1995; Farquhar et al. 1985; Jacobs et al. 1986), there has been an increase in the number of research studies con-ducted in community settings (Mittelmark et al. 1993).
As the behavioral and social determinants of more diseases are known (e.g., HIV/AIDS, lung cancer, heart attack, stroke), the focus of intervention strategies has broadened from the individual to the population, and the research setting has in some cases moved into the com-munity (Schneiderman and Speers 2000). For example, research on cigarette smoking once focused on cessation efforts, and interventions were targeted at individuals (DiClemente et al. 1991). Now, with the emphasis on prevention of smoking behavior, research interventions are often targeted at particular populations and carried out at the community level (Cummings 1999). With such community-oriented research interventions, defining the research participants and identifying the appropriate participant protections can be difficult.
Increasingly, research is conducted with communities, not on communities (Bracht 1991; George et al. 1996).
Local community groups and organizations often act as collaborative investigators by sharing responsibility with academic investigators in designing and implementing a research study (Hatch et al. 1993). However, this new collaborative role of the community raises many issues related to research infrastructure and oversight. For example, it is unclear when community groups must have an IRB and how to build capacity within the com-munity to carry out these regulatory responsibilities.
Issues related to just what individual or which group speaks for the community as a whole and how to obtain community input or consent are continuing challenges to conducting such research.
Major Challenges Facing the Current
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such as IRB membership, education of IRB members and investigators, institutional commitment, IRB initial and continuing review of protocols, review of protocols involving vulnerable persons, and procedures for obtaining voluntary informed consent.
The recent academic literature regarding the current oversight system for the protection of human research supports many of the findings from these reports (Edgar and Rothman 1995; Moreno et al. 1998; Phillips 1996;
Snyderman and Holmes 2000; Woodward 1999). There is general recognition that because the nature and context of research have changed, the nature and structure of the oversight of research also must change. For example, Moreno et al. argue that the federal regulations should be revised to reflect changes that have affected the nature and context of research, such as the increased importance of multi-site studies (1998). They also argue that the federal regulations should be responsive to certain needed protections that have been identified, but were not enacted when the Common Rule was issued (e.g., protections for individuals categorized as vulnerable).
Others, including Edgar and Rothman, argue that the expansion of the scientific frontier requires that ethics review mechanisms other than local IRBs should be con-sidered, such as national, topic-specific advisory panels (1995). Edgar and Rothman also characterize the local IRB as a “paper tiger,” buried in paperwork and often unable to deal effectively with ethical issues (1995).
While more protection may be needed in some areas, another concern is the overwhelming burden that is placed on IRBs and investigators and the extent to which unnecessary paperwork requirements are displacing a focus on important ethical issues. For example, Phillips points to the growing frustration among investigators and IRBs that has resulted from the increase in administrative and regulatory requirements without a commensurate increase in protection (1996). Some support the need for oversight while still perceiving regulatory and compliance mechanisms, such as reporting requirements, as difficult to interpret, redundant, and inefficient (Snyderman and Holmes 2000).
Others perceive the problems with the current over-sight system as failures to address such issues as inade-quate funding, lack of adeinade-quate education for IRB
members and investigators, and insufficient focus on conflicts of interest in research (Amdur 2000; Shamoo 1994; Snyderman and Holmes 2000; Sugarman 2000).
Overall, there is broad agreement in the academic literature that the current oversight system is in need of improvement.
Inconsistent Interpretation and Implementation of the Regulations by Federal Agencies
The creation of the Common Rule (see Appendix C) provided significant unification in the language of federal regulations for the protection of human research partici-pants. However, the Common Rule did not create a shared mechanism for interpreting and implementing the regulations at the federal level. In the absence of a formal mechanism, OHRP sometimes acts as a de facto reference point and consensus builder among federal agencies, even though it has no congressional or executive authority to do so. Moreover, some other departments have not established offices comparable to OHRP for interpreting and implementing the regulations; in some cases, a single individual is responsible for oversight activities. Thus, the ability to coordinate oversight among the depart-ments is weak, leading departdepart-ments and agencies bound to the Common Rule potentially to interpret regulatory requirements differently (see Exhibit 1.2). In addition to varying substantive interpretations of the regulations, departments and agencies use different procedures to ensure compliance. This issue is further discussed in Chapter 2.
Incomplete Protection of Individuals Considered Vulnerable
Some federal departments have supplemented the Common Rule with additional regulations and policies.
For example, DHHS provides additional protections for pregnant women and fetuses, prisoners, and children (45 CFR 46 Subparts B, C, and D).22 The Central Intelli-gence Agency and the Social Security Administration (SSA) also follow these regulations for groups that are considered vulnerable. The Department of Education has adopted protections for children (34 CFR 97 Subpart D), and the Department of Justice has adopted protections for research conducted within the Bureau of Prisons (28 CFR 512). In addition, although FDA’s regulations do not include
Exhibit 1.2: Examples of Inconsistencies Among Agencies Bound to the Common Rule
There is wide variation among federal departments and agencies regarding their policies and procedures for deter-mining whether a research activity is exempt from the federal regulations (45 CFR 46.101). Differences could be due to the variability in the types of research sponsored; however, they also could be due in part to inconsistent inter-pretation of the regulations. As shown in Table 1.1, many agencies report that all, or nearly all, of the research that they conduct or sponsor is exempt from the federal regulations.
The procedures used to make these determinations vary across agencies. In general, agencies use their IRB chair to determine whether research conducted by the agency is exempt, and a combination of technical and legal staff determine exemptions for human participant research sponsored through grants and contracts. Some agencies have customized administrative mechanisms for making these determinations. For example, the Census Bureau consid-ers all of its research to be exempt under Federal Policy 15 CFR 27.101 (b)(3)(ii), which exempts survey procedures if “federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and hereafter.” However, privacy and confidentiality issues that relate to human participants are brought to the Census Bureau’s Policy Office. The Census Bureau’s Disclosure Review Board has primary responsibility for ensuring confidentiality in published reports and data products.
SSA does not have an IRB, because it claims that all of its research is exempt. This exemption took effect on April 4, 1983,23as a result of a final DHHS rule published on March 4, 1983. Research carried out under section 1110(b) of the Social Security Act, however, remains subject to the Common Rule’s informed consent requirements. The 1983 notice states that “[i]n order to insure the continued protection of human subjects participating in such [otherwise exempt] research activity, the Department is adding a specific requirement of written, informed consent in any instance, not reviewed by an IRB, in which the Secretary determines that the research activity presents a danger to the physical, mental, or emotional well-being of a participant.”24In the case of biomedical and behavioral research, in the 1983 Federal Registernotice, DHHS makes clear the need for IRB review, but states that such review would be “unnecessary and burdensome in the context of research under the Social Security Act and otherwise.”25DHHS discusses, but rejects, several proposals for IRB review of research and demonstrations to support public benefit or service programs and concluded that “ethical and other problems raised by research in benefit programs will be addressed by the officials who are familiar with the programs and responsible for their successful operations under state and federal law.”26 SSA reviewed the 1983 regulation with OHRP/OPRR and concluded that it continues to apply to SSA research and demonstrations. In 1999, SSA did not conduct any extramural human participant research or demonstrations under section 1110(b).
The Health Resources and Services Administration (HRSA, DHHS) reported that nearly all of its research activity comprises program evaluation or evaluation of demonstration projects, which are considered to be exempt from the federal regulations under the public “benefit and service” criterion. However, HRSA requires such a claim of exemption to be approved by the HRSA Human Subjects Committee. Otherwise IRB oversight is required.27
Furthermore, even within DHHS, both substantive and procedural differences can be found, notably between FDA and DHHS regulations. These differences relate to informed consent, the definition of research, emergency research, assurances of compliance, inspections by the sponsoring agency, sanctions for noncompliance, and additional protections for vulnerable populations.
Whatever the source, inconsistency among departments and agencies can lead to confusion and frustration among some investigators and IRBs28 and can render the oversight system unnecessarily confusing and open to misinterpretation. Not only do different rules apply to different research studies, but a single study may be subject to more than one set of regulations if it is sponsored or conducted by institutions that are required to follow more than one set of rules. IRBs and investigators are often uncertain which rules apply or to whom they must report. For example, an NIH-funded study involving an FDA-regulated investigational drug conducted in a VA hospital would be subject to the regulations and oversight of three different departments or agencies (45 CFR 46; 21 CFR 50,56;
38 CFR 16).
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protections for vulnerable individuals analo-gous to the DHHS subparts, a law passed in 2000 requires DHHS to apply Subpart D of 45 CFR 46 to all research conducted, supported, or regulated by the department, including research regulated by FDA.29FDA subsequently issued an interim rule incorporating Subpart D into its regulations.30It is noteworthy, however, that so few Common Rule signatories have adopted additional protections for individuals who are considered vulnerable, in effect providing incomplete protection for human research participants. (The protection of indi-viduals and groups that are categorized as vul-nerable is discussed in detail in Chapter 4.) Lack of Adaptability
Some of the regulatory challenges are exacer-bated by the fact that the Common Rule is difficult to amend. Amending the Common Rule requires that each signatory agency first agree to a revision before the 15 agencies with regulations go through the rulemaking process to revise the regulations.31 This weakness results in a set of regulations for which no system-wide change is possible. Obtaining concurrence of the departments and agencies on any regulatory change so far has proven impossible, although not because of lack of need or effort.32The addition of regulations to the Common Rule specific to classified research, for example, has not been achieved despite three years of effort, a Presidential Memorandum directing the change, and a challenge in a U.S. District Court.33
Unable to change the regulations, some departments have attempted to make modifica-tions by issuing regulatory guidance, a strategy used by the VA in issuing regulations for providing treatment for injuries resulting from participation in research (38 CFR 17.85).
However, the power of such changes is limited, and because guidance is usually department specific, it promotes inconsistency and under-mines the very unification the Common Rule is Table 1.1: Percent of Human Participants Research
Determined to Be Exempt by Federal Agencies
Agency Estimated Percent
of Human Participants Research Deemed Exempt*
Central Intelligence Agency 0
Department of Commerce 60–100
Department of Defense 80
Department of Education 60
Department of Energy unknown
Department of Health and Human Services
Administration for Children and Families 0
Administration on Aging unknown
Agency for Healthcare Research and Quality 20–90 Centers for Disease Control and Prevention 10
Food and Drug Administration <10
Health Care Financing Administration 100 Health Resources and Services Administration 100
Indian Health Service 20
National Institutes of Health <10 Substance Abuse and Mental Health
Services Administration ~100
Department of Housing and Urban Development 40
Department of Justice 0–80
Department of Transportation 5
Department of Veterans Affairs unknown National Aeronautics and Space Administration 0
National Science Foundation 80–100
Social Security Administration 100
Agency for International Development 50 Consumer Product Safety Commission 50–100
Environmental Protection Agency 3–5
*Some departments reported data for several units. The range represents the differ-ences in data reported.
Source: NBAC, “Federal Agency Survey of Policies and Procedures for the Protection of Human Subjects in Research.” This staff analysis is available in Volume II of this report.
supposed to establish. (Further discussion of this issue and recommendations appear in Chapter 2.)
Limited Scope
The Common Rule was intended to both provide uni-formity across federal departments and expand the scope of regulations to federal departments that previously had none. However, although it marked a significant expan-sion in scope, the Common Rule still does not apply to all federally sponsored research.
Existing regulations also do not apply to many areas of research funded and conducted by businesses, private nonprofit organizations, and state or local agencies, although such research may be subject to federal regula-tion if it involves the development of medical devices or drugs requiring approval by the FDA or if it is conducted at an institution that has voluntarily agreed to apply Common Rule requirements to all research it conducts.
An unknown amount of nonfederally funded research is completely unregulated under the federal system. This research may include experimental surgical techniques, research on reproductive technologies, some uses of approved drugs and medical devices, and research use of private, identifiable data.34 In some cases, nonfederally funded research may be subject to state regulations, or investigators may voluntarily meet federal requirements to reduce research-related liability. (Recommendations regarding expanding the scope of the system to include such research appear in Chapter 2.)
Enforcement Weaknesses
Even for research that is subject to federal regulations, the mechanisms for enforcing them suffer from three potential weaknesses; the lines of enforcement authority are awkward and sometimes isolated; there is a limited repertoire of sanctions to match the range of possible violations; and the oversight and monitoring process is uneven.
First, there is no clear line of authority or system for the federal government as a whole to sanction serious or repeated noncompliance by investigators or institutions.
This results from the dispersion of enforcement functions among various departments and agencies, which weakens the sanctions any one department can impose because
investigators could continue research overseen by a dif-ferent authority. Each federal department that adheres to the Common Rule has the authority to enforce its own codification of the Common Rule for research it conducts or sponsors. However, federal agencies and institutions with assurances of compliance (formal commitments by institutions to the government stating that they comply with federal regulations) from OHRP are subject to enforcement from that office as well. In the case of DHHS grantees and contractors, the enforcement authority is clear because OHRP is part of DHHS. But, when the assurance holder is the grantee of another department, OHRP decisions come from outside the regular reporting line of authority. Additionally, departments that do use the OHRP assurance process may have their own separate systems for enforcement, and there is little coordination among the various offices responsible for ensuring compliance with the Common Rule.
Second, concerns have emerged that enforcement authorities do not have or use an adequate range of sanc-tions to respond to various forms of noncompliance.
Federal regulations give department and agency heads the authority to terminate or suspend funding for research projects that are not in compliance with the regulations (45 CFR 46.123(a)). Common enforcement tools are the requirement of written responses or the enactment of specific changes to address the identified deficiencies; those who grant assurances can also restrict or suspend institutional assurances. Under its regulations, FDA can withhold approval of new studies, prohibit enrollment of new subjects, and terminate studies. FDA can also issue warning letters and can restrict or disqualify investigators, IRBs, or institutions from conducting or reviewing research with investigational products.35 However, a more complete range of sanctions should be considered for enforcement authorities.
Third, any system of sanctions can only be as good as the monitoring and investigating processes that are used to determine their need. The Common Rule does not set out agency responsibilities for monitoring IRBs or inves-tigators. Some agencies, such as DOE, have a program of routine site reviews.36 Other agencies, such as DHHS, conduct only “for cause” investigations, generally because limited budgets do not permit more proactive
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monitoring. Investigations often take a long time (in some instances over a year)37and usually do not include on-site visits (OIG 1998a).
This lack of centralized enforcement authority, pro-portionate sanctions, and active research oversight serves to weaken severely the system for protecting human research participants. Any one of these weaknesses alone or in combination can lead to unnecessary bureaucracy and burden that could be reduced by a unified office for oversight, which could serve to simplify the bureaucratic complexity and lead to improved monitoring and enforcement.
Overemphasis on Procedural Requirements Rather Than Ethical Principles
In addition to the challenges described above, the current regulations suffer from other weaknesses. For example, they do not sufficiently embody and reflect the substantive ethical principles and standards that should govern behavior, but instead focus on the procedural aspects of IRB review. Thus, although IRBs may review research in accordance with an appropriate focus on ethical behavior, they are ultimately held responsible primarily for procedure and documentation. OHRP’s Compliance Activities: Common Findings and Guidance (OHRP 2000) reflects this emphasis on the regulations by focusing on the procedures by which protocols are reviewed—for example, inappropriate use of expedited review and exemptions, lack of a quorum, less than annual continuing review, and failure to document required findings or votes (OHRP 2000). The emphasis by regulators on procedure is frustrating to IRBs and investigators38 and also contributes to an atmosphere in which review of research becomes an exercise in avoid-ing sanctions and liability rather than in maintainavoid-ing appropriate ethical standards and protecting human participants. (Chapters 4 and 5 offer recommendations regarding IRB review and the emphasis on procedural requirements.)
Regulations Not Adequately Addressing All Types of Research
Another weakness in the current regulations is that they fail to adequately address unique ethical issues that arise in different types of research. Although federal
regulations for human research have long applied to the social sciences and humanities as well as biomedical research, their articulation reflects a persistent emphasis on clinical or biomedical research. Indeed, with regard to nonclinical activities, it is sometimes difficult to determine which activities constitute human research and are therefore subject to the regulatory requirements.
In addition, quality improvement studies in health care organizations, public health studies, program evaluation, and humanities research may require review by an IRB in some institutions, but not in others.
Applied to nonclinical research and particularly to the humanities and social science research, the regulatory requirements seem to be either irrelevant or insufficient to provide protection, depending on the type of research.
For example, requirements for written documentation of consent may be inappropriate for some survey and anthropological research. Recently, the Association of American University Professors issued a report stating that IRBs often “mistakenly apply standards of clinical and biomedical research” to social science and historical research, which adversely affects not only the quality of the research but inadequately protects human research participants (AAUP 2000). In other areas, the regulations are insufficient—for example, with regard to protecting privacy and confidentiality. Although the regulations require “adequate provisions” to protect privacy and con-fidentiality, nonphysical harms, such as those resulting from breaches of confidentiality, are often difficult for IRBs to assess without more specific regulatory guidance (45 CFR 46.111(a)(7); 21 CFR 56.111(a)(7)). Much of the difficulty in applying the federal regulations is due to differences in the nature of the risks associated with non-clinical research. For example, physical harms are rarely a concern in nonclinical research, while psychological, social, economic, and legal harms are more likely to occur and should be the primary concern of IRB review.
IRB Burdens
The quality of IRB review is often compromised by the burden of excessive paperwork, because although IRBs are broadly charged with ethical review, in practice they also must fulfill many procedural requirements.
While some of these requirements are designed to ensure compliance with ethical standards (e.g., documentation
of waiver of informed consent), others appear to have little relevance to ethical standards or the protection of participants (e.g., requirements for documentation in meeting minutes). In all of their deliberations, IRBs must keep track of a range of detailed regulations and document the grounds on which they make decisions in accordance with them. In addition, IRBs must comply with numerous regulations regarding their operations. However, some of the regulatory and paperwork requirements governing IRBs are difficult to interpret (NBAC 1999b), unneces-sarily burdensome, and often not commensurate with their contribution to protecting research participants.
One particularly time-consuming task for investiga-tors, IRBs, and institutional officials is the preparation of assurances. Although many domestic research institutions have an MPA, which covers all research and generally needs to be renewed every five years, other institutions must obtain a separate assurance for each funded project (i.e., a Single Project Assurance, or SPA). For multi-site and international research, this process can be particularly time consuming. Even institutions with an MPA must often revise or amend that document to include changing institutional affiliates as well as affiliation agreements between specific investigators and individual physicians, practice plans, and health care institutions.39
In addition, many IRBs lack the basic resources of staff, space, and technology (Sugarman 2000). Without strong professional and clerical support, busy IRBs remain mired in paperwork and are often unable to focus on ethical considerations. One can get a sense of the unmet resource needs of IRBs from the institutional responses to OPRR shutdowns; large institutions are routinely creating several new IRBs to share the review workload and adding several additional full-time IRB staff (Desruisseaux 2000; Phillips 2000).40
Because of the large workload, serving as an IRB member or chair requires a significant time commitment, with many hours spent in and out of meetings reviewing protocols and writing reports. Few IRB members receive compensation or recognition for their efforts. Thus, with little financial or academic support for IRB membership, IRBs must rely heavily on the goodwill of individual members, which can make it difficult to attract and retain members. (Recommendations related to reducing bur-dens on IRBs are discussed in Chapters 4, 5, and 6.)
Multi-Site Research Studies
Multi-site research, discussed further in Chapter 6, poses its own set of problems for local IRBs. The growing importance of multi-site research has challenged funda-mental assumptions about the importance of local review, for the more IRBs duplicate each other’s work by review-ing the same protocols, the more pressure there is to show why multiple local reviews of identical research protocols are needed. Although local review can provide insight about the social and cultural context of a study, the facilities in which it will be carried out, and any local laws or policies that might affect the study, IRBs may be squandering precious resources when dozens or hundreds of them must review all aspects of a single, multi-site protocol when the design and methods are unlikely to be changed.
IRBs are not the only groups frustrated by multi-site research. Investigators and sponsors are discouraged by having to submit protocols to multiple boards, particu-larly because changes requested by one board usually have to be approved by the others, a repetitive process that is labor intensive and that can significantly delay research, with little resulting benefit.
Another difficulty is that local IRBs are sometimes poorly situated to review multi-site research. Although IRBs and institutions have the authority to require changes for their site or to refuse to approve a multi-site study about which they hold serious reservations, in practice they are hesitant to use that authority. Thus, although local IRBs may modify recruitment procedures and consent forms, it may be that no single IRB has the power to require substantive changes to a study design, which must remain standardized across sites.
Multi-site research also poses problems with regard to continuing review (mandated, periodic review of research in progress) and review of adverse events. Many IRBs find themselves reviewing a staggering number of reports of adverse events that have occurred at other sites, often without any context, such as the total number of participants in a protocol or whether an adverse event occurred with the experimental or control intervention.
Even when they have this information, IRBs sometimes lack the expertise to assess its significance in terms of the risks and potential benefits to trial participants.