[Senate Hearing 107-424]
[From the U.S. Government Publishing Office]
S. Hrg. 107-424
PROTECTING HUMAN SUBJECTS IN RESEARCH:
ARE CURRENT SAFEGUARDS ADEQUATE?
=======================================================================
HEARING
BEFORE THE
SUBCOMMITTEE ON PUBLIC HEALTH
OF THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED SEVENTH CONGRESS
SECOND SESSION
ON
EXAMINING CURRENT SAFEGUARDS CONCERNING THE PROTECTION OF HUMAN
SUBJECTS IN RESEARCH, WHILE FACILITATING CRITICAL MEDICAL RESEARCH
__________
APRIL 23, 2002
__________
Printed for the use of the Committee on Health, Education, Labor, and
Pensions
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79-325 WASHINGTON : 2002
___________________________________________________________________________
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COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS
EDWARD M. KENNEDY, Massachusetts, Chairman
CHRISTOPHER J. DODD, Connecticut JUDD GREGG, New Hampshire
TOM HARKIN, Iowa BILL FRIST, Tennessee
BARBARA A. MIKULSKI, Maryland MICHAEL B. ENZI, Wyoming
JAMES M. JEFFORDS (I), Vermont TIM HUTCHINSON, Arkansas
JEFF BINGAMAN, New Mexico JOHN W. WARNER, Virginia
PAUL D. WELLSTONE, Minnesota CHRISTOPHER S. BOND, Missouri
PATTY MURRAY, Washington PAT ROBERTS, Kansas
JACK REED, Rhode Island SUSAN M. COLLINS, Maine
JOHN EDWARDS, North Carolina JEFF SESSIONS, Alabama
HILLARY RODHAM CLINTON, New York MIKE DeWINE, Ohio
J. Michael Myers, Staff Director and Chief Counsel
Townsend Lange McNitt, Minority Staff Director
------
Subcommittee on Public Health
EDWARD M. KENNEDY, Massachusetts, Chairman
TOM HARKIN, Iowa BILL FRIST, Tennessee
BARBARA MIKULSKI, Maryland JUDD GREGG, New Hampshire
JAMES M. JEFFORDS (I), Vermont MICHAEL B. ENZI, Wyoming
JEFF BINGAMAN, New Mexico TIM HUTCHINSON, Arkansas
PAUL D. WELLSTONE, Minnesota PAT ROBERTS, Kansas
JACK REED, Rhode Island SUSAN M. COLLINS, Maine
JOHN EDWARDS, North Carolina JEFF SESSIONS, Alabama
HILLARY RODHAM CLINTON, New York CHRISTOPHER S. BOND, Missouri
David Nexon, Staff Director
Dean A. Rosen, Minority Staff Director
C O N T E N T S
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STATEMENTS
APRIL 23, 2002
Page
Kennedy, Hon. Edward M., Chairman, Committee on Health,
Education, Labor, and Pensions, opening statement.............. 1
Frist, Hon. Bill, a U.S. Senator from the State of Tennessee,
opening statement.............................................. 2
Gregg, Hon. Judd, a U.S. Senator from the State of New Hampshire,
prepared statement............................................. 4
Jeffords, Hon. James M., a U.S. Senator from the State of
Vermont, prepared statement.................................... 4
Mathias, Cherlynn, Manager, Clinical Research Department, Harris
Methodist Fort Worth Hospital, prepared statement.............. 9
Speers, Marjorie A., Executive Director, Association for the
Accreditation of Human Research Protection Programs; Former
Acting Director, National Bioethics Advisory Commission,
prepared statement............................................. 12
Johnson, Charles A., Associate Director of Specialty
Biotherapeutics, Genentech, Inc., on behalf of the
Biotechnology Industry Organization, prepared statement........ 17
Charles, P. David, M.D., Assistant Professor of Neurology,
Vanderbilt University Medical Center, on behalf of the National
Alliance of Medical Researchers and Teaching Physicians,
prepared statement............................................. 21
Murray, Hon. Patty, a U.S. Senator from the State of Washington,
opening statement.............................................. 30
ADDITIONAL MATERIAL
Articles, publications, letters, etc.:
Genel, Myron, M.D............................................ 40
Kelch, Robert P., M.D........................................ 44
Sharpe, Virginia A., Ph.D.................................... 48
Association of Clinical Research Organizations............... 50
PROTECTING HUMAN SUBJECTS IN RESEARCH: ARE CURRENT SAFEGUARDS ADEQUATE?
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TUESDAY, APRIL 23, 2002
U.S. Senate,
Subcommittee on Public Health, of the Committee on Health,
Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 10:02 a.m., in
room SD-430, Dirksen Senate Office Building, Hon. Edward M.
Kennedy [chairman of the committee] presiding.
Present: Chairman Kennedy; Senators Murray, and Frist.
Opening Statement of Senator Edward Kennedy
The Chairman. The hearing will come to order.
Senator Frist will be here in a moment or two.
We have a vote scheduled at around 11 o'clock which is
going to temporarily interrupt the hearing, and then it will
resume, so we want to apologize in advance to our witnesses for
the interruption, but that is something which we had no control
over.
Today's hearing is on the important issue of protecting
patients who volunteer as subjects in clinical trials and other
forms of research. Numerous expert reports and investigations
on our current system of protections have identified serious
flaws that must be corrected, and I look forward to working
with Senator Frist and other members of our committee on
legislation that will improve the current system.
The task is urgent. Transplants, chemotherapy, and
countless medications that we now take for granted today were
once experimental and unproven. These medical miracles are
available to patients today only because they were tested on
people who participated in clinical research studies.
None of us knows what new medical breakthroughs are just
around the corner. We can be sure, however, that any new cure
or treatment will first be tested on human subjects. If
patients fear that their safety is not adequately protected in
medical research, these cures of the future will be placed in
jeopardy. Patients will suffer if we do not protect those who
volunteer to test newly discovered cures.
In an earlier hearing, our committee heard the harrowing
testimony of Paul Gelsinger, whose son Jesse lost his life in a
gene therapy clinical trial. Our investigation of Jesse's death
revealed a failure of our system of protections and allegations
that financial conflicts of interest caused ethical lapses.
Today we will hear from Cherlynn Mathias, who had the
courage to report to Federal investigators the abuses of human
subject protection she witnessed at the University of Oklahoma.
For this act of courage and integrity, she was harassed at work
and forced to leave the job she loved. Congress must not ignore
Paul Gelsinger's loss or Cherlynn Mathias' courage.
Today's hearing continues our committee's long interest in
this issue. Nearly 30 years ago, we heard testimony that
impoverished African Americans at the Tuskegee Institute had
been used as guinea pigs in shameful medical experiments on
syphilis. And we learned that an experimental birth control
drug was tested on women at the Arlington School for the
Mentally Retarded without their knowledge and without the
consent of their legal guardians. We also know about the
sterilization of the Relf girls, and we had hearings on the
CIA, where they effectively provided toxic substances to some
of the agents with the idea of developing antidotes, with a
tragic outcome with regard to one particular family.
In response to these disturbing facts, our committee
approved legislation that established basic protections for
human subjects in federally-funded research. This oversight
structure has served us well for a generation.
But the protections of the past are proving inadequate to
keep up with the pace and volume of new discoveries. When the
original legislation was enacted, clinical trials were
conducted on a few dozen subjects at a single institution. Few
researchers at universities had financial ties to drug
companies, and ``biotechnology'' was not yet even a word, much
less a national industry. But clinical research has changed
significantly since then, and those changes have strained our
system of research protections to the breaking point.
Today, newspapers carry stories about the crisis of
confidence that is causing patients to refuse to participate in
trials and imperils medical progress. Our responsibility is
clear. We must revitalize our system of protections for this
new century of the life sciences.
We must ensure that patients are properly informed about
the research in which they participate. We should make certain
that all patients who volunteer for clinical trials are
protected by a strong and consistent set of safeguards, and we
should prohibit improper financial conflicts of interest that
can put patients at risk. We should ensure effective oversight
of clinical trials by institutional review boards that meet
high professional standards.
I look forward to the testimony of our witnesses and to
working with our colleagues on this important issue.
I want to express my own appreciation to my colleague and
friend, Senator Frist, for his work in this area and look
forward to hearing from him now.
Openint Statement of Senator Bill Frist
Senator Frist. Thank you, Mr. Chairman.
I want to thank you for rescheduling today's nearing to
examine what I regard as one of the most critical but
oftentimes overlooked issues facing America's research
enterprises.
In the past few years, we have witnessed a true explosion
particularly in the realms of biomedical and other scientific
research which is very positive, which gives great hope and
tremendous promise for people who either are suffering today
from debilitating diseases or, as we look to tomorrow, offers
great potential for prevention as well as response and
treatment.
This movement is one in which Congress has been heavily
invested in terms of dollars, in terms of resources--more than
$20 billion last year alone at the National Institutes of
Health.
Last year, more than 2.3 million people completed clinical
trials, and thousands more are currently participating in
trials and other investigations. This is an important part of
the investigative process in order to determine what is in the
best interest of patients long-term.
The environment is producing medical breakthroughs, and it
is one to which patients and families are looking for even more
dramatic advances in our knowledge and ability to fight
disease. As Senator Kennedy mentioned, recent tragedies have
indeed shaken the public's trust and confidence.
Congress has made clear its commitment to biomedical
research. Our research community and Federal research agencies
have made clear their dedication to sound science and
innovation. However, until recently, there has been too little
attention focused on protecting the individuals who are at the
heart of this critical research and who themselves make real
personal sacrifices to make these miracles a reality.
Following the death of Jesse Gelsinger in 1999, we held two
hearings to examine the oversight structures responsible for
ensuring the safety of patients enrolled in gene therapy
clinical trials. Through these hearings, it became clear that
there had been a systemic breakdown of oversight, ranging from
the investigators to the institutional review boards to the
Federal agencies responsible for ensuring the safety of
patients.
Since that time, I have been encouraged by a renewed focus
among individual researchers, among research institutions and
Federal agencies on improving the protections available to
individuals participating in all forms of human subjects
research.
In the past year since this hearing was scheduled, we have
made great strides toward improving our system of protections
and our underlying knowledge base. For instance, the
Administration has put forward proposed modifications of the
privacy rule that we will be discussing over the course of the
morning. In addition, last year, two reports, including one
that we commissioned by the General Accounting Office, helped
shed new light on the issue of financial conflicts of interest.
However, there is much, much more that needs to be done. We
are here today to examine these issues, to weigh and to
evaluate the remaining gaps in our systems of oversight, and to
consider the need for legislative action to improve protections
for research subjects.
Mr. Chairman, I look forward to working with you as we
develop this legislation and look forward to hearing from our
witnesses today.
The Chairman. Very good. Thank you.
Senator Gregg has asked that a statement be included in the
record, and without objection, that will be done.
I also have a prepared statement from Senator Jeffords to
be included in the record.
[The prepared statement of Senator Gregg follows:]
Prepared Statement of Senator Judd Gregg
Clinical trials play a vital role in new product
development. Clinical trials give patients access to the
latest, most innovative cancer therapies, while helping
researchers develop the next generation of treatments and
medicines.
It is equally important, however, that we protect the
rights and welfare of those who agree to participate in such
research. Research must respect the autonomy of participants;
be fair in both conception and implementation; maximize
potential benefits; and minimize possible harms. Many view the
current system of human subjects protections as inconsistent
and inadequate. Some in Congress have called for legislation.
In order to both protect research participants and promote
ethically responsible research, I believe that any legislation
in this area must embody certain fundamental principals. Such
legislation should:
Centralize and streamline the Department of Health
and Human Services' (HHS) oversight structures and regulations;
Establish a single Federal office with authority
over all HHS regulated or sponsored research;
Establish safeguards for research participants
that are strong, yet flexible enough to adapt to new, evolving
research requirements;
Ensure that the subject's participation was
obtained through voluntary, informed consent;
Encourage voluntary accreditation of Institutional
Review Boards (IRBs) and investigators, and provide additional
Federal resources for educating and training IRBs and
investigators;
Develop and distribute best practices;
Improve and ensure oversight of Federal rules for
disclosure, review and management of financial conflicts of
interest; and
Promote the effective and consistent enforcement
of protections for participants in federally-sponsored or
regulated research in the United States and abroad.
New safeguards should not unnecessarily burden and create
disproportionate workload demands on HHS and researchers. In
that regard, such legislation should be developed
collaboratively with HHS, patient groups, investigators,
research institutions, industry and other stakeholders. Our
goal should be a balanced approach that protects research
participants, promotes ethically responsible research, and
ensures the continued development of next-generation treatments
and medicines. I look forward to hearing from our witnesses and
hear their views on how Congress and other stakeholders can
best achieve this goal.
Thank you.
Prepared Statement of Senator James M. Jeffords
Mr. Chairman, I wish to thank you for holding this hearing
on ``Protecting Human Subjects in Research.'' This hearing
continues the HELP Committee's examination of this issue that
began during the last Congress, and you and Senator Frist are
to be commended for your leadership. I would also like to
extend a warm welcome to the panel of expert witnesses here
today. I look forward to your testimonies so that we may all
gain a better understanding of the current controversy
surrounding the use of humans as subjects in clinical trials.
This issue is crucial to improving the safety and health of all
Americans.
Currently, the only universal standard for reviewing
clinical research that involves human participants are
institutional review boards (IRBs), that were created under the
National Research Act of 1974. Under this act, IRBs are
required to review, approve, and monitor all federally-funded
research. However, in light of recent events regarding human
subject testing, it has become clear that more must be done to
protect participants in clinical research trials.
When I read Ms. Mathias' statement, I was astonished at her
description of the Melanoma Clinical Trial. According to Ms.
Mathias, many of the basic guidelines were never followed; and
even more troublesome, many procedures in the study were not
even reviewed, but instead appeared to have been created on the
fly. Cases like this, where there were inappropriate decisions
made with regard to the procedures of the study, and cases such
as the University of Pennsylvania and the Johns Hopkins
University clinical trials, in which subjects actually died,
show us just how much we need to improve our current system of
reviewing and monitoring trials.
Clinical trials are one of the best ways to develop new
treatments and drugs, but they must follow proper procedure, or
the safety of the participants and the legitimacy of the data
will be in question. It is imperative for participants to be
fully informed and for the administrators of the trial to fully
follow their pre-approved procedures. The administrators must
fully disclose all aspects of the trial, including funding and
possible side-effects, and must run the trial in the most
conscientious manner possible. Patients must be fully informed
on all the stages of the trial as to all the possible side
effects or complications that may arise from the treatment
plan; they must know who is providing funding for the trial;
and they must be fully informed on the entire procedure the
doctor plans to follow. That same procedure must be implemented
by the letter or the participants must be informed as to how
and why it is being modified.
There have been many suggestions as to how to improve the
clinical trial procedures for human subjects, and I am looking
forward to hearing from our witnesses today. I agree with our
panelist from the Association of American Medical Colleges, Mr.
Kelch, when he says that accreditation is a good way to
encourage self-review and evaluation while maintaining a high
standard of review. The creation of the Association for the
Accreditation of Human Research Protection Programs (AAHRPP)
was truly an innovative idea that deserves further examination
as it may have a tremendous benefit on improving standards for
clinical trials. Mr. Chairman, I understand that you are
working on a measure that would require all IRB's to be
accredited, an approach that I feel holds great promise. But,
whatever our solution, it needs to speak first to the needs of
the subjects to ensure their safety. I look forward to working
with you on it.
It is of the utmost importance that we move quickly to
protect human subjects in clinical trials. While clinical
trials provide us with one of the best ways to develop
treatments that save lives, they must also be conducted with
safety as the number one priority. Thank you for organizing
these important hearings today, and I am looking forward to
learning more from our witnesses.
The Chairman. We have the privilege today of welcoming a
distinguished panel of experts who will share their views on
protecting human subjects in biomedical research. It often
takes an act of courage to change a flawed system, and our
first witness is such an example of courage.
It would have been easy for Cherlynn Mathias to turn a
blind eye to the abuses of human subject protection she
witnessed as clinical trials manager at the University of
Oklahoma. But instead of taking the easy way out, Ms. Mathias
had the courage to report these abuses, first to her university
and ultimately to the Federal Office of Human Research
Protection. For this act of courage, she was hounded out of
work and forced to leave the job she loved.
Her integrity is an inspiration, and her testimony is an
important reminder of the urgent need to revitalize research
subject protections.
Dr. Marjorie Speers has devoted much of her career to human
subject protection issues in medical research. She is executive
director of the Association for the Accreditation of Human
Research Protection Programs, whose purpose is to ensure high
ethical standards for institutions conducting research.
Previously, she was project director for the excellent report
on human subject protection written by the National Bioethics
Advisory Commission.
Congress is indebted to the fine reports of the Commission
which reflected extraordinary contributions from many
commissioners and the staff.
Dr. Charles Johnson is clinical research director at
Genentech and will be testifying today on behalf of the
Biotechnology Industry Organization. We look forward to his
testimony on the view of biotechnology companies on human
subject protection issues.
Dr. David Charles is chairman of the National Alliance of
Medical Researchers and Teaching Physicians, an organization of
physicians and scientists focused on improving medicine through
technology. Dr. Charles also serves as director of the Movement
Disorders Clinic at Vanderbilt University Medical Center. He
has already contributed to our committee by working as a health
policy fellow in Senator Frist's office a few years ago. We
welcome him back to the committee today.
Cherlynn Mathias, we would be delighted to hear from you.
We want to thank you for coming. We know it is not always easy,
but your message is enormously important and very valuable, and
it will make a difference in terms of trying to help people,
which I know you are very committed to. So we want you to relax
and tell us your story, please.
STATEMENT OF CHERLYNN MATHIAS, MANAGER, CLINICAL RESEARCH
DEPARTMENT, HARRIS METHODIST FORT WORTH HOSPITAL
Ms. Mathias. I am Cherlynn Mathias, a registered nurse
currently working as manager of the Clinical Research
Department at Harris Methodist Fort Worth. Today I am here to
testify about my experiences as a study coordinator at the
University of Oklahoma.
I was hired in June of 1999, and almost immediately, I
realized that ineligible subjects were being enrolled into the
melanoma clinical trial that Dr. J. Michael McGee was
conducting. When I asked about the subjects being ineligible, I
was told that McGee, as the principal investigator, could
enroll whomever he wished and that the conduct of the study was
his responsibility.
I found this perplexing, since I knew that the enrolled
subjects were too old. And enrolling subjects who were still on
other treatments and giving the drug to pregnant women were all
violations of eligibility that FDA would also consider safety
violations.
In late July, Dr. McGee requested that I build a database
and gather statistics for publication. The building of a
database required me to do a retrospective chart review of all
melanoma vaccine patients. I discovered that several patients
had been allowed to self-inject the vaccine. The patients who
were self-injecting were storing the vaccine at home in their
refrigerators. Not only was I alarmed by this finding, because
of the obvious concern of drug accountability recordkeeping and
storage of an experimental drug in an unsecured environment,
but I was also concerned about patient safety.
The vaccine protocol called for the drug to be stored at
the temperature of liquid nitrogen. I wondered if the vaccine
was stable at higher temperatures. Also, the patients were at
risk for drug reactions. It was obvious that adverse event
monitoring was lacking.
In July, after discovering that the monitoring plan had
never been developed, I was able to convince Dr. McGee to
travel to another site in Springfield, Missouri. We discovered
that the drug was being kept in the refrigerator-freezer which
was located in the staff lounge. The drug was not in a secure
location, and there was no temperature monitoring occurring at
all.
Institutional review boards, IRBs, are the gatekeepers for
the safety and welfare of the human subjects, as mandated by
the Federal regulations. However, we found out that the
oncologist had never sought local IRB approval, although he
himself was an IRB member.
In October, I discovered that the current version of the
protocol had never been submitted to the IRB, although it had
been in use for 7 months. However, the Oklahoma University IRB
had approved a change in the informed consent, which new title
and contact information included St. John's Medical Center.
This is significant, because the study was never submitted to
the St. John's IRB even though the St. John's IRB chair was
also a member of the Oklahoma University IRB, and he was
present when the change was voted on.
I informed McGee that we were using an unapproved version
of the protocol and informed consent. He was surprised and
disbelieved the information. After a discussion, he agreed that
I should contact the Oklahoma University IRB administrator.
The administrator met with Dr. McGee and me in late
October, and he gave us some bad advice. He said that the IRB
was not concerned about monitoring or study design issues. He
also said that the problems concerning the other sites and
their approval was none of the IRB's business, but rather an
FDA matter. He instructed us to write protocol amendments that
he would get approved to cover us retrospectively.
In November, retrospective amendments were submitted to the
IRB. They included major changes to the study design. These
changes included a plan to allow patients to self-inject,
increase the size of the trial, addition of a second drug, GM-
CSF, and other modifications to the protocol. These are but a
few examples of where patients' safety and welfare were
compromised as mandated by the Federal regulations.
I continued to be concerned about the trial. I had already
started staying late at night and reading everything I could
find on the FDA website concerning good clinical practices,
good manufacturing practices, and good laboratory practices.
The more I read, the more alarmed I became.
I started asking questions about manufacturing processes
and became convinced that the lab was out of compliance as
well. Many of the required safety testing for new lots of
vaccine had never been completed. Plus the vaccine was not
being manufactured in a sterile environment. In fact, when
these vaccine preparations were tested on experimental animals,
many of the animals either became sick, lost weight, or died.
The failure of the testing clearly presented a clear risk
of infection to the patients. But McGee continued to increase
enrollment.
Soon thereafter, I started following the chain of command
within the medical college and sounding the alarm for what I
saw as serious noncompliance with the Federal regulations that
were put in place to protect human subjects. Eventually, this
led me all the way to the top of the medical college. By the
time I blew the whistle in June of 2000, the university had
formed a committee that included the dean of the medical
college, the director of the office of research, the IRB chair,
the lab director, Dr. McGee, our department chair, and myself.
The committee was engaged in acts of coverup instead of
promptly reporting as required by the Federal regulations.
Since necessary actions were not being taken, I was
compelled to report these violations to the Office of Human
Research Protection. The oath that I took when I became a
registered nurse was that I would be a patient advocate. I was
haunted by the images, but in particular, one image continued
to eat at me. It was the informed consent process. By now, I
knew that it had been coercive to promise subjects that the
melanoma vaccine offered hope for a cure.
Adverse event reporting was practically nonexistent.
Unfortunately, the sad situation of not reporting adverse
events is the same across the Nation, as was found by a study
conducted by the University of Maryland School of Medicine and
Dr. Adil Shamoo.
Today, the university has adopted many positive changes in
the way research is conducted. The president of Oklahoma
University is David Boren. I believe in David Boren. In my
opinion, he is one of Oklahoma's greatest assets. The
university is in the process of implementing a model compliance
program, and David Boren, the president of Oklahoma University,
is committed to doing so. One of the changes he has put in
place is greater protections for whistleblowers.
I am a graduate of Oklahoma University, and actually, in my
own way, I love the university.
Thank you, honorable Senators, for inviting me to speak.
[The prepared statement of Ms. Mathias follows:]
Prepared Statement of Cherlynn Mathias
I am Cherlynn Mathias, a registered nurse currently working as the
manager of the Clinical Research Department at Harris Methodist Fort
Worth, a large community hospital in Texas. However, today I am here to
testify about my experiences as a study coordinator at the University
of Oklahoma.
I was hired in June of 1999, and almost immediately I realized that
ineligible subjects were being enrolled into the melanoma clinical
trial that J. Michael McGee was conducting. The trial had actually
opened 3 years before my employment. When I asked about the subjects
being ineligible, I was told that McGee, as the principal investigator,
(clinical researcher), could enroll whomever he wished and that the
conduct of the study was his responsibility.
In late July, Dr. McGee requested that I build a database, which
contained endpoints not described in his study design. The purpose of
the database was to gather statistics for publication and also for an
upcoming medical conference in which McGee was scheduled to speak. The
building of the database required me to do a retrospective chart review
of all the melanoma vaccine patients. In the course of doing the chart
reviews, I discovered that several patients had been allowed to self-
inject the vaccine. The patients who were self-injecting were storing
the vaccine at home in their refrigerators. Not only was I surprised by
this finding, because of the obvious concern for drug accountability
recordkeeping and storage of the experimental drug in an unsecured
environment, but also I was concerned about patient safety. The vaccine
protocol called for the drug to be stored at the temperature of liquid
nitrogen. I wondered if the vaccine was stable at the higher
temperatures? Also, the patients were at risk for drug reactions that
might be serious and life threatening, such as anaphylactic reactions.
It was obvious that adverse event monitoring was lacking.
In July, after discovering that a monitoring plan had never been
developed, I was able to convince Dr. McGee to travel to another
clinical site. The site was an oncologist office in Springfield,
Missouri. We discovered that the drug was being kept in the
refrigerator-freezer, which was located in the staff lounge. Once
again, the drug was not being stored at the proper temperatures, and
the drug was being subjected to a freeze-thaw cycle. Nor was the drug
in a secure location. In fact, there was not any temperature monitoring
occuring at all. Institutional review boards--IRBs--are the gatekeepers
for the safety and welfare of the human subjects, as mandated by the
Federal regulations. However, we found out that the oncologist had
never sought local IRB approval, although he himself was an IRB member.
In October, I discovered that the current version of the protocol
had never been submitted to the IRB, although it had been in use for 7
months. However, the OU IRB had approved a change in the informed
consent, which new title and contact information included St. John's
Medical Center. This is significant, because the study was never
submitted to the St. John's IRB, even though St. John's IRB chair was
also a member of the OU IRB, and he was present when the change was
voted on.
I informed McGee that we were using an unapproved version of the
protocol and informed consent. He was surprised and disbelieved the
information. After a discussion, he agreed that I should contact the OU
IRB administrator.
The administrator met with Dr. McGee and me in late October. He
gave us some bad advice. He said that the IRB was not concerned about
monitoring, or study design issues. He also said that the problems
concerning the other sites and their approval was none of the IRB's
business, but rather an FDA matter. He instructed us to write protocol
amendments that he would get approved to cover us retrospectively.
In November, protocol amendments were submitted to the IRB. They
included a change to allow patients to self-inject, increase the size
of the trial, change the statistical power, addition of a second drug--
GM-CSF--and other modifications to the protocol that were already
ongoing. These are but a few examples that patients' safety and welfare
were compromised as mandated by the Federal regulations.
I continued to be concerned about the trial. I had already started
staying late and reading everything I could find on the FDA website
concerning good clinical practices, good manufacturing practices, and
good laboratory practices. The more I read, the more alarmed I became.
I started asking questions about the manufacturing process and became
convinced that the lab was out of compliance as well. Many of the
required safety testing for new lots of vaccine had never been
completed. Plus, the vaccine was not being manufactured in a sterile
environment. Dr. McGee continued to increase enrollment.
Soon thereafter, I started following the chain of command within
the medical college and sounding the alarm for what I saw as serious
non-compliance with the Federal regulations that were put in place to
protect human subjects. Eventually, this led me all the way to the top
of the medical college. By the time I blew the whistle in June of 2000,
the university had formed a committee that included the dean of the
medical college, the director of the office of research, the IRB chair,
lab director, Dr. McGee, our department chair and myself. The committee
was engaged in acts of cover-up instead of promptly reporting as
required by the Federal regulations.
What led me to contact the Office of Human Research Protections? It
was the pledge that I took when I became a registered nurse, that I
would be a patient advocate. I was haunted by many images, but
particularly one image continued to eat at me. It was the informed
consent process. By now, I knew that it had been coercive to promise
subjects that the melanoma vaccine offered hope of a cure.
Adverse events reporting were practically non-existent.
Unfortunately, this sad situation of not reporting adverse events is
the same across the Nation as was found by a study conducted by the
University of Maryland School of Medicine, Dr. Adil Shamoo.
Today, the university had adopted many positive changes in the way
research is conducted. The president of OU is David Boren. I believe in
David Boren. In my opinion, he is one of Oklahoma's greatest assets.
The university is in the process of implementing a model compliance
program and David Boren, the president of OU, is committed to doing so.
One of the changes is he has put in place is greater protections for
whistle-blowers. I am a graduate of OU and actually, in my own way, I
love the university.
Thank you, honorable Senators, for inviting me to speak.
______
The Chairman. Thank you very much. We are going to come
back with some questions, but we are very grateful for your
story, which is an enormously distressing. We will come back
for questions.
Dr. Speers.
STATEMENT OF MARJORIE A. SPEERS, EXECUTIVE DIRECTOR,
ASSOCIATION FOR THE ACCREDITATION OF HUMAN RESEARCH PROTECTION
PROGRAMS; FORMER ACTING EXECUTIVE DIRECTOR, NATIONAL BIOETHICS
ADVISORY COMMISSION
Ms. Speers. Good morning. I am Marjorie Speers, Executive
Director of the Association for the Accreditation of Human
Research Protection Programs, AAHRPP, and the former acting
executive director of the National Bioethics Advisory
Commission, NBAC.
While at NBAC--which had a charter that expired on October
3, 2001--I was the project director for a comprehensive report
on human research oversight entitled, ``Ethical and Policy
Issues in Research Involving Human Participants.''
Scientific investigation has enhanced quality of life. In
particular, great strides have been made in human research,
including the social sciences, the humanities, and the
biomedical sciences. As these knowledge areas have developed so
rapidly, the research community has been challenged to keep
pace with the ethical and moral implications of its work.
NBAC scrutinized the adequacy of the entire system for
protecting human research participants. The final report
proposed 30 recommendations for changing the oversight system
that would ensure all research participants received
appropriate protection. Today I will focus on three
recommendations that are essential to improving protection.
First, protection should be available to participants in
both publicly and privately sponsored research. This
recommendation is vitally important, because it responds to
concerns about research conducted by Federal agencies that do
not follow the Common Rule, or privately-funded research that
is not regulated by the Food and Drug Administration. It is
ethically indefensible to not protect each and every
participant in research.
Implementing such a system, however, is difficult given the
current organization of our oversight system. Federal
legislation should be enacted to create a single independent
Federal office to lead and coordinate the oversight system, and
a single set of regulations and guidance should be created that
would apply to all types of research involving human
participants.
These two recommendations are key pieces to building a
comprehensive research oversight system with policies that can
be consistently and uniformly applied.
The Common Rule is separately codified in regulation by 15
Federal agencies and followed by two other Federal agencies.
However, differences exist among the agencies in how they apply
the Common Rule. NBAC stood strongly behind establishing a
single independent Federal office with the authority to issue a
single set of regulations and guidance. Such an office can be
responsive to the changing needs of the research system,
revising policy as necessary, and serving as a centralized
enforcement authority.
Finally, the NBAC report strongly reinforces creating a
culture of concern and respect in the entire research
community. An oversight system will succeed to the extent that
those involved in human research recognize their ethical
obligations to protect participants.
The NBAC report recommends that the Federal Government and
professional organizations promote educational training in
human research protection, certification for individuals, and
accreditation for institutions.
The responsibility for protecting research participants is
a shared one. The Government and private sector have important
roles to play. I am here today to also testify on behalf of
AAHRPP. AAHRPP uses a voluntary, peer-driven, educational model
of accreditation. AAHRPP's goals are to recognize institutions
that meet high standards and assist the research community in
improving its efforts to protect the rights and welfare of
research participants. We believe this voluntary self-
regulation by the research community, along with oversight by
an independent accrediting body, is the best strategy for
making research as safe as it possibly can be.
AAHRPP's standards meet all regulatory requirements and in
some cases exceed them. With these comprehensive standards, we
can raise the level of protection beyond the minimal level set
by the Government. The standards make clear that protecting
research participants is not the sole responsibility of the IRB
but a duty shared by everyone who conducts research.
Institutions now have a clear idea of the high expectations
that they must meet, and because they know the Government
recognizes accreditation as a valuable means for enhancing
human research protection, accreditation will be eagerly
embraced.
Accreditation has an important place in the overall scheme,
improving protection programs, making research safer, and
ultimately, preserving and justifying public confidence in
research.
Thank you for the opportunity to address the committee.
[The prepared statement of Ms. Speers follows:]
Prepared Statement of Marjorie A. Speers
Good morning. I am Marjorie Speers, Executive Director of the
Association for the Accreditation of Human Research Protection
Programs, known by its acronym, AAHRPP. I am the former acting
executive director of the National Bioethics Advisory Commission
(NBAC). While at NBAC--which had a charter that expired on October 3,
2001--I was the project director for a comprehensive report on human
research oversight entitled ``Ethical and Policy Issues in Research
Involving Human Participants.'' That report was presented to the
President on August 20 of last year. In my NBAC capacity, I would like
to share several of the major recommendations from that report with you
today.
Clearly, scientific investigation has extended and enhanced quality
of life, and is one of the foundations of our society's economic,
intellectual, educational, and social progress. In particular, great
strides have been made in human research, including the social
sciences, the humanities, and the biomedical sciences. The American
research enterprise is the leader--not to mention, the envy--of the
international scientific community.
As these capabilities and knowledge areas have developed so
rapidly, the research community has been challenged to keep pace with
the ethical and moral implications and operations of its work. NBAC was
not alone in its deliberations on this matter; numerous studies
addressing participant protection have been conducted by both
governmental and private organizations, including the Institute of
Medicine, the General Accounting Office, the Office of the Inspector
General in the Department of Health and Human Services, the Association
of American Medical Colleges, and the Association of American
Universities. All of these studies have underscored the need for more
careful, thoughtful, systematic human research participant protections.
In preparing its report, NBAC scrutinized the adequacy of the
entire system for protecting human research participants, focusing on
the current patchwork of regulations described as the ``Common Rule''
and examining the full range of research with human beings sponsored by
both the Federal Govemment and the private sector. The final report
proposed 30 recommendations for changing the oversight system at the
national and local levels that would ensure all research participants
receive appropriate protections and remove unnecessary burdens. Today,
I will focus on three recommendations that are essential to improving
protection.
Recommendations 2.1, 2.2, and 2.3 are the crux of NBAC's findings.
``Recommendation 2.1: The Federal oversight system should protect the
rights and welfare of human research participants by (1) independent
review of risks and potential benefits, and (2) voluntary informed
consent protection should be available to participants in both
publicly- and privately-sponsored research. Federal legislation should
be enacted to provide such protection.''
This recommendation is vitally important because it responds to
concems about research conducted by Federal agencies that do not follow
the common rule or privately-funded research that is not regulated by
the Food and Drug Administration (FDA). In both scenarios, research
participants are simply not protected by the current oversight system.
It is ethically indefensible to not protect each and every participant
in research.
Implementing such a recommendation, however, is quite difficult
given the current organization of our oversight system, which leads to
Recommendations 2.2 and 2.3. ``Recornmendation 2.2: To ensure the
protection of the rights and welfare of all research participants,
Federal legislation should be enacted to create a single, independent
Federal office, the National Office for Human Research Oversight
(NOHRO), to lead and coordinate the oversight system. This office
should be responsible for policy development, regulatory reform (see
Recommendation 2.3), research review and monitoring, research ethics
education, and enforcement.''
``Recommendation 2.3: A unified, comprehensive Federal policy
embodied in a single set of regulations and guidance should be created
that would apply to all types of research involving human participants
(see Recommendatlon 2.2).''
These two recommendations are key pieces to building a
comprehensive research oversight system with policies that can be
consistently and uniformly applied. The Common Rule is separately
codified in regulation by 15 Federal agencies and followed by two other
Federal agencies under an Executive Order and public law, but a number
of other Federal agencies that conduct research do not comply with the
Common Rule. Even within the 17 agencies that follow the Common Rule,
differences exist among the agencies in how they apply the Common Rule.
NBAC discovered, for example, that regulatory coverage for vulnerable
populations in research, such as children, is inconsistent across the
Federal Government, which is particularly worrisome given that most
Federal departments conduct research involving individuals who are in
some way vulnerable.
NBAC stood strongly behind the need to establish a single,
independent Federal office with the authority to issue a single set of
regulations and guidance. This recommendation is not meant as a
criticism of the Office of Human Research Protection within the
Department of Health and Human Services; rather, NBAC recognizes the
need for a Federal office to exist independently and outside of a
Federal department or agency that sponsors research and be responsive
to the ethical issues of all fields of research, not just those of
primary concern to the Department of Health and Human Services. Such an
office can be responsive to the changing needs of the research system,
revising policy as necessary, and serving as a centralized enforcement
authority. Currently there is no effective means to do so; the agencies
who are signatories to the Common Rule have not been able to make
changes to it in the last 11 years, even though the need for changes
has existed.
Regulations should address basic ethical standards that are common
across all research types, such as informed consent, vulnerability, and
privacy and confidentiality. In addition, guidance should be offered
that assists in interpreting basic regulations in different areas of
research. A wide variety of research, from clinical trials to social
science methods, is currently regulated under the same set of Federal
rules. However, these rules were originally written at the National
Institutes of Health and do not always appropriately address the
ethical issues in research outside of the biomedical context. With
fewer and flexible regulations and more appropriate guidance on how to
apply the regulations to different types of research, the oversight
system recommended by NBAC would be more responsive to investigators'
and participants' concerns.
While NBAC's primary goal was to make recommendations that would
improve protections for research participants, it was also interested
in identifying ways to reduce the unnecessary burdens within the
current oversight system. Federal regulation and guidance should
require ethics review and oversight that is commensurate with the
nature and level of risk in the research. For example, NBAC
recommiended that the regulations should permit institutions to use
approval procedures other than full IRB review when research involves
no greater than minimal risk.
Adopting NBAC recommendations would go far in ensuring the
protection of research participants in a manner that encourages and
facilitates research that is consistent with accepted ethical
principles.
Finally, the NBAC report strongly reinforces the need for a culture
of concern and respect in the entire research community. An oversight
system will succeed to the extent that those involved in human research
recognize their ethical obligations to protect participants. The NBAC
report recommends that the Federal Government and professional
organizations promote educational training in human research
protection, certification for individuals, and accreditation for
institutions. If this cutural shift can occur, we will arrive at a
comprehensive, flexible system based on ethical principles and focused
on ethically substantive requirements that should maximize protections
for research participants.
The responsibility for protecting research participants is a shared
one. The Government and the private sector, universities in particular,
have important roles to play. I'm here today to also testify on behalf
of a new, private sector organization, AAHRPP.
From my years of overseeing research, to my role at NBAC, to my
current position at AAHRPP, it has become clear to me that there is no
single problem with the current oversight system for protecting
research participants crying out for urgent repair, but there are
several problems that need to be corrected in a comprehensive manner.
This is a time for a fresh start, and for us to examine all aspects of
the oversight system.
In addition to the three major recommendations that I outlined from
the NBAC report, the commission took a stand in favor of accreditation:
``Recommendation 3.4: Sponsors, institutions, and independent
institutional review boards should be accredited in order to conduct or
review research involving human participants. Accreditation should be
premised upon demonstrated competency in core areas through
accreditation programs that are approved by the Federal Government.''
AAHRPP uses a voluntary, peer-driven, educational model of
accreditation. By requiring institutions to meet an explicit set of
standards for protection, AAHRPP's goals are to recognize institutions
that meet these high standards and assist the research community in
continuously improving its efforts to protect the rights and welfare of
research participants. We believe that voluntary self-regulation by the
research community, along with oversight by an independent accrediting
body, is the best strategy for making research as safe as it possibly
can be.
The history of accreditation shows that it is successful when it
arises from the concerns of professionals engaged in the field, such as
in higher education. AAHRPP was founded by seven organizations that
bring diverse perspectives to this new enterprise: the Association of
American Medical Colleges, representing medical schools, teaching
hospitals, and academic societies; Association of American
Universities, representing major research-intensive universities;
Consortium of Social Science Associations, advocating on behalf of
social and behavioral science organizations; Federation of American
Societies of Experimental Biology, the Nation's largest coalition of
biomedical research organizations; National Association of State
Universities and Land Grant Colleges, representing public universities
and land-grant institutions; National Health Council, representing
patient and health-related groups; and Public Responsibility in
Medicine and Research, respected for its more than 3 decades of
improving ethics in both medicine and research through education. The
views of research participants, the public, investigators, and sponsors
of research have been represented since AAHRPP's inception, and that
diverse representation continues on our 21-person board of directors,
our council on accreditation, and among our site visitors.
Now is the time for accreditation to take hold. The time is right
for several reasons: first, the Government has provided leadership and
clear guidance that accreditation has real potential for improving
performance and quality, and that it should be undertaken. Second, the
Government has exercised its enforcement options. Highly publicized
shutdowns of large research programs at academic institutions in the
past several years captured the attention of the research community--
and the Nation, and made it clear that Federal regulations for
protecting research participants were to be taken seriously.
Over the last year, with recognition by the research community of
the need to improve human research protections and the desire to move
deliberatively and swiftly, AAHRPP has taken governmental policy and
developed it, with the input from a diverse range of professionals and
the public, into a clear set of accreditation standards. As the NBAC
report states: ``The choice of standards for these [accreditalion and
certification] programs and the criteria for evaluating whether an
institution has met them are critically important.''
AAHRPP's standards meet all regulatory requirements and, in some
cases, exceed them. With these comprehensive standards, we can raise
the level of protection beyond the minimal level set by the Government.
AAHRPP's standards are significant in several other respects: they are
broad and flexible so that they will be meaningful to a full range of
research types; certainly in clinical research, but also in social
science, historical, and business research. The standards can be
applied in a variety of research settings, including universities,
hospitals, Government agencies, and independent institutional review
boards. Finally, the standards make clear that protecting research
participants is not the sole responsibility of the IRB, but a duty
shared by everyone who conducts research. Entities seeking
accreditation must meet standards that address the obligations relating
to the organization, IRB, investigator, sponsor, and participant. This
is an important point, as much of the dialogue and debate on human
research protections has focused on the role and function of the IRB.
While there is no doubt of the key role played by IRBs, AAHRPP believes
strongly that the protection of human research participants is a
collective responsibility of the entire research community, beginning
with institutional leadership and extending to the most junior staff.
With the introduction of these standards, institutions now have a
clear idea of the high expectations they must meet. And because they
know the Government recognizes accreditation as a valuable means for
enhancing human research protections, accreditation will be eagerly
embraced.
In closing, I'd like to say that the accreditation of human
research protection programs is not a panacea. But in conjunction with
other efforts underway and other recommendations yet to be implemented,
accreditation has an important place in the overall scheme. The
benefits of accreditation seem clear: improving protection programs
across the entire research community, making research safer and
reducing unnecessary harm, and ultimately, preserving and justifying
public confidence in research.
Thank you for the opportunity to address the committee.
The Chairman. Thank you very much.
Dr. Johnson.
STATEMENT OF DR. CHARLES A. JOHNSON, ASSOCIATE DIRECTOR OF
SPECIALTY BIOTHERAPEUTICS, GENENTECH, INC., ON BEHALF OF THE
BIOTECHNOLOGY INDUSTRY ORGANIZATION
Mr. Johnson. Good morning, Mr. Chairman, members of the
committee.
My name is Dr. Charles Johnson. I am Associate Director of
Specialty Biotherapeutics at Genentech, which is a leading
biotechnology company headquartered in South San Francisco,
California.
I am here today representing the Biotechnology Industry
Organization. BIO represents more than 1,000 biotechnology
companies, academic institutions, and State biotechnology
organizations.
Thank you, Mr. Chairman, for holding this hearing on such
an important issue, which is how to facilitate critical medical
research while effectively protecting those who voluntarily
participate.
As you and your colleagues examine this issue, I urge you
to remember two critical facts. First, participants in research
are volunteers, meaning that we must do all we can to ensure
that they have the utmost confidence that they will be
protected. Second, medical research has and will continue to
lead to cures and treatments for millions of Americans
suffering from disease.
Mr. Chairman, medical research is a heavily regulated
activity. Our products and manufacturing processes are
regulated by the Food and Drug Administration. Our research
protocols are reviewed and scrutinized by institutional review
boards. Moreover, virtually all States have developed
regulations that affect research. In addition, the HIPAA
privacy rule imposes a new layer of review and oversight over
our research.
Despite this extensive regulation, some have called for
additional restrictions to be instituted relating to consent,
IRB accreditation and review, and conflicts of interest. From
many different perspectives, reform of the existing system is
not only necessary and desirable, but it appears inevitable.
Based on BIO's analyses, we have identified the following
issues. There are multiple and overlapping layers of review.
There is an already overwhelmed IRB system. There are rules
regarding review of research involving human participants that
are inappropriate for research involving medical archives and
data. There are differing State laws. And finally, there are
perceived conflicts of interest.
The current regulatory system applies multiple overlapping
layers of review for sponsors of every clinical protocol.
Trials that take place in several locations must be reviewed by
several different bodies. Each can require changes in trial
design, the informed consent form, or any other protocol
component.
An additional complication is the HIPAA privacy regulation
which governs the use and disclosure of medical information.
BIO believes that Congress should eliminate these multiple
separate legal reviews. Researchers should be allowed to use
patient information without authorization where those
researchers either secure informed consent or obtain a waiver
of authorization by an IRB or privacy board.
We note that the HHS recently proposed modifications to the
HIPAA privacy rule that would streamline the requirements for
waiver of authorization. BIO supports these proposed changes,
and we urge the HHS to adopt these modifications in its revised
final rule.
In addition, BIO believes that IRBs should be held
accountable, and therefore supports the development of a system
of accreditation. Currently, research studies are reviewed
using the same criteria regardless of the type of risk faced by
the research participant. BIO supports an alternative approach
that makes regulatory oversight commensurate with the risk.
Such a system would establish one set of requirements for
research that involves intervention and a separate set of
requirements tailored to the unique issues raised by research
using medical records and tissue archives.
This new framework would be applicable to all research
regardless of its funding resource. Last year, the National
Bioethics Advisory Commission also endorsed this notion.
A related problem is that researchers are subject to a
patchwork of different and often inconsistent State laws. This
confusing regulatory environment will slow important research
efforts. BIO believes that Congress should create one national,
uniform set of rules governing research. These national
standards would allow researchers to apply strong informed
consent, privacy, and other research protection rules that are
consistent across all States.
Finally, there is a persistent perception that the presence
of private money in the health care setting creates conflicts
of interest. BIO strongly believes that the best way to both
protect patients and the integrity of research is to assure
that research protocols are independently reviewed and that all
financial interests are disclosed. In this regard, BIO and the
National Bioethics Advisory Commission are in agreement.
Mr. Chairman, thank you for this opportunity to testify.
BIO companies believe that it is critical to make sure that
research participants are protected; yet we must also ensure
the continuation of valuable, potentially life-saving research.
Decades of responsible science have shown that protecting
research participants and promoting research are mutually
attainable. BIO looks forward to working with the committee as
it pursues both of these goals.
Thank you.
[The prepared statement of Charles A. Johnson, M.D.
follows:]
Prepared Statement of Charles A. Johnson, M.D.
Good morning, Mr. Chairman and members of the committee. My name is
Dr. Charles Johnson. I am associate director of specialty
biotherapeutics at Genentech, Inc., a leading biotechnology company
headquartered in South San Francisco, California. I am here today
representing the Biotechnology Industry Organization (BIO). BIO
represents more than 1,000 biotechnology companies, academic
institutions and State biotechnology centers in all 50 States and 33
other nations. BlO's members are involved in the research and
development of medical, agricultural, industrial and environmental
biotechnology products.
Most of the hard work in our industry is directed toward research
on currently unmet medical needs: new therapies and cures for various
cancers, Alzheimer's and Parkinson's diseases, diabetes, heart disease
and hundreds of other debilitating and life-threatening illnesses.
Thank you, Mr. Chairman, for holding this hearing on such an
important issue: how to effectively protect those who voluntarily
participate in our research while, at the same time, facilitating
critical medical research. As you and your colleagues examine this
issue, I urge you to remember two critical facts:
First, participants in research are volunteers, meaning that we
must do all we can to ensure that they have the utmost confidence that
they will be protected.
Second, medical research has and will continue to lead to cures and
treatments for millions of Americans suffering from diseases. One-
hundred-seventeen biotechnology products have helped a quarter-billion
people worldwide thus far, and another 350 biotech medicines targeting
more than 250 diseases are in late stage development. Many of these are
diseases that are currently incurable.
Much attention has been given lately to issues surrounding the
protection of the volunteers who participate in our research. As you
are already aware, Mr. Chairman, medical research is a heavily
regulated activity--our products and manufacturing processes are
regulated by the Food and Drug Administration (FDA), and our research
protocols are reviewed and scrutinized by institutional review boards
(IRBs) under an extensive set of Federal regulations governing research
(the Federal Common Rule). Moreover, virtually all States have
developed regulations that affect research. In addition, the HIPAA
privacy rule imposes a new layer of review and oversight over our
research.
Despite this extensive regulation, some have called for additional
restrictions to be instituted relating to consent, IRB accreditation
and review, and conflicts of interest.
From many different perspectives, reform of the existing system is
not only necessary and desirable, but appears inevitable. In light of
this, BIO companies have spent considerable time evaluating the
existing system of research oversight. Based on this analysis, we have
identified several key concerns and areas for improvement. They are:
Multiple and overlapping layers of review, leading to confusion and
inefficiency for participants as well as research sponsors;
New regulations that will increase the burden on an already
overwhelmed IRB system;
An existing framework for review of research involving human
participants that is inappropriate for research involving medical
archives or data;
Differing State laws govern and complicate the form of research
review and format of consent required in each State; and
A strong and persistent perception that the presence of private
money in the health care setting creates conflicts of interest in
researchers that may affect results and the quality of care provided to
research participants.
Multiple Layers of Review
The current system of research review relies heavily on IRBs.
Historically, they have filled the important role of providing
independent review of research projects. However, the current
regulatory system applies multiple overlapping layers of review for
sponsors of every clinical protocol. Specifically, FDA regulations
require the sponsor to obtain review by an IRB, and each investigator
affiliated with an academic institution must have its IRB separately
review and approve every aspect of the research protocol under Federal
regulations that apply to institutions that receive Federal grant
money. Consequently, trials that take place in several locations must
be reviewed by several different review bodies. Each can require
changes to trial design, the informed consent form, or any other
protocol component. This adds enormous complexity and expense to a
research project.
An additional complication is the HIPAA privacy regulation
governing the use and disclosure of medical information. That
regulation adds an entirely new authorization process to the informed
consent already required from every research participant and/or data
subject. It requires that researchers get an individual's
authorization--or a waiver of authorization from an IRB or privacy
board--to access and use protected health information for research
purposes. The IRB's review of this issue is in addition to its
consideration of the other risks present to research participants.
Thus, two distinct assents are now required of each research
subject: informed consent to participate in research and
``authorization'' to disclose and use an individual's protected health
information in research under the HIPAA privacy regulation.
As to the overall issue of the growing multiple layers of review,
BIO believes Congress should eliminate the multiple separate legal
reviews currently required for clearance of a sponsored clinical
research protocol. Mechanisms should be developed to centralize and
streamline review of research projects. In addition, researchers should
be allowed to use patient information without authorization where
researchers (1) secure individuals' informed consent or (2) obtain a
waiver of consent by an IRB or privacy board, in whole or in part,
where waiver is warranted under existing law. In addition, we support
modifying the criteria for waiver of consent/authorization for use of
patient data and archival information both in the privacy rule and
under the current Common Rule to enhance access to much-needed data
where the confidentiality risks present to the individual are minimal.
In this regard, we note that HHS recently proposed modifications to
the HIPAA privacy rule that would simplify and streamline the
requirements for authorization by IRBs and privacy boards. BIO supports
these proposed changes as an important first step in eliminating
unnecessary and inappropriate regulatory hurdles for the conduct of
research, and we urge HHS to adopt these modifications in its revised
final rule. Without these changes, the existing waiver of authorization
standard, in particular, is unworkable and will have a significant
adverse impact on research activities.
In addition, since IRBs play such an important role in the research
oversight system, BIO believes they should be held accountable for
meeting their responsibilities. Some have recommended that a system of
accreditation for IRBs be developed. BIO is intrigued by the concept of
IRB accreditation and would be supportive of exploring the issues
involved.
Review Commensurate with Risk
Currently, research studies are reviewed using the same criteria
regardless of the type of risk faced by the research participant. For
example, a research study that entailed testing a drug on individuals
will be regulated the same way as a study that relied only on a review
of medical records. This process does not acknowledge the different
types of risk faced by the research subjects in each study.
Participants in the first study will confront safety risks, while
subjects in the second study face risks related almost entirely to
confidentiality.
The regulatory structure stems from the history of our oversight
system that based Federal review on factors other than the risk to the
research participant, such as presence of Federal funding or
regulation. BIO believes that this paradigm is no longer appropriate--
for researchers or research participants. As we learn more about how
genomic information can be used to cure disease, medical records review
and archival research will grow in importance.
Thus, BIO supports an alternative approach that makes regulatory
oversight commensurate with the risk to the research participant. That
type of system would establish one set of requirements for research
that involves intervention or interaction with individual research
participants and a separate set of requirements tailored to the unique
issues raised by research using medical records and tissue archives.
This new framework would be applicable to all research, regardless of
its funding source. It is important to note that in a report issued
last year, the National Bioethics Advisory Commission (NBAC) made a
similar observation, and endorsed the notion that review should be
commensurate with the types of risk presented by the research.
Differing State Laws
A related problem is that researchers are subject to a patchwork of
different, and sometimes inconsistent, State laws. Although there are
extensive Federal rules regarding research, State laws govern issues
such as the form of review and format of additional documentation of
consent.
This is often problematic for researchers. For example, new State
laws pertaining to genetic analysis are quite restrictive, requiring
additional separate consents and imposing onerous requirements
regarding the use and retention of tissue and blood samples that
sometimes are inconsistent with FDA requirements.
A 1999 study of State health privacy laws showed the vast
differences among the States. In addition to existing differences,
State laws in this area are in flux. During the 2000 State legislative
session, 26 States debated laws concerning privacy. This turbulent
environment will slow important research efforts.
It is important to note that the differences among States do not
seem to start from differences in the level or degree of protection,
but reflect different State legislatures' views of the specific
procedures or requirements for accomplishing the same objective.
Nonetheless, the requirements and penalties are different enough to
require every researcher to hire lawyers to assure compliance with the
laws of more than 50 States and local jurisidictions in designing
informed consent documents for a multi-state trial.
To remedy this problem, BIO believes that consideration should be
given to creating one national, uniform set of rules governing
research. National standards would allow researchers to create informed
consent and other procedures that will be legal in all States. These
Federal research standards should pre-empt State laws that create
conflicting obligations regarding research participants from different
States.
Conflicts of Interest
There is a strong and persistent perception that the presence of
private money in the health care setting creates conflicts of interest
in researchers that may affect results and/or the quality of care
provided to research participants. This perception has the potential to
damage the public's trust in biomedical research.
We must take steps to maintain public confidence. However, it is
important to remember that the tremendous investment by the private
sector over the past 2 decades has led to remarkable medical
breakthroughs. Government policy to encourage private investment has
been a major factor in the development of a biotechnology industry in
the United States that is the envy of the world.
The best ways to both protect patients and the integrity of
research is to ensure that research protocols are independently
reviewed and that all financial interests are disclosed. We understand
that the academic institutions are in the process of carefully
reviewing conflict of interest issues and are attempting to generate a
unified position and set of policies regarding financial interests. In
the meantime, BIO agrees with the direction of the NBAC
recommendations, which is to focus the discussion in a way that
encourages disclosure of financial relationships between and among
researchers, investigators and IRBs, but does not prohibit, nor
otherwise impose, rigid restrictions on the existence of such
relationships.
Conclusion
Mr. Chairman, we believe that it is appropriate to review the
existing regulatory structure for research and urge that consideration
be given to BlO's four key principles: (1) eliminate multiple separate
levels of review; (2) modify the regulatory framework so that review is
commensurate with the type of risk involved for the research
participants; (3) preempt State laws that create conflicting
obligations; and (4) work with academic medical centers and other
affected entities and individuals to develop an approach for addressing
real and perceived conflicts of interest.
BIO companies believe that it is critical to make sure that,
despite the changes in our research infrastructure over the years,
participants continue to be protected. We firmly believe that
addressing these key issues described above will enhance the level of
protections we can guarantee participants in our research projects.
In protecting our research participants, we must also ensure the
continuation of valuable--potentially life-saving--research. We are
fortunate to live in an era of enormous promise as scientists begin to
access a vast library of genetic information with the goal of improving
our medical interventions. Decades of responsible science have shown
that protecting research participants and promoting medical research
are mutually attainable.
BIO looks forward to working with the committee as it pursues both
goals.
Thank you.
The Chairman. Thank you very much.
Dr. Charles.
STATEMENT OF DR. P. DAVID CHARLES, ASSISTANT PROFESSOR OF
NEUROLOGY, VANDERBILT UNIVERSITY MEDICAL CENTER, ON BEHALF OF
THE NATIONAL ALLIANCE OF MEDICAL RESEARCHERS AND TEACHING
PHYSICIANS
Dr. Charles. Thank you, Mr. Chairman and members of the
committee.
I appreciate the opportunity to briefly tell you of my
experiences as a clinical investigator and my views on patient
protection. In my role as director of the Movement Disorders
Clinic at Vanderbilt University, I work as a physician treating
patients with Parkinson's disease and related disorders, and
spasticity, which affects children and adults who have suffered
injury to the brain or spinal cord. In my role as neurology
residency program director, I teach young physicians who are
training to become neurologists, and I am responsible for their
educational program.
The work that I do day-to-day, however, is clinical trials
to develop new drugs, new biologics, and new medical devices
for the treatment of Parkinson's disease and related disorders
in spasticity.
In the past, I took leave from my health practice to serve
as a health policy fellow on the staff of this committee, under
the direction of Senator Frist, and while here, I would often
meet people with our Government who felt that technology in
health care was a bad thing, because technology in health care
would increase the cost of health care.
This was surprising to me as a physician, because I knew
that new technologies in health care were responsible for so
many great advances in health care--speeding diagnosis, less
invasive treatments, and improved productivity and quality of
life.
Following my experience here in the U.S. Senate, my family
and I traveled to France, where I served as a Fulbright
Scholar, conducting research on Parkinson's disease to bring a
new line of treatment and investigation back to Vanderbilt.
Upon my return to the United States, my colleagues and I
formed the National Alliance of Medical Researchers and
Teaching Physicians. This is a group of physicians and
researchers who advocate for the benefits of technology in
health care--the electronic medical record, technologies that
speed basic science research, improve diagnostic procedures and
equipment, implanted medical devices, and telemedicine. I felt
this group was needed because I learned that many people inside
our Government do not understand that new technologies improve
our Nation's health care and the health of our Nation and that
clinical research that involves human subjects as how those new
drugs, new biologics, and new medical devices are brought to
everyday use.
At Vanderbilt, I have had the opportunity to serve as
principal or co-investigator in over a dozen clinical trials,
so I present to you the views of a rank-and-file clinical
investigator actively conducting clinical trials. To answer the
question of this hearing, in short: are the current protections
adequate? Yes. Are they disorganized, poorly coordinated, and
in need of improvement? Yes.
The National Alliance of Medical Researchers and Teaching
Physicians supports a single, uniform system for federally-
funded and regulated research that involves human subjects that
follows these basic principles: A comprehensive and uniform set
of Federal protections; strong, informed and independent
oversight by institutional review boards; effective privacy
protections that do not prevent important archival research and
quality improvement; and strong guidelines governing conflicts
of interest that require full disclosure of such arrangements.
Embracing technology in health care will allow terrific
improvements in the quality of care and dramatic cost savings
and improve patient quality of life through the following:
Improving the ability to coordinate care across specialty
fields from both physical and mental health perspectives;
ensuring the use of evidence-based practice of medicine; and
dramatically reducing medical errors.
We all recognize that safeguarding the health of those who
serve as participants in clinical trials and preserving the
integrity of research is essential. These are common goals
supported by the clinical research community, the general
public, and by members of this committee, I am sure.
The joint challenge of the medical profession and the
public policymakers is to strengthen safeguards without
creating new regulations so burdensome that they make it
impossible to complete vital research.
Society loses if regulations to protect the public become
obstacles to serving the public. That principle applies to the
issue of protecting the health of human participants in
clinical trials and to the issue of preventing conflicts of
interest in the research community.
I would just add that clinical researchers share this
committee's urgency to reinforce the safety and integrity of
clinical research practices. Clinical research was essential to
the medical breakthroughs that made the last century the
pivotal century in health care and made America's health care
the best in the world. To build on that record in the 21st
century, we need the full confidence of the American people.
Mr. Chairman, that concludes my remarks. I look forward to
questions.
[The prepared statement of P. David Charles, M.D. follows:]
Prepared Statement of P. David Charles, M.D.
Mr. Chairman and members of the committee, my name is David
Charles. I am a physician and Director of the Movement Disorders Clinic
and Neurology Residency Training Program at Vanderbilt University
Medical Center. I also serve as chairman of the National Alliance of
Medical Researchers and Teaching Physicians, a coalition of doctors,
scientists and health care providers dedicated to the advancement of
medicine through technology. I am testifying today in my role as
chairman of the National Alliance of Medical Researchers and Teaching
Physicians.
It is a special privilege for me to comment on the important issue
before this committee and I greatly appreciate the opportunity.
As a doctor and an American, I am gratified that the Public Health
subcommittee includes some of the most distinguished names in the U.S.
Senate. I am delighted that this committee includes my fellow
Tennessean and clinical researcher, Senator Frist.
My comments represent the perspective of someone who works full-
time in clinical research and teaching. And I might start by asking the
semi-rhetorical question: ``What is clinical research?'' For our
purposes here, let's think of clinical research as the phase of medical
science where the discoveries of the laboratory meet the realities of
the human body.
No drug, no medical device, no surgical procedure will ever prove
its value to cure disease or ease suffering until it has been tested on
people. Yet the investigation of new treatments on humans, even if the
testing may lead to a cure of a devastating disease, arouses our
sensitivities and concerns, as well it should.
We all recognize that safeguarding the health of those who serve as
subjects in clinical trials and preserving the integrity of the
research process is essential. These are common goals supported by the
clinical research community, the general public, and, I am sure, by the
members of this committee.
In terms of the issues under consideration by the committee, I
might paraphrase the oft-quoted Mr. Churchill and say: ``Never have so
many disagreed so little about so much.''
But, I am also reminded of the cynical summary Calvin Coolidge gave
one Sunday afternoon of a sermon he had heard that morning.
``The preacher talked about sin,'' said Coolidge. ``He was against
it.''
Today, we are all against exposing people involved in clinical
trials to excessive risk. We are all opposed to violating the privacy
of medical data during the research process. And certainly, we are all
concerned about potential conflicts of interest among those who conduct
clinical research and the health care companies that sometimes fund
such research.
But, being opposed to those things is the easy part. Improving the
safeguards already in place is much more complicated and difficult.
We have to recognize, for instance, that clinical researchers
testing and refining new drugs or medical devices have to work closely
with the companies that created those products. Vital medical research
couldn't take place without that kind of cooperation.
Can we still conduct clinical research that might involve potential
conflicts of interest? We can so long as there are strong safeguards in
place that protect the outcome of the research and the well-being of
the human subjects.
The joint challenge of the medical profession and public
policymakers is to strengthen safeguards without creating new
regulations so burdensome that they make it impossible to complete
vital research. Let's not throw the baby out with the bath water.
And let me emphasize--my concern about burdensome regulations is
not code for eliminating vigorous oversight, by Government and by our
own profession. Like most doctors, I recognize the need to have others
looking over every step of my work during a clinical trial to safeguard
against potential conflicts of interest and to protect the health,
well-being, and privacy of the people participating. That kind of
scrutiny comes with the territory in our profession.
But, society loses if regulations to protect the public become
obstacles to serving the public. That principle applies to the issue of
protecting the health of human subjects in clinical trials and to the
issue of preventng conflicts of interest in the research community.
When something goes dangerously wrong in a clinical research
effort, it gets public attention and feeds the appetite for more
regulations. That is understandable. For the sake of perspective,
though, let's remember that we are talking about a relative handful of
failures against a century's worth of successes.
The abomination of the Tuskegee Syphilis Study still taints public
attitudes toward human testing, 30 years after the study was ended. The
tragic death of 18-year-old Jesse Gelsinger during a gene transplant
study in 1999 left us asking once again, how can we make the process
even safer?
Much of the regulations and governing philosophy already in place
is effective. All of it is well-intentioned. But the system still gives
conflicting signals to researchers and the hybrid mix of agencies
involved makes it difficult to rationalize those signals. The result
can sometimes be research paralysis.
The practical reality is that it can be very, very difficult to
navigate the extreme caution and regulatory burden necessary to gain
approval to launch a clinical trial. Once the clinical trial is
approved, however, it can be even more difficult to actually identify
people willing to participate in an investigation and to find the
necessary number of people with a particular disease that meet the
requirements of the clinical trial. The thicket of reviews required for
a clinical trial can be dense to the point of being impenetrable. At
times, I feel that I need a second career just to handle the paperwork.
As a result, clinical trials simply aren't being done at the rate
we all recognize that they should. This is an example of regulations
having the right intent, but the wrong results. And it's just one
example.
I think this committee could do this Nation a great service by
simplifying the clinical research regulations and clarify who has
responsibility for enforcing them. I believe this can be done at the
same time you tighten those regulations and promote even more safety
and integrity in the research process.
The National Alliance of Medical Researchers and Teaching
Physicians would like to commend the Federal Department of Health and
Human Services and the General Accounting Office for the study they
have already made of this issue. The Alliance has also given this our
serious attention. As a result, we support the following principles for
any new Federal legislation:
A comprehensive and uniform set of Federal protections.
Strong, informed, and independent oversight by
Institutional Review Boards (IRBs).
Effective privacy protections that do not prevent
important archival research.
Strong guidellnes governing conflicts of interest that
require full disclosure of such arrangements.
As a first principle, we strongly recommend a comprehensive and
uniform set of Federal laws assuring that all research is designed and
carried out in accord with high ethical standards for protecting human
subjects from research risks. As you know, the Federal Government now
relies on what's known as the ``Common Rule.''
This is a set of requirements endorsed by 17 Federal departments
and agencies. The Common Rule is the closest thing the Federal
Government has to a comprehensive, uniform set of regulations covering
human testing. In practice, however, individual agencies routinely
depart from the Common Rule and make policy on their own, to meet what
they see as special circumstances. Today, investigators offen face
overlapping, confusing, and sometimes contradictory regulatory systems.
The Common Rule's provisions for protecting human subjects from the
risks of interventional research should be clarified. Equally
important, any proposed legislation should apply to all federally-
sponsored or regulated research with humans.
The Common Rule badly needs the momentum it would get from being
codified into Federal law. These statutes should include specific rules
for gaining the informed consent of research subjects, and define the
circumstances under which waiver of informed consent is justified.
However, there are legitimate concerns with codifying the Common Rule,
and we should be careful to ensure that the standards under any
legislation be flexible and able to adapt as science continues to
evolve.
Any set of rules is only as good as their enforcement. We recommend
that the enforcement and interpretation of new codified Federal
standards for interventional research be handled primarily by
strengthened institutional review boards (IRBs).
The new institutional review boards would have clearer authority
and more demanding standards for board membership. We recommend that
these new boards be overseen by the existing Office of Human Research
Protection.
These IRBs would be responsible for reviewing and approving or
rejecting all proposed protocols for interventional research.
To protect the independent judgment of these boards, the review
fees of the boards could not be paid with equity interest in the
company sponsoring the proposed research, or as a share of any
royalties arising from the research.
In the important area of protecting the privacy of the medical data
of individuals, we support the Secretary of Health and Human Services'
March 27, 2002, proposal to modify the Federal medical privacy rule. We
support a continued effort to improve guidelines for research that
analyze databanks of medical records, health benefit claims and
archives of biological materials and genetic information. The goal
should be to establish mechanisms that minimize the risk to
individuals' privacy while protecting the ability to conduct much
needed research.
Consumers are already painfully aware of the vulnerability of their
personal data. The perceived lack of data security is the biggest
drawback to doing transactions on the internet. This only reinforces
the need to take the initiative in guaranteeing privacy protection for
medical data used in research.
One final, but major point, addresses the sensitive issue of
conflict-of-interest in the conduct of research.
In the belief that full disclosure is the best form of protection
for all concerned, we recommend that prior to evaluation of a research
protocol, Federal law should require:
That the research investigators disclose to the
appropriate institutional review board what arrangements have been made
for compensation.
That researchers must disclose up-front whether or not
they or their immediate families have a proprietary interest in the
outcome of the proposed research.
In this area of avolding conflicts-of-interest involving
compensation, we also believe it would be beneficial for the IRB to be
authorized to consider whether:
A.--The arrangements for compensating researchers or their
proprietary interests in the research might influence their judgment as
to the risk faced by a human subject participating in the research.
B.--Whether the arrangements for compensating human test subjects
might unfairly induce some prospective subjects to accept unreasonable
risks.
I would just add that clinical researchers share the committee's
urgency to reinforce the safety and integrity of clinical research
practices. Clinical research was essential to the medical breakthroughs
that made the last century the pivotal century in health care and made
America's health care the best in the worid.
To build on that record in the 21st century, we need the full
confidence of the American public.
Thank you.
The Chairman. I want to thank all of you. It will be
wonderful if we can take all the different points of view that
have been expressed here and come out with a recommendation
that incorporates your comments. But we want to let this panel
know, and others, that we are enormously interested in trying
to work through this process to avoid the kinds of egregious
situations that we have seen, and also with the understanding
that, I think, we have on this committee--that this is the
century of the life sciences. Whatever progress we saw made in
physics and math in the last century, it is here and now with
the life sciences, and this is going to be the cutting edge in
terms of health and I think, a wide variety of other areas, not
just the health of our fellow citizens, but many different
aspects of our society.
So we have an important responsibility to try to get this
right, and we need help and assistance, and all of you have
given this a good deal of thought, so we are going to be
drawing on you for your experience.
We will have 8-minute rounds, and I will ask staff to keep
track of the time.
Cherlynn, some people want to rely solely on voluntary
standards to protect subjects. Do you feel that voluntary
standards would prevent the kinds of abuses that you have
described?
Ms. Mathias. No, I do not. I believe that it must be
mandatory. For one thing, I do not think that people will do
voluntary standards. For example, when we think back to JAHCO,
the joint commission, it was not until the joint commission was
tied to Medicare that people really got on board with joint
commission whole-heartedly. I think the standards must be
mandatory, and that also, if it were voluntary, it would take
way too long to implement, and most places simply will not do
them.
The Chairman. Is it your sense that the good research areas
would comply, and you are concerned that some of the others
might not, and they are the ones that you would be the most
concerned about?
Ms. Mathias. Yes. I think the largest institutions and the
ones who have already faced regulatory problems, such as
Oklahoma University, Duke, and a variety of other places, would
be the first to sign up for voluntary compliance and
accreditation. But I think that most community facilities would
bow out of those.
The Chairman. Your story is amazing for so many different
reasons, but the fact is you notified so many different
individuals all the way up the process and the system--I count
at least four different levels--and still, you were shunted
aside and not taken seriously, which is obviously a matter of
enormous concern.
Do you think the violations of the human subject protection
that you described are unique at the University of Oklahoma, or
do you think there are similar problems at other universities?
Ms. Mathias. I think they are very widespread, and I think
it is not just at universities, but in community settings as
well. For example, just in the last several months, I have
become aware of doctors who purposely put people in trials who
were ineligible and gave them wrong doses of drugs on purpose
because they were planning to just treat the patient.
Physicians have a very difficult time distinguishing
between patients and medical practice and research and study
subjects. That ground becomes very hazy to them.
I am also aware of instances that have occurred in the last
6 months in devices where experimental devices were implanted
in people's hearts, and they were never told that they had had
experimental devices placed in their bodies until after the
fact; so they were never given informed consent properly to
have those experimental devices implanted.
I think the problems are widespread, and I see them on a
day-to-day basis, a lot of these problems, repeated over and
over again.
The Chairman. What is your sense about how the financial
conflicts of interest, either for the doctors conducting the
trial or for the university, contribute to the problems you
have described? In many instances, the doctors can receive a
benefit and the university as well.
Ms. Mathias. The conflicts of interest in the university
setting--more and more of the universities are relying upon
moneys generated for research and development. Even at the
University of Oklahoma, Dr. McGee was planning to make quite a
bit of money from patenting his vaccine, and I think that
played a part.
But conflicts of interest are even deeper than that.
The Chairman. Played a part in what? In keeping the
irregularities----
Ms. Mathias. Right, in keeping the irregularities. But even
in my own instance, I face conflicts of interest every day. My
performance is evaluated on how many people I enroll for
clinical trials--not by the quality of the data that I collect.
Rather, every month, I have to prove that I have enrolled so
many people in clinical trials, and that puts me in a very
conflicted situation when I do informed consent, because that
is what I am being judged on--by how many people I get on
trial. Sometimes, that puts you in a situation where you are
trying to talk people into going on clinical trials, and you
should not be talking them into anything.
The Chairman. The whole purpose of informed consent is to
give knowledge to the individuals and make them completely
aware of both the potential advantages and the potential side
effects of this. And you are saying that your evaluation is of
a number of people who are involved, and where you might give
balanced information, there is a financial or job performance
incentive to enroll more people.
Ms. Mathias. It is something that I even struggle with
myself, and I really try to be ethical, but there are times
when I am at the end of the month, and I have not met my quota,
and I think, ``Oh, my God, I have not met my quota of patients
that I am supposed to enroll this month.'' It puts us in a very
conflicted situation.
The Chairman. We did not get into the kind of harassment
that you faced, which was significant, and I did not get into
the work that David Boren, our former colleague, now president
of Oklahoma University, did when he learned about the ethical
abuses committed and instituted a number of measures to try to
deal with those. You have referenced that in a very positive
way, and I want the record to show both points, but I want to
move on if I can to Dr. Speers.
The commission reported that the current overlap of Federal
requirements for research subject protections can be confusing
to researchers and patients. How do you propose to minimize the
overlap without compromising patient safety? As you remember,
the initial panel that we had supported going back a long time
ago, we had a commission made up of ethicists. Their power was
just to propound ethical recommendations in the Federal
Register, and all the various agencies accepted those. Then,
Secretary Califano felt that each of the various Government
agencies and institutions should have their own panel, and we
have seen a lot of these emerge with the kind of challenge that
Dr. Johnson has pointed out, with overlap, duplication,
confusion.
But this is what I want to get to. What did the commission
report concerning the overlap of the requirements which can be
confusing? How do you propose to minimize that confusion?
Ms. Speers. The commission was concerned because it heard
from various groups--from institutions, IRBs, and
investigators--that the current set of regulations was
confusing. The commission recommended that there be a single
set of regulations and guidance and that the ethical principles
and standards that are common to all research should be
codified in regulation, and then, regulations should be
supplemented with guidance that would help investigators and
IRBs interpret how the regulations would be applied to
different types of research.
The Chairman. So effectively, you have an overarching
responsibility, and particular implementations for different
types would be carried out by the various agencies that have
responsibility for different types of research; is that it?
Ms. Speers. Yes, that is correct. The commission was
concerned about two things. One was that the regulations and
guidance would be pertinent to the types of research that were
being conducted, and they wanted to focus attention on the
research that had the greatest risk associated with it. So it
proposes a system where the oversight and review would be
commensurate with the nature and level of risk associated with
the research.
The Chairman. Your organization is doing important work on
accrediting human subject protections at universities on a
voluntary basis. Do you believe it would be appropriate to have
mandatory accreditation, or voluntary?
Ms. Speers. Our organization believes that accreditation
should be voluntary, and the reason that it believes that is
because it believes that accreditation works best when
organizations will make the commitment to change their culture
and behavior in the direction that we wish, which in this case
is to improve human research protection programs.
That, however, has to be done in coordination with the
Federal Government. What I mean by that is it is critically
important for the Government to recognize accreditation and for
there to be incentives for organizations to seek accreditation,
such as a favorable standing with respect to funding, perhaps a
reduction in some of the other burdens associated with
oversight of their research programs.
It is also important for the Government to recognize
accrediting bodies and to monitor the accrediting bodies who in
turn are monitoring the institutions.
The Chairman. My time is up. That was very helpful. Thank
you.
Senator Frist.
Senator Frist. Thank you, Mr. Chairman.
Clearly, our goal needs to be to create and foster an
environment that both protects human participants and allows
and encourages research in a responsible way. That can be done,
and I believe that it is going to take bipartisan legislation
coming out of this committee to accomplish that goal given the
facts that have been presented today and in the past in terms
of the overlap and the confusion and inadequate enforcement of
what is on the books today.
I should add that we have taken an important step in this
committee by including in the Children's Health Act a provision
extending Subpart D of the Common Rule to protect children
participating in FDA-regulated research, and Senators DeWine
and Dodd have been very involved and were critical to that
legislation, and I think our goal needs to be to build in that
same vein as we go forward.
The Common Rule is a line of questioning that Senator
Kennedy began, and I think it is really critical as we look at
the various differences in the regulatory oversight structure,
the fact that we hear concerns about the Common Rule being
impervious to change. But let me move on to an issue--and Dr.
Charles, I will turn to you because you really are on the front
line as an active clinical investigator.
The institutional review boards and the issues surrounding
them--could you describe your interactions with IRBs in
proposing your research and conducting your research. And you
mentioned informed patient content, and what I would like you
to get to in your comments is any suggestions you might have as
to ways that we can improve the training and awareness of
clinical investigators in these issues regarding informed
consent, human subjects protection, and the effectiveness of
the IRB process.
Dr. Charles. The first comment I would have about the
institutional review boards is that in my own institution, it
is the first place that I turn for guidance on procedures for
conducting clinical trials and the protection of the people who
participate in the clinical trials that I lead.
But I find often that they have conflicting information.
They have different rules and regulations that they are trying
to follow and that they are trying to get me to follow. Often,
the regulatory burden to propose a trial, launch a trial, and
then successfully enroll patients and complete the trial can be
so high as to create literally a barrier to being able to
conduct high quality research.
The one thing that would help that barrier the most is an
IRB that effectively educated clinical investigators, helped us
become the best physician advocates for the people
participating in our trials, and also was there to propose
clinical trials, and we design consent forms, and then as we
conduct the clinical trial through the whole course of the
study.
Senator Frist. For my colleagues, could you tell us who
serves on an IRB at your institution, how long they serve, and
what their credentials might be?
Dr. Charles. Because the clinical trials have grown so
tremendously at Vanderbilt University, we now have two IRBs,
often made up of faculty inside the university, people who have
experience in health care, participating in clinical trials.
They are also, though, members from the community who serve on
our clinical trials--medical ethicists, bioethicists,
biostatisticians. The complement of people who serve on the
committees I would say is terrific. The quality and the
expertise is fantastic, and we are fortunate at Vanderbilt to
have such high quality IRBs.
I would add, though, that because of the increased
regulatory burden, the cost to our institution to perform the
oversight of clinical trials is tremendous, and it is not
adequately met by the current reimbursements and overheads that
are provided by federally-funded research or whether it is
industry-sponsored research. The costs are growing
exponentially as we try to improve our system of protecting
human subjects.
Senator Frist. And are persons who serve on the IRB
compensated directly?
Dr. Charles. The members of our IRB are not compensated.
Senator Frist. And how many clinical trials would there be
at, say, Vanderbilt--do you have any idea?
Dr. Charles. I do not have the specific numbers--I could
certainly provide them to the committee--but it would be in the
hundreds. Obviously, at an institution like Vanderbilt and
other academic medical centers in our Nation, the number of
clinical trials has been growing tremendously over the past
decade.
Senator Frist. And what has your own experience been in
informed consent and the regulatory oversight of getting that
informed consent?
Dr. Charles. It can certainly be confusing when it comes to
informed consent. As mentioned earlier by another witness, if
you are participating in a trial that is being conducted at
many centers, each individual center reviews the consent form,
and each individual IRB can change that consent form; so you
are conducting the same trial, but patients at different
centers might read different consent forms.
Then, from the standpoint of writing consent forms, making
sure that you use language that is understood by patients, it
is often focused on documenting that you have informed consent.
I personally, as an investigator, though, am more concerned
that my patient who is considering participating in a trial
understands the implications of the research and the trial we
are about to launch. In early Parkinson's disease, and an
invasive therapy, hopefully supported by the NIH--we will see;
we are submitting a grant application--there is actually a
study within a study where we are going to test whether the
people participating truly have an understanding through the
typical informed consent process, and then we are going to
conduct an expanded informed consent process.
Senator Frist. When you go through the informed consent
process, and you read through the form, and you explain,
typically, what other people will you have in the room in the
process itself?
Dr. Charles. For trials involving adults----
Senator Frist. IRB, clinical trial.
Dr. Charles. [continuing]. Yes. For trials involving
adults, obviously, you are speaking directly with the person
who is considering. Often, there is a family member; many
times, it may be multiple family members, but hopefully, a
spouse or someone directly related to the person if that is
possible--that may not be possible. And the study coordinator
is often present during the informed consent process, and other
health care staff. I am in a teaching institution, so almost
everything I do in the clinic, I have a house officer with me,
medical students.
Senator Frist. Is there any requirement for an objective
observer to be in the room to make sure that the appropriate
things are said? Obviously, when you are one-on-one in a room
with people, whether it is financial conflict of interest or
just motivation to get this study done, biases can enter into
the question. To elevate the level of trust and confidence, is
there any requirement for third party ombudsman-type people to
be in the room?
Dr. Charles. At our institution, obviously, we have a
witness or someone who participates in the informed consent
process as you go through. Whether you could effectively do
that with an ombudsman or someone on the health care staff that
would be independent, I think the informed consent process
could take place without someone who is not employed by the
institution who is completely that insulated. I guess my
personal view is that that is not necessary to achieve the
informed consent necessary.
Remember that while we have heard today an incredible
story, and there are examples in the past, episodes of clinical
research that certainly have gone awry, clinical research in
our country is a thriving process that creates improved health
care for the Nation. I see every day physicians working with
patients, I believe that physicians really hold, first and
foremost, the principle to do no harm.
Senator Frist. Dr. Johnson, let me turn to you. All my
clinical practice has been in academic research institutions,
and I have participated in a number of clinical trials. I
always wanted to avoid being on the IRB. I liked doing the
clinical studies, liked getting the consent, liked putting the
devices in, because you were helping people, and you really
were in many ways taking basic science and getting it to
patients in a way that you knew in the long term was going to
be helpful. But when the call would come about considering
serving for 2 years on an IRB and spending up to a day a week
not being compensated in a direct way, and drawing me away from
research, away from the clinical research that I am interested
in, or academic research, it was pretty frightening, and now it
is getting more and more because there are more and more
clinical trials. I am not sure how we handle that overhead as
we go forward, and who is going to be paying for it, who should
pay for it, is critically important as we go forward.
What is your experience? Again, you are one step away from
these clinical trials in terms of actually getting the consent
at Genentech?
Mr. Johnson. Yes. So my job is to work with the FDA to
write the clinical protocols and make sure that----
Senator Frist. So you are sort of one step away from where
Dr. Charles is. How would you comment on what Dr. Charles has
said in terms of being on the very front line? Would you
correct or restate anything that he said?
Mr. Johnson. No. I think he is exactly accurate. I think
one of the biggest concerns that we have in industry is making
sure that our physician investigators understand their
responsibilities.
Senator Frist. And what do you think the biggest deficiency
in the IRB process is now? You are depending on them doing a
good job for you to do a good job. What changes would you make
in the IRB process that goes on at the hospital?
Mr. Johnson. I think that there should not be just a
volunteer process or a sort of delegation process of having
people on the IRB. I think there should be some sort of
training program so that they truly do understand their
responsibilities.
Senator Frist. And is there today--and my time is up, and I
will end with this question--right now, Dr. Frist is recruited
to be on the IRB at an institution; I go and sit through the
committees, and I am handling probably 50 different studies
that I am commenting on, reading the consent form, looking at
the ethical, and we are having our discussion. Is there any
uniform training, uniform guidelines that are given--I know
there are some guidelines--but how am I, Bill Frist, heart
surgeon, going to be trained to be an IRB specialist?
Mr. Johnson. I think one of the things that people need to
be aware of are the GCP guidelines that are through the FDA and
the International Committee on Harmonization, which are fairly
straightforward in terms of how you are supposed to review
informed consents, how you are supposed to make sure that
adverse events which occur during the course of the trial are
reported to the respective agencies, and to make sure that once
those adverse events are reported, the informed consents are,
in fact, modified appropriately to reflect the new
understanding of the risks involved in the research. I think
that is probably the most important thing that the IRBs need to
be aware of.
Senator Frist. Thank you, Mr. Chairman.
The Chairman. Senator Murray.
Opening Statement of Senator Patty Murray
Senator Murray. Thank you very much, Mr. Chairman, and I
especially want to thank you for scheduling this hearing.
Obviously, the issue of clinical trials has received a lot of
attention in the past year, and there are a lot of clinical
trials that are safe, and certainly they provide a lot of life-
saving treatments to people with terminal illnesses.
I know the Fred Hutchinson Cancer Research Center in
Seattle has gone through some of this in the past year and
taken it very seriously, and I commend them. They actually put
together a committee to review a number of the allegations and
are coming forward with some recommendations that I think will
be helpful to our committee as we look at legislative remedies
to some of the challenges that clinical trials provide.
I certainly think that in order to restore confidence, we
need to look at legislative remedies to ensure patient safety
and improved confidence. So Mr. Chairman, I really appreciate
this hearing, and I think it will really help us work toward
finding some good solutions.
I want to follow up on Dr. Frist's questions on informed
consent, because I think this is a very difficult challenge
that we need to face. I know that oftentimes, patients are just
demanding a drug even without a clinical trial; obviously, if
somebody is in a life-threatening situation, they will do
anything, especially if it is your child or your spouse. And
informed consent is just a difficult issue to deal with.
I would like to ask Dr. Speers, how can a research
institution really ensure that a patient is fully aware of the
risks, is comprehending them as they are in a life-threatening
situation, and what can we do to ensure that informed consent
really is informed consent?
Ms. Speers. I think that informed consent is one of the
major issues that the commission addressed and struggled with
actually over the life of the commission. It addressed informed
consent in many of its reports, not just in the oversight
report.
But, before I talk about informed consent, I want to back
up in the process and say that before one ever gets to the
point of an investigator obtaining voluntary informed consent
from a prospective research subject, we have to remember that
the research is reviewed by an institutional review board. And
one of the very important functions of that institutional
review board is to examine the risks of the study and the
potential benefits of the study, and that board is to look at
those risks and potential benefits, and when it approves the
study, it is to approve it, if you will, stating that what is
being offered to the prospective research subject is a
reasonable choice to participate or not participate in the
study. So that by the time a potential subject is approached,
there has already been review of that research protocol, and it
has been determined to be ethically justified to move forward
to asking an individual to participate in a study.
The commission was very clear to place emphasis on the
informed consent process, not on the informed consent document,
where a lot of attention has been placed in the past. That is
to say, from the moment a subject is recruited with the
announcements, brochures, advertisements about the research to
the time that the prospective subject is told about the study,
agrees to enroll in it and then participates in that study,
that is a process where informed consent occurs during that
entire process.
It is very important when the prospective subject is
originally approached that the process involve very carefully
going over the risks and the potential benefits of the study
and the method that will be involved, and the individual is
given the opportunity to ask questions, to think about the
study, to think about participating in the study.
The more that investigators and IRBs can focus on the
process rather than on the consent document, I think we get a
lot closer to obtaining voluntary informed consent. But it is
an area where I think we need to continue to do more to improve
subjects' understanding and comprehension of research.
Senator Murray. I appreciate that. The risks and the
benefits are a clear part of it. But the other question that I
have is how we can help patients better understand any kind of
financial link that a researcher or institution may have to the
treatment. We are in a market-driven research arena, and I
think it is often difficult to separate what is justifiable
compensation and what was provided as a way of inducing a bias
on the part of the research. So it is a difficult thing. We do
not just have Government providing all of the research; we do
have private research going on, and it is a market-driven
economy, and there are financial links.
How do we make sure--and I would ask both Dr. Speers and
Dr. Johnson to respond--that patients understand that financial
link?
Ms. Speers. The National Bioethics Advisory Commission did
consider conflicts of interest, and it looked not only at
financial conflicts but at other types of conflicts as well. In
looking at conflicts of interest, it pointed out that there
were really three groups, if you will, that could have
conflicts in the research process. There could be financial
conflicts that the institution has; there could be the
financial conflicts that an investigator has; and then, the IRB
members could have conflicts as well.
With respect to financial conflicts either on the part of
the institution or the investigator, NBAC recommended that
those types of conflicts need to be disclosed, and they need to
be managed by the institutions and felt that it was very
important for there to be policies and procedures in place that
specifically deal----
Senator Murray. And that is not the case now?
Ms. Speers. It is not the case now that all institutions
have their own policies and procedures in place; that is
correct.
NBAC also recommended that there would be disclosure of
financial conflicts to the research participants. However, NBAC
was also quick to point out that disclosing to participants
should not be a substitute for institutions managing those
conflicts as well.
Senator Murray. Dr. Johnson.
Mr. Johnson. I would agree. One of the things that we try
to do in industry is make sure that when we do a multi-center
study, the level of reimbursement for services provided by the
physician investigators is consistent across all sites. This
leads to obvious diminution of the perception of conflict of
interest.
The second thing is that the FDA now requires that all
physician investigators disclose their financial connections
with the industry for which they are doing research, and I
think this has helped a great deal.
Senator Murray. Thank you very much. My time is up, but I
do have some other questions that I would like to submit for
the record.
[The responses to Senator Murray's questions were not
received by press time.]
Senator Frist. Could I ask a follow-up question?
The Chairman. Yes, and we will have another round.
Senator Frist. Just one question on follow-up, because it
is still not clear to me. If there is a financial conflict of
interest, right now, you have to report it to the institution--
you have to do that; is that correct--but according to you, Dr.
Speers, the way the institution handles it, there are no
guidelines. They are not obligated to tell the patient, they
are not obligated to write anything into the IRB. Is that
correct?
Ms. Speers. Currently, there is no Federal requirement that
an institution that might have a conflict of interest
committee, that that committee report its findings to the IRB.
Senator Frist. If the investigator has a potential conflict
of interest, does that have to get reported to the institution,
or the IRB?
Ms. Speers. There is not a requirement that an investigator
disclose his or her conflicts of interest to the IRB.
Senator Frist. Thank you.
Thank you, Mr. Chairman.
The Chairman. Just a few final questions, and one for the
whole panel. One of the major problems of the current system is
failure to monitor ongoing trials. What are the best ways to
monitor ongoing trials?
Ms. Mathias. I would like to say something about that. You
have to have monitors in place to monitor them. A lot of NIH
studies are really not being monitored adequately. They seldom
if ever send around a monitor. I have been doing an NIH study
for 4\1/2\ years, and we have never seen a monitor.
Now, if you are doing a pharmaceutical trial, that is
different. Because their bottom line is at stake, they send
monitors around a lot more frequently. But a lot of the NIH
studies which are grant-driven are not adequately being
monitored.
Also, I would like to say something about the informed
consent process. I feel strongly that there needs to be a third
party there to ensure that informed consent is given in such a
way that it is not coercive. Particularly in today's
environment in a community setting, where many, many subjects
are coming from the doctor's own database--they are his
patients--and that sets up a conflict of interest between the
patient and the doctor and being an investigator and a subject.
So I think there really does need to be a third party
there.
The Chairman. It is amazing to me the number of people who
are prepared to volunteer and are willing to be part of these
clinical trials.
Ms. Mathias. It is often because they are desperate.
The Chairman. Dr. Speers, would you like to comment on the
best way to make sure there is adequate monitoring of the
trials?
Ms. Speers. Yes. NBAC considered what happens to research
after it is initially approved by an IRB and made several
recommendations in that area. One was that there should be more
guidance provided to IRBs regarding the conduct of the
continuing review for research and that continuing reviews
really need to be focused on the research that has the greatest
risk associated with it.
Right now under the Federal regulations, all research,
whether it is minimal risk research or it involves much greater
than minimal risk, receives the same type of continuing review.
Clearly, we could strengthen the review for riskier research.
The Commission was also concerned about reports of adverse
events and how those adverse events are reported and evaluated
and recommended that there be a unified system for reporting
adverse events, evaluating them, and then reporting back the
results of that evaluation to investigators and sponsors and
IRBs.
The Chairman. Dr. Johnson.
Mr. Johnson. For most industry-sponsored studies, there are
basically three ways that the data and the investigators are
monitored. We have standard monitors who go out during the
course of the study and check that the data is being accurately
recorded and that things are being reported appropriately. Most
companies also have separate compliance units which go out and
actually audit the sites to really make sure that they are
independently reviewed. And then, third, for many of the
programs, the FDA will send out auditors to check on
investigators.
So currently, I think that industry-sponsored studies are
well-protected and well-monitored.
The Chairman. Dr. Charles.
Dr. Charles. Monitoring takes place in many ways. As was
mentioned, monitoring takes place locally in my institution
right in my division by my own nurse and myself participating
in the trials, and then by my IRB, and then, often by the
sponsors of the trial that I am conducting.
One thing you mentioned, Senator Kennedy, that is
interesting is that it is surprising how many people
participate in the clinical trials. The single factor that
often plays into a person's decision to participate in a
clinical trial is not because they are desperate and hoping for
some cure that is not yet proven or not yet there; in fact,
when giving informed consent for things that have little risk
and sometimes things that have large risk, most of the time,
people are interested in participating in a clinical trial
because their participation may help others with the same
condition in the future, and that is in my opinion and in my
experience the most important motivating factor when people are
making a decision to participate.
The Chairman. Dr. Speers, the Common Rule applies to
federally-funded regulated research. The Commission recommended
applying the standards to all research, whether private or
public. What led you to that conclusion?
Ms. Speers. It was a basic belief that anyone who
participates in research deserves to have their rights and
welfare protected. We found when we talked to various groups
that there was huge support for including all research under a
set of Federal regulations, that much research is included
either because it is federally-funded or because it is
regulated by the Food and Drug Administration.
The Chairman. Your current program does accreditation on a
voluntary basis, but the Bioethics Commission recommended that
all doctors and review boards be accredited. Isn't that a call
for required accreditation? You have that here in your
recommendations.
Ms. Speers. Yes, I do, yes. The National Bioethics Advisory
Commission and AAHRPP, the organization I now work for, I
believe do share a common goal, and that common goal is that we
would like to see all individuals certified, and we would like
to see all institutions accredited. The question is how best to
obtain that goal. AAHRPP believes the best way to obtain it is
through voluntary accreditations where institutions seek it
when they have made the commitment to do so.
The NBAC report in the text that accompanies that
recommendation says that as we are moving closer to
certification and accreditation, there should be some
flexibility initially to test different methods and procedures
with respect to accreditation and noted that highly successful
accreditation programs have tended to be voluntary.
The Chairman. I appears from all the testimony that we have
lots of regulations, but not necessarily the right regulations,
and we need to make sure that structures appropriate for modern
clinical trials truly protect patients. Do you have views about
whether that ought to be an independent agency or where it
ought to be located? That is a bureaucratic kind of question,
but I would be interested if you have a view and reasons for
it--should it be in HHS or FDA--if you have a view, I would be
interested in whatever reasons you might have.
Ms. Speers. The National Bioethics Advisory Commission did
have a view on it, and they spent quite a bit of time
deliberating over the placement of that oversight office, and
they strongly believed that the oversight office should exist
independent of any Federal agency; that is, it should exist
outside of any Federal agency.
The reasons for that thinking were that they wanted the
office to have high visibility to really show the Government's
commitment to protecting human research subjects and for there
to be a central focal point.
They were also concerned that if such an office were placed
within a Federal department that that could potentially create
a conflict of interest between the mission of the independent
office and the mission of that department, meaning that the
department is likely to have a mission to promote and enhance
research, which at times could be in conflict with the mission
of the independent office, which would be to protect human
research participants.
The Chairman. Do others have a view?
Dr. Charles. Certainly in HHS, where in particular I guess
would not be so important to me as an investigator; more
important would be that it was consistent and applied across
all Federal agencies when human subjects are involved.
Ms. Mathias. I would like to say something about that, too.
Not only does it matter if they are independent, but we must
give the regulators the tools necessary to do enforcement. I
know that OHRP, Greg Koski, has asked that they be able to fine
individual investigators up to $250,000 if they are
noncompliant. That is essential. We must give them tools for
enforcement.
The Chairman. Thank you.
Senator Frist.
Senator Frist. Thank you, Mr. Chairman.
We have touched on a number of issues, and I appreciate
everybody's comments. One area that we have not explored quite
as deeply but we have in past hearings is the adverse event
reporting in clinical trials. As I mentioned in my opening
statement, compared to where we were a year ago or even 2 years
ago, I feel that progress is being made. I think that
legislation is going to be required. We have to address these
issues of what is mandatory, what is voluntary, and that is
where a lot of these questions are coming from.
Just in March, the NIH offered a $28 million program to
enhance human subjects oversight. And again, when you look
through those announcements and the way it was presented and
what applicants have to detail, whether it is tracking systems
for monitoring, infrastructure technology development for
tracking human subject protocols, facilitate IRB activities,
coordinate the activities of IRBs--again, a lot of the
individual institutions and programs like NIH are working very
hard. I do believe we are going to need some greater
coordination throughout Government for this and look forward to
working to do that.
On adverse events and reporting, Dr. Johnson, because you
are receiving them, and Dr. Charles, you are again on the front
line, how would you summarize where we are today? I can tell
you that a year-and-a-half ago in a hearing, we spent probably
3 or 4 hours talking about how poorly adverse events are
recorded, interpreted, and then shared, and ending up with
enforcement. Where are we today?
Mr. Johnson. Well, again, I think that industry is
reasonably well-regulated on this. We do understand our
responsibilities. Quite frankly, the worst thing that can
happen to me when I am conducting a clinical trial is that some
unexpected adverse event occurs and that I don't tell everybody
about it. First, I feel bad for the patients, obviously; but
second, we need to let everybody else to know to look for these
things so that we can act early to prevent bad things
happening. And I think we do have in industry mechanisms in
place to deal with that effectively. We are also very closely
regulated by the FDA on this one. We sit around and carefully
review reports of adverse events, determine whether they fit
into various categories of expedited reporting or routine
reporting. We make sure that the informed consents are updated
appropriately and that we have reviewed those with the
institutional review board at each investigative site.
So I think that within industry, the process is pretty
well-established, and people are pretty well-educated. I think
education, possibly, with independent investigators is probably
the most important issue that you would like to address.
Senator Frist. And you report that to the FDA?
Mr. Johnson. Yes.
Senator Frist. To anyone else?
Mr. Johnson. I report it to all of our investigators
whether they are active--so if they participated in previous
studies of the same compound, we report it to all of those
investigators. And certainly for any active trials, the
investigators are required to send that letter on to their
IRBs.
Senator Frist. Do you have any suggestions for the
Government entities to whom you report adverse events? Do they
handle the data correctly, get back with you, give appropriate
oversight?
Mr. Johnson. Oh, yes, absolutely. Usually, when we get an
expedited report, we will actually telephone the medical
reviewer at the FDA and discuss the case with them.
Senator Frist. Dr. Charles, do you have any comment on
adverse events?
Dr. Charles. Certainly in receiving adverse events and
recording them, it is a critical part of the clinical trial
that you are conducting. From the standpoint of an
investigator, I am conducting a clinical trial at this time in
a biologic that is injected. The company, the corporate sponsor
of the trial, is conducting many trials with this drug, and I
am receiving adverse event reports for this agent well outside
my clinical trial. All of those reports come to me, and I
review them, assess the impact that they might have in my
clinical trial--do I need to change my consent form--but in
addition to that, I have to inform my local IRB, and they make
the same assessment with me.
Again, as a clinical investigator, I look to my
institutional review board to guide me on how to report things
that are serious adverse events and how to report adverse
events that are not as serious.
Senator Frist. On the accreditation, it is still unclear to
me. Are we accrediting institutional review boards or programs?
Dr. Speers, I guess you would say programs, or is it an
institution; is it Vanderbilt University, or is it one of the
two IRBs at Vanderbilt University that you would accredit
voluntarily or others mandatorily?
Ms. Speers. We would accredit institutions, and what we are
accrediting within institutions is what we call their human
research protection programs that include their IRBs. The
reason for doing that is that the responsibility for protecting
human research participants is a shared responsibility. It is
not the responsibility solely of the IRB. It is an
institutional responsibility, and it is an investigator
responsibility.
So our accreditation program looks at all of those
responsibilities and has standards that they have to meet in
all of those categories of responsibility.
Senator Frist. And outside of, say, academic health centers
where so many of the clinical trials are, is that easy to do?
Again, we have this huge spectrum of research where you would
like to see oversight over both the private and the public.
Paint the picture of some research that is done out in the
middle of nowhere where nobody knows the research is going on--
which is happening, obviously.
Ms. Speers. Yes. Our organization accredits all types of
research institutions. That is to say, it is not a program that
is geared specifically to the universities. We will accredit
eligible organizations that could include independent review
boards, community hospitals, Government agencies,
pharmaceutical companies that conduct their own research,
contract research organizations--the full array of
organizations that are involved in the research process.
Senator Frist. Thank you.
Thank you, Mr. Chairman.
The Chairman. Just finally, Dr. Speers, we have heard what
is happening in industry, but of course, there is an enormous
amount of research that is being done outside, and we obviously
want to make sure that those human subjects are going to be
protected. How important do you think it is that we make the
changes which are necessary and make them now?
Ms. Speers. I think that it is really very important to
make changes to the oversight system. I think that some of the
basic problems that have been discussed here today--we have
talked, for example, about the system being confusing to
investigators or to IRBs, that there is some research that is
not covered by the system, that IRBs are overburdened, and in
part they are overburdened because the current set of
regulations does not distinguish very well between the less
risky research and the more risky research.
I think that in order to improve the system, to really get
to the level that we all want with protection programs, there
are some basic changes that need to be made to the system,
particularly a single set of regulations, a single office that
can then oversee the oversight system. I think that those are
critical to bringing about the kinds of changes that we want to
see in the system.
The Chairman. Ms. Mathias.
Ms. Mathias. I would like to add to that that in everyday
practice, it is confusing. The adverse event reporting is
confusing. A lot of investigators do not understand it. Also,
to be quite honest, I wish we could clone Dr. Charles, because
it sounds to me like he is----
The Chairman. We have to be careful on that subject now. We
do not want to get Senator Frist all worked up. [Laughter.]
Senator Frist. No, we are both against that kind of
cloning.
The Chairman. You are right on that.
Ms. Mathias. But he is intricately involved with his
clinical research. I have found in my own practice that many,
many physicians leave most of the work up to the study
coordinators, because they are too busy with their day-to-day
practice, and it is the study coordinators who are actually
judging the adverse events and then pass it by the
investigators.
I can promise you that adverse event reporting is still an
area that needs much work. They are not being collected
adequately; they are not being reported adequately, and once
they are given to the IRBs, the IRBs have a tremendous problem
with what to do with them because they are not given all the
information they need from the sponsors. They do not know, when
you report an adverse event to an IRB, if they are on a placebo
or if they are on the active agent. So it makes it very
difficult for an IRB to be able to use that information and
actually review it to where they have something that is valid
to deal with.
So those are still problems that are inherent in the system
that have not been corrected.
The Chairman. And that you believe need change; is that
right?
Ms. Mathias. Definitely.
The Chairman. I do not know if you want to make any
comment, Dr. Charles.
Dr. Charles. For the record, my wife and my chairman would
both like to clone me, but I am firmly against that.
[Laughter.]
The Chairman. Well, this has been enormously informative,
and it has been distressing in the sense of some of the
loopholes that are still out there and the overlap of different
rules and regulations which are bringing in efficiencies and
that clearly have to be recognized. But I think there is
certainly a sense that we have to try to take what has been
suggested here today and other testimony and try to see if we
can upgrade this system to help us protect human subjects and
also ensure that the opportunities for these new breakthroughs
that will enhance health care for so many people will continue.
That is a very important responsibility for our committee, and
we are going to need a lot of help in being able to do it, and
we are going to all work together.
We will leave the record open for 2 weeks if there are
other questions to be directed toward you. We thank you all
very, very much for your appearance here today.
[Additional material follows:]
ADDITIONAL MATERIALS
Prepared Statement of Myron Genel, M.D.
Good morning. I am Myron Genel, M.D., a professor of pediatrics and
associate dean at Yale University School of Medicine where I have
directed the medical school's Office of Government and Community
Affairs. Currently I am Chair of the Advisory Committee of Yale's
Children's Clinical Research Center, having formerly served as its
program director for 16 years and Chief of the Section of Pediatric
Endocrinology, where I remain active clinically. Relevant to these
hearings, I have been a member of the Yale Human Investigation
Committee, the medical school's institutional review board (IRB), for
30 years and am a member of the Children's Workgroup established last
year by the National Human Research Protections Advisory Committee
(NHRPAC). I am also a member of the Institute of Medicine's Clinical
Research Roundtable and past Chair of the American Medical
Association's Council on Scientific Affairs.
I am pleased to be here this morning representing the American
Academy of Pediatrics and its 55,000 pediatricians and pediatric
subspecialists who have committed themselves to helping improve the
health of children. In addition, I am representing the Pediatric
Academic Societies, comprised of the American Pediatric Society, the
Ambulatory Pediatric Association, the Association of Medical School
Pediatric Department Chairs, and the Society for Pediatric Research.
These organizations consist of pediatric researchers, full time
academic and clinical faculty responsible for the training of
pediatricians, and the leadership of medical school pediatric
departments.
These are extraordinary times for advancing the health and well-
being of all members of society, but especially for children. As
pediatricians, we are pleased that significant strides have been made
over the last several years to include infants, children and
adolescents in clinical research. In order for children to benefit from
the wealth of research of how humans learn, grow, and develop and how
science can address disease and illness the pediatric population must
participate in those research opportunities.
But with this awareness and commitment comes the responsibility
that we--pediatricians, politicians, parents, researchers, Government,
academia and industry--must be ever vigilant to ensure that the
pediatric population is fully protected from inappropriate or
unnecessary risk in clinical research.
Congress has provided great leadership in moving pediatric research
forward. The success of the pediatric studies provision within the Food
and Drug Administration Modernization Act of 1997 (FDAMA) has increased
the number of children participating in clinical research. AAP is also
pleased with the enactment of the Best Pharmaceuticals for Children Act
(P.L. 107-109), which reauthorizes the pediatric studies provision and
enhances therapeutic research for children. This law is a result of
legislation championed by Senators Christopher Dodd (D-CT) and Mike
DeWine (R-OH) and Representatives Anna Eshoo (D-CA) and Jim Greenwood
(R-PA).
Especially significant was the October 2000 enactment of the
Children's Health Act (P.L. 106-310), which includes research and
program creation and expansion in many areas of childhood diseases.
Three components of the Children's Health Act are of particular
interest in light of today's hearing: (1) the establishment of the
pediatric research initiative at the National Institutes of Health
(NIH) which will support research that is directly related to
children's health; (2) the provision to evaluate the existing Federal
regulations that protect children (subpart D of part 46 of title 45,
Code of Federal Regulations) and (3) the requirement that all research
involving children that is conducted, supported, or regulated by HHS be
in compliance with Subpart D.
AAP, joined by the pediatric academic societies, was pleased to
provide comments to Dr. Greg Koski, Director of the Office of Human
Research Protections (OHRP) of the U.S. Department of Health and Human
Services (DHHS) on evaluation of existing subpart D regulations. AAP
and the pediatric academic societies agree with the recommendations
made by OHRP in its report ``Protections for Children in Research: A
Report to Congress in Accord with Section 1003 of P.L. 106-310,
Children's Health Act of 2000.'' As a member of the National Human
Research Protections Advisory Committee's (NHRPAC) children's
workgroup, I was pleased to play a role in the development of this
report. The report recommends that subpart D should not be modified at
this time. In addition, the report states that HHS should provide
detailed guidance relevant to the complex issues inherent in both the
conduct of research involving children and the interpretation of the
provisions of the regulations under subpart D to all parties engaged in
the conduct and oversight of research involving children. AAP and the
pediatric academic societies look forward to working closely with
NHRPAC and OHRP on these recommendations in the future.
In July 2001, the AAP also provided comments to the Food and Drug
Administration on the Interim Rule that was issued on April 24, 2001 in
compliance with the Children's Health Act provision requiring research
protections for children throughout HHS. AAP strongly supports the
FDA's adoption of the safeguards provided in subpart D. However, we
provided several specific comments [attached].
Children in Clinical Research: To begin with, the conduct of
research in children carries with it the same ethical obligations as
research in adults. However, children comprise an especially vulnerable
population and must be provided added protection against violation of
their individual rights and exposure to undue risk. This situation
imposes special considerations when inviting participation in studies,
assessing risks and benefits, and ensuring equitable participation and
benefits in clinical research. There are three general principles of
pediatric research that have been the tenets of AAP policy:
1. Children need to be involved in research so that medical
advances can continue to be made and so that children can enjoy equal
access to beneficial medical treatments.
2. Adequate protection needs to be in place to protect the rights
of the children who are actually participating in research.
3. Local institutional review boards (IRBs) are capable of
protecting the rights of children, but it is imperative that these IRBs
have proper pediatric expertise and adequate institutional support.
partners in research
There are multiple partners in the conduct of sound research. No
one individual or institution can stand alone in creating an
environment that ensures scientific rigor and protections for pediatric
patients.
Investigators: The investigator's competence and ethical conduct
are the most important safeguards for the protection of the child. The
investigator must understand the developmental and ethical issues
involved in research with children. In addition, they must be able to
recognize adverse events that occur in children and have sufficient
pediatric expertise to ensure safety of children in pediatric research.
The investigator should make every attempt to appreciate the
feelings of all parties concerned, and attempt to understand the fears
and concerns of the children. The investigator should be an effective
communicator to the subjects and their parents in order to decrease
fears about the clinical protocol and its procedures. These
considerations are important, because children and their parents may be
unable or unwilling to voluntarily communicate their feelings and
fears. The investigator should endeavor to understand the attitudes and
motivations of the parent and other individuals qualified to act on the
child's behalf.
Institutional review boards: The primary responsibility of the
institutional review board (IRB) is to protect the rights of the
research subject. This includes responsibility for interpreting the
Federal guidelines and determining whether or not each study is
designed ethically in compliance with the Federal guidelines, local and
State law, and the local IRB directives. Any individual or institution
under whose auspices clinical research is conducted must assure that
the research protocol is reviewed by an appropriately constituted IRB.
The AAP believes that local IRBs are capable of protecting the
rights of children involved in research. Flexibility in the current
Federal regulations allows for local interpretation and definition, and
the regulations recognize that individual IRBs can adopt strict
guidelines for assessing acceptable risk in order to protect children.
It is however, imperative that IRBs have at a minimum one member
present when research involving children is reviewed who has
appropriate expertise in pediatric medical care. Consistent with the
Food and Drug Administration's draft Guidance on Clinical
Investigations of Medicinal Products in the Pediatric Population (ICH
E-11) ``there should be IRB members or experts consulted by the IRB who
are knowledgeable in pediatric ethical, clinical, and psychosocial
issues.''
In addition, the IRB should establish a mechanism to assure that no
child is enrolled in more studies than is consistent with his or her
welfare. There may be reasons to enroll the same child in more than one
study simultaneously. In most instances this does not jeopardize the
child's welfare or safety, but in some situations the child's
participation in more than one study may be detrimental to the child or
may confound the scientific validity of the studies.
Parents/Guardians: The key role of the parent or guardian is to act
in the interest of the child. An essential element is to give his or
her permission before the minor is approached for his or her assent.
For research that does not offer the prospect of direct benefit and has
greater than minimal risk and for research requiring the approval of
the DHHS Secretary, both parents or guardian/s must give their
permission if feasible.
Ethical Considerations: Areas of concern in designing and
performing pediatric research include determination of benefits and
risks, obtaining informed parental permission and child assent to
participate, protection for vulnerable populations, and specific
aspects of research design.
Determination of Benefits and Risks: The AAP believes that benefits
of research should be construed broadly and should be considered
carefully by local IRBs. The AAP further supports the clear separation
of benefits that directly improve an individual subject's well-being
and that provide generalizable knowledge regarding that child's
condition or in childhood health and disease more generally. The
evaluation of direct benefits should primarily take into account
treatment for the subject's own benefit. Even when this is not the
primary purpose of a study, the child may directly benefit from the
knowledge gained from the study itself or by being in the active arm of
a placebo-controlled trial, where appropriate. The understanding by the
child that he or she has contributed to the study of a childhood
disease or the biology of children should be considered secondarily.
The risks to the child should also be evaluated in the broadest
context. These incorporate known and predictable effects of the
treatment and procedures including discomfort, inconvenience, pain,
fright, separation from parents and familiar surroundings, effects on
growth and development, and the size or volume of biologic samples.
Remuneration for Participation in Research: An area that has
received considerable attention is whether payment (financial or
otherwise) may be provided to a child or his or her parent or guardian
for the participation of the child in research, and if so, the amount
and type given.
AAP believes that it is in accord with the traditions and ethics of
society to pay people to participate and cooperate in activities that
benefit others. However, serious ethical questions can arise when
payment is offered to adults acting on behalf of minors in return for
allowing minors to participate as research subjects. The AAP believes
parents should not profit from placing their child in research and thus
remuneration should not be beyond out-of-pocket expenses and a token
gesture of appreciation for participation. If remuneration is to be
provided to the child, it is best if it is not discussed before the
study's completion. This will help assure that the remuneration is not
part of the reasons that a child volunteered or is volunteered for a
study.
The study also may make funds and facilities available to reimburse
the child (or the family) for any direct or indirect costs incurred
because of the child's involvement in the study and a waiver of medical
costs associated with treatment under a research study may be permitted
in certain circumstances. However, the investigators and the IRB must
be certain that the compensation offered is fair and does not become an
inducement for the participation of a child subject and the IRB should
carefully review any proposed remuneration to be assured that the
possibility for coercion has been avoided.
Permission/Assent/Consent: In pediatric studies, the investigator
is required to obtain written permission from the parents and, when
applicable, assent from the child before the study except when
specifically exempted by the IRB. In certain cases, such as when
emancipated or mature minors are studied, consent from the adolescent
is necessary and permission from the parents may be waived by the IRB.
Assent of the Child: Assent should be obtained from children who
are capable of assent. The purpose, risks, and benefits of a study
should be explained to the subjects at a level appropriate to their
intellectual age. In addition, parental permission is required before
the child's participation in a research protocol. Assent must be an
active affirmation by the research subject and should usually be
obtained from any child with an intellectual age of 7 years or more.
Assent may be waived in therapeutic research studies in which, in the
opinions of the IRB, the research holds out a prospect of direct
benefit that is important to the child's health or well-being and is
not available outside of the research.
Quality Assurance and Accreditation: The task of ensuring that
ethical principles indeed are being adhered to when children
participate in research is formidable. The Office for Human Research
Protections clearly has expanded its reach over the past year by
initiatives to increase the number of institutions filing Federal-wide
assurances of research protections. Moreover, the building movement
toward voluntary accreditation of human protections programs has the
potential to further improve the system.
At the same time, the accreditation standards must not become
overly idealistic nor should they focus excessively on administrative
paperwork within IRBs and human protections programs. Now is the time
to assure this new accrediting body focuses on the meaningful issues
most important to protecting human subjects and not inconsequential
details. Of highest priority should be investigator/patient
communication or relationships. We encourage the Government to examine
a variety of approaches to quality assurance.
We applaud the recent grant money made available by NIH within the
``Human Subjects Research Enhancements Program'' to improve human
protections activities. This is a good example of innovative approaches
to encourage ethical research. Another potentially productive, but
underutilized, avenue to assess quality assurance is patient outcomes
and parent/patient post-study feedback in research studies. Comparisons
of non-randomized control groups have indicated that children involved
in research, even those assigned to non-treatment arms of studies, have
better outcomes than those not involved at all in the research. Better
collection of data showing the direct benefits of research for patients
need to be collected to demonstrate that parents and children are
satisfied that they are respected and cared for ethically within
research studies and that they are content with their participation
decisions.
conclusion
While AAP is pleased with progress being made to include more
children in research, we are disheartened with a recent proposal by the
Administration to potentially suspend all or part of the 1998 Pediatric
Rule. Both Congress and the Executive Branch have been proactive in
moving children's health to a more visible position within the research
community. We are beginning to get more and better scientifically-valid
and ethically appropriate information related to children's health. Now
is not the time to consider delaying or rolling back the advances being
made in therapeutics for children. AAP strongly urges Congress to
continue to encourage and support efforts to advance the health and
well-being of children through research initiatives.
A concrete example of the advances made for children's health is
the increased number children in clinical drug studies and the prospect
of more children participating in this research. This is testimony to
the success of pediatric studies provision in FDAMA and now the Best
Pharmaceuticals for Children Act. Through these important clinical
studies, information is generated and then disseminated for use by
pediatricians and other health professionals. What is the alternative
to including children in these well-controlled, scientifically-valid
pediatric studies? Having hundreds of thousands of children taking
medications in office settings or at home that have not been properly
studied. Subjecting children to daily uncontrolled, unregulated, and
unreported practices versus including a significantly smaller number of
children (thousands vs. hundreds of thousands) in controlled clinical
research studies is a much-preferred alternative.
The pediatric community believes we must be continually diligent to
ensure that children are protected in clinical trials but also that
children are afforded every opportunity to participate in essential
clinical research. The pediatric community, as represented by the AAP
and the pediatric academic and research societies, is confident that a
framework exists to provide these protections. We must all work
together to ensure that all aspects of this system are working in
harmony to achieve these common goals.
recommendations
AAP and the pediatric academic societies believe that efforts to
review and modify human research protections for the entire pediatric
population are extremely valuable. AAP and the pediatric academic
societies would propose the following recommendations:
While the regulations under subpart D of part 46 of title 45, Code
of Federal Regulations are sound, there is unacceptable variability in
the interpretation of the regulations and the expertise of the IRBs and
investigators. Clear guidance from the Federal Government can assist in
this unjustified variability of the interpretations of the regulations.
With the Office of Human Research Protections (OHRP), ensure there
is staff with expertise in pediatrics designated to address human
subject research protection issues, both ethical and clinical,
specifically related to pediatric populations.
Formalize an independent pediatric workgroup within OHRP. The
purpose of this pediatric workgroup would be to inform, advise, and
participate in activities and recommendations developed by OHRP and the
National Research Protections Advisory Committee (NHRPAC).
The AAP is pleased that the Best Pharmaceuticals for Children Act
includes a provision that instructs the Secretary of HHS to contract
with the Institute of Medicine to conduct a review of Federal
regulations, reports and evidence-based research involving children. We
note that this report is due by January 2004 and would encourage the
Secretary of HHS to ensure that the IOM begins developing their review
and recommendations in the immediate future.
FDA should adopt a modified version of section 46.408(c) subpart D
pertaining to waivers of informed consent for adolescents. FDA decision
not to adopt this provision fails to appreciate that there are limited
circumstances when the rights of participants would be better protected
by requiring adolescent assent in combination with appropriate
alternative protections rather than guardian consent.
As a component of ensuring adequate, well-controlled, ethically
appropriate and scientifically valid research, the FDA should consider
making public written requests issued to pharmaceutical companies under
the Best Pharmaceuticals for Children Act (P.L. 107-109). Such a
requirement would help assure through public discussion the appropriate
protections of children enrolled in pharmaceutical research.''
The 1998 Pediatric Rule established a therapeutic foundation for
children and works in conjunction with the Best Pharmaceuticals for
Children Act. To ensure that safe and effective therapies are available
for infants, children and adolescents, Congress should legislatively
codify the 1998 Pediatric Rule.
I appreciate the opportunity to present the thoughts and
recommendations of the American Academy of Pediatrics and the pediatric
academic societies. I would be pleased to answer any questions you may
have.
______
Prepared Statement of Robert P. Kelch, M.D.
Mr. Chairman and members of the subcommittee, I am Bob Kelch, M.D.,
Dean of the University of Iowa's Roy J. and Lucille A. Carver College
of Medicine. I also serve as the Chair of the Advisory Panel on
Research for the Association of American Medical Colleges (AAMC). The
AAMC represents the 125 accredited U.S. medical schools; the 16
accredited Canadian medical schools; some 400 major teaching hospitals,
including 74 Veterans Administration medical centers; more than 105,000
faculty in 98 academic and scientific societies; and the Nation's
66,000 medical students and 97,000 resident physicians. Our member
institutions conduct a very large share of the biomedical and
behavioral research performed in this country, and we have been the
source of many of the dramatic breakthroughs that have revolutionized
biology and are transforming medicine. My testimony today will focus on
how the AAMC, on behalf of our members, has undertaken significant new
initiatives aimed at strengthening the protection of the many thousands
of human patients and volunteers who participate in medical research
each year.
The AAMC commends the subcommittee for convening this hearing to
explore the issues surrounding the protection of human research
participants. We recognize that academic medicine and the American
public have forged a special relationship rooted in trust that is
nowhere more evident--or more fragile--than in clinical research
involving human participants. We are troubled by recent reports of
lapses in the oversight of clinical research in some of our most
prestigious members, reports that threaten public confidence in our
Nation's system for protecting research participants. And we are
disturbed by allegations that the financial interests of faculty
investigators or their institutions may have compromised their
independence and credibility, and threatened the welfare of research
participants as well as scientific integrity.
AAMC and its members are vitally concerned for the safety and well-
being of the patients and healthy individuals who participate in our
research programs. We believe that their protection can be most
reliably achieved and effectively sustained in settings that place a
high priority on, and devote significant attention to, research ethics,
as well as compliance with legal and regulatory requirements. We agree
with OHRP Director, Dr. Greg Koski, that the most effective programs of
protection of human research participants will occur in institutions
that go beyond compliance to foster ``a culture of conscience and
responsibility'' that lodges not just in institutional review boards
(IRBs), but in every principal investigator and all of those who engage
in clinical research.
To assist our members to create and maintain such a desired culture
of conscience and responsibility, and to achieve uniformly high
standards of human research protections across the entire community of
academic medicine, we have organized national research compliance
conferences, and have worked jointly with the organization Public
Responsibility in Medicine and Research (PRIM&R), to sponsor focused
regional educational programs for institutional review board members
and staff, faculty who conduct clinical research, and institutional
officials responsible for its oversight in our member institutions. All
of these efforts have been enthusiastically received and over-
subscribed. A year ago the AAMC created a compliance website
(www.aamc.org/research/dbr/compliance/startcom.htm) to publicize and
make accessible the most promising initiatives developed by our members
to address the education and credentialing of clinical investigators. A
number of attractive approaches were already in development by our
members well before October 2000, when the NIH made such educational
programs mandatory for its awardees. The credentialing of clinical
investigators, an approach initiated by the University of Rochester
Medical Center, is becoming widespread and will soon be a requirement.
Visitors to the AAMC compliance website can locate a rich set of
information related to Federal regulations, model policies and
procedures, and available educational resources.
During the remainder of my testimony, I will emphasize two major
new initiatives in which the AAMC is heavily engaged: initiatives
designed to ensure the safety and well-being of the patients and
healthy individuals who volunteer to participate in our research
programs. First, we have worked to establish a system of voluntary
accreditation of institutional programs of human research participant
protections; second, we have developed and published our first report,
including detailed guidelines to address the concerns that have been
raised about financial conflicts of interests in clinical research.
accreditation
Despite the existence for more than 25 years of an evolving code of
Federal regulations (since 1991 commonly dubbed ``the Common Rule'')
and policies to protect the rights and welfare of human research
participants, there has been increasing concern in recent years that
the system for protecting these participants needs improvement. These
concerns were dramatically underscored by the recent wave of Federal
suspensions of research at various institutions around the country,
which indicated to many that systemic improvements in human research
protection programs are necessary. While acknowledging that researchers
and IRB members are generally adhering to the Federal requirements for
protecting human research participants, the Inspector General of the
Department of Health and Human Services observed that the national
system for protecting research subjects is currently under strain and
facing increasing pressure in a rapidly changing research environment.
IRBs have a significant number of weighty responsibilities. Under
the terms of the assurances their institutions provide to Federal
funding agencies, IRBs must make certain that the research they oversee
is conducted in accordance with Federal policies and all applicable
State and Federal laws. To assure that the risks to human participants
are minimized, IRBs must assess these risks in hundreds or even
thousands of research protocols, while meeting exacting procedural
requirements and maintaining detailed records. Moreover, even as the
complexity of clinical research and the volume of research protocols
are increasing, IRBS must respond to an ever-expanding array of Federal
and State requirements that, in the aggregate, have become procedurally
onerous, and, some argue, distracting.
Given that within the academic community IRB members are almost
always volunteers with major responsibilities in teaching, research,
and often, patient care, it is not surprising that they are finding it
difficult to accept progressively increasing new burdens of oversight,
or finding the time and resources to undertake periodic self-
assessment. The AAMC agrees with Dr. Koski that responsibility for
ensuring the well-being of human research participants in this rapidly
changing environment of clinical research, can no longer be considered
primarily to rest on IRBs, but must become the duty of all who are
engaged in the enterprise. The British code of medical ethics speaks of
a solemn ``duty of care'' that rests on every physician; the AAMC
suggests that same ethical ``duty of care'' should rest on every
physician-investigator who conducts research on human participants.
Universities, medical schools, and teaching hospitals must work to
instill across their campuses, in all who engage in human participant
research, a new sense of shared obligation and a new culture of
individual responsibility. The AAMC believes, based on its long
experience with many different kinds of academic accreditation
programs, that establishing a mechanism of voluntary accreditation of
human research protection programs would be very helpful to our
members, as well as the broader academic community, in accomplishing
the changes in faculty attitude and institutional culture that are
necessary. The idea of creating such an accreditation mechanism had
been debated within PRIM&R circles for several years. In May 1999
PRIM&R announced that it would develop a program of accreditation for
human research protection programs, which it dubbed AAHRPP (Association
for the Accreditation of Human Research Protection Programs), and
formed a committee to begin to draft accreditation standards. Since
that time, as I will describe, the AAMC has partnered with PRIM&R to
bring this concept into existence in a way that is consonant with our
traditional and uniquely American model of voluntary, peer-driven,
educationally focused accreditation of academic institutions and their
components.
The accreditation model, while necessarily conforming to all
applicable statutory and regulatory requirements, is importantly
different from the regulatory model, common in other countries, which
focuses purely upon regulatory compliance. Accreditation fosters a
process of self-examination and a culture of self-improvement that is
stimulated and nurtured by the accreditation process itself. AAMC
shares with PRIM&R the belief that such an accreditation process for
human subjects protection programs should combine objective, outcome-
oriented performance standards with on-site reviews involving collegial
dialogue and education. An approach that is collaborative yet based
upon clearly-defined standards will encourage institutions to strive
for ever higher levels of performance beyond the threshold of
compliance. The ultimate objective of accreditation will be to foster a
commitment to continuing quality improvement within each institution's
system for the protection of human research participants.
The AAMC conceived of AAHRPP as a non-profit member corporation, in
which the members would be the large Washington-based associations
representing America's universities (Association of American
Universities and National Association of State Universities and Land-
Grant Colleges), medical schools and teaching hospitals (AAMC),
biomedical scientists (Federation of American Societies for
Experimental Biology), behavioral and social scientists (Consortium of
Social Science Associations), patient advocacy organizations (National
Health Council), and IRB experts (the Boston based PRIM&R). AAMC took
the lead in forging this alliance, securing funding, and bringing
AAHRPP into existence; AAHRPP was incorporated in the State of Maryland
on April 23, 2001. AAHRPP's mission is to provide a process of
voluntary, peer-driven, educationally-focused accreditation and
continuing quality improvement for academic institutions and other
organizations concerned with research involving human participants.
AAHRPP's goal is to create and administer a highly respected program of
accreditation that is viewed by the larger research enterprise, the
Federal Government, and the public as safeguarding and improving the
protection of human research participants. AAHRPP is now operational
and a full slate of site visits is anticipated to be performed this
year.
AAHRPP is governed by a 21 member board of directors that includes
5 public representatives and has full authority over the organization
and its accreditation programs and activities. The founding members
serve in a trustee role, with strictly circumscribed fiduciary
responsibilities; the members will have no role whatever in the
operations of AAHRPP or its decision-making processes. The executive
director of AAHRPP is Marjorie Speers, Ph.D. and the president is David
Skorton, M.D., from the University of Iowa.
The AAMC is very pleased to have been able to play a major role in
the creation of AAHRPP and is prepared to continue to do whatever it
may be asked to ensure its success. We believe that AAHRPP will
contribute in important ways to the change in culture of human
participant research, which Dr. Koski has repeatedly called for, and to
which our members and we unequivocally subscribe.
conflicts of interest
Following the reports of several tragic events that occurred in
gene transfer experiments in which both faculty and their sponsoring
institutions were perceived to have significant financial interests,
the Administration, the Congress, and the media began to question the
sufficiency of current Federal conflict-of-interest guidelines, the
credibility of institutional conflict-of-interest policies, and the
dependability of academic institutions in complying with their own
policies. Driving this concern was the fear that financial conflicts of
interest may jeopardize the safety of research participants and the
integrity of research data. This topic had last captured public
attention in the 1980s, when congressional hearings cast a harsh light
on several instances in which financial conflicts of interest seemed
linked to scientific misconduct in clinical research.
More than a decade ago, the AAMC developed and published guidelines
to aid its membership in addressing faculty conflicts of interest in
research. These guidelines were a necessary response to the emerging
paradigm of university/industry collaboration spurred by the Bayh-Dole
Act, which in 1980 gave universities title to inventions arising from
federally-sponsored research. Bayh-Dole created fertile ground for
nurturing the transfer of basic research findings to the developers of
beneficial products, but also gave rise to new incentives for
investigators and their institutions to pursue financial interests in
the course of scientific research.
Although the AAMC guidelines have served as a useful model for
conflict of interest policies developed by individual medical schools
and teaching hospitals, recent studies have indicated that across the
academic community, approaches to identifying and managing individual
financial conflicts of interest vary widely. Of particular concern is
the absence of consensus regarding the proper management of related
financial interests in clinical research that involves human
participants. Moreover, neither the AAMC guidelines nor most
institutional policies address the conflicts that may arise from the
financial interests of the institutions themselves, which have
increased substantially in the past decade from both royalty streams
and equity holdings. Although conflicts of interest are ubiquitous and
inevitable in academic life, as they are in all professions, the
existence of related financial interests of either individual
investigators or their institutions in research involving human
participants raises special concerns. Yet, such interests have become
particularly widespread in academic medicine, which has spawned a
flourishing biotechnology industry, generated an insatiable public
appetite and impatience for ever more wondrous treatments, and
contributed importantly to the intense public and political interest in
universities as sources of regional economic prosperity.
Our collective experience with the increasingly commercial nature
of academic research and our obligation to be responsible compel a
thorough reexamination of how the academic medical community manages
financial interests in research involving human participants. The AAMC
believes it imperative that our community take the initiative in
reassuring the public and policymakers that neither institutional nor
faculty financial interests will be permitted to compromise the safety
of human participants or the integrity of biomedical research. AAMC
President Jordan Cohen, M.D., made financial conflicts of interest the
theme of his address at the AAMC 2000 Annual Meeting, where he
announced the formation of a high level Task Force on Financial
Conflicts of Interest in Clinical Research. The association chose to
focus the efforts of the task force upon financial conflicts of
interest involving human participants, in part because we perceive an
urgent need to rethink and revise our guidance in this area, and in
part to complement the activities of an AAU Task Force on the
Responsible Conduct of Research, which examined some of these same
issues from the campus-wide perspective of university presidents. In
composing our task force and developing its charge, we were
particularly sensitive to the special relationship of trust that
academic medicine enjoys with the American public. The work of the task
force was guided by our commitment to sustain that trust in the context
of the new, extraordinarily promising, and far more entrepreneurial
environment in which we now conduct research.
Chaired by William Danforth, M.D., chancellor emeritus of
Washington University, the task force published its recommendations in
December 2001. An overview of our work was also published this January
in the New England Journal of Medicine. The task force roster is
contained in the final report, which is appended to this testimony, as
is a copy of the summary article. We request that this material be
entered into the record of this hearing. (The documentation was not
available at press time, however copies are maintained in the committee
files.) Among the 28 members of the AAMC Task Force on Financial
Conflicts of Interest in Clinical Research are prominent
representatives from the fields of academic medicine, law, industry,
bioethics, patient advocacy, the media and politics.
The task force was charged with examining the appropriate limits of
financial interests for faculty, students, and staff involved in the
conduct of research with human participants, and whether certain types
of financial interests should be prohibited. The task force considered
the most effective means by which significant related financial
interests in research involving human participants should be disclosed
to the institution, the research participants, and to the public, and
under what circumstances, if any, it is acceptable for institutions to
invest in and sponsor faculty entrepreneurial activities involving
human participants. For those circumstances that may be deemed
acceptable, the task force proposed mechanisms to ensure that
institutional oversight of faculty activities is responsible and
credible.
Quoting from my summary article: The guidelines offered by the AAMC
task force are based on some core principles. The first guideline makes
it clear that the welfare of the patient is paramount. The second
guideline addresses the circumstances under which researchers with
financial conflicts might be allowed to participate in human research.
The other guidelines define institutional responsibilities for the
oversight and management of conflicts of interest, as well as the
individual responsibilities of faculty members, staff members, and
students. For example, the task force recommends that full initial and
updated reporting of any relevant activity be required. Moreover,
institutional policies should be comprehensive, unambiguous, well
publicized, consistently applied, and enforced by means of effective
sanctions. The document states that ``Transparency must be the
watchword for the oversight of financial interests'' and that
``transparency is achieved through full and ongoing internal reporting
and external disclosure.'' The task force recognized that some
conflicts pose little threat to the physician-patient relationship and
may even advance its primacy; they therefore adopted, as part of the
complex definition of ``significant financial interest in research,''
the threshold established by the Public Health Service of $10,000 of
total interest in companies related to the research in question for a
conflict of interest in any given research project.
The report lists the requirements that must be met as institutions
develop their own policies. For example, the key responsibilities of
the committee that assesses conflicts of interest are identified. In
addition, detailed guidance is provided on reporting requirements, the
certification of investigators, disclosure practices, monitoring
procedures, the protection of students and trainees, legal obligations,
and sanctions. Advice is also provided on the implementation of such
policies, including consideration of information flow, resources,
written acknowledgment by those involved in clinical research that they
have read and understood the policy, education and training of
researchers, and accreditation of institutional research review
processes.
The greatest challenge for the task force was reaching a consensus
on the best way to ensure that the welfare of the patient remains the
top priority. One sentence in the first guideline deserves further
discussion; it states that, ``institutional policies should establish
the rebuttable presumption that an individual who holds a significant
financial interest in research involving human subjects may not conduct
such research.'' Some members of the task force and some research
organizations, such as the American Society of Gene Therapy, believe
that any financial conflict should preclude involvement in such
research. The privilege of conducting research involving human subjects
in cases which investigators have substantial financial conflicts of
interest should be restricted to instances in which there are
compelling reasons for an exception to be made. The AAMC task force
recommended that it should be the responsibility of the researcher who
has such a conflict to persuade an institutional committee that it is
in the best interest of the subjects to allow the investigator to have
direct involvement in the research.
Addressing investigator conflicts of interests is only part of the
challenge. It is also necessary to address the management of
institutional conflicts of interest. The AAMC's institutional conflict
of interest task force is confronting this issue. The task force's
complete report will provide detailed guidelines for the recognition
and management of all institutional conflicts of interest.
The AAMC respectfully urges the subcommittee to afford academic
medicine the opportunity to demonstrate that we can--and will--take the
actions necessary to sustain the public trust in our institutions, our
investigators, and the integrity of biomedical research, while
continuing to play a seminal role in translating the remarkable fruits
of the ``Golden Age of Biology'' into public benefit.
To conclude, the AAMC and its members are firmly committed to the
protection of the rights and welfare of every individual who elects to
participate in human research, and we look forward to continue working
with the members of this subcommittee to achieve this goal.
______
Prepared Statement of Virginia A. Sharpe, Ph.D.
I am Virginia Ashby Sharpe, Ph.D., Director of the Integrity in
Science Project at the Center for Science in the Public Interest.
Before coming to the Center for Science in the Public Interest, I was
the Deputy Director of the Hastings Center, where my research focused
on issues related to ethics and adverse medical events. The Integrity
in Science project addresses the role that corporate interests play in
scientific research, oversight, and science-based policy and advocates
for full disclosure of funding sources by individuals and governmental
and non-governmental organizations that conduct, regulate, or provide
oversight of scientific investigation or promote specific scientific
findings.
As you know, over the last 3 decades, a number of factors have
spurred the commercialization of science in the United States and
around the world. The genomics revolution, judicial decisions
supporting patent protection for bioengineered molecules, laws
strengthening intellectual property rights both in the United States
and in the context of international trade, and the 1980 Bayh-Dole Act
authorizing licensing and patenting of results from federally-sponsored
research have created new incentives for clinicians, academic
institutions, and researchers to join forces with for-profit industry
in an unprecedented array of entrepreneurial activities.
At the same time, companies seeking to expand their market share in
biomedicine, biotechnology, and other fields provide clinicians,
scientists, and academic institutions with research support,
consultancies, honoraria, royalty arrangements, all-expenses-paid
conferences, and other gifts. Infusions of corporate money to resource-
constrained public universities may be seen by legislators as a welcome
alternative to the expenditure of limited State funds.
The upshot of these trends for human subjects research is that 70
percent of funding for clinical drug trials now comes from industry,
and a significant number of those trials are conducted by for-profit
contract institutions and private office-based physicians who operate
outside the context and oversight of academic research institutions.
Office-based physicians are paid to recruit patient-subjects into these
drug trials and are financially rewarded if they succeed in keeping
patient-subjects in a study to its conclusion.
The oversight of human subjects research within academic
institutions has also increasingly come under scrutiny. Because
institutional IRB membership is largely voluntary, members may have
neither the time nor the commitment to pursue rigorous review of
protocols. Likewise, if only those who have an incentive to move
research forward at an institution volunteer for this task, there may
be inappropriate incentives and quid pro quos built into the oversight
process. In addition, academic institutions have increasingly come
under scrutiny as they begin to have ownership stakes in new drugs and
biologics whose investigational protocols are reviewed by their own
institutional review boards.
Although many have cheered these partnerships between industry and
clinicians, researchers, hospitals, and academic medical centers, it is
also generally acknowledged that they introduce potentially biasing
financial incentives into the decisionmaking of precisely those
individuals and institutions who are charged with maintaining the
integrity of science and the protection of human subjects.
We believe that legislation to strengthen human research
protections should:
1. Apply protections in the ``Common Rule'' uniformly to all
research on humans regardless of setting or funding source.
2. Enhance regulatory oversight of human subjects research by
creating an independent body outside of existing Federal agencies.
3. Mandate accreditation of institutional and non-institutional
review boards.
4. Mandate training for institutional and non-institutional review
board members.
5. Mandate comprehensive information collection by oversight bodies
of financial and other relevant conflicts-of-interest or perceived
conflicts-of-interest of individual investigators and research
institutions engaged in human research.
6. Mandate full disclosure to research subjects and the public of
financial and other relevant conflicts-of-interest or perceived
conflicts-of-interest of individual investigators, research
institutions, and oversight bodies.
Because the term ``disclosure'' can be used ambiguously, any new
legislation should clearly distinguish between ``information
collection'' and ``disclosure.'' Information collection should refer to
the required provision of information by an individual to an oversight
authority, such as a university conflict-of-interest committee, a
review board, or Government agency. ``Disclosure,'' on the other hand,
should refer to the subsequent provision of that information by the
oversight body to research subjects (or valid proxies) and the public.
We believe that, in the context of human subject protection, it is
misleading to state that a researcher or institution has ``disclosed''
information if that information never reaches the research subject (or
valid proxy) and the public. Because financial and other conflicts-of-
interest may place subjects at risk, they are entitled to information
about such conflicts as part of the informed consent process.
The underlying assumption that information collection by an
oversight body is an adequate safeguard against inappropriate
conflicts-of-interest is that the oversight body can ensure that
financial and other factors have not unduly influenced or compromised
the reported activity. However, as is attested by the American
Association of Medical Colleges' efforts to address institutional
conflicts-of-interest and the General Accounting Office recommendations
regarding the risks of institutional conflicts,\5\ there is widespread
acknowledgement that institutional bodies are doing an inadequate job,
in part, because they also may have significant conflicts-of-interest
that compromise their ability to provide independent oversight.
---------------------------------------------------------------------------
\5\ General Accounting Office. ``HHS Direction Needed to Address
Financial Conflicts of Interest.'' GAO-02-89. November 2001. See http:/
/www.gao.gov/new.items/dO289.pdf.
---------------------------------------------------------------------------
When a hospital has an equity stake in a company whose product is
being proposed for clinical trial to the institution's IRB, how can
independent oversight be assured? When a university ostensibly
dedicated to academic freedom stands to lose a major company gift if
one of its researchers is critical of the company's products, how can
the university be trusted not to silence the researcher? This
persistent problem is summed up in the phrase: ``Who watches the
watchers?''
The Integrity in Science project believes that in a democracy,
transparency through public disclosure and disclosure to research
subjects is an essential minimum requirement for managing conflicts-of-
interest and curbing abuses in the conduct and oversight of human
subjects research. We believe that researchers, research institutions,
and oversight bodies are accountable ultimately to those placed at
specific risk either as research subjects in the service of science or
as consumers through exposure to the drugs and devices marketed on the
basis of research.
Accreditation guidelines for human subjects research review boards
will undoubtedly require that boards have substantive conflict-of-
interest statements and conflict management strategies, such as
firewalls, threshold amounts of financial support, and recusal. We
believe that the credibility and effectiveness of those substantive
standards will depend on the transparency with which they are
implemented. In other words, the legitimacy of substantive conflict
management strategies will, at minimum, depend on disclosure of
relevant financial and other conflicts-of-interest to subjects and the
public.
Thus, we urge you to include mandatory disclosure of financial and
other conflicts of interest in any new legislation.
Endnotes:
\1\ Diamond v. Chakrabarty, 447 U.S. 303 (1980).
\2\ The Patent and Trademark Act Amendments of 1980.
Pub. L. No. 96-517, 94 Stat. 3019 (codified at 35 U.S.C. Sec. Sec. 200-
11 (1982).
\3\ T. Bodenheimer, ``Uneasy Alliance: Clinical
Investigators and the Pharmaceutical Industry.'' N. Engl. J. Med. 2000
May 18; 342(20):1539-44.
\4\ AAMC Taskforce on Financial Conflicts of Interest in
Clinical Research. ``Protecting Subjects, Preserving Trust, Promoting
Progress.'' (December 2001). See http://www.aumc.org/members/coiff/
chartercharge.htm for forthcoming reports.
______
Policy Statement of the Association of Clinical Research Organizations
Chairman Kennedy, Senator Frist, members of the subcommittee: The
Association of Clinical Research Organizations (ACRO) applauds the
subcommittee for today's examination of the protections afforded to
human participants in biomedical research. We believe strongly that the
public must be fully confident that researchers place the well-being of
human volunteers first and foremost in all clinical trials research,
and that Federal regulators have available the tools to provide a high
level of oversight to the system of research that has powered the
development of the most advanced health care system in the world.
The members of ACRO--Covance Inc., Kendle International Inc.,
PAREXEL International Corp., Pharmaceutical Product Development, Inc.
(PPD) and Quintiles Transnational Corp.--assist pharmaceutical,
biotechnology and medical device companies with the conduct of
thousands of clinical trials every year. We provide a wide range of
research services, including consultation in study design, facilitation
of the recruitment of investigators and study patients, assurance of
the protection of patients, assurance of the integrity of the research
data and the data analysis to maximize the quality of the research, and
guidance through a very complex regulatory environment.
Whether providing limited support, such as assisting with the
training of research site staff, or assuming full regulatory
responsibility on behalf of a sponsor for all aspects of the conduct of
a clinical trial, we are committed to putting the safety of research
participants first. Today, ACRO members are full partners in the drug
development cycle, and we are proud to be part of the clinical research
that produces new drugs, new medical devices, and new treatments that
improve health and save lives.
Because an uncompromising commitment to safety and quality is the
hallmark of ethical research, ACRO supports new legislation to improve
the protection of human subjects. We believe that such legislation
should embody three basic principles:
1. Federal oversight mechanisms should be extended to as much
research that includes human subject volunteers as possible.
2. Uniform human research subject protection requirements should
apply to all research subject to Federal oversight, regardless of the
source of funding for the research or the site where the research is
conducted.
3. The Department of Health and Human Services (HHS) should be
directed to review and move to ``harmonize'' the human subject
protection requirements of current FDA regulations (21 CFR) and the
``Common Rule'' (45 CFR), with the intent of promulgating standards
that combine the strengths of the two regulatory approaches and
improving the protection of human research subjects.
Why Clinical Trials are Crucial to Advances in Medicine
Until the mid-20th century the practice of medicine relied largely
on observation. Physicians knew what worked or didn't work based on the
experience of their own patients, and the case studies described by
their colleagues. With this model of anecdotal reporting, advances in
understanding and treatment were often slow and painstaking, and
sometimes hampered by observations that were misleading, if not simply
wrong.
In the mid- to late-1940s two British physicians designed what were
perhaps the first truly randomized, controlled evaluation of competing
treatments (for tuberculosis) and laid the groundwork for the single
greatest advance in the science of medicine in our time: the carefully
conducted clinical trial that is designed to test the safety and
efficacy of new drugs and new treatments in humans.
By demonstrating the importance of studying sufficiently large
groups of patients in a controlled and methodical way, and developing
the rigorous scientific and statistical methods necessary to obtain
reliable and reproducible results, the clinical trial led directly to
the concept of ``evidence-based'' medicine. More importantly, the
widespread adoption of the clinical trial led to spectacular advances
in lifespan and quality of life. The advance of clinical trials made
possible the confident introduction of breakthrough drugs and
treatments--new medicines to lower cholesterol and reduce the risk of
heart attack; increasingly effective treatments for depression and
other serious mental disorders; drugs that make AIDS more and more a
disease that can be managed medically over time and not inevitably a
death sentence, to cite just a few examples. In addition, the
evidentiary power of clinical trials has allowed an understanding of
the potential complications and serious adverse events of new
treatments, such as high-dose chemotherapy with autologous bone marrow
transplantation, and a sound evaluation of treatment risk. It is
because of clinical trials that ever-increasing numbers of cancers and
other deadly diseases can be ``cured'' or put into remission.
It is important to note that the occurrence of a serious, avoidable
injury during the course of a well-designed and well-conducted clinical
trial is extremely rare. Nonetheless, we recognize that there have been
well-publicized and genuinely tragic injuries and even deaths in
clinical research projects in recent years, and that the current system
of Federal oversight is complex and increasingly overtaxed. While there
can be no doubt that clinical trials are essential to medical progress,
current protections and safeguards can be strengthened and the clinical
research organizations of ACRO are strongly supportive of initiatives
that will improve research practice and increase public confidence, and
thereby facilitate life-saving research.
The Role of the Clinical Research Organization (CRO) in Protecting
Patients
In the remarks concerning the protection of human research
participants to follow, ACRO encourages the subcommittee to keep in
mind three characteristics of the clinical research organization:
ACRO members have a broad perspective--on clinical research, a
perspective that is global in nature and interwoven into the activities
of all the participants involved in clinical trials research,
including--most importantly--patients. Oftentimes, we are the only
entity that has an overview of all the players on the field.
The clinical research organization has a unique role--as associate,
partner, intermediary, monitor, and auditor, in relation to sponsors,
investigators, patients, and regulators. Our central task is to ensure
compliance with regulations, regulations that embody the application of
good clinical practices and ethical behavior on a global basis.
We are committed to safety and quality--because without both we
would be unable to ensure the participation in research of our most
crucial partners, the patients whose willingness to take part in
clinical trials is essential to making new drugs and new treatments
available.
In providing research services to a sponsor, ACRO may become
responsible for various aspects of the conduct of the study. Indeed,
pharmaceutical companies often transfer to an ACRO member some or all
of the clinical trial regulatory responsibilities stipulated by the
Food and Drug Administration (FDA). Thus, the clinical research
organization is involved on behalf of a sponsor in how a study is
conducted--but, at the same time, may have the characteristics of an
institution, if by that we mean an entity that may identify clinical
investigators, provide dedicated research facilities, conduct any or
all phases of the research, and interact with Federal and overseas
regulators. Further, the ACRO's role as both associate and intermediary
in relation to the sponsor, the investigator, the participant, and even
the regulator makes for an extremely broad view of drug development
processes, including the implementation of patient protections.
In theory, the current system for both approval and oversight of
clinical research depends heavily upon institutional review boards, or
IRBs. In practice, however--at least for FDA-regulated research--while
the IRB undertakes the determination of whether a research protocol is
appropriately designed and broadly meets a risk-benefit analysis, when
the study is actually conducted it falls to sponsors and their CRO
partners to provide specific individual investigator and patient-by-
patient oversight: to assess the planned and actual recruitment of
participants, the execution of informed consent, the collection and
safeguarding of data, the reporting of adverse events and the use of
data and safety monitoring boards (DSMBs), deviations from and changes
to study protocols, and the like. In particular, the role of the study
monitor--a research professional who is employed by the sponsor or CRO
to monitor the actual conduct of the study, and who has an ``on the
ground'' presence that is not within the scope of an IRB--is critical
to the protection of clinical trial volunteers and to the integrity of
the research data.
In practical terms, many of the services that a CRO furnishes to a
sponsor have a direct bearing on the protection of clinical trial
participants. For instance, we may provide: access to a database of
well-trained, experienced investigators, especially those who provide
clinical care to the appropriate patient population; experience with
multi-center protocols, and international studies; trained research
coordinators and research monitors; central laboratory and data
management capacities; and central quality assurance functions.
All of which put us squarely on the line when it comes to
protecting patient safety.
It is important to note that the CRO's function is to ensure the
quality of the research effort, not the result of any particular study.
Our ``bias,'' if we call it that, is to facilitate quality research in
the timeliest manner possible--and speed combined with accuracy can
simply never be gained by cutting corners or skimping on patient
protections. In short, the integrated role of the CRO provides a unique
perspective on the task of overseeing the conduct of research, and the
protection of human subjects, as the CRO acts on behalf of--but is also
independent of--the sponsor; and in addition acts as a resource for--
but, at the same time, monitor of--the investigator and site staff.
Because the large majority of our work relates to the development
of drugs or devices regulated by the FDA, CROs are highly experienced
with a strict regulatory approach to the protection of human subjects.
We believe that with the current good clinical practices (GCP)
guidelines and standards, the FDA provides excellent guidance for
meeting the patient protections required in regulation. Similarly, the
standards of the International Conference on Harmonization (ICH) and
the Council for International Organizations of Medical Sciences (CIOMS)
guide us in the conduct of international trials. In every trial the
question for us is: do we do what the regulations call for, and can we
prove that with appropriate documentation? This regulatory approach can
be contrasted with that of the Common Rule, which utilizes a paradigm
based on assurances, where the question is: has the responsible party
assured that it can, and will, observe the relevant requirements?
Now some have argued that the weakness of the regulatory model is
that its oversight relies on after-the-fact review of documentation
rather than ongoing monitoring. But the answer to that problem, in our
view, is not to ask IRBs to do something they simply are not designed
or equipped to do--particularly since CRO coordinators, monitors, data
managers, biostatisticians and others are, in fact, coordinating the
performance and monitoring the actual conduct of the research in real-
time today. Instead, perhaps we need a combined approach, an approach
to oversight that integrates the ``assurance'' and ``regulatory
compliance'' models in a way that both trusts and verifies--because, in
ACRO's view the highest ethical and scientific aspirations mean little
unless we actually protect our patients and we can prove it.
Improving Current Protections
The current system of human research participant protections is
neither as uncontrolled and inadequate as some seem to think, nor as
over-regulated and stymied by bureaucracy as some protest. It is a
system that relies on the training and ethics of physicians and many
others to conduct scientifically rigorous, meaningful and useful
research. In truth, it is largely successful--enabling spectacular
advances in drug treatments and other therapeutic interventions, and in
overwhelming measure it wins a vote of confidence from its most
important constituents: the human research volunteers themselves. At
the same time, however, we recognize that existing regulations are
inconsistent, overlapping and do not cover all human subject research--
and that patients, investigators, IRBs, and all research participants
would be better served by a set of regulations that could be uniformly
and consistently applied.
In our experience, current FDA and international regulations
provide strong protections for volunteers enrolled in clinical trials
intended to test new drugs, new devices, and new treatments. This
regulatory framework, however, does not extend to many studies,
including much Government-funded research and an unknown amount of
private research that is not intended for submission to the FDA, and we
applaud the subcommittee's examination today of gaps and weaknesses in
the oversight system.
Again, ACRO believes that legislation intended to improve the
protection of human subjects should embody three basic principles:
1. Federal oversight mechanisms should be extended to as much
research that includes human subject volunteers as possible.
2. Uniform human research subject protection requirements should
apply to all research subject to Federal oversight, regardless of the
source of funding for the research or the site where the research is
conducted.
3. The Department of Health and Human Services (HHS) should be
directed to review and move to ``harmonize'' the human subject
protection requirements of current FDA regulations (21 CFR) and the
``Common Rule'' (45 CFR), with the intent of promulgating standards
that combine the strengths of the two regulatory approaches and the
goal of improving the protection of human research subjects.
Specific issues relevant to the protection of human subjects that
should be examined by the Secretary of HHS include initiatives to help:
clarify and improve the informed consent process; strengthen and
provide additional support to the IRB system; clarify and improve the
processes for evaluating and, when necessary, disclosing potential
financial conflicts of investigators, institutions and IRBs that may
affect the conduct of research; assure the familiarity of all parties
involved with clinical research with the scientific and ethical
principles that underlie the protection of human subjects; and, in
general, to strengthen consistent regulatory compliance, and the
conduct of highest quality research.
For our part, ACRO does not intend to wait for Congressional action
but has already begun to consider both smaller and larger scale
initiatives aimed at improving still further a record of safety and
quality of which we are very proud. For instance, many CROs strongly
encourage the certification of study coordinators (CRCs) and study
monitors (CRAs) as a basic indicator of research and regulatory
knowledge and experience. Similarly, we have strongly supported
investigator participation in education and training opportunities
offered by the Office for Human Research Protections (OHRP), the FDA
and the NIH. And we have begun to look at a number of other issues that
may impact the conduct of clinical research and the protection of human
subjects, such as: the recruitment and training of investigators, with
special attention to first-time investigators; ``best practices'' for
patient enrollment and the execution of informed consent; the use of
voluntary certifications for investigators and other personnel;
mitigating negative effects of financial conflicts of interest, and
examining policies regarding the use of financial incentives for both
patients and investigators; and participation in self-regulatory
initiatives, such as taking part in the educational and quality
improvement initiatives undertaken by the OHRP.
Conclusion
The Association of Clinical Research Organizations (ACRO) thanks
Chairman Kennedy, Senator Frist and the members of the subcommittee for
today's hearing. Your recognition of the need to improve the safety of
those who volunteer to participate in clinical research and, at the
same time, to increase public confidence in the system of medical
research that produces new drugs and new treatments to improve health
and save lives every day is vitally important to what Senator Kennedy
has called ``the century of the life sciences.'' ACRO appreciates the
opportunity to share our views with the subcommittee, and our members
stand ready to work closely with you on legislation of great importance
to all Americans.
The hearing stands in recess.
[Whereupon, at 11:35 a.m., the hearing was adjourned.]