Chapter 14 -- Current Federal Policies Governing Human Subject Research

Chapter 14: Introduction

Each year many thousands of people participate in biomedical and behavioral research projects conducted, sponsored, or regulated by federal agencies. The federal government invests roughly $3.5 billion annually in research that involves human subjects.[1] The Committee wanted to establish what the federal government currently does to protect the rights and interests of these subjects. The answers to this question all emanate from a seminal event in the history of human subjects research, the adoption of what is widely known as the "Common Rule."

A single, general set of regulatory provisions governing human subjects protections was adopted by sixteen federal departments and agencies[2] in 1991; the Common Rule specifies how research that involves human subjects is to be conducted and reviewed, including specific rules for obtaining informed consent.[3] The Common Rule was developed in response to recommendations made by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research in 1981 calling for the adoption by all federal agencies of Department of Health and Human Services regulations then in effect for the protection of human subjects of research.[4] In mid-1982 the President's science adviser, the head of the Office of Science and Technology Policy (OSTP), appointed an ad hoc committee that included the federal departments and agencies engaged in research involving human subjects to address these recommendations.[5] Nine years later, the Common Rule was the result of this committee's efforts.

History of the Common Rule Since 1974[a]

a . For a brief history of federal protections for human subjects prior to 1974, see chapter 3.

The promulgation of the Common Rule was a significant achievement. The ability of the Common Rule to protect the rights and interests of human subjects is, however, at least partially dependent on how the departments and agencies to which the Common Rule applies implement and oversee its provisions. As a foundation for the Advisory Committee's recommendations concerning contemporary policies and practices regarding human subjects, we asked the sixteen federal agencies and departments that conduct human subjects research to provide us with information on the relevant policies and practices currently in place. In this brief descriptive overview, we focus on six agencies within the scope of the Advisory Committee's charter: the Department of Defense (DOD), Department of Energy (DOE), Department of Health and Human Services (DHHS), Department of Veterans Affairs (VA), National Aeronautics and Space Administration (NASA), and the Central Intelligence Agency (CIA). (Information on the ten other agencies covered by the Common Rule is provided in a supplemental volume to this report.)

The following sections briefly describe the institutional structures, review mechanisms, and policies prescribed by the Common Rule and the variety of ways in which federal agencies attempt to ensure that human subjects are adequately protected in the conduct of research. The chapter closes with a review of an issue of particular importance to the Advisory Committee--the status of protections for human subjects of classified research.[6]



Chapter 14: The Federal Policy for Human Subject Protections (The Common Rule)

The Common Rule applies to all federally funded research conducted both intra- and extramurally. The rule directs a research institution to assure the federal government that it will provide and enforce protections for human subjects of research conducted under its auspices. These institutional assurances constitute the basic framework within which federal protections are effected. Local research institutions remain largely responsible for carrying out the specific directives of the Common Rule. They must assess research proposals in terms of their risks to subjects and their potential benefits, and they must see that the Common Rule's requirements for selecting subjects and obtaining informed consent are met.

As discussed below, central to the process of ensuring that the rights and well-being of human subjects are protected are institutional review boards (IRBs). The Common Rule requires that a research institution, as a condition for receiving federal research support, establish and delegate to an IRB the authority to review, stipulate changes in, approve or disapprove, and oversee human subjects protections for all research conducted at the institution. IRBs are generally composed of some combination of physicians, scientists, administrators, and community representatives, usually at the local research institution, but sometimes at an agency that conducts intramural research.[7] IRBs have the authority to suspend the conduct of any research found to entail unexpected or undue risk to subjects or research that does not conform to the Common Rule or the institution's additional protections.

A prominent feature of the Common Rule is the informed consent requirement. The informed consent of a competent subject, along with adequate safeguards to protect the interests of a subject who is unable to give consent, is a cornerstone of modern research ethics, reflecting respect for the subject's autonomy and for his or her capacity for choice. Informed consent is an ongoing process of communication between researchers and the subjects of their research. It is not simply a signed consent form and does not end at the moment a prospective subject agrees to participate in a research project.

The required elements of informed consent stipulated by the Common Rule are summarized as follows:

The Common Rule includes several additional elements of consent that may be appropriate under particular circumstances[9] and describes the conditions under which an IRB may modify or waive the informed consent requirement in particular research projects.[10]

When an IRB reviews and approves a research project, it must pay particular attention to the project's plan for obtaining subjects' informed consent and to the documentation of informed consent. The IRB may require changes in the investigator's procedure for obtaining informed consent and in the consent documents. The board also must be allowed to observe the informed consent process if the IRB considers such oversight important in ascertaining that subjects are being adequately protected by that process.[11]



Chapter 14: Research Involving Ionizing Radiation

Beyond the strictures of the Common Rule, research involving either external radiation or radioactive drugs usually undergoes additional reviews for safety and risk (including a review of radiation dose) prior to IRB review at the local research institution. Most medical institutions have a radiation safety committee (RSC) responsible for evaluating the risks of medical activities involving radiation, whether for diagnostic, treatment, or research purposes, and limiting the exposure of both employees and subjects to radiation. In addition, research and medical institutions that perform basic research involving human subjects and radioactive drugs must have such studies reviewed and approved by a radioactive drug research committee (RDRC)--a local institutional committee approved by the Food and Drug Administration (FDA) to ensure that safeguards, including limitations on radiation dose, in the use of such drugs are met.[12] Notwithstanding the prior review and approval of either or both of these radiation committees, the IRB must also assess the risks and potential benefits of the proposed research before approving it.[13]



Chapter 14: Scope of Programs of Research Involving Human Subjects

The six federal departments and agencies (DHHS, DOD, DOE, NASA, VA, and CIA) all conduct or support research involving human subjects. Each agency's program is distinctive in terms of its scope, organization, and focus, all of which reflect the primary mission of the agency.

DHHS is the largest federal sponsor of research involving human subjects, with approximately $367 million in intramural funding and $2.4 billion in extramural support for clinical research in fiscal year 1992, the latest year for which an estimate of extramural research funding is available.[14] Intramural research is usually conducted by agency staff members at various field sites, while extramural research is conducted outside the agency by contractors or grantees such as universities. Most of this research is biomedical, and some involves the use of radiation in experimental diagnostic and therapeutic procedures or as tracers in basic biomedical research.[15] The U.S. Public Health Service (PHS) is the operating division of DHHS and the principal health agency of the federal government.[16]

The DOD conducts biomedical and behavioral research involving human subjects within each of the military services and through several additional defense agencies, primarily in areas that support the mission of the department. In fiscal year 1994 DOD spent an estimated $77 million on intramural and $107 million on extramural human subjects research.[17]

The VA operates 171 inpatient medical centers, including short-term hospitals, psychiatric and rehabilitation facilities, and nursing homes. The VA's largely intramural biomedical research program focuses on the health care needs of veterans. The VA spends approximately $114 million annually in appropriated research money on human subjects research, along with another $110 million in staff clinicians' time. Other federal agencies and private entities also support research in VA facilities.[18]

The DOE conducts and supports research, both intramurally and extramurally, involving human subjects that ranges from diagnostic and therapeutic applications in nuclear medicine to epidemiological and occupational health studies. DOE laboratories also receive funding from other federal agencies such as the NIH and from private sponsors of research. DOE spends $46 million annually on human subjects research, more than $20 million of which is devoted to the Radiation Effects Research Foundation (RERF) in Japan, which is charged with studying the health effects of exposure to radiation from atomic weapons.[19]

Both intramurally and extramurally, NASA conducts ground-based and in-flight biomedical research involving human subjects related to space life. In fiscal year 1994 NASA spent approximately $25 million on ground-based human subjects research.[20]

The CIA supports or conducts a small number of intramurally and extramurally conducted studies involving human subjects each year.[21] No figure for the annual dollar amount spent by the CIA was made available to the Advisory Committee.



Chapter 14: Administrative Structures and Procedures for Research Oversight

The following is an overview of the administrative structures and procedures used by the six departments and agencies to ensure compliance with human subjects ethics rules, particularly as they relate to the Common Rule. The Advisory Committee asked each of these agencies to provide the following information on its program of protections for human subjects involved in research:

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]



Chapter 14: Federal Responses to Violations of Human Subjects Protections

In the event that the Common Rule is violated in the conduct of federally sponsored research involving human subjects, there are various responses that can affect both investigators and grantee institutions, such as withdrawal or restriction of an institution's or project's assurance and, with that action, of research funding and suspension or termination of IRB approval of the research. In addition, an IRB is authorized by the Common Rule to suspend or terminate its approval of research that fails to comply with the IRB's requirements or when a research subject suffers an adverse event.[37] No federal department or agency may continue to fund a project from which IRB approval has been withdrawn or at an institution whose assurance has been withdrawn.[38]

An institution's or investigator's prior performance with respect to human subjects protections may affect future federal funding as well. If human subjects protection regulations are willfully violated, the department secretary or agency head may bar the organization or individual from receiving funding from any federal source.[39] Such debarment must be for a specified length of time and, in some extreme cases, may be permanent.

Federal agencies may also take disciplinary action against employees involved in human subjects research for failure to follow human subjects protection rules. For example, DOD sanctions for noncompliance by intramural researchers include loss of investigator privileges. For military personnel, potential sanctions are letters of reprimand, nonjudicial punishment, and sanctions under the Military Code of Justice; for civilian DOD personnel, sanctions include reprimands, suspension, or termination of employment.

No requirement of the Common Rule can preempt state and local laws governing the conduct of human subjects research that are stricter or provide additional protections for subjects. Of those states with any laws governing research involving human subjects, only California authorizes sanctions for failure to obtain a subject's informed consent.[40] The California statute authorizes monetary awards for negligent failure to obtain a subject's informed consent (up to $1,000), for willful failure to obtain such consent (up to $5,000) and, if a subject is thereby exposed to "a known substantial risk of serious injury either bodily harm or psychological harm," jail terms of up to one year and/or fines of up to $10,000.



Chapter 14: Protections for Human Subjects in Classified Research

We were advised that the only classified studies involving human subjects currently conducted by the six federal agencies are a small number of projects sponsored by the DOD and the CIA.[41] The Common Rule does not distinguish between classified and unclassified research in terms of the requirements or procedures it imposes to protect human subjects.

The Department of Defense reported that it currently sponsors a small number of classified research studies involving human subjects.[42] When such research is proposed, IRBs review classified protocols in one of two ways. The chair of the IRB may remove the classified portions of the protocol if he or she judges that those classified portions have no effect on the risks imposed on human subjects. Alternatively, the IRB may be composed of people with appropriate security clearances who then review the protocol in its entirety. A person not affiliated with the institution but with appropriate security clearance is included as a voting member of such IRBs.

The CIA indicated that it is currently performing classified human research projects.[43] The agency informed the Advisory Committee that all human subjects are informed of the CIA's sponsorship and of the specific nature of the study in which they are participating, even if the general purposes of the research are classified.[44]

Although DOE has the authority to conduct or support classified human subjects research projects, it reports that it is not currently conducting such research.[45] According to DOE guidelines, IRB review of classified research may take one of two forms.[46] If the chair of the IRB determines that none of the classified information in a proposal is relevant to the protection of human subjects and that the research can be accurately and fully described to the IRB, the proposed research will be reviewed at a regular IRB meeting without disclosure of any classified information. If the proposed research cannot be reviewed in the foregoing manner, however, the IRB must meet in a secure environment. (The Advisory Committee was advised that to date this has not occurred.) To review classified research, each member of the IRB must have the appropriate security clearance. The member of the IRB who is not affiliated with the institution conducting the research must also have security clearance to participate in the review of classified research. DOE guidelines recommend that IRBs expecting to review classified research obtain clearance for their nonaffiliated members so that they are not excluded from such reviews.

DHHS neither conducts nor sponsors any classified research. Some FDA personnel hold security clearances so that they may review classified investigational new drug or device applications submitted by the DOD, if the need to study or use these items in secret arises.[47] The VA does not now conduct any classified research and does not have original classification authority.[48] NASA currently conducts no classified research that involves human subjects and has not in the past. NASA does have classification authority, however, and conducts some classified research that does not involve human subjects.[49]

Research that involves human subjects and is classified for reasons of national security raises special issues for IRB review and for the process of obtaining informed consent, particularly with respect to the level of disclosure and waivers of informed consent. Specifically, the IRB must consider whether the prospective research subject will be adequately informed about the nature of classified research if some aspects of the research will not be disclosed in the informed consent process, whether security clearances are needed for IRB members, and whether information about classified studies must be partitioned from other IRB study reviews. Institutional review boards can determine that some aspect of a classified research project, if only the identity of the research sponsor, is irrelevant to the process of obtaining a subject's informed consent to participate. IRB members can decide that sponsorship information or complete disclosure of the purpose of the research need not be provided to potential subjects (in contrast to information about physical risk).

The Common Rule grants IRBs the authority to approve modifications in, or to waive entirely, informed consent requirements, but only for research involving no more than minimal risk.[50] A separate provision grants an agency head the authority to waive any requirement of the Common Rule for any kind of human subject research as long as advance notice is given to OPRR and the action is announced in the Federal Register.52 As indicated above, the rule makes no distinction between classified and unclassified research, so this latter route to an informed consent exception would appear to pose a tension between duties to disclose and the need to keep information secret.



Chapter 14: Conclusion

The Common Rule, adopted by the sixteen federal agencies and departments that conduct human subjects research, is another step in the evolution of human subject research protections policies begun in the 1940s. While those protections are crucial, gaps still remain.

With respect to classified research, the current requirement of informed consent is not absolute; if consent is waived, the research may proceed in ways that do not adequately protect the research subject. Also, military research involves special considerations because of the nature of the subject population, whose voluntary participation must be especially guarded. In addition, nonfederally funded research is not subject to the Common Rule, except under the umbrella of an institution's multiple project assurance.

Further, oversight mechanisms generally are limited to audits for cause and review of paperwork requirements. These offer little in the way of assurances that the prospective review process is working and do not give an indication of the quality or consistency of IRB review, either among IRBs or within a single board. An effective system of oversight relies on the detection of violations of policies and the imposition of appropriate sanctions.

The Committee's recommendations for remedying these and other shortcomings are discussed in chapter 18 of the final report. The remaining two chapters of part III report what documents used by IRBs suggest about the protection of human subjects and what patients think about the enterprise of human subject research.



Table 1: Human Subjects Research & Protections in Seven Departments and Agencies Part I

Table 1: Human Subjects Research & Protections in Seven Departments and Agencies Part I


Table 1. Part II

Table 1: Part II

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