<DOC> [106th Congress House Hearings] [From the U.S. Government Printing Office via GPO Access] [DOCID: f:70580.wais] HUMAN SUBJECT RESEARCH PROTECTIONS ======================================================================= HEARING before the SUBCOMMITTEE ON CRIMINAL JUSTICE, DRUG POLICY, AND HUMAN RESOURCES of the COMMITTEE ON GOVERNMENT REFORM HOUSE OF REPRESENTATIVES ONE HUNDRED SIXTH CONGRESS SECOND SESSION __________ MAY 3, 2000 __________ Serial No. 106-198 __________ Printed for the use of the Committee on Government Reform Available via the World Wide Web: http://www.gpo.gov/congress/house http://www.house.gov/reform U.S. GOVERNMENT PRINTING OFFICE 70-580 WASHINGTON : 2001 _______________________________________________________________________ For sale by the Superintendent of Documents, U.S. Government Printing Office Internet: bookstore.gpo.gov Phone: (202) 512-1800 Fax: (202) 512-2250 Mail: Stop SSOP, Washington, DC 20402-0001 COMMITTEE ON GOVERNMENT REFORM DAN BURTON, Indiana, Chairman BENJAMIN A. GILMAN, New York HENRY A. WAXMAN, California CONSTANCE A. MORELLA, Maryland TOM LANTOS, California CHRISTOPHER SHAYS, Connecticut ROBERT E. WISE, Jr., West Virginia ILEANA ROS-LEHTINEN, Florida MAJOR R. OWENS, New York JOHN M. McHUGH, New York EDOLPHUS TOWNS, New York STEPHEN HORN, California PAUL E. KANJORSKI, Pennsylvania JOHN L. MICA, Florida PATSY T. MINK, Hawaii THOMAS M. DAVIS, Virginia CAROLYN B. MALONEY, New York DAVID M. McINTOSH, Indiana ELEANOR HOLMES NORTON, Washington, MARK E. SOUDER, Indiana DC JOE SCARBOROUGH, Florida CHAKA FATTAH, Pennsylvania STEVEN C. LaTOURETTE, Ohio ELIJAH E. CUMMINGS, Maryland MARSHALL ``MARK'' SANFORD, South DENNIS J. KUCINICH, Ohio Carolina ROD R. BLAGOJEVICH, Illinois BOB BARR, Georgia DANNY K. DAVIS, Illinois DAN MILLER, Florida JOHN F. TIERNEY, Massachusetts ASA HUTCHINSON, Arkansas JIM TURNER, Texas LEE TERRY, Nebraska THOMAS H. ALLEN, Maine JUDY BIGGERT, Illinois HAROLD E. FORD, Jr., Tennessee GREG WALDEN, Oregon JANICE D. SCHAKOWSKY, Illinois DOUG OSE, California ------ PAUL RYAN, Wisconsin BERNARD SANDERS, Vermont HELEN CHENOWETH-HAGE, Idaho (Independent) DAVID VITTER, Louisiana Kevin Binger, Staff Director Daniel R. Moll, Deputy Staff Director David A. Kass, Deputy Counsel and Parliamentarian Lisa Smith Arafune, Chief Clerk Phil Schiliro, Minority Staff Director ------ Subcommittee on Criminal Justice, Drug Policy, and Human Resources JOHN L. MICA, Florida, Chairman BOB BARR, Georgia PATSY T. MINK, Hawaii BENJAMIN A. GILMAN, New York EDOLPHUS TOWNS, New York CHRISTOPHER SHAYS, Connecticut ELIJAH E. CUMMINGS, Maryland ILEANA ROS-LEHTINEN, Florida DENNIS J. KUCINICH, Ohio MARK E. SOUDER, Indiana ROD R. BLAGOJEVICH, Illinois STEVEN C. LaTOURETTE, Ohio JOHN F. TIERNEY, Massachusetts ASA HUTCHINSON, Arkansas JIM TURNER, Texas DOUG OSE, California JANICE D. SCHAKOWSKY, Illinois DAVID VITTER, Louisiana Ex Officio DAN BURTON, Indiana HENRY A. WAXMAN, California Sharon Pinkerton, Staff Director and Chief Counsel Lisa Wandler, Professional Staff Member Ryan McKee, Clerk Cherri Branson, Minority Counsel C O N T E N T S ---------- Page Hearing held on May 3, 2000...................................... 1 Statement of: Curtin, Richard, human subject, Falls Church, VA; Charles R. McCarthy, senior research fellow, Kennedy Institute of Ethics, Georgetown University; and Robert Amdur, M.D., associate professor, associate chair, clinical affairs, Department of Radiology and Oncology, University of Florida 60 Grob, George, Deputy Inspector General for Evaluation and Inspections, Office of Inspector General, Department of Health and Human Services; Mark Yessian, Ph.D., regional Inspector General for Evaluation and Inspections, Department of Health and Human Services; William Raub, Ph.D., Deputy Assistant Secretary, Science Policy, Office of the Secretary, Health and Human Services; Gary Ellis, Ph.D., Acting Director, Office of Protection from Research Risks; and Daniel Michels, Director of Enforcement, Office of Regulatory Affairs, Food and Drug Administration........ 10 Letters, statements, etc., submitted for the record by: Amdur, Robert, M.D., associate professor, associate chair, clinical affairs, Department of Radiology and Oncology, University of Florida, prepared statement of............... 122 Curtin, Richard, human subject, Falls Church, VA, prepared statement of............................................... 63 Grob, George, Deputy Inspector General for Evaluation and Inspections, Office of Inspector General, Department of Health and Human Services, prepared statement of........... 12 McCarthy, Charles R., senior research fellow, Kennedy Institute of Ethics, Georgetown University, prepared statement of............................................... 70 Mica, Hon. John L., a Representative in Congress from the State of Florida, prepared statement of.................... 5 Raub, William, Ph.D., Deputy Assistant Secretary, Science Policy, Office of the Secretary, Health and Human Services, prepared statement of...................................... 34 Waxman, Hon. Henry A., a Representative in Congress from the State of California, prepared statement of................. 49 HUMAN SUBJECT RESEARCH PROTECTIONS ---------- WEDNESDAY, MAY 3, 2000 House of Representatives, Subcommittee on Criminal Justice, Drug Policy, and Human Resources, Committee on Government Reform, Washington, DC. The subcommittee met, pursuant to notice, at 2:36 p.m., in room 2247, Rayburn House Office Building, Hon. John L. Mica (chairman of the subcommittee) presiding. Present: Representatives Mica, Cummings, and Kucinich. Staff present: Sharon Pinkerton, staff director; Steve Dillingham, special counsel; Don Deering, congressional fellow; Lisa Wandler, professional staff member; Ryan McKee, clerk; Alex McKinnon, intern; Cherri Branson, minority counsel; and Earley Green, minority staff assistant. Mr. Mica. Good afternoon. I'd like to call this hearing of the Subcommittee on Criminal Justice, Drug Policy, and Human Resources to order. I apologize for the delay. There is a full committee hearing going on at this time, but with the consent of the minority, we are going to proceed. We have two panels today, and we do want to finish this hearing this afternoon. It is an important hearing, entitled ``Human Subject Research Protections,'' one of which I'm pleased to work with my colleague Mr. Kucinich, the gentleman from Ohio, and this is the second hearing we've conducted on this matter. I am going to start with the regular order of business. We may at some time have to recess for a vote, either in committee or on the floor, but we'll proceed with opening statements, recognizing myself first and then the gentleman from Ohio. This hearing before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources will examine a critical problem for which reforms have been recommended by the Office of Inspector General [OIG], to the Department of Health and Human Services [HHS]. Last December, we conducted a hearing on this topic in New York City where past issues had surfaced regarding the protections of persons participating in human research projects. The December hearing also coincided with revelations regarding the tragic death of 18-year-old Jesse Gelsinger of Tucson, AZ. Jesse died just 4 days after being injected with a cold virus and engineered genes. Researchers were shocked and a national debate ensued on gene therapy experiments and the reporting of adverse effects. The National Institutes of Health [NIH], issued a solicitation to the medical community requesting help. Even in today's Washington Post, I read that there were reports of more deaths which were not reported to authorities and which also put more lives at risk. The question I pose today is whether HHS heeded this cry for help and has that agency acted promptly to prevent future tragedies. Our December hearing included testimony from both OIG and also from HHS. At that time, it was apparent that HHS had not implemented the Office of Inspector General recommended reforms for protecting human research subjects. Today, we'll revisit this important issue. We will hear in fact that more deaths of participants in human research have been reported, and that, in fact, more violations of required human subject protections have been revealed. The Office of Protections Against Research Risk [OPRR], is one component of the HHS agency with special responsibilities for protecting human research subjects. The Food and Drug Administration [FDA], is another. Apparently neither has received the support and commitment from the administration and the Health and Human Services Secretary that is needed; indeed, that is required to enhance the protections for research subjects. Furthermore, the Department continues to putter around with this important issue, virtually ignoring most of the sound OIG recommendations and dragging their feet. Why is HHS so reluctant to act proactively in reforming its programs and increasing the protections for those participating in research? That's a question we have to ask today. What justification is there for continued delays? From the evidence supplied to date, the answer is not likely to prove comforting, especially as human research projects multiply and new research frontiers emerge. Protecting the lives of those involved in research should be foremost in HHS thinking, research practices and also in its regulatory priorities. Last December, this subcommittee asked the question, what actions are being taken to reduce unnecessary health and safety risks to human subjects? We should receive an answer today better than that given to us last year, which was an admission that practically nothing had been done. According to the most recent OIG report, however, it appears that not much has changed from our last hearing. I think there's a bipartisan agreement that this inaction is unacceptable. The June 1998 recommendations of OIG appear both in my opinion reasonable. They're also urgently needed and generally propose strengthening the Institutional Review Boards [IRBs], that approve and oversee human research projects. The OIG made the following recommendations and observations relating to IRBs. First, they said they face major changes in the research environment. They also said they review too much too quickly. Furthermore, they said they conduct minimal continuing review of approved research. They face conflicts that threaten their independence. They provide little training for investigators and board members and neither the IRBs nor HHS devote much attention to evaluating IRB effectiveness, and again, these are some of the points that were raised about the IRBs. The Office of Inspector General recommended reforms in some of the following areas: First, Federal requirements such as performance evaluations; second, strengthen protections, including enhanced IRB monitoring; third, educational requirements, including educating IRB members; fourth, preventing conflicts of interest and also the question of broadening representation on IRBs; fifth, reducing IRB workloads, and sixth, improving Federal oversight, including IRB registration. To date, the responses by HHS have indeed been most disappointing. The latest OIG report findings include, and let me cite them, first of all, minimal progress has been made in recasting Federal IRB requirements so that they grant IRBs greater flexibility and hold them more accountable. Another of these findings stated, minimal progress has been made in strengthening continuing protections for human subjects participating in research. Another finding, no educational requirements have been enacted for investigators or IRB members. Another recent finding here is that there has been no progress in insulating IRBs from conflicts that can compromise their mission in protecting human subjects, and we heard testimony about some problems in this area in our last hearing. Another more recent finding and update tells us that minimal progress has been made in moderating workload pressures of the IRBs. And finally, minimal progress has been made in reengineering the Federal oversight process. All of these really are disappointing to the subcommittee and me, particularly after our last hearing. We thought we would see some additional actions in some of these areas. As indicated in our previous hearing, HHS annually invests approximately $5 billion of its research dollars in approximately 16,000 research projects that involve human beings. To provide oversight for these research projects, OPRR has agreements with more than 4,000 federally funded institutions, each with an IRB. Under OPRR guidelines, research subjects must be fully briefed on the purpose, the duration and the procedures of the research project before agreeing to participate. OPRR has the authority to investigate and require corrective action and suspend funding to an institution. Last month, it was reported in the Los Angeles Times that specialists overseeing a clinical trial of the diabetes drug Rezulin did not follow the required procedures for monitoring a volunteer who died after taking the medication. Less than 10 days ago press reports announced the death of a 42-year-old Massachusetts woman participating in a drug study sponsored by the Nation's top medical research agency. She died after receiving the wrong kind of blood. As we'll hear today, the OPRR has acted to suspend research at a growing number of universities where research requirements have been violated. What is required to convince HHS to take additional needed actions to prevent more harms and also to save more lives? While I'm glad to hear that some improvements are underway, I don't think that the agency can truthfully testify here today that in fact enough has been done or is being done. If it does, we should consider placing this responsibility elsewhere. I take no joy in holding another hearing on this topic within 5 months of the previous hearing, but if inaction continues in the face of mounting dangers and death, we may need further oversight hearings and further investigation into this. We also may have to work with the Appropriations Committee and some of the other committees to put some caveats on spending this significant number of dollars, some $5 billion, in research that involves human subjects, and we'll look at those options. I thank the witnesses who have come before us today to testify. We appreciate your willingness to appear before this subcommittee and to share your knowledge and experience as we strive to address this urgent public health priority. Time is of the essence in this matter, and further delay must be avoided. I'm pleased again to have the cooperation on this issue and active participation and leadership of the gentleman from Ohio. Let me recognize Mr. Kucinich at this time for his opening statement. [The prepared statement of Hon. John L. Mica follows:] [GRAPHIC] [TIFF OMITTED] T0580.001 [GRAPHIC] [TIFF OMITTED] T0580.002 [GRAPHIC] [TIFF OMITTED] T0580.003 Mr. Kucinich. Thank you very much, Chairman Mica, and I want to especially commend you for calling this hearing and for your continuing efforts to demonstrate your dedication to the protection, the health and the welfare of the American public in clinical research trials. I think this Congress is fortunate to have your leadership in this area. I'd like to thank the witnesses for testifying regarding the Inspector General's report on the protection of human research subjects. I'll begin by saying that I am disappointed in the lackluster response to the recommendations as the Inspector General's report finds, but I am not surprised. The state of Federal and local human research subject protections has been lacking for quite some time. The subject has only been highlighted in the past couple of years due to high profile cases with respect to gene therapy that have prompted Federal inquiries on the oversight of human research protections. However, I believe that human research protections extends far beyond the narrow scope of gene therapy. All aspects of human biomedical research must be monitored and everyone must be protected from risks involved in medical experimentation. The Inspector General's report in 1998 I believe outlined specific changes that could be made to improve the current protections in place. However, the current IG report indicates that the Department of Health and Human Services has done little to implement these recommendations, enacting only two. With respect to recommendations on oversight and protections by Institutional Review Boards, the report states that, ``minimal progress has been made in strengthening continuing protections for human subjects participating in research.'' Regarding Federal oversight it states that, ``minimal progress has been made in reengineering the Federal oversight process. Federal oversight of IRBs is not equipped to respond effectively to the changing pressures and needs of the current system of protections.'' Well, this is unacceptable. The Federal Government provides funds for a vast complex of experiments that involve human subjects. More than $16 billion per year in Federal funds are used for such research. Some 20,000 experiments at more than 4,000 universities, hospitals and other institutions are involved. Duke University alone has $175 million per year in Federal research grants. The lives of tens of thousands of people are at stake along with the reputation and integrity of very important research institutions. The Federal Government's system to monitor these institutions and ensuring the safety of human research subjects continues to be outdated, ineffective, underfunded and understaffed. The only bright spot in this dismal area of Federal activity is the positive efforts being made by the Office of Protection from Research Risk under the direction of Dr. Gary Ellis. In spite of the lack of funds, lack of staff and enormous institutional pressures, Dr. Ellis continues to make progress in the monitoring and investigating of research institutions which conduct human experimentation. His work on behalf of the American public should be commended and recognized. I know that I as well as the subcommittees will want to be apprised of the office's ongoing investigations. I look forward to hearing from you in the future. I am glad we have representatives here from HHS who will be able to address the Inspector General's report. I look forward to hearing your testimony. Thank you very much, Mr. Chairman. Mr. Mica. I thank the gentleman and there being no further opening statements at this time we're going to proceed with our first panel as the order of business. The first panel today consists of George Grob, and he is the Deputy Inspector General for Evaluation and Inspections at the Office of Inspector General, Department of Health and Human Services. The second witness is Dr. William Raub, and he is the Deputy Assistant Secretary for Science Policy of the Office of the Secretary of Health and Human Services. We have also accompanying these two witnesses Dr. Mark Yessian, who's the Regional Inspector General for Evaluation and Inspections in the Department of Health and Human Services. we have Dr. Gary Ellis, Acting Director of the Office of Protection from Research Risks. We have Daniel Michels, and he is the Director of Enforcement of the Office of Regulatory affairs at the Food and Drug Administration. This is an investigation and oversight subcommittee of Congress. We will swear you in in just a minute. All of our witnesses appear under oath. Furthermore, if you have any lengthy statements or documentation you'd like to have made part of the record, upon request through the Chair and with the concurrence of the minority that will be granted. Those are basically the rules and the way we'll proceed today. At this time let me confer. Without objection Mr. Kucinich has moved that the record be left open for additional comments or submissions for 2 weeks. So ordered. Mr. Kucinich. Thank you, Mr. Chairman. Mr. Mica. And we now will proceed and I'll ask our witnesses if they'd stand and be sworn. [Witnesses sworn.] Mr. Mica. The witnesses answered in the affirmative. We'll now hear first from the Deputy Inspector General for Evaluations and Inspection, George Grob. He has submitted rather lengthy findings for the subcommittee and Mr. Kucinich moves without objection that they be made part of the record. So ordered. So we will have your complete testimony in here. We'd like each of our witnesses today to try to limit their presentations, oral presentations, to 5 minutes if possible. I know we have two that are making presentations I think with this panel, and we will submit any additional data or testimony upon request. With that, let me recognize George Grob, Deputy Inspector General for Evaluation and Inspections. You're recognized, sir. STATEMENTS OF GEORGE GROB, DEPUTY INSPECTOR GENERAL FOR EVALUATION AND INSPECTIONS, OFFICE OF INSPECTOR GENERAL, DEPARTMENT OF HEALTH AND HUMAN SERVICES; MARK YESSIAN, PH.D., REGIONAL INSPECTOR GENERAL FOR EVALUATION AND INSPECTIONS, DEPARTMENT OF HEALTH AND HUMAN SERVICES; WILLIAM RAUB, PH.D., DEPUTY ASSISTANT SECRETARY, SCIENCE POLICY, OFFICE OF THE SECRETARY, HEALTH AND HUMAN SERVICES; GARY ELLIS, PH.D., ACTING DIRECTOR, OFFICE OF PROTECTION FROM RESEARCH RISKS; AND DANIEL MICHELS, DIRECTOR OF ENFORCEMENT, OFFICE OF REGULATORY AFFAIRS, FOOD AND DRUG ADMINISTRATION Mr. Grob. Thank you, Mr. Chairman and Mr. Kucinich. The system which was designed to protect the human subjects of research has inherent vulnerabilities, most of which remain even after the best efforts of our Department to address them. To understand why this is the case we must go back to its origins. The protections were gradually developed after the Second World War in response to research atrocities that came to light during the Second World War and other troublesome research experiments that arose shortly thereafter. In 1966 the Surgeon General issued a human subject policy for the Department of Health, Education and Welfare, and in 1974 the National Research Act required reviews by Institutional Review Boards for all research sponsored by the Department of Health, Education and Welfare. In 1991 those procedures were adopted by 15 other Federal Departments in what has come to be known as the Common Rule. These and other developmental events during that period were among the prouder days of American science with respect to protection of human subjects. However, during this same period research exploded in size and complexity and numbers, in amounts of money spent. The Institutional Review Boards were overwhelmed and left behind. Vulnerabilities subtly emerged, at first unnoticed. Lately we've begun to notice them. In 1998, at the request of the Food and Drug Administration, we conducted a study of the unauthorized marketing of investigational medical devices, and during the course of this report we stumbled upon some problems with the Institutional Review Boards and other systems designed to protect the human subjects of this research. For example, in one experiment the researcher was authorized to implant 75 investigational devices for surgery, and reported to the Investigational Review Board that 37 had been implanted. We found that 264 had in fact been implanted. We found other discrepancies in the surgery reports of other investigators: 15 devices were implanted during the 6- week period in which the research had been suspended by the Institutional Review Board; we found changes not made to the research protocols requested by the board and reported as having been made; we found informed consent forms missing, in some cases consent forms obtained after the surgery was performed and other similar results. As a result of stumbling upon these kind of findings, we decided that a more systematic look was required at the Institutional Review Boards and others systems designed to protect human subject research, and based on that work we published in June 1998 a more comprehensive review that provided an early warning of troubles and vulnerabilities in the system. To get a better sense of the problems that the institutions were facing at the time let me just rattle off some of the circumstances that made it more difficult for them to do their jobs. When they began this work in the sixties and seventies most research consisted of research at a single site. Today it's mostly multi-sites across the country, sometimes even the world. It used to involve a single investigator. Now it involves hundreds of investigators. It used to be a small cohort of subjects. Now it's thousands. Most funding came from government offices. Now a lot of it comes from commercial sponsors. A lot of it used to be done at teaching hospitals. Now it's done at clinics, doctors offices and in other settings. There's been a rise of patient consumerism and demands for access to investigational procedures, drugs and devices, and new types of research have emerged. In 1978 there were about 500 institutions with Institutional Review Boards. Now there is somewhere between 3,000 and 5,000 of them. They used to review an average of 43 proposals a year. Now it's up to about 300. Adverse event reports are flooding their offices, in some cases being stored in boxes on the floor without being reviewed. In one case we found a couple of hundred of these reports coming in per month at one of the Institutional Review Boards. With such a change in circumstances, the Institutional Review Boards were not able to keep up. They had insufficient resources. They have been unable to stay on top of the research that's being performed so that while they might give a review of the proposals before the research starts, they can seldom look beyond that. We found insufficient training, little evaluation and oversight, and we made corresponding recommendations which have already been cited in the opening statements. Recently the Department has attempted to deal with these problems and has taken a number of steps which Mr. Raub will summarize for you. I particularly want to point out the stepped up enforcement that NIH has been doing. Recently 10 onsite visits were made and seven institutions had their research suspended. I think the sentinel effect of these efforts has been very strong and has sent a wave through the research community indicating that improper practices will not be tolerated. But fundamental vulnerabilities remain and we're reminded too often of the consequences of this. I know that Departmental officials are engaged in attempting to address these vulnerabilities and our own work is continuing, but I would like to add to my statement here a note that the solutions don't depend entirely on the Department. The companies which sponsor research, the investigators, the universities and medical centers, their Institutional Review Boards--they're all involved and they're responsible too. Their talent, energy, creativity and dedication is what fueled the boom in research that overwhelmed the human subject protection system. These same forces now need to be directed to bring it back into balance. [The prepared statement of Mr. Grob follows:] [GRAPHIC] [TIFF OMITTED] T0580.004 [GRAPHIC] [TIFF OMITTED] T0580.005 [GRAPHIC] [TIFF OMITTED] T0580.006 [GRAPHIC] [TIFF OMITTED] T0580.007 [GRAPHIC] [TIFF OMITTED] T0580.008 [GRAPHIC] [TIFF OMITTED] T0580.009 [GRAPHIC] [TIFF OMITTED] T0580.010 [GRAPHIC] [TIFF OMITTED] T0580.011 [GRAPHIC] [TIFF OMITTED] T0580.012 [GRAPHIC] [TIFF OMITTED] T0580.013 [GRAPHIC] [TIFF OMITTED] T0580.014 [GRAPHIC] [TIFF OMITTED] T0580.015 [GRAPHIC] [TIFF OMITTED] T0580.016 [GRAPHIC] [TIFF OMITTED] T0580.017 [GRAPHIC] [TIFF OMITTED] T0580.018 [GRAPHIC] [TIFF OMITTED] T0580.019 [GRAPHIC] [TIFF OMITTED] T0580.020 [GRAPHIC] [TIFF OMITTED] T0580.021 [GRAPHIC] [TIFF OMITTED] T0580.022 [GRAPHIC] [TIFF OMITTED] T0580.023 Mr. Mica. Thank you. Does that conclude your opening statement? Mr. Grob. Yes, thank you. Mr. Mica. Let me now recognize, if I may, Dr. William Raub, who's the Deputy Assistant Secretary for Science Policy, the Office of the Secretary of Health and Human Services. You're recognized, sir. Welcome. Dr. Raub. Good afternoon, Mr. Chairman and members of the subcommittee. I am William Raub, Deputy Assistant Secretary for Science Policy at the Department of Health and Human Services. I am accompanied today by Gary Ellis, Director of the NIH Office for the Protection of Research Risks, and Daniel Michels, Director of Enforcement at the Food and Drug Administration. Thank you for this opportunity to testify regarding the protection of human research subjects. For more than 50 years HHS and its predecessors have led the Nation and the world in protecting human research subjects from unnecessary risks. Our approach is rooted in the Nuremberg Code, whose principles have been adopted, reinforced and built upon in a succession of policies culminating in the current Federal regulations governing research with human subjects. HHS led the way in developing the core of these regulations, the so-called Common Rule, which has been promulgated by 17 different departments and independent agencies. In addition, FDA has carefully tailored its regulations for the product oriented clinical research it oversees so that they harmonize with the Common Rule. The primary foci for implementing these regulations are the Institutional Review Boards [IRBs]. They are responsible for reviewing proposed research protocols and associated informed consent statements before subjects are recruited and clinical research begins. No covered project may commence without IRB approval. Further, IRBs are responsible for continuing review, that is, oversight of approved research projects throughout their life cycle. If in the course of continuing review the responsible IRB were to find cause for concern regarding the safety of research subjects, the IRB could halt the project temporarily or permanently or otherwise require the investigators to take whatever protective or corrective actions it deems appropriate. Two types of IRBs exist: IRBs operated by research institutions such as academic health centers and IRBs that operate as private entities. Two HHS components share responsibilities for overseeing IRBs, the OPRR and the FDA. OPRR oversees IRBs operated by HHS awardee institutions. FDA oversees IRBs that review clinical research related to the products it regulates, irrespective of whether that research is ongoing at HHS awardee institutions or other sites. HHS is very concerned that the effectiveness of IRBs is in jeopardy. Although the Inspector General's investigation did not reveal either significant instances of actual harm to research subjects or evidence of any widespread pattern of outright IRB failure, we must not let that be cause for complacency. Many IRBs face unacceptably large workloads with too little time and too few resources to do their job properly. The fact that instances of actual harm to research subjects have been few and far between is a credit to the extraordinary dedication and prudent decisionmaking of IRB members and the commitment of investigators to the integrity of their work. In the wake of the June 1998 reports by the Inspector General, OPRR and FDA stepped up the pace of their inspections. Taken together, their findings reinforce the conclusion that the IRB system is under considerable strain. Moreover, for several institutions the OPRR and FDA inspections led to partial or complete suspension of clinical research at those sites until the institution's deficiencies were corrected, often only after major revamping of the IRB structure and commitment of substantial additional resources by the research institutions. These examples make clear that we must intensify our work to strengthen human subjects' protection before more-- and more serious--failures ensue. An imminent organizational change within HHS will do much to facilitate our intensified efforts. Last year acting on the results of the study commissioned by the Director of the National Institutes of Health, Secretary Shalala determined that the human subjects component of the OPRR should be elevated to the Office of Public Health and Science within the Office of the Secretary. Further, the Secretary directed the Assistant Secretary for Health to carry out a national search to fill the position and to assess the resource requirements for the new office--to be called the Office of Human Research Protection. Further, she authorized the creation of a public advisory committee to help guide the new office specifically and the Department overall. We agree with the Inspector General that the creation of the Office of Human Research Protection and its associated advisory committee presents, ``a new opportunity to exert Federal leadership in protecting human research subjects.'' At the same time we urge research institutions to strengthen their local efforts to protect human research subjects in accord with the Inspector General's recommendations. In particular, we urge research institutions to give their IRBs the standing and resources they need to do their job, especially during the continuing review phase. Human subjects protection is a shared responsibility among the Federal Government, research institutions, IRBs, investigators, and sponsors. HHS is committed to doing its part, and we will continue to expect others to do theirs. My full statement describes a series of actions by HHS agencies in recent years to enhance protection of human research subjects. We view these steps as a strong beginning but concur with the Inspector General that much more remains to be done. With your permission, Mr. Chairman, I will submit my full statement for the record. Mr. Mica. Without objection so ordered. Dr. Raub. On behalf of Secretary Shalala and my senior HHS colleagues, I assure the subcommittee that HHS is firmly committed to protecting human research subjects and to working actively with the research community to achieve that end. We believe that the Inspector General has provided a timely wake up call for everyone involved. Thank you, Mr. Chairman. [The prepared statement of Mr. Raub follows:] [GRAPHIC] [TIFF OMITTED] T0580.024 [GRAPHIC] [TIFF OMITTED] T0580.025 [GRAPHIC] [TIFF OMITTED] T0580.026 [GRAPHIC] [TIFF OMITTED] T0580.027 [GRAPHIC] [TIFF OMITTED] T0580.028 [GRAPHIC] [TIFF OMITTED] T0580.029 [GRAPHIC] [TIFF OMITTED] T0580.030 [GRAPHIC] [TIFF OMITTED] T0580.031 [GRAPHIC] [TIFF OMITTED] T0580.032 [GRAPHIC] [TIFF OMITTED] T0580.033 [GRAPHIC] [TIFF OMITTED] T0580.034 [GRAPHIC] [TIFF OMITTED] T0580.035 [GRAPHIC] [TIFF OMITTED] T0580.036 [GRAPHIC] [TIFF OMITTED] T0580.037 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:] [GRAPHIC] [TIFF OMITTED] T0580.038 Mr. Mica. And I believe we just had those two witnesses who had statements at this time, is that correct, and the others are available for answering questions. We'll start with some questions that I have and I'm going to address these first to Mr. Grob, Deputy Inspector General for Evaluation and Inspection. I guess sort of a basic question to start out with is, what do you consider to be the reasons for HHS' failure to implement that 1998 recommendation? Mr. Grob. I think Mr. Raub could probably address it better than I can, but I'm willing to speculate. Mr. Mica. You did a review here. Maybe you could tell the subcommittee what the basic problems are, one, two, three. Mr. Grob. I think the basic problems are that the Institutional Review Boards are simply overwhelmed, and they're not able to carry out their responsibilities, particularly the oversight of research that is ongoing. I think once the research starts they don't have the ability to stay on top of it, and I think that the problems occur at that level. Mr. Mica. We heard a description of this human research, and some of these activities started off in a fairly isolated context and numbers of universities or whoever was doing it. It's exploded. It sounds like it's difficult for the Department to get its hands around it, and then we have several agencies involved here. But we have the element of responsibility to the public. It may be jumping the gun a little bit, but maybe we should look at restructuring this whole thing or some other procedure to again keep up with the sheer volume that you described. Do you have an opinion about that? Mr. Grob. I think it's time to think in those terms. I don't know that marginal changes around the edges will really be able to do it. I think the fundamental structure was a good idea and it worked when it started and it worked for a while, but I just think the research took off. It became far more complicated, and in a way it's almost as if the IRBs figuratively were still using manual typewriters trying to keep up with the power notebooks of the researchers. It's just something--it's a different world today, and I don't think that system has kept pace with the world. So I think it's a fair thing to say that we might need to look at different structures. Mr. Mica. Complete reorganization of the approach. Now what about HHS, is this a priority on their scale? The other thing, too, is that Congress has also raised questions about what's going on in the oversight as we view government agency responsibility. It appears that there's been minor action and a lot of inaction. I believe, too, we had testimony that many things could be done without a lot of cost, some improvements without a great deal of costs. Maybe you could tell me first, does this appear to be a priority? Has it gotten their attention? And then, why haven't they instituted some things that were basic that could be done without a great deal of cost? Mr. Grob. It's my feeling right now that certainly there is an intense effort being made in the Department to address these things, the problems that have been raised. I think the publicity of the troubling cases and just the general desire to do it right, the congressional hearings, the interest of the scientists in the Department are all there. It's coming to a head. I think the interest is there now and I do expect to see some substantial changes coming down the pike. As far as things that could be done fairly quickly, I think training and education could be done pretty well and fairly quickly. The National Institutes for Health, for example, on their own have developed training which they require their researchers to follow. They have put it up on the Web. They have got some training courses that they have made available. What's lacking is a requirement for the training and requirement for any particular standards of training, but the resources seem to be there. If they require all of their researchers, as they do, for example, to take the course that's on the Web, it seems to me that all of the grantees could take that course on the Web as well and could avail themselves of the resources. So I think that education and training of the researchers and the board members could be done pretty fast if there were a requirement to do it. Mr. Mica. Well in 1998 you came out with a list of specific recommendations for improvement. Has HHS developed a schedule or timeframe or worked to give you any implementation schedule? Mr. Grob. I haven't seen a time schedule like that, that went recommendation by recommendation with a time schedule. Mr. Mica. Let me just ask a quick question now. Of course, every agency comes to Members of Congress now and says just give us more resources and we can handle the job. But we had recommendations that had been made that folks testified to that could be implemented with fairly low cost and things that could be done to improve oversight, operation and function. I have two questions then for Dr. Raub. One, what's the status of those low cost things that could be done within budget? And then second, I guess you have already submitted your 2001 budget. What kinds of requests for additional resources or personnel were included in the Secretary's request? Dr. Raub. Thank you, Mr. Chairman. With respect to the overall question, we've taken the recommendations of the Inspector General to heart and have in fact undertaken some substantial efforts over the last several years and will continue to do so. As I indicated in my prepared statement, we think they're, while substantial, that nowhere near enough; and we will continue to intensify that effort. Among the things we have done within the available resources are the following. I indicated the stepped up investigations and inspections, both by the OPRR and the FDA. Mr. Mica. Is that what was referred to from 1 to 10? Mr. Grob. It's a lot more than that. My opening statement was of course in the 5-minutes, but there have been increases in the number of non-onsite reviews that the NIH has made, and the FDA has made about a 50 percent increase in the number of site visits that it makes. Mr. Mica. Is that adequate? Mr. Grob. No. We need more. Mr. Mica. So those are some things you started. I'm sorry, Dr. Raub, continue. Dr. Raub. And along that line, just continuing Mr. Grob's thought there, while the returns on those investigations have been disappointing in the sense of identifying some widespread pattern of problems and have led to enforcement actions, those enforcement actions have a secondary effect in the sense of promoting compliance elsewhere--indicated by the Inspector General as a sentinel effect. So we believe that the expenditure of those funds dealing with individual problems has in fact had a positive effect in terms of making the larger community sensitive to the need for more attention and more investment of resources in these activities. Mr. Mica. Now, enforcement. When we had the hearing last time, there was one instance of a suspension reported, one or two. Since that time, what's the status? Usually enforcement would indicate that there's some penalty or there's some suspension of funds taking place. What's taken place in that regard? Dr. Raub. I'll comment generally, and, if I might, ask Dr. Ellis and Mr. Michels if they want to add some details to it; but in essence the thrust of the suspensions is not only to stop the activity and put an immediate protection in place but, more important, to require certain remedial actions on the part of the institutions to ensure that the problems are solved and the protections are in place. And that's been a pattern on these various ones. Mr. Mica. My question dealt with has there been any suspension of funds since the last hearing or penalty actions? Remedial actions are fine, but I want to know, if somebody gets some penalty, then does it have an effect down the line on others to sort of straighten up their act? Dr. Raub. Let me ask my colleagues to address that. Mr. Mica. Identify yourself for the record, please. Mr. Ellis. My name is Gary Ellis, Director of the Office of Protection from Research Risks, and chairman of the Interagency Human Subjects Committee. For research that is funded by the Department of Health and Human Services the ultimate penalty is a cessation of funding. Mr. Mica. Has there been any since the last time? Now what we've discovered there are more problems than we anticipate and the Inspector General talked about finding a pattern of problems far in excess of what I think we even expected. Then we heard that we were taking some enforcement actions that were part of the corrective pattern. My question is, what type of enforcement actions? Mr. Ellis. Well, since the June 1998 hearing and the Inspector General's report, OPRR has evaluated the protection of human subjects at a couple dozen institutions. There have probably been about 10 site visits during that period, and in virtually every case we've made findings of shortcomings with regard to human subject regulations and required remedial action. In a few noteworthy cases at the Duke University Medical Center in May 1999 and just a small number of other institutions, we have actually ordered an interruption in research. Virginia Commonwealth University in January 2000 as with Duke, we ordered an interruption in research. These are extreme cases and an extreme action was taken, the interruption of research. Mr. Mica. In two cases? Mr. Ellis. There were other cases where we imposed restrictions but we didn't have the suspension that you note. The Food and Drug Administration took an action---- Mr. Mica. Was it the suspension of the program or suspension of funding or both? Mr. Ellis. Suspension of the program. The Food and Drug Administration took action at the University of Colorado Health Sciences Center, and Dan might want to talk about that. Mr. Mica. Identify yourself for the record. Mr. Michels. Yes, sir. I am Daniel Michels, Director of the Office of Enforcement at FDA. I think you've put your finger on an important issue from the standpoint that the action available to both our organizations is an extreme one; that is, the authority to shut down an operation in its entirety. The threat of that most frequently causes either a voluntary shutdown before we need to deal with that or else a great deal of willingness to do the right thing and get back on the right track. One of the things that we are exploring is the possibility of asking the Congress for intermediate remedies that might be less than throwing the atom bomb, if you will, to deal with these situations. Mr. Mica. You don't feel that you have the authority to do that? Mr. Michels. That is correct in this particular instance, and I want to reinforce and I think Representative Kucinich made the point very eloquently, is too often the IRBs are underfunded. The willingness to do the right thing is there, but they do not have the resources and support to do it, and our taking enforcement action will result hopefully in that kind of funding somewhere downstream, but we would much rather see education happen first, do the right job the first time in a well-funded situation. Mr. Mica. Mr. Cummings, I have additional questions. Did you want me to yield to you at this time and come back, do a second round? Is that OK? Or do you want me to proceed? Mr. Cummings. No. I just have a few. Mr. Mica. All right. I'll recognize Mr. Cummings, and I do have an additional round of questions. Mr. Cummings. I was just wondering, what kind of--following up on what the chairman asked about--what kind of sanctions would you like to see, I mean, would you like to have the authority to use? Mr. Michels. Unfortunately, the thinking is a little bit early on this. One of the things that we've thought about is civil money penalties, but again, fining an organization which is poor already doesn't seem to be a very good option. If we could find something more prescriptive, that is more targeted to the particular problems that an institution has rather than simply shutting down the whole engine, we would be possibly better off than we are now, but that's the best I can do for you at the moment, Congressman. Mr. Cummings. Why would an organization when threatened with a shutdown voluntarily shut down as oppose to say straightening up the matter? I mean I know you said sometimes they do, but sometimes they just go on and shut down. I mean what kind of situations would cause that? Mr. Michels. Well, the recognition that something major needs to happen and rather than having the terms dictated, if you will, by the regulatory agency, they see the light and say OK, before that letter of shutdown is received, here's our plan, this is what we're going to do. In the meantime we are going to suspend some or all of our operation as a signal of good faith. As a regulator, I wouldn't be necessarily too thrilled to see somebody make some offers without doing something immediate and protecting those folks that are at risk. Mr. Cummings. Mr. Ellis, in 1998 I think you told the subcommittee that your office was pursuing about 70 open investigations. Mr. Ellis. That's correct, sir. Mr. Cummings. How many of those cases have been closed? Mr. Ellis. That's something I'll have to get back to you on. A large number remain open. Today we actually have 163 open investigations. Mr. Cummings. So in 2 years the number of open investigations have more than doubled. Mr. Ellis. That's correct. Some of the 70 to which you refer have closed, but many more have opened since that date. Mr. Cummings. Why do you think that is? I mean, that's a lot of cases. I mean, when you look at 70, some have been closed and now you're up to 163. Why is that? Mr. Ellis. We are receiving more complaints. The issue of protecting human subjects in research has been featured in the press. Our complaints come from citizens, they come from research institutions themselves, from employees at research institutions that see things they don't like. In some cases from human subjects who feel they have been harmed or wronged in some way. Our office was not all that prominent, perhaps hard to find, and now it's easier to find for complainants. That's my best explanation. Mr. Cummings. How many employees do you have doing the investigations on human and animal subject research? Mr. Ellis. Our office was originally split so the animal welfare staff are now in a different office, but with regard to human subject investigations we have two full time equivalent investigators. Actually a full time physician, a half time physician and a half time attorney handle 163 cases. Mr. Cummings. And how many do you think you need to do an adequate job? Mr. Ellis. One could work through the arithmetic of what a serious caseload would be for a high level professional. The Public Health Service Act requires a prompt, that's a quote, a prompt resolution of the cases. We could work out the arithmetic if we took prompt to mean 6 months, let's say, how many cases an individual can move and get 6-month closure. It's something I could calculate for you. Mr. Cummings. That's OK. Is there a statutory requirement to report adverse events to your office? Mr. Ellis. There's a regulatory requirement that pertains to research funded or conducted by any of the 17 departments and agencies that have been in place for years, the institutions must report unanticipated problems involving risks to subjects or others. That is one kind of report. The second kind of report is any suspension or termination of Institutional Review Board approval. And the third kind of report is any serious deviation or noncompliance with the regulation. The answer is yes. Mr. Cummings. Those reports that you just talked about, how many have you received over the last year? Mr. Ellis. In 1999 we received 187 reports of that type from I think about 87 institutions. Mr. Cummings. Mr. Raub, back in December Dr. Art Lawrence testified before us in a hearing we held in New York, and at that time Dr. Lawrence assured us that the Office of Protection from Research Risks would be moved to the Office of the Secretary and a new director would be selected by March 2000. It's now May and can you tell us where we are on that? Dr. Raub. Yes, sir. The Department is close to completing those actions, but it has taken somewhat longer than the original estimates. I'm hopeful, as is Assistant Secretary Satcher, that the appointment of a director for the new Office of Human Research Protections is imminent. We hope in the next few weeks at the least for the announcement of that appointment, and with that then the formalization of the move of the office from NIH to the Office of the Secretary and the establishment of the new advisory committee. Mr. Cummings. Well, while in New York Dr. Lawrence also testified, and he even introduced a letter from Dr. Satcher which said that the advisory panel would be created which would be responsible for human subject research protection. Is that the advisory panel you were just talking about? Dr. Raub. Yes, it is. Mr. Cummings. And how do you see that as helping this problem, I mean the appointment of that panel? Dr. Raub. Well, first of all, we see the relocation of the office as giving it the higher visibility in terms of the Office of the Secretary and an underscoring of the Secretary's commitment to this. Second, as part of the move, the Secretary directed Assistant Secretary Satcher to commission a study of resources along the lines of the question that you were just addressing to Mr. Ellis; and that study, as I understand it, is either complete or near so. It will be an important factor in the future budgeting decisions for this office. The advisory committee is intended to ensure that we have a public, high level and highly qualified group of individuals drawn broadly from the research community and the interested general public who can provide a continuing forum of advice and criticism for the Department as we move to set priorities and do what we can to ensure that these human subjects protections are in place. We have not had that kind of forum before in the Department, and we think it's much needed, and I'm optimistic as to what it will be able to provide for us. Mr. Cummings. Right now, do you have to go--is part of the processes that you use the Federal Register? Dr. Raub. For what, sir? Mr. Cummings. For the advisory panel. Dr. Raub. The advisory panel will be created under the terms of the Federal Advisory Committee Act, and those actions have been taken in terms of securing the necessary slot and authorization to do it. Most likely what we will do is announce in the Federal Register the functions and other expectations for the committee, and as we do with many other advisory groups, invite nominations of members from interested members of the public, and then put together a recommended slate or alternative slates for consideration by Dr. Satcher and the Secretary. Mr. Cummings. Thank you. Mr. Mica. Thank you, Mr. Cummings. I didn't get the answer when I yielded to Mr. Cummings about the second part of my question. What was the number of personnel requested in 2000 to 2001. Again, we've identified that there's a problem. Some of the answer is more personnel, more resources. Can you tell me requests for additional slots? Dr. Raub. Sir, I don't have those figures with me. Mr. Mica. Does anybody have them? Dr. Raub. I'll be pleased to provide them for the record. Mr. Mica. Mr. Ellis, do you? You said you could calculate, but this isn't something that just snuck up on us today. It's a problem we've known about, and one of the ways that we resolve it is by applying the necessary resources, putting the requests through the process, and nobody knows what we have requested? Maybe somebody could slip somebody a paper with a magic number on it. No? And you don't have a recommendation to the subcommittee about what kind of resources it would take? Dr. Raub. Again, I don't have the budget figures with me. I'd be glad to provide them for the record, sir. Mr. Mica. Mr. Grob, the situation seems to be mushrooming out of control, both the sheer number of Federal dollars involved in this human experimentation and then this large universe outside of commercial activity. I think you spoke to some of that. What are we looking at as far as percentages in each of these areas of experimentation, federally funded and nonfederally funded? Would you care to venture a guess, Mr. Grob? Mr. Grob. I don't know about the exact number. Certainly we're talking about billions of dollars in both cases. An easy way to think of it is most of the commercially funded research that we're talking about here would be research that's connected with the proposed drugs and medical devices that are overseen by the Food and Drug Administration. So their entire workload of oversight would be commercially funded, whereas the National Institutes of Health would be those that are funded by our Department. Now of course there's these other Federal departments that also fund on the Federal level their research. So I'd say it's billions and billions, but which--you know, what the exact amounts are I can't tell you. Mr. Yessian. My name is Mark Yessian. I am the regional Inspector General. At some of the major medical centers that we visited and talked to, about half the applications that the IRBs are getting are coming from commercial sponsors these days so that helps put it in a little perspective. Mr. Mica. Another question that was raised at the last hearing, which continues to be a concern, is the problem with commercial activities and other interests in this whole operation, the conflict of interest. I think there was a recent Los Angeles Times article that alleged the U.S. Government's top diabetes researcher helped guide a $150 million Federal study involving Rezulin while serving as a paid consultant for the drug manufacturer, which was Warner Lambert Co. What's the Federal Government's policy regarding outside employment and conflicts of interest, Mr. Raub? Dr. Raub. Sir, there are several elements to that. First off, the changes in the nature and the patterns of financial relationships are one of those changing elements that Mr. Grob and his colleagues had mentioned. It's quite a different situation than, say, 20 years ago. A major impetus for that has been some statutory changes designed to promote the commercialization of publicly funded research. And, for the many highly desirable results of that, it has created a pattern of relationships where not only do some of the universities' and academic health centers, for example, receive a substantial amount of funding from the private sector--some on the order of half, as Mr. Yessian indicates--we also have instances where some of the university professors also have either stock holdings or even serve as corporate officials for some of the private organizations, some of which may be sponsoring the research. A major element already in place related to that is a public health service regulation that requires all of the entities funded by the agencies of the Public Health Service, that is the universities and other recipients of awards, to have in place a policy and a system to identify actual or apparent conflicts of interests that might affect the scientists' participation and to take such steps as are necessary to manage those conflicts--in some instances removing the conflict, in others putting certain safeguards in place. One of the areas where we will be intensifying our effort is trying to find ways to ensure that, as those procedures relate to human subject protections, some of the kinds of safeguards we have in place will be those against the potential coercion of subjects in research as well as guarding against things that would create less than full objectivity in the way experiments are designed, patients are recruited, or results are presented. This will be a continuing challenge for the entire research community. Mr. Mica. Is it necessary for additional legislation, corrective legislation to deal with the new set of emerging conflicts and circumstances? Dr. Raub. In my judgment, sir, no. The Public Health Service regulation to which I referred and, a companion regulation that the Food and Drug Administration has dealing with reporting of financial conflicts of interests, gives a considerable set of tools to use here. I believe the task will be building on those tools and using them most effectively. I am sure the Department won't hesitate to propose legislation if it concludes that's necessary, but we don't think so now. Mr. Mica. I don't want to pick anybody out, but in this case I just cited, this individual who served as a paid consultant to the drug manufacturer was I believe a Dr. Eastman, who had this employment as a consultant, and it appears to be a conflict of interest. Do you know if you all investigated this particular arrangement to see if there was a conflict of interest? Dr. Raub. I don't know the full details, sir. I know that an investigation was carried out at the NIH. I don't know that it's completed. We can provide a report for that to the subcommittee. Mr. Mica. Well, I'd like to know because if you feel that we don't need additional laws then you have at least the authority to proceed, and we want to make certain that there is some attention to the problem of conflict of interest that has been raised to us. I have other cases here and I won't be able to get into all of them. We could submit some of them for questions to you, but it appears that some of the problems we've had--now conflict of interest is one thing. Maybe we picked that up through the media. I think you all have testified that you're picking up problems that have resulted sometimes in death in these experimentation cases where there hasn't been, I think we're going to have witnesses about the full disclosure, prior disclosure about oversight, about the proper functioning of the review process, which is a big concern to us. We have an agency, and maybe it is short on some resources, but in fact we are told that it's somewhat dysfunctional and even no cost or low cost recommendations have not been instituted. So I have to cite these as major concerns of the committee. And then we have another area now, this growing area of a commercial activity that doesn't fit. We don't have the handle because we don't have the Federal funds into the activity, and FDA has some responsibility, but there are some instances here in which there appear to be a gap, which is another problem. Did you want to comment on that briefly, Mr. Grob? Mr. Grob. We don't know the extent of that, but that's probably small but growing, where there is research that's going on that's not connected with any proposal for a Federal approval of a drug or device and they're not the result of a Federal grant. In those cases there are no requirements for Institutional Review Boards or for some of these other protections. Just simply good practice would call for it, but the extent to which it's happening and the type of controls over that is just sort of an area that's not well-known or understood at this time. Mr. Mica. And what's interesting, too, is there are so many new research techniques in biogenetics, I mean, I just can go on and on about things that are happening almost on a daily basis that the law is not keeping up with. I am wondering if we really need to take a closer look at this, some of these gaps and again have in place some mechanism to deal with this in the future. Mr. Michels. Mr. Michels. Yes, sir. Thank you, Mr. Chairman. I just wanted to clarify that the Food and Drug Administration is working in the area of, if you will, noncommercial research from the standpoint that there are requirements from time to time that, notwithstanding the intent to market the product, if it is being used as an experimental agent on people it should be covered by an investigational application. I think what is maybe troublesome to some folks is the zone in between where an investigator, a clinical investigator may also be the entrepreneur who is intending to ultimately develop the product him or herself rather than working as an employee or agent for a major pharmaceutical house, for example. The roles have become very blurred here, and we also are puzzling over where we need to be drawing the lines. I would suggest again we go back to the principle that was laid out very early in your hearing today, and that is we need to be educating all of the scientists, be they clinical investigators, the researchers, the IRBs, as to what the requirements are, minimize their impact so that the right decisions are made on behalf of the subjects being exposed. Mr. Mica. Thank you. I'm not going to give you an opportunity to respond because we have a vote. I have less than 4 minutes to get to the floor. I am going to excuse the panel. We're going to submit some questions. I have some specific questions on cases, Mr. Ellis, but I'll tell you, Mr. Raub, that we've got to do something to get into place some of these recommendations. Mr. Cummings described some of the foot dragging and some of the things in simple appointments, getting people in place, making low cost or no cost recommendations, getting us to recommendations. We have got to do something. If necessary I'll hold another hearing and call everybody back, and we'll subpoena the Secretary if we have to to get something moving in this area. But I just give you that. Without objection, we will submit to you further questions and ask for your written response. We'll stand in recess for approximately 15 minutes, until the conclusion of the next vote. [Recess.] Mr. Mica. I'd like to call the subcommittee back to order. I want to go ahead and proceed. We have our second panel before us at this point. Unfortunately, there may be a vote in the full committee. There's been a full committee hearing going on while we're conducting this subcommittee hearing. We may need to recess at some point if a vote is called in that body. Our second panel consists of Mr. Richard Curtin, and he I believe was a human subject in one of these research experiments. We also have Charles R. McCarthy, and he is a senior research fellow at the Kennedy Institute of Ethics at Georgetown University, and then we also have Dr. Robert Amdur, and Dr. Amdur is the associate professor and associate chair of clinical affairs at the Department of Radiology and Oncology at the University of Florida. Good to see someone from my alma mater here. If we could just get a President now we'd be in good shape. That's an inside matter. I'd like to welcome all three of our panelists this afternoon. Let me go ahead and explain the ground rules. I think you're all new witnesses. We do swear in our witnesses. This is an investigations and oversight subcommittee of Congress. I'll swear you in in just a minute. I'm going to ask you to limit your oral testimony to 5 minutes. Upon request, we'll put in any full statements or additional information in the record deemed appropriate, upon request through the Chair. With that, I will swear you in, if you'd stand, please. [Witnesses sworn.] Mr. Mica. Witnesses answered in the affirmative. I welcome the witnesses. I think we'll call on Richard Curtin, who was involved in one of these research projects. He's from Falls Church, VA. Welcome, sir, and you're recognized. STATEMENTS OF RICHARD CURTIN, HUMAN SUBJECT, FALLS CHURCH, VA; CHARLES R. McCARTHY, SENIOR RESEARCH FELLOW, KENNEDY INSTITUTE OF ETHICS, GEORGETOWN UNIVERSITY; AND ROBERT AMDUR, M.D., ASSOCIATE PROFESSOR, ASSOCIATE CHAIR, CLINICAL AFFAIRS, DEPARTMENT OF RADIOLOGY AND ONCOLOGY, UNIVERSITY OF FLORIDA Mr. Curtin. I'd like to thank the subcommittee for inviting me to appear today, but I have to admit I'm surprised to find myself in the position of being so critical---- Mr. Mica. You might pull that mic a little bit closer if you could. Maybe you can do that with your book there. Mr. Curtin. I'm surprised to find myself being in a position where I'm being so critical of genetic research. I have a Master's Degree in human genetics, and 25 years ago I was working with the Director of NIH in an effort to convince the Congress to go ahead with funding for cutting edge recombinant DNA research. But in September 1998 I was introduced to a different aspect of genetics research when my daughter Allison received the Virginia Twin Study sponsored by Virginia Commonwealth University. The study consisted of a 25-page questionnaire asking hundreds of questions about a person's medical history. When I looked through the questionnaire I was surprised to find that 176 of these questions involved not only my daughter's medical history but also the medical histories of her mother, her brother and me. In other words, she was being asked to comment upon the medical history for the entire family. I was further shocked by the bizarre nature of some of these questions. For example, the study asked if any of us had suffered from depression, infertility, alcoholism, or schizophrenia. It asked if Allison's brother or I had abnormal genitalia, sperm abnormalities or low sperm count, and it asked if Allison's mother had any diseases of the genital tract or if her menstrual periods were unusually long or strong. Nowhere in the study packet were the words ``informed consent'' ever mentioned, and this package was addressed strictly to my daughter. I was outraged that a federally funded project would attempt to violate my family's privacy in this manner. I immediately wrote to the principal investigator of the study and also to the chairman of the Institutional Review Board. All I asked them to do was to remove the columns for the other family members and to send separate questionnaires to each of us. I realized that this would have cost them more and it might have cut down on the response rate, but the data base would have been more accurate, and it also would have avoided the problem with informed consent. The chairman of the Institutional Review Board just didn't bother to respond at all. The principal investigator, responded but her response was so demeaning and so arrogant that it probably would have been better if she hadn't responded either. It became very clear to me that the concerns I raised were not going to be addressed to my satisfaction by the people at Virginia Commonwealth University. So I filed a complain with OPRR. OPRR concluded that the internal controls for the protection of research subjects at the university were so inadequate that all federally funded research had to be shut down until proper controls could be put into place. The sum total of this action was 1,100 research projects suspended. With the chairman's permission, I'd like to enter into the record a summary list that I've prepared listing 19 deficiencies that OPRR listed from its investigation at Virginia Commonwealth University. Mr. Mica. Without objection, that will be made part of the record. Proceed. Mr. Curtin. Thank you. Rather than addressing the legitimacy of the deficiencies found at Virginia Commonwealth, the leadership of the genetics research community decided to take a different approach. They went on the attack. They went after OPRR. I'm especially offended by the positions taken by two of their main leaders, Dr. Edward McCabe, chairman of the Secretary's Advisory Committee on Genetic Testing, and Dr. Francis Collins, Director of the National Human Genome Research Institute at NIH. These gentlemen have argued in writing that, even within a family, once a piece of medical information becomes known to one other person within that family there is no longer any expectation of privacy and there is no need for any researcher to bother getting the informed consent of the family members. A little anecdote, also about this time, my daughter was home for Christmas vacation and asked if I would call the University of Virginia registrar to find out one of her grades. So I made the phone call and explained to the registrar's office that I was her father, but they would not release her grade to me because it was a violation of her privacy. Despite the fact that she was my dependent and I was paying the tuition, they wouldn't tell me her grade. But the people at the Virginia Twin Study fully expected her to go around and tell the most intimate nature of the medical histories of not only herself, which I wouldn't mind her doing, but also of every other member of her family. I've been involved with this issue now for 20 months and I've reached five basic conclusions. One, the public cannot rely upon individual researchers to adhere to the rules and regulations that go along with the acceptance of Federal funding. When a research protocol does not go as planned, the initial reaction of the researcher seems to be to cover it up. No. 2, the public cannot rely upon Institutional Review Boards to ensure that guidelines are followed and that experiments are scientifically and ethically sound. Basically, I don't believe that colleagues at the same institution can be trusted to critically review and police each other's work. If I criticize your work today, what's going to happen when I come in front of the IRB tomorrow? Three, the staffing and funding levels at the Office of Protection from Research Risks have been designed to ensure that OPRR will not be too effective. Other speakers have mentioned this, and it's very, very clear to me that OPRR has been treated as a proverbial stepchild within the NIH family. Four, the research community, in my opinion, is in a state of denial regarding the trouble that it's in. They have allowed a regulatory vacuum to exist and a trust gap to develop, and now others are rushing in to fill this vacuum and to close this gap. The community strategy of stonewalling, covering up and attacking will not, I don't believe, be successful in the long run. Five, potential solutions. It's obvious that OPRR needs to be upgraded, but you also have to be realistic about how much a centralized office here in Washington can do when the research is so decentralized. In my opinion, therefore, the quickest, least expensive and possibly most effective course of action is for each researcher to realize that violations of guidelines and regulations will have very serious consequences. If the probability of getting caught is going to be low, then the consequence of getting caught should be very severe. One of the members asked earlier what other penalties could we possibly have. I have a suggestion. I suggest that a principal investigator who fails to file a timely and accurate adverse event report might be suspended from the project for 1 year. Allow the project to continue so that the benefits of the research aren't lost, but let it continue under someone else's leadership. Mr. Mica. Excuse me, but I'm going to have to recess the hearing for just approximately 10 minutes. We do have a vote in the other committee. We'll continue when I return. [Recess.] Mr. Mica. I will call the subcommittee back to order. I apologize for the delay, but all members of the full committee were summoned. To get back here, let's see, we had Mr. Curtin who was interrupted as he had some closing remarks I believe. So if you would sum up your testimony, Mr. Curtin, you're recognized. Mr. Curtin. Yes, sir. Just finishing up, two possible penalties to suggest. One is, as I was mentioning before, suspension of the principal investigator while his project still goes on. A second possible penalty would be making that investigator unable to compete for future grants or contracts for a certain period of time. Those are two suggestions. I don't think it's that hard to find penalties that fit the problem. I want to thank you for the opportunity to express my concerns and my opinions, and I would like to submit a more lengthy statement for the record with the chairman's permission. [The prepared statement of Mr. Curtin follows:] [GRAPHIC] [TIFF OMITTED] T0580.039 [GRAPHIC] [TIFF OMITTED] T0580.040 [GRAPHIC] [TIFF OMITTED] T0580.041 [GRAPHIC] [TIFF OMITTED] T0580.042 [GRAPHIC] [TIFF OMITTED] T0580.043 [GRAPHIC] [TIFF OMITTED] T0580.044 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:] [GRAPHIC] [TIFF OMITTED] T0580.045 [GRAPHIC] [TIFF OMITTED] T0580.046 [GRAPHIC] [TIFF OMITTED] T0580.047 [GRAPHIC] [TIFF OMITTED] T0580.048 [GRAPHIC] [TIFF OMITTED] T0580.049 [GRAPHIC] [TIFF OMITTED] T0580.050 [GRAPHIC] [TIFF OMITTED] T0580.051 [GRAPHIC] [TIFF OMITTED] T0580.052 [GRAPHIC] [TIFF OMITTED] T0580.053 [GRAPHIC] [TIFF OMITTED] T0580.054 [GRAPHIC] [TIFF OMITTED] T0580.055 [GRAPHIC] [TIFF OMITTED] T0580.056 [GRAPHIC] [TIFF OMITTED] T0580.057 [GRAPHIC] [TIFF OMITTED] T0580.058 [GRAPHIC] [TIFF OMITTED] T0580.059 [GRAPHIC] [TIFF OMITTED] T0580.060 [GRAPHIC] [TIFF OMITTED] T0580.061 [GRAPHIC] [TIFF OMITTED] T0580.062 [GRAPHIC] [TIFF OMITTED] T0580.063 [GRAPHIC] [TIFF OMITTED] T0580.064 [GRAPHIC] [TIFF OMITTED] T0580.065 [GRAPHIC] [TIFF OMITTED] T0580.066 [GRAPHIC] [TIFF OMITTED] T0580.067 [GRAPHIC] [TIFF OMITTED] T0580.068 [GRAPHIC] [TIFF OMITTED] T0580.069 [GRAPHIC] [TIFF OMITTED] T0580.070 [GRAPHIC] [TIFF OMITTED] T0580.071 [GRAPHIC] [TIFF OMITTED] T0580.072 [GRAPHIC] [TIFF OMITTED] T0580.073 [GRAPHIC] [TIFF OMITTED] T0580.074 [GRAPHIC] [TIFF OMITTED] T0580.075 [GRAPHIC] [TIFF OMITTED] T0580.076 [GRAPHIC] [TIFF OMITTED] T0580.077 [GRAPHIC] [TIFF OMITTED] T0580.078 [GRAPHIC] [TIFF OMITTED] T0580.079 [GRAPHIC] [TIFF OMITTED] T0580.080 [GRAPHIC] [TIFF OMITTED] T0580.081 [GRAPHIC] [TIFF OMITTED] T0580.082 [GRAPHIC] [TIFF OMITTED] T0580.083 [GRAPHIC] [TIFF OMITTED] T0580.084 [GRAPHIC] [TIFF OMITTED] T0580.085 [GRAPHIC] [TIFF OMITTED] T0580.086 [GRAPHIC] [TIFF OMITTED] T0580.087 [GRAPHIC] [TIFF OMITTED] T0580.088 [GRAPHIC] [TIFF OMITTED] T0580.089 [GRAPHIC] [TIFF OMITTED] T0580.090 [GRAPHIC] [TIFF OMITTED] T0580.091 [GRAPHIC] [TIFF OMITTED] T0580.092 [GRAPHIC] [TIFF OMITTED] T0580.093 Mr. McCarthy. And I would like to modify even that a little. Since I submitted my testimony I have spent some time in the library and found references to a number of other sources that make recommendations identical to, or similar to the ones that I'm making today. So I will add those, if I may submit those as well. Mr. Mica. Without objection, and within in the time limits that have been announced. Go ahead. Mr. McCarthy. As has been noted earlier in the hearing, Institutional Review Boards were initiated by the Public Health Service in 1966. It's not so well-known that in the late 1960's, and I can't give you a specific year, the National Heart Institute, now National Heart, Lung and Blood Institute, at NIH created an additional kind of oversight body to look at large multi-centered trials, and to collect and analyze data, particularly adverse event data, in those trials. Data and Safety Monitoring Boards, while nowhere near as well-known as IRBs, are indeed almost as old and as honorable as the IRBs. During the seventies Dr. Robert Gordon, who was for a time the Director of the Clinical Center at NIH, and Dr. Curtis Meinert, from Johns Hopkins University, spent a great deal of time refining and defining the work of Data and Safety Monitoring Boards. As the funding patterns for NIH grants changed from grants that were made to a single investigator at a single institution to multi-centered trials where there might be anywhere from 5 to 50 or even 100 different centers, each with itw own investigation carrying out the same protocol. The Data and Safety Monitoring Board has become the instrument most sensitive to being able to receive and process adverse event data and other information about multi-centered trials from many sources; evaluate those data and other information with the help of professional statisticians and thus to get an overview of the trial that is literally impossible to get at any single center or any single institution. We are faced with something of an anomaly. The Data and Safety Monitoring Boards are not established by regulation and exist in less than half of the multi-centered trials that are conducted in this country. They are the bodies that have the best information and carry out the most careful analysis of the data. On the other hand, IRBs are the committees who, according to regulation, have the responsibility of determining whether trials should be stopped, modified or continued. Consequently the most complete knowledge is in one committee, and decisionmaking responsibility is in another committee. It seems to me that we can make a very constructive kind of change in the regulations so that the Data and Safety Monitoring Boards communicate their findings back to the IRBs. If that step is taken, it will, first take some work off the IRBs and begin to address the workload problem identified in the Inspector General's report, and second, it will improve the quality of the information on which the IRB makes its decision to continue, modify or discontinue research projects. All of the kinds of incidents you've addressed today in your hearing seem to me to indicate that now is the time to start afresh. Modify the regulations so that the data held by Data and Safety Monitoring Boards is made available to the IRBs, so that the best possible decisions concerning the continuation and oversight of trials can be made. Typically, as we heard testified earlier from the Inspector General, the IRBs receive adverse event data, but it is raw data. IRBs don't know which arm of the study the adverse event occurred on. They don't know whether it was in an elderly subject or a young subject. They don't know which adverse events result from complications of disease of the subject. They cannot tell whether the adverse event was caused by the research, by the underlying disease condition, or by some inherent condition that pertains to the subject himself or herself. Data and Safety Monitoring Boards display the data in a number of different ways: according to age; gender; race; ethnicity and a whole variety of other categories so that they can evaluate adverse events; tell which ones are very serious; which ones are likely to be associated with the research intervention; and which ones might have occurred anyway because of underlying disease conditions. DSMBs are able to give the kind of analysis that will refine the judgments about the safety of the research, and whether it should continue. So my recommendation to you and to the rest of the committee today is simply that one of the ways the Inspector General's report could be used or could be capitalized upon would be simply to adjust the regulations and by putting some kind of a regulatory link requiring Data and Safety Monitoring Boards under certain conditions and, second, making sure that the data that they gather and analyze is carefully and thoroughly shared with the IRBs so the IRBs then can--with less work and with greater accuracy--meet the responsibilities that are assigned to them. This will not, in my judgment, decrease costs because the Data and Safety Monitoring Boards have full- time statisticians working for them. They have costly experts. I participated in a Data and Safety Monitoring Board meeting yesterday. There was an expert from Germany, one from England, three from the United States and myself. Obviously to have a meeting of that kind is very costly. Statisticians generated--relative to on one study--about 300 pages of data. The DSMB spent the best part of the day evaluating that data to determine whether the study should go on. That's a very costly process, but I can assure you that the subjects in that study received the very best safety efforts that are humanly possible. No one can guarantee that mistakes will not be made, but I think when the data is processed in such a thorough way, the chances of a mistake become exceedingly small. That's what we owe to our research subjects. Even though oversight costs may be raised. On the other hand, the cost to the local IRBs will be reduced because their workload of analyzing large quantities of adverse data will already be done for them by statistical experts. They will be able to make much more enlightened decisions as to the research in their institution. I will be glad, Mr. Chairman, to answer any questions that you may have concerning this issue or any others. Mr. Mica. Thank you, and what we'll do is suspend questioning until we've heard from our final witness. He's also very patient. Dr. Robert Amdur, and he is the associate professor, associate chair of clinical affairs, Department of Radiology and Oncology at the University of Florida. Welcome, and you're recognized, sir. Dr. Amdur. Thank you. Good afternoon, Mr. Chairman, and other committee members. As you mentioned, my name is Robert Amdur. I am a physician at the University of Florida. My qualifications to speak to you today about the protection of human research subjects are that I am a medical researcher who frequently enrolls patients in research studies. For the past 10 years I have played a leadership role in defining and implementing ethical standards for research through my participation in the Institutional Review Board and related national organizations. I am here today representing a national nonprofit organization called PRIM&R, which stands for Public Responsibility in Medicine and Research. For over 25 years, the primary mission of PRIM&R has been to bring researchers, ethicists, and research regulators together to improve our system for protecting the rights and welfare of human research subjects. Since 1974, PRIM&R has sponsored over 100 educational conferences, published hundreds of documents, set up onsite workshops for institutions with special needs, and many other important activities that meaningfully improve the way research is done in this country. I have submitted a written statement which goes into detail about the challenges that currently stress our system of protecting human research subjects, and PRIM&R's plans for helping the research community respond to these challenges. At this time I would like to formally request that a written copy of my testimony be included for the Record. Mr. Mica. Without objection, so ordered. [The prepared statement of Dr. Amdur follows:] [GRAPHIC] [TIFF OMITTED] T0580.094 [GRAPHIC] [TIFF OMITTED] T0580.095 [GRAPHIC] [TIFF OMITTED] T0580.096 [GRAPHIC] [TIFF OMITTED] T0580.097 [GRAPHIC] [TIFF OMITTED] T0580.098 [GRAPHIC] [TIFF OMITTED] T0580.099 [GRAPHIC] [TIFF OMITTED] T0580.100 [GRAPHIC] [TIFF OMITTED] T0580.101 [GRAPHIC] [TIFF OMITTED] T0580.102 [GRAPHIC] [TIFF OMITTED] T0580.103 [GRAPHIC] [TIFF OMITTED] T0580.104 [GRAPHIC] [TIFF OMITTED] T0580.105 [GRAPHIC] [TIFF OMITTED] T0580.106 [GRAPHIC] [TIFF OMITTED] T0580.107 [GRAPHIC] [TIFF OMITTED] T0580.108 Dr. Amdur. In the next few minutes, I would like to emphasize three requests that I hope you will focus on as you decide on new Federal initiatives related to research protections. Request No. 1 is to pass Federal legislation that requires that all research in the United States comply with the same high level of ethical standards, regardless of funding source. The ethicality standards that should be met when conducting research on human subjects are described in the Department of Health and Human Services regulations that are often referred to as the Common Rule. A problem with our current situation is that the authority of the Common Rule does not extend to some situations where research is sponsored by private industry. It makes no sense to have different ethical standards for research depending on funding source. All Americans should be afforded the same high level of protection and oversight. Medical progress will not be compromised by a more comprehensive regulatory structure, and PRIM&R urges you to support legislation that eliminates the two-class system of research protection that we currently have in this country. Request No. 2 is to pass legislation that consolidates the multiple different sets of Federal research regulations that currently exist into a single regulatory reference. The Department of Health and Human Services currently has one set of regulations, the FDA has another, the Department of Education has its own rules, and so on. In many cases, the regulations from these different Federal agencies are congruent, but in other situations they are not. In still others it is unclear what they are. As a result, researchers, industrial sponsors, IRB members, institutional officials, spend a tremendous amount of time and energy trying to figure out what hoops to jump through when different Federal agencies are involved, as is the common situation in both industry-sponsored and federally funded research studies. The situation is ridiculous. There is no reason that we should not have a single set of regulations that applies to all research involving human subjects, regardless of the Federal agency that is involved or the funding source. Request No. 3 is to ask you to support PRIM&R's efforts to create a formal program for accrediting each institution's system for protecting human research subjects. Protecting human subjects requires much more than an accounting type of checklist or audit of IRB paperwork. It requires onsite evaluation by trained professionals of objective and subjective end points, such as the level of institutional support for the IRB, the knowledge of research investigators about ethical standards, the commitment of institutional officials to shielding research regulators from financial conflicts of interest and other pressures, and eventually, to documenting objective end points of ethical behavior, such as the quality of informed consent for the subjects that have been enrolled in research studies. To set up a system for accrediting an institutional program for protecting research subjects, PRIM&R has recently formed an affiliated not-for-profit corporation called the Association for the Accreditation of Human Research Protection Programs. The acronym for it is AAHRPP. The current plan is to make the AAHRPP accreditation program voluntary, and we believe that most institutions will actively seek AAHRPP accreditation as a way of increasing the integrity of their research programs. Time does not permit me to describe the details of the AAHRPP accreditation process. This information is provided in my written statement. I am happy to explain anything related to this in the question session. I would like to conclude my remarks by reminding you that this is not about a bunch of paperwork that enhances the power or budget of some Federal agency or a special interest group. Modern society is stuck between a rock and a hard place. We must conduct complex and often dangerous research with human subjects if we are to improve the condition of life on this planet. There is often a tension between the ethical standards that we need to work within and a scientific agenda. We can create an environment where we promote meaningful research in a way that does not exploit in any way the rights and welfare of research subjects, but we need the strong arm of the Federal Government to make this happen and we need Federal support to be applied correctly. Our current IRB system is a good one. It is a result of the Nuremberg War Crimes Trial that exposed the shameful, unethical research that was conducted by Nazi physicians in the name of medical science during World War II. Earlier this week, the world observed Holocaust Remembrance Day in honor of those who suffered during the awful period in human history. In one remembrance ceremony, the Nobel Laureate Elie Wiesel said, ``Without its ethical dimension, civilization is vulnerable.'' PRIM&R and many other members of the research community hope you will act swiftly and decisively to improve the system of protecting human research subjects in this country. The AAHRPP accreditation program and the other changes that I have mentioned are steps in the right direction. On behalf of PRIM&R, thank you for inviting me. I am happy to provide any other information that would be useful. Thank you. Mr. Mica. Thank you and each of our witnesses on this panel for your testimony. I apologize, again, for the delay in the hearing, but we had floor votes and then we had the required participation in the committee hearing. Again, I would like to proceed with some questions, first maybe to Mr. Curtin. Well, you have all basically criticized some of the current functioning, operation, of the IRBs. Mr. McCarthy did not get into too much of that, he spoke mostly of the DSMBs. But the current system appears to be somewhat flawed. I guess if we started out maybe with informed consent, do you think it might be possible to have a basic standard informed consent procedure that would be good for all human research testing, Mr. Curtin? Mr. Curtin. That seems very bureaucratic to me, very inflexible. I would hope that we would be able to rely upon individual researchers and IRBs to come up with--to develop-- the informed consent that most fits the research project that they are looking at. Maybe that is too theoretical, maybe it cannot be done. Mr. Mica. I don't know if your daughter was afforded informed consent. Was she? Mr. Curtin. Absolutely not. Mr. Mica. Absolutely not. So first of all, there was not any in place? Mr. Curtin. Not for her. Well, if she answered it, obviously, but for other family members, no. Mr. Mica. For her, for herself, she did have informed consent? Mr. Curtin. Yes. Mr. Mica. Were you satisfied with that? Your protest then goes beyond her situation and her giving informed consent. I understand your concern about your privacy, her disclosure of your medical record. But were you satisfied with the informed consent that she was provided? Mr. Curtin. The informed consent really was if she responded to it, that would be considered the informed consent. She would have voluntarily participated if she had filled out the questionnaire and put it in a return envelope and sent it in. Mr. Mica. To step back first, does everybody believe that there should be a requirement for informed consent? Mr. Curtin. I think there should have been a statement in the instructions saying, if you are going to answer for your other family members, you might want to tell them that you are doing that. Mr. Mica. We have not gotten to family yet. We are talking about an individual who is going to participate or someone who is a guardian or legally responsible for that individual. There should be informed consent. Everybody agrees on that? Dr. Amdur. There are situations where it is appropriate and necessary to conduct research without informed consent, and those situations are described and provided for in current HHS regulations. A typical example would be emergency situations where it is not possible to get it, to conduct research with there being informed consent. There are other situations such as health services research involving access to medical records where risk is minimal and it is not possible or practicable to conduct research with a requirement for informed consent. The fundamental ethical standards that we use when we think about these and analyze them and say what is appropriate, what is not, what rights and welfares are important to maintain, need not be violated in certain circumstances without getting informed consent. Mr. Mica. Dr. Amdur, you are the one I thought that had come forward in past Federal law or regulations and set standards. That is what I am trying to get at. I had, sitting where Mr. McCarthy is, the representative of HHS. He said they had all the authority they needed to deal with these situations. It sounded like he did not have any recommendations for legislative changes. You have come forward and recommended something. Maybe you could elaborate on what you envision we should be doing as a Federal Government to again provide that there is adequate informed consent in human patient testing, that there is not a problem with the operation of an IRB. Right now, they cannot even tell me how many IRBs there are, OK? And then the operation of an IRB, should we be more involved in a conflict of interest, making certain there are not conflicts of interest? You heard this explosion and expansion of human research in just the whole biotech industry. All of the breakthroughs in medicine, testing, have just dramatically exploded. We hear something new every day. We as government do not want to stand in the way of research, but you have some basic protections that should be in place. Now, HHS said that they have adequate authority. You are saying that we should have some Federal regulations or laws and set some standards. Maybe you can elaborate. Dr. Amdur. You have raised a number of points. To go into detail about each one I think would be beyond the scope of this discussion, conflict of interest, etc. My response would be that the requests that I listed were specific regulatory changes that will make this current system work better. Mr. Mica. The HHS has the ability to institute regulations, so it is not a matter of changing the law, or is it? Are you aware of where we need to change the law? Dr. Amdur. Perhaps I am mistaken in terms of exactly who initiates the law. Really, though, I think. Mr. Mica. We initiate the law. What we do is when they have the need to be changed from time to time, we defer to HHS and the agencies to institute regulations. Dr. Amdur. I don't know any delicate way to say this. The point is, HHS could have made these changes, should have made these changes. PRIM&R sponsors two national meetings a year. The IRB world knows many changes that need to be made to make the system work better, which is a good system. They have not been made because of Federal bureaucratic inertia, turf wars, whatever. That is the reason that I am saying to you, I don't know what the problem is. Mr. Mica. I was trying to see if you had a recommendation in a legislative context. Most of it appears to be regulatory in nature. The failure of HHS to institute even the recommendations your group has made, we have the same problem. We had the IG sitting next to HHS and telling us that even basic things that were recommended back in 1998 still have not been instituted. We are looking first at the statutory and the larger picture, our responsibility. Then we do have the oversight and investigative responsibility, which we are conducting today through this hearing, asking again HHS why they are not following through with the recommendations. There are two ways they can do that. One, within existing authority, or if they need additional resources to make certain these things are in place. Now, Mr. Curtin has talked about another issue which extends beyond the informed consent but may need some type of tweaking in our laws as far as privacy or disclosure, and that is of course the subject of big discussions now with the tremendous amount of raw information that is coming out about folks. He raises a certain concern. We have heard an abuse here that we may either need to address through regulation or legislation. Dr. Amdur. The IRB system failed to do what should have been done in his case. There is no question about that. We don't need a new system, we just need the IRB at MCV to have functioned the way it should have functioned. Mr. Mica. Many of the IRBs, though, are sort of self- regulating, without a lot of protections. We are going to submit to the doctor and some others instances, but mostly we are reading about it in media accounts of conflict of interest. In our last hearing, we also heard problems ranging in conflict of ethics to having some self-interest in proceeding with the human testing. Again, you are dealing with boards that basically have some interest in participating and moving forward, taking Federal funds for that activity, as opposed to closing it down or not proceeding and not receiving the funds. Then the other problem we have is the huge explosion of all of this. It was just a few doing the testing some time ago. Now we are probably looking at thousands and thousands, plus the commercial and private side, where you do not have Federal funds and we have some loopholes in that regard. What about mandatory registration of IRBs? Dr. Amdur. We need that. That is part of the request of extending the regulations of the Common Rule to all research. The reason that you don't know or nobody knows how many IRBs there are in the country is because the only record of an IRB is if they conduct FDA-regulated research or HHS-funded research. We need to just simply fix that problem. I don't know that HHS can do that. I think it requires a higher level of mandate to pass a Federal law. I don't know that. But the point is, we need to extend the system of protection. Part of that would be a formally certified IRB according to the Common Rule regulations. Then we would not only know how many IRBs there are, but have some common system that they work under. Mr. Mica. Let me ask Mr. McCarthy. You have looked at the Data Safety Monitoring Boards, DSMBs. Do you feel there should be some accreditation or additional regulation mandatory? Mr. McCarthy. Yes, I would like to see some criteria established and required to be implemented. The criteria should state under what circumstances the Data Safety Monitoring Board should be established, what its authorities and responsibilities should be, and what its relationship to the local IRB should be in the centers where research over which it has oversight is being carried out. I do not know whether that can be carried out under present legislation or whether it would require new legislative authority, but I think it is very important, and will be a major step forward if that should occur. I agree with Mr. Curtin, that a kind of cookie cutter approach to informed consent is just what we don't need, because anything that routinizes informed consent, tends to rob it of its important meaning. What I would like with respect to informed consent is to see the Department of HHS spending some money to do research on how to communicate risks and benefits associated with research more effectively. We have a whole new generation of young people coming along who operate much more out of visual cues than out of written cues. To hand people a written, fairly complex document may not actually inform them of very much, whereas a videotape showing the same information might be much more effective. In order to develop that kind of technology, somebody needs to sponsor some imaginative research into how to better inform subjects so that they will know and understand the consequences of their decisions to participate or not to participate in research. Again, I don't know if you need a legislative mandate to carry that out or whether you simply need additional budget resources to carry that out, but I certainly think that ought to be a major function of the new office that is being created in HHS. Even if a new approach to informed consent can be done without new legislation, it certainly cannot be done without additional money, so I would encourage that the Congress bite the bullet and provide the money so that imaginative new ways of communicating with research subjects can be developed and employed, and so that IRBs have a range of ways of communicating the risks and benefits of research to their subjects in meaningful ways. I believe we can respect the dignity of subjects more than we do at the present time with rather complex, long, written consent documents that may not do what they are intended to do. Mr. Mica. Mr. Curtin obviously had a negative experience with the OPRR process. I think he recommended some solutions for corrections. Maybe you could give us those again, Mr. Curtin. Mr. Curtin. Yes, sir. No, I did not have a negative experience with OPRR. The only thing that even could be remotely called negative about it was that it took them almost a year to get around to doing anything with my complaint. But once they did it---- Mr. Mica. That I would interpret as a problem. Mr. Curtin. That is, yes. But once they got on it, they were great. They kept me informed. Mr. Mica. They did? Mr. Curtin. They did. They took some very, very severe action. They closed down 1,100 research projects at Virginia Commonwealth University. Mr. Mica. Your difficult experience was getting attention at the beginning. Mr. Curtin. Right. They explained that to me right off the bat. They said, it is going to be a year before we get around to doing this. A year later I heard from them. I would have liked it to have been sooner, but I understand those kinds of things. Mr. Mica. With the IRB process, you also were critical of the response you got there. Mr. Curtin. From the chairman, yes. Yes. Mr. Mica. You---- Mr. McCarthy. Mr. Chairman, just to fill in that story, because maybe even Mr. Curtin does not know this, but after OPRR took its action, Virginia Commonwealth University hired me, and I have been working about 40 or 50 hours a week since January to educate investigators about their obligations on informed consent and to instruct potential new members of the IRBs. So they are taking the criticism very seriously, and I expect that within a year they will have a system that will be as good as any in the country. Mr. Mica. But it did take a year to get action. What did they say, they could not get to it? Mr. Curtin. They were overworked, backlogged. Mr. Mica. OK. All right. Mr. McCarthy. As a former Director of OPRR, I can say that is a perennial problem. I think the office has always been understaffed and underfunded. Mr. Mica. I am also trying to find out what their recommendations were to us. They have to come to Congress to ask for additional funding through the appropriations process. If we have a deficit there and we have a larger scope of responsibility, we need to see that that is met. Maybe these 1,100 operations should have been closed down after the complaint was made, not a year later. Again, we are just trying to look at where the problems are and what is going wrong and how we correct them. It is a pretty simple process, except I have to get 534 other people to agree on how to fix it. Mr. Curtin. If I might add, sir, the IRB there, they just did not take me seriously. It was as simple as that. They thought they would write me a letter and I would go away. Mr. Mica. All right. It sounds like we have at least Mr. McCarthy and Dr. Amdur's wealth of experience and recommendations. You have a personal experience. I wanted to ask about some recommendations. I didn't make good notes on who said what, but you said consolidate sets of regulations. You cited HHS, FDA, education, and some standards. My staff just gave me the Department of Veterans Affairs standard for protecting human research participants. Did you mean in the context again of protection, some standards that are protections for human research participants, no matter what the Federal agency? Dr. Amdur. Yes, exactly. What I meant was not an abstract thing, but an administrative one, meaning that if you look in the Code of Federal Regulations at 45 CFR 46, you will see HHS regulations. Mr. Mica. Right. Dr. Amdur. If you look at 21 CFR 50 and 52, I guess it is, 56, you will see FDA. Most of it, 90 percent of it, are the exact same words. They are just copies. But then in the remaining 10 percent of this situation, the regulations are different or they are silent on certain situations. There are many examples of that. The Department of Defense has certain requirements, and you know if they sign on to the Common Rule, then they do. The point is that, for example, this adverse event reporting which you have heard so much about, this is the No. 1 workload problem for IRBs. It is the most ridiculous thing. There are boxes and boxes coming into the University of Florida's IRB every week of irrelevant reports that the IRB cannot possibly make any meaningful determination of. It may be a horrible adverse event that is critically important, but because of the things Dr. McCarthy said, the nature of what you need, you need data in safety and monitoring, but the IRB should not be looking at those. Does the IRB need to do that? The regulations say they need to. HHS regulations say certain things that can be interpreted certain ways. FDA regulations say very different things that likewise are interpreted very differently. So what I do on the IRB is sit around every week as chair of an IRB before coming to the University of Florida and try and say, how do we interpret this? Every year we have major discussion sessions at the national meetings: Well, how do we interpret this? And we are scared to turn away these things if there is any question that we need to be stamping them because we are scared of the regulatory consequences. So the point is, what should be done is to say we are only going to have one set of regulations, and it would be very simple. There are people that sit around, and this is all we have thought about and discussed and written papers about, who can suggest and hammer out revised regulations where necessary that make them congruent, just like any revised regulatory process goes. But the thing we need is to say we are only going to have one set of regulations, and it does not matter what agency sponsors the research. I would say we need to extend it. It does not matter if it is privately funded, and I think we need a law for that, not a Federal regulation. But the point is that we only need to have one set of regulations. That is what I mean when I say ``standards,'' regulations that describe the standards: Say you need to go through an IRB. You need to have informed consent under these situations. Here is the form of the informed consent, that situation. We need just one of those. The Common Rule does need a little polishing here and there, but it is basically what we would all come up with if we spent a long time thinking of standards in a regulatory system. It is a good system, and---- Mr. Mica. Are you aware of any formalized document or anything that has been prepared that proposes that and has language that would be acceptable to the vast majority of those who participate? Dr. Amdur. I think that when you say ``vast majority'' the people who are objecting to consolidation of the regulations-- -- Mr. Mica. We are not going to get everyone to agree. Dr. Amdur. Right, but the people who are objecting are the people in the agencies that want to keep their own regulations. Certainly industry sponsors, they just want to figure out: What do I need to do? They don't care what it is. It is so much better if they can just figure out what it is. The International Council on Harmonization would be the closest thing to the answer to your question in that there is now. In order to make it so that companies, pharmaceutical companies, can do business in all different countries, there is a body that has done exactly what you have said, which is establish that we are going to have one uniform requirement. If you want to do business within this group, we are just going to say everybody has to comply with these regulations. We are not interested in your HHS or whatever. If HHS is the exact same, fine. All we know is, here is one set. You know, I think that comes very close to what you are saying, but it would not be very difficult to come up with the one set. I think what is needed is some mandate at a higher level to say, come up with one set. Mr. Mica. Mr. McCarthy, you wanted to respond? Mr. McCarthy. I had some years' experience in OPRR, and of course we tried to do exactly what Dr. Amdur is suggesting; to come as close as humanly possible to a single set of regulations that would apply to all research, whether FDA- regulated or federally funded. We had no authority to reach out to that research which was neither FDA-regulated nor federally funded, so that problem I think is one that requires some congressional action to extend the authority of these offices. But I think the problem is more complex than you have heard. Each agency has its own authorizing legislation, and it is that authorizing legislation that allows it to issue regulations. That legislation differs dramatically from FDA to Department of Defense to HHS to Department of Education. Different congressional committees handle that legislation and draft it, so when you try to write a common set of rules that comply with a vast variety of laws, it is not a simple matter to write a single rule that complies with all of the authorizing legislation of all of the Federal agencies. We did the best we could, and I would disagree, I think between HHS and FDA, the congruency is about 97 percent. What I would point out, however, is that FDA has authority for implementing its rules, and that means different people are doing it, and sometimes they interpret the rules a little differently. That is why I would like to see this new HHS office become at least an HHS-wide office, and I would like the new office to have enough authority so it can be the lead agency to bring the other departments and agencies--that do less research but still a lot of research--into congruence so far as possible, given the plethora of laws that govern them. I think much more can be done, so I am agreeing with Dr. Amdur's point, but I think it is not a simple issue. This is a situation where the Congress itself, by placing certain kinds of goals for the new HHS office and providing it with resources to accomplish those goals, could go a long way toward accomplishing what he wants. I doubt if it can ever be perfect, but we can do lots better. Mr. Mica. Dr. Amdur wanted to respond. Dr. Amdur. You know, Dr. McCarthy has worked in the government too long, because now he is making excuses for it. You know, our role here is simply to say what needs to be done and for you to figure out how to do that. We need a common set of rules, and we do have plenty of models for that in the research world. For example, in 1996 Congress passed the Health Insurance Portability Act. As part of that, it required legislation to be passed that set standards for the protection of privacy of access to the medical record. Federal law said this has to be done. It did not say ``unless FDA objects to it,'' or the FDA--``unless it conflicts with FDA's view of it.'' It said, that is it. America, that is the way it is going to be done. A Federal law passed. We are about to see a law go into effect that supersedes all of our other research baloney of interpretation, of how do we interpret HHS, how do we do that. It is going to be a problem, of course, to implement it because there are problems with the way that law is written. But the point is that mechanism is there to say that, well, research, this is the way it is going to be done, regardless of one Federal agency's policy or another. I think that we can solve this problem. Mr. Mica. I am probably somewhere in between the two of you. Mr. McCarthy. We are not very far apart. We have exactly the same goal. Mr. Mica. Mr. McCarthy has described a political situation of congressional authorization, and there is not just the agency turf jealousy. We also have the committee authorizing jealousy, and to get them to all agree on anything is very difficult. I see your point, though. We have, as you pointed out, in other legislation required some standards. I think everybody agrees that there should be informed consent. I think everybody is agreeing now there should be some registration of at least the IRBs, right? And then we get into some other areas. We have not really talked about accreditation or certification for IRBs or DSMBs. Dr. McCarthy, what do you think about some accreditation or certification standard? Mr. McCarthy. I strongly endorse this effort. As a matter of fact, I have been selected to serve on the board of the new organization that Dr. Amdur cited, and I am dedicated to trying to bring this about as best we can. Mr. Mica. Should that be voluntary or mandatory? Mr. McCarthy. I think that it ought to be voluntary and supplemental to the kind of oversight exercised by the government. I think we have an excellent model in the Association for Accreditation of Laboratory Animal Care, Int. I think it has worked very well for many years as a supplement to government efforts. Mr. Mica. How long has that been in place? Mr. McCarthy. At least since 1970, and if memory serves, about 1965, but a very long time. It has worked exceedingly well, and one of the people serving on the new AAHRPP board is the director of AAALAC, so that we are able to profit from his experience and his guidance. I think the one thing holding up accreditation is funding, and we are now seeking some funding sources in order to get this corporation off the ground. We think it will be self- sustaining because it will be in the best interests of the institutions to be accredited, to get a Good Housekeeping Seal of Approval on their programs, before OPRR or FDA or some other agency comes in and shuts down their research. This way we can make a supplemental contribution to what the government is doing. In no way would I weaken the government's authority or the extent of its oversight, but I think human subjects are so important that we can supplement what government can do and head off many problems before they occur. Mr. Mica. Dr. Amdur, what about certification or accreditation? Dr. Amdur. I think that it needs---- Mr. Mica. Give me your ideas on how that should be accomplished. Dr. Amdur. A program that will work very well for this purpose is not in the planning stages, it is in the very end stages of the planning and about to be implemented by PRIM&R. This is the AAHRPP program. In three pages in the written testimony we explain the mechanics of it. Very briefly, what you do first is--this is about to be completed--you organize a group of experts that then write down basic best practice guidelines for the fundamental aspects of a system of protecting human subjects: The institution, the IRB, education of investigators, management of adverse incidents, etc. You start there, and that has been done. Then you have a written phase where the institution responds to their current status related to those. Then you have an onsite investigation where usually two or three experts go to the institution and have to interact with all the key components of the system and see how it is really working according to objective and there are some subjective aspects of it, and issue a grade, if you will, of the institution related to a whole checklist of things. If the institution meets certain standards, which are outlined in the program, then they get the accreditation for 3 years is the proposal. So PRIM&R has been working very hard to indeed hammer out the details. It is not perfect yet. It has not been tried in the field yet. Like any system, it will obviously iterate and evolve and change and be polished as it is used. The more support it gets, the quicker it can get online, but it is ready to go. I would strongly support a model that is that far along already to get out into the field and get going. We have to accredit everything we do. You go and get the gas tank filled for your gas grill and the people that fill the gas have to have a certification. We need an accreditation process for the protection of human subjects, and that is something that is really long overdue. Institutions will not balk at this, they will embrace it. They want to know, what do I need to do to be doing things correctly. They will embrace it if it is a credible system that is tagged to meaningful evaluations. If it is just an audit system of a bunch of accountants going and checking and looking for pieces of paper that say certain things and the date matches this date, you know, they will do it if they have to because the experts on protecting human subjects are the investigators, in most cases. They know if the IRB is asking the meaningful questions. They know if the institution is providing the right environment to support them and be able to resist conflicts of interest. As long as it is a meaningful, credible process done by people who know what they are doing, the institutions will embrace it. But it needs to be supported as widely as possible. Mr. Mica. Do you endorse the mandatory versus voluntary? Dr. Amdur. I am scared to say yes, mandatory, because we should always have as little required regulation as possible. I just need to see the exact format of how that requirement would be, because when we actually write it down and see how it is implemented, I am concerned. I think it will be enormously effective even if it is voluntary and if the regulations required--I personally right now, don't think it has to be a mandatory, required system. I think HHS regulations and authority already have the authority to put the pressure, as they are trying to do, on institutions to do things correctly. The institution will seek out ways to find out what is correct and improve their system on their own if they are indeed under a regulatory system that evaluates the end point. So I think they will seek the accreditation process on their own and there will be other forces that end up requiring it. For instance, industry will require it. Once there is any meaningful system in place, industry sponsors will require it. They will say, we are not dealing with you unless you are an AAHRPP-accredited institution. So I don't think it has to be mandated at the Federal level. Mr. Mica. I have additional questions we may submit some to you and some of our other witnesses today, but I think we have just passed the 6 o'clock hour. I do want to thank each of you for participating, for being with us this afternoon, for your contribution in helping us improve this entire process, and also the Federal agencies that are responsible for implementing law and Federal policy. There being no further business to come before the subcommittee--and again, I want to thank you for your participation and willingness to provide us with your personal experiences and your expertise on this important issue--this hearing is adjourned. 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