.  They have to function as the

         10   advocate for the research subject.  I guess earlier

         11   this morning you discussed the business about

         12   research, principal investigators, being

         13   altruistic.  We all know that they all aren't. 

         14   Okay. 

         15             And when that occurs, even when it doesn't

         16   occur, who is going to be there for the research

         17   subject if not the IRB.

         18             I disagree strongly with Dr. Botkin, and

         19   we've discussed this by e-mail, and his position

         20   that he thinks that the IRBs are basically okay and

         21   they just need some changing at the margins.  I

         22   think the word he used was "shoe-horning" them into


                                                                      374

          1   the common rule.

          2             From my personal experience, from what

          3   I've read in the paper, from reading the Inspector

          4   General's report for Health and Human Services, I

          5   don't see how anybody can say that this system is

          6   not broken.  It needs to be changed.  You cannot

          7   have an IRB sitting at an institution where the

          8   guys on the IRB go out to lunch and then after

          9   lunch they come back and approve one another's

         10   projects.  And this happens.  I know it happens. 

         11   You know, Dr. Koski's office has proven that it's

         12   happened.  The IRB system has to change.  They have

         13   to be the ones who look out after the research

         14   subjects. 

         15             And I don't mind being called a research

         16   subject because people within a research project

         17   are kind of at the mercy of the principal

         18   investigator.  We aren't equal.  If that's what the

         19   word "participant" kind of suggests, we're kidding

         20   ourselves.  Some people -- as Ms. Terry and the

         21   lady who spoke earlier, you know, she has become so

         22   knowledgeable about this that she probably is a co-


                                                                      375

          1   equal of the principal investigator and she may be

          2   a true participant.  That's a very, very rare

          3   situation.

          4             We are subjects.  We are at a

          5   disadvantage, and we need somebody to level the

          6   playing field.

          7             Thank you. 

          8             CHAIRPERSON MARSHALL:  Can I ask you if

          9   you had a suggestion for the committee in terms of

         10   how to go about leveling that playing field?  What

         11   would it be?

         12             MR. CURTAIN:  Yes, ma'am.  I would

         13   envision -- and this costs money, I understand that

         14   -- I would suggest a regional IRB structure where,

         15   for instance, you would have a Philadelphia IRB. 

         16   You wouldn't have an IRB at Penn in this medical

         17   school and that research institution.  You would

         18   have a regional IRB for that area, there would be a

         19   professional staff there full-time who was

         20   constantly -- who is expert in the rules, the

         21   regulations, knowing what's going on in Dr. Koski's

         22   office and then you would bring in ad hoc groups of


                                                                      376

          1   researchers and community people maybe from that

          2   are to serve on an ad hoc IRB.  You form it, they

          3   do their business, they disband and they go away. 

          4   The projects they're working on are coded so that

          5   they don't know that, gee, this is really the guy

          6   in the cubicle next to me, you know, or the lab

          7   next to me.  This is his project.  That would be my

          8   suggestion. 

          9             You need some kind of a full-time staff,

         10   you need training, and it's expensive, yes, but

         11   what you've got isn't working.  As I've said

         12   before, if you folks don't fix it, Congress is

         13   going to fix it  Because that entire code of

         14   federal regulations that's out there, people who

         15   work for the federal government like me, we just

         16   didn't get up one day and decide to write a right. 

         17   Every regulation in that book shelf was written in

         18   reaction to some kind of an abuse.  Something had

         19   gone wrong. And things in your community have gone

         20   wrong.  And if you don't fix it, and fix it soon,

         21   there's going to be another book in the Code of

         22   Federal Regulations telling you how you're going to


                                                                      377

          1   do your business.

          2             CHAIRPERSON MARSHALL:  I'm sorry that Mr.

          3   Rich isn't here to hear your perspective and point

          4   of view on this issue.

          5             Members of the panel, would anyone -- does

          6   anyone have any words for Mr. Curtain?  

          7             DR. COLLINS:  Mr. Curtain, I think you've

          8   raised our consciousness on a number of issues. 

          9   Let me ask you a more explicit question than what

         10   Dr. Marshall did which is specifically related to

         11   the issue of family members from whom information

         12   is collected by the proband as was the case in the

         13   study that you found you were a participant in

         14   without expecting to be. 

         15             In a very explicit sort of circumstance

         16   such as this, what would you say, based upon your

         17   own experience, should have been done in that

         18   instance in order to facilitate that research and

         19   do you see it as an approach that could be

         20   extrapolated to other types of pedigree research

         21   which many people in this room are very concerned

         22   about not losing as a consequence of some overly


                                                                      378

          1   onerous process. 

          2             MR. CURTAIN:  Dr. Marshall, I'm going to

          3   have to talk just a little bit about these here. 

          4   This, by the way, is the questionnaire that started

          5   it all.  When I received this questionnaire, the

          6   first thing I did was write to the principal

          7   investigator.  I didn't go running to OPRR at the

          8   time.  I wrote to the principal investigator.  I

          9   said -- I suggested, just take off the column that

         10   has "mother, father, and siblings" and when you

         11   send a package to the twin just, you know, Xerox a

         12   few extra copies and ask the twin to distribute

         13   them.  Not a real satisfactory response.  Kind of a

         14   pat on the head, you know, you're nice, we'll take

         15   care of the science, okay, that type of thing. 

         16             [Laughter.]

         17             MR. CURTAIN:  I wrote to the Chairman of

         18   the IRB and he ignored me, so I wrote to the head

         19   of the medical college.  He ignored me.  And then,

         20   you know, it was like three months later, I says,

         21   this isn't going anywhere, so I'll try the Office

         22   of Protection and Research Risks.  I'm certainly


                                                                      379

          1   not suggesting that pedigree research has to be

          2   revised in total.

          3             All I'm saying is, if you've got an IRB

          4   there who can look at something like this and say,

          5   hey, Dr. X, this is not the way to approach this

          6   subject.  The twin is there.

          7             The thing went to my address and I still

          8   want to know and VCU still hasn't answered this,

          9   how did they know that my daughter was at our

         10   current address when it's a different address than

         11   her birth records.  I want to know how they tracked

         12   her down at that address?  Nobody will answer that

         13   question.

         14             So all I'm -- now I've lost my train of

         15   thought.  I'm having a senior moment here. 

         16             [Laughter.] 

         17             MR. CURTAIN:  I'm not asking that the

         18   pedigree research be done away with, but when it's

         19   such an obviously easy thing, I mean, the immediate

         20   family.  Give me a break.

         21             CHAIRPERSON MARSHALL:  Abbey has a

         22   question for you.


                                                                      380

          1             MS. MEYERS:  You've heard us talk about

          2   what the impact of what you -- you've brought this

          3   to our attention and what the impact would be.  For

          4   example, when you go to see a new doctor, and he

          5   asks you what diseases are in your family, you

          6   wouldn't be able to answer that question.  Do you

          7   want that to happen?  Do you think it should?

          8             MR. CURTAIN:  That's a red herring.  I

          9   don't even want to discuss that.  Really.  That has

         10   nothing to do with this issue.  To compare my

         11   doctor with some principal investigator at some

         12   university 100 miles away whom I have never met who

         13   is going to take this information and instead of

         14   putting it in a folder with my name on it and stick

         15   it in his office filing cabinet, instead of that,

         16   this principal investigator is going to dump it all

         17   into a computer database and then this principal

         18   investigator tells me, hey, don't worry.  This

         19   stuff is really secure in my database.  I had to be

         20   the one to tell the principal investigator, no,

         21   it's not.  It's subject to a federal subpoena.  And

         22   then she -- oh, she, right.  You know, this is just


                                                                      381

          1   a red herring, this discussion comparing that

          2   individual with my family. 

          3             MS. MEYERS:  So what you're talking about

          4   you want only to apply to research?  It shouldn't

          5   really affect everyday medicines? 

          6             MR. CURTAIN:  Absolutely.  Absolutely.

          7             If my daughter's gynecologist thinks that

          8   he needs this information about me to promote the

          9   health of my daughter, hey, I'll go and tell them

         10   all about my abnormal genitalia -- 

         11             [Laughter.] 

         12             MR. CURTAIN:  My low sperm count.  You

         13   know, I'll be the first one there to give them the

         14   information. 

         15             CHAIRPERSON MARSHALL:  Does anyone else on

         16   the committee have any remarks or questions for Mr.

         17   Curtain? 

         18             [No response.] 

         19             CHAIRPERSON MARSHALL:  Thank you very much

         20   for being with us today.  We appreciate it. 

         21             We are running behind and I'm mindful of

         22   that.  We are running about 15 minutes behind.  So


                                                                      382

          1   what I would like to do is this -- 

          2             Dr. Collins has just posed a very

          3   interesting question to me.  Has the committee

          4   already discussed who has the authority to rewrite

          5   the regulations?  And the answer to that is, every

          6   agency.  Right.  That we have not discussed that in

          7   particular.  

          8             DR. COLLINS:  I raised the question

          9   because I thought I heard Bob Levine saying, we are

         10   making a mistake by trying to take regulations that

         11   maybe were not as artfully crafted as he would have

         12   liked and were written some time ago and trying to

         13   force the current circumstance through that

         14   particular filter and perhaps we ought to be

         15   bolder.  And I guess I was inquiring whether that

         16   was a realistic option.  

         17             CHAIRPERSON MARSHALL:  I'm just going to

         18   very quickly qualify and remind everyone that

         19   within our purview is to give advice.  So I think

         20   the committee is clear in terms of what its

         21   authority and what its role is.  Bob, if you can

         22   respond on point and then I would like to bring


                                                                      383

          1   some closure to this session and give Dr. Koski the

          2   opportunity to talk about the Declaration of

          3   Helsinki and to bring some closure to that as well.

          4             DR. R. LEVINE:  I think that if we don't

          5   have the authority to recommend that regulations be

          6   revised, and there are plenty of examples of errors

          7   in the regulations that beg for revision, and we

          8   recently saw the entire Subpart B revised after a

          9   delay of about two and a half years which I don't

         10   understand, but if we can't recommend revision in

         11   regulations then we really shouldn't even be

         12   discussing them. 

         13             CHAIRPERSON MARSHALL:  We certainly can

         14   recommend them.  And, you know, I think that in the

         15   various contexts of the subjects that we look at,

         16   we can and we will.  And I know that we have

         17   discussed in the committee the fact that in

         18   relation to children we may find out that there are

         19   regs that are outdated or that need parsing out in

         20   some way, shape, or form, and that we may find that

         21   in the genetics area as well.  And I imagine as our

         22   work unfolds we'll find it in other areas.


                                                                      384

          1             So I could envision a scenario in the

          2   future when we might make some wholesale

          3   recommendations for changes in the regulations. 

          4   Whether we do that subject-by-subject, or whether

          5   we do that en masse at some point in time is

          6   something that we as a committee need to consider. 

          7   And that's a question that I have raised to the

          8   respective chairmen and chairpersons of the working

          9   groups.  And we need to consider that, how we're

         10   going to proceed along those very lines as a

         11   committee.

         12             I'd like to bring some closure today to

         13   our charge.  And perhaps to think about a plan. 

         14   Dr. Collins has provided us with five sort of very

         15   nicely articulate issues that bear explanation and

         16   he has suggested that we focus in terms of a fast

         17   track component to a larger effort, more narrowly

         18   on the issue of family members and privacy issues

         19   and who constitutes a research subject or a

         20   research participant within the context of genetic

         21   research.  We've had other issues brought up as

         22   well, so I imagine that we have a list of probably


                                                                      385

          1   six or seven things that the committee could

          2   consider.  

          3             So it looks to me as though we have

          4   certainly an agenda, or beginning of an agenda for

          5   our working group and what the committee's pleasure

          6   is in terms of proceeding.  Does the notion of

          7   asking our working group to look at the issue of

          8   family members and research and how one defines a

          9   research subject within the context of genetics

         10   research and then moving on to the other issues

         11   that have been articulated, is the committee in

         12   agreement with moving ahead that way? 

         13             DR. CHODOSH:  I would just say that it

         14   would be a waste -- not a waste of time, but a

         15   partial job done if we don't extend it beyond

         16   genetics.  There are just enough situations out

         17   there that are very similar and really should be

         18   resolved if we can, at once. 

         19             CHAIRPERSON MARSHALL:  Bob has a response

         20   to that.  I'm seeing a lot of nods around the table

         21   that we might actually have consensus on something.

         22             DR. R. LEVINE:  What I want to respond to


                                                                      386

          1   is I've heard several propositions this afternoon

          2   that the definition of a research subject should

          3   mean one thing for the FDA and a different thing

          4   for the public health service, and another thing

          5   for genetics.  I think that the government has

          6   repeatedly got itself into trouble by stipulating

          7   definitions or words that are in common usage and

          8   have their own definitions in the dictionary. 

          9   That's why so many of us who think we're talking

         10   about the same thing really aren't.

         11             I think it would be a good idea to have

         12   one good definition of the term research subject

         13   and use it through all of the regulations and in

         14   all of the letters we write to each other about the

         15   regulations.

         16             CHAIRPERSON MARSHALL:  Thank you.

         17             Mary Kay, do you have an interest in this

         18   workgroup and in being our leader?

         19             DR. PELIAS:  I'm willing to explore it. 

         20   Yes, I am. 

         21             CHAIRPERSON MARSHALL:  Thank you very

         22   much.  Are there other committee members?  Kate,


                                                                      387

          1   yes. 

          2             MS. GOTTFRIED:  I just had a request

          3   with respect to the workgroup.  I don't know if we

          4   want to do it right this minute, but to clarify to

          5   some extent what the charge to this workgroup would

          6   be.  Because at this point it's pretty broad.

          7             CHAIRPERSON MARSHALL:  Here is my plan.  I

          8   would like to get a list of people who are

          9   interested; members of the committee who are

         10   interested in working on the workgroup.  We have a

         11   nice list that Dr. Collins has articulated for us

         12   and what I would ask the workgroup to do, over

         13   night is to give us at least a brief list, perhaps

         14   in the morning when we're recapping our first day,

         15   of what they would conceive our charge to be.

         16             I think we've gotten some very concrete

         17   suggestions and we could begin with those.  And

         18   members who are interested in sitting on a working

         19   group can flesh those out overnight.  We would be

         20   interested in hearing about them in the morning.

         21             Dr. Collins. 

         22             DR. COLLINS:  In the way that you operate,


                                                                      388

          1   would this working group potentially also include

          2   other members from outside the committee in order

          3   to flesh out the expertise for some of these areas?

          4             CHAIRPERSON MARSHALL:  Thank you very

          5   much.  And I didn't slip him five dollars under the

          6   table to -- 

          7             [Laughter.] 

          8             CHAIRPERSON MARSHALL:  -- there's no

          9   underhanded financial relationship here. 

         10             Yes.  And we will take Dr. Collins up on

         11   his generous offer of assistance. 

         12             [Laughter.] 

         13             CHAIRPERSON MARSHALL:  Thank you very

         14   much.  I said it publicly.  You can't retract that

         15   now.

         16             And I think we would very much like to

         17   engage the public and others who may have a real

         18   interest in helping us work our way through these

         19   thorny issues, some of which are very fundamental

         20   in terms of their definitions and how we conceive

         21   of the problems.

         22             Yes.  Kate. 


                                                                      389

          1             MS. GOTTFRIED:  Just a footnote that

          2   that would be analogous to some of the other groups

          3   that we already have in existence such as the

          4   children's workgroup.  And I think it's a very

          5   important recommendation and it's worked

          6   exceedingly well thus far.  So we would be remiss

          7   not to do so and I think we do need to expand it to

          8   include the public as well.

          9             On another note, I just want to remind

         10   everyone that the NIH has a TNBC group which has a

         11   workgroup.  And they also are looking at this issue

         12   specifically within the NIH.  And Sarah Carr and

         13   Dr. Jim Hanson so that, Mary Kay, with respect to

         14   your charge, you could have an exchange with this

         15   group as well, invite information and exchange and

         16   work forward towards coming to some more or

         17   obtaining further information. 

         18             CHAIRPERSON MARSHALL:  And those of you

         19   who are members of the committee or who are ex

         20   officio members or who are public members, if you

         21   have an interest in participating in this working

         22   group, then you should let Mary Kay know, and we


                                                                      390

          1   will be appointing a working group once we've had

          2   time to receive input from all of the people who

          3   should be heard from.

          4             Dr. Koski.  The floor is yours and thank

          5   you for being so patient with us today.

          6             DR. KOSKI:  Thank you very much, Mary

          7   Faith.  I'll try to make this quick and give you an

          8   update on the have sort of the status, if you will,

          9   of the ongoing discussion of the revisions of the

         10   Declaration of Helsinki.  You know, we discussed

         11   this at our first meeting of NHRPAC.  The

         12   Declaration of Helsinki was originally issued by

         13   the world medical association in, I believe, 1964,

         14   close, somewhere around there.  And it certainly

         15   has been a valued set of guidelines for the ethical

         16   conduct of human research for nearly four decades

         17   now.

         18             The declaration has been revised from

         19   time-to-time, as you know, most recently in October

         20   of 2000 and the October 2000 revisions included

         21   some respositive statements with respect to

         22   conflict of interests and so on, but there were


                                                                      391

          1   several provisions which have been considered

          2   controversial as well.

          3             In particular, four of those included the

          4   assertion of privacy of the Declaration of Helsinki

          5   over all other codes and regulations for the

          6   conduct of research, the broad proscription of

          7   placebo controlled trials, as it's been viewed, as

          8   well as a requirement for the provision of best-

          9   proven therapy upon completion of the clinical

         10   trial, and finally, a failure to sort of recognize

         11   the very broad scope of human research in its

         12   entirety which extends well beyond the actual

         13   conduct of treatment-oriented clinical trials.

         14             Now, all of these points were discussed at

         15   some length at the last NHRPAC meeting.  We had a

         16   wonderful presentation by Dr. Dixie Snider from the

         17   CDC and a very useful discussion.  And we emerged

         18   from that meeting with a broad agreement that

         19   certainly we would all recognize that it would be

         20   unethical to withhold known effective therapy in a

         21   placebo control arm for trial, and which doing so

         22   would result in serious morbidity or mortality.


                                                                      392

          1             But at the same time, there is a need to

          2   recognize and sort of clarify the interpretation

          3   and scope of the application of the declaration

          4   when extended beyond the particular focus or the

          5   rather narrow focus of the treatment-oriented

          6   clinical trials. 

          7             Now, upon the advice of NHRPAC, we

          8   convened a federal-wide working group that actually

          9   was headed up again by Dr. Stuart Nightingale who

         10   has been extremely useful and it included

         11   representatives from not only the HHS agencies, but

         12   also other government agencies as well under the

         13   auspices of the human subjects research

         14   subcontract.  That group has been working, but it's

         15   not done.  It still has some distance to go.  We

         16   are nowhere near the adoption of a government-wide

         17   policy on this. 

         18             But back in February, I think, the World

         19   Medical Organization in cooperation with the

         20   European Forum on Good Clinical Practice and the

         21   University of Pretoria decided to hold an

         22   interimational conference on the interpretation and


                                                                      393

          1   application of the revised Declaration of Helsinki. 

          2   And this meeting actually occurred a couple of

          3   weeks ago I think now, in Pretoria, South Africa

          4   where delegates from -- I think it must have been

          5   around 40 countries from around the world, I don't

          6   know the exact number, but it was clearly a broad

          7   interimational group that came together in a

          8   serious collegial, collaborative environment to

          9   openly discuss the declaration.  And we have

         10   several people in the room here, I think, if

         11   they're still left, who actually participated in

         12   that conference.

         13             On behalf of the Department of Health and

         14   Human Services, I delivered a prepared statement

         15   copies of which are out at the table.  If you

         16   haven't already seen it, I believe it's been in the

         17   news as well, so that you perhaps have had a chance

         18   to read it.  And it addressed those very issues

         19   that I mentioned earlier.

         20             And I guess I would report to you that

         21   from that meeting I believe it was the sense of

         22   everyone -- or almost everyone -- almost unanimous


                                                                      394

          1   across the board from all of the countries that

          2   indeed there was a need for further clarification

          3   and interpretation of the declaration, possible

          4   change, but that this was something that was going

          5   to require ongoing discussion and dialogue.  So

          6   that no formal policy recommendations were made, a

          7   statement from the organizers of the committee will

          8   be issued.  I haven't seen it yet.  I don't know,

          9   Bob, if you have seen it as yet.  But this is the

         10   expectation. 

         11             There was a statement that was drafted by

         12   the committee and the organizers, and I believe

         13   that we should see this forthcoming soon.  And it

         14   commits the delegates who were at the meeting as

         15   well as other willing participants.  The World

         16   Medical Association providing leadership in the

         17   area, working together with CIOMS, and other

         18   interimational organizations, including Global

         19   Forum on Bioethics to continue this discussion and

         20   reconvene in about a year with a lot of work done

         21   in the interim.  At which time I would expect to

         22   see some finalization, if you will, of the actual


                                                                      395

          1   recommendations.

          2             So I think that in the meantime it's

          3   important that certainly the Department of Health

          4   and Human Services and perhaps a more government-

          5   wide basis, let our institutional review boards

          6   know that there is no change in policy.  That

          7   indeed, you know, the investigators as well as the

          8   IRBs need to understand this.  Clearly every

          9   experimental design needs to have appropriate

         10   control groups justified not only on scientific

         11   grounds, but on ethical grounds.  And, you know,

         12   clearly the protection of the rights and the

         13   interest and the welfare of the human subjects must

         14   be a priority. 

         15             So, the working group that we have

         16   established will continue its work.  We will

         17   continue the dialogue with other interimational

         18   groups and look forward to that and know that we

         19   will emerge from this process with something that

         20   will serve us all well in the long run.  So thank

         21   you.

         22             CHAIRPERSON MARSHALL:  I really don't want


                                                                      396

          1   to open a discussion on this because it is an

          2   update.  So if you have concerns or questions you

          3   could direct them to Dr. Koski.  And I am concerned

          4   for the welfare and the well-being of our guests

          5   and our committee members.  So I would like to

          6   thank you, Dr. Collins, so very much for giving us

          7   a framework within which to think, and for being so

          8   generous of your time today and for moderating the

          9   panel.

         10             Thank you very much. 

         11             [Applause.] 

         12             CHAIRPERSON MARSHALL:  And I would like to

         13   thank our other panelists, Terri Seargent, Sharon

         14   Terry, and Terri Arledge, and Jeff Botkin who is no

         15   longer here for giving us the breadth of vision

         16   that we need in order to move forward in thinking

         17   about these very complex problems.  For sharing

         18   your personal stories with us, and for informing

         19   our values and our thinking as we move ahead.  So,

         20   thank you so much.  We really appreciate it. 

         21             [Applause.] 

         22             CHAIRPERSON MARSHALL:  And we will see you


                                                                      397

          1   tomorrow morning.  Thank you, Mr. Curtain, for

          2   being here. 

          3             [Whereupon, at 5:35 p.m., the meeting was

          4   recessed to be reconvened on Tuesday, April 10,

          5   2001 at 8:30 a.m.]

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