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Vice President, Research and Regulatory Affairs, Capitol Associates, Inc., 426 C. Street NE, Washington DC 20002, md{at}capitolassociates.com
CONGRESS AND THE WHITE HOUSE TAKE CHARGE ON MATTERS OF CLINICAL RESEARCH
At one time the Food and Drug Administration (FDA) was in the driver's seat with regard to clinical research and the conduct of clinical trials. Now, as a result of a series of events bringing into question our national capacity to oversee clinical research, Congress and the White House have taken charge. Discussions surrounding clinical research protections have increased dramatically during the 106th Congress which is set to adjourn on October 6, 2000. This short timetable to resolve any of the emerging issues relative to clinical research and patient protection will likely spill over into the 107th Congress and continue to be an issue addressed through agency actions during the close of the Clinton Administration and in the next Presidency.
Two years ago the Inspector General (IG) issued a report with regard to the integrity of Institutional Review Boards (IRBs), citing substantial deficiencies in the system. This past September, the death of a research study participant, allegedly due to lack of compliance with the research protocol, heightened the scrutiny of the Congress and the Administration on the issue of gene therapy compliance, and more broadly, with regard to clinical research. In the wake of the death of the University of Pennsylvania participant, Congress requested additional IG reports relative to patient protections and Federal capacity for oversight. These reports were completed and published in June 2000. Further, the United States Senate has held several hearings investigating the integrity of our clinical research enterprise as seen through the eyes of gene therapy. In parallel, the White House has announced a variety of specific proposals all directed toward strengthening our national capacity for oversight in clinical trials and clinical research. What follows is an overview of these activities.
CONGRESS AND GENE THERAPY
On February 7, 2000 the Senate Health, Education, Labor, and Pensions Committee (HELP) held a hearing to investigate the events which led to the death of a gene therapy clinical trial participant at the University of Pennsylvania.
Specifically, the concerns raised at the hearing by the Senators on the panel included: the process of informed consent, bias, and coercion in clinical trials; the nature of experimentation on human beings; the role of experimental therapies in medical research; and the appropriate and vigilant oversight of the field of gene therapy and clinical research. While the hearing did not resolve or substantially address any issues, it did establish a Congressional record with regard to a number of important issues relative to the conduct of clinical research:
On May 25, 2000 the Senate HELP Committee held its second hearing on the capacity of the federal agencies to provide oversight of clinical research and, in particular, gene therapy. Concerns similar to those raised in the first hearing were re-stated, but additional issues were also raised. Specifically, the Committee addressed concern regarding the workload of the FDA and Institutional Review Board as well as the lack of harmonization between the requirements of the FDA and the National Institutes of Health (NIH).
Numerous bills have been introduced in Congress addressing issues relative to clinical research and clinical trials including: Medicare coverage of clinical trials; loan repayment programs for individuals pursuing careers in clinical research; incentives for clinical drug development in pediatrics; application of oversight mechanisms to the private sector through the extension of the Common Rule; and tax credits for medical innovation.
Most recently, Representatives Diana DeGette (D-CO), Henry Waxman (D-CA), and John Mica (R-FL) introduced the Human Research Subjects Protection Act of 2000 (H.R. 4605) which would extend the Common Rule and vulnerable-populations protections to private-sector human research subjects. Currently the Common Rule is only enforceable by regulations attached to federal funding of clinical research; thus any privately sponsored research is exempt from compliance. The legislation would place provisions of the rule into the statute, applying them to any research on human subjects regardless of federal funding or involvement. The bill also addresses IRB support, establishes training requirements for investigators and IRB members in human subjects protections, and requires IRBs to be registered and accredited by a nonprofit outside entity within two years of the bills passage. The bill also establishes a legal right to informed consent and conflict of interest disclosure, as well as disclosure of any financial interest to research subjects. There is a clear consensus among the bills sponsors that there is a need to strengthen and expand current protection, due in part to the recent oversight issues raised by gene therapy research and overburdened IRBs. It is likely that this legislation will become the construct for Congressional consideration of this issue in the next Congress.
INSPECTOR GENERAL AND CLINICAL RESEARCH
On May 3, 2000, at a House Government Reform Committee hearing, concerns were raised regarding the Department of Health and Human Services (DHHS) failure to implement changes recommended in the 1998 IG report. These concerns were raised again at a Senate HELP hearing on May 25th. The 1998 IG report addressed the deficiencies within the federal system of oversight to protect human subjects in research. The report recommended reforms to enhance federal requirements, such as performance evaluations; strengthened protections; and enforcement of federal requirements, such as additional IRB monitoring, instituting educational and training requirements for IRB members, preventing conflicts of interest by broadening IRB representation, reducing IRB workloads, and improving Federal oversight. Of the seventeen recommendations made by the IG, the federal government had only addressed two of them by May 2000.
In June 2000, three additional IG reports were released on the subject of protections for human subjects of clinical research. The first two addressed the recruitment of subjects in industry-sponsored clinical trials. The third report examined the FDA's oversight of clinical investigators. In Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research, and a second report establishing guidelines for recruiting human subjects, Recruiting Human Subjects:
Sample Guidelines for Practice, the IG acknowledges that there have been several changes in the field of clinical research which affect the ability to recruit human subjects. Specifically, the increased pressure to enroll patients to decrease the overall costs of drug development, the increase in the number of drugs being developed and the increasing complexity of clinical trials, and the shift of clinical trials from the academic setting to private practice settings as an attempt to increase efficiency have altered the conduct of clinical research. With that said, the IG cited a number of problems in the current system: the erosion of informed consent, due to pressure to recruit quickly and the potential to present information in a manner that does not successfully enable the patient to understand the nature of the research; potential to compromise confidentiality due to physicians actively searching for clinical trials participants; and the potential to enroll ineligible subjects, or individuals with questionable eligibility, in order to meet quotas and satisfy sponsors.
The IG also found problems with IRBs because they are not reviewing the recruitment practices due to a lack of clear guidelines by the DHHS regarding recruitment of subjects to clinical trials. The IG made the following recommendations to the DHHS concerning IRB oversight in recruitment of clinical trials subjects: establish clear guidelines relative to IRB authority to oversee recruitment practices in collaboration with industry and academia; provide appropriate education for investigators regarding the conduct of clinical trials; and strengthen federal oversight of IRBs.
The third study issued by the IG evaluated the capacity of the FDA to provide oversight of clinical investigations. The IG found that overall oversight of clinical investigators is limited and that drug sponsors do not provide adequate monitoring of clinical investigators conducting their clinical trials. More importantly, the IG indicated that data integrity drives the oversight of the FDA and not the protection of human subjects, an issue that is likely to guide any legislative proposals that will be considered in the 107th Congress. Specifically, the FDA's review of clinical trials sites is retrospective, they do not provide any day-to-day oversight of clinical research.
THE WHITE HOUSE
In March 2000, the DHHS announced new initiatives to protect patients in gene therapy trials in response to Congressional concern and directives from the Administration to bolster federal gene therapy oversight, ensure improved monitoring efforts by study sponsors, ensure patient safety, and restore confidence in the integrity of gene therapy trials. The NIH and the FDA are collaborating on a series of Gene Transfer Safety Symposia, approximately four annually, which will include scientists and physicians discussing medical and scientific data regarding their specialities. Additional actions taken by the NIH and the FDA to improve gene therapy quality and oversight include:
In May 2000, the President and Secretary Donna Shalala announced additional initiatives and forthcoming guidance documents from the NIH and the FDA that were intended to bolster federal oversight to protect human subjects in clinical research, a move which took the debate and evaluation beyond gene therapy.
The new initiatives focus on improving federal oversight and requiring research institutions to oversee clinical researchers and IRBs and ensure that ethical standards and federal guidelines are upheld. The initiatives included a collaborative effort led by the NIH, the FDA, and the Office of Protection of Research Risks (OPRR), to improve the education and training of clinical investigators, IRB members, and associated IRB and institutional staff; guidance on informed consent which will be issued by the FDA and the NIH, including the expectation that research institutions and sponsors should audit research records for evidence of informed consent requirements; the NIH will require Phase I and II trial investigators to submit clinical trial monitoring plans to the NIH along with the grant application and to share the plan with IRBs; the FDA will be issuing guidance for data safety monitoring boards (DSMBs) which outline the relationship between DSMBs and IRBs; and, the NIH will issue guidance to clarify existing regulations concerning conflict of interest and NIH-funded research.
In a move which startled the research community as well as the Congress, the White House announced that it would be sending legislation to Capitol Hill that will enable the FDA to impose civil monetary penalties for violations of important research practices, such as informed consent, which can range from a cap of $250,000 per clinical investigator to a cap of $1 million per research institution. In the interim, the NIH, the OPRR, and the FDA will work together to enforce and implement existing penalties, which are either a warning letter or closing down a clinical research protocol or academic institution's capacity to undertake clinical research. The White House views civil monetary penalties to be a middle-of-the-road enforcement tool. The concept of the legislation was discussed at the May 25th Senate HELP hearing; however, it has not been formally pursued as of this writing.
What remains clear is that national scrutiny in clinical research will continue over the coming months and change is inevitable. It will be incumbent upon all who are involved in clinical research to participate in the process which shapes that change.
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