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 research 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 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

BOX 5-1

Changes in Public Health Service Financial Conflict of Interest Regulations Implemented in 2012.

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 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.

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.

Analysis

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 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 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.

Findings

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.

BOX 5-2

Examples of Centralized Databases for Documenting Conflict of Interest Policy Compliance.

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

Analysis

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 resources 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

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 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 associated 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.

Findings

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.

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.

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.

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.

Analysis

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 Faculty 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

Findings

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.