Conclusion

Chapter 14: Administrative Structures and Procedures for Research Oversight

• The scope of its human subjects research programs;
• The organizational structure of its human subjects protection efforts and the resources devoted to such activities;
• The policy issuances and guidances pursuant to the Common Rule that the department or agency has prepared and provides to subsidiary agencies and research institutions engaged in human subjects research;
• Monitoring and enforcement activities for ensuring that the provisions of the Common Rule are met;
• Sanctions available for noncompliance with human subjects protections;
• The rules governing classified research involving human subjects; and
• The use or potential use of waivers of any of the requirements of the Common Rule or the agency's human subjects regulations.

In a supplemental volume to this report we provide greater detail on the departments' and agencies' responses.

Each federal department structures its program of administrative oversight of human subjects research somewhat differently, despite the fact that all operate under the requirements of the Common Rule.[22] Some departments conduct reviews of research documentation out of one central departmental office, while others rely on local review; some provide detailed interpretive guidance on human subjects protections to subsidiary intramural research offices, contractors, and grantees, while others simply reference the Common Rule; and some departments audit or review IRB performance routinely, while others conduct investigations only when problems emerge.

The Office for Protection from Research Risks (OPRR) at the National Institutes of Health (within DHHS) serves not only as the locus for that department's policies for the protection of research subjects but also as the principal federal agent approving the assurances of research institutions to conduct human subjects research sponsored by any of a number of departments.[23]

Scientific peer review of federally sponsored research is one layer of protection for research subjects. Most federal research programs require that committees of scientists, expert in the particular subject under consideration and often from outside the agency (generally known as "study sections"), review both intramural and extramural research proposals for scientific merit and make recommendations regarding funding. When these committees of subject-matter experts review research proposals, they also consider the risks that may be involved for subjects. They may recommend that the sponsoring agency more closely consider the potential risks or that the principal investigator make specific changes in the research protocol prior to any funding.

Local review is a key component of the oversight system. The Common Rule requires IRB review and approval prior to the granting of federal funding for research on human subjects. Almost all federal agencies that conduct human subjects research within their own facilities have intramural IRBs, whose members include agency staff and at least one member who is not affiliated with the facility.[24] Likewise, extramural research projects must undergo IRB review prior to agency funding, usually by an IRB at the site of the research activity--for example, a university, medical school, or hospital. The IRB is an administrative unit that must itself comply with certain requirements of the Common Rule in terms of its composition, review procedures, and substantive review criteria; it must also direct researchers to comply with other requirements of the rule, such as adequate informed consent and fair subject selection procedures.

A research institution that has assured either OPRR or the federal agency sponsoring the research that it conducts human subjects research in compliance with the Common Rule must delegate to its IRB the authority to preclude or halt the conduct of any federally funded research project that does not conform with federal human subjects protections.[25] This delegation of authority applies to IRBs within federal research institutions for intramural research and to those at nonfederal research institutions as well. This authority extends even to research performed by military organizations, where unit commanders cannot overrule safeguards adopted by military IRBs.[26] Thus the IRB is the enforcing agent of federal protections that is situated closest to the conduct of research. Much of the success or failure of the federal regulations governing human subjects research depends on the effectiveness of IRBs in carrying out their responsibilities: assessing research proposals prior to their funding; stipulating any changes in the research protocol or informed consent procedure that strengthen the protections afforded the subjects; disapproving inadequate or excessively risky research proposals; minimizing risks to subjects; reviewing ongoing research at least every twelve months to ascertain that the research poses no undue risks to subjects; and taking action quickly to correct any failings in safeguarding subjects' rights and welfare.[27]

In overseeing human subjects research conducted in-house or supported extramurally, federal agencies acquire the following responsibilities: (1) communication of practice guidelines to research institutions and IRBs based on the policies of the Common Rule, (2) establishment of a structure whereby research proposals involving human subjects are peer reviewed for scientific merit as well as for IRB approval and the adequacy of subject protections, (3) negotiation of assurances with research institutions that ensure that adequate protections will be in place for research subjects, (4) verification that institutions, their IRBs, and researchers are complying with the federal human subjects regulations, and (5) investigation of complaints of noncompliance and adverse outcomes for subjects of research.

Table 1, "Human Subjects Research & Protections in Seven Departments and Agencies" (at the end of this chapter), summarizes information received by the Advisory Committee about human subjects research programs in DHHS, DOD, DOE, VA, NASA, CIA, and FDA (a subagency of DHHS). This chart shows each department's or agency's staffing levels for human subjects protection activities. Both the size of the departments' research programs and their investment of staff resources in oversight activities vary widely. A particularly important distinction in oversight programs is the extent to which they investigate the performance of research institutions and IRBs in carrying out their responsibilities under the Common Rule. Some departments rely heavily on the prospective assurances that research institutions make to the funding agency or to OPRR, while others audit research institutions and IRB records periodically.

The method, intensity, and frequency of research oversight and inspection activities depend entirely on how much staff and budget an agency allots them. OPRR negotiates multiple project assurances (MPAs) with large research institutions that perform a significant amount of research funded by DHHS. If an institution is awarded an MPA by OPRR, the federal agency funding the research must accept that institution's assurance of compliance with federal requirements and may not impose additional assurance requirements on the institution. This provision is intended to avoid duplicative and potentially contradictory enforcement of the federal protections.[28]

OPRR, in overseeing human subjects protections for DHHS-funded research and for all institutions to which it has issued an assurance, generally investigates the conduct of research only in cases where a complaint has been filed; where an institution, IRB, or researcher has reported a problem or adverse outcome; or where a problematic audit finding has been referred to it by the FDA.[29] Principal investigators are required to report to the IRB any adverse outcomes to subjects in the course of their research, and the IRB must have procedures to ensure that the appropriate institutional officials and the funding agency are informed as well. The FDA, in its role regulating new drugs, biologics, and devices for marketing, enforces the somewhat different requirements for human subjects protections of the Food, Drug, and Cosmetic Act through periodic on-site investigations of research institutions (e.g., pharmaceutical firms, university-based research facilities funded by pharmaceutical firms, independent testing laboratories) and their IRBs.[30] The DOD conducts on-site audits of its intramural research programs in addition to negotiating assurances. The DOD also reports that it is common practice in DOD-funded research to appoint independent medical monitors--health care providers qualified by training, experience, or both to monitor human subjects during the conduct of research as advocates for safety of the subjects.[31] The DOE is now planning to institute periodic audits of the research programs that it funds in addition to relying on assurances.[32]

Special Issues Arising in DOD Research

Human subjects research conducted by military agencies and within military settings entails considerations for subject protections and research oversight that are unique to the military context. The activities of military research programs may be difficult to distinguish from innovative training programs and medical interventions undertaken for the protection of the troops. In addition to enforcing policies derived from the requirements of the Common Rule, DOD has in place a parallel set of regulations for managing the risks to which military personnel are exposed in the course of these routine duties.[33] Military leaders are responsible for determining whether human experimentation protections, in addition to the more general risk-assessment requirements, apply to particular practices. A further distinction of the military context is the hierarchical and comprehensive nature of its authority structure, which poses special issues with respect to voluntariness in the recruitment of experimental subjects. In some cases, military researchers have excluded unit officers and senior noncommissioned officers from subject recruitment sessions (e.g., in vaccine trials conducted by Walter Reed Army Medical Center).[34] DOD has regulations that require most more-than-minimal-risk research proposals to be subjected to a second level of review by each military medical service at a central oversight office.[35] The Army, for example, requires greater-than-minimal-risk research protocols to undergo a second level of review at the Human Use Review and Regulatory Affairs Division (HURRAD) and the Human Subjects Research Review Board or the Clinical Investigation Regulatory Office (CIRO).[36]