[House Hearing, 106 Congress]
[From the U.S. Government Printing Office]




                               before the


                                 of the

                              COMMITTEE ON
                           GOVERNMENT REFORM

                        HOUSE OF REPRESENTATIVES

                       ONE HUNDRED SIXTH CONGRESS

                             SECOND SESSION


                              MAY 3, 2000


                           Serial No. 106-198


       Printed for the use of the Committee on Government Reform

  Available via the World Wide Web: http://www.gpo.gov/congress/house

70-580                     WASHINGTON : 2001

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                     DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York         HENRY A. WAXMAN, California
CONSTANCE A. MORELLA, Maryland       TOM LANTOS, California
CHRISTOPHER SHAYS, Connecticut       ROBERT E. WISE, Jr., West Virginia
JOHN M. McHUGH, New York             EDOLPHUS TOWNS, New York
STEPHEN HORN, California             PAUL E. KANJORSKI, Pennsylvania
JOHN L. MICA, Florida                PATSY T. MINK, Hawaii
THOMAS M. DAVIS, Virginia            CAROLYN B. MALONEY, New York
DAVID M. McINTOSH, Indiana           ELEANOR HOLMES NORTON, Washington, 
MARK E. SOUDER, Indiana                  DC
JOE SCARBOROUGH, Florida             CHAKA FATTAH, Pennsylvania
    Carolina                         ROD R. BLAGOJEVICH, Illinois
BOB BARR, Georgia                    DANNY K. DAVIS, Illinois
DAN MILLER, Florida                  JOHN F. TIERNEY, Massachusetts
ASA HUTCHINSON, Arkansas             JIM TURNER, Texas
LEE TERRY, Nebraska                  THOMAS H. ALLEN, Maine
JUDY BIGGERT, Illinois               HAROLD E. FORD, Jr., Tennessee
GREG WALDEN, Oregon                  JANICE D. SCHAKOWSKY, Illinois
DOUG OSE, California                             ------
PAUL RYAN, Wisconsin                 BERNARD SANDERS, Vermont 
HELEN CHENOWETH-HAGE, Idaho              (Independent)

                      Kevin Binger, Staff Director
                 Daniel R. Moll, Deputy Staff Director
           David A. Kass, Deputy Counsel and Parliamentarian
                    Lisa Smith Arafune, Chief Clerk
                 Phil Schiliro, Minority Staff Director

   Subcommittee on Criminal Justice, Drug Policy, and Human Resources

                    JOHN L. MICA, Florida, Chairman
BOB BARR, Georgia                    PATSY T. MINK, Hawaii
MARK E. SOUDER, Indiana              ROD R. BLAGOJEVICH, Illinois
STEVEN C. LaTOURETTE, Ohio           JOHN F. TIERNEY, Massachusetts
ASA HUTCHINSON, Arkansas             JIM TURNER, Texas
DOUG OSE, California                 JANICE D. SCHAKOWSKY, Illinois

                               Ex Officio

DAN BURTON, Indiana                  HENRY A. WAXMAN, California
           Sharon Pinkerton, Staff Director and Chief Counsel
                Lisa Wandler, Professional Staff Member
                           Ryan McKee, Clerk
                    Cherri Branson, Minority Counsel

                            C O N T E N T S

Hearing held on May 3, 2000......................................     1
Statement of:
    Curtin, Richard, human subject, Falls Church, VA; Charles R. 
      McCarthy, senior research fellow, Kennedy Institute of 
      Ethics, Georgetown University; and Robert Amdur, M.D., 
      associate professor, associate chair, clinical affairs, 
      Department of Radiology and Oncology, University of Florida    60
    Grob, George, Deputy Inspector General for Evaluation and 
      Inspections, Office of Inspector General, Department of 
      Health and Human Services; Mark Yessian, Ph.D., regional 
      Inspector General for Evaluation and Inspections, 
      Department of Health and Human Services; William Raub, 
      Ph.D., Deputy Assistant Secretary, Science Policy, Office 
      of the Secretary, Health and Human Services; Gary Ellis, 
      Ph.D., Acting Director, Office of Protection from Research 
      Risks; and Daniel Michels, Director of Enforcement, Office 
      of Regulatory Affairs, Food and Drug Administration........    10
Letters, statements, etc., submitted for the record by:
    Amdur, Robert, M.D., associate professor, associate chair, 
      clinical affairs, Department of Radiology and Oncology, 
      University of Florida, prepared statement of...............   122
    Curtin, Richard, human subject, Falls Church, VA, prepared 
      statement of...............................................    63
    Grob, George, Deputy Inspector General for Evaluation and 
      Inspections, Office of Inspector General, Department of 
      Health and Human Services, prepared statement of...........    12
    McCarthy, Charles R., senior research fellow, Kennedy 
      Institute of Ethics, Georgetown University, prepared 
      statement of...............................................    70
    Mica, Hon. John L., a Representative in Congress from the 
      State of Florida, prepared statement of....................     5
    Raub, William, Ph.D., Deputy Assistant Secretary, Science 
      Policy, Office of the Secretary, Health and Human Services, 
      prepared statement of......................................    34
    Waxman, Hon. Henry A., a Representative in Congress from the 
      State of California, prepared statement of.................    49



                         WEDNESDAY, MAY 3, 2000

                  House of Representatives,
Subcommittee on Criminal Justice, Drug Policy, and 
                                   Human Resources,
                            Committee on Government Reform,
                                                    Washington, DC.
    The subcommittee met, pursuant to notice, at 2:36 p.m., in 
room 2247, Rayburn House Office Building, Hon. John L. Mica 
(chairman of the subcommittee) presiding.
    Present: Representatives Mica, Cummings, and Kucinich.
    Staff present: Sharon Pinkerton, staff director; Steve 
Dillingham, special counsel; Don Deering, congressional fellow; 
Lisa Wandler, professional staff member; Ryan McKee, clerk; 
Alex McKinnon, intern; Cherri Branson, minority counsel; and 
Earley Green, minority staff assistant.
    Mr. Mica. Good afternoon. I'd like to call this hearing of 
the Subcommittee on Criminal Justice, Drug Policy, and Human 
Resources to order. I apologize for the delay. There is a full 
committee hearing going on at this time, but with the consent 
of the minority, we are going to proceed.
    We have two panels today, and we do want to finish this 
hearing this afternoon. It is an important hearing, entitled 
``Human Subject Research Protections,'' one of which I'm 
pleased to work with my colleague Mr. Kucinich, the gentleman 
from Ohio, and this is the second hearing we've conducted on 
this matter.
    I am going to start with the regular order of business. We 
may at some time have to recess for a vote, either in committee 
or on the floor, but we'll proceed with opening statements, 
recognizing myself first and then the gentleman from Ohio.
    This hearing before the Subcommittee on Criminal Justice, 
Drug Policy, and Human Resources will examine a critical 
problem for which reforms have been recommended by the Office 
of Inspector General [OIG], to the Department of Health and 
Human Services [HHS]. Last December, we conducted a hearing on 
this topic in New York City where past issues had surfaced 
regarding the protections of persons participating in human 
research projects. The December hearing also coincided with 
revelations regarding the tragic death of 18-year-old Jesse 
Gelsinger of Tucson, AZ. Jesse died just 4 days after being 
injected with a cold virus and engineered genes. Researchers 
were shocked and a national debate ensued on gene therapy 
experiments and the reporting of adverse effects. The National 
Institutes of Health [NIH], issued a solicitation to the 
medical community requesting help.
    Even in today's Washington Post, I read that there were 
reports of more deaths which were not reported to authorities 
and which also put more lives at risk. The question I pose 
today is whether HHS heeded this cry for help and has that 
agency acted promptly to prevent future tragedies.
    Our December hearing included testimony from both OIG and 
also from HHS. At that time, it was apparent that HHS had not 
implemented the Office of Inspector General recommended reforms 
for protecting human research subjects.
    Today, we'll revisit this important issue. We will hear in 
fact that more deaths of participants in human research have 
been reported, and that, in fact, more violations of required 
human subject protections have been revealed. The Office of 
Protections Against Research Risk [OPRR], is one component of 
the HHS agency with special responsibilities for protecting 
human research subjects. The Food and Drug Administration 
[FDA], is another. Apparently neither has received the support 
and commitment from the administration and the Health and Human 
Services Secretary that is needed; indeed, that is required to 
enhance the protections for research subjects.
    Furthermore, the Department continues to putter around with 
this important issue, virtually ignoring most of the sound OIG 
recommendations and dragging their feet.
    Why is HHS so reluctant to act proactively in reforming its 
programs and increasing the protections for those participating 
in research? That's a question we have to ask today. What 
justification is there for continued delays? From the evidence 
supplied to date, the answer is not likely to prove comforting, 
especially as human research projects multiply and new research 
frontiers emerge. Protecting the lives of those involved in 
research should be foremost in HHS thinking, research practices 
and also in its regulatory priorities.
    Last December, this subcommittee asked the question, what 
actions are being taken to reduce unnecessary health and safety 
risks to human subjects? We should receive an answer today 
better than that given to us last year, which was an admission 
that practically nothing had been done. According to the most 
recent OIG report, however, it appears that not much has 
changed from our last hearing. I think there's a bipartisan 
agreement that this inaction is unacceptable.
    The June 1998 recommendations of OIG appear both in my 
opinion reasonable. They're also urgently needed and generally 
propose strengthening the Institutional Review Boards [IRBs], 
that approve and oversee human research projects. The OIG made 
the following recommendations and observations relating to 
IRBs. First, they said they face major changes in the research 
environment. They also said they review too much too quickly. 
Furthermore, they said they conduct minimal continuing review 
of approved research. They face conflicts that threaten their 
independence. They provide little training for investigators 
and board members and neither the IRBs nor HHS devote much 
attention to evaluating IRB effectiveness, and again, these are 
some of the points that were raised about the IRBs.
    The Office of Inspector General recommended reforms in some 
of the following areas: First, Federal requirements such as 
performance evaluations; second, strengthen protections, 
including enhanced IRB monitoring; third, educational 
requirements, including educating IRB members; fourth, 
preventing conflicts of interest and also the question of 
broadening representation on IRBs; fifth, reducing IRB 
workloads, and sixth, improving Federal oversight, including 
IRB registration.
    To date, the responses by HHS have indeed been most 
disappointing. The latest OIG report findings include, and let 
me cite them, first of all, minimal progress has been made in 
recasting Federal IRB requirements so that they grant IRBs 
greater flexibility and hold them more accountable.
    Another of these findings stated, minimal progress has been 
made in strengthening continuing protections for human subjects 
participating in research.
    Another finding, no educational requirements have been 
enacted for investigators or IRB members.
    Another recent finding here is that there has been no 
progress in insulating IRBs from conflicts that can compromise 
their mission in protecting human subjects, and we heard 
testimony about some problems in this area in our last hearing.
    Another more recent finding and update tells us that 
minimal progress has been made in moderating workload pressures 
of the IRBs.
    And finally, minimal progress has been made in 
reengineering the Federal oversight process.
    All of these really are disappointing to the subcommittee 
and me, particularly after our last hearing. We thought we 
would see some additional actions in some of these areas.
    As indicated in our previous hearing, HHS annually invests 
approximately $5 billion of its research dollars in 
approximately 16,000 research projects that involve human 
beings. To provide oversight for these research projects, OPRR 
has agreements with more than 4,000 federally funded 
institutions, each with an IRB. Under OPRR guidelines, research 
subjects must be fully briefed on the purpose, the duration and 
the procedures of the research project before agreeing to 
participate. OPRR has the authority to investigate and require 
corrective action and suspend funding to an institution.
    Last month, it was reported in the Los Angeles Times that 
specialists overseeing a clinical trial of the diabetes drug 
Rezulin did not follow the required procedures for monitoring a 
volunteer who died after taking the medication. Less than 10 
days ago press reports announced the death of a 42-year-old 
Massachusetts woman participating in a drug study sponsored by 
the Nation's top medical research agency. She died after 
receiving the wrong kind of blood.
    As we'll hear today, the OPRR has acted to suspend research 
at a growing number of universities where research requirements 
have been violated. What is required to convince HHS to take 
additional needed actions to prevent more harms and also to 
save more lives? While I'm glad to hear that some improvements 
are underway, I don't think that the agency can truthfully 
testify here today that in fact enough has been done or is 
being done. If it does, we should consider placing this 
responsibility elsewhere.
    I take no joy in holding another hearing on this topic 
within 5 months of the previous hearing, but if inaction 
continues in the face of mounting dangers and death, we may 
need further oversight hearings and further investigation into 
this. We also may have to work with the Appropriations 
Committee and some of the other committees to put some caveats 
on spending this significant number of dollars, some $5 
billion, in research that involves human subjects, and we'll 
look at those options.
    I thank the witnesses who have come before us today to 
testify. We appreciate your willingness to appear before this 
subcommittee and to share your knowledge and experience as we 
strive to address this urgent public health priority. Time is 
of the essence in this matter, and further delay must be 
    I'm pleased again to have the cooperation on this issue and 
active participation and leadership of the gentleman from Ohio. 
Let me recognize Mr. Kucinich at this time for his opening 
    [The prepared statement of Hon. John L. Mica follows:]

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    Mr. Kucinich. Thank you very much, Chairman Mica, and I 
want to especially commend you for calling this hearing and for 
your continuing efforts to demonstrate your dedication to the 
protection, the health and the welfare of the American public 
in clinical research trials. I think this Congress is fortunate 
to have your leadership in this area.
    I'd like to thank the witnesses for testifying regarding 
the Inspector General's report on the protection of human 
research subjects. I'll begin by saying that I am disappointed 
in the lackluster response to the recommendations as the 
Inspector General's report finds, but I am not surprised. The 
state of Federal and local human research subject protections 
has been lacking for quite some time. The subject has only been 
highlighted in the past couple of years due to high profile 
cases with respect to gene therapy that have prompted Federal 
inquiries on the oversight of human research protections. 
However, I believe that human research protections extends far 
beyond the narrow scope of gene therapy. All aspects of human 
biomedical research must be monitored and everyone must be 
protected from risks involved in medical experimentation.
    The Inspector General's report in 1998 I believe outlined 
specific changes that could be made to improve the current 
protections in place. However, the current IG report indicates 
that the Department of Health and Human Services has done 
little to implement these recommendations, enacting only two. 
With respect to recommendations on oversight and protections by 
Institutional Review Boards, the report states that, ``minimal 
progress has been made in strengthening continuing protections 
for human subjects participating in research.'' Regarding 
Federal oversight it states that, ``minimal progress has been 
made in reengineering the Federal oversight process. Federal 
oversight of IRBs is not equipped to respond effectively to the 
changing pressures and needs of the current system of 
protections.'' Well, this is unacceptable.
    The Federal Government provides funds for a vast complex of 
experiments that involve human subjects. More than $16 billion 
per year in Federal funds are used for such research. Some 
20,000 experiments at more than 4,000 universities, hospitals 
and other institutions are involved. Duke University alone has 
$175 million per year in Federal research grants. The lives of 
tens of thousands of people are at stake along with the 
reputation and integrity of very important research 
    The Federal Government's system to monitor these 
institutions and ensuring the safety of human research subjects 
continues to be outdated, ineffective, underfunded and 
understaffed. The only bright spot in this dismal area of 
Federal activity is the positive efforts being made by the 
Office of Protection from Research Risk under the direction of 
Dr. Gary Ellis. In spite of the lack of funds, lack of staff 
and enormous institutional pressures, Dr. Ellis continues to 
make progress in the monitoring and investigating of research 
institutions which conduct human experimentation. His work on 
behalf of the American public should be commended and 
    I know that I as well as the subcommittees will want to be 
apprised of the office's ongoing investigations. I look forward 
to hearing from you in the future. I am glad we have 
representatives here from HHS who will be able to address the 
Inspector General's report. I look forward to hearing your 
    Thank you very much, Mr. Chairman.
    Mr. Mica. I thank the gentleman and there being no further 
opening statements at this time we're going to proceed with our 
first panel as the order of business. The first panel today 
consists of George Grob, and he is the Deputy Inspector General 
for Evaluation and Inspections at the Office of Inspector 
General, Department of Health and Human Services.
    The second witness is Dr. William Raub, and he is the 
Deputy Assistant Secretary for Science Policy of the Office of 
the Secretary of Health and Human Services.
    We have also accompanying these two witnesses Dr. Mark 
Yessian, who's the Regional Inspector General for Evaluation 
and Inspections in the Department of Health and Human Services. 
we have Dr. Gary Ellis, Acting Director of the Office of 
Protection from Research Risks.
    We have Daniel Michels, and he is the Director of 
Enforcement of the Office of Regulatory affairs at the Food and 
Drug Administration.
    This is an investigation and oversight subcommittee of 
Congress. We will swear you in in just a minute. All of our 
witnesses appear under oath. Furthermore, if you have any 
lengthy statements or documentation you'd like to have made 
part of the record, upon request through the Chair and with the 
concurrence of the minority that will be granted. Those are 
basically the rules and the way we'll proceed today.
    At this time let me confer. Without objection Mr. Kucinich 
has moved that the record be left open for additional comments 
or submissions for 2 weeks. So ordered.
    Mr. Kucinich. Thank you, Mr. Chairman.
    Mr. Mica. And we now will proceed and I'll ask our 
witnesses if they'd stand and be sworn.
    [Witnesses sworn.]
    Mr. Mica. The witnesses answered in the affirmative. We'll 
now hear first from the Deputy Inspector General for 
Evaluations and Inspection, George Grob. He has submitted 
rather lengthy findings for the subcommittee and Mr. Kucinich 
moves without objection that they be made part of the record. 
So ordered. So we will have your complete testimony in here. 
We'd like each of our witnesses today to try to limit their 
presentations, oral presentations, to 5 minutes if possible. I 
know we have two that are making presentations I think with 
this panel, and we will submit any additional data or testimony 
upon request.
    With that, let me recognize George Grob, Deputy Inspector 
General for Evaluation and Inspections. You're recognized, sir.


    Mr. Grob. Thank you, Mr. Chairman and Mr. Kucinich.
    The system which was designed to protect the human subjects 
of research has inherent vulnerabilities, most of which remain 
even after the best efforts of our Department to address them. 
To understand why this is the case we must go back to its 
    The protections were gradually developed after the Second 
World War in response to research atrocities that came to light 
during the Second World War and other troublesome research 
experiments that arose shortly thereafter. In 1966 the Surgeon 
General issued a human subject policy for the Department of 
Health, Education and Welfare, and in 1974 the National 
Research Act required reviews by Institutional Review Boards 
for all research sponsored by the Department of Health, 
Education and Welfare. In 1991 those procedures were adopted by 
15 other Federal Departments in what has come to be known as 
the Common Rule.
    These and other developmental events during that period 
were among the prouder days of American science with respect to 
protection of human subjects. However, during this same period 
research exploded in size and complexity and numbers, in 
amounts of money spent. The Institutional Review Boards were 
overwhelmed and left behind. Vulnerabilities subtly emerged, at 
first unnoticed. Lately we've begun to notice them.
    In 1998, at the request of the Food and Drug 
Administration, we conducted a study of the unauthorized 
marketing of investigational medical devices, and during the 
course of this report we stumbled upon some problems with the 
Institutional Review Boards and other systems designed to 
protect the human subjects of this research. For example, in 
one experiment the researcher was authorized to implant 75 
investigational devices for surgery, and reported to the 
Investigational Review Board that 37 had been implanted. We 
found that 264 had in fact been implanted.
    We found other discrepancies in the surgery reports of 
other investigators: 15 devices were implanted during the 6-
week period in which the research had been suspended by the 
Institutional Review Board; we found changes not made to the 
research protocols requested by the board and reported as 
having been made; we found informed consent forms missing, in 
some cases consent forms obtained after the surgery was 
performed and other similar results.
    As a result of stumbling upon these kind of findings, we 
decided that a more systematic look was required at the 
Institutional Review Boards and others systems designed to 
protect human subject research, and based on that work we 
published in June 1998 a more comprehensive review that 
provided an early warning of troubles and vulnerabilities in 
the system. To get a better sense of the problems that the 
institutions were facing at the time let me just rattle off 
some of the circumstances that made it more difficult for them 
to do their jobs.
    When they began this work in the sixties and seventies most 
research consisted of research at a single site. Today it's 
mostly multi-sites across the country, sometimes even the 
world. It used to involve a single investigator. Now it 
involves hundreds of investigators. It used to be a small 
cohort of subjects. Now it's thousands. Most funding came from 
government offices. Now a lot of it comes from commercial 
sponsors. A lot of it used to be done at teaching hospitals. 
Now it's done at clinics, doctors offices and in other 
    There's been a rise of patient consumerism and demands for 
access to investigational procedures, drugs and devices, and 
new types of research have emerged.
    In 1978 there were about 500 institutions with 
Institutional Review Boards. Now there is somewhere between 
3,000 and 5,000 of them. They used to review an average of 43 
proposals a year. Now it's up to about 300. Adverse event 
reports are flooding their offices, in some cases being stored 
in boxes on the floor without being reviewed. In one case we 
found a couple of hundred of these reports coming in per month 
at one of the Institutional Review Boards.
    With such a change in circumstances, the Institutional 
Review Boards were not able to keep up. They had insufficient 
resources. They have been unable to stay on top of the research 
that's being performed so that while they might give a review 
of the proposals before the research starts, they can seldom 
look beyond that. We found insufficient training, little 
evaluation and oversight, and we made corresponding 
recommendations which have already been cited in the opening 
    Recently the Department has attempted to deal with these 
problems and has taken a number of steps which Mr. Raub will 
summarize for you. I particularly want to point out the stepped 
up enforcement that NIH has been doing. Recently 10 onsite 
visits were made and seven institutions had their research 
suspended. I think the sentinel effect of these efforts has 
been very strong and has sent a wave through the research 
community indicating that improper practices will not be 
    But fundamental vulnerabilities remain and we're reminded 
too often of the consequences of this. I know that Departmental 
officials are engaged in attempting to address these 
vulnerabilities and our own work is continuing, but I would 
like to add to my statement here a note that the solutions 
don't depend entirely on the Department. The companies which 
sponsor research, the investigators, the universities and 
medical centers, their Institutional Review Boards--they're all 
involved and they're responsible too. Their talent, energy, 
creativity and dedication is what fueled the boom in research 
that overwhelmed the human subject protection system. These 
same forces now need to be directed to bring it back into 
    [The prepared statement of Mr. Grob follows:]

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    Mr. Mica. Thank you. Does that conclude your opening 
    Mr. Grob. Yes, thank you.
    Mr. Mica. Let me now recognize, if I may, Dr. William Raub, 
who's the Deputy Assistant Secretary for Science Policy, the 
Office of the Secretary of Health and Human Services. You're 
recognized, sir. Welcome.
    Dr. Raub. Good afternoon, Mr. Chairman and members of the 
subcommittee. I am William Raub, Deputy Assistant Secretary for 
Science Policy at the Department of Health and Human Services. 
I am accompanied today by Gary Ellis, Director of the NIH 
Office for the Protection of Research Risks, and Daniel 
Michels, Director of Enforcement at the Food and Drug 
Administration. Thank you for this opportunity to testify 
regarding the protection of human research subjects.
    For more than 50 years HHS and its predecessors have led 
the Nation and the world in protecting human research subjects 
from unnecessary risks. Our approach is rooted in the Nuremberg 
Code, whose principles have been adopted, reinforced and built 
upon in a succession of policies culminating in the current 
Federal regulations governing research with human subjects. HHS 
led the way in developing the core of these regulations, the 
so-called Common Rule, which has been promulgated by 17 
different departments and independent agencies. In addition, 
FDA has carefully tailored its regulations for the product 
oriented clinical research it oversees so that they harmonize 
with the Common Rule.
    The primary foci for implementing these regulations are the 
Institutional Review Boards [IRBs]. They are responsible for 
reviewing proposed research protocols and associated informed 
consent statements before subjects are recruited and clinical 
research begins. No covered project may commence without IRB 
approval. Further, IRBs are responsible for continuing review, 
that is, oversight of approved research projects throughout 
their life cycle. If in the course of continuing review the 
responsible IRB were to find cause for concern regarding the 
safety of research subjects, the IRB could halt the project 
temporarily or permanently or otherwise require the 
investigators to take whatever protective or corrective actions 
it deems appropriate.
    Two types of IRBs exist: IRBs operated by research 
institutions such as academic health centers and IRBs that 
operate as private entities. Two HHS components share 
responsibilities for overseeing IRBs, the OPRR and the FDA. 
OPRR oversees IRBs operated by HHS awardee institutions. FDA 
oversees IRBs that review clinical research related to the 
products it regulates, irrespective of whether that research is 
ongoing at HHS awardee institutions or other sites.
    HHS is very concerned that the effectiveness of IRBs is in 
jeopardy. Although the Inspector General's investigation did 
not reveal either significant instances of actual harm to 
research subjects or evidence of any widespread pattern of 
outright IRB failure, we must not let that be cause for 
complacency. Many IRBs face unacceptably large workloads with 
too little time and too few resources to do their job properly. 
The fact that instances of actual harm to research subjects 
have been few and far between is a credit to the extraordinary 
dedication and prudent decisionmaking of IRB members and the 
commitment of investigators to the integrity of their work.
    In the wake of the June 1998 reports by the Inspector 
General, OPRR and FDA stepped up the pace of their inspections. 
Taken together, their findings reinforce the conclusion that 
the IRB system is under considerable strain. Moreover, for 
several institutions the OPRR and FDA inspections led to 
partial or complete suspension of clinical research at those 
sites until the institution's deficiencies were corrected, 
often only after major revamping of the IRB structure and 
commitment of substantial additional resources by the research 
institutions. These examples make clear that we must intensify 
our work to strengthen human subjects' protection before more--
and more serious--failures ensue.
    An imminent organizational change within HHS will do much 
to facilitate our intensified efforts. Last year acting on the 
results of the study commissioned by the Director of the 
National Institutes of Health, Secretary Shalala determined 
that the human subjects component of the OPRR should be 
elevated to the Office of Public Health and Science within the 
Office of the Secretary. Further, the Secretary directed the 
Assistant Secretary for Health to carry out a national search 
to fill the position and to assess the resource requirements 
for the new office--to be called the Office of Human Research 
Protection. Further, she authorized the creation of a public 
advisory committee to help guide the new office specifically 
and the Department overall.
    We agree with the Inspector General that the creation of 
the Office of Human Research Protection and its associated 
advisory committee presents, ``a new opportunity to exert 
Federal leadership in protecting human research subjects.'' At 
the same time we urge research institutions to strengthen their 
local efforts to protect human research subjects in accord with 
the Inspector General's recommendations.
    In particular, we urge research institutions to give their 
IRBs the standing and resources they need to do their job, 
especially during the continuing review phase. Human subjects 
protection is a shared responsibility among the Federal 
Government, research institutions, IRBs, investigators, and 
sponsors. HHS is committed to doing its part, and we will 
continue to expect others to do theirs.
    My full statement describes a series of actions by HHS 
agencies in recent years to enhance protection of human 
research subjects. We view these steps as a strong beginning 
but concur with the Inspector General that much more remains to 
be done. With your permission, Mr. Chairman, I will submit my 
full statement for the record.
    Mr. Mica. Without objection so ordered.
    Dr. Raub. On behalf of Secretary Shalala and my senior HHS 
colleagues, I assure the subcommittee that HHS is firmly 
committed to protecting human research subjects and to working 
actively with the research community to achieve that end. We 
believe that the Inspector General has provided a timely wake 
up call for everyone involved.
    Thank you, Mr. Chairman.
    [The prepared statement of Mr. Raub follows:]

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    Mr. Mica. Thank you for your testimony. I'm pleased now to 
recognize the gentleman from Maryland, Mr. Cummings, for his 
opening statement.
    Mr. Cummings. Thank you, Mr. Chairman. Conducting safe 
clinical trials of breakthrough medicines and treatments are 
critical if we are to win the war against disease and physical 
ailment. I can think of nothing more noble than putting your 
life on the line for the good of humanity. Our soldiers do it 
on the battlefield, and human research subjects do it in the 
hospitals. While both groups put their lives in danger, we must 
do everything we can to minimize the risks.
    Today, we are here to discuss what can be done to ensure 
the highest level of safety possible for those who consent to 
enroll in clinical trials. The death last September of Jesse 
Gelsinger and subsequent revelations of three other deaths in a 
gene therapy experiment last year sponsored by Harvard Medical 
School has raised serious questions about current oversight 
procedures. Jesse's father Paul told a Senate panel earlier 
this year that researchers did not disclose that laboratory 
monkeys died following a procedure similar to the one done on 
his son or that several earlier human subjects sustained 
serious liver damage.
    After the boy's death, the National Institutes of Health 
sent letters to researchers reminding them that they must 
report serious, adverse events to the NIH and the Food and Drug 
Administration. NIH subsequently received a flood of filings, 
disclosing nearly 700 previously unreported incidents of 
problems arising from gene therapy experiments. I think this is 
simply unacceptable. Seven hundred unreported incidents puts 
too many lives at risk. We must do better and we will. 
Something is failing if 700 incidents were unreported. If a 
real estate company withheld that many problems with their 
properties they would be out of business.
    Today, we will hear from those who carry out the mission of 
oversight at the Department of Health and Human Services and 
the Food and Drug Administration. I'm eager to hear how they 
plan to address these oversight problems, and Mr. Chairman, 
again, I thank you for holding this hearing.
    Mr. Mica. Thank you, Mr. Cummings, and Mr. Cummings also 
moves that the statement by Mr. Waxman, the ranking member of 
the full committee, be submitted for the record. Without 
objection, so ordered.
    [The prepared statement of Hon. Henry A. Waxman follows:]
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    Mr. Mica. And I believe we just had those two witnesses who 
had statements at this time, is that correct, and the others 
are available for answering questions.
    We'll start with some questions that I have and I'm going 
to address these first to Mr. Grob, Deputy Inspector General 
for Evaluation and Inspection. I guess sort of a basic question 
to start out with is, what do you consider to be the reasons 
for HHS' failure to implement that 1998 recommendation?
    Mr. Grob. I think Mr. Raub could probably address it better 
than I can, but I'm willing to speculate.
    Mr. Mica. You did a review here. Maybe you could tell the 
subcommittee what the basic problems are, one, two, three.
    Mr. Grob. I think the basic problems are that the 
Institutional Review Boards are simply overwhelmed, and they're 
not able to carry out their responsibilities, particularly the 
oversight of research that is ongoing. I think once the 
research starts they don't have the ability to stay on top of 
it, and I think that the problems occur at that level.
    Mr. Mica. We heard a description of this human research, 
and some of these activities started off in a fairly isolated 
context and numbers of universities or whoever was doing it. 
It's exploded. It sounds like it's difficult for the Department 
to get its hands around it, and then we have several agencies 
involved here. But we have the element of responsibility to the 
public. It may be jumping the gun a little bit, but maybe we 
should look at restructuring this whole thing or some other 
procedure to again keep up with the sheer volume that you 
described. Do you have an opinion about that?
    Mr. Grob. I think it's time to think in those terms. I 
don't know that marginal changes around the edges will really 
be able to do it. I think the fundamental structure was a good 
idea and it worked when it started and it worked for a while, 
but I just think the research took off. It became far more 
complicated, and in a way it's almost as if the IRBs 
figuratively were still using manual typewriters trying to keep 
up with the power notebooks of the researchers. It's just 
something--it's a different world today, and I don't think that 
system has kept pace with the world. So I think it's a fair 
thing to say that we might need to look at different 
    Mr. Mica. Complete reorganization of the approach. Now what 
about HHS, is this a priority on their scale? The other thing, 
too, is that Congress has also raised questions about what's 
going on in the oversight as we view government agency 
responsibility. It appears that there's been minor action and a 
lot of inaction. I believe, too, we had testimony that many 
things could be done without a lot of cost, some improvements 
without a great deal of costs. Maybe you could tell me first, 
does this appear to be a priority? Has it gotten their 
attention? And then, why haven't they instituted some things 
that were basic that could be done without a great deal of 
    Mr. Grob. It's my feeling right now that certainly there is 
an intense effort being made in the Department to address these 
things, the problems that have been raised. I think the 
publicity of the troubling cases and just the general desire to 
do it right, the congressional hearings, the interest of the 
scientists in the Department are all there. It's coming to a 
head. I think the interest is there now and I do expect to see 
some substantial changes coming down the pike.
    As far as things that could be done fairly quickly, I think 
training and education could be done pretty well and fairly 
quickly. The National Institutes for Health, for example, on 
their own have developed training which they require their 
researchers to follow. They have put it up on the Web. They 
have got some training courses that they have made available. 
What's lacking is a requirement for the training and 
requirement for any particular standards of training, but the 
resources seem to be there. If they require all of their 
researchers, as they do, for example, to take the course that's 
on the Web, it seems to me that all of the grantees could take 
that course on the Web as well and could avail themselves of 
the resources. So I think that education and training of the 
researchers and the board members could be done pretty fast if 
there were a requirement to do it.
    Mr. Mica. Well in 1998 you came out with a list of specific 
recommendations for improvement. Has HHS developed a schedule 
or timeframe or worked to give you any implementation schedule?
    Mr. Grob. I haven't seen a time schedule like that, that 
went recommendation by recommendation with a time schedule.
    Mr. Mica. Let me just ask a quick question now. Of course, 
every agency comes to Members of Congress now and says just 
give us more resources and we can handle the job. But we had 
recommendations that had been made that folks testified to that 
could be implemented with fairly low cost and things that could 
be done to improve oversight, operation and function. I have 
two questions then for Dr. Raub. One, what's the status of 
those low cost things that could be done within budget? And 
then second, I guess you have already submitted your 2001 
budget. What kinds of requests for additional resources or 
personnel were included in the Secretary's request?
    Dr. Raub. Thank you, Mr. Chairman. With respect to the 
overall question, we've taken the recommendations of the 
Inspector General to heart and have in fact undertaken some 
substantial efforts over the last several years and will 
continue to do so. As I indicated in my prepared statement, we 
think they're, while substantial, that nowhere near enough; and 
we will continue to intensify that effort.
    Among the things we have done within the available 
resources are the following. I indicated the stepped up 
investigations and inspections, both by the OPRR and the FDA.
    Mr. Mica. Is that what was referred to from 1 to 10?
    Mr. Grob. It's a lot more than that. My opening statement 
was of course in the 5-minutes, but there have been increases 
in the number of non-onsite reviews that the NIH has made, and 
the FDA has made about a 50 percent increase in the number of 
site visits that it makes.
    Mr. Mica. Is that adequate?
    Mr. Grob. No. We need more.
    Mr. Mica. So those are some things you started. I'm sorry, 
Dr. Raub, continue.
    Dr. Raub. And along that line, just continuing Mr. Grob's 
thought there, while the returns on those investigations have 
been disappointing in the sense of identifying some widespread 
pattern of problems and have led to enforcement actions, those 
enforcement actions have a secondary effect in the sense of 
promoting compliance elsewhere--indicated by the Inspector 
General as a sentinel effect. So we believe that the 
expenditure of those funds dealing with individual problems has 
in fact had a positive effect in terms of making the larger 
community sensitive to the need for more attention and more 
investment of resources in these activities.
    Mr. Mica. Now, enforcement. When we had the hearing last 
time, there was one instance of a suspension reported, one or 
two. Since that time, what's the status? Usually enforcement 
would indicate that there's some penalty or there's some 
suspension of funds taking place. What's taken place in that 
    Dr. Raub. I'll comment generally, and, if I might, ask Dr. 
Ellis and Mr. Michels if they want to add some details to it; 
but in essence the thrust of the suspensions is not only to 
stop the activity and put an immediate protection in place but, 
more important, to require certain remedial actions on the part 
of the institutions to ensure that the problems are solved and 
the protections are in place. And that's been a pattern on 
these various ones.
    Mr. Mica. My question dealt with has there been any 
suspension of funds since the last hearing or penalty actions? 
Remedial actions are fine, but I want to know, if somebody gets 
some penalty, then does it have an effect down the line on 
others to sort of straighten up their act?
    Dr. Raub. Let me ask my colleagues to address that.
    Mr. Mica. Identify yourself for the record, please.
    Mr. Ellis. My name is Gary Ellis, Director of the Office of 
Protection from Research Risks, and chairman of the Interagency 
Human Subjects Committee. For research that is funded by the 
Department of Health and Human Services the ultimate penalty is 
a cessation of funding.
    Mr. Mica. Has there been any since the last time? Now what 
we've discovered there are more problems than we anticipate and 
the Inspector General talked about finding a pattern of 
problems far in excess of what I think we even expected. Then 
we heard that we were taking some enforcement actions that were 
part of the corrective pattern. My question is, what type of 
enforcement actions?
    Mr. Ellis. Well, since the June 1998 hearing and the 
Inspector General's report, OPRR has evaluated the protection 
of human subjects at a couple dozen institutions. There have 
probably been about 10 site visits during that period, and in 
virtually every case we've made findings of shortcomings with 
regard to human subject regulations and required remedial 
action. In a few noteworthy cases at the Duke University 
Medical Center in May 1999 and just a small number of other 
institutions, we have actually ordered an interruption in 
research. Virginia Commonwealth University in January 2000 as 
with Duke, we ordered an interruption in research. These are 
extreme cases and an extreme action was taken, the interruption 
of research.
    Mr. Mica. In two cases?
    Mr. Ellis. There were other cases where we imposed 
restrictions but we didn't have the suspension that you note. 
The Food and Drug Administration took an action----
    Mr. Mica. Was it the suspension of the program or 
suspension of funding or both?
    Mr. Ellis. Suspension of the program. The Food and Drug 
Administration took action at the University of Colorado Health 
Sciences Center, and Dan might want to talk about that.
    Mr. Mica. Identify yourself for the record.
    Mr. Michels. Yes, sir. I am Daniel Michels, Director of the 
Office of Enforcement at FDA.
    I think you've put your finger on an important issue from 
the standpoint that the action available to both our 
organizations is an extreme one; that is, the authority to shut 
down an operation in its entirety. The threat of that most 
frequently causes either a voluntary shutdown before we need to 
deal with that or else a great deal of willingness to do the 
right thing and get back on the right track. One of the things 
that we are exploring is the possibility of asking the Congress 
for intermediate remedies that might be less than throwing the 
atom bomb, if you will, to deal with these situations.
    Mr. Mica. You don't feel that you have the authority to do 
    Mr. Michels. That is correct in this particular instance, 
and I want to reinforce and I think Representative Kucinich 
made the point very eloquently, is too often the IRBs are 
underfunded. The willingness to do the right thing is there, 
but they do not have the resources and support to do it, and 
our taking enforcement action will result hopefully in that 
kind of funding somewhere downstream, but we would much rather 
see education happen first, do the right job the first time in 
a well-funded situation.
    Mr. Mica. Mr. Cummings, I have additional questions. Did 
you want me to yield to you at this time and come back, do a 
second round? Is that OK? Or do you want me to proceed?
    Mr. Cummings. No. I just have a few.
    Mr. Mica. All right. I'll recognize Mr. Cummings, and I do 
have an additional round of questions.
    Mr. Cummings. I was just wondering, what kind of--following 
up on what the chairman asked about--what kind of sanctions 
would you like to see, I mean, would you like to have the 
authority to use?
    Mr. Michels. Unfortunately, the thinking is a little bit 
early on this. One of the things that we've thought about is 
civil money penalties, but again, fining an organization which 
is poor already doesn't seem to be a very good option. If we 
could find something more prescriptive, that is more targeted 
to the particular problems that an institution has rather than 
simply shutting down the whole engine, we would be possibly 
better off than we are now, but that's the best I can do for 
you at the moment, Congressman.
    Mr. Cummings. Why would an organization when threatened 
with a shutdown voluntarily shut down as oppose to say 
straightening up the matter? I mean I know you said sometimes 
they do, but sometimes they just go on and shut down. I mean 
what kind of situations would cause that?
    Mr. Michels. Well, the recognition that something major 
needs to happen and rather than having the terms dictated, if 
you will, by the regulatory agency, they see the light and say 
OK, before that letter of shutdown is received, here's our 
plan, this is what we're going to do. In the meantime we are 
going to suspend some or all of our operation as a signal of 
good faith. As a regulator, I wouldn't be necessarily too 
thrilled to see somebody make some offers without doing 
something immediate and protecting those folks that are at 
    Mr. Cummings. Mr. Ellis, in 1998 I think you told the 
subcommittee that your office was pursuing about 70 open 
    Mr. Ellis. That's correct, sir.
    Mr. Cummings. How many of those cases have been closed?
    Mr. Ellis. That's something I'll have to get back to you 
on. A large number remain open. Today we actually have 163 open 
    Mr. Cummings. So in 2 years the number of open 
investigations have more than doubled.
    Mr. Ellis. That's correct. Some of the 70 to which you 
refer have closed, but many more have opened since that date.
    Mr. Cummings. Why do you think that is? I mean, that's a 
lot of cases. I mean, when you look at 70, some have been 
closed and now you're up to 163. Why is that?
    Mr. Ellis. We are receiving more complaints. The issue of 
protecting human subjects in research has been featured in the 
press. Our complaints come from citizens, they come from 
research institutions themselves, from employees at research 
institutions that see things they don't like. In some cases 
from human subjects who feel they have been harmed or wronged 
in some way. Our office was not all that prominent, perhaps 
hard to find, and now it's easier to find for complainants. 
That's my best explanation.
    Mr. Cummings. How many employees do you have doing the 
investigations on human and animal subject research?
    Mr. Ellis. Our office was originally split so the animal 
welfare staff are now in a different office, but with regard to 
human subject investigations we have two full time equivalent 
investigators. Actually a full time physician, a half time 
physician and a half time attorney handle 163 cases.
    Mr. Cummings. And how many do you think you need to do an 
adequate job?
    Mr. Ellis. One could work through the arithmetic of what a 
serious caseload would be for a high level professional. The 
Public Health Service Act requires a prompt, that's a quote, a 
prompt resolution of the cases. We could work out the 
arithmetic if we took prompt to mean 6 months, let's say, how 
many cases an individual can move and get 6-month closure. It's 
something I could calculate for you.
    Mr. Cummings. That's OK. Is there a statutory requirement 
to report adverse events to your office?
    Mr. Ellis. There's a regulatory requirement that pertains 
to research funded or conducted by any of the 17 departments 
and agencies that have been in place for years, the 
institutions must report unanticipated problems involving risks 
to subjects or others. That is one kind of report. The second 
kind of report is any suspension or termination of 
Institutional Review Board approval. And the third kind of 
report is any serious deviation or noncompliance with the 
regulation. The answer is yes.
    Mr. Cummings. Those reports that you just talked about, how 
many have you received over the last year?
    Mr. Ellis. In 1999 we received 187 reports of that type 
from I think about 87 institutions.
    Mr. Cummings. Mr. Raub, back in December Dr. Art Lawrence 
testified before us in a hearing we held in New York, and at 
that time Dr. Lawrence assured us that the Office of Protection 
from Research Risks would be moved to the Office of the 
Secretary and a new director would be selected by March 2000. 
It's now May and can you tell us where we are on that?
    Dr. Raub. Yes, sir. The Department is close to completing 
those actions, but it has taken somewhat longer than the 
original estimates. I'm hopeful, as is Assistant Secretary 
Satcher, that the appointment of a director for the new Office 
of Human Research Protections is imminent. We hope in the next 
few weeks at the least for the announcement of that 
appointment, and with that then the formalization of the move 
of the office from NIH to the Office of the Secretary and the 
establishment of the new advisory committee.
    Mr. Cummings. Well, while in New York Dr. Lawrence also 
testified, and he even introduced a letter from Dr. Satcher 
which said that the advisory panel would be created which would 
be responsible for human subject research protection. Is that 
the advisory panel you were just talking about?
    Dr. Raub. Yes, it is.
    Mr. Cummings. And how do you see that as helping this 
problem, I mean the appointment of that panel?
    Dr. Raub. Well, first of all, we see the relocation of the 
office as giving it the higher visibility in terms of the 
Office of the Secretary and an underscoring of the Secretary's 
commitment to this. Second, as part of the move, the Secretary 
directed Assistant Secretary Satcher to commission a study of 
resources along the lines of the question that you were just 
addressing to Mr. Ellis; and that study, as I understand it, is 
either complete or near so. It will be an important factor in 
the future budgeting decisions for this office.
    The advisory committee is intended to ensure that we have a 
public, high level and highly qualified group of individuals 
drawn broadly from the research community and the interested 
general public who can provide a continuing forum of advice and 
criticism for the Department as we move to set priorities and 
do what we can to ensure that these human subjects protections 
are in place. We have not had that kind of forum before in the 
Department, and we think it's much needed, and I'm optimistic 
as to what it will be able to provide for us.
    Mr. Cummings. Right now, do you have to go--is part of the 
processes that you use the Federal Register?
    Dr. Raub. For what, sir?
    Mr. Cummings. For the advisory panel.
    Dr. Raub. The advisory panel will be created under the 
terms of the Federal Advisory Committee Act, and those actions 
have been taken in terms of securing the necessary slot and 
authorization to do it. Most likely what we will do is announce 
in the Federal Register the functions and other expectations 
for the committee, and as we do with many other advisory 
groups, invite nominations of members from interested members 
of the public, and then put together a recommended slate or 
alternative slates for consideration by Dr. Satcher and the 
    Mr. Cummings. Thank you.
    Mr. Mica. Thank you, Mr. Cummings. I didn't get the answer 
when I yielded to Mr. Cummings about the second part of my 
question. What was the number of personnel requested in 2000 to 
2001. Again, we've identified that there's a problem. Some of 
the answer is more personnel, more resources. Can you tell me 
requests for additional slots?
    Dr. Raub. Sir, I don't have those figures with me.
    Mr. Mica. Does anybody have them?
    Dr. Raub. I'll be pleased to provide them for the record.
    Mr. Mica. Mr. Ellis, do you? You said you could calculate, 
but this isn't something that just snuck up on us today. It's a 
problem we've known about, and one of the ways that we resolve 
it is by applying the necessary resources, putting the requests 
through the process, and nobody knows what we have requested? 
Maybe somebody could slip somebody a paper with a magic number 
on it. No? And you don't have a recommendation to the 
subcommittee about what kind of resources it would take?
    Dr. Raub. Again, I don't have the budget figures with me. 
I'd be glad to provide them for the record, sir.
    Mr. Mica. Mr. Grob, the situation seems to be mushrooming 
out of control, both the sheer number of Federal dollars 
involved in this human experimentation and then this large 
universe outside of commercial activity. I think you spoke to 
some of that. What are we looking at as far as percentages in 
each of these areas of experimentation, federally funded and 
nonfederally funded? Would you care to venture a guess, Mr. 
    Mr. Grob. I don't know about the exact number. Certainly 
we're talking about billions of dollars in both cases. An easy 
way to think of it is most of the commercially funded research 
that we're talking about here would be research that's 
connected with the proposed drugs and medical devices that are 
overseen by the Food and Drug Administration. So their entire 
workload of oversight would be commercially funded, whereas the 
National Institutes of Health would be those that are funded by 
our Department. Now of course there's these other Federal 
departments that also fund on the Federal level their research. 
So I'd say it's billions and billions, but which--you know, 
what the exact amounts are I can't tell you.
    Mr. Yessian. My name is Mark Yessian. I am the regional 
Inspector General. At some of the major medical centers that we 
visited and talked to, about half the applications that the 
IRBs are getting are coming from commercial sponsors these days 
so that helps put it in a little perspective.
    Mr. Mica. Another question that was raised at the last 
hearing, which continues to be a concern, is the problem with 
commercial activities and other interests in this whole 
operation, the conflict of interest. I think there was a recent 
Los Angeles Times article that alleged the U.S. Government's 
top diabetes researcher helped guide a $150 million Federal 
study involving Rezulin while serving as a paid consultant for 
the drug manufacturer, which was Warner Lambert Co. What's the 
Federal Government's policy regarding outside employment and 
conflicts of interest, Mr. Raub?
    Dr. Raub. Sir, there are several elements to that. First 
off, the changes in the nature and the patterns of financial 
relationships are one of those changing elements that Mr. Grob 
and his colleagues had mentioned. It's quite a different 
situation than, say, 20 years ago. A major impetus for that has 
been some statutory changes designed to promote the 
commercialization of publicly funded research. And, for the 
many highly desirable results of that, it has created a pattern 
of relationships where not only do some of the universities' 
and academic health centers, for example, receive a substantial 
amount of funding from the private sector--some on the order of 
half, as Mr. Yessian indicates--we also have instances where 
some of the university professors also have either stock 
holdings or even serve as corporate officials for some of the 
private organizations, some of which may be sponsoring the 
    A major element already in place related to that is a 
public health service regulation that requires all of the 
entities funded by the agencies of the Public Health Service, 
that is the universities and other recipients of awards, to 
have in place a policy and a system to identify actual or 
apparent conflicts of interests that might affect the 
scientists' participation and to take such steps as are 
necessary to manage those conflicts--in some instances removing 
the conflict, in others putting certain safeguards in place.
    One of the areas where we will be intensifying our effort 
is trying to find ways to ensure that, as those procedures 
relate to human subject protections, some of the kinds of 
safeguards we have in place will be those against the potential 
coercion of subjects in research as well as guarding against 
things that would create less than full objectivity in the way 
experiments are designed, patients are recruited, or results 
are presented. This will be a continuing challenge for the 
entire research community.
    Mr. Mica. Is it necessary for additional legislation, 
corrective legislation to deal with the new set of emerging 
conflicts and circumstances?
    Dr. Raub. In my judgment, sir, no. The Public Health 
Service regulation to which I referred and, a companion 
regulation that the Food and Drug Administration has dealing 
with reporting of financial conflicts of interests, gives a 
considerable set of tools to use here. I believe the task will 
be building on those tools and using them most effectively. I 
am sure the Department won't hesitate to propose legislation if 
it concludes that's necessary, but we don't think so now.
    Mr. Mica. I don't want to pick anybody out, but in this 
case I just cited, this individual who served as a paid 
consultant to the drug manufacturer was I believe a Dr. 
Eastman, who had this employment as a consultant, and it 
appears to be a conflict of interest. Do you know if you all 
investigated this particular arrangement to see if there was a 
conflict of interest?
    Dr. Raub. I don't know the full details, sir. I know that 
an investigation was carried out at the NIH. I don't know that 
it's completed. We can provide a report for that to the 
    Mr. Mica. Well, I'd like to know because if you feel that 
we don't need additional laws then you have at least the 
authority to proceed, and we want to make certain that there is 
some attention to the problem of conflict of interest that has 
been raised to us. I have other cases here and I won't be able 
to get into all of them. We could submit some of them for 
questions to you, but it appears that some of the problems 
we've had--now conflict of interest is one thing. Maybe we 
picked that up through the media. I think you all have 
testified that you're picking up problems that have resulted 
sometimes in death in these experimentation cases where there 
hasn't been, I think we're going to have witnesses about the 
full disclosure, prior disclosure about oversight, about the 
proper functioning of the review process, which is a big 
concern to us. We have an agency, and maybe it is short on some 
resources, but in fact we are told that it's somewhat 
dysfunctional and even no cost or low cost recommendations have 
not been instituted. So I have to cite these as major concerns 
of the committee.
    And then we have another area now, this growing area of a 
commercial activity that doesn't fit. We don't have the handle 
because we don't have the Federal funds into the activity, and 
FDA has some responsibility, but there are some instances here 
in which there appear to be a gap, which is another problem. 
Did you want to comment on that briefly, Mr. Grob?
    Mr. Grob. We don't know the extent of that, but that's 
probably small but growing, where there is research that's 
going on that's not connected with any proposal for a Federal 
approval of a drug or device and they're not the result of a 
Federal grant. In those cases there are no requirements for 
Institutional Review Boards or for some of these other 
protections. Just simply good practice would call for it, but 
the extent to which it's happening and the type of controls 
over that is just sort of an area that's not well-known or 
understood at this time.
    Mr. Mica. And what's interesting, too, is there are so many 
new research techniques in biogenetics, I mean, I just can go 
on and on about things that are happening almost on a daily 
basis that the law is not keeping up with. I am wondering if we 
really need to take a closer look at this, some of these gaps 
and again have in place some mechanism to deal with this in the 
future. Mr. Michels.
    Mr. Michels. Yes, sir. Thank you, Mr. Chairman. I just 
wanted to clarify that the Food and Drug Administration is 
working in the area of, if you will, noncommercial research 
from the standpoint that there are requirements from time to 
time that, notwithstanding the intent to market the product, if 
it is being used as an experimental agent on people it should 
be covered by an investigational application.
    I think what is maybe troublesome to some folks is the zone 
in between where an investigator, a clinical investigator may 
also be the entrepreneur who is intending to ultimately develop 
the product him or herself rather than working as an employee 
or agent for a major pharmaceutical house, for example. The 
roles have become very blurred here, and we also are puzzling 
over where we need to be drawing the lines. I would suggest 
again we go back to the principle that was laid out very early 
in your hearing today, and that is we need to be educating all 
of the scientists, be they clinical investigators, the 
researchers, the IRBs, as to what the requirements are, 
minimize their impact so that the right decisions are made on 
behalf of the subjects being exposed.
    Mr. Mica. Thank you. I'm not going to give you an 
opportunity to respond because we have a vote. I have less than 
4 minutes to get to the floor. I am going to excuse the panel. 
We're going to submit some questions. I have some specific 
questions on cases, Mr. Ellis, but I'll tell you, Mr. Raub, 
that we've got to do something to get into place some of these 
    Mr. Cummings described some of the foot dragging and some 
of the things in simple appointments, getting people in place, 
making low cost or no cost recommendations, getting us to 
recommendations. We have got to do something. If necessary I'll 
hold another hearing and call everybody back, and we'll 
subpoena the Secretary if we have to to get something moving in 
this area. But I just give you that.
    Without objection, we will submit to you further questions 
and ask for your written response. We'll stand in recess for 
approximately 15 minutes, until the conclusion of the next 
    Mr. Mica. I'd like to call the subcommittee back to order. 
I want to go ahead and proceed. We have our second panel before 
us at this point. Unfortunately, there may be a vote in the 
full committee. There's been a full committee hearing going on 
while we're conducting this subcommittee hearing. We may need 
to recess at some point if a vote is called in that body.
    Our second panel consists of Mr. Richard Curtin, and he I 
believe was a human subject in one of these research 
experiments. We also have Charles R. McCarthy, and he is a 
senior research fellow at the Kennedy Institute of Ethics at 
Georgetown University, and then we also have Dr. Robert Amdur, 
and Dr. Amdur is the associate professor and associate chair of 
clinical affairs at the Department of Radiology and Oncology at 
the University of Florida. Good to see someone from my alma 
mater here. If we could just get a President now we'd be in 
good shape. That's an inside matter.
    I'd like to welcome all three of our panelists this 
afternoon. Let me go ahead and explain the ground rules. I 
think you're all new witnesses. We do swear in our witnesses. 
This is an investigations and oversight subcommittee of 
Congress. I'll swear you in in just a minute. I'm going to ask 
you to limit your oral testimony to 5 minutes. Upon request, 
we'll put in any full statements or additional information in 
the record deemed appropriate, upon request through the Chair. 
With that, I will swear you in, if you'd stand, please.
    [Witnesses sworn.]
    Mr. Mica. Witnesses answered in the affirmative. I welcome 
the witnesses. I think we'll call on Richard Curtin, who was 
involved in one of these research projects. He's from Falls 
Church, VA. Welcome, sir, and you're recognized.


    Mr. Curtin. I'd like to thank the subcommittee for inviting 
me to appear today, but I have to admit I'm surprised to find 
myself in the position of being so critical----
    Mr. Mica. You might pull that mic a little bit closer if 
you could. Maybe you can do that with your book there.
    Mr. Curtin. I'm surprised to find myself being in a 
position where I'm being so critical of genetic research. I 
have a Master's Degree in human genetics, and 25 years ago I 
was working with the Director of NIH in an effort to convince 
the Congress to go ahead with funding for cutting edge 
recombinant DNA research. But in September 1998 I was 
introduced to a different aspect of genetics research when my 
daughter Allison received the Virginia Twin Study sponsored by 
Virginia Commonwealth University.
    The study consisted of a 25-page questionnaire asking 
hundreds of questions about a person's medical history. When I 
looked through the questionnaire I was surprised to find that 
176 of these questions involved not only my daughter's medical 
history but also the medical histories of her mother, her 
brother and me. In other words, she was being asked to comment 
upon the medical history for the entire family.
    I was further shocked by the bizarre nature of some of 
these questions. For example, the study asked if any of us had 
suffered from depression, infertility, alcoholism, or 
schizophrenia. It asked if Allison's brother or I had abnormal 
genitalia, sperm abnormalities or low sperm count, and it asked 
if Allison's mother had any diseases of the genital tract or if 
her menstrual periods were unusually long or strong. Nowhere in 
the study packet were the words ``informed consent'' ever 
mentioned, and this package was addressed strictly to my 
    I was outraged that a federally funded project would 
attempt to violate my family's privacy in this manner. I 
immediately wrote to the principal investigator of the study 
and also to the chairman of the Institutional Review Board. All 
I asked them to do was to remove the columns for the other 
family members and to send separate questionnaires to each of 
us. I realized that this would have cost them more and it might 
have cut down on the response rate, but the data base would 
have been more accurate, and it also would have avoided the 
problem with informed consent.
    The chairman of the Institutional Review Board just didn't 
bother to respond at all. The principal investigator, responded 
but her response was so demeaning and so arrogant that it 
probably would have been better if she hadn't responded either. 
It became very clear to me that the concerns I raised were not 
going to be addressed to my satisfaction by the people at 
Virginia Commonwealth University.
    So I filed a complain with OPRR. OPRR concluded that the 
internal controls for the protection of research subjects at 
the university were so inadequate that all federally funded 
research had to be shut down until proper controls could be put 
into place. The sum total of this action was 1,100 research 
projects suspended.
    With the chairman's permission, I'd like to enter into the 
record a summary list that I've prepared listing 19 
deficiencies that OPRR listed from its investigation at 
Virginia Commonwealth University.
    Mr. Mica. Without objection, that will be made part of the 
record. Proceed.
    Mr. Curtin. Thank you. Rather than addressing the 
legitimacy of the deficiencies found at Virginia Commonwealth, 
the leadership of the genetics research community decided to 
take a different approach. They went on the attack. They went 
after OPRR. I'm especially offended by the positions taken by 
two of their main leaders, Dr. Edward McCabe, chairman of the 
Secretary's Advisory Committee on Genetic Testing, and Dr. 
Francis Collins, Director of the National Human Genome Research 
Institute at NIH. These gentlemen have argued in writing that, 
even within a family, once a piece of medical information 
becomes known to one other person within that family there is 
no longer any expectation of privacy and there is no need for 
any researcher to bother getting the informed consent of the 
family members.
    A little anecdote, also about this time, my daughter was 
home for Christmas vacation and asked if I would call the 
University of Virginia registrar to find out one of her grades. 
So I made the phone call and explained to the registrar's 
office that I was her father, but they would not release her 
grade to me because it was a violation of her privacy. Despite 
the fact that she was my dependent and I was paying the 
tuition, they wouldn't tell me her grade. But the people at the 
Virginia Twin Study fully expected her to go around and tell 
the most intimate nature of the medical histories of not only 
herself, which I wouldn't mind her doing, but also of every 
other member of her family.
    I've been involved with this issue now for 20 months and 
I've reached five basic conclusions. One, the public cannot 
rely upon individual researchers to adhere to the rules and 
regulations that go along with the acceptance of Federal 
funding. When a research protocol does not go as planned, the 
initial reaction of the researcher seems to be to cover it up.
    No. 2, the public cannot rely upon Institutional Review 
Boards to ensure that guidelines are followed and that 
experiments are scientifically and ethically sound. Basically, 
I don't believe that colleagues at the same institution can be 
trusted to critically review and police each other's work. If I 
criticize your work today, what's going to happen when I come 
in front of the IRB tomorrow?
    Three, the staffing and funding levels at the Office of 
Protection from Research Risks have been designed to ensure 
that OPRR will not be too effective. Other speakers have 
mentioned this, and it's very, very clear to me that OPRR has 
been treated as a proverbial stepchild within the NIH family.
    Four, the research community, in my opinion, is in a state 
of denial regarding the trouble that it's in. They have allowed 
a regulatory vacuum to exist and a trust gap to develop, and 
now others are rushing in to fill this vacuum and to close this 
gap. The community strategy of stonewalling, covering up and 
attacking will not, I don't believe, be successful in the long 
    Five, potential solutions. It's obvious that OPRR needs to 
be upgraded, but you also have to be realistic about how much a 
centralized office here in Washington can do when the research 
is so decentralized. In my opinion, therefore, the quickest, 
least expensive and possibly most effective course of action is 
for each researcher to realize that violations of guidelines 
and regulations will have very serious consequences. If the 
probability of getting caught is going to be low, then the 
consequence of getting caught should be very severe.
    One of the members asked earlier what other penalties could 
we possibly have. I have a suggestion. I suggest that a 
principal investigator who fails to file a timely and accurate 
adverse event report might be suspended from the project for 1 
year. Allow the project to continue so that the benefits of the 
research aren't lost, but let it continue under someone else's 
    Mr. Mica. Excuse me, but I'm going to have to recess the 
hearing for just approximately 10 minutes. We do have a vote in 
the other committee. We'll continue when I return.
    Mr. Mica. I will call the subcommittee back to order. I 
apologize for the delay, but all members of the full committee 
were summoned. To get back here, let's see, we had Mr. Curtin 
who was interrupted as he had some closing remarks I believe. 
So if you would sum up your testimony, Mr. Curtin, you're 
    Mr. Curtin. Yes, sir. Just finishing up, two possible 
penalties to suggest. One is, as I was mentioning before, 
suspension of the principal investigator while his project 
still goes on. A second possible penalty would be making that 
investigator unable to compete for future grants or contracts 
for a certain period of time. Those are two suggestions. I 
don't think it's that hard to find penalties that fit the 
    I want to thank you for the opportunity to express my 
concerns and my opinions, and I would like to submit a more 
lengthy statement for the record with the chairman's 
    [The prepared statement of Mr. Curtin follows:]

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    Mr. Mica. Without objection your entire statement will be 
welcome and included as part of the record, and we did leave 
the record open for a period of 2 weeks. I'll now recognize, 
and we'll come back for questions a little bit later, Mr. 
Charles R. McCarthy, and he's a senior research fellow, most 
patient one, at the Kennedy Institute of Ethics at Georgetown 
University. Thank you and you're recognized, sir.
    Mr. McCarthy. Mr. Chairman, thank you. I'm honored to be 
able to testify before you today. I think the matters on which 
you're deliberating are of extraordinary importance, and I hope 
we can make some contribution to protecting human subjects. 
Your staff asked me to comment on just one aspect of the 
Inspector General's report; namely, recommendations concerning 
utilization of Data and Safety Monitoring Boards to supplement 
the work of IRBs. I have focused my attention almost 
exclusively on that issue. I will summarize here very quickly. 
I have submitted a longer statement for the record.
    Mr. Mica. Without objection, that entire statement will be 
included in the record.
    [The prepared statement of Mr. McCarthy follows:]

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    Mr. McCarthy. And I would like to modify even that a 
little. Since I submitted my testimony I have spent some time 
in the library and found references to a number of other 
sources that make recommendations identical to, or similar to 
the ones that I'm making today. So I will add those, if I may 
submit those as well.
    Mr. Mica. Without objection, and within in the time limits 
that have been announced. Go ahead.
    Mr. McCarthy. As has been noted earlier in the hearing, 
Institutional Review Boards were initiated by the Public Health 
Service in 1966. It's not so well-known that in the late 
1960's, and I can't give you a specific year, the National 
Heart Institute, now National Heart, Lung and Blood Institute, 
at NIH created an additional kind of oversight body to look at 
large multi-centered trials, and to collect and analyze data, 
particularly adverse event data, in those trials. Data and 
Safety Monitoring Boards, while nowhere near as well-known as 
IRBs, are indeed almost as old and as honorable as the IRBs.
    During the seventies Dr. Robert Gordon, who was for a time 
the Director of the Clinical Center at NIH, and Dr. Curtis 
Meinert, from Johns Hopkins University, spent a great deal of 
time refining and defining the work of Data and Safety 
Monitoring Boards. As the funding patterns for NIH grants 
changed from grants that were made to a single investigator at 
a single institution to multi-centered trials where there might 
be anywhere from 5 to 50 or even 100 different centers, each 
with itw own investigation carrying out the same protocol. The 
Data and Safety Monitoring Board has become the instrument most 
sensitive to being able to receive and process adverse event 
data and other information about multi-centered trials from 
many sources; evaluate those data and other information with 
the help of professional statisticians and thus to get an 
overview of the trial that is literally impossible to get at 
any single center or any single institution. We are faced with 
something of an anomaly. The Data and Safety Monitoring Boards 
are not established by regulation and exist in less than half 
of the multi-centered trials that are conducted in this 
country. They are the bodies that have the best information and 
carry out the most careful analysis of the data. On the other 
hand, IRBs are the committees who, according to regulation, 
have the responsibility of determining whether trials should be 
stopped, modified or continued. Consequently the most complete 
knowledge is in one committee, and decisionmaking 
responsibility is in another committee. It seems to me that we 
can make a very constructive kind of change in the regulations 
so that the Data and Safety Monitoring Boards communicate their 
findings back to the IRBs. If that step is taken, it will, 
first take some work off the IRBs and begin to address the 
workload problem identified in the Inspector General's report, 
and second, it will improve the quality of the information on 
which the IRB makes its decision to continue, modify or 
discontinue research projects.
    All of the kinds of incidents you've addressed today in 
your hearing seem to me to indicate that now is the time to 
start afresh. Modify the regulations so that the data held by 
Data and Safety Monitoring Boards is made available to the 
IRBs, so that the best possible decisions concerning the 
continuation and oversight of trials can be made.
    Typically, as we heard testified earlier from the Inspector 
General, the IRBs receive adverse event data, but it is raw 
data. IRBs don't know which arm of the study the adverse event 
occurred on. They don't know whether it was in an elderly 
subject or a young subject. They don't know which adverse 
events result from complications of disease of the subject. 
They cannot tell whether the adverse event was caused by the 
research, by the underlying disease condition, or by some 
inherent condition that pertains to the subject himself or 
    Data and Safety Monitoring Boards display the data in a 
number of different ways: according to age; gender; race; 
ethnicity and a whole variety of other categories so that they 
can evaluate adverse events; tell which ones are very serious; 
which ones are likely to be associated with the research 
intervention; and which ones might have occurred anyway because 
of underlying disease conditions. DSMBs are able to give the 
kind of analysis that will refine the judgments about the 
safety of the research, and whether it should continue.
    So my recommendation to you and to the rest of the 
committee today is simply that one of the ways the Inspector 
General's report could be used or could be capitalized upon 
would be simply to adjust the regulations and by putting some 
kind of a regulatory link requiring Data and Safety Monitoring 
Boards under certain conditions and, second, making sure that 
the data that they gather and analyze is carefully and 
thoroughly shared with the IRBs so the IRBs then can--with less 
work and with greater accuracy--meet the responsibilities that 
are assigned to them. This will not, in my judgment, decrease 
costs because the Data and Safety Monitoring Boards have full-
time statisticians working for them. They have costly experts.
    I participated in a Data and Safety Monitoring Board 
meeting yesterday. There was an expert from Germany, one from 
England, three from the United States and myself. Obviously to 
have a meeting of that kind is very costly. Statisticians 
generated--relative to on one study--about 300 pages of data. 
The DSMB spent the best part of the day evaluating that data to 
determine whether the study should go on. That's a very costly 
process, but I can assure you that the subjects in that study 
received the very best safety efforts that are humanly 
    No one can guarantee that mistakes will not be made, but I 
think when the data is processed in such a thorough way, the 
chances of a mistake become exceedingly small. That's what we 
owe to our research subjects. Even though oversight costs may 
be raised. On the other hand, the cost to the local IRBs will 
be reduced because their workload of analyzing large quantities 
of adverse data will already be done for them by statistical 
experts. They will be able to make much more enlightened 
decisions as to the research in their institution.
    I will be glad, Mr. Chairman, to answer any questions that 
you may have concerning this issue or any others.
    Mr. Mica. Thank you, and what we'll do is suspend 
questioning until we've heard from our final witness. He's also 
very patient. Dr. Robert Amdur, and he is the associate 
professor, associate chair of clinical affairs, Department of 
Radiology and Oncology at the University of Florida. Welcome, 
and you're recognized, sir.
    Dr. Amdur. Thank you. Good afternoon, Mr. Chairman, and 
other committee members.
    As you mentioned, my name is Robert Amdur. I am a physician 
at the University of Florida. My qualifications to speak to you 
today about the protection of human research subjects are that 
I am a medical researcher who frequently enrolls patients in 
research studies. For the past 10 years I have played a 
leadership role in defining and implementing ethical standards 
for research through my participation in the Institutional 
Review Board and related national organizations.
    I am here today representing a national nonprofit 
organization called PRIM&R, which stands for Public 
Responsibility in Medicine and Research. For over 25 years, the 
primary mission of PRIM&R has been to bring researchers, 
ethicists, and research regulators together to improve our 
system for protecting the rights and welfare of human research 
    Since 1974, PRIM&R has sponsored over 100 educational 
conferences, published hundreds of documents, set up onsite 
workshops for institutions with special needs, and many other 
important activities that meaningfully improve the way research 
is done in this country.
    I have submitted a written statement which goes into detail 
about the challenges that currently stress our system of 
protecting human research subjects, and PRIM&R's plans for 
helping the research community respond to these challenges.
    At this time I would like to formally request that a 
written copy of my testimony be included for the Record.
    Mr. Mica. Without objection, so ordered.
    [The prepared statement of Dr. Amdur follows:]

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    Dr. Amdur. In the next few minutes, I would like to 
emphasize three requests that I hope you will focus on as you 
decide on new Federal initiatives related to research 
    Request No. 1 is to pass Federal legislation that requires 
that all research in the United States comply with the same 
high level of ethical standards, regardless of funding source. 
The ethicality standards that should be met when conducting 
research on human subjects are described in the Department of 
Health and Human Services regulations that are often referred 
to as the Common Rule.
    A problem with our current situation is that the authority 
of the Common Rule does not extend to some situations where 
research is sponsored by private industry. It makes no sense to 
have different ethical standards for research depending on 
funding source. All Americans should be afforded the same high 
level of protection and oversight. Medical progress will not be 
compromised by a more comprehensive regulatory structure, and 
PRIM&R urges you to support legislation that eliminates the 
two-class system of research protection that we currently have 
in this country.
    Request No. 2 is to pass legislation that consolidates the 
multiple different sets of Federal research regulations that 
currently exist into a single regulatory reference. The 
Department of Health and Human Services currently has one set 
of regulations, the FDA has another, the Department of 
Education has its own rules, and so on. In many cases, the 
regulations from these different Federal agencies are 
congruent, but in other situations they are not. In still 
others it is unclear what they are.
    As a result, researchers, industrial sponsors, IRB members, 
institutional officials, spend a tremendous amount of time and 
energy trying to figure out what hoops to jump through when 
different Federal agencies are involved, as is the common 
situation in both industry-sponsored and federally funded 
research studies.
    The situation is ridiculous. There is no reason that we 
should not have a single set of regulations that applies to all 
research involving human subjects, regardless of the Federal 
agency that is involved or the funding source.
    Request No. 3 is to ask you to support PRIM&R's efforts to 
create a formal program for accrediting each institution's 
system for protecting human research subjects. Protecting human 
subjects requires much more than an accounting type of 
checklist or audit of IRB paperwork. It requires onsite 
evaluation by trained professionals of objective and subjective 
end points, such as the level of institutional support for the 
IRB, the knowledge of research investigators about ethical 
standards, the commitment of institutional officials to 
shielding research regulators from financial conflicts of 
interest and other pressures, and eventually, to documenting 
objective end points of ethical behavior, such as the quality 
of informed consent for the subjects that have been enrolled in 
research studies.
    To set up a system for accrediting an institutional program 
for protecting research subjects, PRIM&R has recently formed an 
affiliated not-for-profit corporation called the Association 
for the Accreditation of Human Research Protection Programs. 
The acronym for it is AAHRPP. The current plan is to make the 
AAHRPP accreditation program voluntary, and we believe that 
most institutions will actively seek AAHRPP accreditation as a 
way of increasing the integrity of their research programs.
    Time does not permit me to describe the details of the 
AAHRPP accreditation process. This information is provided in 
my written statement. I am happy to explain anything related to 
this in the question session.
    I would like to conclude my remarks by reminding you that 
this is not about a bunch of paperwork that enhances the power 
or budget of some Federal agency or a special interest group. 
Modern society is stuck between a rock and a hard place. We 
must conduct complex and often dangerous research with human 
subjects if we are to improve the condition of life on this 
    There is often a tension between the ethical standards that 
we need to work within and a scientific agenda. We can create 
an environment where we promote meaningful research in a way 
that does not exploit in any way the rights and welfare of 
research subjects, but we need the strong arm of the Federal 
Government to make this happen and we need Federal support to 
be applied correctly.
    Our current IRB system is a good one. It is a result of the 
Nuremberg War Crimes Trial that exposed the shameful, unethical 
research that was conducted by Nazi physicians in the name of 
medical science during World War II. Earlier this week, the 
world observed Holocaust Remembrance Day in honor of those who 
suffered during the awful period in human history.
    In one remembrance ceremony, the Nobel Laureate Elie Wiesel 
said, ``Without its ethical dimension, civilization is 
vulnerable.'' PRIM&R and many other members of the research 
community hope you will act swiftly and decisively to improve 
the system of protecting human research subjects in this 
country. The AAHRPP accreditation program and the other changes 
that I have mentioned are steps in the right direction.
    On behalf of PRIM&R, thank you for inviting me. I am happy 
to provide any other information that would be useful. Thank 
    Mr. Mica. Thank you and each of our witnesses on this panel 
for your testimony. I apologize, again, for the delay in the 
hearing, but we had floor votes and then we had the required 
participation in the committee hearing.
    Again, I would like to proceed with some questions, first 
maybe to Mr. Curtin. Well, you have all basically criticized 
some of the current functioning, operation, of the IRBs. Mr. 
McCarthy did not get into too much of that, he spoke mostly of 
the DSMBs. But the current system appears to be somewhat 
    I guess if we started out maybe with informed consent, do 
you think it might be possible to have a basic standard 
informed consent procedure that would be good for all human 
research testing, Mr. Curtin?
    Mr. Curtin. That seems very bureaucratic to me, very 
inflexible. I would hope that we would be able to rely upon 
individual researchers and IRBs to come up with--to develop--
the informed consent that most fits the research project that 
they are looking at.
    Maybe that is too theoretical, maybe it cannot be done.
    Mr. Mica. I don't know if your daughter was afforded 
informed consent. Was she?
    Mr. Curtin. Absolutely not.
    Mr. Mica. Absolutely not. So first of all, there was not 
any in place?
    Mr. Curtin. Not for her. Well, if she answered it, 
obviously, but for other family members, no.
    Mr. Mica. For her, for herself, she did have informed 
    Mr. Curtin. Yes.
    Mr. Mica. Were you satisfied with that? Your protest then 
goes beyond her situation and her giving informed consent. I 
understand your concern about your privacy, her disclosure of 
your medical record. But were you satisfied with the informed 
consent that she was provided?
    Mr. Curtin. The informed consent really was if she 
responded to it, that would be considered the informed consent. 
She would have voluntarily participated if she had filled out 
the questionnaire and put it in a return envelope and sent it 
    Mr. Mica. To step back first, does everybody believe that 
there should be a requirement for informed consent?
    Mr. Curtin. I think there should have been a statement in 
the instructions saying, if you are going to answer for your 
other family members, you might want to tell them that you are 
doing that.
    Mr. Mica. We have not gotten to family yet. We are talking 
about an individual who is going to participate or someone who 
is a guardian or legally responsible for that individual. There 
should be informed consent.
    Everybody agrees on that?
    Dr. Amdur. There are situations where it is appropriate and 
necessary to conduct research without informed consent, and 
those situations are described and provided for in current HHS 
    A typical example would be emergency situations where it is 
not possible to get it, to conduct research with there being 
informed consent. There are other situations such as health 
services research involving access to medical records where 
risk is minimal and it is not possible or practicable to 
conduct research with a requirement for informed consent.
    The fundamental ethical standards that we use when we think 
about these and analyze them and say what is appropriate, what 
is not, what rights and welfares are important to maintain, 
need not be violated in certain circumstances without getting 
informed consent.
    Mr. Mica. Dr. Amdur, you are the one I thought that had 
come forward in past Federal law or regulations and set 
standards. That is what I am trying to get at.
    I had, sitting where Mr. McCarthy is, the representative of 
HHS. He said they had all the authority they needed to deal 
with these situations. It sounded like he did not have any 
recommendations for legislative changes.
    You have come forward and recommended something. Maybe you 
could elaborate on what you envision we should be doing as a 
Federal Government to again provide that there is adequate 
informed consent in human patient testing, that there is not a 
problem with the operation of an IRB.
    Right now, they cannot even tell me how many IRBs there 
are, OK? And then the operation of an IRB, should we be more 
involved in a conflict of interest, making certain there are 
not conflicts of interest?
    You heard this explosion and expansion of human research in 
just the whole biotech industry. All of the breakthroughs in 
medicine, testing, have just dramatically exploded. We hear 
something new every day.
    We as government do not want to stand in the way of 
research, but you have some basic protections that should be in 
place. Now, HHS said that they have adequate authority. You are 
saying that we should have some Federal regulations or laws and 
set some standards. Maybe you can elaborate.
    Dr. Amdur. You have raised a number of points. To go into 
detail about each one I think would be beyond the scope of this 
discussion, conflict of interest, etc.
    My response would be that the requests that I listed were 
specific regulatory changes that will make this current system 
work better.
    Mr. Mica. The HHS has the ability to institute regulations, 
so it is not a matter of changing the law, or is it? Are you 
aware of where we need to change the law?
    Dr. Amdur. Perhaps I am mistaken in terms of exactly who 
initiates the law. Really, though, I think.
    Mr. Mica. We initiate the law. What we do is when they have 
the need to be changed from time to time, we defer to HHS and 
the agencies to institute regulations.
    Dr. Amdur. I don't know any delicate way to say this. The 
point is, HHS could have made these changes, should have made 
these changes. PRIM&R sponsors two national meetings a year. 
The IRB world knows many changes that need to be made to make 
the system work better, which is a good system. They have not 
been made because of Federal bureaucratic inertia, turf wars, 
whatever. That is the reason that I am saying to you, I don't 
know what the problem is.
    Mr. Mica. I was trying to see if you had a recommendation 
in a legislative context. Most of it appears to be regulatory 
in nature. The failure of HHS to institute even the 
recommendations your group has made, we have the same problem. 
We had the IG sitting next to HHS and telling us that even 
basic things that were recommended back in 1998 still have not 
been instituted.
    We are looking first at the statutory and the larger 
picture, our responsibility. Then we do have the oversight and 
investigative responsibility, which we are conducting today 
through this hearing, asking again HHS why they are not 
following through with the recommendations.
    There are two ways they can do that. One, within existing 
authority, or if they need additional resources to make certain 
these things are in place.
    Now, Mr. Curtin has talked about another issue which 
extends beyond the informed consent but may need some type of 
tweaking in our laws as far as privacy or disclosure, and that 
is of course the subject of big discussions now with the 
tremendous amount of raw information that is coming out about 
    He raises a certain concern. We have heard an abuse here 
that we may either need to address through regulation or 
    Dr. Amdur. The IRB system failed to do what should have 
been done in his case. There is no question about that. We 
don't need a new system, we just need the IRB at MCV to have 
functioned the way it should have functioned.
    Mr. Mica. Many of the IRBs, though, are sort of self-
regulating, without a lot of protections. We are going to 
submit to the doctor and some others instances, but mostly we 
are reading about it in media accounts of conflict of interest.
    In our last hearing, we also heard problems ranging in 
conflict of ethics to having some self-interest in proceeding 
with the human testing. Again, you are dealing with boards that 
basically have some interest in participating and moving 
forward, taking Federal funds for that activity, as opposed to 
closing it down or not proceeding and not receiving the funds.
    Then the other problem we have is the huge explosion of all 
of this. It was just a few doing the testing some time ago. Now 
we are probably looking at thousands and thousands, plus the 
commercial and private side, where you do not have Federal 
funds and we have some loopholes in that regard.
    What about mandatory registration of IRBs?
    Dr. Amdur. We need that. That is part of the request of 
extending the regulations of the Common Rule to all research. 
The reason that you don't know or nobody knows how many IRBs 
there are in the country is because the only record of an IRB 
is if they conduct FDA-regulated research or HHS-funded 
    We need to just simply fix that problem. I don't know that 
HHS can do that. I think it requires a higher level of mandate 
to pass a Federal law. I don't know that. But the point is, we 
need to extend the system of protection. Part of that would be 
a formally certified IRB according to the Common Rule 
regulations. Then we would not only know how many IRBs there 
are, but have some common system that they work under.
    Mr. Mica. Let me ask Mr. McCarthy. You have looked at the 
Data Safety Monitoring Boards, DSMBs. Do you feel there should 
be some accreditation or additional regulation mandatory?
    Mr. McCarthy. Yes, I would like to see some criteria 
established and required to be implemented. The criteria should 
state under what circumstances the Data Safety Monitoring Board 
should be established, what its authorities and 
responsibilities should be, and what its relationship to the 
local IRB should be in the centers where research over which it 
has oversight is being carried out.
    I do not know whether that can be carried out under present 
legislation or whether it would require new legislative 
authority, but I think it is very important, and will be a 
major step forward if that should occur.
    I agree with Mr. Curtin, that a kind of cookie cutter 
approach to informed consent is just what we don't need, 
because anything that routinizes informed consent, tends to rob 
it of its important meaning.
    What I would like with respect to informed consent is to 
see the Department of HHS spending some money to do research on 
how to communicate risks and benefits associated with research 
more effectively.
    We have a whole new generation of young people coming along 
who operate much more out of visual cues than out of written 
cues. To hand people a written, fairly complex document may not 
actually inform them of very much, whereas a videotape showing 
the same information might be much more effective.
    In order to develop that kind of technology, somebody needs 
to sponsor some imaginative research into how to better inform 
subjects so that they will know and understand the consequences 
of their decisions to participate or not to participate in 
    Again, I don't know if you need a legislative mandate to 
carry that out or whether you simply need additional budget 
resources to carry that out, but I certainly think that ought 
to be a major function of the new office that is being created 
in HHS.
    Even if a new approach to informed consent can be done 
without new legislation, it certainly cannot be done without 
additional money, so I would encourage that the Congress bite 
the bullet and provide the money so that imaginative new ways 
of communicating with research subjects can be developed and 
employed, and so that IRBs have a range of ways of 
communicating the risks and benefits of research to their 
subjects in meaningful ways. I believe we can respect the 
dignity of subjects more than we do at the present time with 
rather complex, long, written consent documents that may not do 
what they are intended to do.
    Mr. Mica. Mr. Curtin obviously had a negative experience 
with the OPRR process. I think he recommended some solutions 
for corrections.
    Maybe you could give us those again, Mr. Curtin.
    Mr. Curtin. Yes, sir. No, I did not have a negative 
experience with OPRR. The only thing that even could be 
remotely called negative about it was that it took them almost 
a year to get around to doing anything with my complaint. But 
once they did it----
    Mr. Mica. That I would interpret as a problem.
    Mr. Curtin. That is, yes. But once they got on it, they 
were great. They kept me informed.
    Mr. Mica. They did?
    Mr. Curtin. They did. They took some very, very severe 
action. They closed down 1,100 research projects at Virginia 
Commonwealth University.
    Mr. Mica. Your difficult experience was getting attention 
at the beginning.
    Mr. Curtin. Right. They explained that to me right off the 
bat. They said, it is going to be a year before we get around 
to doing this. A year later I heard from them. I would have 
liked it to have been sooner, but I understand those kinds of 
    Mr. Mica. With the IRB process, you also were critical of 
the response you got there.
    Mr. Curtin. From the chairman, yes. Yes.
    Mr. Mica. You----
    Mr. McCarthy. Mr. Chairman, just to fill in that story, 
because maybe even Mr. Curtin does not know this, but after 
OPRR took its action, Virginia Commonwealth University hired 
me, and I have been working about 40 or 50 hours a week since 
January to educate investigators about their obligations on 
informed consent and to instruct potential new members of the 
    So they are taking the criticism very seriously, and I 
expect that within a year they will have a system that will be 
as good as any in the country.
    Mr. Mica. But it did take a year to get action. What did 
they say, they could not get to it?
    Mr. Curtin. They were overworked, backlogged.
    Mr. Mica. OK. All right.
    Mr. McCarthy. As a former Director of OPRR, I can say that 
is a perennial problem. I think the office has always been 
understaffed and underfunded.
    Mr. Mica. I am also trying to find out what their 
recommendations were to us. They have to come to Congress to 
ask for additional funding through the appropriations process. 
If we have a deficit there and we have a larger scope of 
responsibility, we need to see that that is met. Maybe these 
1,100 operations should have been closed down after the 
complaint was made, not a year later.
    Again, we are just trying to look at where the problems are 
and what is going wrong and how we correct them. It is a pretty 
simple process, except I have to get 534 other people to agree 
on how to fix it.
    Mr. Curtin. If I might add, sir, the IRB there, they just 
did not take me seriously. It was as simple as that. They 
thought they would write me a letter and I would go away.
    Mr. Mica. All right.
    It sounds like we have at least Mr. McCarthy and Dr. 
Amdur's wealth of experience and recommendations. You have a 
personal experience.
    I wanted to ask about some recommendations. I didn't make 
good notes on who said what, but you said consolidate sets of 
regulations. You cited HHS, FDA, education, and some standards. 
My staff just gave me the Department of Veterans Affairs 
standard for protecting human research participants.
    Did you mean in the context again of protection, some 
standards that are protections for human research participants, 
no matter what the Federal agency?
    Dr. Amdur. Yes, exactly. What I meant was not an abstract 
thing, but an administrative one, meaning that if you look in 
the Code of Federal Regulations at 45 CFR 46, you will see HHS 
    Mr. Mica. Right.
    Dr. Amdur. If you look at 21 CFR 50 and 52, I guess it is, 
56, you will see FDA. Most of it, 90 percent of it, are the 
exact same words. They are just copies.
    But then in the remaining 10 percent of this situation, the 
regulations are different or they are silent on certain 
situations. There are many examples of that. The Department of 
Defense has certain requirements, and you know if they sign on 
to the Common Rule, then they do.
    The point is that, for example, this adverse event 
reporting which you have heard so much about, this is the No. 1 
workload problem for IRBs. It is the most ridiculous thing. 
There are boxes and boxes coming into the University of 
Florida's IRB every week of irrelevant reports that the IRB 
cannot possibly make any meaningful determination of. It may be 
a horrible adverse event that is critically important, but 
because of the things Dr. McCarthy said, the nature of what you 
need, you need data in safety and monitoring, but the IRB 
should not be looking at those. Does the IRB need to do that? 
The regulations say they need to.
    HHS regulations say certain things that can be interpreted 
certain ways. FDA regulations say very different things that 
likewise are interpreted very differently. So what I do on the 
IRB is sit around every week as chair of an IRB before coming 
to the University of Florida and try and say, how do we 
interpret this? Every year we have major discussion sessions at 
the national meetings: Well, how do we interpret this? And we 
are scared to turn away these things if there is any question 
that we need to be stamping them because we are scared of the 
regulatory consequences.
    So the point is, what should be done is to say we are only 
going to have one set of regulations, and it would be very 
simple. There are people that sit around, and this is all we 
have thought about and discussed and written papers about, who 
can suggest and hammer out revised regulations where necessary 
that make them congruent, just like any revised regulatory 
process goes. But the thing we need is to say we are only going 
to have one set of regulations, and it does not matter what 
agency sponsors the research.
    I would say we need to extend it. It does not matter if it 
is privately funded, and I think we need a law for that, not a 
Federal regulation. But the point is that we only need to have 
one set of regulations. That is what I mean when I say 
``standards,'' regulations that describe the standards: Say you 
need to go through an IRB. You need to have informed consent 
under these situations. Here is the form of the informed 
consent, that situation. We need just one of those.
    The Common Rule does need a little polishing here and 
there, but it is basically what we would all come up with if we 
spent a long time thinking of standards in a regulatory system. 
It is a good system, and----
    Mr. Mica. Are you aware of any formalized document or 
anything that has been prepared that proposes that and has 
language that would be acceptable to the vast majority of those 
who participate?
    Dr. Amdur. I think that when you say ``vast majority'' the 
people who are objecting to consolidation of the regulations--
    Mr. Mica. We are not going to get everyone to agree.
    Dr. Amdur. Right, but the people who are objecting are the 
people in the agencies that want to keep their own regulations. 
Certainly industry sponsors, they just want to figure out: What 
do I need to do? They don't care what it is. It is so much 
better if they can just figure out what it is.
    The International Council on Harmonization would be the 
closest thing to the answer to your question in that there is 
now. In order to make it so that companies, pharmaceutical 
companies, can do business in all different countries, there is 
a body that has done exactly what you have said, which is 
establish that we are going to have one uniform requirement. If 
you want to do business within this group, we are just going to 
say everybody has to comply with these regulations. We are not 
interested in your HHS or whatever. If HHS is the exact same, 
fine. All we know is, here is one set.
    You know, I think that comes very close to what you are 
saying, but it would not be very difficult to come up with the 
one set. I think what is needed is some mandate at a higher 
level to say, come up with one set.
    Mr. Mica. Mr. McCarthy, you wanted to respond?
    Mr. McCarthy. I had some years' experience in OPRR, and of 
course we tried to do exactly what Dr. Amdur is suggesting; to 
come as close as humanly possible to a single set of 
regulations that would apply to all research, whether FDA-
regulated or federally funded. We had no authority to reach out 
to that research which was neither FDA-regulated nor federally 
funded, so that problem I think is one that requires some 
congressional action to extend the authority of these offices.
    But I think the problem is more complex than you have 
heard. Each agency has its own authorizing legislation, and it 
is that authorizing legislation that allows it to issue 
regulations. That legislation differs dramatically from FDA to 
Department of Defense to HHS to Department of Education.
    Different congressional committees handle that legislation 
and draft it, so when you try to write a common set of rules 
that comply with a vast variety of laws, it is not a simple 
matter to write a single rule that complies with all of the 
authorizing legislation of all of the Federal agencies.
    We did the best we could, and I would disagree, I think 
between HHS and FDA, the congruency is about 97 percent. What I 
would point out, however, is that FDA has authority for 
implementing its rules, and that means different people are 
doing it, and sometimes they interpret the rules a little 
    That is why I would like to see this new HHS office become 
at least an HHS-wide office, and I would like the new office to 
have enough authority so it can be the lead agency to bring the 
other departments and agencies--that do less research but still 
a lot of research--into congruence so far as possible, given 
the plethora of laws that govern them.
    I think much more can be done, so I am agreeing with Dr. 
Amdur's point, but I think it is not a simple issue. This is a 
situation where the Congress itself, by placing certain kinds 
of goals for the new HHS office and providing it with resources 
to accomplish those goals, could go a long way toward 
accomplishing what he wants. I doubt if it can ever be perfect, 
but we can do lots better.
    Mr. Mica. Dr. Amdur wanted to respond.
    Dr. Amdur. You know, Dr. McCarthy has worked in the 
government too long, because now he is making excuses for it. 
You know, our role here is simply to say what needs to be done 
and for you to figure out how to do that.
    We need a common set of rules, and we do have plenty of 
models for that in the research world. For example, in 1996 
Congress passed the Health Insurance Portability Act. As part 
of that, it required legislation to be passed that set 
standards for the protection of privacy of access to the 
medical record.
    Federal law said this has to be done. It did not say 
``unless FDA objects to it,'' or the FDA--``unless it conflicts 
with FDA's view of it.'' It said, that is it. America, that is 
the way it is going to be done. A Federal law passed.
    We are about to see a law go into effect that supersedes 
all of our other research baloney of interpretation, of how do 
we interpret HHS, how do we do that. It is going to be a 
problem, of course, to implement it because there are problems 
with the way that law is written. But the point is that 
mechanism is there to say that, well, research, this is the way 
it is going to be done, regardless of one Federal agency's 
policy or another.
    I think that we can solve this problem.
    Mr. Mica. I am probably somewhere in between the two of 
    Mr. McCarthy. We are not very far apart. We have exactly 
the same goal.
    Mr. Mica. Mr. McCarthy has described a political situation 
of congressional authorization, and there is not just the 
agency turf jealousy. We also have the committee authorizing 
jealousy, and to get them to all agree on anything is very 
    I see your point, though. We have, as you pointed out, in 
other legislation required some standards. I think everybody 
agrees that there should be informed consent. I think everybody 
is agreeing now there should be some registration of at least 
the IRBs, right? And then we get into some other areas.
    We have not really talked about accreditation or 
certification for IRBs or DSMBs. Dr. McCarthy, what do you 
think about some accreditation or certification standard?
    Mr. McCarthy. I strongly endorse this effort. As a matter 
of fact, I have been selected to serve on the board of the new 
organization that Dr. Amdur cited, and I am dedicated to trying 
to bring this about as best we can.
    Mr. Mica. Should that be voluntary or mandatory?
    Mr. McCarthy. I think that it ought to be voluntary and 
supplemental to the kind of oversight exercised by the 
government. I think we have an excellent model in the 
Association for Accreditation of Laboratory Animal Care, Int. I 
think it has worked very well for many years as a supplement to 
government efforts.
    Mr. Mica. How long has that been in place?
    Mr. McCarthy. At least since 1970, and if memory serves, 
about 1965, but a very long time. It has worked exceedingly 
well, and one of the people serving on the new AAHRPP board is 
the director of AAALAC, so that we are able to profit from his 
experience and his guidance.
    I think the one thing holding up accreditation is funding, 
and we are now seeking some funding sources in order to get 
this corporation off the ground. We think it will be self-
sustaining because it will be in the best interests of the 
institutions to be accredited, to get a Good Housekeeping Seal 
of Approval on their programs, before OPRR or FDA or some other 
agency comes in and shuts down their research. This way we can 
make a supplemental contribution to what the government is 
    In no way would I weaken the government's authority or the 
extent of its oversight, but I think human subjects are so 
important that we can supplement what government can do and 
head off many problems before they occur.
    Mr. Mica. Dr. Amdur, what about certification or 
    Dr. Amdur. I think that it needs----
    Mr. Mica. Give me your ideas on how that should be 
    Dr. Amdur. A program that will work very well for this 
purpose is not in the planning stages, it is in the very end 
stages of the planning and about to be implemented by PRIM&R. 
This is the AAHRPP program. In three pages in the written 
testimony we explain the mechanics of it.
    Very briefly, what you do first is--this is about to be 
completed--you organize a group of experts that then write down 
basic best practice guidelines for the fundamental aspects of a 
system of protecting human subjects: The institution, the IRB, 
education of investigators, management of adverse incidents, 
etc. You start there, and that has been done.
    Then you have a written phase where the institution 
responds to their current status related to those. Then you 
have an onsite investigation where usually two or three experts 
go to the institution and have to interact with all the key 
components of the system and see how it is really working 
according to objective and there are some subjective aspects of 
it, and issue a grade, if you will, of the institution related 
to a whole checklist of things.
    If the institution meets certain standards, which are 
outlined in the program, then they get the accreditation for 3 
years is the proposal. So PRIM&R has been working very hard to 
indeed hammer out the details. It is not perfect yet. It has 
not been tried in the field yet. Like any system, it will 
obviously iterate and evolve and change and be polished as it 
is used. The more support it gets, the quicker it can get 
online, but it is ready to go.
    I would strongly support a model that is that far along 
already to get out into the field and get going.
    We have to accredit everything we do. You go and get the 
gas tank filled for your gas grill and the people that fill the 
gas have to have a certification. We need an accreditation 
process for the protection of human subjects, and that is 
something that is really long overdue.
    Institutions will not balk at this, they will embrace it. 
They want to know, what do I need to do to be doing things 
correctly. They will embrace it if it is a credible system that 
is tagged to meaningful evaluations. If it is just an audit 
system of a bunch of accountants going and checking and looking 
for pieces of paper that say certain things and the date 
matches this date, you know, they will do it if they have to 
because the experts on protecting human subjects are the 
investigators, in most cases. They know if the IRB is asking 
the meaningful questions. They know if the institution is 
providing the right environment to support them and be able to 
resist conflicts of interest.
    As long as it is a meaningful, credible process done by 
people who know what they are doing, the institutions will 
embrace it. But it needs to be supported as widely as possible.
    Mr. Mica. Do you endorse the mandatory versus voluntary?
    Dr. Amdur. I am scared to say yes, mandatory, because we 
should always have as little required regulation as possible. I 
just need to see the exact format of how that requirement would 
be, because when we actually write it down and see how it is 
implemented, I am concerned.
    I think it will be enormously effective even if it is 
voluntary and if the regulations required--I personally right 
now, don't think it has to be a mandatory, required system. I 
think HHS regulations and authority already have the authority 
to put the pressure, as they are trying to do, on institutions 
to do things correctly. The institution will seek out ways to 
find out what is correct and improve their system on their own 
if they are indeed under a regulatory system that evaluates the 
end point.
    So I think they will seek the accreditation process on 
their own and there will be other forces that end up requiring 
it. For instance, industry will require it. Once there is any 
meaningful system in place, industry sponsors will require it. 
They will say, we are not dealing with you unless you are an 
AAHRPP-accredited institution. So I don't think it has to be 
mandated at the Federal level.
    Mr. Mica. I have additional questions we may submit some to 
you and some of our other witnesses today, but I think we have 
just passed the 6 o'clock hour.
    I do want to thank each of you for participating, for being 
with us this afternoon, for your contribution in helping us 
improve this entire process, and also the Federal agencies that 
are responsible for implementing law and Federal policy.
    There being no further business to come before the 
subcommittee--and again, I want to thank you for your 
participation and willingness to provide us with your personal 
experiences and your expertise on this important issue--this 
hearing is adjourned.
    [Whereupon, at 6:02 p.m., the subcommittee was adjourned.]
    [Additional information submitted for the hearing record