The focus of this chapter is regulatory requirements related to the conduct of research, specifically those regulations and policies that protect the wellbeing of research participants (both human and animal) and ensure the integrity and credibility of research findings. The specific areas of consideration are conflict of interest (COI), human subjects research, and animal subjects research.
CONFLICT OF INTEREST
A number of organizations have defined COIs in research and medicine. The Institute of Medicine has defined COI broadly as a set of circumstances resulting in a risk that a person’s professional judgments or actions regarding a primary interest will be unduly influenced by a secondary interest.1 The Public Health Service (PHS) has taken a narrower view and specifically defined financial conflict of interest (FCOI) as a significant financial interest that could directly and significantly affect the design, conduct, or reporting of PHS-funded research, but has extended required oversight to the researcher’s other institutional responsibilities.2
COIs are common in all professions, and the professions have over time developed normative behavioral and transactional processes to prevent or mitigate the undue influence of these conflicts on professional judgments, choices, and decisions.3 Secondary interests that may produce conflicts are diverse, but financial gain has been the major focus of federal policies. In the research context, the question is whether the financial interest might have an effect on the design, conduct, or reporting of research being directed or performed by the researcher. Federal policies also often define monetary thresholds for financial
1Institute of Medicine, Conflict of Interest in Medical Research, Education, and Practice (Washington, DC: The National Academies Press, 2009), p. 46.
3David Korn, “Conflicts of Interest in Biomedical Research,” JAMA 284, no. 17 (2000).
interests of concern. COIs are inevitable at research institutions, whose missions include the promotion of the public good by both creating new knowledge and facilitating the transfer of that knowledge to the private sector. Research universities, and the scientific profession itself, encourage faculty to engage in activities that fulfill this mission not only through publications but also by outside speaking engagements at conferences and professional meetings, consulting with commercial and nonprofit entities, and the commercialization of technologies derived from their basic research through university technology licensing offices. While it is appropriate for faculty to be rewarded for their activities that are part of the university’s mission to benefit the larger society, the individual and the university must closely monitor these activities for COIs to ensure that an individual’s decisions or actions are not unduly influenced by considerations of personal financial gain.4
Outside professional activities allow researchers to provide their expertise to commercial and nonprofit organizations beyond their institution and compensation for this work is appropriate; consequently, it is critical to note that having FCOIs is not research misconduct. The federal definition of research misconduct is fabrication, falsification, or plagiarism in proposing, performing, or reviewing research or in reporting results.5 FCOIs have accompanied instances of research misconduct, thus contributing to conflation of the two in the minds of the public, the media, and legislators. Research misconduct is by definition a severe threat to the research enterprise and is addressed by federal and institutional policies. In marked contrast, most circumstances where an investigator’s financial interests are related to her or his research responsibilities can be evaluated and managed to ensure that the individual’s professional decisions are not unduly influenced by potential financial gain.
Nature of Concern
Beginning in the mid-1970s and continuing through the 1980s, a series of widely publicized episodes of scientific misconduct and of harm to human re-
4Institutions also have financial interests (e.g., patent income) that must be managed to avoid impact on university research, but this section focuses on COIs of individual investigators and related federal COI policies. Research institutions also have institutional COI policies. In the late 1990s, reports from the HHS OIG and the Government Accountability Office, among others, raised questions about the effectiveness of institutional review boards (IRBs) and how well the safety of human research subjects was being protected. These reports raised the question of institutional COIs: that is, IRBs are institutional committees, and if the institutions themselves had financial interests in research outcomes, would that not necessarily bias the IRBs’ reviews? Between 1998 and 2001, the deaths of three research subjects led to substantial media attention, further enhancing the publics’ and legislators’ concerns about the effectiveness of IRBs.
search subjects, some accompanied by FCOIs, aroused congressional ire and resulted in highly contentious hearings in both the House and Senate, culminating in the 1990 report from the House Committee on Government Operations entitled Are Scientific Misconduct and Conflicts of Interest Hazardous to Your Health? In the 1985 reauthorization of the Public Health Act, Congress directed the PHS to regulate scientific misconduct (the regulation was issued in 1989). In acrimonious hearings in 1988 of the House Subcommittee on Oversight and Investigations, Chairman Dingell first raised the matter of ordering the Department of Health and Human Services (HHS) to issue a regulation addressing FCOIs, and the HHS began this effort even though formal authorizing language would not appear until 1993.
The FCOI regulation was issued in 1995. It defined FCOIs in research, and required research institutions to implement and enforce their own COI policies. It also required institutions, whenever they discovered that a grant recipient had a conflicting financial interest, to address the problem by eliminating, mitigating, or managing the conflict. No details or information had to be reported to the agency.
During the first decade of the 2000s, the Office of the Inspector General (OIG) in HHS issued regular reports expressing its concerns about the management of FCOIs in research institutions and the effectiveness of National Institutes of Health (NIH) oversight. In 2008, the OIG issued a report6 that was critical of the NIH’s oversight of FCOIs in awardee institutions, describing them as “grossly inadequate.” That report called for modification of the 1995 regulation to require institutions to provide NIH with details of their investigator’s COIs and their management plans. In 2009, the OIG further criticized research institutions’ oversight and management of faculty COIs.7 Among other things, the report criticized institutions for trusting their faculty members’ reports of financial interests possibly related to their research, and it recommended that NIH require grantee institutions to “develop and disseminate guidance on methods to verify researchers’ financial interests.”
Under continuing heavy pressure from the OIG, in the spring of 2009 the NIH issued an Advanced Notice of Proposed Rulemaking (ANPRM) that incorporated most of the OIG’s recommendations. The ANPRM elicited a flood of critical comments from the research community, though these comments were not reflected in the Notice of Proposed Rulemaking (NPRM) issued a year later, nor in the final rule issued in August 2011, to become effective in August 2012. The PHS COI policy is scheduled for a formal review in August 2015. Major
6National Institutes of Health: Conflict of Interest in Extramural Research (OEI-0306-00460) (Washington, DC: Office of the Inspector General, U.S. Department of Health and Human Services, 2008), https://oig.hhs.gov/oei/reports/oei-03-07-00700.pdf.
7Daniel R. Levinson, How Grantees Manage Financial Conflicts of Interest in Research Funded by the National Institutes of Health (OEI-03-07-00700) (Washington, DC: Office of the Inspector General, U.S. Department of Health and Human Services, 2009), https://oig.hhs.gov/oei/reports/oei-03-07-00700.pdf.
elements of the new regulation are shown in Box 5-1. This reissuance of the PHS regulation failed to acknowledge that institutions were aware of deficiencies in implementing the previous regulation and had taken steps to address these deficiencies—as outlined in their public comments to the agency during the negotiated rulemaking process.8
Many investigators and institutions also must conform to the National Science Foundation’s (NSF) COI policy. NSF, which had essentially adopted the 1995 PHS regulation soon after it was issued, did not adopt the new 2011 PHS regulation or revise its existing policy. NSF requires that investigators disclose all significant financial interests that “would reasonably appear to be affected by the research or educational activities funded or proposed for funding by NSF.”9 This contrasts with the PHS policy that expands disclosures to any significant financial interests that “would reasonably appear to be related to the investigator’s institutional responsibilities which include: research and other scholarly activities; clinical care activities; teaching or educational activities; and administrative activities.”10
The Uniform Guidance directs all federal agencies to create COI policies and requires award recipients to disclose any potential conflicts of interest.11 This is a significant departure from the PHS and NSF policies that focus on existing significant financial interests, not potential conflicts of interest. Furthermore, despite an attempt to have uniform guidance across all federal agencies, the regulation as currently written gives wide latitude to each agency to create its own COI policies—thereby creating the possibility that investigators and institutions would have to comply with multiple different policies issued by different funding agencies, adding substantially to the burden associated with COI compliance. For example, the Environmental Protection Agency (EPA) has defined COI as “an actual or potential situation that undermines, or may undermine, the impartiality of an individual or non-Federal entity because their self-interest conflicts, or may conflict, with their duty and obligations to EPA and the public in performing an EPA financial assistance agreement” (italics added).12,13
8Carol Blum, COGR Comment on RIN 0925-AA53; NIH-2010-0001, Promoting Objectivity in Research for which PHS Funding is Sought (Washington, DC: Council on Governmental Relations, An Association of Research Universities, 2008), http://www.cogr.edu/viewDoc.cfm?DocID=151760.
9“Grant Policy Manual: NSF 05-131,” National Science Foundation, July 2005, accessed August 24, 2015, http://www.nsf.gov/pubs/manuals/gpm05_131/index.jsp?org=EF.
10Promoting Objectivity in Research, 42 CFR 50 (f) (2000).
11“Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards,” Federal Register 78, no. 248 (December 26, 2013): 78590, http://www.gpo.gov/fdsys/pkg/FR-2013-12-26/pdf/2013-30465.pdf.
12“EPA’s Revised Interim Financial Assistance Conflict of Interest Policy,” U.S. Environmental Protection Agency, 2015, accessed August 24, 2015, http://www.epa.gov/ogd/epa_revised_interim_financial_assistance_coi_policy_5_22_15.htm.
13While assessments of impartiality may be relevant in the context of procurement, agency COI policies should recognize the difference between COIs related to an
No other agency has introduced the notion of impartiality to definitions of COIs. This new EPA definition is yet another troubling departure from the PHS and NSF policies that focus on significant FCOIs.
investigator’s personal financial interests that have the potential to bias research, and institutional procurement issues.
The scientific research community recognizes the necessity of appropriately managing FCOIs to ensure the integrity and credibility of scientific findings and the protection of research subjects, and it supports rigorous management approaches. However, several major elements that were included in the expanded scope of the current PHS COI regulation impose undue, and in the committee’s opinion, unnecessary, time and cost burdens on investigators and their institutions (as described below), with no benefit to the integrity of the scientific enterprise and research subjects. The lack of harmonization of COI requirements among different federal research funding agencies emerging from the Uniform Guidance threatens to further and substantially increase these burdens.
Three recent surveys have attempted to characterize and quantify the costs and benefits associated with the new 2011 PHS FCOI regulation. As noted, the new regulation is far more than a “revision” of the 1995 regulation. It is a new regulation. The Association of American Medical Colleges (AAMC) Conflict of Interest Metrics Policy Project surveyed AAMC member institutions in the year before and the year after implementation of the new regulation.14 As reported in a March 2015 letter, the Council on Governmental Relations (COGR), an association of more than 190 research universities and affiliated medical centers, also surveyed its members regarding changes at their institutions in FCOI disclosures and associated costs to administer the new rule.15 Finally, the National Science Board’s (NSB) Task Force on Administrative Burden in 2013–2014 conducted a large qualitative survey of federally funded researchers at colleges, universities, and nonprofit institutions.16
AAMC invited all of its member medical schools and teaching hospitals to participate in the study and collected data on institutional COI policies, the number of full-time equivalent employees who oversaw the administration of COI policies, the number of significant financial interests (SFIs) disclosed to the institution, and the number of FCOIs reported to the NIH (or other PHS funding agency) during two 12-month periods (the year prior to implementation and the year after implementation). FCOIs are those that meet the threshold for SFI and
14Heather H. Pierce, Anurupa Dev, and Daria Grayer, “Implementing the Regulations on Financial Conflicts of Interest: Results from the AAMC Conflict of Interest Metrics Project,” AAMC Analysis in Brief 15, no. 4 (2015).
15Lisa Nichols, NIH Request for 3-year Extension of Reporting Requirements Associated with Revised FCOI Requirements (Washington, DC: Council on Governmental Relations, An Association of Research Universities, 2015), http://www.cogr.edu/viewDoc.cfm?DocID=152147.
are then deemed to have the potential to affect the individual’s conduct of her or his institutional responsibilities.
Among the 74 AAMC member institutions that responded, more than 79 percent reported an increase in the number of disclosed SFIs after implementation of the revised rule, which lowered the definition of SFI from $10,000 to $5,000. However, there was only a 13 percent increase in the number of FCOIs reported to a PHS funding agency. Perhaps most important, the percentage of SFIs found to be FCOIs decreased from 4.8 percent to 1.4 percent after implementation of the regulation.
In its 2011 Notice of Proposed Rule Making, the NIH estimated annualized burden hours for compliance with the regulation to be 676,130 hours at an estimated cost of $23 million across roughly 2,000 awardee institutions.17 However, the AAMC survey indicated that just 70 institutions spent $22.6 million to implement the rule.18,19 COGR also reported that, among its 34 member institutions that provided data on compliance costs, there was a combined additional cost of approximately $2 million (for a total of $10 million) to implement the new regulation, relative to combined costs of approximately $8 million during the year prior to implementation (although these costs do not include the ongoing incremental expense of meeting the expanded regulations).20 Finally, like the AAMC survey project, COGR observed that while institutions reported a 110 percent increase in the number of SFI disclosures made in the year subsequent to the implementation of the new rule, these did not lead to concomitant increases in FCOIs that needed to be managed by the institution or reported to the funding agency. The NSB survey also concluded that the new regulations resulted in substantial increases in administrative burden and financial costs, but limited perceived benefit in terms of increased protections against FCOIs.21
Together, the results of the AAMC, COGR, and NSB surveys indicate that implementation of the new 2011 PHS FCOI regulation resulted in an increase in the number of SFIs that had to be reviewed by institutions, but without a proportional increase in the number of FCOIs that warranted reporting to PHS funding
17Lisa Nichols, NIH Request for 3-year Extension of Reporting Requirements Associated with Revised FCOI Requirements (Washington, DC: Council on Governmental Relations, An Association of Research Universities, 2015), http://www.cogr.edu/viewDoc.cfm?DocID=152147.
19Heather H. Pierce, Anurupa Dev, and Daria Grayer, “Implementing the Regulations on Financial Conflicts of Interest: Results from the AAMC Conflict of Interest Metrics Project,” AAMC Analysis in Brief 15, no. 4 (2015).
20Lisa Nichols, NIH Request for 3-year Extension of Reporting Requirements Associated with Revised FCOI Requirements (Washington, DC: Council on Governmental Relations, An Association of Research Universities, 2015), http://www.cogr.edu/viewDoc.cfm?DocID=152147.
agencies. These observations call into question whether the new COI rule is accomplishing its intended goal of protecting the integrity of the scientific process and the welfare of research subjects, especially given the documented increases in administrative burden to institutions and investigators in the year following implementation of the rule. Put differently, the new regulation led to a substantially bigger haystack without significantly increasing the number of needles found.
COIs are common and expected in all professions, and the scientific community, like other professions, has over time developed normative behavioral and transactional processes to prevent or mitigate the effects of conflicts that might influence or bias professional judgments, choices, and decisions.
It is critical that research institutions appropriately identify and manage FCOIs related to research in order to ensure the protection of research subjects and the integrity and credibility of scientific findings. Institutional management of faculty COIs is also essential to protect the interests of trainees from constraints on the scope and direction of their research or use of their time and expertise for personal financial gain of the research supervisor, as may occur, for example, when the faculty advisor is involved in a start-up company.
The 2011 revision of the PHS FCOI regulation has resulted in increased time and cost burdens to investigators and institutions that are disproportionate to any resulting benefit to the scientific enterprise and research subjects.
The 2013 Uniform Guidance, which directs all federal agencies to create COI policies, includes troublesome provisions and nonspecific language that may result in multiple COI policies across the federal government. This lack of harmonization across the agencies will result in substantial increases in burden to investigators and institutions.
Centralized clearinghouses, or databases, allow individual investigators to document that they are in compliance with PHS and other agency FCOI policies and allow organizations interested in certifying this compliance (for funding or other purposes) the ability to access this information via a web-based portal (see Box 5-2). They can substantially mitigate the administrative burdens associated with oversight and the reporting of COIs.
5.1. The committee recommends that Congress, in concert with the White House Office of Science and Technology Policy and in partnership with research institutions, develop, within the upcoming fiscal year, a federal-wide financial conflicts of interest policy to be used by all research funding agencies.
The policy should incorporate the following elements:
- The policy should return to research institutions accountability for review and management of significant financial interests that might reasonably appear to be related to the design, conduct, or reporting of the funded research. Investigator disclosures should be limited to all financial interests related to the investigator’s federally funded research responsibilities rather than to “academic responsibilities” that involve education, clinical care, institutional administrative responsibilities, and institutional and public service. Institutions, at their discretion, may set different standards for disclosure. Institutional accountability includes responsibility for imposing sanctions when individuals fail to adhere to COI policies.
- The policy should not require information and reporting on the details of investigator-provided disclosures of financial interests and subse-
quent institutional responses. If an institution requires disclosure of interests related to an aspect of the individual’s institutional responsibilities but unrelated to the funded research, the institution should not be required to report this information to an agency.
- The policy should differentiate requirements for financial interest disclosure and management for research that does and does not involve human subjects, and among human subjects studies based on the level of risk as determined by the institutional review board (IRB), and should raise the monetary thresholds used to define significant financial interests above those established in the 2011 regulation. Institutions should also be able to elect, at their discretion, to require investigators to disclose all financial interests regardless of the threshold without requiring additional reporting by the institution. The policy should prohibit enrollment of subjects in the research study unless the significant financial interest is eliminated, or a plan for mitigating potential harm to subjects or threat to the integrity of the research has been approved and will be overseen by the institution.
- The policy should not require disclosure and management when income is provided in return for services to nonprofit entities (e.g., professional societies, conferences, journals) that are not created or overseen by, or otherwise related to, a company or other for-profit entity.
- The policy should streamline training requirements to limit repetitive training sessions when there has been no change in COI policies.
- The policy should make individual researchers responsible for disclosures of all related financial interests in publications and public presentations. Institutional policies should state that this responsibility lies with individual investigators and failure to comply is subject to sanctions.
HUMAN SUBJECTS RESEARCH
Research involving human subjects that is conducted using federal funding, or that falls under the jurisdiction of the U.S. Food and Drug Administration (FDA), is subject to a comprehensive regimen of regulatory oversight. Eighteen federal agencies have signed on to the Common Rule, the federal policy for the protection of human subjects in research studies.22 Statutory authority for the Common Rule derives from the National Research Act of 1974. Regulations governing research that falls under the jurisdiction of the FDA23 are similar, but,
22The Common Rule is codified at Protection of Human Subjects, 45 CFR 46 (2009). Additional subparts apply to research involving pregnant women, human fetuses, and neonates (Subpart B), prisoners (Subpart C), and children (Subpart D).
23Protection of Human Subjects, 21 CFR 50 (2011) and Institutional Review Boards, 21 CFR 56 (2009).
importantly, not identical, to the Common Rule. Finally, the Privacy Rule under the Health Insurance Portability and Accountability Act (HIPAA) of 199624 mandates additional requirements related to the privacy and confidentiality of protected health information used in research. Compliance enforcement rests with offices established within each department or funding agency. For example, the HHS Office of Human Research Protections (OHRP) enforces compliance of HHS-sponsored research with the Common Rule.
The Common Rule creates two layers of procedural protections for human subjects. Applicable human subjects research must be approved by an IRB before investigators are permitted to initiate research. Before approving a protocol, the IRB must find that the protocol meets specified criteria related to risk and benefit, equitable subject selection, confidentiality, and informed consent, as well as criteria designed to ensure participant safety. In addition, the IRB must continue to review the research and provide approvals at least annually. The IRB must approve all protocol amendments except those necessary to eliminate immediate hazards to participants and be notified of unanticipated problems involving risks to participants or others or of any serious or continuing noncompliance with policy. Second, before they are enrolled in research, candidate study participants or their legal proxies must give informed consent to participate in the study. The Common Rule requires that investigators make a specified set of disclosures, typically in writing, prior to obtaining the potential participant’s or proxy’s informed consent. In limited situations of minimal-risk research where a requirement for informed consent would make the research impracticable, the Common Rule permits an IRB to waive the requirement for informed consent. 25
The applicability of the Common Rule is not limited to biomedical research. Instead, the rule is applicable to a wide range of social, behavioral, and educational research. The scope of the applicability of the Common Rule is the subject of debate. Critics have criticized officials for extending the applicability of the Common Rule far beyond the type biomedical and behavioral studies originally envisioned by its framers.26,27
In anticipation of revisions to the Common Rule, HHS published an ANPRM in July 2011. The Common Rule NPRM was issued on September 2,
24General Administrative Requirements, 45 CFR 160 (2000), and Security and Privacy, 45 CFR 164 (2007). HIPAA was updated under the Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009.
25This is not generally the case with FDA regulations except in the case of emergency research involving in vitro diagnostic device studies using excess, anonymized human specimens. See Common Rule, 45 CFR 46 (2009) and FDA alignment of the Common Rule [Protection of Human Subjects, 21 CFR 50 (2011)].
26C. K. Gunsalus, Edward M. Bruner, Nicholas C. Burbules, et al., “Mission Creep in the IRB World,” Science 312, no. 5779 (2006): 1441.
27National Research Council, Proposed Revisions to the Common Rule for the Protection of Human Subjects in the Behavioral and Social Sciences (Washington, DC: The National Academies Press, 2014).
2015, as the current report was going to press. As the committee firmly believed that it was important to consider human subjects research regulations in the current report, the July 2011 ANPRM is the focus of the committee’s comments. The committee considers additional issues related to human subjects research in Part 2 of this report and comments on the NPRM’s proposed revisions to the Common Rule. 28
Regulations for protecting human subjects in biomedical and behavioral research were born following revelations of unethical and harmful research, such as the PHS-sponsored Tuskegee Study of Untreated Syphilis in the Negro Male.29 More recent revelations of unethical federally sponsored research conducted during earlier eras, including the radiation experiments that took place during the Cold War and PHS-sponsored studies in the 1940s that deliberately exposed people in Guatemala to sexually transmitted infections without their consent, reinforce the need for oversight of human subjects research.30,31
Over the past half century, the research enterprise has undergone dramatic changes that raise questions about whether the Common Rule and other applicable human research regulations are the most appropriate regulatory framework. Much current research seeks to evaluate the safety and efficacy of new drugs or biological agents and devices designed to treat or prevent human disease or to compare the safety and efficacy of existing drugs and devices. Much of this research offers potential benefit to individuals who participate in the research. The result is often less a demand for protection by possible participants than a demand for access.32 In addition, NIH and other agencies now emphasize the need for inclusion of groups (such as women, members of ethnic and racial minorities, and children) who were historically underrepresented in research and therefore did not benefit fully from the knowledge that research produced.33,34 In addition, federally sponsored research increasingly extends to the social, behavioral, and educational sciences; health care services and systems; research involving electronic health rec-
29Moral Science: Protecting Participants in Human Subjects Research (Washington, DC: Presidential Commission for the Study of Bioethical Issues, 2012), http://bioethics.gov/sites/default/files/Moral%20Science%20June%202012.pdf.
31Advisory Committee on Human Radiation Experiments, The Human Radiation Experiments: Final Report of the Advisory Committee on Human Radiation Experiments (New York, NY: Oxford University Press, 1996), 620.
32A. Mastroianni and J. Kahn, “Swinging on the Pendulum: Shifting Views of Justice in Human Subjects Research,” Hastings Center Report 31, no. 3 (2001): 21-28.
33Additional regulatory protections directed at children and pregnant women created further barriers to their participation and contributed to their underrepresentation in research.
34National Research Council, Proposed Revisions to the Common Rule for the Protection of Human Subjects in the Behavioral and Social Sciences (Washington, DC: The National Academies Press, 2014).
ords and “big data”; and research involving biological specimens. Much of this research does not involve physical risk to participants; rather, risks are limited to the more remote possibility of informational harm resulting from the inadvertent release of confidential information.
Nature of the Concern
The current regulatory framework governing human subjects research may not be appropriately calibrated to the risks associated with the type of research performed. In addition, research has become increasingly multicentered and collaborative in nature, with individual studies potentially involving tens or hundreds of sites, and there are questions as to whether the system of site-specific institutional review, with its roots in local review of single-site studies, has evolved in response to the trend towards multicenter research. Furthermore, HIPAA protections may be inappropriate for human subjects research, as HIPAA policies fail to align with those of the OHRP that enforces the Common Rule. 35,36, 37,38 In addition, proposed changes to the Common Rule would require researchers to obtain written consent to use biospecimens, even those that have been de-identified, creating additional administrative burden without adding to the protections of human research subjects. Finally, there is lack of harmonization of human subjects research regulations, policies, and processes, even among the 18 federal agencies that follow the Common Rule.39
36“Regulatory and Financial Reform of Federal Research Policy Recommendations to the NRC Committee on Research Universities,” Association of American Universities, Association of Public and Land-Grant Universities, Council on Governmental Relations, January 21, 2011, accessed September 9, 2015, https://www.aau.edu/WorkArea/DownloadAsset.aspx?id=11662.
37Federation of American Societies for Experimental Biology, Findings of the FASEB Survey on Administrative Burden (2013), http://www.faseb.org/portals/2/pdfs/opa/6.7.13%20FASEB%20NSB%20Survey%20findings.pdf.
38Institute of Medicine, Beyond the HIPAA Privacy Rule: Enhancing Priavcy, Improving Health Through Research (Washington, DC: The National Academies Press, 2009).
39The 18 agencies that have signed on to the Common Rule are the Central Intelligence Agency, Consumer Product and Safety Commission, National Aeronautics and Space Administration, National Science Foundation, U.S. Agency for International Development, U.S. Department of Agriculture, U.S. Department of Commerce, U.S. Department of Defense, U.S. Department of Education, U.S. Department of Energy, U.S. Department of Health and Human Services, U.S. Department of Homeland Security, U.S. Department of Housing and Urban Development, U.S. Department of Justice - National Institute of Justice, U.S. Department of Transportation, U.S. Department of Veterans Affairs, U.S. Environmental Protection Agency, and the U.S. Social Security Admin-
Federally sponsored research involving human subjects traverses a spectrum of risk, ranging from the innocuous (e.g., analysis of electronic health system data in which patients are identified only by a code or the administration of surveys that do not address sensitive topics) to the substantially risky (e.g., the use of invasive procedures to collect biological specimens for research or first-in-human administration of drugs with unknown risks). The review and approval procedures specified by the Common Rule are risk stratified. Research that falls within specified categories (e.g., select research involving educational tests, surveys or interviews or research that involves preexisting data or specimens so long as researchers do not retain identifiers) is exempt from Common Rule requirements. For such research, there is no regulatory burden. Researchers must, however, demonstrate exemption eligibility. Other minimal-risk research that falls within defined categories40 may be approved under expedited procedures (i.e., by the IRB chair or by an experienced designated IRB member, rather than by the full board). However, research that does not qualify for exemption or expedited review, including much minimal-risk research, requires review and approval by a full IRB. Full-board review can be particularly burdensome, time consuming, and delay prone. For example, one study of federally funded cancer trials showed that initial review and approval of a single trial required an average of 14 hours of research staff time and 3.9 hours of IRB staff time, and that time from starting IRB paperwork to initial approval averaged 62.3 days.41 Expedited review can shorten time lines to approval because it does not require review by a convened IRB at a meeting that may take place only once or twice a month. Fearing federal compliance actions, many institutions have increased procedural oversight, requiring detailed applications from investigators in order for the institution to determine exemption and full protocol submissions for minimal-risk research. This can result in self-imposed administrative burden that delays the approval process and increases the workload for both investigators and reviewers.
Regulatory changes that further calibrate appropriate oversight requirements to the risk of the research would considerably reduce regulatory burden on investigators conducting minimal-risk research, while preserving the re-
istration. Amongst these agencies, there is variation in the implementation of the Common Rule.
40“Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure,” U.S. Department of Health & Human Services: Office for Human Research Protections (OHRP), accessed August 24, 2015, http://www.hhs.gov/ohrp/policy/expedited98.html.
41T. H. Wagner, C. Murray, J. Goldberg, J. M. Alder, and J. Adams, “Costs and Benefits of the National Cancer Institute Central Institutional Review Board,” Journal of Clinical Oncology 28, no. 4 (2010): 662–666.
sources of IRBs to focus on protecting participants in higher-risk research.42,43 At the one extreme, the lowest-risk categories of research should not require prospective IRB review and approval. Rather, as a National Research Council committee recommended in 2014, a requirement simply to register the study with the responsible IRB—ensuring transparency, a tracking mechanism, and the possibility of audit—will suffice to protect participants and ensure investigator accountability.44 At the other extreme, research that involves greater than minimal risk should continue to require full-board review and approval, with modest reductions in ancillary requirements such as the minimum frequency of continuing review. Research that falls between these two extremes should continue to be approvable via expedited procedures, and should no longer be required to undergo periodic continuing review.
Although both OHRP and FDA permit an institution to delegate another institution’s IRB as the IRB of record, or to use a central IRB model, research institutions frequently opt for local review. This insistence on local ethics review may stem from concerns about legal liability, from habit and tradition, or from lack of confidence in the quality of review at other institutions. Yet evidence suggests that redundant local review does not improve, and paradoxically may even compromise, the quality of research protocols and consent forms.45, 46 As contemplated in the Common Rule ANPRM and as recommended by the Presidential Commission for the Study of Bioethical Issues, a regulatory mandate or presumption that a single IRB serve as the IRB of record for all domestic sites, with narrow exceptions for sites with community sovereignty concerns such as those within Native American reservations, would reduce redundancy and inconsistency while enhancing efficiency of review.47,48,49
42“Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators,” Federal Register 76, no. 143 (July 26, 2011): 44512, http://www.gpo.gov/fdsys/pkg/FR-2011-0726/pdf/2011-18792.pdf.
43National Research Council, Proposed Revisions to the Common Rule for the Protection of Human Subjects in the Behavioral and Social Sciences (Washington, DC: The National Academies Press, 2014).
45D. K. Check, K. P. Weinfurt, C. B. Dombeck, J. M. Kramer, K. E. Flynn, “Use of Central Institutional Review Boards for Multicenter Clinical Trials in the United States: A Review of the Literature,” Clinical Trials 10, no. 4 (2013): 560–567.
46W. J. Burman, R. R. Reves, D. L. Cohn, and R. T. Schooley, “Breaking the Camel’s Back: Multicenter Clinical Trials and Local Institutional Review Boards,” Annals of Internal Medicine 134, no. 2 (2001): 152–157.
47Moral Science: Protecting Participants in Human Subjects Research (Washington, DC: Presidential Commission for the Study of Bioethical Issues, 2012), http://bioethics.gov/sites/default/files/Moral%20Science%20June%202012.
48“Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators,” Federal Register 76, no. 143 (July 26, 2011): 44512, http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/pdf/2011-18792.pdf.
There is a lack of harmonization among agencies that follow the Common Rule. The Department of Defense (DOD) and NIH differ in policies for research-related injuries, while the NIH and the FDA differ in their definitions of “human subject.”50 The Common Rule and FDA have different policies for the maintenance and storage of research documents. Unlike other agencies, the FDA does not allow for waivers or modification of the requirement for informed consent for minimal-risk research in instances51 where requiring informed consent would make the research impracticable. The NIH now requires IRB review and informed consent for protocols that would share large-scale genomic research data, which would otherwise not be required under the Common Rule. Furthermore, although DOD has accepted the Common Rule, it has promulgated additional regulations and policies that depart from the Rule and are unique to research funded by DOD. Finally, FDA and NIH have different requirements for data-monitoring committees.52,53
Biospecimens are materials taken from the human body and can include tissue, blood, saliva, and urine, among others.54 Currently, the Common Rule
49Moral Science: Protecting Participants in Human Subjects Research (Washington, DC: Presidential Commission for the Study of Bioethical Issues, 2012), http://bioethics.gov/sites/default/files/Moral%20Science%20June%202012.pdf.
50The basic HHS policy for the protection of human research subjects defines a human subject as “a living individual about whom an investigator (whether professional or student) conducting research obtains (1) Data through intervention or interaction with the individual, or (2) Identifiable private information.” See Common Rule, 45 CFR 46.102(f) (2009). FDA defines a human subject as “an individual who is or becomes a participant in research, either as a recipient of the test article or as a control.” See Protection of Human Subjects, 21 CFR 50.3(g) (2011).
51Such instances can have logistical causes, such as needing to obtain informed consent from thousands of participants for retrospective use of discarded specimens, or scientific causes, such as the informed consent requirement leading to selection biases in large-scale epidemiological studies based on data from clinical registries (see Jack Tu, Donald Willison, Frank Silver, Jiming Fang, et al., “Impracticability of Informed Consent in the Registry of the Canadian Stroke Network,” The New England Journal of Medicine 350, (2004): 1414-1421.
52A data-monitoring committee is a committee of experts, typically including clinicians, statisticians, and often patient representatives, ethicists, and others, who review confidential interim data from a clinical trial and may recommend changes, including early termination of the trial, based on emerging evidence of benefit, harm, or other outcomes.
53Several prior reports have called for harmonization of human subjects research regulations and policies between statutes and among federal agencies. See, e.g., National Science Foundation, Reducing Investigators’ Administrative Workload for Federally Funded Research (NSB-14-18) (Arlington, VA, 2014), http://nsf.gov/pubs/2014/nsb1418/nsb1418.pdf and Federation of American Societies for Experimental Biology, Findings of the FASEB Survey on Administrative Burden (2013), http://www.faseb.org/portals/2/pdfs/opa/6.7.13%20FASEB%20NSB%20Survey%20findings.pdf.
54“Patient Corner: What are Biospecimens and Biorepositories,” National Cancer Institute: Biorepositories and Biospecimen Research Branch, accessed August 24, 2015, http://biospecimens.cancer.gov/patientcorner/.
allows for research to be performed using existing biospecimens without informed consent as long as the specimens are deidentified. In the 2011 ANPRM, HHS indicated that it is considering requiring written consent for research using biospecimens, even those that have been de-identified.55 The HHS Secretary’s Advisory Committee on Human Research Protections, in its 2011 comments on the Common Rule ANPRM, noted that the proposed revisions would add administrative burden without providing any additional protections for research participants.56
In 2014, the NSB Task Force on Administrative Burden published a report that detailed the administrative workload of investigators who receive federal funding for their research. The report presented the results of a survey of more than 3,000 investigators and a series of roundtable discussions with research faculty and administrators. Research involving human subjects and IRB requirements were among those that respondents identified as having the highest level of administrative workload. Respondents suggested that federal regulations and IRB requirements have become increasingly complex, yet are not calibrated to risks.57 Several respondents suggested that increased scrutiny by IRBs has not resulted in an appreciable improvement in participant safety.58 Finally, respondents conducting multisite research studies reported that submission to multiple IRBs was time consuming due to both a lack of standardization of forms and procedures and the requirement that the institutional protocols and informed consent documents conform across research sites, requiring multiple iterative reviews for minor changes in wording. Often this results in research projects being significantly delayed.59
The Federation of American Societies for Experimental Biology (FASEB) surveyed its members in response to the NSB’s request for information and concluded that human subjects regulations and IRB policies are a major source of administrative burden for research institutions and investigators.60 Respondents to the FASEB survey noted that regulations are not calibrated to the level of risk posed by a given research study and that multisite research protocols are associ-
55“Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators,” Federal Register 76, no. 143 (July 26, 2011): 44512, http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/pdf/2011-18792.pdf.
56Secretary’s Advisory Committee on Human Research Protections (SACHRP). Letter to Kathleen Sebelius (Secretary of Health and Human Services) October 13, 2011. http://www.hhs.gov/ohrp/sachrp/commsec/sachrpanprmcommentsfinal.pdf.
60Federation of American Societies for Experimental Biology, Findings of the FASEB Survey on Administrative Burden (2013), http://www.faseb.org/portals/2/pdfs/opa/6.7.13%20FASEB%20NSB%20Survey%20findings.pdf.
ated with long delays due to a lack of standardization of IRB procedures at different sites. FASEB suggested that regulations affecting human subjects research be streamlined so that IRBs can focus on higher-risk studies, relative to research protocols that pose minimal risk to participants.61, 62 Like both the NSB and FASEB surveys, the 2012 Federal Demonstration Partnership (FDP) Faculty Workload Survey concluded that IRB requirements are among the most time consuming and burdensome investigator administrative responsibilities. Respondents suggested that the amount of work required to obtain IRB approval for minimal-risk research was unnecessary and that completing multiple IRB submissions for multisite research studies was time consuming and redundant.63
Regulations for the protection of human subjects in biomedical and behavioral research are essential to protect the rights and welfare of the participants, as well as to preserve the public’s trust and confidence in the research enterprise. However, as currently written, interpreted, and enforced, the regulations impose considerable burden on investigators and institutions conducting research, without a foundation of convincing evidence of commensurate benefit in terms of the goals and values that they are intended to serve. Modest revisions to ensure that regulations are calibrated to the nature and risk of the particular project and are reflective of the changing nature of federally sponsored research—particularly its evolution towards multicenter studies—can substantially reduce burden without compromising robust protections for human subjects in research.
Federally sponsored research involving human subjects encompasses a wide range of risk to participants.
The review and approval procedures specified by the Common Rule are risk stratified only to a limited extent.
Improved calibration of regulations and oversight procedures to the level of risk posed to participants would both reduce administrative burden on investigators conducting minimal risk research and allow IRBs to focus on protecting participants in higher-risk research studies.
There is a high level of administrative burden associated with conducting multisite research studies. This burden is likely to continue to increase, given the increasing prevalence of studies involving multiple research centers within an increasingly collaborative scientific enterprise.
63Sandra Schneider, Kristen Ness, Sara Rockwell, Kelly Shaver, Randy Brutkiewicz, Federal Demonstration Partnership (FDP): 2012 Faculty Workload Survey Research Report (2014), 19–20, http://sites.nationalacademies.org/cs/groups/pgasite/documents/webpage/pga_087667.pdf.
There is a lack of harmonization of human subjects research regulations, policies, and processes, even among the 18 federal agencies that follow the Common Rule.
Requiring consent for all research involving biospecimens, as contemplated by the ANPRM, would substantially increase administrative burdens on investigators, research staff, and institutions, and would markedly hinder the conduct of critical science.
5.2. The committee recommends that Congress direct federal agencies following the Common Rule to institute a risk-stratified system of human subjects protections that substantially reduces regulatory burden on minimal-risk research while reserving more intensive regulatory oversight for higher-risk research.64
- The committee recommends the following designations:65
- Category One: Excused Research
- Most observational research that does not involve invasive procedures for the collection of research data satisfies criteria for minimal risk and should be placed in an “excused” category. Investigators should be required to register excused research with the responsible IRB using a brief form. One week after filing the form, investigators should be permitted to begin their research unless, during that week, the IRB has requested additional information or has notified the investigators that the research does not qualify for excused status.
- OHRP and other relevant agencies may define narrowly circumscribed categories of observational research that do not qualify for excused status and that require additional review for the protection of human subjects. Examples might include certain categories of research involving vulnerable populations such as prisoners, research involving sensitive information, or research involving collection of information that might place participants at legal risk.
64This is consistent with the 2014 NAS Committee on Revisions to the Common Rule for the Protection of Human Subjects in Research in the Behavioral and Social Sciences and the proposed changes in the 2011 Common Rule ANPRM. The committee’s recommendation differs from the 2014 proposal in advising that all minimal-risk research not meeting criteria for the “excused” category be eligible for expedited review. The committee nevertheless agrees with the proposal in the 2011 Common Rule ANPRM to eliminate the requirement for annual continuing review for studies qualifying for expedited review.
65These are consistent with the recommendations of the report of the 2014 NAS Committee on Revisions to the Common Rule for the Protection of Human Subjects in Research in the Behavioral and Social Sciences and the ANPRM.
Any categorical determination that would elevate observational research to a higher level of review should be reviewed by the responsible regulatory agency no less than every 2 years.
- Excused research should not require the filing of annual continuing reviews or amendments, unless a proposed amendment changes the risk level such that expedited or full-board review is required.
- Category Two: Minimal-Risk Research Not Meeting Criteria for Excused Status
- All minimal-risk research not meeting criteria for excused status should be eligible for expedited rather than full-board review.
- Annual continuing review should not be required for minimal-risk research that qualifies for approval by expedited procedures.
- Category Three: Research Involving Greater than Minimal Risk
- Research involving greater than minimal risk should continue to require full-board approval by the responsible IRB.
- Research involving greater than minimal risk should undergo continuing review and approval at least every 2 years. IRBs may choose to require continuing review for a particular project more frequently than every 2 years, as they deem appropriate in light of the risks or other characteristics of the research.
- Continuing reviews should no longer be required once study interventions that impose greater than minimal risk have ceased and the study enters the follow-up or data analysis phase.
5.3. The committee recommends that Congress direct federal agencies following the Common Rule to require, for multisite research studies, that a single IRB with the necessary staff and infrastructure serve as the IRB of record for all domestic sites.66
- The requirement for single-site review should not be applied to sites subject to Native American or Alaska Native tribal sovereignty. Such sites may choose, but should not be required, to participate in single IRB review mechanisms.
- Within a designated period of time, a standard set of policies and procedures should be developed for single-site review of multisite trials.
66The committee also endorses a proposal contemplated by the 2011 Common Rule ANPRM to mandate single ethics review, and a single IRB of record, for all domestic sites in a multisite trial. The committee’s recommendation differs from the ANPRM’s proposal in exempting Native American and Alaska Native sites from this requirement, given sovereignty concerns. The committee’s proposal aligns with that in the 2011 report of the Presidential Commission for the Study of Bioethical Issues, (see Moral Science: Protecting Participants in Human Subjects Research (Washington, DC: Presidential Commission for the Study of Bioethical Issues, 2012, http://bioethics.gov/sites/default/files/Moral%20Science%20June%202012.pdf) but goes further in mandating rather than simply establishing a presumption of single-site review.
In the absence of standardized policies and procedures, administrative burden will be significantly increased as each study team must try to learn and comply with different processes and policies for each protocol with which they participate. Further, a nationally uniform, work-flow-based informatics infrastructure should be developed to support a coordinated system of single-site review for multisite research.
5.4. The committee recommends that Congress direct agencies, within a designated period of time, to align and harmonize their regulations (and definitions) concerning the protection of human subjects.
- While 18 agencies have signed on to a part of the Common Rule, many have, over time, developed additional regulations that diverge from the standard.
- Furthermore, forms used for applying to, maintaining compliance with, and reporting to the cognizant agencies should be aligned and invariant, and electronically accessed, signed, and submitted.
5.5. In instances of minimal-risk research where requiring informed consent would make the research impracticable, the committee recommends that Congress amend the FDA’s authority so as to allow the FDA to develop criteria for waiver or modification of the requirement of informed consent for minimal-risk research.
- The criteria for waiver or modification of informed consent should harmonize with those in the Common Rule.
5.6. The committee recommends that Congress instruct HHS to work with other agencies to ensure that research involving biospecimens is eligible for a waiver or modification of informed consent, so long as the proposed research meets the conditions for waiver or modification of informed consent as specified in the Common Rule.
- Informed consent should not be required for the use of biospecimens that have been previously collected and are no longer needed for clinical use. Further, secondary research using identifiable data and specimens should be deemed to be minimal risk following the procedures for excused research described in Recommendation 1 above.
The relationship between the research community and research animals has received special attention because of the relationship between humans and animals, especially with respect to the important role animals have played in our
understanding of human health and disease. Animal-based research has contributed in many significant ways to our understanding of fundamental mechanisms
of life, human and animal health and disease, and the development of new treatments and devices. An additional feature of the relationship is the interaction between the scientific community and the public, especially with those most concerned about the rights and treatment of animals.
Much of the general public continues to recognize the importance of animal-based research for the advancement of treatments and cures of animal and human disease. Over the years, improvements in animal care have paralleled the emergence of laboratory animal science and of animal welfare groups. Rising research budgets resulted in an increased use of animals in the discovery process. Laboratory animal medicine and an understanding of husbandry needs of animals have evolved as well. There also has been an increase in the efforts by animal rights groups wishing to stop all research involving animals. While some of these efforts have led to a more nuanced approach to the care and treatment of animals, other efforts have resulted in unproductive harassment or even violent actions against researchers and their families. Research institutions and researchers, along with federal agencies, share a desire to use animals in research in the most appropriate manner possible, providing the best care and treatment.
The oversight of the care and use of research animals is complex and is governed by multiple laws as well as by policies and conditions of specific funding agencies. The U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (1985) and the Animal Welfare Act (AWA; enacted in 1966) apply to all agencies. Depending on the proposed work, the regulatory and policy requirements of individual agencies may be applicable as well. The AWA, enforced by the U.S. Department of Agriculture (USDA), applies to certain species67 regardless of funding agency. NIH-funded activities are governed by the Health Research Extension Act (HREA; enacted in 1985), and the PHS Policy applies to all vertebrate animals in PHS-funded activities. Individual agencies are authorized to oversee animal use through other regulations as well (see Table 5-1). Compliance with all laws is required as applicable. Several agencies have chosen to adopt the AWA and, in some cases, the HREA in addition to their own guiding legislation and policies. Many of the requirements to protect research animals are the same from agency to agency, and in some instances, one agency will simply adopt another agency’s requirements. In some instances, agencies disseminate guidance documents without specifying them as suggested policies, leaving investigators and institutions to interpret them as regulatory documents.
67The AWA covers cats, dogs, hamsters, rabbits, nonhuman primates, guinea pigs, and any other warm-blooded animal as determined by the Secretary of Agriculture for research or pet keeping. Birds, rats of the genus Rattus, and mice of the genus Mus, bred for use in research, as well as all cold-blooded animals, are excluded from AWA coverage.
|U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training|
|International Guiding Principles for Biomedical Research Involving Animals (Council for International Organizations of Medical Sciences and International Council for Laboratory Animal Science)|
|Public Law 89-544; Animal Welfare Act; 7USC Sect 2131-2156; 9CFR, Ch1, Subch A, Pt 2|
|Public Law 99-158; Health Research Extension Act; 42USC 6A, Subch II, Pt A Section 283e and Pt H Section 289d|
|Public Law 92-522; Marine Mammal Protection Act; 16 USC Ch 31|
|Public Law 102-40; VA Authorization; 38USC Pt V, Ch73, SubchI, Sect 7303|
|Public Law 107-188; Select Agents and Toxins; 42 CFR Part 73|
|Public Law 89-544?; Care and Use of Animals in the Conduct of NASA Activities; 42 USC Sect 2451; 14 CFR Part 1232.|
|Agency Policy and Directives|
|Public Health Service Policy on Humane Care and Use of Laboratory Animals|
|Guide for the Care and Use of Laboratory Animals (National Research Council)|
|Guidelines for the Euthanasia of Animals (American Veterinary Medical Association)|
|NSF Grants Policy|
|NASA Policy Directive 8910.1|
|NASA Procedural Requirements 8910.1|
|DHS Management Directive 10200.1 (Care and Use of Animals in Research)|
|Technology Innovation Program. Guidelines and Documentation Requirements for Research Involving Human and Animal Subjects|
|USDA-NIFA Grants Policy|
|Use of Animals in DoD Programs. Directive 3216.1|
|VA Handbook Directive 1200.07|
|Biosafety in Microbiological and Biomedical Laboratories (US Center for Disease Control and Prevention)|
|Occupational Helath and Safety in the Care and Use of Research Animals (National Research Council)|
|Guide for the Care and Use of Agricultural Animals in Research and Teaching (Federation of Animal Science Societies)|
|Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (National Institutes of Health)|
|Guidelines for the Care and Use of Mammals in Neuroscience and Behavior Research (National Research Council)|
SOURCE: Courtesy of Joseph R. Haywood.
Oversight is further complicated by agencies having different missions (e.g., enforcement versus funding) and specific mechanism(s) of oversight (inspection versus assurance versus terms and conditions of grant awards). For example, the NIH uses the approval of an assurance by the Office of Laboratory Animal Welfare (OLAW) combined with a wide range of terms and conditions of the NIH Grants Policy, PHS Policy, the National Research Council’s Guide for the Care and Use of Laboratory Animals, and other guidelines. Most agencies use conditions of funding as an oversight mechanism relying on the force of the AWA and the PHS assurance process to ensure that basic requirements are met by grantees. Specific requirements relevant to an agency’s mission are often added to the baseline requirements. For example, the National Aeronautics and Space Administration includes space-related care and the National Oceanic and Atmospheric Administration includes marine mammals. Because there are so many different regulations and policies applied to animal research, there is redundancy, omission, confusion, and sometimes contradiction in the regulations of the present oversight system.
Nature of Concern
The research community takes its responsibility to protect the health and well-being of research animals seriously. As early as 1952, when dogs were the primary research animal model, the scientific community developed best practices in Standards for the Care of Dogs Used in Medical Research. Almost a decade later this document evolved into the Guide for Laboratory Animal Facilities and Care. In 1965, the second edition of the guide was released68 and the voluntary accreditation body, the American Association for the Accreditation of Laboratory Animal Care (AAALAC; now Association for the Assessment and Accreditation of Laboratory Animal Care, International), was incorporated. These were important attempts by the scientific community to assure the public that serious efforts were being made to care for animals involved in research. However, also in 1965, a series of articles brought to public attention use of animals in university research. A Sports Illustrated article revealed the theft of pets that were sold for research, and an article in Life focused on pet theft and poor treatment of those animals. The public response was profound, and in a few short months the AWA was passed. Although much of the AWA was devoted to requirements related to general animal well-being and animal health, the focus was stolen pets, licensing animal dealers, registration of research facilities, research activities, and reporting requirements. The AWA changed the conduct of research using animals. The development of the regulations to implement the AWA took 23 years, during which time there were amendments to the AWA, and the passage of and amendments to the HREA.
68The guide is now in its the eighth edition published by the National Research Council.
The myriad rules, regulations, documents, assurances, grant conditions, Frequently Asked Questions, and conveyance of guidance over the last 30 years has contributed to considerable confusion in the scientific community. The complexity of the system creates problems such as contradictions in process and redundancy in reporting. For many researchers, it has been difficult to distinguish between regulations, grant requirements, and best practices. This has been further exaggerated by the AAALAC’s accreditation process. In striving to have a risk-free animal research program, universities have sometimes conflated regulations and best practices. This has led to additional and unnecessary burden for investigators, leading some institutions to treat AAALAC best practices as regulation. It takes considerable expertise to sort through the regulations, rules, guidance, and best practices that have been established and have evolved over time. Consequently, institutions have tended to over-interpret the requirements so as to err conservatively and not be out of compliance or inconsistent with what could be construed as grant conditions. For various reasons, many institutions have tried to maintain a zero tolerance for risk of noncompliance in their programs. In many cases, the result has arguably been unnecessary burdens borne by institutions and investigators.
An example of contradiction in the present system is the protocol review process. Before any animal research can begin, the proposed work must be reviewed and approved by an institutional animal care and use committee (IACUC). This is a common feature of the laws and agency requirements described above. However, beyond the initial review of the protocol, the agencies sometimes differ or remain silent on the process. The USDA requires continuing review of the whole protocol, while the NIH requires only triennial review. Since protocols are frequently amended during the course of a research project, the annual and triennial reviews become redundant. In addition, many institutions have initiated post-approval monitoring programs. Unfortunately, less emphasis is placed on this continuing review of protocol amendments and post-approval monitoring than the initial protocol review process, yet the latter can be an effective means of both ensuring appropriate oversight and protecting the welfare of research animals.
Like protocol reviews, requirements for assurances and reporting vary significantly from agency to agency. All agencies require at least an annual report of progress of work. In addition to the annual report, the NIH requires an annual report from the Animal Care and Use Program regarding any changes in the program. In addition, the institution must report any noncompliance events as they occur, regardless of the level of significance or the impact on the health and/or safety of the research animals. NIH also requires an institutional assurance that is renewed every 4 years that describes specific aspects of the program, including IACUC functions, protocol review, occupational health, and congruency between the animal care procedures specified in grant proposals and those carried out in the laboratory setting. All of these activities suggest that NIH is striving for a zero-risk system. The NIH has set itself apart from other agencies in the redundancy of processes, the detailed guidance to institutions, and reporting requirements.
In 2014, the NSB Task Force on Administrative Burden published a report that detailed the administrative workload of investigators who receive federal funding for their research. The Task Force surveyed more than 3,100 individuals through a request for information disseminated to universities and scientific and professional societies. The Task Force also held a series of roundtable discussions with more than 200 faculty and administrators. Research involving animal subjects and IACUC requirements were among those that respondents associated with the greatest administrative workload. Burden was linked primarily to escalating regulations, prescriptive guidance, institutional and accrediting body requirements exceeding federal requirements, and duplicative federal agency and institutional review of grants and protocols.69
Respondents noted that many of the requirements increased their administrative workload, such as USDA’s requirement that proposals include literature searches for alternative experimental models that reduce, replace, and/or refine the procedures using animals, but did not seem to improve the care and treatment of animals. Many noted that the requirement for annual and triennial IACUC reviews of animal protocols was redundant, as protocols are continually amended. Specifically, while institutional requirements demand that protocols include the exact numbers of animals that will be used in a given study, it is impossible to predict the direction of research, leading to numerous and continual protocol amendments over the lifetime of a project.70
The FASEB, a professional society that represents the nation’s largest coalition of biological and biomedical researchers, also concluded, after surveying its members in response to the NSB’s request for information, that animal care and use regulations are a major source of administrative burden for investigators and institutions. FASEB suggested that an important first step to reduce this burden would be to distinguish the responsibilities for review of grants and protocols between IACUCs and the federal agencies.71 This would help reduce duplication and align requirements more closely to their original intent. FASEB also suggested that complete reviews of animal care and use protocols be brought into alignment with the time frame of a typical grant.72 FASEB’s conclusions based on its survey of members are consistent with those of the 2012 FDP Fac-
71Federation of American Societies for Experimental Biology, Findings of the FASEB Survey on Administrative Burden (2013), http://www.faseb.org/portals/2/pdfs/opa/6.7.13%20FASEB%20NSB%20Survey%20findings.pdf.
ulty Workload Survey.73 The FDP survey respondents ranked IACUC issues highly on their list of concerns. Among the FDP member respondents that performed animal research, IACUC-related issues received the greatest level of dissatisfaction among all areas of regulatory compliance. The faculty responses indicated that protocol reviews are excessive and that inconsistencies between federal agency requirements and institutional requirements contribute significantly to administrative burden, without necessarily improving the care and treatment of animals.74
The complexity of the multiple oversight systems associated with the care and use of animals is a significant source of regulatory burden. USDA and NIH have attempted to coordinate their rulemaking and oversight activities since the late 1990s; however, the differences in agency mission and approach to oversight have resulted in significant variations in requirements between these two agencies. While other agencies have largely used the requirements of the USDA and NIH, on occasion they issue agency-specific documents, further adding to the complexity of compliance. The resulting burdens are placed not only on investigators but also on institutions, which must develop detailed compliance procedures and processes for different funding agencies. The use of different systems (e.g., inspection versus assurance) requires additional processes to be in place. This is further complicated by multiple systems of verification of assurances for multiple agencies. There is growing concern that this wide range of requirements and processes negatively affects the ability of the institution to oversee animal research.
There are three document-intensive processes that require significant commitment by the institution and the investigator without any direct significant benefit for animals.
Federal and Institutional Assurances
Federal agencies usually provide oversight of the use of animals in research through conditions of the grant or contract or reliance on the U.S. Government Principles and the AWA (Table 5-1); however, the submission of documents to the agencies assuring and reporting the status of animal oversight and
73See Sandra Schneider, Kristen Ness, Sara Rockwell, Kelly Shaver, and Randy Brutkiewicz, 2012 Faculty Workload Survey: Research Report, (Washington, DC: Federal Demonstration Partnership, 2014).
74Sandra Schneider, Kristen Ness, Sara Rockwell, Kelly Shaver, Randy Brutkiewicz, Federal Demonstration Partnership (FDP): 2012 Faculty Workload Survey Research Report (2014), 19-20, http://sites.nationalacademies.org/cs/groups/pgasite/documents/webpage/pga_087667.pdf.
animal health has generally been limited to PHS funding. Until very recently only the PHS (NIH, FDA, Centers for Disease Control and Prevention) has required institutions to provide an assurance by the institution that describes oversight function.75 Typically, when an institution accepts an award, it is viewed by agencies as acceptance that the institution will abide by the terms and conditions of the award. For PHS, the institutional assurance is submitted every 4 years and describes detailed descriptions and processes for IACUC functions (including protocol review, semiannual review of the program and facilities, reporting concerns about animal use), institutional program evaluation and accreditation, recordkeeping, reporting, institutional policy, and institutional leadership. However, documentation is not limited to a single Assurance. An annual report indicating any changes in the program, documentation of the semiannual program and facility reviews, and IACUC membership is also submitted. If an institution is not AAALAC accredited, it is also required to submit its most recent semiannual review to OLAW with its Assurance. Finally, OLAW requires submission of reports of noncompliance (NOT-OD-05-034) within a reasonable amount of time of any such event. While these multiple reports are reviewed and responded to, they can take a significant amount of time.
There is redundancy in the protocol review process and submission of grants to NIH. No animal research can be initiated without approval of an IACUC for the work. However, PHS applications also require that applications have Vertebrate Animal Sections that include a significant amount of detail about the procedures and care of animals in the proposed study. This information is part of the peer review of the proposed work and is included in the grant score. The same information has been (or will be reviewed “just in time”) by the local IACUC. Furthermore, according to NIH Grant Policy Statement, the institution is charged with verifying congruency between the proposed work in the application and the protocol reviewed by the IACUC. These processes result in unnecessary additional work by investigators on review panels and institutional staff to oversee the legal mandate to the local IACUC.
Within an institution, any proposed research must be reviewed by the IACUC. The protocol review includes a description of the research, approaches to minimize animal numbers, justification for the use of animals, and information on alleviation of pain and distress, methods of euthanasia, and veterinary care, among other topics. All of this is prospective, since approval must be granted before work can begin. There also is a requirement for periodic or continuing review. Additionally, as a research plan evolves, approval for modifica-
75In 2015, NSF entered into a Memorandum of Understanding with OLAW requiring grantee institutions to have an approved PHS assurance. See Office of Laboratory Animal Welfare - MOU Between NIH and NSF, available at: http://grants.nih.gov/grants/olaw/references/mou_nsf.htm).
tions must be sought from and granted by an IACUC before work can be continued. The process has become extensive and burdensome with a focus on proposed work at the expense of monitoring ongoing research.
The USDA, DOD, and NIH require annual reports about the care and use of animals. In addition, the NIH requires reports of noncompliance as they occur, regardless of the severity of the effect the noncompliance event had on the health and welfare of the research animal.
The committee recommends that:
5.7. Congress direct the White House Office of Science and Technology Policy to convene within one fiscal year representatives from federal agencies that fund animal research and representatives from the research community to assess and report back to Congress on the feasibility and utility of developing a unified federal approach for the development, promulgation, and management of policies and regulations pertaining to the care and use of research animals.
- This feasibility assessment should consider whether harmonization might be best achieved using a Federalwide Assurance mechanism.
- The Assurance mechanism should ensure that regulations and policy are evidence based and should distinguish the regulatory aspects of animal research oversight from the terms and conditions of grants, so as to ensure that consistent oversight is applied to all animals.
- The Assurance mechanism should empower IACUCs to streamline the protocol review process and change the emphasis of institutional efforts to the ongoing protection of research animals through targeted and effective training and post-approval monitoring of animal use activities.
5.8. Reporting, assurances, and verifications to agencies should be reduced and streamlined. Agencies should adjust their requirements for reporting such that animal-related noncompliance reports are tiered to the level of significance or impact on animals and included in an annual report rather than submitted on an individual event basis. Annual reports to individual agencies about animal care programs should be replaced by a single annual report under the proposed Federalwide Assurance mechanism. Processes that are redundant to the IACUC approval process, such as the Vertebrate
Animal section of PHS grant applications and the DOD central administrative protocol review, should be eliminated.
5.9. Research institutions should assess their own regulatory processes to determine where their compliance activities can be streamlined to ensure effective use of indirect research recovery costs, while still meeting the requirements of federal regulations.
- Processes that should be reviewed include the following:
- Full IACUC review of all animal use protocols.
- Multiple individuals involved in designated member review of animal use protocols.
- Performing annual and triennial reviews of protocols instead of using a continuing review process and “restarting the clock” after each review.
- Applying USDA and PHS standards to all processes and protocol reviews where they do not apply (e.g., literature searches on rodent protocols not covered by the USDA).
- Accepting suggestions made by accrediting bodies and other nonfederal entities as if these suggested best practices had the force of agency regulations or policy.
- Performing unnecessary training on topics that do not directly benefit research animals (e.g., training on procedures irrelevant to their day-to-day activities or regulatory background that does not pertain to active protocols).