A significant proportion of biomedical research is conducted through clinical trials, which involve testing new drugs, devices, or treatments with human subjects. Many of these trials are spread across hundreds of sites, sometimes at sites outside of the United States, and are performed not only in academic medical centers but also by physicians and other providers in the community. Although there are no comprehensive data on the number of individuals enrolled in research studies, this number has likely increased as federal spending for medical and health research has doubled in recent years and industry spending has been growing even faster. The principal federal policy for protecting human research subjects is called the Common Rule. It is a set of requirements, embodied in regulation, agreed to by 17 federal departments and agencies, including HHS, and applies only to federally funded or sponsored research. Broadly speaking, the Common Rule focuses on obtaining the research subject’s voluntary, informed consent by specifying, among other things, that subjects must be told of the expected benefits and potential risks to which they could be exposed; setting criteria for review panels—known as institutional review boards (IRB)—that are responsible for performing initial and ongoing reviews of research; and obtaining a formal written assurance of compliance with federal standards from institutions engaged in research studies. A federal agency cannot change the Common Rule without the agreement of the other 16 agencies that agreed to and are governed by the rule. Thus, to adapt regulations to emerging ethical issues or new scientific developments, some agencies have issued their own regulations or guidance, which has produced a varied array of policies across the federal agencies. Major responsibility for federal oversight of human subjects protection in HHS-related clinical research rests with three entities: the Office for Human Research Protection (OHRP), NIH, and the Food and Drug Administration (FDA). OHRP oversees all research conducted or funded by HHS that uses human subjects. OHRP’s oversight activities are directed chiefly at HHS-supported research, including research conducted at universities, hospitals, and other medical and behavioral research institutions. One of OHRP’s principal duties is to approve and renew an institution’s “assurance,” which is a written and signed agreement that details the terms of the institution’s promise to comply with federal human subjects protection requirements and policies. In addition, OHRP investigates problems involving noncompliance with human subjects protection that have been identified at institutions and conducts occasional on-site evaluations. NIH, the principal federal agency that provides funds for biomedical research, is charged with ensuring that the research it funds is in compliance with HHS regulations and with any additional terms it negotiates with an individual research institution. NIH also issues its own guidelines for certain aspects of human subjects research, such as data and safety monitoring and the education of investigators. FDA is responsible for ensuring the protection of the rights and welfare of human subjects enrolled in research on the products it regulates—drugs, medical devices, biological products, foods, and cosmetics. It oversees public and private research investigators, sponsors of research, such as pharmaceutical companies and biotechnology companies, and IRBs that review FDA-regulated research. Some of this research is not federally funded and thus does not fall under the Common Rule, but FDA has adopted a separate set of human subjects protection regulations that are similar, but not identical, to the Common Rule that apply to the research on products it regulates. A primary concern for FDA is assuring the quality and integrity of research data involved in the testing or licensing of medical products. FDA enforces compliance with its regulations through on-site inspections of IRBs, clinical investigators, and sponsors. In recent years, a number of concerns have been raised about human subjects protection. In a 1996 study, we found that various time, resource, and other pressures had reduced or threatened to reduce the effectiveness of oversight by federal agencies and IRBs. Two years later, a series of reports issued by the HHS Office of the Inspector General (OIG) confirmed the intense pressures on IRBs and the limitations of their effectiveness and made specific recommendations for action. In April 2000, the OIG reported that HHS had taken few actions in response to these recommendations. In 1999 the National Bioethics Advisory Commission (NBAC) was asked to conduct a thorough review of the federal oversight system for human subjects protection. NBAC has released a series of drafts of its report entitled “Ethical and Policy Issues in Research Involving Human Participants” and is scheduled to issue a final report in the summer of 2001. NBAC’s report is expected to address all federal oversight for research involving human participants, and NBAC is not expected to limit its recommendations to areas within HHS’ purview. In response to concerns raised by Congress and the research community, HHS, in particular, three of its components—OHRP, NIH, and FDA—has begun several initiatives to enhance the protection of subjects in HHS- funded and FDA-regulated research. These efforts are largely in the initial stages of implementation. HHS has taken steps to give the issue of human subjects protection greater prominence. Until recently, NIH’s Office for Protection from Research Risks (OPRR) was responsible for oversight and enforcement of regulations when HHS funding was involved. Because the office was located at NIH, it was not clear that its authority extended beyond NIH- funded research. There was also the perception that its autonomy was compromised by its location within an agency that also funds research. To address these concerns about authority and autonomy, HHS established OHRP in the Office of the HHS Secretary, Office of Public Health and Science in June 2000, enhancing the status and visibility of human subjects protection activities. OHRP assumed the human subjects protection functions of the former OPRR. OHRP has a 2-year plan to organize and coordinate the department’s diverse human subjects protection activities and reengineer the system for protection of human subjects in research. In March 2001, FDA formally elevated and centralized its human subjects protection activities by creating the Office for Human Research Trials and locating it in the Office of the Commissioner. At FDA, human subjects protection activities previously were diffuse, dispersed across various centers and the Office of the Commissioner. The new office is involved with intra-agency coordination of policy, education, and oversight relating to human subjects protection. OHRP, FDA, and NIH officials told us they are now working together more closely to coordinate and utilize resources for human subjects protection activities. The three HHS components have also sought to improve the mechanisms they use to conduct oversight and enforcement activities related to human subjects protection. To reduce regulatory burden and enhance its oversight capabilities, OHRP has recently revised its assurance process. The research community had concerns about the assurance approval and renewal processes. They contended that the processes had been unnecessarily burdensome and created disproportionate workload demands on HHS and research institution staff who are needed to meet other, equally important and time-consuming human subjects protection requirements. To address these problems, OHRP undertook, as one of its first major initiatives, implementation of a simplified assurance process that is less administratively burdensome. The streamlined assurance process, which is currently being phased in, is designed to reduce the paperwork burden that characterized the former process. OHRP, in collaboration with FDA, has initiated IRB registration as another step to improve its ability to conduct oversight and facilitate compliance. Previous HHS efforts to monitor IRBs and communicate with them about policies and guidance had been hampered because HHS did not have a comprehensive list of all IRBs, estimated to number in the thousands. As part of the new assurance process, institutions will be required to register their IRBs. Registration will enable HHS to build an IRB database, which will facilitate the identification of and communication with officials who actively review projects using human subjects. OHRP also seeks to enhance IRB compliance by adopting a monitoring and quality improvement strategy intended to prevent problems before they occur. We and others have reported that this office’s predecessor made few site visits to review compliance. Those conducted, moreover, were “for cause,” that is, in response to complaints of noncompliance. OHRP has plans to conduct quality improvement evaluations (although not necessarily through site visits) at every major medical school in the United States within the next 18 months, insofar as resources permit. OHRP seeks to expand its compliance activities through enhanced coordination and communication with FDA’s inspection program. In fiscal year 2000, NIH also began a process of not-for-cause site visits, intended to assess institutional understanding of federal policies and regulations (including those involving human subjects protection), minimize or eliminate noncompliance, and foster a productive partnership between NIH and its grantee institutions. To date, it has completed 10 of these visits; NIH officials told us that more are planned for fiscal year 2001. HHS is also considering ways to address the research community’s concerns that its range of options for enforcement of regulations is too limited. In the event that serious violations are uncovered, OHRP can restrict or suspend an institution’s assurance. Such an action would seriously disrupt ongoing research at that institution because federally funded human subjects research cannot be conducted without an assurance in place. FDA can withhold approval of new studies, withhold approval for enrollment of new subjects, and terminate studies. FDA can also issue warning letters and restrict or disqualify investigators, IRBs, or institutions from conducting or reviewing research. As a granting agency, NIH can place a restriction on an award if the grantee institution is not in compliance with regulations. Nonetheless, some critics have argued that there are too few sanctions to match the range of violations that occur. Acknowledging this problem, HHS is considering a proposal for legislation that would enable FDA to levy civil monetary penalties for violations of the informed consent process and other important research practices. HHS has taken some actions to improve the review and monitoring of clinical trials by research institutions. HHS has taken steps to improve institutional research reviews while reducing IRB workload by issuing guidance regarding adverse events and financial relationships.