[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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          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

                              ----------                              

                               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?

                              ----------                              


                        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.]
  

                                
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