[House Hearing, 105 Congress]
[From the U.S. Government Publishing 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
U. S. GOVERNMENT PRINTING OFFICE
44-389 WASHINGTON : 1997
___________________________________________________________________________
For Sale by the Superintendent of Documents, U.S. Government Printing Office
Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; (202) 512-1800
Fax: (202) 512-2250 Mail: Stop SSOP, Washington, DC 20402-0001
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:]
[GRAPHIC] [TIFF OMITTED] T4389.004
[GRAPHIC] [TIFF OMITTED] T4389.005
[GRAPHIC] [TIFF OMITTED] T4389.006
[GRAPHIC] [TIFF OMITTED] T4389.007
[GRAPHIC] [TIFF OMITTED] T4389.008
[GRAPHIC] [TIFF OMITTED] T4389.009
[GRAPHIC] [TIFF OMITTED] T4389.010
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:]
[GRAPHIC] [TIFF OMITTED] T4389.011
[GRAPHIC] [TIFF OMITTED] T4389.012
[GRAPHIC] [TIFF OMITTED] T4389.013
[GRAPHIC] [TIFF OMITTED] T4389.014
[GRAPHIC] [TIFF OMITTED] T4389.015
[GRAPHIC] [TIFF OMITTED] T4389.016
[GRAPHIC] [TIFF OMITTED] T4389.017
[GRAPHIC] [TIFF OMITTED] T4389.018
[GRAPHIC] [TIFF OMITTED] T4389.019
[GRAPHIC] [TIFF OMITTED] T4389.020
[GRAPHIC] [TIFF OMITTED] T4389.021
[GRAPHIC] [TIFF OMITTED] T4389.022
[GRAPHIC] [TIFF OMITTED] T4389.023
[GRAPHIC] [TIFF OMITTED] T4389.024
[GRAPHIC] [TIFF OMITTED] T4389.025
[GRAPHIC] [TIFF OMITTED] T4389.026
[GRAPHIC] [TIFF OMITTED] T4389.027
[GRAPHIC] [TIFF OMITTED] T4389.028
[GRAPHIC] [TIFF OMITTED] T4389.029
[GRAPHIC] [TIFF OMITTED] T4389.030
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:]
[GRAPHIC] [TIFF OMITTED] T4389.031
[GRAPHIC] [TIFF OMITTED] T4389.032
[GRAPHIC] [TIFF OMITTED] T4389.033
[GRAPHIC] [TIFF OMITTED] T4389.034
[GRAPHIC] [TIFF OMITTED] T4389.035
[GRAPHIC] [TIFF OMITTED] T4389.036
[GRAPHIC] [TIFF OMITTED] T4389.037
[GRAPHIC] [TIFF OMITTED] T4389.038
[GRAPHIC] [TIFF OMITTED] T4389.039
[GRAPHIC] [TIFF OMITTED] T4389.040
[GRAPHIC] [TIFF OMITTED] T4389.041
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:]
[GRAPHIC] [TIFF OMITTED] T4389.042
[GRAPHIC] [TIFF OMITTED] T4389.043
[GRAPHIC] [TIFF OMITTED] T4389.044
[GRAPHIC] [TIFF OMITTED] T4389.045
[GRAPHIC] [TIFF OMITTED] T4389.046
[GRAPHIC] [TIFF OMITTED] T4389.047
[GRAPHIC] [TIFF OMITTED] T4389.048
[GRAPHIC] [TIFF OMITTED] T4389.049
[GRAPHIC] [TIFF OMITTED] T4389.050
[GRAPHIC] [TIFF OMITTED] T4389.051
[GRAPHIC] [TIFF OMITTED] T4389.052
[GRAPHIC] [TIFF OMITTED] T4389.053
[GRAPHIC] [TIFF OMITTED] T4389.054
[GRAPHIC] [TIFF OMITTED] T4389.055
[GRAPHIC] [TIFF OMITTED] T4389.056
[GRAPHIC] [TIFF OMITTED] T4389.057
[GRAPHIC] [TIFF OMITTED] T4389.058
[GRAPHIC] [TIFF OMITTED] T4389.059
[GRAPHIC] [TIFF OMITTED] T4389.060
[GRAPHIC] [TIFF OMITTED] T4389.061
[GRAPHIC] [TIFF OMITTED] T4389.062
[GRAPHIC] [TIFF OMITTED] T4389.063
[GRAPHIC] [TIFF OMITTED] T4389.064
[GRAPHIC] [TIFF OMITTED] T4389.065
[GRAPHIC] [TIFF OMITTED] T4389.066
[GRAPHIC] [TIFF OMITTED] T4389.067
[GRAPHIC] [TIFF OMITTED] T4389.068
[GRAPHIC] [TIFF OMITTED] T4389.069
[GRAPHIC] [TIFF OMITTED] T4389.070
[GRAPHIC] [TIFF OMITTED] T4389.071
[GRAPHIC] [TIFF OMITTED] T4389.072
[GRAPHIC] [TIFF OMITTED] T4389.073
[GRAPHIC] [TIFF OMITTED] T4389.074
[GRAPHIC] [TIFF OMITTED] T4389.075
[GRAPHIC] [TIFF OMITTED] T4389.076
[GRAPHIC] [TIFF OMITTED] T4389.077
[GRAPHIC] [TIFF OMITTED] T4389.078
[GRAPHIC] [TIFF OMITTED] T4389.079
[GRAPHIC] [TIFF OMITTED] T4389.080
[GRAPHIC] [TIFF OMITTED] T4389.081
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:]
[GRAPHIC] [TIFF OMITTED] T4389.082
[GRAPHIC] [TIFF OMITTED] T4389.083
[GRAPHIC] [TIFF OMITTED] T4389.084
[GRAPHIC] [TIFF OMITTED] T4389.085
[GRAPHIC] [TIFF OMITTED] T4389.086
[GRAPHIC] [TIFF OMITTED] T4389.087
[GRAPHIC] [TIFF OMITTED] T4389.088
[GRAPHIC] [TIFF OMITTED] T4389.089
[GRAPHIC] [TIFF OMITTED] T4389.090
[GRAPHIC] [TIFF OMITTED] T4389.091
[GRAPHIC] [TIFF OMITTED] T4389.092
[GRAPHIC] [TIFF OMITTED] T4389.093
[GRAPHIC] [TIFF OMITTED] T4389.094
[GRAPHIC] [TIFF OMITTED] T4389.095
[GRAPHIC] [TIFF OMITTED] T4389.096
[GRAPHIC] [TIFF OMITTED] T4389.097
[GRAPHIC] [TIFF OMITTED] T4389.098
[GRAPHIC] [TIFF OMITTED] T4389.099
[GRAPHIC] [TIFF OMITTED] T4389.100
[GRAPHIC] [TIFF OMITTED] T4389.101
[GRAPHIC] [TIFF OMITTED] T4389.102
[GRAPHIC] [TIFF OMITTED] T4389.103
[GRAPHIC] [TIFF OMITTED] T4389.104
[GRAPHIC] [TIFF OMITTED] T4389.105
[GRAPHIC] [TIFF OMITTED] T4389.106
[GRAPHIC] [TIFF OMITTED] T4389.107
[GRAPHIC] [TIFF OMITTED] T4389.108
[GRAPHIC] [TIFF OMITTED] T4389.109
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:]
[GRAPHIC] [TIFF OMITTED] T4389.110
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.
[The information referred to follows:]
[GRAPHIC] [TIFF OMITTED] T4389.111
[GRAPHIC] [TIFF OMITTED] T4389.112
[GRAPHIC] [TIFF OMITTED] T4389.113
[GRAPHIC] [TIFF OMITTED] T4389.114
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:]
[GRAPHIC] [TIFF OMITTED] T4389.115
[GRAPHIC] [TIFF OMITTED] T4389.116
[GRAPHIC] [TIFF OMITTED] T4389.117
[GRAPHIC] [TIFF OMITTED] T4389.118
[GRAPHIC] [TIFF OMITTED] T4389.119
[GRAPHIC] [TIFF OMITTED] T4389.120
[GRAPHIC] [TIFF OMITTED] T4389.121
[GRAPHIC] [TIFF OMITTED] T4389.122
[GRAPHIC] [TIFF OMITTED] T4389.123
[GRAPHIC] [TIFF OMITTED] T4389.124
[GRAPHIC] [TIFF OMITTED] T4389.125
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:]
[GRAPHIC] [TIFF OMITTED] T4389.126
[GRAPHIC] [TIFF OMITTED] T4389.127
[GRAPHIC] [TIFF OMITTED] T4389.128
[GRAPHIC] [TIFF OMITTED] T4389.129
[GRAPHIC] [TIFF OMITTED] T4389.130
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:]
[GRAPHIC] [TIFF OMITTED] T4389.131
[GRAPHIC] [TIFF OMITTED] T4389.132
[GRAPHIC] [TIFF OMITTED] T4389.133
[GRAPHIC] [TIFF OMITTED] T4389.134
[GRAPHIC] [TIFF OMITTED] T4389.135
[GRAPHIC] [TIFF OMITTED] T4389.136
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:]
[GRAPHIC] [TIFF OMITTED] T4389.137
[GRAPHIC] [TIFF OMITTED] T4389.138
[GRAPHIC] [TIFF OMITTED] T4389.139
[GRAPHIC] [TIFF OMITTED] T4389.140
[GRAPHIC] [TIFF OMITTED] T4389.141
[GRAPHIC] [TIFF OMITTED] T4389.142
[GRAPHIC] [TIFF OMITTED] T4389.143
[GRAPHIC] [TIFF OMITTED] T4389.144
[GRAPHIC] [TIFF OMITTED] T4389.145
[GRAPHIC] [TIFF OMITTED] T4389.146
[GRAPHIC] [TIFF OMITTED] T4389.147
[GRAPHIC] [TIFF OMITTED] T4389.148
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.
[The information referred to follows:]
[GRAPHIC] [TIFF OMITTED] T4389.149
[GRAPHIC] [TIFF OMITTED] T4389.150
[GRAPHIC] [TIFF OMITTED] T4389.151
[GRAPHIC] [TIFF OMITTED] T4389.152
[GRAPHIC] [TIFF OMITTED] T4389.153
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.]