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In recent years, clinical research has become increasingly complex and has been accompanied by an increase in new ethical and conflict-of-interest considerations. HHS has recognized the need for human subject protections to be strengthened even further, and, as a result, on May 23, 2000 HHS Secretary Donna E. Shalala announced several new efforts designed to improve human research subject safety; to further strengthen government oversight of all medical research, including gene transfer research; and to reinforce clinical researchers' responsibility to follow federal guidelines.

Background

For more than 50 years, HHS agencies have been committed to protecting individuals from possible abuse or harm in clinical trials and to ensuring that prospective and enrolled participants understand the potential risks and potential benefits, if any, of being a research subject. In the 1960s, for example, amendments to the U.S. Food, Drug and Cosmetic Act established requirements that, at a minimum, people must consent to participating in an experimental therapy. A 1967 FDA policy clarified the procedure further to ensure that informed consent be obtained in writing.

In the 1970s, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research furthered protections with recommendations for IRBs, ethical oversight committees that are responsible for ensuring that people who agree to participate in studies fully understand the nature of the research and willingly consent to participate.

In 1972, the Office for Protection from Research Risks (OPRR) was created as part of NIH to ensure the safety and welfare of people who participate in HHS-sponsored research. And in 1981, FDA followed up by revising its regulations to require written informed consent in all studies of products that FDA regulates.

In 1999, the Advisory Committee to the Director of NIH recommended that the role of the OPRR be expanded and that the office be elevated from NIH to HHS-wide placement. In June 2000, the Office for Human Research Protections was established in the Office of the Secretary to elevate its stature and effectiveness. In addition, an independent National Human Research Protections Advisory Committee was established to provide broad scientific and ethical guidance to OHRP in its oversight role.

Today, with new leadership by OHRP, FDA, NIH and other agencies continue to play important and complementary roles in overseeing research and protecting the human subjects involved, a responsibility they share with research institutions and individual researchers.

Federal Oversight and the IRB Process

OHRP has the primary responsibility within the federal government for developing and implementing the policies, procedures, and regulations to protect human subjects involved in HHS-sponsored research. In carrying out its mission, OHRP has formal agreements with more than 4,000 federally-funded universities, hospitals and other medical and behavioral research institutions in the United States and abroad. These agreements or "assurances" outline each institution's commitment to conduct its research projects in an ethically sound manner and to protect the welfare of people involved in these projects.

In accordance with these agreements, each institution sets up one or more IRBs, which are responsible for ensuring that people who agree to participate in studies fully understand the nature of the research and willingly consent to participate. This "informed consent" process requires that potential participants be given an explanation of purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures that are experimental, among other necessary information.

The membership of an institution's IRB typically includes physicians, scientists, patient representatives and others who are charged with regularly monitoring the design, development and progress of the research projects being conducted at the institution. Federal regulations require that a non-scientist and an individual not affiliated with the institution be included on every IRB.

OHRP provides guidance to IRB members as well as to scientists and research administrators on the complex ethical issues relating to the involvement of human subjects in medical or behavioral research. The office conducts national educational workshops and provides on-site, technical assistance to institutions conducting HHS-sponsored research.

In addition to its educational activities, OHRP also has a regulatory role. OHRP monitors and evaluates an institution's compliance with the rules governing research subjects. If complaints or concerns arise regarding an institution's oversight practices, OHRP has the authority to investigate and, if necessary, require corrective action or even suspend human subjects research at an institution until the problems are resolved. Since 1993, OHRP has undertaken more than 30 site visits to various institutions to review compliance with their oversight process.

FDA has oversight responsibility for all clinical trials aimed at testing a new drug, biological product or medical device, and their respective IRBs, including IRBs in industry-sponsored trials. FDA must review the design of all clinical trials designed to test a new medical product before those trials may begin. FDA monitors adverse events during clinical trials and can suspend those trials when problems arise. Its investigators inspect approximately 600 clinical investigators, as well as 250 to 300 IRBs, every year.

Guaranteeing Effective Oversight

As the number of research projects and study volunteers increases and clinical research becomes increasingly complex, it is critical that the integrity of research be maintained.

Recognizing the need for further enhancements to existing human subject protections, Secretary Shalala announced on May 23, 2000, several new efforts designed to improve human research subject safety, to further strengthen government oversight of all medical research, and to reinforce clinical researchers' responsibility to follow federal guidelines.

Education and Training. HHS will undertake an aggressive effort to improve the education and training of clinical investigators, IRB members, and associated IRB and institutional staff. NIH, FDA and the Office of Protections from Research Risks (OHRP) will work closely together to ensure that all clinical investigators, research administrators, IRB members and IRB staff receive appropriate research bioethics training and human subjects research training. Such training will be a requirement of all clinical investigators receiving NIH funds and will be a condition of the NIH grant award process and of the OHRP assurance process.

Informed Consent. NIH and FDA will issue specific guidance on informed consent, clarifying that research institutions and sponsors are expected to audit records for evidence of compliance with informed consent requirements. For particularly risky or complex clinical trials, IRBs will be expected to take additional measures, which, for example, could include third-party observation of the informed consent process. The guidance will also reassert the obligation of investigators to reconfirm informed consent of participants upon the occurrence of any significant trial-related event that may affect a subject's willingness to participate in the trial.

Improved Monitoring. NIH will now require investigators conducting smaller-scale early clinical trials (Phase I and Phase II) to submit clinical trial monitoring plans to the NIH at the time of grant application, and will expect investigators to share these plans with IRBs. The NIH already requires investigators to have such plans and they also require large scale (Phase III) trials to have Data and Safety Monitoring Boards (DSMBs). For research on medical products intended to be marketed, FDA will also issue guidelines for DSMBs that will delineate the relationship between DSMBs and IRBs, and define when DSMBs should be required, when they should be independent, their responsibilities, confidentiality issues, operational issues and qualified membership.

Further, OHRP is streamlining its assurance procedures for research institutions. In addition, NIH has issued new guidance allowing grant applicants to defer IRB review of proposed research protocols until after completing the initial phase of NIH peer review but before final funding approval. Previously, NIH asked for IRB review and approval to be documented in all grant applications, even though fewer than half of all applications submitted to NIH are actually funded.

Conflict of Interest. NIH will issue additional guidance to clarify its regulations regarding conflict of interest, which will apply to all NIH-funded research. HHS will also hold public discussions this summer to find new ways to manage conflicts of interest so that research subjects are appropriately informed, and to further ensure that research results are analyzed and presented objectively. In addition, these public discussions also will focus on clarifying and enhancing the informed consent process. Based on these public forums, NIH and FDA will work together to develop new policies for the broader biomedical research community, which will require, for example, that any researchers' financial interest in a clinical trial be disclosed to potential participants.

Civil Monetary Penalties. HHS will pursue legislation to enable FDA to levy civil monetary penalties for violations of informed consent and other important research practices-up to $250,000 per clinical investigator and up to $1 million per research institution. While FDA can currently issue warning letters or impose regulatory sanctions that halt research until problems are rectified, financial penalties will give the agency additional tools to sanction research institutions, sponsors and researchers who do not follow federal guidelines. As an interim step, NIH, OHRP and FDA will work more closely together to enforce and target existing penalties.

Gene Transfer Research

Recent reports of gene transfer trials in which human subjects were not adequately protected and apparent financial conflicts of interest have clarified the urgency and importance of additional steps in protecting human research subjects and crystallized the new pressures facing medical researchers, research institutions and IRBs. As a result, in March 2000 HHS announced two new initiatives: gene transfer research sponsors are now required to routinely submit monitoring plans in advance to FDA; and NIH and FDA have initiated a series of gene transfer safety symposia.

FDA also has increased the number of inspections they conduct, adding additional oversight to that IRBs already provide. Also, NIH and FDA are working to strengthen and streamline their collaborative efforts to monitor gene transfer trials.

In recent months, FDA has issued warning letters to some gene transfer researchers for failure to comply with federal guidelines for clinical research, to fully inform participants of its risks and benefits, or to report adverse events promptly.

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Note: For other HHS Press Releases and Fact Sheets pertaining to the subject of this announcement, please www.os.dhhs.gov/news/press/ .