[House Hearing, 105 Congress]
[From the U.S. Government Printing Office]



 

   OVERSIGHT OF NIH AND FDA: BIOETHICS AND THE ADEQUACY OF INFORMED 
                                CONSENT
=======================================================================

                                HEARING

                               before the

                    SUBCOMMITTEE ON HUMAN RESOURCES

                                 of the

                        COMMITTEE ON GOVERNMENT
                          REFORM AND OVERSIGHT
                        HOUSE OF REPRESENTATIVES

                       ONE HUNDRED FIFTH CONGRESS

                             FIRST SESSION

                               __________

                              MAY 8, 1997

                               __________

                           Serial No. 105-49

                               __________

Printed for the use of the Committee on Government Reform and Oversight








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              COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT

                     DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York         HENRY A. WAXMAN, California
J. DENNIS HASTERT, Illinois          TOM LANTOS, California
CONSTANCE A. MORELLA, Maryland       ROBERT E. WISE, Jr., West Virginia
CHRISTOPHER SHAYS, Connecticut       MAJOR R. OWENS, New York
STEVEN SCHIFF, New Mexico            EDOLPHUS TOWNS, New York
CHRISTOPHER COX, California          PAUL E. KANJORSKI, Pennsylvania
ILEANA ROS-LEHTINEN, Florida         GARY A. CONDIT, California
JOHN M. McHUGH, New York             CAROLYN B. MALONEY, New York
STEPHEN HORN, California             THOMAS M. BARRETT, Wisconsin
JOHN L. MICA, Florida                ELEANOR HOLMES NORTON, Washington, 
THOMAS M. DAVIS, Virginia                DC
DAVID M. McINTOSH, Indiana           CHAKA FATTAH, Pennsylvania
MARK E. SOUDER, Indiana              ELIJAH E. CUMMINGS, Maryland
JOE SCARBOROUGH, Florida             DENNIS J. KUCINICH, Ohio
JOHN B. SHADEGG, Arizona             ROD R. BLAGOJEVICH, Illinois
STEVEN C. LaTOURETTE, Ohio           DANNY K. DAVIS, Illinois
MARSHALL ``MARK'' SANFORD, South     JOHN F. TIERNEY, Massachusetts
    Carolina                         JIM TURNER, Texas
JOHN E. SUNUNU, New Hampshire        THOMAS H. ALLEN, Maine
PETE SESSIONS, Texas                 HAROLD E. FORD, Jr., Tennessee
MICHAEL PAPPAS, New Jersey                       ------
VINCE SNOWBARGER, Kansas             BERNARD SANDERS, Vermont 
BOB BARR, Georgia                        (Independent)
ROB PORTMAN, Ohio
                      Kevin Binger, Staff Director
                 Daniel R. Moll, Deputy Staff Director
                       Judith McCoy, Chief Clerk
                 Phil Schiliro, Minority Staff Director
                                 ------                                

                    Subcommittee on Human Resources

                CHRISTOPHER SHAYS, Connecticut, Chairman
VINCE SNOWBARGER, Kansas             EDOLPHUS TOWNS, New York
BENJAMIN A. GILMAN, New York         DENNIS J. KUCINICH, Ohio
DAVID M. McINTOSH, Indiana           THOMAS H. ALLEN, Maine
MARK E. SOUDER, Indiana              TOM LANTOS, California
MICHAEL PAPPAS, New Jersey           BERNARD SANDERS, Vermont (Ind.)
STEVEN SCHIFF, New Mexico            THOMAS M. BARRETT, Wisconsin

                               Ex Officio

DAN BURTON, Indiana                  HENRY A. WAXMAN, California
            Lawrence J. Halloran, Staff Director and Counsel
              Anne Marie Finely, Professional Staff Member
                       R. Jared Carpenter, Clerk
                    Cherri Branson, Minority Counsel















                            C O N T E N T S

                              ----------                              
                                                                   Page
Hearing held on May 8, 1997......................................     1
Statement of:
    Caplan, Arthur, professor of bioethics, University of 
      Pennsylvania; Benjamin Wilfond, professor of pediatrics, 
      University of Arizona; Peter Lurie, professor of medicine, 
      University of California-San Francisco; and Laurie Flynn, 
      director, National Alliance for the Mentally Ill...........   160
    Raub, William, Deputy Assistant Secretary for Science Policy, 
      Department of Health and Human Services; David Satcher, 
      Centers for Disease Control and Prevention; Harold Varmus, 
      Director, National Institutes of Health; and Mary 
      Pendergast, Deputy Commissioner, Food and Drug 
      Administration.............................................     9
Letters, statements, etc., submitted for the record by:
    Caplan, Arthur, professor of bioethics, University of 
      Pennsylvania, prepared statement of........................   164
    Flynn, Laurie, director, National Alliance for the Mentally 
      Ill:
        Information concerning ways to protect mentally ill 
          research participants..................................   213
        Prepared statement of....................................   198
    Lurie, Peter, professor of medicine, University of 
      California-San Francisco, prepared statement of............   188
    Pendergast, Mary, Deputy Commissioner, Food and Drug 
      Administration:
        Information concerning waiver of informed consent........   155
        Prepared statement of....................................    61
    Raub, William, Deputy Assistant Secretary for Science Policy, 
      Department of Health and Human Services, prepared statement 
      of.........................................................    14
    Satcher, David, Centers for Disease Control and Prevention, 
      prepared statement of......................................    25
    Shays, Hon. Christopher, a Representative in Congress from 
      the State of Connecticut, prepared statement of............     3
    Towns, Hon. Edolphus, a Representative in Congress from the 
      State of New York, letters concerning the subject of Public 
      Citizen's news release.....................................   115
    Varmus, Harold, Director, National Institutes of Health:
        Information concerning clinical trials...................   144
        Prepared statement of....................................    48
    Wilfond, Benjamin, professor of pediatrics, University of 
      Arizona, prepared statement of.............................   179



















   OVERSIGHT OF NIH AND FDA: BIOETHICS AND THE ADEQUACY OF INFORMED 
                                CONSENT

                              ----------                              


                         THURSDAY, MAY 8, 1997

                  House of Representatives,
                   Subcommittee on Human Resources,
              Committee on Government Reform and Oversight,
                                                    Washington, DC.
    The subcommittee met, pursuant to notice, at 10:05 a.m., in 
room 2247, Rayburn House Office Building, Hon. Christopher 
Shays (chairman of the subcommittee) presiding.
    Present: Representatives Shays, Snowbarger, Pappas, Towns, 
and Kucinich.
    Staff present: Lawrence J. Halloran, staff director and 
counsel; Anne Marie Finley, professional staff member; R. Jared 
Carpenter, clerk; and Cherri Branson, minority counsel.
    Mr. Shays. I call this hearing to order. Next week the 
President will formally apologize to the survivors of the 40-
year Tuskegee experiment, a federally funded study in which 
black men were allowed to suffer and die of a curable disease--
syphilis--in the name of scientific research. Last week, this 
subcommittee heard testimony from Gulf war veterans ordered to 
take a potentially toxic drug for an experimental use without 
being informed of any possible side effects.
    The road from Tuskegee to Baghdad is lined with other 
landmarks of scientific arrogance and human tragedy. 
Thalidomide, radiation experiments, the EZ measles vaccine 
trials--those notorious lapses in the protection of human 
research subjects and the complex ethical implications of 
emerging biomedical issues like cloning, gene therapies, and 
AIDS vaccine trials compel us to ask: How effective are current 
mechanisms to review ethical issues and detect violations of 
informed consent requirements?
    What needs to be done so patient protections keep pace with 
scientific advances? Do we need a permanent national panel to 
serve as the arbiter of biomedical ethics issues? Physicians 
have a moral duty to inform human research subjects of the 
foreseeable risks of participation, and a duty to minimize 
those risks. The discipline of bioethics has evolved from the 
Hippocratic oath to the Nuremberg Code to current national and 
international standards to protect the health and human dignity 
of all who submit themselves to help advance scientific 
knowledge.
    But the current system of bioethics review appears to be 
showing signs of age and disrepair. Multiple layers of review 
and enforcement provide a false sense of security that 
difficult issues are being confronted. The regulatory scheme 
lacks specific provisions to protect mentally ill, drug 
addicted and cognitively impaired persons involved in 
biomedical research. Local institutional review boards--the 
IRBs--considered the cornerstone of the entire bioethics review 
structure, are often hard-pressed to monitor research protocols 
and informed consent procedures on an ongoing basis.
    By one recent estimate, more than half the federally funded 
research projects inspected by the FDA between 1977 and 1995 
failed in some way to inform research subjects fully of the 
experimental nature of the medical procedure. Multi-site 
research studies further challenge the capacity of local IRBs 
to control the research nominally under their purview. The 
National Institutes of Health--NIH--are charged with the 
potentially conflicting duties to fund research, conduct 
research, and enforce bioethics regulations. As a result, the 
NIH Office of Protection for Research Risks--the OPRR--faces 
both institutional barriers and logistic obstacles in 
attempting to police thousands of research projects.
    The third leg of what is supposed to be the national 
bioethics triad doesn't even exist. Department of Health and 
Human Services--HHS--regulations call for a permanent ethics 
advisory board--the EAB--to advise the Secretary of bioethics 
issues. The EAB has been without members since 1979, supplanted 
by a series of temporary commissions to study particular 
bioethics problems. The latest, the National Bioethics Advisory 
Commission--the NBAC--was directed in 1995 to make their first 
priority protection of the rights and welfare of human research 
subjects. Only recently staffed, the commission has now been 
directed by the President to focus their attention on cloning, 
and will not review ethical issues arising from specific 
research projects.
    Given these constraints, can the NBAC function in the role 
envisioned by the permanent Ethics Advisory Board? The weakness 
of the current system became more apparent recently when the 
NIH had to convene an ad hoc panel to review serious ethical 
questions presented by a proposed randomized needle exchange 
study in Alaska. Intravenous drug users are at high risk of 
contracting hepatitis and AIDS. For some, participation in the 
study to increase the avoidable risk of getting hepatitis B, 
for which there is an effective vaccine. A series of reviews by 
the local IRB and NIH failed to correct that ethical deficiency 
or detect flaws in the proposed informed consent materials.
    This self-policing, self-validating, and in some ways self-
satisfied system of bioethics review and enforcement may be 
vulnerable to institutional pressures to conform and to 
cronyism. Missing are the periodic evaluations and external 
oversight needed to maintain a rigorous bioethical review 
system. We begin our part of that external oversight today. And 
we look to our witnesses for suggestions to improve patient 
protections and informed consent procedures. At this time I 
would recognize the ranking member and an equal partner in this 
effort, Mr. Towns.
    [The prepared statement of Hon. Christopher Shays follows:] 

[GRAPHIC] [TIFF OMITTED] T4389.001

[GRAPHIC] [TIFF OMITTED] T4389.002

[GRAPHIC] [TIFF OMITTED] T4389.003

    Mr. Towns. Thank you very much, Mr. Chairman. African-
Americans have had a long and unhappy history of involuntary 
participation in medical studies. From 1932 to 1972, U.S. 
Public Health Service embarked on a 40-year study of African-
American men who had contracted syphilis. Known as the Tuskegee 
Study, the Government agency withheld treatment and 
administration of a cure in order to study the effects of the 
disease on the black male. In the 1950's, a University of 
Cincinnati Medical Center exposed 82 charity ward patients to 
10 times the amount of radiation that was known to be safe at 
the time.
    In this study on the effects of full body radiation, three-
quarters of the patients in the study were low income black men 
and women. Their consent signatures had been forged. During the 
1970's, one group of parents in Baltimore thought they were 
enrolling their boys in a free child program at John Hopkins 
University. During the course of these 3 years, NIH-funded 
study of 7,000 boys, over 90 percent African-American, had 
their blood drawn. This blood was subjected to genetic testing 
without the knowledge or consent of any of the parents.
    This long and troubling history has made the African-
American community extremely leery of medical research, and let 
me also add, the medical community. Although representing about 
15 percent of the general population, they account for only 
about 2 to 4 percent of volunteers in cancer prevention trials. 
For instance, overall, African-Americans have lower cancer 
survival rates than whites. However, blacks who participate in 
clinical trials have survival rates equal to those of whites.
    In some instances, this unwillingness to participate in 
trials may hamper later treatment. There is a lot of evidence 
that racial minorities and other vulnerable groups have been 
exploited doing medical research. I believe it is the 
powerlessness of these groups which make them targets for 
medical exploitation. Surely we cannot allow some members of 
this society to be sacrificed for the health and well-being of 
others.
    On the other hand, there's evidence that research improves 
the overall health of the population. We must strike the right 
balance and ensure that any opportunity for exploitation is 
eliminated. Current Federal guidelines require the inclusion of 
women and minorities in clinical research to ensure that 
biomedical and behavior research findings are applicable to all 
populations. Therefore, the HHS, CDC, NIH, and FDA must ensure 
active recruitment of volunteers in minority communities.
    However, the Federal Government must also ensure that 
researchers and research facilities fairly represent the 
American people. Federal reviewers and local review boards 
should become suspicious when minorities seem to be purposely 
excluded or seem to be the exclusive subjects. We may be able 
to accomplish these modest goals by enacting additional 
safeguards to protect the rights of the patient. We may need to 
expand the membership on the institutional review boards, 
provide additional advocates for patients, include greater 
participation by those not associated with the research 
facilities and provide a Federal ombudsman specifically to 
receive questions or complaints of study participants.
    I hope that this hearing does not advocate eliminating 
Federal research support or placing regulatory restrictions on 
the receipt of Government funding for research that few 
institutions are able to meet. I don't want to see that happen. 
I hope that we can use this opportunity today to build on the 
existing framework of the Federal regulations to improve our 
system for the benefit of all future patients and study 
participants. That's what I hope to accomplish. Mr. Chairman, 
thank you for raising this important issue--and it is 
important. I look forward to working with you on this issue and 
hearing the testimony of today's witnesses, to determine in 
terms of what we can do to correct the wrongs and to try to 
move forward by making them right. Thank you so much.
    Mr. Shays. I thank the gentleman. At this time the Chair 
recognizes Mr. Pappas, Congressman Pappas from New Jersey.
    Mr. Pappas. Thank you, Mr. Chairman. I want to thank you 
for calling this hearing and focusing on an issue that I think 
more and more Americans are becoming concerned about. The 
examples that both you and the ranking member, Mr. Towns, 
mentioned both about the Tuskegee experiment as well as that 
which some of our Persian Gulf war veterans may have 
experienced. I'll just point out that the ends do not always 
justify the means. And there are many people in our country 
that have a great deal of concern that in folks' 
overzealousness and excitement with regard to the advances that 
are being made in research that people could not necessarily 
just be helped by some of the research and advances that are 
taking place. So I welcome the opportunity to hear from the 
panelists here today. Thank you.
    Mr. Shays. I thank the gentleman. Congressman Kucinich of 
Ohio.
    Mr. Kucinich. Thank you very much, Mr. Chairman and members 
of the committee. I want to thank the Chair for holding a 
hearing on this subject, join with Mr. Pappas' comments, and 
also express my concern with my good friend Congressman Towns 
about the way in which minorities are treated on issues like 
this. The central concern of my constituents is, can public 
trust and confidence be maintained in such programs? We're 
concerned about how risks are identified and how they're 
communicated to human subjects. All of us clearly understand 
that medical technology and research is part of the unfolding 
of the possibilities for improved public health.
    But we also know that we have a moral and ethical 
responsibility to see to it that anyone participating in any 
type of experiment receives the information that they need so 
that they know what the risks are and that they know what their 
rights are. There are ethical issues that we'll be reviewing 
today. And we want to see the extent to which violations of 
informed consent requirements, whether those requirements were 
ethical, or in fact rules and regulations may have been 
violated. It's very clear this is an area of public policy that 
the Federal Government needs to step up to.
    A few years ago we had a couple of laws which regulated 
bioethics. The National Commission for the Protection of Human 
Subjects of Biomedical Research and also the President's 
Commission for the Study of Ethical Providence in Medicine and 
Biomedical and Behavioral Research were established. Neither 
are in existence today. And with the exception of the common 
rule, which only applies to Federal agency, there's no 
provision of U.S. law explicitly requiring informed consent and 
independent review of research involving human subjects.
    As we review the biomedical ethics questions here today I 
am confident that this committee with the cooperation of those 
who will be testifying will be able to lead the way to 
establishing some new standards which will derive from ethical 
considerations. And I'm very grateful, Mr. Chairman, that you 
have chosen this moment to bring this issue to the forefront.
    Mr. Shays. I thank the gentleman. And we are joined by the 
vice-chairman of the subcommittee, Mr. Snowbarger, who is from 
Kansas and would just as soon we get on with the hearing. So 
we're going to do what we do at all our hearings. We swear in 
our witnesses, including any Member of Congress, who come and 
testify. So if you would stand and raise your right hands, 
we'll swear you in.
    [Witnesses sworn.]
    Mr. Shays. Thank you. Note for the record that our 
witnesses have responded in the affirmative. And I will tell 
you who our witnesses are for the record. We have Dr. William 
Raub, acting executive director, National Bioethics Advisory 
Committee and Deputy Assistant Secretary, Department of Health 
and Human Services. We have Dr. David Satcher, Director, Center 
for Disease Control and Prevention. We have Dr. Harold Varmus, 
who is Director, National Institutes of Health. And we have 
Mary Pendergast, who is Deputy Commissioner, Food and Drug 
Administration.
    I would prefer that we go in the order that I mentioned our 
witnesses: Dr. Raub, Dr. Satcher, then Dr. Varmus, and then Ms. 
Pendergast. We'll go in that order. And we don't have our 
traditional clock. We have asked that you speak for about 5 
minutes. But we do recognize that this is a very important 
subject. And we do want your testimony on the record.
    We will just deal with two housekeeping issues and ask 
unanimous consent that the members of the subcommittee be 
permitted to place any opening statement in the record and that 
the record remain open for 3 days for that purpose. And without 
objection, so ordered. I also ask unanimous consent that all 
witnesses be permitted to include their written statements in 
the record. And without objection, so ordered.
    Your testimony is important. And we want to make sure that 
we cover it. So if you go over, a little over the 5 minutes, we 
recognize, because this is a very important subject. I just say 
for the four witnesses that will be following, we're happy to 
have you listen to some of the questions that are asked of the 
first panel and include them in your opening statements as 
well. So if you want to just make some notes and so on, that's 
fine as well. So we'll start with you, Dr. Raub, and welcome.
    Mr. Raub. Thank you, Mr. Chairman.
    Mr. Shays. Maybe since you haven't started it would make 
sense for us to vote and then come back. And then we won't have 
the interruption. And I might say if we have any students here, 
we will allow students to sit in those first three seats there 
to give a little more room. So we'll be back. We stand at 
recess. And we will hustle.
    [Recess.]
    Mr. Shays. I feel I have tremendous power with this. What 
I'd like to do, I understand that some of our witnesses have 
others who have accompanied them who might assist them in 
responding to questioning, which we actually would want to 
encourage. But we do need to swear them in. So if any of you 
have someone you would like to respond to a question, I think 
it would be good to take care of that now. So do any of you 
have a witness that might----
    Mr. Raub. Yes, we do.
    Mr. Shays. Would you identify who they might be? They can 
just stand where they are for now. Here's what we're going to 
have to do. We will swear all of you in. And then if you do 
testify for the recorder, we'll then ask you to give your name 
then. Let's do it that way. And I'll try to remember faces.
    [Witnesses sworn.]
    Mr. Shays. Thank you very much. I really appreciate your 
cooperation in this regard. And then if you testify, if you 
would be prepared just to leave your full name and title for 
our recorder so he makes sure that he has it. Dr. Raub, we 
welcome your testimony and you're on.

  STATEMENTS OF WILLIAM RAUB, DEPUTY ASSISTANT SECRETARY FOR 
SCIENCE POLICY, DEPARTMENT OF HEALTH AND HUMAN SERVICES; DAVID 
  SATCHER, CENTERS FOR DISEASE CONTROL AND PREVENTION; HAROLD 
   VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH; AND MARY 
 PENDERGAST, DEPUTY COMMISSIONER, FOOD AND DRUG ADMINISTRATION

    Mr. Raub. Thank you, Mr. Chairman, and good morning.
    Mr. Shays. Good morning.
    Mr. Raub. I'm the Deputy Assistant Secretary for Science 
Policy within the Office of the Assistant Secretary for 
Planning and Evaluation in the Department of Health and Human 
Services. I also serve as the acting executive director of the 
National Bioethics Advisory Commission, heretofore labeled as 
NBAC, pending completion of recruitment for that position. I 
appreciate this opportunity to present background information 
on NBAC and to describe its current activities.
    President Clinton established NBAC by Executive order dated 
October 3, 1995. The order describes that function as follows:

    (a) NBAC shall provide advice and make recommendations to 
the National Science and Technology Council and to other 
appropriate government entities regarding the following 
matters:
    (1) the appropriateness of departmental, agency or other 
governmental programs, policies, assignments, missions, 
guidelines, and regulations as they relate to bioethical issues 
arising from research on human biology and behavior; and
    (2) applications, including the clinical applications of 
that research.
    (b) NBAC shall identify broad principles to govern the 
ethical conduct of research, citing specific projects only as 
illustrations for such principles.
    (c) NBAC shall not be responsible for the review and 
approval of specific projects.
    (d) In addition to responding to requests for advice and 
recommendations from the National Science and Technology 
Council, NBAC also may accept suggestions of issues for 
consideration from both the Congress and the public. NBAC also 
may identify other bioethical issues for the purpose of 
providing advice and recommendations, subject to the approval 
of the National Science and Technology Council.

    The order also indicates that NBAC will terminate on 
October 3, 1997 unless extended prior to that date.
    The Assistant to the President for Science and Technology 
issued the charter for NBAC in July 1996. In describing the 
functions of NBAC the charter indicates the following:

    As a first priority, the Commission will direct its 
attention to consideration of:
    A. Protection of the rights and welfare of human research 
subjects; and
    B. Issues in the management and use of genetic information 
including but not limited to human gene patenting.

    Also in July 1996, the President appointed the members of 
NBAC. The chairman is Harold T. Shapiro, Ph.D., president of 
Princeton University.
    NBAC held its first meeting on October 4, 1996. Following a 
series of background presentations and a general discussion of 
the President's charge to NBAC, Chairman Shapiro elected to 
create two subcommittees. The human subjects subcommittee, 
chaired by James Childress, Ph.D., of the University of 
Virginia, has the responsibility for examining the current 
system of protections for human research subjects with emphasis 
on determining whether research sponsors and performers are 
adhering to the so-called ``common rule''--that is, a set of 
essentially identical regulations issued simultaneously by 16 
agencies of the Federal Government on July 18, 1991--and 
whether the rule itself is adequate to assess the ethical 
issues associated with current and future research endeavors. 
The genetics subcommittee chaired by Thomas H. Murray, Ph.D., 
of Case Western Reserve University has responsibility for 
examining the management and use of genetic information with 
emphasis on the bioethical issues associated with the use of 
human tissue samples in genetics research.
    Each of the two subcommittees has held a series of meetings 
toward fulfillment of their respective tasks. They have 
identified information needs, discussed alternative strategies 
for meeting them, and set priorities for followup efforts by 
individual commissioners and/or NBAC staff. For example, as 
both subcommittees identify leading experts from relevant 
disciplines from whom they wish to receive oral and/or written 
testimony, NBAC staff make the requisite contractual and 
logistical arrangements.
    In addition, with respect to the assessment of the common 
rule, a DHHS staff group, with guidance from the human subjects 
subcommittee, is gathering pertinent information from the 
participating agencies so that the subcommittee and ultimately 
the full NBAC will have a strong data base and set of analyses 
to facilitate its assessment as to how well the system of 
protection for human research subjects is working. As I will 
describe in more detail in a few minutes, President Clinton's 
request for a study of the legal and ethical issues associated 
with cloning technology added a substantial task to NBAC's 
agenda, one that demands and is receiving intensive effort from 
all the commissioners.
    This unforeseen development cause both subcommittees to 
reformulate their work plans for this year with the view to 
making them less labor- and time-intensive than they otherwise 
would have been. Nevertheless, both subcommittees are intent 
upon important substantive contributions in their respective 
areas in a sufficiently timely manner so that by October 1997, 
the full NBAC can report findings and recommendations regarding 
human subjects protection and genetic testing over and beyond 
whatever findings and recommendations it provides within the 
next few weeks with respect to cloning.
    NBAC's operating priorities for this year changed abruptly 
in the wake of the press announcements on February 23, 1997, 
that scientists in Scotland had cloned a lamb from a single 
cell from the mammary tissue of a 6-year-old ewe. The 
scientists' research report appeared in that week's edition of 
the scientific journal Nature. On February 24, President 
Clinton sent a letter to NBAC Chairman Shapiro, requesting that 
the National Bioethics Advisory Commission undertake a thorough 
review of the legal and ethical issues associated with the use 
of this technology--namely, cloning--and report back to him 
within 90 days with recommendations on possible Federal actions 
to prevent its abuse.
    Further, on March 4, President Clinton issued to the heads 
of executive departments and agencies a memorandum entitled, 
``Prohibition on Federal Funding for Cloning of Human Beings.'' 
In that memorandum he mentioned his assignment to NBAC, noting 
that cloning technology offers the potential for enormous 
scientific breakthroughs that could offer benefits in such 
areas as medicine and agricultural while raising profound 
ethical issues, particularly with respect to its possible use 
to clone humans.
    Since February 25, NBAC has devoted an extraordinary effort 
toward fulfilling President Clinton's request. The 
commissioners quickly developed a preliminary framework for the 
issues they wished to address and organized themselves into 
several informal working groups so that they initially could 
pursue various subsets of these issues in parallel. Then they 
identified within each issue area the specific topics for which 
they desired additional information, and they provided guidance 
to NBAC staff regarding leading experts in relevant scientific 
or professional disciplines who might be sources of or at least 
links to sources of such information.
    Using this guidance, NBAC staff contracted for a series of 
special analyses on a variety of topics including the state of 
the science related to cloning, the current array of State and 
local level statutes that might affect cloning and/or cloning 
related research, and the historical experience with moratoria 
associated with other areas where rapid scientific advances 
raised major ethical issues--that is, fetal research, gene 
therapy, and recombinant DNA research.
    Further, NBAC staff invited experts in science, religion, 
ethics and other relevant subject matter areas to address the 
commission directly and participate in indepth discussions of 
critical issues. Moreover, NBAC staff made special efforts to 
accommodate within each meeting agenda those members of the 
public who requested an opportunity to address the commission. 
To date the full NBAC has held three meetings largely or wholly 
devoted to the cloning assignment.
    Between meetings, the informal subgroups have pursued their 
respective assignments through special meetings, conference 
calls or e-mail exchanges, and the NBAC staff has maintained 
regular, often daily contact with Chairman Shapiro and the 
other commissioners in anticipation of their needs for 
assistance or in response to specific requests. The 
commissioners are optimistic that they can produce a thorough, 
well reasoned report to President Clinton on or about the end 
of this month.
    The NBAC charter assigns to the Department of Health and 
Human Services the responsibility for providing management and 
administrative support services for NBAC. Secretary Shalala 
initially delegated this responsibility to the Director, 
National Institutes of Health, who redelegated it to the 
Director, Office for the Protection from Research Risks. The 
Director, OPRR established the NBAC office, recruited the 
initial complement of staff, and participated with them and 
Chairman Shapiro in planning and implementation of the initial 
NBAC activities.
    During the fall 1996, the Director, NIH expressed concern 
that the organizational placement of the NBAC office could 
create the appearance of conflict of interest. That is, because 
NBAC inevitably will focus on many issues that fall within the 
purview of the OPRR, any NBAC assessments that relate to OPRR's 
activities, whether favorable or otherwise, might lack 
credibility in the eyes of some observers. After weighing these 
concerns, Secretary Shalala, on November 1, 1996, reassigned 
responsibility for NBAC management and administrative support 
to the Assistant Secretary for Health, who in turn requested 
that I provide day to day oversight of the NBAC staff in my 
capacity as his science advisor.
    Subsequently, I also assumed the role of acting executive 
director, pending the recruitment of an appropriately qualified 
individual to fill this position on a regular basis. And I 
arranged for a DHHS staff member thoroughly experienced in 
working with advisory commissions to serve as Acting Deputy 
Director. The Department recently published the vacancy 
announcement for the position of NBAC executive director. The 
position is classified within the senior executive service, 
and, depending upon the qualifications of the individual 
selected, offers an annual salary in the range of $104,000 to 
$120,000 and possibility higher if the individual selected is a 
physician.
    We expect significant competition for this vacancy and look 
forward to receipt of applications by the deadline, June 4, 
1997. The NBAC staff currently consists of eight full-time and 
four part-time individuals. As NBAC activities continue to 
evolve, future staffing needs will be assessed by the executive 
director in consultation with Chairman Shapiro and in context 
of available resources.
    The budget for NBAC this year is approximately $1.6 
million. Almost half of those funds--$760,000--are being 
provided by agencies of the U.S. public health service, namely 
the NIH, the CDC, the FDA and the Agency for Health Care Policy 
and Research. The remainder of the funds--$850,000--are being 
provided by six other departments or agencies, namely the 
Department of Defense, the Department of Veterans Affairs, the 
Department of Energy, the Department of Agriculture, the 
National Aeronautics and Space Administration, and the National 
Science Foundation. The Office of Science and Technology Policy 
within the executive office of the President was instrumental 
in facilitating the arrangements for joint funding of NBAC.
    Mr. Chairman, I know that I speak for my colleagues as well 
as
myself in saying that we are eager to facilitate the work of 
NBAC as best we can, and that we feel privileged to work with 
this capable and dedicated group of commissioners. If you have 
questions I will be pleased to respond either now or for the 
record.
    [The prepared statement of Mr. Raub follows:] 
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    Mr. Shays. Thank you, Doctor. We'll have questions when 
we've heard from everyone. But you'll be asked questions about 
why the EAB couldn't be doing this why would you be hiring 
someone in June when it's going to come to a conclusion in 
October. To help sort that out for us. Dr. Satcher.
    Dr. Satcher. Thank you, Mr. Chairman and members of the 
subcommittee. Let me say that I'm pleased to be able to join 
you for this very important discussion. I think recently I've 
had opportunities to testify before this subcommittee, dealing 
with issues such as the safety of the blood supply and the 
safety of the food supply in this country. I think those are 
very critical issues for us and I think today's discussion of 
informed consent is equally critical.
    CDC is committed to protecting all persons who agree to 
participate in research studies. We make every effort to comply 
fully with the Title 45 Code of Federal Regulations, Part 46 
for the protection of human subjects.
    Mr. Shays. Doctor, I'm going to just ask you to pause a 
second.
    Dr. Satcher. Sure.
    Mr. Shays. But we're kind of getting a ring. And I don't 
know why. It's not your fault. But I'm just wondering in the 
case of that mic, we'll just pull it away and see if it's----
    Dr. Satcher. OK.
    Mr. Shays. No. The mic will work--no pull away--just a 
little further. Yes. Maybe that will help. Let's try it here.
    Dr. Satcher. OK.
    Mr. Shays. You have such a nice-sounding voice, but we're 
getting this little echo.
    Dr. Satcher. Well, despite the commitment which we----
    Mr. Shays. No. I think if you turn that mic away. Let's 
turn it away. Let's try that. Sorry.
    Dr. Satcher. Despite our commitment and the fact that we 
make every effort to comply with Title 45 CFR, Part 46 for the 
protection of human subjects, we are, however, aware of 
incidents that indicate lapses in our efforts to protect 
individuals who have participated in research that we have 
conducted. I'm confident that the corrective actions that we 
have taken and that we continue to work on will continue to 
improve our protection of research subjects. I would like to 
address specifically two examples of these lapses.
    First, the EZ measles vaccine study. From 1989 to 1991, the 
United States experienced a measles epidemic with more than 
55,000 cases and more than 120 deaths, mostly in young 
children, many of them under 1 year of age. Many cases occurred 
in this age group that was considered too young to be 
vaccinated with the standard measles vaccine--Moraten. During 
the 1980's, multiple studies conducted around the world 
indicated that another vaccine, the Edmonston-Zagreb [EZ] 
measles vaccine administered at 10- to 100-fold greater potency 
than the standard dose for measles vaccine, was showing 
promising results in children under 12 months of age. Because 
of measles cases and deaths in children less than 12 months of 
age in this country, CDC undertook a study, in May 1990, of 
U.S. infants to determine whether results found in other 
countries could be duplicated in this country. And there were 
several studies in other countries carried out by the World 
Health Organization. In fact, over 200 million doses of this 
[EZ] vaccine had been administered. And who had recommended it 
in cases like this.
    Beginning in June 1990, under the auspices of the Kaiser 
Foundation Research Institute and the Los Angeles County Health 
Department, approximately 1,500 children were enrolled and 
randomly allocated into five different study groups and 
received either higher or standard dosages of EZ vaccine and 
standard doses of the Moraten vaccine. The protocol for the 
study was reviewed and approved by the IRB at CDC prior to 
awarding a contract to Kaiser, and was later approved by the 
IRB at Kaiser.
    The parents or parent's representatives for each child 
enrolled in the measles study signed the consent form which 
described the purpose of the study, the procedures to be 
followed, and the benefits and risks of participation. Thus, 
the parents of the children who participated in the study were 
aware that they were participating in a vaccine study. However, 
we later acknowledged that the consent form was deficient 
because the EZ measles vaccine was not identified clearly as 
experimental and parents were not given adequate description of 
the foreseeable risks of vaccination and alternative 
treatments.
    During the time the EZ measles study was being conducted 
data became available from a study in Senegal, West Africa 
suggesting lower survival in girls who received high potency 
measles vaccine compared to girls who received the standard 
potency vaccine. So October 1991, as additional information 
became available from a study of this same high potency measles 
vaccine in Haiti, suggesting that girls vaccinated with this 
level of potency were at increased risk of dying in the 2 or 3 
years following the vaccination, CDC stopped all use of EZ 
vaccines in Los Angeles County in October 1991.
    Following the termination of the EZ measles vaccine study, 
all children who participated in the study were asked to enter 
a followup study to determine whether the vaccine had any 
adverse health effects. Parents were informed of the reason for 
the followup study, including the fact that some studies had 
found lower survival in those children who received high 
potency vaccine. To date, of all the children who have been 
evaluated, no child who took part in this study and received 
the high potency EZ vaccine has suffered a significant health 
problem that can be associated with the vaccine.
    And in fact, the death rate in the group of participants is 
no different from the rest of the population of children. In a 
thorough review of this study, the Office of Protection from 
Research Risks [OPRR] concluded in 1995 that the EZ measles 
vaccine study was scientifically and ethically justified, 
however, the consent form was deficient. In response to the 
recommendations from OPRR, a letter signed by Kaiser Permanente 
was sent in June 1996 covering the topics required by OPRR and 
approved by the IRB at both institutions.
    In addition, CDC and Kaiser sent a jointly signed letter of 
apology in September 1996, to the parents of the children 
enrolled in the trials. In this letter, an apology was made for 
the mistake on the consent form of the study, acknowledging 
that the parents who enrolled their children in the study were 
not adequately informed. The issue was informed consent.
    Now there is another example which I will discuss only 
briefly. And that has to do with the hepatitis A vaccine prior 
to its licensure. While the incidence of hepatitis A has 
declined substantially since 1950, more than 28,000 cases were 
reported to CDC in 1996. And we estimate that there are about 
150,000 cases of hepatitis A in this country each year. 
American Indians have a rate of hepatitis A infection that is 
20 times higher than for whites and African-Americans.
    It was anticipated that several American Indian communities 
in North and South Dakota would have hepatitis A epidemics 
during the early 1990's. The prevention of hepatitis A has been 
somewhat problematic and has primarily relied on improvement in 
hygienic conditions. In the 1980's a number of prototype 
hepatitis A vaccines were developed and offered the potential 
to control and prevent the disease. And let me say briefly, in 
South Dakota, before the hepatitis A trials were launched, 
there was informed consent on the part of the parents and 
assent on the part of children over the age of 7.
    In addition to the CDC Institutional Review Board, there 
was also a review by the Indian Health Service Institutional 
Review Boards. And the tribal councils in South Dakota also had 
to approve the study as this was the Pine Ridge Reservation in 
South Dakota. The study was approved in 1990 and over 500 
children were enrolled in the study. But in this particular 
case there was concern expressed by many people early, so only 
one child was ever vaccinated in South Dakota.
    Later, however, in North Dakota on the Standing Rock 
Reservation--we also implemented a study with the consent of 
our IRB, the Indian Health Service Institutional Review Board, 
the tribal councils on the reservations, and, again, the 
parents and the children. The study began by enrolling 245 
children and about 245 children were vaccinated before the 
study was stopped. The study was stopped, again, because of 
concern expressed by people on the reservation that this was a 
study where about 60 percent of the participants were American 
Indians. And the concern was, why was the study being done on 
American Indians primarily. So the study was stopped after 
vaccinating 245 children.
    Later, in Thailand, based on some work done by others, it 
was demonstrated that the hepatitis A vaccine was in fact 
effective at preventing hepatitis A. Since that time, American 
Indians have been vaccinated against hepatitis A. And the 
epidemics that occurred every 5 to 7 years in the past seem to 
be under control.
    Our position is, and I think most who have reviewed these 
studies agree, that in the case of the hepatitis A--unlike the 
EZ vaccine--in the case of the hepatitis A there was full 
informed consent. Not only was it reviewed by the IRBs at CDC 
and the Indian Health Service, but also the tribal councils 
approved. However, I think what this points out--and I think 
it's a very important point that some of you have made--is that 
because we were dealing with a minority population that often 
feels that it does not have access to the full value of medical 
therapy in this country, when a study disproportionately 
involves those populations, they often are suspicious. And I 
think most of us can understand why.
    So this study was stopped because of the suspicion of the 
members of the reservation that they were being selected out 
for a study. Today, everyone agrees that the hepatitis A 
vaccine is effective in preventing hepatitis A in a very high 
percentage of the cases.
    Mr. Chairman, I would like to say that there are two things 
that we would like to leave with you. No. 1, we believe that 
the systems that we have in place to protect the human subjects 
are better than they've ever been, but we don't believe that 
they are good enough. We have invested significantly in 
upgrading our office of human subject protection. We review the 
consent forms, and we made sure that there is certain 
information in every consent form. We require that any 
researcher at CDC is trained in bioethics and the implications 
of serving on the institutional review board. And we've had 
several leadership director's forums to discuss these issues. 
However, despite all these efforts, much remains to be done and 
we will continue to work to improve these systems.
    However, I think this will be relevant later this morning. 
There are certain ethical principles about which there will 
continue to be debate, especially when one ethical principle 
seems to compete with another. And hopefully we will have an 
opportunity to discuss that later. Thank you.
    [The prepared statement of Dr. Satcher follows:] 
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    Mr. Shays. I thank you. And we'll be happy to have you 
bring it up if we don't. Dr. Varmus.
    Dr. Varmus. Thank you, Mr. Chairman. I want to join my 
colleagues in thanking you and your colleagues for conducting a 
hearing on this most important topic. Let me briefly introduce 
the colleagues who came with me today--four institute directors 
who have serious concerns about issues and cases that your 
staff has brought to our attention: Dr. Duane Alexander, 
Director of the National Institute of Child Health and Human 
Development; Dr. Anthony Fauci, Director of the National 
Institute of Allergy and Infectious Diseases; Dr. Steve Hyman, 
Director of the National Institute of Mental Health; and Dr. 
Alan Leshner, Director of the National Institute on Drug Abuse. 
I'm also accompanied by Dr. Wendy Baldwin, my deputy director 
for extramural research, who has administrative oversight over 
the Office for Protection from Research Risks.
    I'm going to talk briefly about protection of human 
subjects in research. I'll begin with a very brief description 
of our system for protecting research volunteers and then 
briefly speak to some of the initiatives we have underway to 
improve the system. A much longer statement describing these 
activities will be submitted for the record. The forerunners 
for the current system that you will be hearing about are the 
Nuremberg Code, which was developed to provide standards for 
judging human experimentation by the Nazis, and the Declaration 
of Helsinki, which was issued in 1964 by the World Medical 
Association.
    These statements establish the principles of autonomy, 
beneficence and justice that underline many of the activities 
we'll be talking about. And as Dr. Satcher has just indicated, 
those principles are complex and sometimes even in opposition.
    The NIH issued its policies for the protection of human 
subjects in 1966 and these were then established by the 
Department as regulations in May 1974.
    Our regulations are not a set of rigid rules for 
determining whether research activity is right or wrong. 
Instead, they provide a framework for insuring that all serious 
efforts are made to protect the rights and the welfare of human 
research subjects. Responsibility for protection of human 
subjects is shared by a number of groups and institutions: the 
clinical investigator, the local institutional board--so-called 
IRB--in some cases a data and safety monitoring board, 
officials at the institutions that receive grants from the NIH 
and the CDC, as well as officials of the NIH. At each level of 
review, there is the authority to raise concerns about human 
subjects issues, to request further evaluation, and to suggest 
corrections of any identified problems. The Department's Office 
for Protection from Research Risks--the OPRR--while lodged 
administratively at NIH, exerts extensive oversight over the 
entire process involving a number of departmental agencies, 
especially providing oversight at those sites at which the 
research is carried out, often, for example, through assurances 
of compliance with our regulations.
    A crucial part of the system is the requirement for 
informed consent, the topic of this hearing. The elements of 
informed consent are designed to ensure that before subjects 
enroll in a study, they are fully informed about the study, 
about their rights regarding participation, and about the full 
range of risks and benefits of participation.
    I want to speak briefly about the particular attention that 
needs to be paid to certain categories of research subjects. 
These are those people judged more likely than others to be 
vulnerable to coercion or undue influence to participate in a 
study. Our regulations contain specific protections for 
pregnant women, prisoners, children, and fetuses. And reviewers 
also are asked to pay particular attention to studies involving 
individuals with mental disabilities or reduced cognitive 
capacities, drug abusers and people who are economically or 
educationally disadvantaged.
    Now, we believe the system we have created is generally 
effective, but it's not perfect. And occasionally, as you have 
heard, it seems to fail. For this reason we are continually 
working to enhance the system for protecting our subjects. I 
want to take a few final minutes to highlight a number of NIH 
activities that are aimed at making the system better. Many of 
these relate to the specific vulnerable populations I've just 
mentioned.
    First, the NIH in collaboration with the Department of 
Energy and the Department of Veterans Affairs has jointly 
issued a request for applications for original research 
regarding ``Informed Consent in Research Involving Human 
Participants.'' The goals are to test and develop alternative 
strategies that are relevant for diverse populations and to 
determine optimal ways to obtain informed consent. We have 
received more than 80 proposals at the time of the deadline for 
applications, and each of the three agencies has set aside 
funds in this fiscal year to support projects in response.
    Second, six NIH institutes will soon cosponsor a workshop 
to develop principles to guide informed consent in the case of 
subjects who may be cognitively impaired. The cosponsoring 
institutions are the National Institute of Mental Health, the 
National Institute on Drug Abuse, the National Institute of 
Neurological Disorders and Stroke, the National Institute on 
Aging, the National Institute of Alcohol Abuse and Alcoholism, 
and the National Institute on Child Health and Human 
Development. Three of those institutes are represented here 
today. This workshop has been in the planning stage for some 
time, and we hope to have it by next fall.
    Third, the advisory council of the National Institute on 
Drug Abuse recently has issued guidelines for research 
involving administration of drugs, especially drugs of misuse 
and abuse to human subjects. These guidelines for IRBs address 
the ethics of both human subject research in general and 
studies involving special populations. We've provided a copy of 
those guidelines to the subcommittee's staff. The National 
Institute of Mental Health--NIMH--has a number of additional 
activities underway. They have recently cosponsored a 
conference that addressed the specific ethical challenges 
involved in mental health research with children and 
adolescents.
    In collaboration with the National Alliance for the 
Mentally Ill, the NIMH has cosponsored a series of meetings to 
discuss ethical issues of medical research involving human 
subjects with mental illnesses. In addition, the NIH and the 
Office for Protection from Research Risks cosponsor annual 
regional workshops that focus on human subjects issues in 
mental health clinical research. The National Institute on 
Aging issued an announcement in the NIH Guide in October 1996 
on implementation of policies for intervention studies, 
especially involving those subjects who may be mentally 
impaired.
    And as one final item, the Clinical Center at the NIH, 
together with OPRR and several NIH institutes, has pioneered 
the concept of durable power of attorney applied to research 
participation. This procedure allows individuals, while they 
are mentally competent, to identify someone to represent their 
best interest and to provide proxy informed consent should they 
later become cognitively impaired.
    Mr. Chairman, the people who volunteer to be research 
subjects are invaluable partners with us in the pursuit for new 
knowledge in medical science. Research investigators, research 
institutions, the NIH, and our partner agencies in the 
Department of Health and Human Services have a responsibility 
to protect those volunteers' rights and welfare. We take that 
responsibility very seriously. Thank you, Mr. Chairman. I'll be 
pleased to answer any questions you may have.
    [Note.--The ``OPRR Reports, NIH, PHS, HHS, Protection of 
Human Subjects'' can be found in subcommittee files.]
    [The prepared statement of Dr. Varmus follows:] 
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    Mr. Shays. Thank you, Dr. Varmus. Thank you. And Ms. 
Pendergast.
    Ms. Pendergast. Thank you, Mr. Chairman, members of the 
subcommittee. Good morning.
    Mr. Shays. Good morning.
    Ms. Pendergast. The Food and Drug Administration has put 
forward a longer written statement concerning the human subject 
protection system and the FDA's bio-research monitoring 
program. This morning I would like to briefly describe to you 
our regulations concerning research in life or death emergency 
situations.
    Medical research is important. But the rights of human 
subjects in clinical trials are more important. Our attitude is 
grounded in the laws, in the ethical principles set forth in 
the post-World War II Nuremberg Code, in the Declaration of 
Helsinki, and above all in our conscious as individuals and as 
officials responsible for the protection of consumers and the 
public health.
    We fully believe that medical research, which is 
intrinsically hazardous, must be conducted with complete 
integrity, that it must not be carried out at the expense of 
human subjects, and the their informed consent is the bedrock 
protection of their rights and self-interest. Therefore, when 
we had to consider the possibility of research without informed 
consent, we approached the task with great caution. We were 
asked to explore this option because new technology makes 
possible products that hold out the promise of saving lives in 
emergencies that were regarded as hopeless only a few years 
ago: lives of people who are close to death, cannot 
communicate, and require immediate treatment but whose 
condition has no proven remedy. To make this type of critical 
research possible while providing the maximum protection for 
the patient, we conducted extensive, indepth consultations with 
leading ethics, legal, research, patient advocacy, and minority 
communities.
    With their assistance, and in cooperation with the National 
Institutes of Health, we issued in September 1995 a proposal 
that drew 16 negative comments, mostly from individuals who 
believed that informed consent should never be waived under any 
circumstances whatsoever. The other 74 commenters were strongly 
supportive. They included the National Stroke Association, the 
Brain Injury Consortium, the National Head Injury Foundation, 
the American Heart Association Emergency Cardiac Care 
Committee, the American College of Emergency Physicians, and 
the Applied Research Ethics National Association.
    Our rule, Mr. Chairman, demands that informed consent be 
obtained whenever possible, but it also allows a waiver of 
informed consent in extremely limited emergency situations 
while safeguarding the subject's rights with overlapping layers 
of protection. The basic preconditions of the waiver are that 
the subject's life is threatened by an extremely serious 
condition, such as heart attack, stroke, or traumatic head 
injury; there is no proven or approved treatment; the 
intervention must be studied to determine what intervention is 
most beneficial; and informed consent of the subject or the 
legal representative is not feasible for several clearly 
defined reasons.
    If all of these preconditions are met, the IRB--the 
Institutional Review Board--can waive the consent requirement 
in a particular trial, but the subject's rights are protected 
in other ways. The IRB must find that the research holds out 
the possibility of direct benefit to the subjects. We call this 
clinical equipoise. The FDA must engage in a heightened review. 
We apply higher standards than usual to this research. There 
must be public disclosure of the proposed study to the 
community in which the research will take place. And the 
Institutional Review Board must consult with that community. 
The community must be engaged in the question of whether or not 
the research should go forward in their community. There must 
be public disclosure when the study is done. And there must be 
an independent safety and monitoring board. Finally, the 
researchers must continue to search out family members, next of 
kin, legal representatives, so that they or the person who, if 
the person becomes conscious, can be told about this study and 
asked whether they want to continue with it.
    Mr. Chairman, these are merely the highlights of a complex 
system that is more fully described in my written statement. 
Let me close by assuring you that we and the many ethicists 
with whom we worked did our utmost to devise a system that 
exhaustively protects the subjects while saving their lives. 
The rules are too recent to pass any judgment on them. But we 
are committed to careful oversight of the rule's used. And we 
will modify the rule if needed. Thank you for your attention.
    [The prepared statement of Ms. Pendergast follows:] 
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    Mr. Shays. Thank you. I think what I'd like to do is start 
with you, Ms. Pendergast. And what I would like you to do, if 
you don't mind, if you would read your statement and put it in 
the record orally beginning on page 37. I think that's where it 
begins. I'll tell you where. This relates to the Desert Storm 
issue. And if you could start with the second paragraph. And if 
you just read that paragraph, I'd like that on the record. And 
then I'd like to ask you questions about it.
    Ms. Pendergast. The paragraph that begins ``Under this 
regulation?''
    Mr. Shays. Yes.
    Ms. Pendergast. All right. We're referring now to a 
regulation that the FDA promulgated in December 1991 regarding 
waivers of informed consent during military combat situations.

    Under this regulation, waivers were granted for two 
products during Operation Desert Storm/Desert Shield: 
pyridostigmine bromide and botulinum toxoid vaccine. Although 
FDA had concluded that informed consent was not feasible, FDA 
did obtain the Department of Defense's agreement to provide 
accurate, fair and balanced information to those who would 
receive the investigational products. To do this, the 
Department of Defense developed information leaflets on both 
products with FDA's inputs and these leaflets received final 
FDA approval.
    Following the cessation of combat activities, the Assistant 
Secretary of Defense for Health Affairs notified the 
Commissioner in a March 1991 letter that the Department of 
Defense considered the two waivers granted under the interim 
rule to be no longer in effect. He also informed the 
Commissioner that the Department of Defense had ultimately 
decided to administer the botulinum toxoid vaccine on a 
voluntary basis.
    Since that time, the Presidential Advisory Committee on 
Gulf War Veterans Illnesses has recommended that we ``solicit 
timely, public and expert comment on any rule that permits 
waiver of informed consent for use of investigational products 
in military exigencies.'' Final report, page 52. FDA has 
carefully evaluated the committee's recommendations as well as 
other information that has come to its attention. FDA has 
engaged in discussions within the Agency, with the Department 
of Defense, and with others on this important topic. As a 
result of these discussions, the Agency will solicit public 
comment in line with the committee's report. The public comment 
will be directed towards whether the FDA should finalize the 
interim rule, modify it, or eliminate it completely.

    Mr. Shays. Let me ask you this to start my questions: Did 
the Department of Defense violate the conditions of the FDA's 
waiver of the informed consent requirement by not providing 
military personnel with information about the experimental 
drugs they were required to take?
    Ms. Pendergast. As a condition of the waiver, we did 
negotiate an agreement with them where they would provide 
information sheets to the soldiers so that the soldiers, while 
not being allowed to decide whether they wanted to take the 
drug, they at least knew what they were taking, what it's risks 
were, what it's purported benefits would be. Unfortunately, we 
are advised by the Defense Department that they did not give 
all soldiers those information sheets.
    Mr. Shays. So what is your answer to the question?
    Ms. Pendergast. It's not clear to me that it's a violation 
of the regulation, but it is a violation of our agreement.
    Mr. Shays. No. I asked is it a violation of the conditions 
of the FDA waiver. They didn't inform.
    Ms. Pendergast. They didn't. No. There's no dispute about 
the facts, sir. I am only questioning because I have to look at 
the waiver document itself to ascertain whether that was in the 
waiver document and one of the preconditions for the waiver. 
And I'm afraid I'd have to submit that for the record.
    Mr. Shays. The war took place 7 years ago. Basically, 6 
years ago. And you're telling me that the FDA still hasn't 
determined whether or not the Department of Defense was in 
violation of the notification requirement as a condition of 
waiving the informed consent?
    Ms. Pendergast. No. I think that there's no dispute about 
the facts. We know that the information sheets were not 
provided to all of the soldiers.
    Mr. Shays. OK.
    Ms. Pendergast. You're asking me a different and more 
specific question.
    Mr. Shays. Well, I don't think they were really provided to 
practically any of the soldiers. We've had eight hearings on 
the Gulf war. So this should show up on your radar screen. It's 
not something you need to check now. You need to make a 
determination of whether they were in violation or not. And I'm 
asking a question that it seemed to me that you could have 
responded 2 years ago. And so I'm going to repeat the question. 
Are they in violation of the agreement that the FDA had?
    Ms. Pendergast. If you'll give me one moment, sir?
    Mr. Shays. Sure.
    Ms. Pendergast. The actual requirement that the information 
being given to the soldiers is not contained as a precondition 
in the actual written waiver document. So as a technical 
matter, it could be disputed that they were in violation of the 
waiver agreement. However, and more importantly from the 
soldiers' point of view and from our point of view, it was a 
promise that was not met.
    Mr. Shays. So you're saying they promised to do it, but 
technically didn't sign an agreement to do it?
    Ms. Pendergast. That's my understanding, sir.
    Mr. Shays. What did they technically agree to?
    Ms. Pendergast. There were a number of things that they 
agreed to do basically.
    Mr. Shays. Not the promise, the technical.
    Ms. Pendergast. No. The technical agreement. What it is, is 
we have regulations that describe the responsibilities of 
anyone who is conducting an investigation. And they basically 
go to the control of the drug, recordkeeping with respect to 
the administration of the drug, and recordkeeping pertaining to 
the adverse events or not of the administration of the drug. So 
there is a basic set of requirements. Because it was war, we 
recognized at the time that not all of the standard 
requirements would be capable of being met. This isn't 
administration in a hospital.
    The pyridostigmine would have been given out in field 
combat situations. So what we did is we limited their 
requirements to a more limited set of requirements pertaining 
to information. If the worst possible thing happened and our 
troops were exposed to chemical or biological weapons then 
there were lots of obligations that kicked in, in terms of 
finding out what happened and whether or not the 
administration----
    Mr. Shays. Ms. Pendergast, this is kind of painful here.
    Ms. Pendergast. Yes.
    Mr. Shays. The soldiers did take the PB pills. They did 
take them. They were under orders to take the pills. The Army 
was allowed to order them to take the pills because the FDA 
made a determination that the pyridostigmine bromide--the PB 
pills would be allowed to be used for a use that it had not yet 
been licensed for. You are telling me that the Department of 
Defense promised but did not sign an agreement that they would 
inform. Is it conceivable that they FDA would have allowed our 
soldiers to be required to take these pills without their being 
informed, at least that they may have a bad chemical reaction, 
that this was an experimental pill for this use? Is it 
conceivable the FDA would allow our soldiers to not be 
informed?
    Ms. Pendergast. No, sir. As I indicated, we suggested and 
then worked with the Defense Department to create these 
information sheets so that the soldiers would have 
information----
    Mr. Shays. They weren't informed. And you're telling me 
that they are technically not in violation of the consent 
because it was not a contracted, written agreement they 
promised to. But that was not part of the agreement 
technically. Was it part of the agreement technically that they 
would keep records?
    Ms. Pendergast. Yes, it was.
    Mr. Shays. OK. Did they keep records?
    Ms. Pendergast. They kept some records. In our judgment 
they did not keep sufficient records.
    Mr. Shays. So let me repeat my question. Were they in 
violation of the agreement?
    Ms. Pendergast. In that sense, yes.
    Mr. Shays. OK. So it terms of not informing our soldiers, 
they weren't in violation technically, but they were clearly in 
technical violation as well as in the spirit in terms of not 
keeping records of who was given these drugs and so on.
    Ms. Pendergast. That is correct.
    Mr. Shays. OK. So what is the Department doing about that? 
What is your agency doing about it?
    Ms. Pendergast. Well, we've done a number of things. We 
have worked with the Defense Department to see if additional 
information could be provided to us. We have written them 
asking that if they have additional information on certain 
specific points that it be provided to us. In 1994, we sent 
them basically a ``lessons learned'' letter describing what was 
in our judgment the problems that we saw in the 1991 
administration of the products and what could have been done 
better. And we are--as we indicate in our testimony--we are 
working to see whether or not this kind of a system worked and 
could work in the future differently or perhaps be abandoned.
    Mr. Shays. So what I'm basically to infer from what you've 
said is, clearly the spirit of the law--for them to get this 
waiver of informed consent, the spirit of the law was they were 
at least to inform the soldiers that this was an experimental 
drug first and that the spirit of the law was clearly to keep 
records, but technically they were not required to inform the 
soldiers, which blows my mind. And you're saying technically 
they were required to keep records, which they didn't. And you 
sent out a letter in 1994 and they have ignored your 
interaction and communication and you're satisfied?
    Ms. Pendergast. Sir, we've never said we were satisfied. We 
recognize that this did not go well. We are, if anything, 
disappointed that it didn't go better.
    Mr. Shays. No. Disappointed isn't good enough. Because this 
committee feels that some of our soldiers may have suffered 
severe physical problems as a result of taking an experimental 
drug in cases where maybe they took it after they were exposed 
to chemicals as opposed to before, and not knowing the 
relationship of when they should have taken these pills. So 
disappointed isn't good enough for us.
    Ms. Pendergast. Let me explain. The law states quite 
clearly that informed consent may permissibly be waived if the 
obtaining of informed consent is not feasible or not in the 
best interest of the subject. That's our law. It was written in 
1962.
    Mr. Shays. Well, it was feasible. When they were given 
these pills, it was feasible to inform them. And that's the 
least they deserved.
    Ms. Pendergast. At the time we wrote a regulation that 
addressed the question of whether or not informed consent was 
feasible in a military combat exigency, the testimony and the 
record at that time showed that the Defense Department 
indicated to us that during a military combat exigency, because 
of military command and in order to preserve the health and 
well-being, not just of the individual soldier, but of the 
other soldiers that would have to protect the soldier that had 
fallen as well as the troops as a whole, that informed consent 
was not feasible. The Food and Drug Administration accepted 
that representation.
    Mr. Shays. I understand why they may have decided not to 
allow for soldiers to consent. I have no sympathy whatsoever 
they couldn't have informed the soldiers. And I am pained that 
after so many years have passed that you would concur in some 
way that they did not need to inform, that there was some 
military impossibility for informing.
    Ms. Pendergast. Sir, I have not made that representation. 
The Defense Department has to answer the question as to why it 
was unable to give them the information sheets.
    Mr. Shays. No. You have to enforce the requirements that 
they are technically required to. And have you enforced it?
    Ms. Pendergast. Yes. I believe we have.
    Mr. Shays. I wish you had just said ``no'' and we could 
have gone on. Because you haven't you have sent out a letter. 
There will be no response from the audience, please. You have 
basically said you have sent out a letter. You have basically 
accepted and put on the record that military activity prevented 
them from even living up to the technical requirements and 
certainly the spirit. And I want to know specifically now, 
given that you said you are enforcing this, I want to know 
specifically what you've done to enforce their failure to live 
with the spirit and the technical requirement that they agreed 
to.
    Ms. Pendergast. As I indicated, we have expressed to the 
Defense Department in writing the problems we have found with 
their conduct of the administration of these drugs during 
Desert Storm. And we have been working with the Defense 
Department and with others and the Presidential Commission on 
Gulf War Syndrome to ascertain what could be a better way of 
doing this.
    Mr. Shays. You're talking about in the future. And I'm 
talking about the hundreds of thousands of soldiers who were 
sent into this conflict. And you have not told me how you have 
enforced their requirement. Have you asked for all their 
records?
    Ms. Pendergast. Yes.
    Mr. Shays. OK. How many have you received?
    Ms. Pendergast. I can't tell you how many inches.
    Mr. Shays. Pardon me?
    Ms. Pendergast. I mean, we have received safety information 
and the other information that was required to be submitted 
under their investigational new drug exemption. As I indicated 
to you, it was not the type or quantity of information we would 
have hoped for----
    Mr. Shays. That's an understatement.
    Ms. Pendergast. We don't disagree with you. This was war. 
This was the first time. And it didn't work particularly well. 
We are in full agreement with you on that.
    Mr. Shays. This isn't the first time the military has 
conducted themselves this way. And as long as they know the FDA 
is going to be a paper tiger with the military, they will 
continue to do this. They will continue to basically say ``bug 
off.'' And as far as I'm concerned that's what they've said and 
that's what you've accepted. And you have said under oath that 
they have sent you information, you have asked for information. 
So it's just really important that you provide this 
subcommittee with specific requests and that you provide this 
subcommittee the results of what you requested. And we'll just 
continue this later.
    I want to go on record as saying that I think this was an 
obvious question for me to ask you. I would have thought that 
you would have been very prepared to respond to it. And I think 
that if we didn't ask these questions after having eight 
hearings on this issue, that we would be derelict in our duty. 
And so we are going to pursue this with the FDA. Because in my 
judgment the FDA allowed the military to do what they have to 
do in time of war, to have gotten a waiver from informed 
consent.
    They should have required that the troops technically, not 
just in spirit, be notified. And they should have made sure 
that it was being enforced. And the technical requirement of 
information, which is an outrage that it was not kept and data 
was not kept. And the FDA has not, in fact, really overseen 
this and sought to. And frankly, if you had said to me, we 
really blew it, just like the military, I could accept it. But 
you're defending it. So now we're going to pursue it. I have 
other questions for the other witnesses, but at this time I'm 
going to give Mr. Towns as much time as he'd like to consume.
    Mr. Towns. I yield to my colleague from Ohio.
    Mr. Kucinich. Thank you very much, Mr. Towns, Mr. Chairman. 
I'm new to this subcommittee and to the Congress, but I have 
followed the Chair's tireless efforts to get to the bottom of 
the Gulf War Syndrome. And it's interesting to listen to this 
testimony, Mr. Chairman, with respect to the FDA's non-
supervisory status. I would like to ask the representative from 
the FDA, if she could answer this question? Since we've seen 
that the waiving of PB for military personnel in the Persian 
Gulf, waiving a consent for any reason can have serious 
consequences, do you agree that based on that experience there 
should be an immediate moratorium on waivers for any reason 
until some of the ethical problems that are being brought 
forward are addressed with comprehensive and stringent 
protocols for informed consent?
    Ms. Pendergast. Yes; basically I agree with you. There are 
no waivers in effect at this time, and haven't been for a 
number of years. And the 1994 letter that we sent to the 
Defense Department was an indication that were there ever to be 
another waiver request considered--and there was no judgment 
made as to whether we would ever say yes again--but were we to 
even consider another waiver request, the specific standards 
would have to be much higher and more rigorous because of the 
failures.
    Mr. Kucinich. So you're saying this would never happen 
again? Is that what you're saying?
    Ms. Pendergast. Not the way it happened this time. No.
    Mr. Kucinich. And do you feel that the Department of 
Defense ran roughshod over the FDA here?
    Ms. Pendergast. It is difficult for us to say that. I think 
that the persons that we were dealing with were well-meaning. I 
also think that the FDA, which is an agency staffed with 
doctors and scientists, and not soldiers, has a very limited 
ability to second-guess what was going on in the Persian Gulf 
during the time of the war, and so----
    Mr. Kucinich. But when it comes to medical matters and 
matters related to bioethics, who should make the decision, a 
general or a doctor?
    Ms. Pendergast. There is an obligation on the part of the 
Defense Department to have doctors in charge of making sure 
that the troops received the drugs properly and that the 
information was given to them, and that adverse events were 
reported back to the FDA. Doctors had to be in charge. That was 
part of the system that was in place as we went forward to 
permit the Defense Department to administer these products.
    Mr. Kucinich. So you're saying military doctors made the 
decision?
    Ms. Pendergast. Military doctors.
    Mr. Kucinich. But are they subject to review by the FDA?
    Ms. Pendergast. The military doctors basically had to 
report back to the FDA what they accomplished and what they 
failed to accomplish. And the reasons why the military doctors 
were able or unable to do particular things is a broader 
question of military logistics and chain of command during a 
theater of war. But from where we sat, we were talking to the 
military doctors who had obligations to do certain things and 
report back to the agency.
    Mr. Kucinich. You know, one of the things, if I may, and 
I'll let this go, Mr. Chairman, because I think that you've set 
the inquiry on a track that will eventually get the truth out, 
but something occurs to me about hearing this discussion. It's 
very disturbing, because the whole idea of consent--in a way, 
it's a matter of a time sequence. Troops are gathered to the 
Persian Gulf, they're put in staging areas, they're engaged to 
the field. At some point along the way, even before people were 
sent out to the Persian Gulf, there was an understanding that 
they could run into an environment where nerve gas could be 
used. The idea of having PB came up, I'm sure, years before our 
troops went out there. And it just makes me wonder, Mr. 
Chairman, how this could have happened.
    Because we're talking about a pick-up game, like a street 
basketball or street baseball game--everybody gets together and 
you make up the rules as you go along. People knew years before 
that if we were engaged in the Persian Gulf that nerve gas was 
a possibility. And for that reason it seemed to me that the 
exigencies of which we speak in combat are not a defensible 
argument for not providing informed consent. Because there was 
plenty of time to let anyone who would be in the Persian Gulf, 
Mr. Chairman--anyone who was going to be sent out there could 
have been told far in advance of being deployed to the field 
that they would be subject to taking a drug that could have 
certain consequences.
    But the uniformed personnel never had that opportunity. And 
that's where I think the FDA has failed. And that's where, 
also, I think the Department of Defense failed our enlisted men 
and women. So I sat in a hearing which the chairman called, and 
we listened to men and women who are the victims of Persian 
Gulf Syndrome--they weren't told. So I have--I want you to know 
that I have a lot of respect for the role that the FDA plays in 
our society--I mean, to make sure that food and drugs that 
people consume are safe.
    It's not a small matter. We all rely on it. It's like a 
basic trust that we have. But in order to rescue that trust, 
the FDA needs to come forward with a comprehensive statement of 
what went wrong and what you intend to do to make sure it will 
never happen again. Because it's very clear that there have 
been ethical breaches which undermine not only public trust but 
which have put human health on some kind of a foreign altar. 
And we ought never again be in a situation where this happens 
to our people.
    Ms. Pendergast. May I respond?
    Mr. Kucinich. Please.
    Ms. Pendergast. I think, Congressman Kucinich, you raise an 
incredibly important point. One of the things that we are 
looking at now is the question of, having accepted the fact 
that war may happen, is it possible to obtain basically 
anticipatory consent from troops? As in the question of, if you 
were ordered to take it, would you take it? And then only field 
the people into war zones who are willing to say or whatever. 
But that's a Defense Department question that I'm fully 
prepared--but that is the kind of debate that is going on.
    I think if you go back and look at fall 1990, this issue 
first came up when the Defense Department was preparing for 
war. And I think in the view of hindsight we know that there 
may have been better ways of doing it. But at the time, they 
were trying to basically protect their troops. And I would like 
to say that these two products--pyridostigmine bromide and 
botulinum toxoid--are products that, although not approved for 
this use, had been widely and extensively used by people. 
Pyridostigmine bromide is approved and has been since the 
1950's at doses 20 times higher than the troops used. And 
people take it every day. And so we knew that it was a very 
safe product. Did we know it would work to protect them against 
nerve gas? No. Monkey trials showed it would. Did we know it 
would protect humans? No. But we had no way of knowing. Because 
it's not ethical to give somebody a prophylactic drug and then 
expose them to nerve gas and if you're wrong say, ``Oh, I'm 
sorry.'' You just died. So you can't ethically test it. You do 
your best----
    Mr. Shays. Excuse me. If the gentleman will----
    Mr. Towns. It's my time. I'll yield.
    Mr. Shays. If it's not ethical, then why did we do it to 
hundreds of thousands of our troops?
    Ms. Pendergast. Because based on the information we had, it 
was indisputably safe and----
    Mr. Shays. No. But you just made a comment.
    Ms. Pendergast [continuing]. And we thought it was their 
best shot against nerve gas. You can't ethically expose someone 
to nerve gas as part of a clinical trial. That is the point 
where it's unethical. Nobody in the United States was ever 
going to expose our troops to nerve gas. The enemy was going to 
expose them. The question is what could we give our troops that 
would give them the best shot at making it through that adverse 
war time situation. We knew pyridostigmine bromide was safe. We 
had been giving it to people for 40 years. And we knew that in 
monkeys it had protected them against nerve gas. It was better 
than nothing. With respect to the botulinum----
    Mr. Shays. Let me just say to you, if that's the logic you 
used, then apply it to the private sector as well. And you 
don't. I thank the gentleman for yielding.
    Ms. Pendergast. With respect to the botulinum toxoid, that 
botulinum toxoid is used routinely by the scientists at the 
Centers for Disease Control and by other public health 
officials. Again, you can't ethically test biological and 
chemical weapons, even against volunteers. But that has been 
tested in animals. And it is used routinely by public health 
officials on themselves. Again, we though at the time that it 
was the best possible treatment or prophylaxis for our troops, 
that if we were going to war, if our children were going to 
war, we would want them to have that protection.
    Mr. Shays. I'm sorry. If the gentleman----
    Mr. Towns. I yield further.
    Mr. Shays. No. I don't--I can even accept that you would 
ultimately have done that. I cannot accept for the life of me 
that you would not have required technically under law to have 
informed the soldiers. That I cannot accept. And I cannot 
accept once the war had ended, that the FDA wouldn't have been 
extraordinary vocal and active early on in making sure that 
records were kept. And if they weren't kept that they heard big 
time from the FDA in such a way that they would never even want 
to consider doing something like that in the future. And 
frankly, the response of the FDA, the anemic response of the 
FDA, tells me that the military knows they can be comfortable 
to do it again.
    Mr. Towns. Let me move to another area, I think one even 
more basic. I'm concerned about the language used in some of 
these consent forms. It seems to me that you would have to be a 
person with a Ph.D., almost to understand the content of these 
forms. I know that there is an effort to provide simple verbal 
explanation. However, I wonder whether you can provide a simple 
written explanation? So why don't I go to you, Ms. Pendergast, 
first, and then let others comment about it--because the 
consent form itself.
    Ms. Pendergast. I'm not sure which consent form you're 
referring to. But it is one of the requirements of informed 
consent that it be written in a way that the subjects of the 
trial--the human volunteers--can understand it. So it has to be 
written--the regulations require that it be written in a way 
that the people who are receiving the information can 
understand it.
    Mr. Towns. How do we arrive at that particular form? You 
see, have you seen some of those forms, those consent forms? I 
mean, all of them--that you find that, in terms of the way 
they're written, is just not clear. Just the average person 
would not be able to understand it.
    Ms. Pendergast. The institutional review boards that must 
review research before it is allowed to go forward looked at--
--
    Mr. Towns. That's another problem. Go ahead. I don't want 
to cut you off.
    Ms. Pendergast. They're the ones that are closest to the 
community where the research is going to take place. So we look 
to them for that--their job is to protect the human subjects. 
And their job is to stand in the shoes of the volunteers to 
make sure that the volunteers are treated properly. And they 
are asked to look at those consent forms and make sure that 
those consent forms are appropriate for the people in their 
community who will be subject to the research. Whether they do 
it right all the time or not--I'm sure they don't. I'm sure 
mistakes are made. But if you look at the system, those are 
people who we turn to and say, is it in the right language, is 
it the right reading level, does it use too tough words, is it 
at the college level, should it be at the sixth grade or eighth 
grade reading level? Those are things that we turn to the 
institutional review boards to do.
    Mr. Towns. But you know, I think maybe if you make your 
answers a little shorter you might not have as many problems.
    Ms. Pendergast. Thank you.
    Mr. Towns. Because what you're saying is, the review 
board--only CDC really--the review board--reflects the 
composition of the people that are going to be involved in the 
research. So why would you say--because that doesn't make a 
difference. Because if you have people that are involved in the 
review board that do not reflect the people that are going to 
be in the study, then what good does that do?
    I don't understand how you're answering that. I can see CDC 
answering it that way, because there seems to be an effort to 
make certain that the people that are going to be in the 
study--actually that's the people that would be on the review 
board. Now, that's the only one I know--does anybody else?
    Dr. Varmus. That's true, also, Mr. Towns, of the review 
board that would review a proposal that's being carried out 
under the terms of an NIH grant. Virtually all of our grants go 
to academic institutions and research institutions which have 
review boards at the institutions composed of people who 
represent the community--diverse with respect to gender and 
race. They are asked to interpret the consent form to be sure 
that it is understandable by the subjects. Now you're raising 
an important question, because if the language is too watered 
down you could argue that the study is not being adequately 
explained.
    We work with these institutions through the Office for 
Protection from Research Risks to try to provide guidance. 
We've had tremendous experience at our OPRR, and we work with 
our institutions to be sure that they can find the happy 
medium.
    Mr. Towns. Ms. Pendergast, can you say that?
    Ms. Pendergast. Yes. The same rules are true for all the 
research that the FDA regulates. The review boards have to have 
gender and racial diversity. There have to be representatives 
from the community. And if the research involves children or 
other vulnerable populations, experts from those fields should 
be consulted.
    Dr. Satcher. Congressman Towns, let me----
    Mr. Towns. Yes. Go ahead.
    Dr. Satcher. I just briefly want to say two things. I think 
the issue of informed consent is a very difficult issue. And 
I've been struggling with it for at least--well, going back to 
the sickle cell research center in Watts in the early 1970's, 
and I agree with Dr. Varmus. I think on the one hand, the 
critical issue is do people understand what you're saying. On 
the other hand, are you including enough content so that they 
really are able to explore the substance of what's going to go 
on with them. I think we just have to continue to struggle with 
this. I don't think we have perfect informed consent forms. Or 
IRBs, for that matter. I think we continue to make sure that 
the institutional review boards reflect the community. And it 
is a continuing struggle. Because sometimes you get people 
because you think they reflect their community and you find out 
later that they don't.
    Mr. Towns. Right.
    Dr. Satcher. And then you put together an informed consent 
form, and then you find out sometimes the people don't read 
them. A lot of us do that. Not just people who have trouble 
reading. But a lot of us sign things without taking the time to 
read them. So we're struggling with all of those things. But 
what I think what we're trying to do is to improve 
communication between our institutions and the public that 
we're trying to serve.
    Mr. Towns. Right. Dr. Raub, do you want to comment? Thank 
you very much, Dr. Satcher.
    Mr. Raub. I can add only in reinforcing my colleagues that 
the institutional review board is the first line of protection 
here. And every day they struggle with getting the message 
clear enough yet not so simplified that it misleads, and when 
they do explain a risk, explaining that risk in a way that is 
accurate without being so frightening or unnecessarily detailed 
as to mislead the subjects. There's been the constant struggle 
over the last several decades especially in a very litigious 
society where every time the risk is not disclosed adequately 
it then creates legal problems. So I think each board must 
struggle with getting the information as simple and clear as 
possible without being inaccurate or misleading or otherwise 
exploiting the individuals involved.
    Mr. Towns. Right. Let me just sort of go back to something 
that was raised earlier. And I think that we have to be honest. 
I think that the chairman said something that I think that we 
need to really make certain that we put everything on the 
table. I'm concerned about the illusion of consents in certain 
circumstances. And of course, in the military or in prison, 
people are not free to say no. And I think we might as well go 
on and recognize this and admit it and let's move on. And I 
think that that's a fact.
    And I think that, the chairman raising his question--also 
the gentleman from Ohio--that there is no need to dance around 
those kind of issues. There are certain situations and certain 
circumstances where people cannot say no, not in the true sense 
of no. We have to recognize that and then determine in terms of 
what we might try to do to begin to work on those kinds of 
things in order to make certain that people's rights are not 
violated. And I think that's an open and honest kind of 
discussion.
    And I think that if we go about it any other way, I think 
that we're not really being fair to ourselves and the time that 
we're spending here together. So I want to lay that on the 
line, Ms. Pendergast, and to say to you that that's what we 
have to acknowledge. That's a fact. And of course--begin to 
deal with it. One more question, Mr. Chairman, and then I'm 
going to yield back, because I know that our time has been----
    Mr. Shays. Mr. Kucinich will go after you. But you have 
more time.
    Mr. Towns. OK. Fine. I'm concerned about the HIV trials 
being conducted in Africa, in the Caribbean and in Asia. There 
are allegations that these trials would have never been 
conducted in the United States. On the other hand, there are 
those who say that if these trials are halted, it would be 
difficult to conduct future drug trials in Third World 
countries. I would like each of you to comment on where we 
should strike the balance when considering drug trials in other 
countries.
    Dr. Satcher. Could I start? And the only reason I want to 
start is because that is the issue that I was referring to at 
the end of my testimony----
    Mr. Towns. Yes.
    Dr. Satcher [continuing]. When I mentioned that sometimes 
there can be, if you will, what seem to be competing ethical 
principles. I think the AZT trials in Africa and Thailand and 
some of the other places throughout the world that are being 
carried out by NIH and CDC are funded in this country but also 
carried out by the World Health Organization and the United 
Nations AIDS program are an example of that in many ways. And 
recently a group, Public Citizen, raised some of those issues. 
And I want to say that it's a group that I respect.
    And I agree with them on most of the issues. I disagree on 
this particular one. I believe the AZT trials that we're 
supporting and carrying out in Cote d'Ivoire and Thailand--and 
I'll just speak to those two for CDC--in fact do meet ethical 
principles. The debate is whether, in fact, they would be 
conducted that way in this country. As you know, the 076 trials 
were carried out primarily in this country and in France--well-
developed countries. And they received long-term, high dose AZT 
treatment to prevent the spread of HIV from mother to child, 
sometimes 16-24 weeks of therapy.
    In the host countries where we're conducting those trials, 
there is no AZT treatment which is now standard in this country 
and in France and some other places. And the reason that there 
is no AZT treatment has to do with cost and complexity of the 
076 regimen. The international community has never accepted the 
076 regimen as appropriate for developing countries. So what we 
did in working with our host countries in Cote d'Ivoire and 
Thailand was to respond to their concerns about AZT, their 
desire to implement AZT, but their recognition that they 
couldn't do it the way we were doing it in this country.
    Now, the two ethical principles--No. 1, there is an ethical 
principle about when you enroll people in a study: Do you ever 
give any group less than what is the accepted standard of care? 
In this case, the accepted standard of care in this country is 
not the accepted standard of care in those countries. The other 
ethical principle is, do you respect the host country? Do you 
answer the questions that the host countries have? Do you 
conduct studies that you are going to be able to implement the 
outcome after the studies are over?
    And we have decided that in order to make a difference in 
those countries and to save lives we need to have the kind of 
studies in which we have a placebo control versus short-term 
AZT, like 3 to 4 weeks, as opposed to the 16 to 24 weeks. And 
therefore, our studies are looking at: Can we make a difference 
using short-term AZT therapy that costs about $50 as compared 
to $800 to $1,000 for the 076 approach that we use in this 
country, in countries where the average expenditures for health 
are $10 per capita. Those are the issues, I think, in the AZT 
trials. And that's why they're done differently. And those are 
the debates. I hope I've captured the essence of----
    Mr. Towns. You have, but there are still some problems that 
I have. It is my understanding that when you have this going 
on, that the doctor who's in charge of it is also responsible 
for the overall medical supervision for the patient. I'm not 
sure that's safe. If I'm involved in research and I see a 
certain type of behavior that I think that somebody else should 
be able to evaluate and determine whether it should be 
continued or stopped.
    Dr. Satcher. Right.
    Mr. Towns. I have so much invested in it as a person who's 
providing the research, that I won't stop even though I see 
signs that----
    Dr. Satcher. Exactly. I think it's a very important point. 
These studies had to be approved by the CDC institutional 
review boards before they were funded. They also had to be 
approved by the host countries' review boards, in Cote d'Ivoire 
and in Thailand. They have an oversight board. Not the 
physicians treating the patients, but a board of people 
constituted to look at the proposed studies and to answer the 
question: Are they appropriate for this population? The rules 
also say that they are to revisit those studies periodically 
and say, ``Has anything changed in terms of benefits and risks? 
If so, then should we continue these studies?''
    One of the studies in Cote d'Ivoire, for example, we 
observed very early that there is a 10 percent still-birth rate 
among participants in the study. It turns out that whether 
people were receiving AZT or the placebo, they all--in that 
country there is a 10 percent rate of still-births among women 
who have HIV infection. So if we did not have the placebo 
group, we would not have known that. We obviously would have 
thought that it was the AZT that was causing the still-births. 
So I think the studies are organized in such a way and the 
oversight is done in such a way as to protect against the 
concern which you have. And I think it's a valid concern. I 
think if we relied on the people who were just treating the 
patients to carry out these studies, I think you're absolutely 
right. It would violate the rights of the patient.
    Mr. Towns. Any other comments? Yes?
    Dr. Varmus. Mr. Towns, may I just comment briefly? I agree 
with many of the comments made by my colleague, Dr. Satcher. 
The issues that were raised by Public Citizen and that have 
been brought to your attention are not new ones. The 076 trials 
that demonstrated the efficacy of AZT in preventing maternal to 
infant transmission in this country and France were brought to 
conclusion. The World Health Organization organized a meeting 
in Geneva to consider the implications of those studies for the 
developing parts of the world where the transmission rate is, 
in fact, at its highest.
    It was generally agreed that in thinking about how we could 
translate the success of 076 to the other parts of the world 
where transmission was so frequent, we had to confront what is 
an evident fact to anyone who travels in many parts of the 
world: Namely what we in Europe and North America and other 
places receive from advanced medicine simply is not available 
nor affordable in those countries. The 076 trial was a very 
complex trial, and the methodology was very expensive and 
sophisticated.
    It was generally agreed by representatives of both 
developing and developed countries that any effort to carry out 
studies that would be effective and feasible in the developing 
world would have to involve studies that actually could be 
used. In fact, one injustice that could be perpetrated upon 
those countries would be to go there and do studies that were 
only applicable in parts of the world that could afford the 
therapies.
    There are many examples of that principle. It is one that 
is uncomfortable, because all of us would like to feel that the 
advanced medicine that is available to us could be available to 
all. But it's a fact of life that it's not. There are simple, 
cheap therapies that do work. A classical example is, as the 
trial carried out some years ago in Bangladesh, to ask whether 
oral hydration therapy for patients with cholera would work 
when we knew that in this part of the world intravenous 
hydration is effective. Well, intravenous hydration would not 
be a very feasible therapy in small villages.
    Oral rehydration works. It turns out, when the trial was 
done it was extremely beneficial. That's a good example of why 
doing the appropriate trial can be of immense benefit. These 
are complex issues. We believe that the trials being carried 
out, which have been subjected to many review processes that 
Dr. Satcher has alluded to, have satisfied all the criteria for 
responsible review.
    Mr. Towns. Dr. Raub.
    Mr. Raub. I don't believe I need to add any further detail 
to that. I share the basic principles that Dr. Satcher and Dr. 
Varmus have enunciated.
    Mr. Towns. Thank you.
    Dr. Varmus. Mr. Towns, I would be pleased to provide for 
the record, if you would like, some letters that we have 
received from institutions both in African countries and in 
this country that are carrying out the collaborative work, who 
have responded to the letter from Public Citizen. I think you 
would find them reassuring. And I would be pleased to provide 
them for you, if you'd like.
    Dr. Satcher. I just want to add one thing because I think 
there is another critical issue here. I don't know all of the 
history behind some of the studies that have gone on, but I 
have visited Cote d'Ivoire and I know the people there and have 
worked with the people there in terms of what they really want 
to achieve from these studies. I know their concern about not 
being able to use AZT. I've met with the Minister of Health and 
the U.S. Ambassador there.
    We have funded the virology laboratory there. We are 
training people who in the future will be able to conduct 
studies like this and even more sophisticated ones in their own 
countries. I don't want you to think that this is just a study 
that we're going in, doing a study and coming out. Our 
commitment in these countries is to develop the kind of 
relationship that they will be able to buildupon. I think 
that's happening.
    Certainly in Cote d'Ivoire. And I think it's happening in 
Thailand. I'm going to visit there in July. But I think what 
we're trying to do is to develop relationships that will be 
supportive and ongoing. And they're doing the same thing. 
They're visiting us, and in many cases contributing to what 
we're trying to do in very useful ways.
    Mr. Towns. Mr. Chairman, I have a letter I'd like to add to 
the record, which is the subject of Public Citizen's news 
release. And it says--it's actually a letter to Dr. Varmus. And 
I'd like to include in the record--from Uganda Cancer 
Institute. So I'd like to make it a part of the record, as 
well. And it talks about, ``I read with dismay and disbelief 
the above-mentioned documents regarding clinical trials in 
developing countries with special emphasis on those taking 
place in Uganda.'' So I'd like to make this a part of the 
record.
    Mr. Shays. OK.
    [The letters referred to follows:] 
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    Mr. Towns. Thank you very much.
    Mr. Shays. Thank you. Mr. Kucinich.
    Mr. Kucinich. I just have a quick question of Dr. Varmus. 
If NIH believes that only placebo controlled studies can 
provide answers to the questions most relevant in developing 
countries, why then is the NIH funding one Harvard study in 
Thailand in which no women will receive a placebo and all with 
receive anti-viral drugs?
    Dr. Varmus. Well, we don't believe that that is the only 
way to achieve results. Thailand, of course, is a somewhat 
different situation than some of the African countries we're 
discussing today, because of the more--the stronger economy and 
the ability of the country to provide drugs that are more 
expensive and would be unaffordable in Africa.
    Mr. Kucinich. And if it's true that using placebo controls 
reduces the number of subjects needed to demonstrate 
statistical significance, why does NIH funded non-placebo 
controlled study in Thailand anticipate in enrolling fewer 
subjects than the U.N. AIDS program study in Tanzania, Uganda 
and South Africa? For example, you have, I think, 1,554 
subjects in Thailand versus 1,900 in a combined U.N. AIDS 
study.
    Dr. Varmus. 1,500 subjects being enrolled in Thailand. I'm 
not quite sure what the question is, Mr. Kucinich.
    Mr. Kucinich. I'm asking why, if you are using placebo 
controls--if you're saying that reduces the number of subjects 
that you need to have statistical significance--do you agree 
that you do that?
    Dr. Varmus. Yes.
    Mr. Kucinich. OK. Then why do you--why does this funded 
non-placebo controlled study in Thailand anticipate enrolling 
fewer subjects than the study that's going on with the U.N. 
AIDS program in Tanzania, Uganda, and South Africa. I'm trying 
to compare your policies with the other.
    Dr. Varmus. I would have to look at the details of the 
protocols more closely to give you a direct answer to that 
question. I'd be happy to do that for the record.
    [The information referred to follows:] 
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    Mr. Kucinich. OK. I'll pass for now.
    Dr. Satcher. I may have contributed to some of the 
confusion. There are two or three reasons why we feel the 
placebo control studies are important and I'll just briefly 
mention them. You know, I mentioned what the countries are 
wanting to learn from these studies. One issue is safety. They 
want to be certain that AZT is safe as it relates to the mother 
and a developing fetus. And it's a question that can only be 
answered by using, from our perspective, placebo controlled 
studies. We can't answer it satisfactorily comparing short-term 
dose with a long-term dose of AZT.
    I gave one example of that. There are also complicated 
statistical reasons why we couldn't answer that question using 
short-term AZT comparing it with long-term AZT. And so I think 
there are questions that the host countries have asked that we 
can only answer, certainly in Africa, by using the placebo 
controls.
    Mr. Kucinich. Well, one quick followup based on this 
colloquy with Dr. Varmus. Did you say that using the placebo 
controls is not the only way to do a study?
    Dr. Varmus. You can get information. It may be less 
reliable. It may take more enrollees. Again, I don't know the 
details of the protocols you're alluding to. One obvious reason 
why the study populations might differ in size is because of 
the frequency of infection or the prevalence of infection in 
those populations.
    Mr. Kucinich. Do ethical considerations come up when you 
get into those matters?
    Dr. Varmus. They might depending, again, on the 
availability of support systems to provide the drugs that might 
be used.
    Mr. Kucinich. Would you advocate that the most ethical way 
always be used in designing your protocols?
    Dr. Varmus. Well, I think you have to be clear about what 
the most ethical way is.
    Mr. Kucinich. Yes, we do. That's what we're here.
    Dr. Varmus. Yes. I know. But it can be difficult. It may 
vary from country to country.
    Mr. Shays. Gentlemen, we're going to probably need to ask 
questions for another 30 minutes. We have a vote now. I'd like 
to say to the second panel it's very unlikely that we would get 
to you before 1 o'clock. And so you may want to get something 
to eat. We're going to have a vote and we're going to come 
right back. We consider this an expert panel.
    Not to be compared to many others we have had. You are an 
excellent panel and we really want to get some things on the 
record. So we're going to vote and come back. We may then end 
up with another vote 10 minutes later, and I apologize. But 
we'll make the best of it. So I would just say to the second 
panel, if you're back by 1 o'clock, we'll begin with the second 
panel at 1 o'clock. I don't think sooner. And so you don't need 
to be here sooner. I want to be clear. Second panel does not 
need to be here before 1 o'clock. We stand at recess.
    [Recess.]
    Mr. Shays. Dr. Raub, let me start with you and ask why has 
HHS not abided by the regulations by making appointments to the 
Ethics Advisory Board? And it goes back a long ways. I'm not 
throwing stones here. But it goes back to 1979. I'd like the 
short reason.
    Mr. Raub. I'll do my best, sir.
    Mr. Shays. OK.
    Mr. Raub. The Department believes that it is operating in 
conformance with both the law and the regulation with respect 
to the Ethics Advisory Board. The 1975 regulation did several 
interrelated things: It imposed strict limits on research with 
fetuses and with pregnant women; put an outright ban on in 
vitro fertilization research; and then defined a process for 
exceptions. And the Ethics Advisory Board, or boards, were the 
vehicle where exceptions could be considered to either the ban 
on in vitro fertilization research or the restrictions on 
research with fetuses and pregnant women.
    Mr. Shays. I had interpreted the Ethics Advisory Board had 
broad discretion over ethics in medicine, not limited to just a 
certain area.
    Mr. Raub. The regulation is framed where the secretary has 
the discretion to have an ethics advisory board for specific 
tasks of that sort or for a broad set of issues.
    Mr. Shays. So it's not one board that's supposed to make a 
ruling on lots of different issues?
    Mr. Raub. No, sir. The regulation allows for the 
possibility of several different boards.
    Mr. Shays. Or just one.
    Mr. Raub. Or just one.
    Mr. Shays. Yes. But why would it be in our best interest to 
establish commissions and not have a board that is fully funded 
and has a staff. For instance, you're getting an executive 
director, basically a replacement--you're acting as the 
executive director, correct, of the commission?
    Mr. Raub. Yes, sir.
    Mr. Shays. And I don't understand why that would be a 
logical way to proceed. It seems too ad hoc to me.
    Mr. Raub. OK. Well, one of the options available to the 
administration was to invoke the secretary's authorities to 
create an ethics advisory board. And it could have addressed 
essentially the same agenda that the NBAC is. However, we view 
it as clearly more desirable for this to be a Presidential 
level commission, especially giving it the span of involvement 
of multiple agencies in the Government that are involved in 
research on human subjects.
    Mr. Shays. How many people are employed on this board?
    Mr. Raub. There are 17 members of the board, 17 
commissioners.
    Mr. Shays. Yes.
    Mr. Raub. And the staff supporting it involves eight full-
time staff and four who are part-time.
    Mr. Shays. Now, your testimony, I thought, said it 
continues or authorized until, what, October?
    Mr. Raub. That is correct.
    Mr. Shays. What's the logic of that?
    Mr. Raub. The Executive order signed by the President 
covered 2 years from the date of the President's signature. And 
the Executive order allows that it expires on that date unless 
extended by an Executive order.
    Mr. Shays. Right. So what's going to happen?
    Mr. Raub. Well, the administration is now considering 
extending the NBAC charter via amendment to the Executive order 
because of the additional work load that has developed and 
because of the additional issues that have been identified.
    Mr. Shays. Well, it seems to me like a no-brainer that we 
need this work done. I don't quite understand why this wouldn't 
be a permanent board. In other words, when I'm looking to see 
what we have, we have basically local institutional review 
boards. We have those. We have the institutes of health and 
their boards and we have the Ethics Advisory Board not 
constituted. I see a gigantic void here. And you don't see a 
big void?
    Mr. Raub. Sir, I believe you'll find many advocates within 
the Government as well as outside for the notion of a 
continuing body with functions similar to that of NBAC to 
address these issues just in the way you're suggesting. Many 
are looking to the experience with NBAC as getting additional 
evidence and information as to the desirability of such a 
board. And I believe that's one of the major issues under 
consideration right now.
    Mr. Shays. Why would someone take a job that basically 
they're not guaranteed that they're going to have it go until 
October?
    Mr. Raub. I would share that concern, sir. And we're 
hopeful that by the time we are ready to make a selection we 
will have had some resolution as to the extension of the board.
    Mr. Shays. OK. Dr. Satcher, what specific steps would your 
agency take to detect what is called the--I guess we call it 
the therapeutic illusion. Really, let me ask it in the way I 
think makes sense to me. Some testing is a healing agent, and 
you want to test whether it really succeeds in doing what it's 
projected to do. Others you might just do testing for safety. 
How do you notify someone in a clinical trial that really all 
they're doing--they may get sicker, we just want to know if 
it's safe? What are the requirements that you feel have to be 
made ethically?
    Dr. Satcher. Let me say that in most cases we're asking 
both the efficacy and the safety question. It's just, again----
    Mr. Shays. But not always. And I want to be clear. The only 
reason I would participate in some kind of clinical test is the 
thought that I might get healed and I'm willing to take the 
chance. And you're going to warn me of all the potential 
downsides and I'm still going to do it. But I want to know if 
there is a requirement to tell someone that along with talking 
about, well, this may not be safe here, there's no promise that 
it's going to help you?
    Dr. Satcher. I think definitely we're required. And the 
informed consent form should make that very clear, that they 
are involved in a study that may not benefit them personally at 
all. And if an informed consent form does not make that clear, 
then I would say that it's inadequate.
    Mr. Shays. Dr. Varmus.
    Dr. Varmus. Mr. Shays, I think you're referring mainly to 
phase 1 clinical trials for which NIH probably has more 
responsibility than the CDC.
    Mr. Shays. Right.
    Dr. Varmus. Our consent forms do explicitly make clear that 
there is no intent to--no expectation of clinical benefit. This 
does not exclude the possibility of there being benefit, but 
the expectation is that they will be testing here for safety. 
That will allow some determination of what doses might be used, 
and then you can proceed into a phase 2 trial.
    Mr. Shays. Are you suggesting, though, that there may still 
be the hope that the person has that this could result in some 
healing benefit?
    Dr. Varmus. There is in some cases that possibility, but we 
stress to the patients in these very limited studies that the 
intent of the phase 1 is to establish safety and that they are 
performing a service through their participation and research. 
This is why we take these consent forms so seriously, 
particularly in that phase of the experimentation.
    Mr. Shays. Now, with the Office for Protection from 
Research Risk, that basically is an in-house. I'm trying to 
understand----
    Dr. Varmus. The OPRR----
    Mr. Shays. I'm trying to deal with the issue of how you 
avoid a conflict of interest. You're an independent ``watch 
dog.'' And yet, you're basically providing for research. You're 
involved in the whole ethics of whether it's allowed, but 
you're funding it.
    Dr. Varmus. Well, let me address that issue, Mr. Shays.
    Mr. Shays. I'm sorry?
    Dr. Varmus. Let me address that issue.
    Mr. Shays. OK.
    Dr. Varmus. The OPRR does provide oversight for activities 
that are carried out by the NIH institutes and also by the CDC 
and FDA and other organizations within the Department. It has 
administrative housing and some administrative oversight from 
Dr. Baldwin's office, the Office for Extramural Research. It's 
important to remember that the office does not have any vested 
interest in seeing the research go forward in the sense that my 
office would be funding the research. The research is being 
funded by the CDC or by institutes, each of which has its own 
authorization and its own appropriation. It is the institutes 
that are responsible for funding those studies. So there really 
isn't the conflict of interest that I think you're----
    Mr. Shays. I'm missing something. Because it's the same 
organization. You're just saying a division within the 
organization.
    Dr. Varmus. Well, there is fiscal independence and a 
responsibility for funding a study that lies outside of the 
office of the director in which the administrative housing 
occurs.
    Mr. Shays. And you're satisfied that that would meet an 
independent's test?
    Dr. Varmus. I think it does. As you heard from Dr. Raub, I 
was concerned about having the NBAC housed within the NIH 
because the NBAC is, of course, looking at much broader issues 
that establish the principles in which informed consent or 
protection of individuals of abuse of genetic information might 
be carried out. The OPRR is following regulations that were 
issued by the Department. And it's governing compliance with 
already established rules and regulations.
    Mr. Shays. Doctor, do you believe that mentally ill 
individuals and those who are addicted should have a different 
protocol, should be covered explicitly by HHS regulations?
    Dr. Varmus. Yes, but special care needs to be taken in 
overseeing studies that involve patients that may be 
cognitively compromised. I discussed that in my testimony. This 
is a very difficult issue, which accounts for the large number 
of studies and work shops and consultations that the institutes 
involved in such studies are involved in.
    Mr. Shays. With regard to Alzheimer's patients, do you have 
written guidelines for informed consent?
    Dr. Varmus. The National Institute on Aging, which has a 
major responsibility for such patients is working on such 
guidelines. They will be participating very actively in the 
upcoming work shop this fall in which we expect to confront the 
issue of consent in such patients as a special case study 
during the proceedings.
    Mr. Shays. Why wouldn't have that already occurred?
    Dr. Varmus. Attention has been given to it. But, of course, 
there is always the need to proceed further and evaluate what 
has been done. We were not oblivious to the fact that patients 
with cognitive disorders of aging present special problems. But 
we do believe that as we gain increased experience, we should 
be profiting from that by further contemplating the issue.
    Mr. Shays. This is an issue, Dr. Satcher that you have 
already addressed. But I want to just clarify it for when we 
write a report or recommend legislation. It deals with 
generally the issue that was being raised by my colleagues of 
trials done overseas. And I'm gathering that in Thailand the 
CDC is funding placebo control trials.
    Dr. Satcher. Right.
    Mr. Shays. And the answer is yes to that. The NIH has 
another program where there's no placebos. And I think I heard 
your response, which I'm not critical of, because I'm just--I 
may be critical of it, but it seems like an interesting issue 
to deal with; you're saying that overseas some patients 
wouldn't have gotten AZT anyway.
    Dr. Satcher. That's exactly right.
    Mr. Shays. Pardon me?
    Dr. Satcher. It's not the standard of care.
    Mr. Shays. Right. But isn't there an incredible temptation 
that we have to be careful of, of suggesting that a lot of 
things, health care that people don't get overseas----
    Dr. Satcher. Yes. I think you're right.
    Mr. Shays. And it almost becomes your proving ground--the 
rich United States with all our good laws and all the medicine 
that's available to American citizens. But overseas you can 
say, you wouldn't have had this anyway, so you're not losing 
anything. And I'm just curious how we sort that out. Because I 
think it's potentially a dangerous road to travel.
    Dr. Satcher. I think so. I think it's a complex issue. And 
I think it has to be looked at just as you have described it. 
Let me say that there is an international community involved 
here, and it's not just the United States. I think the U.N. 
AIDS program, which is very important in this, as well as the 
World Health Organization have both looked at the AZT regimen 
that we use in this country and that's used in some European 
countries.
    I think the critical issue--and I think it's referred to in 
the international guidelines for research--has to do with the 
host country and the extent to which the research is meeting 
the needs and interests of the host country and is going to 
result in benefit for the host country. I think these are 
really the key issues that we're struggling with when we try to 
resolve the question that you raise which is so important--To 
what extent will the host country benefit from this study? To 
what extent are they asking the questions that your study is 
seeking to answer?
    Mr. Shays. Yes.
    Dr. Satcher. History is very important as you know. And we 
were just talking earlier when you were away that the hepatitis 
B vaccine studies that were done in China in the early 80's--
very similar to what we're discussing now in Africa and 
Thailand--a major problem in China--hepatitis B. We had the 
immune globulin in this country. It was a little different 
situation in terms of what we were able to afford and what was 
being used. However, that study was very important and of great 
interest to the Chinese. Of course it resulted in showing the 
efficacy and safety of the hepatitis B vaccine.
    It's benefited China significantly, but it has also 
benefited us. And as you know now, it's a major part of our 
vaccine regimen in this country. But it was done because of the 
interest of the Chinese primarily. The same thing is true here 
in terms of the short course of AZT therapy. Obviously, the 
interest of the people in the Ivory Coast and in Thailand is 
that we don't feel that we can use the 076 regimen. We would 
like to know if there's another way we can use AZT to intervene 
to prevent the spread of AIDS from mother to child. Is there a 
cheaper way? Is it safe? Is it efficacious?
    Mr. Shays. I just want to highlight the issue, though, that 
it's almost this imperialism of the United States of having one 
standard overseas and another standard here because we say, 
well, it's a different culture, different society, different 
wealth, different standards. And then we can then end up doing 
things there that we would never conceive of doing here.
    Dr. Satcher. I don't think we should unless it's in the 
interest of that country and unless that country is making it 
very clear that it's in their interest and it responds to their 
questions. I understand your point. And I agree that there is a 
danger that we could, in fact, exploit other countries.
    Mr. Shays. OK. I'm going to ask the other two to followup. 
At the same time I'm just going to ask this question: Do 
infrastructure problems of malnutrition and poor water supply 
ultimately distort the finding of a clinical study that may 
give us a result different overseas than in the United States? 
But I'd like the first question--I'd like all three of our 
other panelists to respond to the ethics of experiments 
overseas based on different laws overseas and based on lack of 
wealth that says that they would have been denied certain 
health care that they would get in this country. Dr. Raub.
    Mr. Raub. Well, first of all, Mr. Chairman, I agree with 
your principle that we must be sensitive from the beginning and 
all through that what we may pursue with the best of intentions 
and compassion might somehow slip into being exploitive or 
imperialistic. And so that must be a caution all the way 
through. From my point of view I believe there are four 
principles that affect these studies. My colleagues have spoken 
to them in various ways. But just very quickly.
    That the treatment that is involved, in the judgment of 
experts, have a reasonable chance of working; that the 
treatment be well matched to the health care system of that 
host country, that is something that could be adopted and 
become the standard of care if the results of the trial were 
sufficiently positive. Third, that the placebo control be used 
only when necessary, that is only when the historical 
information is so bad that it would be worthless and would not 
lead to either good science or an ethical study. Finally, that 
there be full participation of public health officials in that 
host country from the beginning, in terms as Dr. Satcher was 
indicating--the design of the studies and the implementation.
    I believe that those four principles can be held through 
with systematic use of IRBs and wherever possible to avoid the 
conflicts of interest. Then I think we have an excellent chance 
of doing things that are good both for the host country and 
this Nation.
    Mr. Shays. And I'm going to come back to the infrastructure 
issue and the malnutrition issue in a second. Dr. Varmus.
    Dr. Varmus. Mr. Chairman, I don't want to reiterate what 
has been said, but I also would point out that the issue of 
exploitation, which is that one that's currently being 
addressed, presents a number of problems. Perhaps the most 
egregious of these, in my view, would be to carry out in a 
developing country a trial which only produced results that 
would be of benefit elsewhere and not in that country. That's 
why the design of the studies we're talking about need to be 
one that could lead to an outcome that would be beneficial to 
the country in which the study is being carried out.
    Mr. Shays. So that would be a primary determinate for all 
three of the panelists. Ms. Pendergast, do you want to comment 
on this issue?
    Ms. Pendergast. No. I would just reiterate the comments of 
my colleagues. I think we all recognize that this is an 
incredibly complex ethical and scientific question that 
reasonable minds can and do debate. And I think that the debate 
is healthy. And I think it behooves us all to continue to 
critically explore these issues to make sure that we are on and 
stay on the proper path.
    Mr. Shays. OK. It's my intention to end at 1 o'clock. Dr. 
Varmus, you have to be over there at 1 o'clock?
    Dr. Varmus. I believe so. Yes.
    Mr. Shays. OK. We'll make sure you have a car ride over and 
get you over there unless you have 10 people with you.
    Dr. Varmus. No.
    Mr. Shays. OK. I would like to be clear on--just very 
quickly. Not a lot of time on this. But the nutrition 
conditions of an individual overseas, malnutrition, other 
issues that are cultural in terms of wealth, does that distort 
findings making them applicable to the United States? Just go 
down the line.
    Dr. Satcher. It can definitely. I think there are instances 
in which the nutritional or status of the participants--and 
maybe even in the cases that we've been discussing--has impact. 
Those are the kinds of things that we want to understand 
better. But there are instances where we think that we can. 
One--if I could just get back for 1 second to the EZ studies?
    Mr. Shays. Yes, sir.
    Dr. Satcher. There are many who believe that the 
differential mortality that was observed in the countries in 
Senegal and Haiti could well have been related to the 
nutritional status of the participant. Now, we haven't had 
enough studies to know, but there are many who think so.
    Mr. Shays. Fair enough. OK.
    Dr. Varmus. I would just comment that the hope of obtaining 
a useful and convincing result in studies carried out and in 
environments that, as you point out, may be affected by a 
number of other contributing factors like sanitation, can be 
most effectively pursued with a randomized control trial.
    Mr. Shays. Private sector--we haven't even gotten into the 
issue of when the private sector conducts--we haven't focused 
on it--their own studies, who oversees the ethical conduct of 
those studies?
    Ms. Pendergast. The Food and Drug Administration does, sir.
    Mr. Shays. So basically you're the operative force in those 
areas?
    Ms. Pendergast. Yes. For products that the FDA regulates, 
we do.
    Mr. Shays. OK. CDC doesn't get involved, Institutes of 
Health don't get involved unless----
    Dr. Varmus. We do if there is a collaboration with an NIH 
supported institution.
    Mr. Shays. OK.
    Dr. Satcher. Same with the CDC.
    Mr. Shays. HHS? Through FDA.
    Mr. Raub. Through FDA or, as Dr. Varmus and Dr. Satcher 
indicated, when there is a collaborative arrangement with work 
funded by them.
    Mr. Shays. OK. Dr. Varmus, why don't we let you get on your 
way so you have some time to get there at 1 p.m.
    Dr. Varmus. I appreciate it.
    Mr. Shays. And we're going to end in just a few minutes, 
but let me just pursue this. Ms. Pendergast, Dr. Satcher and 
Dr. Raub, if you could just participate in this last part. How 
does the process work in the private sector in terms of 
informed consent? Tell me how the process would work, the 
oversight process of FDA.
    Ms. Pendergast. The----
    Mr. Shays. In other words, I'm looking for--you don't have 
a board. Do you have a separate board that oversees the 
informed consent issue? Who deals with that issue?
    Ms. Pendergast. The system is very parallel to what governs 
Federal research. Before a study can be conducted in the United 
States, the company has to seek the FDA's approval of the 
trial. The informed consent, and making sure that the trial is 
ethical, and that the risks are outweighed by the benefits is, 
again, handled by an institutional review board, which has to 
be a diverse group of people who will review this study. So you 
have overlapping responsibilities with the sponsor of the trial 
who has to make sure that the trial is properly designed and 
that the clinical investigators are competent.
    The clinical investigator is obliged to get informed 
consent. The institutional review board is obliged to oversee 
the study and the consent. And then the FDA has a bioresearch 
monitoring program where we do inspections of all three: the 
sponsors, the clinical investigators, and the institutional 
review boards in an effort to make certain that they are living 
up to their commitments.
    Mr. Shays. OK. I'm not quite clear if this is an individual 
or a board that oversees this process.
    Ms. Pendergast. With respect to the FDA, we have employees 
in all of our different centers and across the United States 
that work on this. We did 1,000 inspections last year with 
respect to research integrity issues. So there are many people 
at the FDA involved in this. But every clinical trial has a 
specific institutional review board at the institution, whether 
it's a hospital or academic center, that reviews the study 
before it goes forward as well as the FDA.
    Mr. Shays. Are there any questions that you wish we had 
asked that you were prepared to answer, that you would like to 
answer? Ask the question and answer it; something you feel we 
should have asked?
    Dr. Satcher. I just want to say that, if we haven't said it 
before, that I think this discussion is very important, and 
despite our defense of what we do we understand that these 
issues require a lot more discussion and debate continually. 
And I think that's what's going to get us where we want to be 
in terms of protecting the rights of people in this country and 
throughout the world. So we appreciate the discussion, and we 
plan to continue to participate in it, here and outside.
    Mr. Shays. Doctor, I thank you. This is something that this 
subcommittee--we have extraordinary oversight because we 
oversee five departments. And HHS is so gigantic as the 
Department has a larger budget than most gross domestic 
products of other countries. So how HHS puts everything 
together and is able to fulfill its mandate is quite something. 
We have always tried not to take pot shots at any of you in 
this business.
    We know that we have not always provided the resources for 
you to do the job, and there is so much that needs to be done. 
The one thing that we've always liked is candidness. And we're 
not trying to dig people into holes and then have them climb 
out. I just want to know, Ms. Pendergast, if you have any 
comment you want to make, any question you wish we asked or any 
qualifying statement on anything that you said?
    Ms. Pendergast. Thank you. I think it's important to 
recognize that we share your basic concern that the troops 
during the Persian Gulf conflict were not given the information 
that we had hoped they would get. Perhaps I was too 
bureaucratic in my response. We were disappointed. We let the 
Defense Department know that. And we will submit for the record 
the precise documents, where they made the promises and our 
responses back so that you can see what the agency did back 
then. But I think it's fair to say that that experience taught 
us a lot. And we will not move forward with other kinds of 
waivers of informed consent in
the military until there has been another round of public 
discussion, rulemaking, where we take into account the views of 
the veterans, take into account all that we learned as a result 
of this effort, and take into account the concerns raised by 
the Presidential Commission on the Gulf War. We learned a lot, 
and we will use that information as we go forward.
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    Mr. Shays. I appreciate that comment. Let me just say it's 
not meant to be an aggressive statement on my part, but words 
like ``hoped'' and ``disappointed''--it's not that we want the 
hope that they do it--and the mere fact that that word is still 
being used--and I'm not trying to nit-pick here. I just think 
that what we will probably, as a subcommittee, give you plenty 
of warning before we have a hearing just on the whole issue of 
what the military was supposed to do with the waiver, and how 
they responded and then how you responded.
    And I'm hopeful that maybe that hearing won't be necessary. 
We'll look at what you have given us. But I'm going to just 
suggest it. It may be what will be required to have it publicly 
understood how strongly you feel about it and how strongly 
Congress feels about it as well, so that it will be an added 
incentive for the people that take your place. Because, God 
help us, we won't have this kind of need for many years in the 
future, if ever. Any other comments that others might want to 
make? Yes, sir.
    Mr. Raub. Mr. Chairman, just the comment of thanks to you 
for focusing on these issues. In particular, the notion of 
having some continuing mechanism to address ethical issues has 
not always received a lot of attention, its significance not 
always understood. I believe your hearings have sharpened those 
questions and provided an important set of information.
    Mr. Shays. Well, I thank you. I have to say that as I 
talked about a permanent advisory board, I was thinking, there 
you go again. You say you want to reduce the size of 
Government, and you want something permanent. So I acknowledge 
that in this area I think that there needs to be something a 
bit more permanent. And maybe I'm wrong and maybe I'll 
reconsider. But I will look forward to the dialog that we'll 
have. It's always been a constructive dialog with the FDA, the 
Institutes of Health, HHS, and CDC. We've really always 
appreciated the cooperation we've received and the staff has 
received.
    I thank you all, and I thank all those of you who were 
sworn in who never got to testify. I really frankly probably 
would have learned more from all of you. I just wish I knew 
that question that would have triggered you to come forward. 
Thank you, and we'll hear the next panel. Thank you all.
    Ms. Pendergast. Thank you.
    Mr. Shays. This committee will call forward Arthur Caplan, 
professor of bioethics, University of Pennsylvania, Benjamin 
Wilfond, who is professor of pediatrics, University of Arizona; 
Dr. Peter Lurie, professor of medicine, University of 
California; and Laurie Flynn, executive director, National 
Alliance for the Mentally Ill.
    So we will proceed in the order of Dr. Caplan, Dr. Wilfond, 
Dr. Lurie, and then Ms. Flynn. Do we have all of the witnesses 
here? And I'm going to catch you before you sit down, Ms. 
Flynn, because we're going to have everybody stand and I'll 
swear you in.
    [Witnesses sworn.]
    Mr. Shays. Thank you. For the record, we had five who stood 
up and four witnesses who will actually testify. And all 
responded in the affirmative. I'm sorry. We have a vote. I've 
gotten you sworn in; that's one task. We have a 15-minute vote 
and a 5-minute vote. So I will say that it's unlikely that we 
will be back until 1:30 p.m. And I'm sorry about that. I will 
say before we recess that I am very grateful to the four of you 
for coming to testify and listening to the first panel, and 
will welcome your response and observations of what you've 
heard from the first panel. So you can digress a bit from your 
statement to also include comments about that. And we will 
recess. And given the vote, we will probably not be here until 
1:30 p.m.
    [Recess.]
    Mr. Shays. This hearing is called to order. Do any of you 
have plans for this evening? I think, Dr. Caplan, we're going 
to begin with you. And welcome.

STATEMENTS OF ARTHUR CAPLAN, PROFESSOR OF BIOETHICS, UNIVERSITY 
  OF PENNSYLVANIA; BENJAMIN WILFOND, PROFESSOR OF PEDIATRICS, 
  UNIVERSITY OF ARIZONA; PETER LURIE, PROFESSOR OF MEDICINE, 
   UNIVERSITY OF CALIFORNIA-SAN FRANCISCO; AND LAURIE FLYNN, 
        DIRECTOR, NATIONAL ALLIANCE FOR THE MENTALLY ILL

    Mr. Caplan. Thank you, Mr. Chairman. I'm very pleased to 
have the chance to testify before you and the committee. The 
question of whether the time has come to consider changes in 
the way Americans are recruited to and participate in 
biomedical research is of obvious importance, as we've heard 
some of the issues discussed this morning. I think research is 
very crucial to the high level of care Americans receive and 
that is available to them. But it also does require the 
participation, the sacrifice and even the voluntary altruism of 
people who are going to be subjects.
    And so protecting their interests and their rights is 
crucial in order for continuing progress to be made in the 
quality of care we receive. It seems to me that this Nation has 
not always done what it ought to do to ensure the welfare and 
dignity of those who make themselves available as subjects. 
We've heard reference already this morning to incidents in our 
own past--the Tuskegee study and some of the exploitation of 
people in the military in the 1950's and 60's involved in 
radiation experiments, mentally retarded children.
    So we know we have to do better. We have to be vigilant. 
And at the same time I think we've tried to institute a series 
of protections--informed consent and peer review by IRBs--that 
will keep us away from some of our most egregious failures in 
the past. Really what I want to do is talk just a bit. You have 
my written statement. So I'd like to just concentrate on a few 
areas where I think those two protections are in jeopardy. 
We've heard a lot today about one of the areas that I want to 
especially focus in on.
    That is the IRB system. I've been on IRBs for a long time. 
I have chaired a number of IRBs at different institutions. I 
think I have a very good understanding of what IRBs--
institutional review boards--can do. And their charge, in part, 
is to make sure that people do get informed consent by looking 
at the informed consent forms, by weighing risk and benefit 
that is put before them. But Mr. Chairman, I think there are a 
number of factors in the research world as we now know it that 
are impairing the ability of the IRBs to do their jobs.
    We've had reference briefly to the phenomena of 
privatization of research funding. More and more of our 
research is now supported by private sources, not the NIH and 
not Federal sources. We find ourselves in situations where 
private sources are beginning to put restrictions on 
information that is available to not only subjects but to IRBs.
    And in this area in particular I'd like to note for the 
Chair that we've had incidents where private companies have now 
stepped forward and said research cannot be published because 
it is held as a secret or that it has been contracted with an 
institution, that it will be done with condition that the 
company must sign off. A recent example of this was Boots, now 
the Knoll Pharmaceutical Co., with its drug Synthroid--is one 
such example of restriction of information.
    Mr. Chairman, if an IRB cannot get all the information that 
it needs to have about conflict of interest, financial sources 
of funding, if a firm is in a position to say that it will not 
publish legitimate findings about a particular drug or device, 
then the interest of subjects cannot be protected. So if we 
need to--and I feel we must--we have to ensure that IRBs have 
the information available to them so they can know when a 
researcher has a conflict of interest. We need to make sure 
that secrecy and provisions of restriction on findings of 
information are not part of what goes on in American 
institutions. In the end, to fail to publish findings--and I 
say this knowingly and deliberately--but to fail to publish 
findings that you have is a betrayal of what is owed to human 
subjects. If you don't get results out, if you don't put them 
in the peer reviewed literature, then you've asked people to 
carry burden, be involved in risk, face a sacrifice in coming 
to and from experimentation, for no purpose.
    And so for me, one of the most sad and unfortunate 
consequences of what we're asking our IRBs to do is we're 
asking them to work sometimes without the information, without 
the access that they need to have to do the job right.
    That makes me cite a secondary issue, which I think the 
chair should pay close attention to. I'm very impressed with 
the previous panel and its comments about the role of IRBs and 
making sure that informed consent forms are understandable and 
that people have information.
    But Mr. Chairman, I feel we have a system now that is 
spending too much time at the front end of research, looking at 
the written informed consent forms--that's what IRBs do. And 
the ones that I've served on--I would estimate that 97 to 99 
percent of the time is spent in a room looking at an informed 
consent form, trying to translate medical jargon back to 
English. Sometimes that works and sometimes it doesn't. 
Sometimes subjects know more than you think because they've 
been involved with the disease process and have learned a lot 
about medical issues. So what looks difficult to understand to 
the outsider may be understandable to those subjects.
    But where the system is not doing its job is in monitoring 
and making sure that what is on that form is actually taking 
place in the research setting. Very rarely do IRBs spend any 
time talking to subjects. Very rarely do they debrief anybody. 
Very rarely, if ever, do they find themselves in contact with 
researchers, actually going out and saying, did you sign this 
form, did you understand this form, is it capturing the things 
that turned out to have been of interest and concern to you as 
you were a subject in research?
    In other words, the feedback loop that ought to be there 
between actual subjects and actual research, and what goes on 
in practice, and what you see at the front end when someone 
says, here is what I propose to do, and here is what the form 
is to accompany it, is broken. It is simply broken. And we have 
to do something to restore that loop of information so that 
when an IRB is taking a look at a research protocol it can say, 
we've been out and talked to some of these subjects, we know 
that the researchers are doing what they told us they would do.
    We need more audit. We need more oversight. We need to get 
more time available for IRB members to spend talking with 
subjects. In this era--and I'm just going to make two more 
points and then I'll stop in the interest of time--in the era 
of IRB and informed consent work, there's something else that's 
missing, Mr. Chairman.
    If you were to ask any of the officials who were with us in 
the previous panel, tell me; who is in research? What is the 
composition in America of who participates? What are the 
statistics about who is involved in the military? From the 
ranks of those with mental disability or mental illness? 
Minority people? Poor people?
    That can't be answered. We have never insisted as a Nation 
that we collect basic statistics and demographics on who is 
involved. Are women over or underrepresented? Are the elderly 
over or underrepresented? Are Native Americans getting the 
access that they might have? We don't know. There is no data 
collected. In fact, sadly, incredibly, we collect more 
standardized data on animal use than we do for people in this 
country. And it seems to me some of the questions of informed 
consent, the adequacy of how research proceeds, and fairness 
and equity and access to research and, how well people are 
treated, require basic information for answers.
    That leads me to the last point I'd like to make. In 
looking at research and informed consent it is clear to anyone 
who wants to look out here--and you've talked about some of 
this this morning already, and I have to confess given the tone 
of direction of some questions, I'm on that Presidential 
Advisory Committee for Gulf War Illnesses, and the interest of 
research in the military has been of special concern to me as a 
member of that committee. But, I have to tell you, Mr. 
Chairman, that for our vulnerable populations--people who are 
impaired or unable to consent on their own for reasons of age 
or mental disability or institutional settings like a prison or 
service in the Army or even being a student, a medical student 
dare I say--it is clear that informed consent has its limits, 
that there are just people out there who want to be in 
research, who want the opportunity to be in research, who, one 
way or other, are not going to be able to give a full informed 
consent to their participation in research.
    We have not yet, I think written the regulations and put 
the kind of oversight in that would help those people. I'm 
sorry to tell you, Mr. Chairman, I don't think we have a policy 
today that is any different from what we had in 1990 prior to 
the Gulf war about research in the military. I think the issue 
could arise tomorrow as to what could or couldn't be done with 
soldiers or sailors or people in the armed forces with respect 
to research and who would approve that and how that would 
proceed. We are operating with an interim, temporary rule in 
that area right now. We have been for 6 years.
    And it seems to me we ought to fix that. When we look at 
issues involving research with the mentally ill or people who 
are institutionalized with Alzheimer's and see the number of 
problems and scandals and difficult cases that have arisen--at 
UCLA, the Medical College of Georgia--there are many, many 
settings where people have, I would say, been taken advantage 
of or not understood what is happening to them in terms of 
recruitment to research. The time has come, I think, to toughen 
those regulations and perhaps to add more than just IRB 
oversight. It may be time to say that we need to have some 
national or regional review of certain kinds of high risk 
groups involved in research and certain types of high risk 
research itself, that local IRB review may not be enough.
    So Mr. Chairman, in summary, I think that the system we've 
got is better than what we once had, but it hasn't been much 
changed since 1981. That's the last time the rules of informed 
consent and IRB review got a thorough going over. I think it's 
overdue. I think there are some concrete steps that could be 
taken to toughen those regulations and afford better protection 
to those who make the gift of themselves to participate in 
research so that they and others may benefit.
    [The prepared statement of Mr. Caplan follows:] 
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    Mr. Shays. Thank you very much. And I guess we are going 
next to Dr. Wilfond.
    Dr. Wilfond. I thank you, Mr. Chairman.
    Mr. Shays. I didn't say your name well, so when you heard 
me say it, you wondered who the heck is he talking about. Is it 
Wilfond?
    Dr. Wilfond. Wilfond.
    Mr. Shays. Thank you, Dr. Wilfond.
    Dr. Wilfond. I'd like to thank you for inviting me to 
participate in this meeting. Currently, I'm an assistant 
professor of pediatrics in the sections of pediatric 
pulmonology and medical and molecular genetics at the 
University of Arizona in Tucson. As a pulmonologist I care for 
children with cystic fibrosis and asthma as well as other lung 
disorders. I also teach bioethics, and I'm a member of the 
American Academy of Pediatrics Bioethics Committee. I've been a 
member of IRBs for the last 9 years, and I have a particular 
interest in research issues related to children.
    Informed consent has been a central tenet of research 
ethics since the Nuremberg trials 50 years ago. In fact, as a 
legacy of the trials, in the 1970's there was great debate 
whether children ever should be able to participate in 
research, since they are unable to give their consent. This 
debate was considered in the Belmont Report and expressed in 
the Federal regulations by acknowledging that parents give 
permission and not consent for their children to participate in 
research.
    This distinction is important, although it's subtle. But it 
provides a conceptual justification for IRBs having a greater 
role in terms of the review of projects on children. For those 
studies that involve greater minimal risk, the IRB is to make a 
normative judgment about whether or not the risks are balanced 
by the benefits before the parents are able to give the 
decision to allow their child to participate. I think this is a 
very good thing, although there still remains a lot of 
conceptual vagueness in exactly how this is carried out. There 
is room for a more conceptual work trying to understand even 
what counts as minimal or a minor increase over minimal risk as 
a regulation state or considering this review.
    Although the regulations tend to be more careful in how 
research is done on children, often the regulations are 
misinterpreted and are used as a justification for why research 
in children is not done on a more routine basis. In fact, as a 
pediatrician, often because of a lack of research, there are 
many circumstances in which clinical judgments must be made 
without the availability of sound clinical data. Additionally, 
many drugs that are used on children are off label.
    In fact, taking care of patients with asthma, there are 
very few drugs that have been approved by the FDA for the use 
in children. I don't think, though, this problem is really 
because of the regulatory mechanisms for research. I actually 
think that it's more related to the lack of incentives for 
conducting research on children. Once a new drug is approved, 
pharmaceutical companies have few incentives to conduct studies 
in children. And so that there need to be requirements to 
conduct studies in children concomitantly with those of adults. 
Because it's better to expose children to the risks of research 
than to the risks of unscientific practices.
    What I'd like to do is talk about what I see as some of the 
problems with IRBs. What I'd like to do is mention five 
problems I see, but only will talk in detail about one of them. 
As was alluded to earlier, there needs to be a better mechanism 
for the oversight and monitoring of multicenter trials. This is 
a real challenge for IRBs when they review a study that's being 
done at 10 different places. And if one IRB has problems 
there's no opportunity for us to correct those problems at all 
centers. All we can do is choose whether or not we want to 
accept or reject the proposal.
    As was mentioned before, some research that's done in the 
private sector does not fall under FDA or NIH purview. And so 
there can be some research that could be done without the 
involvement of either oversight institution or organization. 
But I think more importantly and related to that, there needs 
to be a single mechanism for oversight of IRBs that includes 
not only the FDA and NIH but for all research. But what I'd 
like to do is to talk with you about one particular problem.
    Mr. Shays. I just missed your point. And it's a very 
important point.
    Dr. Wilfond. OK.
    Mr. Shays. You said there may not be review by either FDA 
or----
    Dr. Wilfond. If--OK. Certainly any study that involves the 
use of drugs or investigational devices will come under FDA. 
Any study that is done with NIH funding will come under the 
review of NIH. Any study that is done at an institution that 
has a multiple project assurance from either of those 
organizations will come under their review. But if----
    Mr. Shays. Come under their review?
    Dr. Wilfond. Come under the review of a local IRB.
    Mr. Shays. Of a local IRB?
    Dr. Wilfond. Right.
    Mr. Shays. But you're basically telling me that the FDA--
the question I had put to FDA was: Who oversees the private 
sector? And you're suggesting that there's some private sector 
that they don't oversee.
    Dr. Wilfond. If there's research that's being conducted 
that does not involve an investigational drug or 
investigational device or even one that's been approved for 
other purposes, then--for example, nutritional modifications or 
behavioral issues, that it's being done by somebody----
    Mr. Shays. Let me just clarify something. I'm making a leap 
here. My mind is thinking this way.
    Dr. Wilfond. Sure.
    Mr. Shays. If something is not going to the marketplace, 
are you suggesting that the FDA wouldn't be involved?
    Dr. Wilfond. That is correct.
    Mr. Shays. There are a lot of circumstances where something 
isn't coming to the marketplace. That isn't being funded. Well, 
who the heck----
    Mr. Kucinich. Nobody.
    Ms. Flynn. No one.
    Mr. Caplan. No one.
    Dr. Wilfond. But actually, even when it does come under 
FDA--actually what I'd like to do is talk to you about a 
particular problem in more detail.
    Mr. Shays. Do you all have any other little secrets you 
want to tell me about?
    Dr. Wilfond. Well, actually, the next one is the one I want 
to tell you about in more detail----
    Mr. Shays. OK.
    Dr. Wilfond [continuing]. Which has to do with researchers 
who are in private practice where they have greater incentives 
for recruiting patients--and this is a case where the IRB 
mechanism is very different, and essentially are for-profit 
IRBs. Let me try to explain what I mean by that. Recently at 
the University of Arizona, we reviewed a study for a new anti-
inflammatory treatment for childhood asthma.
    Mr. Shays. Don't feel you have to read so quickly. You can 
slow down a bit.
    Dr. Wilfond. OK.
    Mr. Shays. OK.
    Dr. Wilfond. We reviewed the study for a new treatment for 
asthma. The study involved putting patients either on this new 
anti-inflammatory treatment or a placebo. The problem is that 
there already are currently available good treatments--anti-
inflammatory treatments for asthma. When our IRB looked at this 
proposal we said this is unethical to do because it denies half 
of the patients a known effective therapy.
    Even with the permission or consent of the parents we felt 
that this was unfair and unsafe to expose children to this 
risk. So this was a multicenter trial. All we could do is say, 
you can't do it here. Two miles down the road there is a 
physician in private practice who also was doing the same 
study. What he did was, he had it reviewed by an IRB in another 
State, and he paid the IRB to review the study and they 
approved it.
    And so I think there are two problems here. One is the 
obvious problem of the investigator specifically paying an IRB 
to review their protocol. But more importantly, this review 
occurred in another State. And I think it completely subverts 
the whole notion of an institutional review board. In other 
words, this person was not from the community. And I think that 
becomes really a challenging thing. I'm not sure I would agree 
with this. The way IRBs really work is not only looking at the 
consent forms but trying to be careful that we understand that 
the investigators, when they present the information, hopefully 
will do it in a non-coercive way.
    Because we don't really have a good way of monitoring 
exactly how well they do that. The best we can do is to know 
about the integrity of the investigators. And I want to give 
you an example of how this happened with this particular study. 
When it was submitted to the University of Arizona the patients 
were going to be paid $250 to participate in the study. Our 
policy is that if payment is going to be made for children two 
things must happen. First, it cannot be advertised in 
newspapers in terms of a dollar amount. Our concern is that 
parents will see a dollar amount. That may be an incentive for 
them if they're a little short of cash that month to have their 
children enroll in studies. So we exclude dollar amounts.
    Second, although money may be paid, it's usually paid in 
the form of a savings bond that is made out in the name of the 
child. The physicians in private practice usually will have 
advertisements with dollar amounts. But often the dollar 
amounts are much higher than we would have otherwise approved. 
So for example this one study that we looked at, the dollar 
amount at the university setting was $250, but at the private 
sector it was $750 that the parents would be paid. And this is 
being advertised in local newspapers. I see this as being a 
very big problem.
    You know, in the community setting there is greater 
financial benefit to the investigator to recruit patients. They 
have increased promotional activities. The studies themselves 
may be more risky and they're getting less review. And I think 
this is really one of the biggest issues I think that needs to 
be addressed. Because I think more and more research will be 
happening outside of academic institutions. My recommendation 
would be that whenever feasible all research be reviewed within 
the same community and that the same IRB have a jurisdiction 
over all the particular investigator's protocols. One of the 
problems that the investigator can mail his protocol to 
different IRBs. So if he gets turned down at one place he can 
go somewhere else. And I think there needs to be some way of 
having some control over that.
    Mr. Shays. Elaborate a little bit on that.
    Dr. Wilfond. OK. For example, if a person is in private 
practice, and he sends it to IRB A and IRB A turns it down, he 
could send it to IRB B and have them approve it. There's not 
one designated IRB--whereas in the university setting, at the 
University of Arizona, if we don't approve a protocol, that 
investigator essentially can't do that study.
    Mr. Shays. If you're not part of the university and you're 
in the same town as the university, tell me where you would go?
    Dr. Wilfond. Wherever you want. Whoever gives you the 
lowest price. There are IRBs around the country that are 
essentially commercial IRBs that are set up, where they will 
receive protocols from investigators who mail in a check and 
mail in the protocol and they will review it.
    Mr. Shays. I wish this panel had gone first.
    Mr. Caplan. It's called IRB shopping, by the way.
    Ms. Flynn. Yes. IRB shopping.
    Mr. Shays. OK. Keep going.
    Dr. Wilfond. That's really the main thing I wanted to say. 
I think this is the biggest issue. I agree with Art about the 
issue of monitoring in the future. But I think this is really a 
problem that needs careful evaluation. I think at this point 
I'll stop and let the other people go.
    [The prepared statement of Dr. Wilfond follows:] 
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    Mr. Shays. I just don't quite understand. Literally, you 
could live in Florida and you could----
    Dr. Wilfond. Absolutely.
    Mr. Shays. Oh, yes? I didn't finish my question.
    Mr. Caplan. No, he just meant you could live in Florida.
    Dr. Wilfond. I'm sorry.
    Mr. Shays. So absolutely means that if I made an 
application in St. Louis, I could?
    Dr. Wilfond. Yes.
    Mr. Shays. Or New York or Alaska or Hawaii?
    Dr. Wilfond. Mm-hmm.
    Dr. Lurie. Please don't send it to Alaska.
    Mr. Shays. I hear you.
    Dr. Wilfond. I think the problem is, we do face very 
challenging--in terms of the IRB in Arizona--with our own 
investigators, they're often very challenging decisions. Often 
we will have the investigators come before us and talk with us, 
try to hash things out, try to come to a compromise that seems 
to work. And we know who the investigators are. But when you 
mail to somewhere else in another State, it's not as easily 
done. The thing I also want to point out as an example of this 
is that these studies are being done around the country.
    So it's not just a problem only out of the community IRB, 
but what ideally would be the best would be some way of there 
being some sort of additional centralized mechanism of review 
of these multicentered trials. Because what happened is, as of 
the study, the investigator came to us and said, look, if we 
don't do it they will do it somewhere else. Unfortunately, 
there was no way of us being able to communicate our concerns 
about the ethics of this study to someone else. It essentially 
was just up to us to say, it can't happen in Tucson. But there 
was nobody just who was looking out for everybody else.
    Mr. Caplan. Just a quick comment on this point.
    Mr. Shays. Sure. And then we'll get to you, Dr. Lurie.
    Mr. Caplan. There are many situations, Mr. Chairman, in 
which local IRBs feel threatened by a private researcher 
saying, well, if you don't approve it, they will do it down the 
road, and we'll be down the road in no time. And that can cast 
a pall over a local IRB's willingness to get tough with a 
particular informed consent form or a particular protocol. 
Because it's well understood that there are other places to go 
for the private researcher.
    Mr. Shays. Can I make an assumption that there are no 
conflicts on those who serve on those boards?
    Mr. Caplan. Well, the conflict--you're right. You can't.
    Mr. Shays. I cannot?
    Mr. Caplan. You cannot make that assumption.
    Mr. Shays. OK. We'll come back to this. You've whetted my 
appetite. Dr. Lurie.
    Dr. Lurie. Good afternoon.
    Mr. Shays. Good afternoon.
    Dr. Lurie. I'm going to talk about three separate subjects 
today. I'm going to talk first about HIV vaccine trials. I'm 
going to second talk about the NIH-funded study in Anchorage, 
AK, on needle exchange. And then I'm going to talk as well 
about the African, Caribbean, Thai mother to infant 
transmission studies that were discussed this morning.
    Mr. Shays. Can you do that in 10 minutes?
    Dr. Lurie. I would say so.
    Mr. Shays. Yes. OK.
    Dr. Lurie. There are several things that link these. One is 
the difficulty of obtaining informed consent in vulnerable 
populations. A second is the need to provide research subjects 
with state-of-the-art medical care. And the third is the 
conflict of interest between the purported needs of researchers 
about which we heard much this morning and the clear needs of 
research subjects about which we sometimes heard less.
    Let me talk about the HIV vaccine trials first. We know 
that behavioral interventions such as safe sex counseling, the 
provision of condoms, the provision of sterile syringes have 
the ability to reduce the number of new HIV infections in any 
given group. And if you're setting up an HIV vaccine trial it 
therefore becomes ethically necessary to provide state-of-the-
art counseling and other interventions to the subjects.
    Now, the problem is that, to the extent that you are 
successful, there will be fewer HIV infections in your 
subjects. And that creates the ``problem'' over time of having 
more difficulty in establishing that, say, the vaccine is more 
effective than a placebo. This, I think, creates a real 
conflict of interest which I believe is best resolved with the 
following. Creating an independent group of people to provide 
counseling in these kinds of HIV vaccine trials separate from 
the investigators. Unfortunately, every time that this is 
raised as a proposal I always encounter resistance from people 
in Government and researchers. But I do think that that is a 
straight-forward answer to what is a real problem.
    A second issue in HIV vaccine research involves the so-
called gp120 HIV preventive vaccines. Now, back in June 1994 
the AIDS Research Advisory Council, otherwise known as ARAC, 
found that the data were insufficient to support Government-
funded studies in this country. But what we have now is a San 
Francisco based company named Vaxgen which is planning, with 
logistical and statistical help from the Centers for Disease 
Control and Prevention, to conduct an efficacy trial of gp120 
in Thailand even though the vaccine has been rejected for 
efficacy trials by another arm of HHS--NIH--in this very 
country.
    It seems unethical. It seems exploitative. Particularly 
because there really is no guarantee that Thai citizens will 
ultimately have access to any vaccine that's proven effective.
    Subject 2, subject of the needle exchange program in 
Anchorage, AK. Since 1991, there have now been seven--count 
them--seven federally funded studies looking at whether or not 
needle exchange programs reduce the number of new HIV 
infections and whether they increase drug use or not, and every 
one of them has concluded that, yes, they reduce HIV infection, 
and no, they do not increase drug use. Despite that there is a 
plan to do a randomized control trial of needle exchange in 
Anchorage, AK. This despite that fact that the seventh of the 
studies that I mentioned was an NIH Consensus Development Panel 
which reached the same conclusion as its six predecessors.
    Now we have NIH with a $2.8 million study in which people 
are going to be randomized either to needle exchange or else to 
a so-called enhanced pharmacy intervention, which means that if 
you try to get--they were going to give you information about 
how to walk, how to talk, how to dress when you go into a 
pharmacy and try to purchase syringes. Now, we see three 
problems with this study. Problem one, if you're not in the 
study you cannot go to the needle exchange. Problem two, if 
you're in the study, you only stand a 50-50 chance of going to 
the needle exchange. Now, that seems a problem seeing as though 
the researchers themselves admit in their protocol that this 
``represents the withholding of a potentially life saving 
service,'' the very thing that is precluded by the Nuremberg 
Code and practically every code thereafter.
    The third problem with the study involves hepatitis B. And 
here the problem confronted by the researchers is that 
fortunately there is relatively little HIV in the drug users of 
Anchorage. And so they're using hepatitis B as a kind of a 
proxy marker because it's more common than HIV is. The problem 
is that there happens to be a very effective vaccine for 
hepatitis B, and so the researcher has a conflict of interest 
again, much like the situation with the behavioral intervention 
in the vaccine trials, whereby, to the extent that people are 
vaccinated, there will be fewer clinical outcomes and therefore 
it will be more difficult to show a difference between the two 
study groups.
    Those are the problems that we raised in a series of 
letters to Dr. Varmus in the beginning of October 1996. And he 
immediately put the study on hold and convened a 10-person 
panel to review our concerns. The panel did not include anybody 
who was either a drug user or might be otherwise expected to 
represent their interests--like someone who runs a needle 
exchange. And it had a bunch of academics, many of whom were 
themselves recipients of grants from the National Institutes 
for Drug Abuse, in fact that very same division within the 
National Institutes of Drug Abuse and so, themselves, might 
have been reluctant to criticize the Institute.
    That committee said, no, actually there's no problem with 
the study at all, it's fine. They signed off on the study 
completely. Fortunately, to his credit, Dr. Varmus went beyond 
what they had done and said, you need to do more to provide 
hepatitis B vaccine to people, although in our view he still 
didn't go far enough, because he should have required onsite 
vaccination of the subjects. And that didn't happen. To 
summarize, this unethical research proposal passed six levels 
of review. No. 1: the IRB at the University of Alaska. No. 2: 
the OPRR. No. 3----
    Mr. Shays. Slow down. What was the second?
    Dr. Lurie. The OPRR. The Office for Protection----
    Mr. Shays. Yes. Right.
    Dr. Lurie. Right. The third: the NIH AIDS Review Committee. 
The fourth: the panel that Dr. Varmus pulled together to review 
our complaint. The fifth: Advisory Committee to Dr. Varmus. And 
then finally: Dr. Varmus himself. Yet, despite this--and as Dr. 
Caplan quite accurately pointed out--the meat and potatoes of 
Ethics Review Committee work is looking at informed consent 
forms. There was no mention of any inadequacies in the informed 
consent form, despite the fact that the informed consent form 
failed to include such basic information as that the researcher 
believed--again, in their own words--that this was a 
potentially life saving service, that the researchers estimate 
that the drug users in the pharmacy group were at up to four 
times increased risk of getting hepatitis B.
    And importantly it didn't explain that if you were a drug 
user assigned to the pharmacy and you showed up at the needle 
exchange, they'd ask you for your card, if your card showed 
that you were, in fact, somebody assigned to the pharmacy 
group, they'd send you packing with more information about how 
to walk and talk and a buildings map for Alaska so that you 
could find the pharmacies. And finally, it didn't make any 
mention whatsoever of hepatitis B vaccine.
    The informed consent form had other problems. A readability 
analysis was done--and, again, this was alluded to earlier--and 
the degree of schooling that was needed for this was 15 years 
of schooling to be able to read the informed consent form, this 
despite the fact that Dr. Fisher, who had done readability 
analyses with the drug users of Anchorage had himself concluded 
that the drug users of Anchorage read with a ninth grade level. 
And the informed consent form, which all six of these reviews 
said was OK, finally, because of the attention that we drew to 
it, was reviewed and reviewed and reviewed and revised and 
revised and revised over and over again until instead of being 
two pages long, it is five pages long.
    Even so, it still contains a new fiction which had not been 
in the previous ones, which is that there is no other needle 
exchange program in Anchorage. And that is incorrect. Back in 
December 1996, a new needle exchange did open. And this was 
trumpeted on the front page of the Anchorage Daily News. The 
investigator acknowledged it in a national magazine. And it was 
on Anchorage television station as well. So this is a well 
known, blatant falsehood right there in the informed consent 
form.
    Mr. Shays. Let me do this. We have 15 minutes. I'd like Ms. 
Flynn to kind of get some on the record before we break. So if 
you want to----
    Dr. Lurie. I just want to talk about the Africa stuff----
    Ms. Flynn. It's all right.
    Mr. Shays. OK. I think what I want to do, Ms. Flynn, is 
have you go, and then we'll come back to you.
    Dr. Lurie. OK.
    Mr. Shays. We'll be able to get that on the record.
    [The prepared statement of Dr. Lurie follows:] 
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    Ms. Flynn. All right. Thank you. Thank you, Chairman Shays. 
I appreciate very much the opportunity to appear before the 
subcommittee today. I am a member of the President's National 
Bioethics Advisory Council. Within my day-to-day work for the 
past 12\1/2\ years, I've served as executive director of the 
National Alliance for the Mentally Ill, which is a large, grass 
roots, family and consumer organization concerned with issues 
that affect the lives of people with severe mental illnesses, 
including schizophrenia, bipolar disorder, major depression and 
other disabling mental illnesses.
    We are families. We are patients. We are the grass roots. 
We are the folks who rely on the kinds of protections of human 
subjects that have been addressed repeatedly today. From the 
beginning of our organization we have been very strong 
supporter and advocates for biomedical research on severe 
mental illnesses. Such research has yielded remarkable 
breakthroughs in the understanding and treatment of these 
disorders, which are among the most devastating known to 
mankind.
    We particularly look to the development of promising new 
medications for the treatment of schizophrenia and other 
debilitating brain disorders, which have occurred as a direct 
result of biomedical research. We've also had great advances in 
understanding the ideology of brain disorders, advances that we 
believe may ultimately lead to much better control of symptoms 
and even potentially cures. And it's important, as has been 
noted several times today that none of these advances that have 
been so dramatic in treatment of mental disorders would have 
been possible without the participation of individuals who 
suffer from these disorders.
    And I think it's important to note that they are not just 
subjects but indeed participants in the research, which I think 
is a stronger term and a more appropriate term. And at least in 
the view of NAMI members, they are really the heroes here in 
the research arena. It is, however, very important, as we 
confront these issues, to try to strike the balance so that we 
can maintain a healthy climate for research, which all of us 
view as the long-term hope for conquering these illnesses.
    And so it's important that we look at the issues that 
surround many of the complex ethical questions that you have 
raised with this hearing. The use of human subjects in research 
presumes that individuals who participate are capable of 
comprehending the nature and scope of the research and, 
therefore, can participate in an informed way and consent to 
their participation. But as you know, the nature of severe 
mental illnesses often renders individuals with these disorders 
sometimes incapable of such consent. It is good to see the 
dialog we've had today. And it is good to note that scientists 
join bioethicists and advocates in being committed to balancing 
the importance of creating and maintaining a healthy climate 
for vital research with the equally important paramount concern 
of protecting vulnerable subjects who may lack the capacity to 
fully understand the nature, the risks and the benefits of the 
research they're asked to participate in.
    Recently, there have been a number of issues which have 
received a great deal of attention, including revelation 
several years ago about specific research protocols at UCLA 
Neuropsychiatric Research Institute, in which it has been 
alleged and, indeed confirmed, that there were flaws in the 
informed consent procedures. And there continue to be concerns 
about whether this research was conducted in the highest 
possible ethical manner. Members of NAMI obviously looked at 
this situation with great concern.
    And for the past several years we have brought our concerns 
about this study to the officials at the National Institute of 
Mental Health and the Office for Protection from Research 
Risks. The entire lay board of the National Alliance, after 
hearing from a great many experts, consultants, family members 
moved forward in February 1995 to adopt some very 
straightforward and, we think, very helpful concrete 
suggestions as policies that I would like to share with you at 
this hearing.
    Mr. Shays. Can you say the last statement you made? I got 
distracted. What was the last point?
    Ms. Flynn. That in February 1995 the lay board of the 
National Alliance, again, made up of families and patients, 
adopted some specific policies that I would like to share with 
the subcommittee today, which we think will offer some of the 
concrete guidance that you are looking for and ways to 
strengthen the climate that we currently have. I guess I'm not 
certain, sir, whether you want me to try to deliver my entire--
--
    Mr. Shays. No. You have about 3 or 4 more minutes, if you'd 
like to continue.
    Ms. Flynn. OK. Well, let me try to move forward, then, and 
just try to capsulize. Because my written statement does go 
into greater detail. Let me just try to move forward and try to 
highlight what the specific policies are that we think need to 
be adopted.
    Mr. Shays. And we'll be able to cover some of it in the 
questioning part as well.
    Ms. Flynn. OK. Thank you.
    Mr. Towns. The entire statement will be included in the 
record.
    Mr. Shays. Yes.
    Ms. Flynn. I appreciate that. We would like to see national 
standards developed to govern voluntary consent, comprehensive 
exchange of information and related protections of persons with 
cognitive impairments who become research subjects, and that 
the development of these national standards must include 
individuals who have these disorders, their family care givers, 
who are directly involved and directly affected. We note that 
there is not currently existing in Federal regulations specific 
protections for this vulnerable population, although they have 
been highlighted by several prior national ethical bodies as 
needing this kind of support.
    We believe that the National Institute of Mental Health, 
which funds the great bulk of research on severe mental 
illnesses, should take the lead in the development of such 
national standards. And we are pleased to see that Dr. Steven 
Hyman, the new NIMH director has moved forward to convene a 
group that will be looking at the development of not only 
standards, but potentially best practices and other guidance to 
the research community to strengthen the way in which informed 
consent and other psychiatric issues in research are handled.
    We think it's important to note that informed consent as 
has been referenced is not just the gaining of a signature at 
the front end of a research protocol. But particularly for 
vulnerable subjects who may be cognitively impaired, it needs 
to be seen as an ongoing process. Comprehensive information 
needs to be provided both orally and in writing, including 
information that makes clear not only the risks and benefits of 
research, the scope, scale and objectives of the research, but 
also other modes of treatment, other options than the research 
that may be available.
    This is important because of unique characteristics of most 
people in this country with serious mental illness, Mr. 
Chairman, who frequently do not have health care coverage 
except through the public mental health system. These folks are 
uniquely vulnerable to the potentially coercive effects of 
being able to access novel or experimental or potentially more 
valuable treatment through research settings.
    We believe that it is very, very important that the 
capacity of individuals to participate in research be assessed 
not only at the outset, should there be any question, but also 
be able to be assessed continuously through the research should 
there be any question of their continuing ability to consent, 
and that that should be conducted by someone not directly 
involved in the research, as I think has been noted previously. 
Should it be determined that the individual lacks decisional 
capacity, surrogate consent should be sought from family 
members, if they are willing and able. And here we are 
particularly concerned that family members are often not 
involved, not informed, and not able to then participate on 
behalf of a relative that may have fluctuating ability to 
consent and participate.
    Institutional review boards which review research on mental 
illness must include consumers and family members with direct 
personal experience with these severe and debilitating 
illnesses. It has been our experience that most IRBs do not get 
this kind of representation from the community, even when they 
do a regular review of psychiatric research protocols. This is 
something that can be addressed easily. This is something that 
our organization is in a position to be a resource on. And we 
think there should be strong guidance to IRBs, that they should 
include representatives of the community of individuals with 
psychiatric illness.
    We believe that investigators must ensure that individuals 
who participate in research as outpatients, where most of this 
research, including research on new medications is conducted, 
they need to be linked to appropriate care, treatment and 
supports for the entire duration of the research.
    Mr. Shays. I need you to finish up here because we have two 
votes.
    Ms. Flynn. All right. One final point, then. Let me say 
that many people enter into research on new medications because 
they hope for great improvement in their treatment. We then 
find that when the research is over--9 weeks, 12 weeks--that 
the medication is no longer available to them. We find this 
unethical. We find this a procedure that truly can be very 
damaging. And we believe that when there are protocols approved 
that involved offering new
medications to individuals who may have no other way to get 
them, that they must be guaranteed that they will be able to 
continue if the medication has been seen as safe and effective 
even beyond their tenure in the research program.
    [The prepared statement of Ms. Flynn follows:] 
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    Mr. Shays. Thank you, Ms. Flynn. I'm sorry we've been 
pushing you a bit. Dr. Lurie, we'll be able to come back. And 
then you can tell us about Africa. And then we'll start our 
questioning. We have two votes, and we'll be back after that.
    [Recess.]
    Mr. Shays. The subcommittee will come to order. Dr. Lurie.
    Dr. Lurie. Yes. Thank you very much. I just want to talk 
briefly about the Africa, Asia, Caribbean vertical transmission 
studies. To start off by just making very clear----
    Mr. Shays. Let me just--I'm sorry. First, some of you need 
to be on your way by when?
    Mr. Caplan. Twenty of.
    Mr. Shays. Twenty of? OK.
    Mr. Caplan. But I have a substitute behind me.
    Ms. Flynn. I do, too.
    Mr. Shays. Well, you know what, I'm not going to have 
substitutes. We'll just deal. You can stay later?
    Dr. Lurie. Excuse me?
    Mr. Shays. You can stay later?
    Dr. Lurie. I can.
    Mr. Shays. OK. Why don't we just deal with the issue, then, 
that I'm finding absolutely fascinating. The local 
institutional review boards are licensed by whom?
    Dr. Wilfond. The institutional review boards usually will 
have to file what is called a multiple project assurance with 
the OPRR at universities or hospitals.
    Mr. Shays. What happens if the OPRR isn't involved?
    Dr. Wilfond. Well, generally for any sort of large 
institution like a university it will be.
    Mr. Shays. No, no. You've already told me under two 
circumstances where there's basically no review.
    Dr. Wilfond. Correct.
    Mr. Shays. Yes.
    Mr. Caplan. The OPRR is not always involved.
    Mr. Shays. They're only involved if Federal dollars are 
involved.
    Mr. Caplan. Or IRBs if there is a new medical innovation 
that doesn't involve a drug or device that--the FDA is 
triggered there. And it has to be, I might add, for interstate 
commerce. If it's a new innovation in surgery, rehabilitation 
medicine, nursing, where there's no drug or device, there is no 
necessity of IRB review or OPRR connection or any review at all 
unless there is some commercial purpose involved and unless 
this work is being done at an institution that is getting NIH 
money for other purposes. So if it's privately funded within 
the State, no commercial purpose--a good example, by the way, 
Mr. Congressman, would be the Baby Fay baboon transplant. That 
looks pretty experimental--technically did not have to be 
reviewed by an IRB. It was privately funded, not done for a 
commercial purpose.
    Mr. Shays. Now, these IRBs are commercial or not 
commercial? I'm not clear on that issue. At bottom line first, 
they don't have to be licensed?
    Mr. Caplan. No.
    Mr. Shays. Unless they might have to be reviewed if they 
are involved with the Institutes of Health.
    Mr. Caplan. Correct. And they have regulations pertaining 
to their composition from the Code of Federal Regulations that 
require, I think, a minimum of five people, one lay person to 
be involved--and that lay person represents the community, 
although the community----
    Mr. Shays. Do they have to register with some national 
board?
    Mr. Caplan. The NIH, basically.
    Dr. Wilfond. Or the FDA. So for example, these for-profit 
IRBs are almost exclusively----
    Mr. Shays. Do they register with one or the other or both?
    Dr. Wilfond. They could do both.
    Mr. Shays. Do we know how many there are out there?
    Mr. Caplan. No, we do not.
    Ms. Flynn. No.
    Mr. Shays. This is getting a little silly.
    Mr. Caplan. No, we do not.
    Ms. Flynn. It's very unregulated.
    Mr. Caplan. And the definition of community member could be 
a community member in which the research is being conducted or 
10 States away.
    Mr. Shays. Dr. Lurie, do you want to comment on this?
    Dr. Lurie. No. I think just to make a point that the IRBs 
have too much ``I'' and not enough ``R.'' I mean, there's too 
many people from the institutions themselves and reviews that 
are occurring, are occurring much too quickly. I mean, these 
people are spending 1, 2 minutes on a proposal many times. But 
I think that, as pointed out, the financial incentives here are 
very powerful. And I do think there's a role for some 
regulation of this.
    Mr. Shays. OK. Explain to me the whole concept of 
commercial IRBs.
    Dr. Wilfond. Maybe I could try this again a little more 
carefully.
    Mr. Shays. Yes.
    Dr. Wilfond. I think Peter is right, that even within 
institutions like universities, there may be some conflicts of 
interest. But the point is that if a person is in private 
practice, they don't belong to any institution, the FDA still 
requires a review by an IRB. So where that IRB comes from is 
usually somebody who has set up their own IRB, files their own 
forms with the FDA, calls themselves an IRB, and then receives 
money from the investigators who want them to review their 
projects.
    Mr. Shays. Are those what are referred to as commercial 
IRBs?
    Dr. Wilfond. Yes.
    Mr. Shays. OK. What is a non-commercial IRB?
    Dr. Wilfond. A non-commercial IRB would be an IRB from an 
institution like a university or a hospital that would be 
reviewing all the projects within there. They would also have 
their own conflicts, but they won't be as egregious 
potentially.
    Mr. Caplan. It's important to point out, too, about the 
institutionally based, which is university and hospital 99 
percent of the time, IRBs--that they don't get paid and don't 
receive any money.
    Ms. Flynn. They're volunteers.
    Mr. Caplan. They are volunteers who then work as overhead--
that's where those overhead fees that the NIH charges and puts 
onto its grant. So there's no payment. And what you've got is 
some very hard--I don't want to just beat up on the IRB 
members--you've got some very hardworking volunteers who are 
asked to carry a ball that in the commercial sector they would 
be paid fairly well for.
    Mr. Shays. Any questions? Again, Dr. Caplan, you need to 
leave in about 7 minutes. Dr. Wilfond, you need to leave when?
    Dr. Wilfond. I don't leave until 5 o'clock.
    Ms. Flynn. As soon as possible.
    Mr. Shays. As soon as possible? OK.
    Ms. Flynn. Yes, sir. Thank you.
    Mr. Shays. Do you have any comment you want to make before, 
and I'll just let you get on your way?
    Ms. Flynn. Beyond the comments that I was making in my 
statement in the record, I just want to reinforce the concerns 
that are being expressed about the IRB procedures. I think the 
IRB is the crux of protecting human subjects. And it is 
enormously variable across the country. And I think we have 
been very slow to recognize the training needs at IRBs, to 
recognize the potential importance of looking at community 
participation as more than just fellow physicians in the same 
hospital or fellow members of the same research community.
    And that some of the issues we're hearing about commercial 
IRBs are particularly important. Because to the degree that you 
can buy approval--or the appearance is there, that you can buy 
approval--to that degree is public trust in the IRB process 
tremendously diminished. So I appreciate the chairman's raising 
these subjects and the time and attention that has been devoted 
to it is not beyond what is needed. And I think we've just 
begun a dialog that I hope will continue.
    Mr. Shays. I thank you. And I do recognize that we have 
kept this panel extraordinary late. I apologize. And we've had 
lots of interruptions. We would have been out hours ago without 
the interruptions. So I do apologize. Ms. Flynn wants to get on 
her way. Should we let her get on her way?
    Mr. Towns. You can put it in writing to me.
    Mr. Shays. Sure.
    Mr. Towns. You made a comment earlier that I'm very 
concerned about in terms of mental patients, in terms of the 
competency, in terms of privacy and all that. And I would like 
for you to sort of give us something in writing as to what you 
think we might be able to do to protect them. For instance, 
especially with the medication that they're getting. If it's 
helping them, and all of a sudden the medication disappears--
and I guess sometimes it's probably the cost factor as the 
reason why they are not able to get it. So I would like for you 
to give us some suggestions. Because I think some of these 
things are going to require legislation.
    Ms. Flynn. I appreciate that, sir, and would be glad to 
provide you with some concrete and specific suggestions in 
writing.
    Mr. Towns. Right. Thank you.
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    Mr. Shays. And if the gentleman will yield. Dr. Caplan, we 
do need on the record one question and then you can have 
someone who was sworn in take your place. And we will honor 
that. The question I need to ask you is, in what ways do you 
feel that the FDA's waiver of informed consent would permit DOD 
to use PB and botulism toxin vaccines on Gulf war troops was 
ill-advised or unethical?
    Mr. Caplan. I think the handling of the waiver with respect 
to the troops was unethical in three ways. First, I think they 
did not demand and insist upon followup, so that people who 
were exposed to these substances who were de facto, acting as 
subjects or even guinea pigs, would know whether or not there 
were harms or problems that arose, which may have happened now 
in terms of Gulf War Syndrome. I'm not sure that's true. At 
least they failed in the obligation that was owed to followup. 
They failed in the obligation to disclose what was done to 
these troops. You were asking the FDA in the previous panel, 
were you satisfied that they were in compliance with what the 
agreement was?
    Well, I will say that I think they failed dismally and they 
have not--the Defense Department. Those military agencies did 
not do what they needed to do to, after the fact; inform people 
when they were exposed to innovative or experimental 
substances.
    The last area of failure is, there's still been no 
formulation of a policy about what to do with respect to 
research on our troops. We don't have it today. We didn't have 
it 6 years ago. And I find it incredible that we have not had 
more than an interim rule to guide us with respect to research 
in the military.
    Mr. Shays. And clearly we've had enough time.
    Mr. Caplan. I would say we've had more than enough time.
    Dr. Wilfond. Can I just add something?
    Mr. Shays. Sure.
    Dr. Wilfond. I think it was not convinced this morning that 
they ever gave a clear reason why it was not feasible to have 
asked for consent in the first place. Presumably, if you asked 
the soldiers, you may be exposed to nerve gas, this medication 
may help you but we really don't know, and we would like to do 
a project, would you like to participate, most would probably 
say yes.
    Mr. Caplan. We took a lot of testimony at the Presidential 
Advisory Committee on this matter.
    Mr. Shays. Yes.
    Mr. Caplan. And it was summed up fairly well by one of our 
people who came to testify to us who said, if someone is 
shooting very large bullets at you which may be filled with 
biological weapons, the likelihood of you refusing an antidote 
is zero. So that we could assume that most people would, in 
fact, have taken the opportunity to get the best protection 
possible.
    Mr. Shays. Yes.
    Mr. Caplan. I wouldn't deny it. But the opportunity to ask 
was there. And even if it was difficult due to the quick 
mustering up of forces, after the fact notification is an 
absolute--it's just something that has to be done.
    Mr. Shays. Yes.
    Dr. Wilfond. But my point is that there's still no--it's 
not clear that they couldn't have done it ahead of time either.
    Mr. Shays. Dr. Caplan, you've been terrific to wait so 
long. Did you want to ask him a question before he left? Yes.
    Mr. Towns. Yes. This whole thing about ethical standards, 
there seems to be some disagreement on the meaning of the term. 
Some people think it means having standard operating procedures 
to review proposals. And other people think it means that the 
contents of the proposal should be reviewed to determine 
whether they meet some kind of moral standards. Can you tell me 
what you believe the requirements are for ethical standards in 
reviewing research proposals?
    Mr. Caplan. Well, I'll try to answer that simply, 
Congressman Towns, by saying this. I think the job of the IRB 
in terms of ethical standards is to make sure that 
comprehensible information is given to the person so they can 
use their values to decide how they want to deal with risk and 
benefit. So the real moral principle that has to guide what the 
IRB is doing with the informed consent forms and all the rest 
of it is, can we make it so that we empower the person to be 
able to make a choice. The problem is that we put a lot of 
weight right now in our review on the front end, what's on 
paper, what happens at the start.
    And there's very little in the middle and at the end 
whereby we go back and say, did you understand it, do you think 
we picked up the right issues, are we doing our job as 
committees, as people trying to empower you? But the moral 
principle, I would say is, empower the subject to make a 
choice. That's really what the job is of these IRBs, public, 
private, whatever they are supposed to be. They are trying to 
let people make choices according to their best values. Not 
everybody will agree.
    There's no right answer about when is it too risky, when is 
it too dangerous, is it worth the benefit for me? But you do 
need information and you do need time and you do need to make 
sure that the person giving you that information is giving you 
all your choices. That's what those committees have to do. And 
I don't think they're doing it as well as they ought to.
    Mr. Towns. Dr. Wilfond, your comment?
    Mr. Shays. Thank you, Dr. Caplan.
    Dr. Wilfond. Well, actually, I would take it a little 
further----
    Mr. Shays. And let me just--excuse me. We will be having 
join us Dr. Jonathan Moreno, who was sworn in, I believe. Is 
that correct?
    Mr. Moreno. I was.
    Mr. Shays. Yes. And welcome.
    Mr. Moreno. Thank you.
    Dr. Wilfond. Yes. I think at least for children the IRBs 
are expected to do much more than just make sure that people 
have information. They are supposed to make some sort of 
judgment about the balance of the benefits and the risks. And 
the regulations are very detailed in terms of the various 
categories of benefits and risks. I think one of the challenges 
is that for research that is identified of being no direct 
benefit can only be approved if it--and these are the exact 
words--``if it is a minor increase over minimal risk.''
    The problem is, it's not clear what counts as minor 
increase over minimal risk. And many medical journals or ethics 
journals are spent discussing these issues, of what counts as a 
minor increase over minimal risk. So I think there is really a 
need to conceptual clarity to be improved to allow the IRBs to 
do this better.
    Mr. Towns. All right. Thank you.
    Dr. Lurie. Yes. Let me add to what Dr. Wilfond is saying. 
Obviously, adequately informing people is critical, but it's at 
times not sufficient. So as bad as the informed consent form 
was in the Alaska study, it couldn't have made the study 
ethical. So an unethical study is an unethical study. And the 
IRBs need to stop those from proceeding regardless of how good 
the informed consent form is. And the same thing, I believe, is 
true in the African studies, which we'll get to later. There 
may indeed be problems with informed consent. We haven't looked 
at all the informed consent forms yet. But there is no informed 
consent form that could satisfy me that these studies are 
ethical. The study is unethical by design. And you can't 
informed consent your way out of that.
    Mr. Towns. Right. Let me just ask one more question, Mr. 
Chairman. May I?
    Mr. Shays. Yes.
    Mr. Towns. I'm concerned about when these studies go wrong, 
they seem to be conducted on poor people, minorities in 
particular, and in some instances their children. I wonder if 
one factor considered in the approval process is the economic 
status of the people to be studied. Wouldn't the economic 
status have a bearing on nutrition, other factors that could 
influence the outcome of the study?
    Mr. Moreno. Perhaps I could address that.
    Mr. Towns. Sure.
    Mr. Moreno. Incidentally, I work at the Health Science 
Center at Brooklyn----
    Mr. Shays. Yes. Would you----
    Mr. Moreno. My name is Jonathan Moreno. I'm a professor of 
bioethics at the Health Science Center at Brooklyn State 
University of New York.
    Mr. Shays. OK.
    Mr. Towns. That's a very important place, Mr. Shays.
    Mr. Shays. It is a very important place. Not the most 
important, but a very important place.
    Mr. Towns. Thank you.
    Mr. Moreno. It's near Connecticut, at least. We deal with 
this issue all the time at an institution like ours. As you 
know, we have a large minority population and many subjects who 
don't have economic means and are vulnerable. The one ethical 
principle that has, I think, been the most difficult to 
interpret and apply in our system that came from the National 
Commission in the late 1970's is justice. And according to the 
National Commission, justice in the context of the use of human 
subjects in research means that you don't overburden any 
population in the society with respect to research 
participation, and that you also, importantly, make sure that 
the fruits of research are available across the board, through 
the whole society.
    That's really very hard to do, partly because when people 
don't have economic means they may not have the ability to 
participate in research because they are, for example, taking 
care of older people or younger people, or they don't have the 
money to come to the center to be part of a study, or because 
of the possibility that they could get sick from being on a 
drug, and to be taken off-line from work or taking care of 
those other people, could represent a serious practical 
obstacle to being in a study.
    So there are problems on both ends, I would say, 
Congressman. One problem is that, yes, it's true that people 
who are in the position you've described may be more 
vulnerable. At the same time, we aren't very good at recruiting 
them to research that could benefit them or could benefit other 
people in their circumstances.
    Mr. Towns. Yes. Would you like to add anything to that?
    Dr. Wilfond. It goes--he's correct. It goes both ways. It's 
a problem both on the side of recruiting appropriate subjects. 
And in fact, the NIH has really tried over the last few years 
to try to increase the enrollment of minorities and women in 
studies. I think there also is a problem of inappropriate 
recruitment. One problem that I see which I alluded to in my 
comments has to do with the issue of reimbursement for money. 
We were asked at one point to review a study on volunteers. 
Well, why didn't they get 8 hours of general anesthesia for the 
cost--for which they would be paid $1,000. And we thought that 
this was potentially risky. And we thought that the only people 
who would be willing to do this would be people who really 
needed that money.
    And so we actually did not approve that study. But for 
precisely that reason, that, as Peter mentioned, it's not just 
the risks but what will make people do it. And often it's for 
the money.
    Dr. Lurie. I think you're raising a very important point. 
And let me emphasize it by saying that I think your observation 
is accurate, that I think the anecdotes that are being brought 
up today illustrate your very point. I mean, I've talked about 
injection drug users. I've talked about poor people in 
developing countries. People talk about people with mental 
illness. People in the military whose ability to refuse 
participation is limited. I mean, I think it's absolutely 
consistent with your point.
    Let me illustrate it perhaps by comparison. In the needle 
exchange study, there was no hepatitis B vaccine, at least in 
the initial phase, planned to be administered in any important 
way to the subjects. And so the idea was to watch people and 
see whether or not they got hepatitis B even though there was a 
vaccine. Now, let's imagine a study of young infants in which 
the question was did they get tetanus or not, and the 
researchers just kind of watched to see if they did without 
providing them with tetanus vaccine.
    It's inconceivable. Nobody would have done anything like 
that. But when it's injection drug users I think somehow 
there's an acceptance of the poor quality of medical care that 
often is afforded to these people. The same thing is true with 
regard to the degree of evidence that we now seem to require of 
needle exchange programs. There are no randomized controlled 
trials of whether or not condoms work to prevent the 
transmission of HIV.
    Yet suddenly, primarily for political reasons, people 
dredge up the idea that we need randomized control trials for 
needle exchange. No one dreams of a randomized control trial of 
condoms for gay men, for example, because as discriminated 
against as gay men, in fact, are in this country, they are 
still better organized than drug users. So I think both of 
those points really emphasize what you say. And I think in many 
ways that's what's operating the African, Asian and Caribbean 
studies where there is in fact an incentive now.
    If we're saying we only have to provide the standard of 
care that exists in these impoverished countries that can't 
afford our overpriced drugs, what we're saying is, there's 
really an incentive for people to go overseas and find the 
place with the least medical care, and then we can get away 
with doing nothing. Provide getting a bunch of information that 
may or may not benefit them. And we may very well take the 
results back to our countries ourselves where our people will 
benefit. That is exactly--so I highly endorse the concern that 
you're raising.
    Mr. Towns. Last question and then I'm going to----
    Mr. Shays. No, that's fine. We want to make sure that, Dr. 
Lurie, that you get to talk about Africa.
    Mr. Towns. Africa. Yes. Maybe this can lead him into it. I 
have this feeling--I'm not certain--but based on the 
information that I've received, and reading in terms of the way 
in many times these programs are structured, in terms of 
research programs are structured, that you have a physician in 
a foreign country doing research. And he's so involved and 
wrapped up in his research, that he's really not paying 
attention to some of the other symptoms of the patient that 
might give him signs that certain things are happening. But 
they just continue with their research, because, after all, 
that's what I'm into, my research.
    As a result, in many instances, patients that are lost 
should not be lost. If this patient had a physician that was 
responsible for the medical care while the other person is 
responsible for the research, that it seemed to me that some of 
the things that occur might not occur. Now, am I right in my 
assumption that this is the structure, when I have my patients 
and I am involved in the research--and, of course, you do not 
have a physician that's responsible for the day-to-day health.
    Dr. Lurie. Well, Dr. Jay Katz--that's for you, Congressman 
Shays--a nice mention of Connecticut----
    Mr. Towns. Right. Yes.
    Dr. Lurie [continuing]. Has the notion of a physician 
researcher, people who have, in fact, these dual 
responsibilities and should really take both of them into 
account when acting as researchers either in this country or in 
a foreign location. And I think that is the way that we need to 
be thinking about it. Unfortunately, there's been a kind of a 
specialization of function in which people consider themselves 
to be one or the other, and say, well, that's not my job, I'm 
doing the research here, somebody else is providing clinical 
care, that's not my problem.
    So I think that is exactly right. The problem, in fact, 
becomes, as I indicated in my testimony, that sometimes there 
is, in fact, a conflict or an apparent conflict between what 
the researcher thinks that he or she needs and what it is that 
the people in the trial need. Those women who are HIV positive 
and pregnant and stand a 25 percent at least chance of 
delivering an HIV positive baby, they don't need research. 
Those women need AZT.
    Mr. Towns. Yes.
    Dr. Lurie. It works. Not 100 percent, but it works. It 
works better than most other things we have to prevent HIV in 
this country. It works. That's what they need. They don't need 
more research. Yet, somehow what we heard a lot of this morning 
was the idea that yes, it's true that these women might be 
placed at risk, but there are going to be future benefits.
    And one of the clearest principles that came out of the 
Nazi experiments during World War II was the notion that you 
can't place individuals at risk in the present for potential 
future benefits, that the people in the study have their own 
integrity, that they have to be protected in and of themselves, 
and that you can't justify any old research simply by saying, 
well, we're going to get good information from this and other 
women like this are going to benefit in the future. It may 
never happen, and it's a slippery slope to some very, very 
dangerous places.
    Mr. Moreno. Clinical investigators are often called double 
agents in the bioethics literature.
    Mr. Shays. Say that again.
    Mr. Moreno. A double agent problem is the problem that 
Congressman Towns alluded to, namely that, ``I've got a grant 
and I'm doing some research, and I'm also using some patients 
in the study who in a certain sense may assume that I'm 
primarily concerned with their individual care.'' And while I 
may indeed be concerned with their well being, I also want to 
get some data. That's a problem, though, not only on the side 
of the physician investigator--I worked for the President's 
Advisory Committee on Human Radiation Experiments, and we did 
focus groups with hundreds of people who are in studies.
    We found that even through they were theoretically and 
documentedly informed that this was primarily research, that it 
was not intended to benefit them--and most research is not 
intended to benefit the subject--nevertheless, they had a hard 
time integrating that information. It's very hard to face that 
when you're sick and you're looking for an answer. So this is 
not something perhaps too amenable to legislation. It's human 
psychology. It's often very difficult for people to accept that 
they're making a big personal investment of both time and hope. 
And it may not help them.
    We did find that as people went on through the course of 
their disease, they were more willing to accept that their 
participation was not going to help them, but might well help 
somebody else. We also find--I want to point this out--from the 
point of view of the person who is sick and in a study--this 
work we did for the Advisory Committee on Human Radiation 
Experiments--we also found that a very important motivation for 
people to be in studies is that they trust the institutions 
that are sponsoring the studies.
    This is a guy in a white coat who has a lot of knowledge 
and a lot of power and a lot of authority. This is a great 
institution. Look at these buildings. Look at the labs. Look at 
all the nurses. This is an important place in my community--the 
State University of New York. Surely what they're doing is 
going to be good for me. Trust is a very--what I'm saying is 
something that you already know: trust is a very delicate 
thing.
    Mr. Shays. That's very true, Doctor, and very important to 
point out. Dr. Lurie, how long do you think it will take you 
to--because I do have some follow questions, and we're going to 
go to a vote soon. But I do want you to deal with Africa. But 
give me a sense of how long it will take you to describe the 
clinical research?
    Dr. Lurie. I'd say probably 3 minutes.
    Mr. Shays. Let's do it.
    Dr. Lurie. Let me just emphasize from the beginning that 
there is nothing in the position that we have taken that states 
that we are opposed to randomized, controlled trials. And 
there's nothing in our statement that says we are opposed to 
placebo controlled trials per se. We are in this particular 
situation. But not in general. We're also not opposed to 
international research. What we are opposed to is double 
standards. And we don't like a double standard where, for 
example--there are two American studies in which AZT is 
provided, or something similar to AZT is provided to the 
treatment groups, yet the minute people go overseas, it's like 
they check their research ethics at the customs desk. Only 1 
out of the 16 studies that are being done in developing 
countries provides AZT to all treatment groups. That's a double 
standard.
    And it is that particular one study that in many cases 
illustrates the inconsistency and lack of coordination that 
have plagued this particular set of studies. How can it be that 
the National Institutes of Health is funding a non-placebo 
controlled trial of these mother-to-infant transmission 
prevention interventions in the very same country that the 
Centers for Disease Control is conducting a placebo controlled 
trial?
    How can that be? And I think that perhaps the most 
important thing that I heard, at least with regard to the 
African studies or Thai studies, was what Dr. Varmus said this 
morning, which was, when asked that very question by Mr. 
Kucinich, he responded that the placebo controlled trial was 
``not the only way to achieve results.'' That's exactly right. 
It is not the only way to achieve results. And the difference 
between the method that has been chosen by the CDC in Thailand 
and the NIH and the CDC in other places is not the only way to 
achieve results.
    Unfortunately, one result that it will achieve is that if 
you add together the American and the foreign-funded studies, 
there will be 1,500 HIV positive babies in this world which 
need not happen. Even though we have a big research 
infrastructure that goes in, it doesn't cost that much to 
provide AZT. In many cases you get it free form the drug 
company. And yet we're effectively staring those women in the 
eye and saying, no, we need a placebo controlled trial. And 
consequently there are 1,500 HIV positive babies that will 
exist within a couple years from now when they need not.
    The final point I wanted to make was about the IRBs. And we 
heard a lot about how this all went through the IRB in these 
local countries. I think that Dr. Wilfond, Dr. Caplan and 
others spoke very well to the problems of IRBs in this country.
    Mr. Shays. I'm not clear. There are IRBs in other countries 
just like in the United States?
    Dr. Lurie. Well, whether it's reasonable to call them per 
se an IRB, I'm not exactly sure. I'm sure they are not 
constituted necessarily with the kinds of regulations that we 
have in this country.
    Mr. Shays. So you're basically talking about the health 
ministries of the country?
    Dr. Lurie. In many cases there is some kind of review 
committee that will review this. I mean, myself, I've conducted 
quite a bit of research----
    Mr. Shays. Is that set up by international agreement, World 
Health----
    Dr. Lurie. My understanding is that it's understood that 
studies like this will be reviewed, but there is not the same 
kind of detailed information about who will sit on these 
things. I don't believe that there is a requirement----
    Mr. Shays. Let me just say something. I'm truly exposing my 
ignorance in this area. But it does blow my mind. I mean, the 
value that someone like I bring to this is, I know nothing.
    Dr. Lurie. Yes. That's right.
    Mr. Shays. But I come with a clean slate. And there are 
things that just frankly have blown my mind about what I've 
learned today. Because I made assumptions. I made assumptions 
about a lot of things that are very different than what I've 
learned. And so there will definitely be followup at the urging 
of my ranking member, as well. This is an issue we're going to 
get into with a lot more interest than we've shown in the past. 
Why don't you finish your point.
    Dr. Lurie. Well, you know, I think you are exactly the 
right person to be making a judgment about these kinds of 
things. I mean, the scientists are themselves too close to the 
problem. And I think that's a lot of what we heard this 
morning, that there are people standing up and basically 
defending either their government institution or otherwise 
their university. We've heard a lot of that. I think it's the 
kind of distance that a sort of naive observer like yourself 
has to offer.
    And the common sense thing is no; 1,500 lives that could be 
saved. Why not do it? Why not do it if you can get data that 
are good enough to make decisions, which even Dr. Varmus 
himself says are good enough to make decisions. I think they're 
too close. I think that's part of the problem. Anne Marie 
Finley used the expression from a song recently: ``blinded by 
science.'' And I think that's part of what the problem is. It's 
too much on the science, not enough on the broad of social and 
ethical contexts of things.
    Mr. Shays. OK.
    Dr. Lurie. My final comment with regard to IRBs, then, is, 
can we trust the IRBs overseas? And as somebody, as I said, who 
has done quite a bit of research in Africa and Asia, I've used 
IRBs in those countries myself. I have no confidence in the 
fact that they say that my research is OK. It does nothing for 
me. At least the research I have done. I am sure that the 
research committees, the ethics committees established for 
these studies, are in fact better than the ones that I have run 
my research through. There's nothing I can do about that.
    Of course, it runs through an ethics committee in our 
country, as well. But if you take, for example, some FDA 
inspections from the period of 1977 through 1995 published here 
in the Cleveland Plain Dealer, the United States--there were 32 
percent of studies in these inspections which deviated from 
protocol. And their inspections of foreign IRBs, there were 54 
percent that so deviated. And with regard to the keeping of 
adequate or accurate records, there were 27 percent of American 
IRBs that had inadequate or inaccurate records. And in that 
same period, the percentage in foreign countries was 53 
percent.
    So there is reason to believe that, for starters, the very 
same pressures so well described by Dr. Wilfond and Dr. Caplan 
that exist in this country exist over there. And seeing as 
though these committees are much newer, they don't have the 
same research infrastructure, there are fewer people with 
formal training in ethics than exist in this country, I think 
it's reasonable--and the data support the idea--that ethical 
review over there is likely to be poor.
    Mr. Shays. I just have about four more questions. And I can 
go through them fairly quickly. I don't know if the answers 
will be quick. But it's Dr. Moreno.
    Mr. Moreno. Moreno.
    Mr. Shays. Moreno. I'm sorry. Dr. Moreno. How is data 
collection and monitoring of animal subjects more extensive 
than required for human subjects? First, is it? And if so----
    Mr. Moreno. I think it is. I sat on an animal care and use 
committee in my school a number of years ago. So my memory may 
not be fresh. But as I recall--and I hope other people will 
correct me if I'm wrong--there is annual auditing of animal 
care and use committees. And I believe that they are 
unannounced. There is at least regular auditing of animal care 
and use committee records. And I believe they are unannounced. 
In the case of human subject review committees, I believe that 
they can take place every several years and they are announced.
    Mr. Shays. Well, we will be looking into that. But the 
bottom line is----
    Mr. Moreno. The bottom line is there is less regulation for 
human subjects than there is for animals, in that sense, in the 
sense of auditing by a Government body.
    Mr. Shays. OK. Dr. Wilfond, how would a functioning HHS 
ethics advisory board provide greater oversight of informed 
consent in the United States? One, should we allow that board 
to continue to just sit there or should we activate it?
    Dr. Wilfond. Well, I think it should be activated. I think 
there are two things that having a functioning board--a 
permanent board could do. One would be, as I alluded to, trying 
to help over time develop some more conceptual clarity about 
how to resolve ethical issues. But I think more importantly it 
could be a mechanism for having one singular mechanism of 
oversight of IRBs and make sure that all research goes through 
those IRBs, make sure that those IRBs are at a community level, 
and make sure that the IRBs do ongoing monitoring of the 
research. And the only way that can be done is by having one 
single agency who is responsible for doing all this stuff.
    Mr. Shays. Yes.
    Mr. Moreno. Can I just add to that, also?
    Mr. Shays. Sure.
    Mr. Moreno. There are big philosophical and policy issues 
emerging that local IRBs may not be comfortable in settling. 
For example, the use of AZT in pregnant women, which I dealt 
with in Brooklyn a few years ago. That also could be subject to 
an open public review that would take some of the moral 
pressure off the local institutions.
    Mr. Shays. Do you have anything to respond to those two 
questions?
    Dr. Lurie. No.
    Mr. Shays. We have a vote. I think what we're going to do 
is call it quits here. You have definitely encouraged this 
subcommittee to move forward as this is an extraordinary issue. 
I've made assumptions about the local boards and their powers 
in oversight. I've made assumptions about what the FDA has done 
or hasn't done. I've made assumptions about the Institutes of 
Health that are quite the same as I thought. And I know 
everybody is wrestling with this issue. But it strikes me that 
we'll be able to focus in a little bit more. I'll be able to do 
some homework in the meantime to make sure that we don't let 
the first panel get away without asking some of them these 
questions. So with that--do you have anything to add, Mr. 
Towns?
    Mr. Towns. No. I think it was terrific in terms of 
information that they were able to share with us. I really 
appreciate it. Thank you very much.
    Mr. Shays. Yes. I'd just like to thank the staffs on both 
sides who worked close together and have provided very helpful 
information to prepare us and have gotten us some excellent 
witnesses. So thank you for coming. Do any of you just wish to 
say something before leaving? Is there any one last parting 
comment you want to make?
    Dr. Wilfond. Actually, I do have one.
    Mr. Shays. Yes?
    Dr. Wilfond. Since I haven't really spoken to the issue of 
the studies of the AZT trials I think there's two points I want 
to emphasize.
    Mr. Shays. Sure.
    Dr. Wilfond. One is that Peter is correct that these 
studies could be done using AZT as the control, but it would 
take more time and it would cost more money. So essentially, 
the ethical question is whether or not it's appropriate to 
spend that time and money. And I think we need to understand 
that. The second thing was a comment that I heard earlier that 
the reason why those studies were justified is because the host 
countries thought it was appropriate. Well, the host country 
thought that Tuskegee was appropriate. So the fact that people 
agree in a country that a study should be done it doesn't make 
it ethical or unethical itself.
    Mr. Shays. Right. That's a very good point.
    Dr. Wilfond. And so, be careful about that.
    Mr. Shays. Very good point.
    Dr. Lurie. If I just may respond to that, about more time 
or money. You know, it is quite unclear that's necessarily so. 
It depends to a certain degree where the short version of AZT 
falls out, whether it turns out to be closer in effectiveness 
to placebo or closer in effectiveness to the 076 regimen. So 
the answer is, it depends. And again, as we pointed out 
earlier, oddly enough, the placebo controlled trial that is 
being done with four arms involved 1,900 subjects, whereas the 
only other four arm study which was not placebo-controlled, 
oddly enough, required less. So I don't think it's necessarily 
true. But most importantly, whatever increment in additional 
money is necessary to make the studies ethical should be money 
that we're willing to pay. if it costs double the money to do 
the study, as far as I'm concerned, that's money we need to 
spend, and we cannot afford to be unethical.
    Mr. Shays. No, we can't. We do have to be very up front 
with the point that everything is an opportunity cost. And I 
would say it's unethical to spend money on research that may 
not optimize the results. Maybe it's more ethical to spend 
money on something that will give better results and help more 
people. There are lots of ways to evaluate the concept of 
money. I want to be very clear. I'm not disputing that you 
should never, whenever money is spent, you shouldn't spend it 
on research that isn't ethical and done properly. But we make 
choices in how best to allocate a resource.
    Dr. Lurie. I think it's a reasonable point. But let's not 
forget that in this particular case, the choice involves not 
only money, not only time, but actually involves people's 
lives, which in many cases in some of the other studies that 
we've talked about--as terrible as they may be--you could not 
predict the number of deaths that were likely to ensue as the 
case here. If it costs double the amount of money, and 1,500 
more babies are alive to see their 7th or 10th birthday because 
we did our studies better, I'd be willing to pay that.
    Mr. Shays. I hear you. And I think most would. Any other 
comment, or should we call this hearing to a close. I guess it 
would be, again, appropriate to thank you all for your 
flexibility with all the votes we had today. And those of you 
who have attended and sat through this hearing, we thank you 
for your participation. I was thinking as we were going on that 
with the powers invested in me as a chairman some time, I'd 
like to just invite people from the audience sometimes after 
they've heard it, you know, at random to allow four or five, 
because I see nodding of head and shaking of head. And I'd love 
to know why you nodded your head or shook your head.
    With that, we'll call this hearing to a close.
    [Whereupon, at 3:10 p.m., the subcommittee was adjourned.]