HHS Secretary Donna E. Shalala today announced several new initiatives to further strengthen protections of human research subjects in clinical trials, including those involving gene transfer. The department's actions are designed to heighten government oversight of biomedical research and to reinforce to research institutions their responsibility to oversee their clinical researchers and institutional review boards (IRBs). "In the last few years, we've seen dramatic advances in the effort to find new therapies for cancer and other diseases, and we've taken new steps to protect the safety of patients in clinical trials," Secretary Shalala said. "But the explosion in biomedical research has also brought new challenges, as more researchers are becoming involved in commercial ventures that may create new ethical dilemmas. Today's actions are designed to further strengthen government oversight of all biomedical research, including gene transfer research, and to reinforce institutions' and researchers' responsibility to follow internationally accepted ethical standards and federal guidelines."

The actions taken by HHS today focus on expanding education and training for all clinical investigators and IRB members and staff; enhancing the informed consent process and ensuring more vigilant monitoring and oversight; ensuring that researchers understand and comply with federal conflict of interest regulations; and pursuing efforts to provide the Food and Drug Administration (FDA) with additional enforcement tools to enhance its oversight role. They also respond to a request from President Clinton to examine ways to ensure patient safety and increase public confidence in clinical trials.

Secretary Shalala also stressed the responsibility of the leaders of universities and academic medical centers to oversee IRBs. "Recent reports of problems in gene transfer trials have highlighted the new pressures facing researchers, IRBs, and research institutions themselves," she said. "Protecting patient safety, and ensuring informed consent, is a shared responsibility. I want to urge university presidents, leaders of our academic medical centers, and others involved in biomedical research to take a hard look at oversight of clinical trials, their partnerships with the private sector, their own ethical guidelines, and the support and guidance they give their IRBs. Public confidence in clinical trials is essential to the continued advances in medicine we all hope to see in the next century." "We must ensure that patients are well protected and properly informed when they choose to enroll in a clinical trial," said FDA Commissioner Jane E. Henney, M.D. "By maintaining high standards and requiring that all investigators adhere to them, we can be sure that the nation's biomedical research enterprise will continue to earn the trust of research subjects." "We are constantly exploring new and effective ways to enhance systems to strengthen protections for human research subjects without unduly burdening IRBs," added Ruth Kirschstein, M.D., acting director of the National Institutes of Health (NIH). "These new initiatives should significantly improve communication among researchers, patients and the IRBs."

Today's announcements address the following issues:

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 for Protection from Research Risks (OPRR) 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 OPRR 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. 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, OPRR and FDA will work more closely together to enforce and target existing penalties.

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 benefits, if any, of being a research subject. In 1972, OPRR was created as part of NIH to ensure the safety and welfare of people who participate in research sponsored by HHS. In 1981, FDA followed up by revising its regulations to require written informed consent in all studies of products that FDA regulates. Today, FDA, NIH and OPRR continue to play important and complementary roles in overseeing research and protecting the human subjects involved. More resources may be needed to fully implement these responsibilities in the years ahead. These agencies work with IRBs to ensure 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, the expected duration of the subject's participation, a description of the procedures to be followed and their potential risks and benefits, and identification of any procedures that are experimental. Research institutions such as academic health centers and universities have the ultimate responsibility to ensure that clinical investigators adhere to this informed consent process.

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