[House Hearing, 106 Congress]
[From the U.S. Government Publishing Office]
HUMAN SUBJECT RESEARCH PROTECTIONS
=======================================================================
HEARING
before the
SUBCOMMITTEE ON CRIMINAL JUSTICE,
DRUG POLICY, AND HUMAN RESOURCES
of the
COMMITTEE ON
GOVERNMENT REFORM
HOUSE OF REPRESENTATIVES
ONE HUNDRED SIXTH CONGRESS
SECOND SESSION
__________
MAY 3, 2000
__________
Serial No. 106-198
__________
Printed for the use of the Committee on Government Reform
Available via the World Wide Web: http://www.gpo.gov/congress/house
http://www.house.gov/reform
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_______________________________________________________________________
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COMMITTEE ON GOVERNMENT REFORM
DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York HENRY A. WAXMAN, California
CONSTANCE A. MORELLA, Maryland TOM LANTOS, California
CHRISTOPHER SHAYS, Connecticut ROBERT E. WISE, Jr., West Virginia
ILEANA ROS-LEHTINEN, Florida MAJOR R. OWENS, New York
JOHN M. McHUGH, New York EDOLPHUS TOWNS, New York
STEPHEN HORN, California PAUL E. KANJORSKI, Pennsylvania
JOHN L. MICA, Florida PATSY T. MINK, Hawaii
THOMAS M. DAVIS, Virginia CAROLYN B. MALONEY, New York
DAVID M. McINTOSH, Indiana ELEANOR HOLMES NORTON, Washington,
MARK E. SOUDER, Indiana DC
JOE SCARBOROUGH, Florida CHAKA FATTAH, Pennsylvania
STEVEN C. LaTOURETTE, Ohio ELIJAH E. CUMMINGS, Maryland
MARSHALL ``MARK'' SANFORD, South DENNIS J. KUCINICH, Ohio
Carolina ROD R. BLAGOJEVICH, Illinois
BOB BARR, Georgia DANNY K. DAVIS, Illinois
DAN MILLER, Florida JOHN F. TIERNEY, Massachusetts
ASA HUTCHINSON, Arkansas JIM TURNER, Texas
LEE TERRY, Nebraska THOMAS H. ALLEN, Maine
JUDY BIGGERT, Illinois HAROLD E. FORD, Jr., Tennessee
GREG WALDEN, Oregon JANICE D. SCHAKOWSKY, Illinois
DOUG OSE, California ------
PAUL RYAN, Wisconsin BERNARD SANDERS, Vermont
HELEN CHENOWETH-HAGE, Idaho (Independent)
DAVID VITTER, Louisiana
Kevin Binger, Staff Director
Daniel R. Moll, Deputy Staff Director
David A. Kass, Deputy Counsel and Parliamentarian
Lisa Smith Arafune, Chief Clerk
Phil Schiliro, Minority Staff Director
------
Subcommittee on Criminal Justice, Drug Policy, and Human Resources
JOHN L. MICA, Florida, Chairman
BOB BARR, Georgia PATSY T. MINK, Hawaii
BENJAMIN A. GILMAN, New York EDOLPHUS TOWNS, New York
CHRISTOPHER SHAYS, Connecticut ELIJAH E. CUMMINGS, Maryland
ILEANA ROS-LEHTINEN, Florida DENNIS J. KUCINICH, Ohio
MARK E. SOUDER, Indiana ROD R. BLAGOJEVICH, Illinois
STEVEN C. LaTOURETTE, Ohio JOHN F. TIERNEY, Massachusetts
ASA HUTCHINSON, Arkansas JIM TURNER, Texas
DOUG OSE, California JANICE D. SCHAKOWSKY, Illinois
DAVID VITTER, Louisiana
Ex Officio
DAN BURTON, Indiana HENRY A. WAXMAN, California
Sharon Pinkerton, Staff Director and Chief Counsel
Lisa Wandler, Professional Staff Member
Ryan McKee, Clerk
Cherri Branson, Minority Counsel
C O N T E N T S
----------
Page
Hearing held on May 3, 2000...................................... 1
Statement of:
Curtin, Richard, human subject, Falls Church, VA; Charles R.
McCarthy, senior research fellow, Kennedy Institute of
Ethics, Georgetown University; and Robert Amdur, M.D.,
associate professor, associate chair, clinical affairs,
Department of Radiology and Oncology, University of Florida 60
Grob, George, Deputy Inspector General for Evaluation and
Inspections, Office of Inspector General, Department of
Health and Human Services; Mark Yessian, Ph.D., regional
Inspector General for Evaluation and Inspections,
Department of Health and Human Services; William Raub,
Ph.D., Deputy Assistant Secretary, Science Policy, Office
of the Secretary, Health and Human Services; Gary Ellis,
Ph.D., Acting Director, Office of Protection from Research
Risks; and Daniel Michels, Director of Enforcement, Office
of Regulatory Affairs, Food and Drug Administration........ 10
Letters, statements, etc., submitted for the record by:
Amdur, Robert, M.D., associate professor, associate chair,
clinical affairs, Department of Radiology and Oncology,
University of Florida, prepared statement of............... 122
Curtin, Richard, human subject, Falls Church, VA, prepared
statement of............................................... 63
Grob, George, Deputy Inspector General for Evaluation and
Inspections, Office of Inspector General, Department of
Health and Human Services, prepared statement of........... 12
McCarthy, Charles R., senior research fellow, Kennedy
Institute of Ethics, Georgetown University, prepared
statement of............................................... 70
Mica, Hon. John L., a Representative in Congress from the
State of Florida, prepared statement of.................... 5
Raub, William, Ph.D., Deputy Assistant Secretary, Science
Policy, Office of the Secretary, Health and Human Services,
prepared statement of...................................... 34
Waxman, Hon. Henry A., a Representative in Congress from the
State of California, prepared statement of................. 49
HUMAN SUBJECT RESEARCH PROTECTIONS
----------
WEDNESDAY, MAY 3, 2000
House of Representatives,
Subcommittee on Criminal Justice, Drug Policy, and
Human Resources,
Committee on Government Reform,
Washington, DC.
The subcommittee met, pursuant to notice, at 2:36 p.m., in
room 2247, Rayburn House Office Building, Hon. John L. Mica
(chairman of the subcommittee) presiding.
Present: Representatives Mica, Cummings, and Kucinich.
Staff present: Sharon Pinkerton, staff director; Steve
Dillingham, special counsel; Don Deering, congressional fellow;
Lisa Wandler, professional staff member; Ryan McKee, clerk;
Alex McKinnon, intern; Cherri Branson, minority counsel; and
Earley Green, minority staff assistant.
Mr. Mica. Good afternoon. I'd like to call this hearing of
the Subcommittee on Criminal Justice, Drug Policy, and Human
Resources to order. I apologize for the delay. There is a full
committee hearing going on at this time, but with the consent
of the minority, we are going to proceed.
We have two panels today, and we do want to finish this
hearing this afternoon. It is an important hearing, entitled
``Human Subject Research Protections,'' one of which I'm
pleased to work with my colleague Mr. Kucinich, the gentleman
from Ohio, and this is the second hearing we've conducted on
this matter.
I am going to start with the regular order of business. We
may at some time have to recess for a vote, either in committee
or on the floor, but we'll proceed with opening statements,
recognizing myself first and then the gentleman from Ohio.
This hearing before the Subcommittee on Criminal Justice,
Drug Policy, and Human Resources will examine a critical
problem for which reforms have been recommended by the Office
of Inspector General [OIG], to the Department of Health and
Human Services [HHS]. Last December, we conducted a hearing on
this topic in New York City where past issues had surfaced
regarding the protections of persons participating in human
research projects. The December hearing also coincided with
revelations regarding the tragic death of 18-year-old Jesse
Gelsinger of Tucson, AZ. Jesse died just 4 days after being
injected with a cold virus and engineered genes. Researchers
were shocked and a national debate ensued on gene therapy
experiments and the reporting of adverse effects. The National
Institutes of Health [NIH], issued a solicitation to the
medical community requesting help.
Even in today's Washington Post, I read that there were
reports of more deaths which were not reported to authorities
and which also put more lives at risk. The question I pose
today is whether HHS heeded this cry for help and has that
agency acted promptly to prevent future tragedies.
Our December hearing included testimony from both OIG and
also from HHS. At that time, it was apparent that HHS had not
implemented the Office of Inspector General recommended reforms
for protecting human research subjects.
Today, we'll revisit this important issue. We will hear in
fact that more deaths of participants in human research have
been reported, and that, in fact, more violations of required
human subject protections have been revealed. The Office of
Protections Against Research Risk [OPRR], is one component of
the HHS agency with special responsibilities for protecting
human research subjects. The Food and Drug Administration
[FDA], is another. Apparently neither has received the support
and commitment from the administration and the Health and Human
Services Secretary that is needed; indeed, that is required to
enhance the protections for research subjects.
Furthermore, the Department continues to putter around with
this important issue, virtually ignoring most of the sound OIG
recommendations and dragging their feet.
Why is HHS so reluctant to act proactively in reforming its
programs and increasing the protections for those participating
in research? That's a question we have to ask today. What
justification is there for continued delays? From the evidence
supplied to date, the answer is not likely to prove comforting,
especially as human research projects multiply and new research
frontiers emerge. Protecting the lives of those involved in
research should be foremost in HHS thinking, research practices
and also in its regulatory priorities.
Last December, this subcommittee asked the question, what
actions are being taken to reduce unnecessary health and safety
risks to human subjects? We should receive an answer today
better than that given to us last year, which was an admission
that practically nothing had been done. According to the most
recent OIG report, however, it appears that not much has
changed from our last hearing. I think there's a bipartisan
agreement that this inaction is unacceptable.
The June 1998 recommendations of OIG appear both in my
opinion reasonable. They're also urgently needed and generally
propose strengthening the Institutional Review Boards [IRBs],
that approve and oversee human research projects. The OIG made
the following recommendations and observations relating to
IRBs. First, they said they face major changes in the research
environment. They also said they review too much too quickly.
Furthermore, they said they conduct minimal continuing review
of approved research. They face conflicts that threaten their
independence. They provide little training for investigators
and board members and neither the IRBs nor HHS devote much
attention to evaluating IRB effectiveness, and again, these are
some of the points that were raised about the IRBs.
The Office of Inspector General recommended reforms in some
of the following areas: First, Federal requirements such as
performance evaluations; second, strengthen protections,
including enhanced IRB monitoring; third, educational
requirements, including educating IRB members; fourth,
preventing conflicts of interest and also the question of
broadening representation on IRBs; fifth, reducing IRB
workloads, and sixth, improving Federal oversight, including
IRB registration.
To date, the responses by HHS have indeed been most
disappointing. The latest OIG report findings include, and let
me cite them, first of all, minimal progress has been made in
recasting Federal IRB requirements so that they grant IRBs
greater flexibility and hold them more accountable.
Another of these findings stated, minimal progress has been
made in strengthening continuing protections for human subjects
participating in research.
Another finding, no educational requirements have been
enacted for investigators or IRB members.
Another recent finding here is that there has been no
progress in insulating IRBs from conflicts that can compromise
their mission in protecting human subjects, and we heard
testimony about some problems in this area in our last hearing.
Another more recent finding and update tells us that
minimal progress has been made in moderating workload pressures
of the IRBs.
And finally, minimal progress has been made in
reengineering the Federal oversight process.
All of these really are disappointing to the subcommittee
and me, particularly after our last hearing. We thought we
would see some additional actions in some of these areas.
As indicated in our previous hearing, HHS annually invests
approximately $5 billion of its research dollars in
approximately 16,000 research projects that involve human
beings. To provide oversight for these research projects, OPRR
has agreements with more than 4,000 federally funded
institutions, each with an IRB. Under OPRR guidelines, research
subjects must be fully briefed on the purpose, the duration and
the procedures of the research project before agreeing to
participate. OPRR has the authority to investigate and require
corrective action and suspend funding to an institution.
Last month, it was reported in the Los Angeles Times that
specialists overseeing a clinical trial of the diabetes drug
Rezulin did not follow the required procedures for monitoring a
volunteer who died after taking the medication. Less than 10
days ago press reports announced the death of a 42-year-old
Massachusetts woman participating in a drug study sponsored by
the Nation's top medical research agency. She died after
receiving the wrong kind of blood.
As we'll hear today, the OPRR has acted to suspend research
at a growing number of universities where research requirements
have been violated. What is required to convince HHS to take
additional needed actions to prevent more harms and also to
save more lives? While I'm glad to hear that some improvements
are underway, I don't think that the agency can truthfully
testify here today that in fact enough has been done or is
being done. If it does, we should consider placing this
responsibility elsewhere.
I take no joy in holding another hearing on this topic
within 5 months of the previous hearing, but if inaction
continues in the face of mounting dangers and death, we may
need further oversight hearings and further investigation into
this. We also may have to work with the Appropriations
Committee and some of the other committees to put some caveats
on spending this significant number of dollars, some $5
billion, in research that involves human subjects, and we'll
look at those options.
I thank the witnesses who have come before us today to
testify. We appreciate your willingness to appear before this
subcommittee and to share your knowledge and experience as we
strive to address this urgent public health priority. Time is
of the essence in this matter, and further delay must be
avoided.
I'm pleased again to have the cooperation on this issue and
active participation and leadership of the gentleman from Ohio.
Let me recognize Mr. Kucinich at this time for his opening
statement.
[The prepared statement of Hon. John L. Mica follows:]
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Mr. Kucinich. Thank you very much, Chairman Mica, and I
want to especially commend you for calling this hearing and for
your continuing efforts to demonstrate your dedication to the
protection, the health and the welfare of the American public
in clinical research trials. I think this Congress is fortunate
to have your leadership in this area.
I'd like to thank the witnesses for testifying regarding
the Inspector General's report on the protection of human
research subjects. I'll begin by saying that I am disappointed
in the lackluster response to the recommendations as the
Inspector General's report finds, but I am not surprised. The
state of Federal and local human research subject protections
has been lacking for quite some time. The subject has only been
highlighted in the past couple of years due to high profile
cases with respect to gene therapy that have prompted Federal
inquiries on the oversight of human research protections.
However, I believe that human research protections extends far
beyond the narrow scope of gene therapy. All aspects of human
biomedical research must be monitored and everyone must be
protected from risks involved in medical experimentation.
The Inspector General's report in 1998 I believe outlined
specific changes that could be made to improve the current
protections in place. However, the current IG report indicates
that the Department of Health and Human Services has done
little to implement these recommendations, enacting only two.
With respect to recommendations on oversight and protections by
Institutional Review Boards, the report states that, ``minimal
progress has been made in strengthening continuing protections
for human subjects participating in research.'' Regarding
Federal oversight it states that, ``minimal progress has been
made in reengineering the Federal oversight process. Federal
oversight of IRBs is not equipped to respond effectively to the
changing pressures and needs of the current system of
protections.'' Well, this is unacceptable.
The Federal Government provides funds for a vast complex of
experiments that involve human subjects. More than $16 billion
per year in Federal funds are used for such research. Some
20,000 experiments at more than 4,000 universities, hospitals
and other institutions are involved. Duke University alone has
$175 million per year in Federal research grants. The lives of
tens of thousands of people are at stake along with the
reputation and integrity of very important research
institutions.
The Federal Government's system to monitor these
institutions and ensuring the safety of human research subjects
continues to be outdated, ineffective, underfunded and
understaffed. The only bright spot in this dismal area of
Federal activity is the positive efforts being made by the
Office of Protection from Research Risk under the direction of
Dr. Gary Ellis. In spite of the lack of funds, lack of staff
and enormous institutional pressures, Dr. Ellis continues to
make progress in the monitoring and investigating of research
institutions which conduct human experimentation. His work on
behalf of the American public should be commended and
recognized.
I know that I as well as the subcommittees will want to be
apprised of the office's ongoing investigations. I look forward
to hearing from you in the future. I am glad we have
representatives here from HHS who will be able to address the
Inspector General's report. I look forward to hearing your
testimony.
Thank you very much, Mr. Chairman.
Mr. Mica. I thank the gentleman and there being no further
opening statements at this time we're going to proceed with our
first panel as the order of business. The first panel today
consists of George Grob, and he is the Deputy Inspector General
for Evaluation and Inspections at the Office of Inspector
General, Department of Health and Human Services.
The second witness is Dr. William Raub, and he is the
Deputy Assistant Secretary for Science Policy of the Office of
the Secretary of Health and Human Services.
We have also accompanying these two witnesses Dr. Mark
Yessian, who's the Regional Inspector General for Evaluation
and Inspections in the Department of Health and Human Services.
we have Dr. Gary Ellis, Acting Director of the Office of
Protection from Research Risks.
We have Daniel Michels, and he is the Director of
Enforcement of the Office of Regulatory affairs at the Food and
Drug Administration.
This is an investigation and oversight subcommittee of
Congress. We will swear you in in just a minute. All of our
witnesses appear under oath. Furthermore, if you have any
lengthy statements or documentation you'd like to have made
part of the record, upon request through the Chair and with the
concurrence of the minority that will be granted. Those are
basically the rules and the way we'll proceed today.
At this time let me confer. Without objection Mr. Kucinich
has moved that the record be left open for additional comments
or submissions for 2 weeks. So ordered.
Mr. Kucinich. Thank you, Mr. Chairman.
Mr. Mica. And we now will proceed and I'll ask our
witnesses if they'd stand and be sworn.
[Witnesses sworn.]
Mr. Mica. The witnesses answered in the affirmative. We'll
now hear first from the Deputy Inspector General for
Evaluations and Inspection, George Grob. He has submitted
rather lengthy findings for the subcommittee and Mr. Kucinich
moves without objection that they be made part of the record.
So ordered. So we will have your complete testimony in here.
We'd like each of our witnesses today to try to limit their
presentations, oral presentations, to 5 minutes if possible. I
know we have two that are making presentations I think with
this panel, and we will submit any additional data or testimony
upon request.
With that, let me recognize George Grob, Deputy Inspector
General for Evaluation and Inspections. You're recognized, sir.
STATEMENTS OF GEORGE GROB, DEPUTY INSPECTOR GENERAL FOR
EVALUATION AND INSPECTIONS, OFFICE OF INSPECTOR GENERAL,
DEPARTMENT OF HEALTH AND HUMAN SERVICES; MARK YESSIAN, PH.D.,
REGIONAL INSPECTOR GENERAL FOR EVALUATION AND INSPECTIONS,
DEPARTMENT OF HEALTH AND HUMAN SERVICES; WILLIAM RAUB, PH.D.,
DEPUTY ASSISTANT SECRETARY, SCIENCE POLICY, OFFICE OF THE
SECRETARY, HEALTH AND HUMAN SERVICES; GARY ELLIS, PH.D., ACTING
DIRECTOR, OFFICE OF PROTECTION FROM RESEARCH RISKS; AND DANIEL
MICHELS, DIRECTOR OF ENFORCEMENT, OFFICE OF REGULATORY AFFAIRS,
FOOD AND DRUG ADMINISTRATION
Mr. Grob. Thank you, Mr. Chairman and Mr. Kucinich.
The system which was designed to protect the human subjects
of research has inherent vulnerabilities, most of which remain
even after the best efforts of our Department to address them.
To understand why this is the case we must go back to its
origins.
The protections were gradually developed after the Second
World War in response to research atrocities that came to light
during the Second World War and other troublesome research
experiments that arose shortly thereafter. In 1966 the Surgeon
General issued a human subject policy for the Department of
Health, Education and Welfare, and in 1974 the National
Research Act required reviews by Institutional Review Boards
for all research sponsored by the Department of Health,
Education and Welfare. In 1991 those procedures were adopted by
15 other Federal Departments in what has come to be known as
the Common Rule.
These and other developmental events during that period
were among the prouder days of American science with respect to
protection of human subjects. However, during this same period
research exploded in size and complexity and numbers, in
amounts of money spent. The Institutional Review Boards were
overwhelmed and left behind. Vulnerabilities subtly emerged, at
first unnoticed. Lately we've begun to notice them.
In 1998, at the request of the Food and Drug
Administration, we conducted a study of the unauthorized
marketing of investigational medical devices, and during the
course of this report we stumbled upon some problems with the
Institutional Review Boards and other systems designed to
protect the human subjects of this research. For example, in
one experiment the researcher was authorized to implant 75
investigational devices for surgery, and reported to the
Investigational Review Board that 37 had been implanted. We
found that 264 had in fact been implanted.
We found other discrepancies in the surgery reports of
other investigators: 15 devices were implanted during the 6-
week period in which the research had been suspended by the
Institutional Review Board; we found changes not made to the
research protocols requested by the board and reported as
having been made; we found informed consent forms missing, in
some cases consent forms obtained after the surgery was
performed and other similar results.
As a result of stumbling upon these kind of findings, we
decided that a more systematic look was required at the
Institutional Review Boards and others systems designed to
protect human subject research, and based on that work we
published in June 1998 a more comprehensive review that
provided an early warning of troubles and vulnerabilities in
the system. To get a better sense of the problems that the
institutions were facing at the time let me just rattle off
some of the circumstances that made it more difficult for them
to do their jobs.
When they began this work in the sixties and seventies most
research consisted of research at a single site. Today it's
mostly multi-sites across the country, sometimes even the
world. It used to involve a single investigator. Now it
involves hundreds of investigators. It used to be a small
cohort of subjects. Now it's thousands. Most funding came from
government offices. Now a lot of it comes from commercial
sponsors. A lot of it used to be done at teaching hospitals.
Now it's done at clinics, doctors offices and in other
settings.
There's been a rise of patient consumerism and demands for
access to investigational procedures, drugs and devices, and
new types of research have emerged.
In 1978 there were about 500 institutions with
Institutional Review Boards. Now there is somewhere between
3,000 and 5,000 of them. They used to review an average of 43
proposals a year. Now it's up to about 300. Adverse event
reports are flooding their offices, in some cases being stored
in boxes on the floor without being reviewed. In one case we
found a couple of hundred of these reports coming in per month
at one of the Institutional Review Boards.
With such a change in circumstances, the Institutional
Review Boards were not able to keep up. They had insufficient
resources. They have been unable to stay on top of the research
that's being performed so that while they might give a review
of the proposals before the research starts, they can seldom
look beyond that. We found insufficient training, little
evaluation and oversight, and we made corresponding
recommendations which have already been cited in the opening
statements.
Recently the Department has attempted to deal with these
problems and has taken a number of steps which Mr. Raub will
summarize for you. I particularly want to point out the stepped
up enforcement that NIH has been doing. Recently 10 onsite
visits were made and seven institutions had their research
suspended. I think the sentinel effect of these efforts has
been very strong and has sent a wave through the research
community indicating that improper practices will not be
tolerated.
But fundamental vulnerabilities remain and we're reminded
too often of the consequences of this. I know that Departmental
officials are engaged in attempting to address these
vulnerabilities and our own work is continuing, but I would
like to add to my statement here a note that the solutions
don't depend entirely on the Department. The companies which
sponsor research, the investigators, the universities and
medical centers, their Institutional Review Boards--they're all
involved and they're responsible too. Their talent, energy,
creativity and dedication is what fueled the boom in research
that overwhelmed the human subject protection system. These
same forces now need to be directed to bring it back into
balance.
[The prepared statement of Mr. Grob follows:]
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Mr. Mica. Thank you. Does that conclude your opening
statement?
Mr. Grob. Yes, thank you.
Mr. Mica. Let me now recognize, if I may, Dr. William Raub,
who's the Deputy Assistant Secretary for Science Policy, the
Office of the Secretary of Health and Human Services. You're
recognized, sir. Welcome.
Dr. Raub. Good afternoon, Mr. Chairman and members of the
subcommittee. I am William Raub, Deputy Assistant Secretary for
Science Policy at the Department of Health and Human Services.
I am accompanied today by Gary Ellis, Director of the NIH
Office for the Protection of Research Risks, and Daniel
Michels, Director of Enforcement at the Food and Drug
Administration. Thank you for this opportunity to testify
regarding the protection of human research subjects.
For more than 50 years HHS and its predecessors have led
the Nation and the world in protecting human research subjects
from unnecessary risks. Our approach is rooted in the Nuremberg
Code, whose principles have been adopted, reinforced and built
upon in a succession of policies culminating in the current
Federal regulations governing research with human subjects. HHS
led the way in developing the core of these regulations, the
so-called Common Rule, which has been promulgated by 17
different departments and independent agencies. In addition,
FDA has carefully tailored its regulations for the product
oriented clinical research it oversees so that they harmonize
with the Common Rule.
The primary foci for implementing these regulations are the
Institutional Review Boards [IRBs]. They are responsible for
reviewing proposed research protocols and associated informed
consent statements before subjects are recruited and clinical
research begins. No covered project may commence without IRB
approval. Further, IRBs are responsible for continuing review,
that is, oversight of approved research projects throughout
their life cycle. If in the course of continuing review the
responsible IRB were to find cause for concern regarding the
safety of research subjects, the IRB could halt the project
temporarily or permanently or otherwise require the
investigators to take whatever protective or corrective actions
it deems appropriate.
Two types of IRBs exist: IRBs operated by research
institutions such as academic health centers and IRBs that
operate as private entities. Two HHS components share
responsibilities for overseeing IRBs, the OPRR and the FDA.
OPRR oversees IRBs operated by HHS awardee institutions. FDA
oversees IRBs that review clinical research related to the
products it regulates, irrespective of whether that research is
ongoing at HHS awardee institutions or other sites.
HHS is very concerned that the effectiveness of IRBs is in
jeopardy. Although the Inspector General's investigation did
not reveal either significant instances of actual harm to
research subjects or evidence of any widespread pattern of
outright IRB failure, we must not let that be cause for
complacency. Many IRBs face unacceptably large workloads with
too little time and too few resources to do their job properly.
The fact that instances of actual harm to research subjects
have been few and far between is a credit to the extraordinary
dedication and prudent decisionmaking of IRB members and the
commitment of investigators to the integrity of their work.
In the wake of the June 1998 reports by the Inspector
General, OPRR and FDA stepped up the pace of their inspections.
Taken together, their findings reinforce the conclusion that
the IRB system is under considerable strain. Moreover, for
several institutions the OPRR and FDA inspections led to
partial or complete suspension of clinical research at those
sites until the institution's deficiencies were corrected,
often only after major revamping of the IRB structure and
commitment of substantial additional resources by the research
institutions. These examples make clear that we must intensify
our work to strengthen human subjects' protection before more--
and more serious--failures ensue.
An imminent organizational change within HHS will do much
to facilitate our intensified efforts. Last year acting on the
results of the study commissioned by the Director of the
National Institutes of Health, Secretary Shalala determined
that the human subjects component of the OPRR should be
elevated to the Office of Public Health and Science within the
Office of the Secretary. Further, the Secretary directed the
Assistant Secretary for Health to carry out a national search
to fill the position and to assess the resource requirements
for the new office--to be called the Office of Human Research
Protection. Further, she authorized the creation of a public
advisory committee to help guide the new office specifically
and the Department overall.
We agree with the Inspector General that the creation of
the Office of Human Research Protection and its associated
advisory committee presents, ``a new opportunity to exert
Federal leadership in protecting human research subjects.'' At
the same time we urge research institutions to strengthen their
local efforts to protect human research subjects in accord with
the Inspector General's recommendations.
In particular, we urge research institutions to give their
IRBs the standing and resources they need to do their job,
especially during the continuing review phase. Human subjects
protection is a shared responsibility among the Federal
Government, research institutions, IRBs, investigators, and
sponsors. HHS is committed to doing its part, and we will
continue to expect others to do theirs.
My full statement describes a series of actions by HHS
agencies in recent years to enhance protection of human
research subjects. We view these steps as a strong beginning
but concur with the Inspector General that much more remains to
be done. With your permission, Mr. Chairman, I will submit my
full statement for the record.
Mr. Mica. Without objection so ordered.
Dr. Raub. On behalf of Secretary Shalala and my senior HHS
colleagues, I assure the subcommittee that HHS is firmly
committed to protecting human research subjects and to working
actively with the research community to achieve that end. We
believe that the Inspector General has provided a timely wake
up call for everyone involved.
Thank you, Mr. Chairman.
[The prepared statement of Mr. Raub follows:]
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Mr. Mica. Thank you for your testimony. I'm pleased now to
recognize the gentleman from Maryland, Mr. Cummings, for his
opening statement.
Mr. Cummings. Thank you, Mr. Chairman. Conducting safe
clinical trials of breakthrough medicines and treatments are
critical if we are to win the war against disease and physical
ailment. I can think of nothing more noble than putting your
life on the line for the good of humanity. Our soldiers do it
on the battlefield, and human research subjects do it in the
hospitals. While both groups put their lives in danger, we must
do everything we can to minimize the risks.
Today, we are here to discuss what can be done to ensure
the highest level of safety possible for those who consent to
enroll in clinical trials. The death last September of Jesse
Gelsinger and subsequent revelations of three other deaths in a
gene therapy experiment last year sponsored by Harvard Medical
School has raised serious questions about current oversight
procedures. Jesse's father Paul told a Senate panel earlier
this year that researchers did not disclose that laboratory
monkeys died following a procedure similar to the one done on
his son or that several earlier human subjects sustained
serious liver damage.
After the boy's death, the National Institutes of Health
sent letters to researchers reminding them that they must
report serious, adverse events to the NIH and the Food and Drug
Administration. NIH subsequently received a flood of filings,
disclosing nearly 700 previously unreported incidents of
problems arising from gene therapy experiments. I think this is
simply unacceptable. Seven hundred unreported incidents puts
too many lives at risk. We must do better and we will.
Something is failing if 700 incidents were unreported. If a
real estate company withheld that many problems with their
properties they would be out of business.
Today, we will hear from those who carry out the mission of
oversight at the Department of Health and Human Services and
the Food and Drug Administration. I'm eager to hear how they
plan to address these oversight problems, and Mr. Chairman,
again, I thank you for holding this hearing.
Mr. Mica. Thank you, Mr. Cummings, and Mr. Cummings also
moves that the statement by Mr. Waxman, the ranking member of
the full committee, be submitted for the record. Without
objection, so ordered.
[The prepared statement of Hon. Henry A. Waxman follows:]
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Mr. Mica. And I believe we just had those two witnesses who
had statements at this time, is that correct, and the others
are available for answering questions.
We'll start with some questions that I have and I'm going
to address these first to Mr. Grob, Deputy Inspector General
for Evaluation and Inspection. I guess sort of a basic question
to start out with is, what do you consider to be the reasons
for HHS' failure to implement that 1998 recommendation?
Mr. Grob. I think Mr. Raub could probably address it better
than I can, but I'm willing to speculate.
Mr. Mica. You did a review here. Maybe you could tell the
subcommittee what the basic problems are, one, two, three.
Mr. Grob. I think the basic problems are that the
Institutional Review Boards are simply overwhelmed, and they're
not able to carry out their responsibilities, particularly the
oversight of research that is ongoing. I think once the
research starts they don't have the ability to stay on top of
it, and I think that the problems occur at that level.
Mr. Mica. We heard a description of this human research,
and some of these activities started off in a fairly isolated
context and numbers of universities or whoever was doing it.
It's exploded. It sounds like it's difficult for the Department
to get its hands around it, and then we have several agencies
involved here. But we have the element of responsibility to the
public. It may be jumping the gun a little bit, but maybe we
should look at restructuring this whole thing or some other
procedure to again keep up with the sheer volume that you
described. Do you have an opinion about that?
Mr. Grob. I think it's time to think in those terms. I
don't know that marginal changes around the edges will really
be able to do it. I think the fundamental structure was a good
idea and it worked when it started and it worked for a while,
but I just think the research took off. It became far more
complicated, and in a way it's almost as if the IRBs
figuratively were still using manual typewriters trying to keep
up with the power notebooks of the researchers. It's just
something--it's a different world today, and I don't think that
system has kept pace with the world. So I think it's a fair
thing to say that we might need to look at different
structures.
Mr. Mica. Complete reorganization of the approach. Now what
about HHS, is this a priority on their scale? The other thing,
too, is that Congress has also raised questions about what's
going on in the oversight as we view government agency
responsibility. It appears that there's been minor action and a
lot of inaction. I believe, too, we had testimony that many
things could be done without a lot of cost, some improvements
without a great deal of costs. Maybe you could tell me first,
does this appear to be a priority? Has it gotten their
attention? And then, why haven't they instituted some things
that were basic that could be done without a great deal of
cost?
Mr. Grob. It's my feeling right now that certainly there is
an intense effort being made in the Department to address these
things, the problems that have been raised. I think the
publicity of the troubling cases and just the general desire to
do it right, the congressional hearings, the interest of the
scientists in the Department are all there. It's coming to a
head. I think the interest is there now and I do expect to see
some substantial changes coming down the pike.
As far as things that could be done fairly quickly, I think
training and education could be done pretty well and fairly
quickly. The National Institutes for Health, for example, on
their own have developed training which they require their
researchers to follow. They have put it up on the Web. They
have got some training courses that they have made available.
What's lacking is a requirement for the training and
requirement for any particular standards of training, but the
resources seem to be there. If they require all of their
researchers, as they do, for example, to take the course that's
on the Web, it seems to me that all of the grantees could take
that course on the Web as well and could avail themselves of
the resources. So I think that education and training of the
researchers and the board members could be done pretty fast if
there were a requirement to do it.
Mr. Mica. Well in 1998 you came out with a list of specific
recommendations for improvement. Has HHS developed a schedule
or timeframe or worked to give you any implementation schedule?
Mr. Grob. I haven't seen a time schedule like that, that
went recommendation by recommendation with a time schedule.
Mr. Mica. Let me just ask a quick question now. Of course,
every agency comes to Members of Congress now and says just
give us more resources and we can handle the job. But we had
recommendations that had been made that folks testified to that
could be implemented with fairly low cost and things that could
be done to improve oversight, operation and function. I have
two questions then for Dr. Raub. One, what's the status of
those low cost things that could be done within budget? And
then second, I guess you have already submitted your 2001
budget. What kinds of requests for additional resources or
personnel were included in the Secretary's request?
Dr. Raub. Thank you, Mr. Chairman. With respect to the
overall question, we've taken the recommendations of the
Inspector General to heart and have in fact undertaken some
substantial efforts over the last several years and will
continue to do so. As I indicated in my prepared statement, we
think they're, while substantial, that nowhere near enough; and
we will continue to intensify that effort.
Among the things we have done within the available
resources are the following. I indicated the stepped up
investigations and inspections, both by the OPRR and the FDA.
Mr. Mica. Is that what was referred to from 1 to 10?
Mr. Grob. It's a lot more than that. My opening statement
was of course in the 5-minutes, but there have been increases
in the number of non-onsite reviews that the NIH has made, and
the FDA has made about a 50 percent increase in the number of
site visits that it makes.
Mr. Mica. Is that adequate?
Mr. Grob. No. We need more.
Mr. Mica. So those are some things you started. I'm sorry,
Dr. Raub, continue.
Dr. Raub. And along that line, just continuing Mr. Grob's
thought there, while the returns on those investigations have
been disappointing in the sense of identifying some widespread
pattern of problems and have led to enforcement actions, those
enforcement actions have a secondary effect in the sense of
promoting compliance elsewhere--indicated by the Inspector
General as a sentinel effect. So we believe that the
expenditure of those funds dealing with individual problems has
in fact had a positive effect in terms of making the larger
community sensitive to the need for more attention and more
investment of resources in these activities.
Mr. Mica. Now, enforcement. When we had the hearing last
time, there was one instance of a suspension reported, one or
two. Since that time, what's the status? Usually enforcement
would indicate that there's some penalty or there's some
suspension of funds taking place. What's taken place in that
regard?
Dr. Raub. I'll comment generally, and, if I might, ask Dr.
Ellis and Mr. Michels if they want to add some details to it;
but in essence the thrust of the suspensions is not only to
stop the activity and put an immediate protection in place but,
more important, to require certain remedial actions on the part
of the institutions to ensure that the problems are solved and
the protections are in place. And that's been a pattern on
these various ones.
Mr. Mica. My question dealt with has there been any
suspension of funds since the last hearing or penalty actions?
Remedial actions are fine, but I want to know, if somebody gets
some penalty, then does it have an effect down the line on
others to sort of straighten up their act?
Dr. Raub. Let me ask my colleagues to address that.
Mr. Mica. Identify yourself for the record, please.
Mr. Ellis. My name is Gary Ellis, Director of the Office of
Protection from Research Risks, and chairman of the Interagency
Human Subjects Committee. For research that is funded by the
Department of Health and Human Services the ultimate penalty is
a cessation of funding.
Mr. Mica. Has there been any since the last time? Now what
we've discovered there are more problems than we anticipate and
the Inspector General talked about finding a pattern of
problems far in excess of what I think we even expected. Then
we heard that we were taking some enforcement actions that were
part of the corrective pattern. My question is, what type of
enforcement actions?
Mr. Ellis. Well, since the June 1998 hearing and the
Inspector General's report, OPRR has evaluated the protection
of human subjects at a couple dozen institutions. There have
probably been about 10 site visits during that period, and in
virtually every case we've made findings of shortcomings with
regard to human subject regulations and required remedial
action. In a few noteworthy cases at the Duke University
Medical Center in May 1999 and just a small number of other
institutions, we have actually ordered an interruption in
research. Virginia Commonwealth University in January 2000 as
with Duke, we ordered an interruption in research. These are
extreme cases and an extreme action was taken, the interruption
of research.
Mr. Mica. In two cases?
Mr. Ellis. There were other cases where we imposed
restrictions but we didn't have the suspension that you note.
The Food and Drug Administration took an action----
Mr. Mica. Was it the suspension of the program or
suspension of funding or both?
Mr. Ellis. Suspension of the program. The Food and Drug
Administration took action at the University of Colorado Health
Sciences Center, and Dan might want to talk about that.
Mr. Mica. Identify yourself for the record.
Mr. Michels. Yes, sir. I am Daniel Michels, Director of the
Office of Enforcement at FDA.
I think you've put your finger on an important issue from
the standpoint that the action available to both our
organizations is an extreme one; that is, the authority to shut
down an operation in its entirety. The threat of that most
frequently causes either a voluntary shutdown before we need to
deal with that or else a great deal of willingness to do the
right thing and get back on the right track. One of the things
that we are exploring is the possibility of asking the Congress
for intermediate remedies that might be less than throwing the
atom bomb, if you will, to deal with these situations.
Mr. Mica. You don't feel that you have the authority to do
that?
Mr. Michels. That is correct in this particular instance,
and I want to reinforce and I think Representative Kucinich
made the point very eloquently, is too often the IRBs are
underfunded. The willingness to do the right thing is there,
but they do not have the resources and support to do it, and
our taking enforcement action will result hopefully in that
kind of funding somewhere downstream, but we would much rather
see education happen first, do the right job the first time in
a well-funded situation.
Mr. Mica. Mr. Cummings, I have additional questions. Did
you want me to yield to you at this time and come back, do a
second round? Is that OK? Or do you want me to proceed?
Mr. Cummings. No. I just have a few.
Mr. Mica. All right. I'll recognize Mr. Cummings, and I do
have an additional round of questions.
Mr. Cummings. I was just wondering, what kind of--following
up on what the chairman asked about--what kind of sanctions
would you like to see, I mean, would you like to have the
authority to use?
Mr. Michels. Unfortunately, the thinking is a little bit
early on this. One of the things that we've thought about is
civil money penalties, but again, fining an organization which
is poor already doesn't seem to be a very good option. If we
could find something more prescriptive, that is more targeted
to the particular problems that an institution has rather than
simply shutting down the whole engine, we would be possibly
better off than we are now, but that's the best I can do for
you at the moment, Congressman.
Mr. Cummings. Why would an organization when threatened
with a shutdown voluntarily shut down as oppose to say
straightening up the matter? I mean I know you said sometimes
they do, but sometimes they just go on and shut down. I mean
what kind of situations would cause that?
Mr. Michels. Well, the recognition that something major
needs to happen and rather than having the terms dictated, if
you will, by the regulatory agency, they see the light and say
OK, before that letter of shutdown is received, here's our
plan, this is what we're going to do. In the meantime we are
going to suspend some or all of our operation as a signal of
good faith. As a regulator, I wouldn't be necessarily too
thrilled to see somebody make some offers without doing
something immediate and protecting those folks that are at
risk.
Mr. Cummings. Mr. Ellis, in 1998 I think you told the
subcommittee that your office was pursuing about 70 open
investigations.
Mr. Ellis. That's correct, sir.
Mr. Cummings. How many of those cases have been closed?
Mr. Ellis. That's something I'll have to get back to you
on. A large number remain open. Today we actually have 163 open
investigations.
Mr. Cummings. So in 2 years the number of open
investigations have more than doubled.
Mr. Ellis. That's correct. Some of the 70 to which you
refer have closed, but many more have opened since that date.
Mr. Cummings. Why do you think that is? I mean, that's a
lot of cases. I mean, when you look at 70, some have been
closed and now you're up to 163. Why is that?
Mr. Ellis. We are receiving more complaints. The issue of
protecting human subjects in research has been featured in the
press. Our complaints come from citizens, they come from
research institutions themselves, from employees at research
institutions that see things they don't like. In some cases
from human subjects who feel they have been harmed or wronged
in some way. Our office was not all that prominent, perhaps
hard to find, and now it's easier to find for complainants.
That's my best explanation.
Mr. Cummings. How many employees do you have doing the
investigations on human and animal subject research?
Mr. Ellis. Our office was originally split so the animal
welfare staff are now in a different office, but with regard to
human subject investigations we have two full time equivalent
investigators. Actually a full time physician, a half time
physician and a half time attorney handle 163 cases.
Mr. Cummings. And how many do you think you need to do an
adequate job?
Mr. Ellis. One could work through the arithmetic of what a
serious caseload would be for a high level professional. The
Public Health Service Act requires a prompt, that's a quote, a
prompt resolution of the cases. We could work out the
arithmetic if we took prompt to mean 6 months, let's say, how
many cases an individual can move and get 6-month closure. It's
something I could calculate for you.
Mr. Cummings. That's OK. Is there a statutory requirement
to report adverse events to your office?
Mr. Ellis. There's a regulatory requirement that pertains
to research funded or conducted by any of the 17 departments
and agencies that have been in place for years, the
institutions must report unanticipated problems involving risks
to subjects or others. That is one kind of report. The second
kind of report is any suspension or termination of
Institutional Review Board approval. And the third kind of
report is any serious deviation or noncompliance with the
regulation. The answer is yes.
Mr. Cummings. Those reports that you just talked about, how
many have you received over the last year?
Mr. Ellis. In 1999 we received 187 reports of that type
from I think about 87 institutions.
Mr. Cummings. Mr. Raub, back in December Dr. Art Lawrence
testified before us in a hearing we held in New York, and at
that time Dr. Lawrence assured us that the Office of Protection
from Research Risks would be moved to the Office of the
Secretary and a new director would be selected by March 2000.
It's now May and can you tell us where we are on that?
Dr. Raub. Yes, sir. The Department is close to completing
those actions, but it has taken somewhat longer than the
original estimates. I'm hopeful, as is Assistant Secretary
Satcher, that the appointment of a director for the new Office
of Human Research Protections is imminent. We hope in the next
few weeks at the least for the announcement of that
appointment, and with that then the formalization of the move
of the office from NIH to the Office of the Secretary and the
establishment of the new advisory committee.
Mr. Cummings. Well, while in New York Dr. Lawrence also
testified, and he even introduced a letter from Dr. Satcher
which said that the advisory panel would be created which would
be responsible for human subject research protection. Is that
the advisory panel you were just talking about?
Dr. Raub. Yes, it is.
Mr. Cummings. And how do you see that as helping this
problem, I mean the appointment of that panel?
Dr. Raub. Well, first of all, we see the relocation of the
office as giving it the higher visibility in terms of the
Office of the Secretary and an underscoring of the Secretary's
commitment to this. Second, as part of the move, the Secretary
directed Assistant Secretary Satcher to commission a study of
resources along the lines of the question that you were just
addressing to Mr. Ellis; and that study, as I understand it, is
either complete or near so. It will be an important factor in
the future budgeting decisions for this office.
The advisory committee is intended to ensure that we have a
public, high level and highly qualified group of individuals
drawn broadly from the research community and the interested
general public who can provide a continuing forum of advice and
criticism for the Department as we move to set priorities and
do what we can to ensure that these human subjects protections
are in place. We have not had that kind of forum before in the
Department, and we think it's much needed, and I'm optimistic
as to what it will be able to provide for us.
Mr. Cummings. Right now, do you have to go--is part of the
processes that you use the Federal Register?
Dr. Raub. For what, sir?
Mr. Cummings. For the advisory panel.
Dr. Raub. The advisory panel will be created under the
terms of the Federal Advisory Committee Act, and those actions
have been taken in terms of securing the necessary slot and
authorization to do it. Most likely what we will do is announce
in the Federal Register the functions and other expectations
for the committee, and as we do with many other advisory
groups, invite nominations of members from interested members
of the public, and then put together a recommended slate or
alternative slates for consideration by Dr. Satcher and the
Secretary.
Mr. Cummings. Thank you.
Mr. Mica. Thank you, Mr. Cummings. I didn't get the answer
when I yielded to Mr. Cummings about the second part of my
question. What was the number of personnel requested in 2000 to
2001. Again, we've identified that there's a problem. Some of
the answer is more personnel, more resources. Can you tell me
requests for additional slots?
Dr. Raub. Sir, I don't have those figures with me.
Mr. Mica. Does anybody have them?
Dr. Raub. I'll be pleased to provide them for the record.
Mr. Mica. Mr. Ellis, do you? You said you could calculate,
but this isn't something that just snuck up on us today. It's a
problem we've known about, and one of the ways that we resolve
it is by applying the necessary resources, putting the requests
through the process, and nobody knows what we have requested?
Maybe somebody could slip somebody a paper with a magic number
on it. No? And you don't have a recommendation to the
subcommittee about what kind of resources it would take?
Dr. Raub. Again, I don't have the budget figures with me.
I'd be glad to provide them for the record, sir.
Mr. Mica. Mr. Grob, the situation seems to be mushrooming
out of control, both the sheer number of Federal dollars
involved in this human experimentation and then this large
universe outside of commercial activity. I think you spoke to
some of that. What are we looking at as far as percentages in
each of these areas of experimentation, federally funded and
nonfederally funded? Would you care to venture a guess, Mr.
Grob?
Mr. Grob. I don't know about the exact number. Certainly
we're talking about billions of dollars in both cases. An easy
way to think of it is most of the commercially funded research
that we're talking about here would be research that's
connected with the proposed drugs and medical devices that are
overseen by the Food and Drug Administration. So their entire
workload of oversight would be commercially funded, whereas the
National Institutes of Health would be those that are funded by
our Department. Now of course there's these other Federal
departments that also fund on the Federal level their research.
So I'd say it's billions and billions, but which--you know,
what the exact amounts are I can't tell you.
Mr. Yessian. My name is Mark Yessian. I am the regional
Inspector General. At some of the major medical centers that we
visited and talked to, about half the applications that the
IRBs are getting are coming from commercial sponsors these days
so that helps put it in a little perspective.
Mr. Mica. Another question that was raised at the last
hearing, which continues to be a concern, is the problem with
commercial activities and other interests in this whole
operation, the conflict of interest. I think there was a recent
Los Angeles Times article that alleged the U.S. Government's
top diabetes researcher helped guide a $150 million Federal
study involving Rezulin while serving as a paid consultant for
the drug manufacturer, which was Warner Lambert Co. What's the
Federal Government's policy regarding outside employment and
conflicts of interest, Mr. Raub?
Dr. Raub. Sir, there are several elements to that. First
off, the changes in the nature and the patterns of financial
relationships are one of those changing elements that Mr. Grob
and his colleagues had mentioned. It's quite a different
situation than, say, 20 years ago. A major impetus for that has
been some statutory changes designed to promote the
commercialization of publicly funded research. And, for the
many highly desirable results of that, it has created a pattern
of relationships where not only do some of the universities'
and academic health centers, for example, receive a substantial
amount of funding from the private sector--some on the order of
half, as Mr. Yessian indicates--we also have instances where
some of the university professors also have either stock
holdings or even serve as corporate officials for some of the
private organizations, some of which may be sponsoring the
research.
A major element already in place related to that is a
public health service regulation that requires all of the
entities funded by the agencies of the Public Health Service,
that is the universities and other recipients of awards, to
have in place a policy and a system to identify actual or
apparent conflicts of interests that might affect the
scientists' participation and to take such steps as are
necessary to manage those conflicts--in some instances removing
the conflict, in others putting certain safeguards in place.
One of the areas where we will be intensifying our effort
is trying to find ways to ensure that, as those procedures
relate to human subject protections, some of the kinds of
safeguards we have in place will be those against the potential
coercion of subjects in research as well as guarding against
things that would create less than full objectivity in the way
experiments are designed, patients are recruited, or results
are presented. This will be a continuing challenge for the
entire research community.
Mr. Mica. Is it necessary for additional legislation,
corrective legislation to deal with the new set of emerging
conflicts and circumstances?
Dr. Raub. In my judgment, sir, no. The Public Health
Service regulation to which I referred and, a companion
regulation that the Food and Drug Administration has dealing
with reporting of financial conflicts of interests, gives a
considerable set of tools to use here. I believe the task will
be building on those tools and using them most effectively. I
am sure the Department won't hesitate to propose legislation if
it concludes that's necessary, but we don't think so now.
Mr. Mica. I don't want to pick anybody out, but in this
case I just cited, this individual who served as a paid
consultant to the drug manufacturer was I believe a Dr.
Eastman, who had this employment as a consultant, and it
appears to be a conflict of interest. Do you know if you all
investigated this particular arrangement to see if there was a
conflict of interest?
Dr. Raub. I don't know the full details, sir. I know that
an investigation was carried out at the NIH. I don't know that
it's completed. We can provide a report for that to the
subcommittee.
Mr. Mica. Well, I'd like to know because if you feel that
we don't need additional laws then you have at least the
authority to proceed, and we want to make certain that there is
some attention to the problem of conflict of interest that has
been raised to us. I have other cases here and I won't be able
to get into all of them. We could submit some of them for
questions to you, but it appears that some of the problems
we've had--now conflict of interest is one thing. Maybe we
picked that up through the media. I think you all have
testified that you're picking up problems that have resulted
sometimes in death in these experimentation cases where there
hasn't been, I think we're going to have witnesses about the
full disclosure, prior disclosure about oversight, about the
proper functioning of the review process, which is a big
concern to us. We have an agency, and maybe it is short on some
resources, but in fact we are told that it's somewhat
dysfunctional and even no cost or low cost recommendations have
not been instituted. So I have to cite these as major concerns
of the committee.
And then we have another area now, this growing area of a
commercial activity that doesn't fit. We don't have the handle
because we don't have the Federal funds into the activity, and
FDA has some responsibility, but there are some instances here
in which there appear to be a gap, which is another problem.
Did you want to comment on that briefly, Mr. Grob?
Mr. Grob. We don't know the extent of that, but that's
probably small but growing, where there is research that's
going on that's not connected with any proposal for a Federal
approval of a drug or device and they're not the result of a
Federal grant. In those cases there are no requirements for
Institutional Review Boards or for some of these other
protections. Just simply good practice would call for it, but
the extent to which it's happening and the type of controls
over that is just sort of an area that's not well-known or
understood at this time.
Mr. Mica. And what's interesting, too, is there are so many
new research techniques in biogenetics, I mean, I just can go
on and on about things that are happening almost on a daily
basis that the law is not keeping up with. I am wondering if we
really need to take a closer look at this, some of these gaps
and again have in place some mechanism to deal with this in the
future. Mr. Michels.
Mr. Michels. Yes, sir. Thank you, Mr. Chairman. I just
wanted to clarify that the Food and Drug Administration is
working in the area of, if you will, noncommercial research
from the standpoint that there are requirements from time to
time that, notwithstanding the intent to market the product, if
it is being used as an experimental agent on people it should
be covered by an investigational application.
I think what is maybe troublesome to some folks is the zone
in between where an investigator, a clinical investigator may
also be the entrepreneur who is intending to ultimately develop
the product him or herself rather than working as an employee
or agent for a major pharmaceutical house, for example. The
roles have become very blurred here, and we also are puzzling
over where we need to be drawing the lines. I would suggest
again we go back to the principle that was laid out very early
in your hearing today, and that is we need to be educating all
of the scientists, be they clinical investigators, the
researchers, the IRBs, as to what the requirements are,
minimize their impact so that the right decisions are made on
behalf of the subjects being exposed.
Mr. Mica. Thank you. I'm not going to give you an
opportunity to respond because we have a vote. I have less than
4 minutes to get to the floor. I am going to excuse the panel.
We're going to submit some questions. I have some specific
questions on cases, Mr. Ellis, but I'll tell you, Mr. Raub,
that we've got to do something to get into place some of these
recommendations.
Mr. Cummings described some of the foot dragging and some
of the things in simple appointments, getting people in place,
making low cost or no cost recommendations, getting us to
recommendations. We have got to do something. If necessary I'll
hold another hearing and call everybody back, and we'll
subpoena the Secretary if we have to to get something moving in
this area. But I just give you that.
Without objection, we will submit to you further questions
and ask for your written response. We'll stand in recess for
approximately 15 minutes, until the conclusion of the next
vote.
[Recess.]
Mr. Mica. I'd like to call the subcommittee back to order.
I want to go ahead and proceed. We have our second panel before
us at this point. Unfortunately, there may be a vote in the
full committee. There's been a full committee hearing going on
while we're conducting this subcommittee hearing. We may need
to recess at some point if a vote is called in that body.
Our second panel consists of Mr. Richard Curtin, and he I
believe was a human subject in one of these research
experiments. We also have Charles R. McCarthy, and he is a
senior research fellow at the Kennedy Institute of Ethics at
Georgetown University, and then we also have Dr. Robert Amdur,
and Dr. Amdur is the associate professor and associate chair of
clinical affairs at the Department of Radiology and Oncology at
the University of Florida. Good to see someone from my alma
mater here. If we could just get a President now we'd be in
good shape. That's an inside matter.
I'd like to welcome all three of our panelists this
afternoon. Let me go ahead and explain the ground rules. I
think you're all new witnesses. We do swear in our witnesses.
This is an investigations and oversight subcommittee of
Congress. I'll swear you in in just a minute. I'm going to ask
you to limit your oral testimony to 5 minutes. Upon request,
we'll put in any full statements or additional information in
the record deemed appropriate, upon request through the Chair.
With that, I will swear you in, if you'd stand, please.
[Witnesses sworn.]
Mr. Mica. Witnesses answered in the affirmative. I welcome
the witnesses. I think we'll call on Richard Curtin, who was
involved in one of these research projects. He's from Falls
Church, VA. Welcome, sir, and you're recognized.
STATEMENTS OF RICHARD CURTIN, HUMAN SUBJECT, FALLS CHURCH, VA;
CHARLES R. McCARTHY, SENIOR RESEARCH FELLOW, KENNEDY INSTITUTE
OF ETHICS, GEORGETOWN UNIVERSITY; AND ROBERT AMDUR, M.D.,
ASSOCIATE PROFESSOR, ASSOCIATE CHAIR, CLINICAL AFFAIRS,
DEPARTMENT OF RADIOLOGY AND ONCOLOGY, UNIVERSITY OF FLORIDA
Mr. Curtin. I'd like to thank the subcommittee for inviting
me to appear today, but I have to admit I'm surprised to find
myself in the position of being so critical----
Mr. Mica. You might pull that mic a little bit closer if
you could. Maybe you can do that with your book there.
Mr. Curtin. I'm surprised to find myself being in a
position where I'm being so critical of genetic research. I
have a Master's Degree in human genetics, and 25 years ago I
was working with the Director of NIH in an effort to convince
the Congress to go ahead with funding for cutting edge
recombinant DNA research. But in September 1998 I was
introduced to a different aspect of genetics research when my
daughter Allison received the Virginia Twin Study sponsored by
Virginia Commonwealth University.
The study consisted of a 25-page questionnaire asking
hundreds of questions about a person's medical history. When I
looked through the questionnaire I was surprised to find that
176 of these questions involved not only my daughter's medical
history but also the medical histories of her mother, her
brother and me. In other words, she was being asked to comment
upon the medical history for the entire family.
I was further shocked by the bizarre nature of some of
these questions. For example, the study asked if any of us had
suffered from depression, infertility, alcoholism, or
schizophrenia. It asked if Allison's brother or I had abnormal
genitalia, sperm abnormalities or low sperm count, and it asked
if Allison's mother had any diseases of the genital tract or if
her menstrual periods were unusually long or strong. Nowhere in
the study packet were the words ``informed consent'' ever
mentioned, and this package was addressed strictly to my
daughter.
I was outraged that a federally funded project would
attempt to violate my family's privacy in this manner. I
immediately wrote to the principal investigator of the study
and also to the chairman of the Institutional Review Board. All
I asked them to do was to remove the columns for the other
family members and to send separate questionnaires to each of
us. I realized that this would have cost them more and it might
have cut down on the response rate, but the data base would
have been more accurate, and it also would have avoided the
problem with informed consent.
The chairman of the Institutional Review Board just didn't
bother to respond at all. The principal investigator, responded
but her response was so demeaning and so arrogant that it
probably would have been better if she hadn't responded either.
It became very clear to me that the concerns I raised were not
going to be addressed to my satisfaction by the people at
Virginia Commonwealth University.
So I filed a complain with OPRR. OPRR concluded that the
internal controls for the protection of research subjects at
the university were so inadequate that all federally funded
research had to be shut down until proper controls could be put
into place. The sum total of this action was 1,100 research
projects suspended.
With the chairman's permission, I'd like to enter into the
record a summary list that I've prepared listing 19
deficiencies that OPRR listed from its investigation at
Virginia Commonwealth University.
Mr. Mica. Without objection, that will be made part of the
record. Proceed.
Mr. Curtin. Thank you. Rather than addressing the
legitimacy of the deficiencies found at Virginia Commonwealth,
the leadership of the genetics research community decided to
take a different approach. They went on the attack. They went
after OPRR. I'm especially offended by the positions taken by
two of their main leaders, Dr. Edward McCabe, chairman of the
Secretary's Advisory Committee on Genetic Testing, and Dr.
Francis Collins, Director of the National Human Genome Research
Institute at NIH. These gentlemen have argued in writing that,
even within a family, once a piece of medical information
becomes known to one other person within that family there is
no longer any expectation of privacy and there is no need for
any researcher to bother getting the informed consent of the
family members.
A little anecdote, also about this time, my daughter was
home for Christmas vacation and asked if I would call the
University of Virginia registrar to find out one of her grades.
So I made the phone call and explained to the registrar's
office that I was her father, but they would not release her
grade to me because it was a violation of her privacy. Despite
the fact that she was my dependent and I was paying the
tuition, they wouldn't tell me her grade. But the people at the
Virginia Twin Study fully expected her to go around and tell
the most intimate nature of the medical histories of not only
herself, which I wouldn't mind her doing, but also of every
other member of her family.
I've been involved with this issue now for 20 months and
I've reached five basic conclusions. One, the public cannot
rely upon individual researchers to adhere to the rules and
regulations that go along with the acceptance of Federal
funding. When a research protocol does not go as planned, the
initial reaction of the researcher seems to be to cover it up.
No. 2, the public cannot rely upon Institutional Review
Boards to ensure that guidelines are followed and that
experiments are scientifically and ethically sound. Basically,
I don't believe that colleagues at the same institution can be
trusted to critically review and police each other's work. If I
criticize your work today, what's going to happen when I come
in front of the IRB tomorrow?
Three, the staffing and funding levels at the Office of
Protection from Research Risks have been designed to ensure
that OPRR will not be too effective. Other speakers have
mentioned this, and it's very, very clear to me that OPRR has
been treated as a proverbial stepchild within the NIH family.
Four, the research community, in my opinion, is in a state
of denial regarding the trouble that it's in. They have allowed
a regulatory vacuum to exist and a trust gap to develop, and
now others are rushing in to fill this vacuum and to close this
gap. The community strategy of stonewalling, covering up and
attacking will not, I don't believe, be successful in the long
run.
Five, potential solutions. It's obvious that OPRR needs to
be upgraded, but you also have to be realistic about how much a
centralized office here in Washington can do when the research
is so decentralized. In my opinion, therefore, the quickest,
least expensive and possibly most effective course of action is
for each researcher to realize that violations of guidelines
and regulations will have very serious consequences. If the
probability of getting caught is going to be low, then the
consequence of getting caught should be very severe.
One of the members asked earlier what other penalties could
we possibly have. I have a suggestion. I suggest that a
principal investigator who fails to file a timely and accurate
adverse event report might be suspended from the project for 1
year. Allow the project to continue so that the benefits of the
research aren't lost, but let it continue under someone else's
leadership.
Mr. Mica. Excuse me, but I'm going to have to recess the
hearing for just approximately 10 minutes. We do have a vote in
the other committee. We'll continue when I return.
[Recess.]
Mr. Mica. I will call the subcommittee back to order. I
apologize for the delay, but all members of the full committee
were summoned. To get back here, let's see, we had Mr. Curtin
who was interrupted as he had some closing remarks I believe.
So if you would sum up your testimony, Mr. Curtin, you're
recognized.
Mr. Curtin. Yes, sir. Just finishing up, two possible
penalties to suggest. One is, as I was mentioning before,
suspension of the principal investigator while his project
still goes on. A second possible penalty would be making that
investigator unable to compete for future grants or contracts
for a certain period of time. Those are two suggestions. I
don't think it's that hard to find penalties that fit the
problem.
I want to thank you for the opportunity to express my
concerns and my opinions, and I would like to submit a more
lengthy statement for the record with the chairman's
permission.
[The prepared statement of Mr. Curtin follows:]
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Mr. Mica. Without objection your entire statement will be
welcome and included as part of the record, and we did leave
the record open for a period of 2 weeks. I'll now recognize,
and we'll come back for questions a little bit later, Mr.
Charles R. McCarthy, and he's a senior research fellow, most
patient one, at the Kennedy Institute of Ethics at Georgetown
University. Thank you and you're recognized, sir.
Mr. McCarthy. Mr. Chairman, thank you. I'm honored to be
able to testify before you today. I think the matters on which
you're deliberating are of extraordinary importance, and I hope
we can make some contribution to protecting human subjects.
Your staff asked me to comment on just one aspect of the
Inspector General's report; namely, recommendations concerning
utilization of Data and Safety Monitoring Boards to supplement
the work of IRBs. I have focused my attention almost
exclusively on that issue. I will summarize here very quickly.
I have submitted a longer statement for the record.
Mr. Mica. Without objection, that entire statement will be
included in the record.
[The prepared statement of Mr. McCarthy follows:]
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Mr. McCarthy. And I would like to modify even that a
little. Since I submitted my testimony I have spent some time
in the library and found references to a number of other
sources that make recommendations identical to, or similar to
the ones that I'm making today. So I will add those, if I may
submit those as well.
Mr. Mica. Without objection, and within in the time limits
that have been announced. Go ahead.
Mr. McCarthy. As has been noted earlier in the hearing,
Institutional Review Boards were initiated by the Public Health
Service in 1966. It's not so well-known that in the late
1960's, and I can't give you a specific year, the National
Heart Institute, now National Heart, Lung and Blood Institute,
at NIH created an additional kind of oversight body to look at
large multi-centered trials, and to collect and analyze data,
particularly adverse event data, in those trials. Data and
Safety Monitoring Boards, while nowhere near as well-known as
IRBs, are indeed almost as old and as honorable as the IRBs.
During the seventies Dr. Robert Gordon, who was for a time
the Director of the Clinical Center at NIH, and Dr. Curtis
Meinert, from Johns Hopkins University, spent a great deal of
time refining and defining the work of Data and Safety
Monitoring Boards. As the funding patterns for NIH grants
changed from grants that were made to a single investigator at
a single institution to multi-centered trials where there might
be anywhere from 5 to 50 or even 100 different centers, each
with itw own investigation carrying out the same protocol. The
Data and Safety Monitoring Board has become the instrument most
sensitive to being able to receive and process adverse event
data and other information about multi-centered trials from
many sources; evaluate those data and other information with
the help of professional statisticians and thus to get an
overview of the trial that is literally impossible to get at
any single center or any single institution. We are faced with
something of an anomaly. The Data and Safety Monitoring Boards
are not established by regulation and exist in less than half
of the multi-centered trials that are conducted in this
country. They are the bodies that have the best information and
carry out the most careful analysis of the data. On the other
hand, IRBs are the committees who, according to regulation,
have the responsibility of determining whether trials should be
stopped, modified or continued. Consequently the most complete
knowledge is in one committee, and decisionmaking
responsibility is in another committee. It seems to me that we
can make a very constructive kind of change in the regulations
so that the Data and Safety Monitoring Boards communicate their
findings back to the IRBs. If that step is taken, it will,
first take some work off the IRBs and begin to address the
workload problem identified in the Inspector General's report,
and second, it will improve the quality of the information on
which the IRB makes its decision to continue, modify or
discontinue research projects.
All of the kinds of incidents you've addressed today in
your hearing seem to me to indicate that now is the time to
start afresh. Modify the regulations so that the data held by
Data and Safety Monitoring Boards is made available to the
IRBs, so that the best possible decisions concerning the
continuation and oversight of trials can be made.
Typically, as we heard testified earlier from the Inspector
General, the IRBs receive adverse event data, but it is raw
data. IRBs don't know which arm of the study the adverse event
occurred on. They don't know whether it was in an elderly
subject or a young subject. They don't know which adverse
events result from complications of disease of the subject.
They cannot tell whether the adverse event was caused by the
research, by the underlying disease condition, or by some
inherent condition that pertains to the subject himself or
herself.
Data and Safety Monitoring Boards display the data in a
number of different ways: according to age; gender; race;
ethnicity and a whole variety of other categories so that they
can evaluate adverse events; tell which ones are very serious;
which ones are likely to be associated with the research
intervention; and which ones might have occurred anyway because
of underlying disease conditions. DSMBs are able to give the
kind of analysis that will refine the judgments about the
safety of the research, and whether it should continue.
So my recommendation to you and to the rest of the
committee today is simply that one of the ways the Inspector
General's report could be used or could be capitalized upon
would be simply to adjust the regulations and by putting some
kind of a regulatory link requiring Data and Safety Monitoring
Boards under certain conditions and, second, making sure that
the data that they gather and analyze is carefully and
thoroughly shared with the IRBs so the IRBs then can--with less
work and with greater accuracy--meet the responsibilities that
are assigned to them. This will not, in my judgment, decrease
costs because the Data and Safety Monitoring Boards have full-
time statisticians working for them. They have costly experts.
I participated in a Data and Safety Monitoring Board
meeting yesterday. There was an expert from Germany, one from
England, three from the United States and myself. Obviously to
have a meeting of that kind is very costly. Statisticians
generated--relative to on one study--about 300 pages of data.
The DSMB spent the best part of the day evaluating that data to
determine whether the study should go on. That's a very costly
process, but I can assure you that the subjects in that study
received the very best safety efforts that are humanly
possible.
No one can guarantee that mistakes will not be made, but I
think when the data is processed in such a thorough way, the
chances of a mistake become exceedingly small. That's what we
owe to our research subjects. Even though oversight costs may
be raised. On the other hand, the cost to the local IRBs will
be reduced because their workload of analyzing large quantities
of adverse data will already be done for them by statistical
experts. They will be able to make much more enlightened
decisions as to the research in their institution.
I will be glad, Mr. Chairman, to answer any questions that
you may have concerning this issue or any others.
Mr. Mica. Thank you, and what we'll do is suspend
questioning until we've heard from our final witness. He's also
very patient. Dr. Robert Amdur, and he is the associate
professor, associate chair of clinical affairs, Department of
Radiology and Oncology at the University of Florida. Welcome,
and you're recognized, sir.
Dr. Amdur. Thank you. Good afternoon, Mr. Chairman, and
other committee members.
As you mentioned, my name is Robert Amdur. I am a physician
at the University of Florida. My qualifications to speak to you
today about the protection of human research subjects are that
I am a medical researcher who frequently enrolls patients in
research studies. For the past 10 years I have played a
leadership role in defining and implementing ethical standards
for research through my participation in the Institutional
Review Board and related national organizations.
I am here today representing a national nonprofit
organization called PRIM&R, which stands for Public
Responsibility in Medicine and Research. For over 25 years, the
primary mission of PRIM&R has been to bring researchers,
ethicists, and research regulators together to improve our
system for protecting the rights and welfare of human research
subjects.
Since 1974, PRIM&R has sponsored over 100 educational
conferences, published hundreds of documents, set up onsite
workshops for institutions with special needs, and many other
important activities that meaningfully improve the way research
is done in this country.
I have submitted a written statement which goes into detail
about the challenges that currently stress our system of
protecting human research subjects, and PRIM&R's plans for
helping the research community respond to these challenges.
At this time I would like to formally request that a
written copy of my testimony be included for the Record.
Mr. Mica. Without objection, so ordered.
[The prepared statement of Dr. Amdur follows:]
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Dr. Amdur. In the next few minutes, I would like to
emphasize three requests that I hope you will focus on as you
decide on new Federal initiatives related to research
protections.
Request No. 1 is to pass Federal legislation that requires
that all research in the United States comply with the same
high level of ethical standards, regardless of funding source.
The ethicality standards that should be met when conducting
research on human subjects are described in the Department of
Health and Human Services regulations that are often referred
to as the Common Rule.
A problem with our current situation is that the authority
of the Common Rule does not extend to some situations where
research is sponsored by private industry. It makes no sense to
have different ethical standards for research depending on
funding source. All Americans should be afforded the same high
level of protection and oversight. Medical progress will not be
compromised by a more comprehensive regulatory structure, and
PRIM&R urges you to support legislation that eliminates the
two-class system of research protection that we currently have
in this country.
Request No. 2 is to pass legislation that consolidates the
multiple different sets of Federal research regulations that
currently exist into a single regulatory reference. The
Department of Health and Human Services currently has one set
of regulations, the FDA has another, the Department of
Education has its own rules, and so on. In many cases, the
regulations from these different Federal agencies are
congruent, but in other situations they are not. In still
others it is unclear what they are.
As a result, researchers, industrial sponsors, IRB members,
institutional officials, spend a tremendous amount of time and
energy trying to figure out what hoops to jump through when
different Federal agencies are involved, as is the common
situation in both industry-sponsored and federally funded
research studies.
The situation is ridiculous. There is no reason that we
should not have a single set of regulations that applies to all
research involving human subjects, regardless of the Federal
agency that is involved or the funding source.
Request No. 3 is to ask you to support PRIM&R's efforts to
create a formal program for accrediting each institution's
system for protecting human research subjects. Protecting human
subjects requires much more than an accounting type of
checklist or audit of IRB paperwork. It requires onsite
evaluation by trained professionals of objective and subjective
end points, such as the level of institutional support for the
IRB, the knowledge of research investigators about ethical
standards, the commitment of institutional officials to
shielding research regulators from financial conflicts of
interest and other pressures, and eventually, to documenting
objective end points of ethical behavior, such as the quality
of informed consent for the subjects that have been enrolled in
research studies.
To set up a system for accrediting an institutional program
for protecting research subjects, PRIM&R has recently formed an
affiliated not-for-profit corporation called the Association
for the Accreditation of Human Research Protection Programs.
The acronym for it is AAHRPP. The current plan is to make the
AAHRPP accreditation program voluntary, and we believe that
most institutions will actively seek AAHRPP accreditation as a
way of increasing the integrity of their research programs.
Time does not permit me to describe the details of the
AAHRPP accreditation process. This information is provided in
my written statement. I am happy to explain anything related to
this in the question session.
I would like to conclude my remarks by reminding you that
this is not about a bunch of paperwork that enhances the power
or budget of some Federal agency or a special interest group.
Modern society is stuck between a rock and a hard place. We
must conduct complex and often dangerous research with human
subjects if we are to improve the condition of life on this
planet.
There is often a tension between the ethical standards that
we need to work within and a scientific agenda. We can create
an environment where we promote meaningful research in a way
that does not exploit in any way the rights and welfare of
research subjects, but we need the strong arm of the Federal
Government to make this happen and we need Federal support to
be applied correctly.
Our current IRB system is a good one. It is a result of the
Nuremberg War Crimes Trial that exposed the shameful, unethical
research that was conducted by Nazi physicians in the name of
medical science during World War II. Earlier this week, the
world observed Holocaust Remembrance Day in honor of those who
suffered during the awful period in human history.
In one remembrance ceremony, the Nobel Laureate Elie Wiesel
said, ``Without its ethical dimension, civilization is
vulnerable.'' PRIM&R and many other members of the research
community hope you will act swiftly and decisively to improve
the system of protecting human research subjects in this
country. The AAHRPP accreditation program and the other changes
that I have mentioned are steps in the right direction.
On behalf of PRIM&R, thank you for inviting me. I am happy
to provide any other information that would be useful. Thank
you.
Mr. Mica. Thank you and each of our witnesses on this panel
for your testimony. I apologize, again, for the delay in the
hearing, but we had floor votes and then we had the required
participation in the committee hearing.
Again, I would like to proceed with some questions, first
maybe to Mr. Curtin. Well, you have all basically criticized
some of the current functioning, operation, of the IRBs. Mr.
McCarthy did not get into too much of that, he spoke mostly of
the DSMBs. But the current system appears to be somewhat
flawed.
I guess if we started out maybe with informed consent, do
you think it might be possible to have a basic standard
informed consent procedure that would be good for all human
research testing, Mr. Curtin?
Mr. Curtin. That seems very bureaucratic to me, very
inflexible. I would hope that we would be able to rely upon
individual researchers and IRBs to come up with--to develop--
the informed consent that most fits the research project that
they are looking at.
Maybe that is too theoretical, maybe it cannot be done.
Mr. Mica. I don't know if your daughter was afforded
informed consent. Was she?
Mr. Curtin. Absolutely not.
Mr. Mica. Absolutely not. So first of all, there was not
any in place?
Mr. Curtin. Not for her. Well, if she answered it,
obviously, but for other family members, no.
Mr. Mica. For her, for herself, she did have informed
consent?
Mr. Curtin. Yes.
Mr. Mica. Were you satisfied with that? Your protest then
goes beyond her situation and her giving informed consent. I
understand your concern about your privacy, her disclosure of
your medical record. But were you satisfied with the informed
consent that she was provided?
Mr. Curtin. The informed consent really was if she
responded to it, that would be considered the informed consent.
She would have voluntarily participated if she had filled out
the questionnaire and put it in a return envelope and sent it
in.
Mr. Mica. To step back first, does everybody believe that
there should be a requirement for informed consent?
Mr. Curtin. I think there should have been a statement in
the instructions saying, if you are going to answer for your
other family members, you might want to tell them that you are
doing that.
Mr. Mica. We have not gotten to family yet. We are talking
about an individual who is going to participate or someone who
is a guardian or legally responsible for that individual. There
should be informed consent.
Everybody agrees on that?
Dr. Amdur. There are situations where it is appropriate and
necessary to conduct research without informed consent, and
those situations are described and provided for in current HHS
regulations.
A typical example would be emergency situations where it is
not possible to get it, to conduct research with there being
informed consent. There are other situations such as health
services research involving access to medical records where
risk is minimal and it is not possible or practicable to
conduct research with a requirement for informed consent.
The fundamental ethical standards that we use when we think
about these and analyze them and say what is appropriate, what
is not, what rights and welfares are important to maintain,
need not be violated in certain circumstances without getting
informed consent.
Mr. Mica. Dr. Amdur, you are the one I thought that had
come forward in past Federal law or regulations and set
standards. That is what I am trying to get at.
I had, sitting where Mr. McCarthy is, the representative of
HHS. He said they had all the authority they needed to deal
with these situations. It sounded like he did not have any
recommendations for legislative changes.
You have come forward and recommended something. Maybe you
could elaborate on what you envision we should be doing as a
Federal Government to again provide that there is adequate
informed consent in human patient testing, that there is not a
problem with the operation of an IRB.
Right now, they cannot even tell me how many IRBs there
are, OK? And then the operation of an IRB, should we be more
involved in a conflict of interest, making certain there are
not conflicts of interest?
You heard this explosion and expansion of human research in
just the whole biotech industry. All of the breakthroughs in
medicine, testing, have just dramatically exploded. We hear
something new every day.
We as government do not want to stand in the way of
research, but you have some basic protections that should be in
place. Now, HHS said that they have adequate authority. You are
saying that we should have some Federal regulations or laws and
set some standards. Maybe you can elaborate.
Dr. Amdur. You have raised a number of points. To go into
detail about each one I think would be beyond the scope of this
discussion, conflict of interest, etc.
My response would be that the requests that I listed were
specific regulatory changes that will make this current system
work better.
Mr. Mica. The HHS has the ability to institute regulations,
so it is not a matter of changing the law, or is it? Are you
aware of where we need to change the law?
Dr. Amdur. Perhaps I am mistaken in terms of exactly who
initiates the law. Really, though, I think.
Mr. Mica. We initiate the law. What we do is when they have
the need to be changed from time to time, we defer to HHS and
the agencies to institute regulations.
Dr. Amdur. I don't know any delicate way to say this. The
point is, HHS could have made these changes, should have made
these changes. PRIM&R sponsors two national meetings a year.
The IRB world knows many changes that need to be made to make
the system work better, which is a good system. They have not
been made because of Federal bureaucratic inertia, turf wars,
whatever. That is the reason that I am saying to you, I don't
know what the problem is.
Mr. Mica. I was trying to see if you had a recommendation
in a legislative context. Most of it appears to be regulatory
in nature. The failure of HHS to institute even the
recommendations your group has made, we have the same problem.
We had the IG sitting next to HHS and telling us that even
basic things that were recommended back in 1998 still have not
been instituted.
We are looking first at the statutory and the larger
picture, our responsibility. Then we do have the oversight and
investigative responsibility, which we are conducting today
through this hearing, asking again HHS why they are not
following through with the recommendations.
There are two ways they can do that. One, within existing
authority, or if they need additional resources to make certain
these things are in place.
Now, Mr. Curtin has talked about another issue which
extends beyond the informed consent but may need some type of
tweaking in our laws as far as privacy or disclosure, and that
is of course the subject of big discussions now with the
tremendous amount of raw information that is coming out about
folks.
He raises a certain concern. We have heard an abuse here
that we may either need to address through regulation or
legislation.
Dr. Amdur. The IRB system failed to do what should have
been done in his case. There is no question about that. We
don't need a new system, we just need the IRB at MCV to have
functioned the way it should have functioned.
Mr. Mica. Many of the IRBs, though, are sort of self-
regulating, without a lot of protections. We are going to
submit to the doctor and some others instances, but mostly we
are reading about it in media accounts of conflict of interest.
In our last hearing, we also heard problems ranging in
conflict of ethics to having some self-interest in proceeding
with the human testing. Again, you are dealing with boards that
basically have some interest in participating and moving
forward, taking Federal funds for that activity, as opposed to
closing it down or not proceeding and not receiving the funds.
Then the other problem we have is the huge explosion of all
of this. It was just a few doing the testing some time ago. Now
we are probably looking at thousands and thousands, plus the
commercial and private side, where you do not have Federal
funds and we have some loopholes in that regard.
What about mandatory registration of IRBs?
Dr. Amdur. We need that. That is part of the request of
extending the regulations of the Common Rule to all research.
The reason that you don't know or nobody knows how many IRBs
there are in the country is because the only record of an IRB
is if they conduct FDA-regulated research or HHS-funded
research.
We need to just simply fix that problem. I don't know that
HHS can do that. I think it requires a higher level of mandate
to pass a Federal law. I don't know that. But the point is, we
need to extend the system of protection. Part of that would be
a formally certified IRB according to the Common Rule
regulations. Then we would not only know how many IRBs there
are, but have some common system that they work under.
Mr. Mica. Let me ask Mr. McCarthy. You have looked at the
Data Safety Monitoring Boards, DSMBs. Do you feel there should
be some accreditation or additional regulation mandatory?
Mr. McCarthy. Yes, I would like to see some criteria
established and required to be implemented. The criteria should
state under what circumstances the Data Safety Monitoring Board
should be established, what its authorities and
responsibilities should be, and what its relationship to the
local IRB should be in the centers where research over which it
has oversight is being carried out.
I do not know whether that can be carried out under present
legislation or whether it would require new legislative
authority, but I think it is very important, and will be a
major step forward if that should occur.
I agree with Mr. Curtin, that a kind of cookie cutter
approach to informed consent is just what we don't need,
because anything that routinizes informed consent, tends to rob
it of its important meaning.
What I would like with respect to informed consent is to
see the Department of HHS spending some money to do research on
how to communicate risks and benefits associated with research
more effectively.
We have a whole new generation of young people coming along
who operate much more out of visual cues than out of written
cues. To hand people a written, fairly complex document may not
actually inform them of very much, whereas a videotape showing
the same information might be much more effective.
In order to develop that kind of technology, somebody needs
to sponsor some imaginative research into how to better inform
subjects so that they will know and understand the consequences
of their decisions to participate or not to participate in
research.
Again, I don't know if you need a legislative mandate to
carry that out or whether you simply need additional budget
resources to carry that out, but I certainly think that ought
to be a major function of the new office that is being created
in HHS.
Even if a new approach to informed consent can be done
without new legislation, it certainly cannot be done without
additional money, so I would encourage that the Congress bite
the bullet and provide the money so that imaginative new ways
of communicating with research subjects can be developed and
employed, and so that IRBs have a range of ways of
communicating the risks and benefits of research to their
subjects in meaningful ways. I believe we can respect the
dignity of subjects more than we do at the present time with
rather complex, long, written consent documents that may not do
what they are intended to do.
Mr. Mica. Mr. Curtin obviously had a negative experience
with the OPRR process. I think he recommended some solutions
for corrections.
Maybe you could give us those again, Mr. Curtin.
Mr. Curtin. Yes, sir. No, I did not have a negative
experience with OPRR. The only thing that even could be
remotely called negative about it was that it took them almost
a year to get around to doing anything with my complaint. But
once they did it----
Mr. Mica. That I would interpret as a problem.
Mr. Curtin. That is, yes. But once they got on it, they
were great. They kept me informed.
Mr. Mica. They did?
Mr. Curtin. They did. They took some very, very severe
action. They closed down 1,100 research projects at Virginia
Commonwealth University.
Mr. Mica. Your difficult experience was getting attention
at the beginning.
Mr. Curtin. Right. They explained that to me right off the
bat. They said, it is going to be a year before we get around
to doing this. A year later I heard from them. I would have
liked it to have been sooner, but I understand those kinds of
things.
Mr. Mica. With the IRB process, you also were critical of
the response you got there.
Mr. Curtin. From the chairman, yes. Yes.
Mr. Mica. You----
Mr. McCarthy. Mr. Chairman, just to fill in that story,
because maybe even Mr. Curtin does not know this, but after
OPRR took its action, Virginia Commonwealth University hired
me, and I have been working about 40 or 50 hours a week since
January to educate investigators about their obligations on
informed consent and to instruct potential new members of the
IRBs.
So they are taking the criticism very seriously, and I
expect that within a year they will have a system that will be
as good as any in the country.
Mr. Mica. But it did take a year to get action. What did
they say, they could not get to it?
Mr. Curtin. They were overworked, backlogged.
Mr. Mica. OK. All right.
Mr. McCarthy. As a former Director of OPRR, I can say that
is a perennial problem. I think the office has always been
understaffed and underfunded.
Mr. Mica. I am also trying to find out what their
recommendations were to us. They have to come to Congress to
ask for additional funding through the appropriations process.
If we have a deficit there and we have a larger scope of
responsibility, we need to see that that is met. Maybe these
1,100 operations should have been closed down after the
complaint was made, not a year later.
Again, we are just trying to look at where the problems are
and what is going wrong and how we correct them. It is a pretty
simple process, except I have to get 534 other people to agree
on how to fix it.
Mr. Curtin. If I might add, sir, the IRB there, they just
did not take me seriously. It was as simple as that. They
thought they would write me a letter and I would go away.
Mr. Mica. All right.
It sounds like we have at least Mr. McCarthy and Dr.
Amdur's wealth of experience and recommendations. You have a
personal experience.
I wanted to ask about some recommendations. I didn't make
good notes on who said what, but you said consolidate sets of
regulations. You cited HHS, FDA, education, and some standards.
My staff just gave me the Department of Veterans Affairs
standard for protecting human research participants.
Did you mean in the context again of protection, some
standards that are protections for human research participants,
no matter what the Federal agency?
Dr. Amdur. Yes, exactly. What I meant was not an abstract
thing, but an administrative one, meaning that if you look in
the Code of Federal Regulations at 45 CFR 46, you will see HHS
regulations.
Mr. Mica. Right.
Dr. Amdur. If you look at 21 CFR 50 and 52, I guess it is,
56, you will see FDA. Most of it, 90 percent of it, are the
exact same words. They are just copies.
But then in the remaining 10 percent of this situation, the
regulations are different or they are silent on certain
situations. There are many examples of that. The Department of
Defense has certain requirements, and you know if they sign on
to the Common Rule, then they do.
The point is that, for example, this adverse event
reporting which you have heard so much about, this is the No. 1
workload problem for IRBs. It is the most ridiculous thing.
There are boxes and boxes coming into the University of
Florida's IRB every week of irrelevant reports that the IRB
cannot possibly make any meaningful determination of. It may be
a horrible adverse event that is critically important, but
because of the things Dr. McCarthy said, the nature of what you
need, you need data in safety and monitoring, but the IRB
should not be looking at those. Does the IRB need to do that?
The regulations say they need to.
HHS regulations say certain things that can be interpreted
certain ways. FDA regulations say very different things that
likewise are interpreted very differently. So what I do on the
IRB is sit around every week as chair of an IRB before coming
to the University of Florida and try and say, how do we
interpret this? Every year we have major discussion sessions at
the national meetings: Well, how do we interpret this? And we
are scared to turn away these things if there is any question
that we need to be stamping them because we are scared of the
regulatory consequences.
So the point is, what should be done is to say we are only
going to have one set of regulations, and it would be very
simple. There are people that sit around, and this is all we
have thought about and discussed and written papers about, who
can suggest and hammer out revised regulations where necessary
that make them congruent, just like any revised regulatory
process goes. But the thing we need is to say we are only going
to have one set of regulations, and it does not matter what
agency sponsors the research.
I would say we need to extend it. It does not matter if it
is privately funded, and I think we need a law for that, not a
Federal regulation. But the point is that we only need to have
one set of regulations. That is what I mean when I say
``standards,'' regulations that describe the standards: Say you
need to go through an IRB. You need to have informed consent
under these situations. Here is the form of the informed
consent, that situation. We need just one of those.
The Common Rule does need a little polishing here and
there, but it is basically what we would all come up with if we
spent a long time thinking of standards in a regulatory system.
It is a good system, and----
Mr. Mica. Are you aware of any formalized document or
anything that has been prepared that proposes that and has
language that would be acceptable to the vast majority of those
who participate?
Dr. Amdur. I think that when you say ``vast majority'' the
people who are objecting to consolidation of the regulations--
--
Mr. Mica. We are not going to get everyone to agree.
Dr. Amdur. Right, but the people who are objecting are the
people in the agencies that want to keep their own regulations.
Certainly industry sponsors, they just want to figure out: What
do I need to do? They don't care what it is. It is so much
better if they can just figure out what it is.
The International Council on Harmonization would be the
closest thing to the answer to your question in that there is
now. In order to make it so that companies, pharmaceutical
companies, can do business in all different countries, there is
a body that has done exactly what you have said, which is
establish that we are going to have one uniform requirement. If
you want to do business within this group, we are just going to
say everybody has to comply with these regulations. We are not
interested in your HHS or whatever. If HHS is the exact same,
fine. All we know is, here is one set.
You know, I think that comes very close to what you are
saying, but it would not be very difficult to come up with the
one set. I think what is needed is some mandate at a higher
level to say, come up with one set.
Mr. Mica. Mr. McCarthy, you wanted to respond?
Mr. McCarthy. I had some years' experience in OPRR, and of
course we tried to do exactly what Dr. Amdur is suggesting; to
come as close as humanly possible to a single set of
regulations that would apply to all research, whether FDA-
regulated or federally funded. We had no authority to reach out
to that research which was neither FDA-regulated nor federally
funded, so that problem I think is one that requires some
congressional action to extend the authority of these offices.
But I think the problem is more complex than you have
heard. Each agency has its own authorizing legislation, and it
is that authorizing legislation that allows it to issue
regulations. That legislation differs dramatically from FDA to
Department of Defense to HHS to Department of Education.
Different congressional committees handle that legislation
and draft it, so when you try to write a common set of rules
that comply with a vast variety of laws, it is not a simple
matter to write a single rule that complies with all of the
authorizing legislation of all of the Federal agencies.
We did the best we could, and I would disagree, I think
between HHS and FDA, the congruency is about 97 percent. What I
would point out, however, is that FDA has authority for
implementing its rules, and that means different people are
doing it, and sometimes they interpret the rules a little
differently.
That is why I would like to see this new HHS office become
at least an HHS-wide office, and I would like the new office to
have enough authority so it can be the lead agency to bring the
other departments and agencies--that do less research but still
a lot of research--into congruence so far as possible, given
the plethora of laws that govern them.
I think much more can be done, so I am agreeing with Dr.
Amdur's point, but I think it is not a simple issue. This is a
situation where the Congress itself, by placing certain kinds
of goals for the new HHS office and providing it with resources
to accomplish those goals, could go a long way toward
accomplishing what he wants. I doubt if it can ever be perfect,
but we can do lots better.
Mr. Mica. Dr. Amdur wanted to respond.
Dr. Amdur. You know, Dr. McCarthy has worked in the
government too long, because now he is making excuses for it.
You know, our role here is simply to say what needs to be done
and for you to figure out how to do that.
We need a common set of rules, and we do have plenty of
models for that in the research world. For example, in 1996
Congress passed the Health Insurance Portability Act. As part
of that, it required legislation to be passed that set
standards for the protection of privacy of access to the
medical record.
Federal law said this has to be done. It did not say
``unless FDA objects to it,'' or the FDA--``unless it conflicts
with FDA's view of it.'' It said, that is it. America, that is
the way it is going to be done. A Federal law passed.
We are about to see a law go into effect that supersedes
all of our other research baloney of interpretation, of how do
we interpret HHS, how do we do that. It is going to be a
problem, of course, to implement it because there are problems
with the way that law is written. But the point is that
mechanism is there to say that, well, research, this is the way
it is going to be done, regardless of one Federal agency's
policy or another.
I think that we can solve this problem.
Mr. Mica. I am probably somewhere in between the two of
you.
Mr. McCarthy. We are not very far apart. We have exactly
the same goal.
Mr. Mica. Mr. McCarthy has described a political situation
of congressional authorization, and there is not just the
agency turf jealousy. We also have the committee authorizing
jealousy, and to get them to all agree on anything is very
difficult.
I see your point, though. We have, as you pointed out, in
other legislation required some standards. I think everybody
agrees that there should be informed consent. I think everybody
is agreeing now there should be some registration of at least
the IRBs, right? And then we get into some other areas.
We have not really talked about accreditation or
certification for IRBs or DSMBs. Dr. McCarthy, what do you
think about some accreditation or certification standard?
Mr. McCarthy. I strongly endorse this effort. As a matter
of fact, I have been selected to serve on the board of the new
organization that Dr. Amdur cited, and I am dedicated to trying
to bring this about as best we can.
Mr. Mica. Should that be voluntary or mandatory?
Mr. McCarthy. I think that it ought to be voluntary and
supplemental to the kind of oversight exercised by the
government. I think we have an excellent model in the
Association for Accreditation of Laboratory Animal Care, Int. I
think it has worked very well for many years as a supplement to
government efforts.
Mr. Mica. How long has that been in place?
Mr. McCarthy. At least since 1970, and if memory serves,
about 1965, but a very long time. It has worked exceedingly
well, and one of the people serving on the new AAHRPP board is
the director of AAALAC, so that we are able to profit from his
experience and his guidance.
I think the one thing holding up accreditation is funding,
and we are now seeking some funding sources in order to get
this corporation off the ground. We think it will be self-
sustaining because it will be in the best interests of the
institutions to be accredited, to get a Good Housekeeping Seal
of Approval on their programs, before OPRR or FDA or some other
agency comes in and shuts down their research. This way we can
make a supplemental contribution to what the government is
doing.
In no way would I weaken the government's authority or the
extent of its oversight, but I think human subjects are so
important that we can supplement what government can do and
head off many problems before they occur.
Mr. Mica. Dr. Amdur, what about certification or
accreditation?
Dr. Amdur. I think that it needs----
Mr. Mica. Give me your ideas on how that should be
accomplished.
Dr. Amdur. A program that will work very well for this
purpose is not in the planning stages, it is in the very end
stages of the planning and about to be implemented by PRIM&R.
This is the AAHRPP program. In three pages in the written
testimony we explain the mechanics of it.
Very briefly, what you do first is--this is about to be
completed--you organize a group of experts that then write down
basic best practice guidelines for the fundamental aspects of a
system of protecting human subjects: The institution, the IRB,
education of investigators, management of adverse incidents,
etc. You start there, and that has been done.
Then you have a written phase where the institution
responds to their current status related to those. Then you
have an onsite investigation where usually two or three experts
go to the institution and have to interact with all the key
components of the system and see how it is really working
according to objective and there are some subjective aspects of
it, and issue a grade, if you will, of the institution related
to a whole checklist of things.
If the institution meets certain standards, which are
outlined in the program, then they get the accreditation for 3
years is the proposal. So PRIM&R has been working very hard to
indeed hammer out the details. It is not perfect yet. It has
not been tried in the field yet. Like any system, it will
obviously iterate and evolve and change and be polished as it
is used. The more support it gets, the quicker it can get
online, but it is ready to go.
I would strongly support a model that is that far along
already to get out into the field and get going.
We have to accredit everything we do. You go and get the
gas tank filled for your gas grill and the people that fill the
gas have to have a certification. We need an accreditation
process for the protection of human subjects, and that is
something that is really long overdue.
Institutions will not balk at this, they will embrace it.
They want to know, what do I need to do to be doing things
correctly. They will embrace it if it is a credible system that
is tagged to meaningful evaluations. If it is just an audit
system of a bunch of accountants going and checking and looking
for pieces of paper that say certain things and the date
matches this date, you know, they will do it if they have to
because the experts on protecting human subjects are the
investigators, in most cases. They know if the IRB is asking
the meaningful questions. They know if the institution is
providing the right environment to support them and be able to
resist conflicts of interest.
As long as it is a meaningful, credible process done by
people who know what they are doing, the institutions will
embrace it. But it needs to be supported as widely as possible.
Mr. Mica. Do you endorse the mandatory versus voluntary?
Dr. Amdur. I am scared to say yes, mandatory, because we
should always have as little required regulation as possible. I
just need to see the exact format of how that requirement would
be, because when we actually write it down and see how it is
implemented, I am concerned.
I think it will be enormously effective even if it is
voluntary and if the regulations required--I personally right
now, don't think it has to be a mandatory, required system. I
think HHS regulations and authority already have the authority
to put the pressure, as they are trying to do, on institutions
to do things correctly. The institution will seek out ways to
find out what is correct and improve their system on their own
if they are indeed under a regulatory system that evaluates the
end point.
So I think they will seek the accreditation process on
their own and there will be other forces that end up requiring
it. For instance, industry will require it. Once there is any
meaningful system in place, industry sponsors will require it.
They will say, we are not dealing with you unless you are an
AAHRPP-accredited institution. So I don't think it has to be
mandated at the Federal level.
Mr. Mica. I have additional questions we may submit some to
you and some of our other witnesses today, but I think we have
just passed the 6 o'clock hour.
I do want to thank each of you for participating, for being
with us this afternoon, for your contribution in helping us
improve this entire process, and also the Federal agencies that
are responsible for implementing law and Federal policy.
There being no further business to come before the
subcommittee--and again, I want to thank you for your
participation and willingness to provide us with your personal
experiences and your expertise on this important issue--this
hearing is adjourned.
[Whereupon, at 6:02 p.m., the subcommittee was adjourned.]
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