Conflicts of interest in human subjects research.

We must manage research scrupulously so that neither individual nor institutional financial interests result in danger to participants.

Conflict of interest in biomedical research first came to public notice in the 1980s via a number of cases of scientific misconduct in which perpetrators had financial interests in the outcome of their research. The cases, highly publicized, were summarized in the 1990 report of the House Committee on Government Operations entitled "Are Scientific Misconduct and Conflicts of Interest Hazardous to Our Health?" and spurred the issuance of federal regulations in 1995. The linkage of misconduct with financial self-interest was unfortunate, because it seemed to fix in the public mind the belief that any financial interest of investigators in their research is inevitably problematic. It is noteworthy that during this period concern centered mainly on individual faculty interests and their threat to scientific integrity, and the communal threat to public health posed by falsified scientific information. At the time, the academic community made thoughtful attempts to address these concerns, as reflected in several notable reports.

Recently, public uneasiness about financial conflicts of interest has resurfaced, but now the focus is on both individual and institutional financial interests and their possible linkage to endangerment of individual human research subjects. Moreover, the concerns recur in a larger context of growing skepticism about the adequacy of the federal regime for protecting the welfare of human research subjects, a topic addressed in numerous well-publicized reports from the General Accounting Office (GAO), the Department of Health and Human Services (HHS), the HHS Inspector General, the National Institutes of Health, the National Bioethics Advisory Commission, the Institute of Medicine, and the Office for Human Research Protections.

The most recent GAO report, issued in November 2001, concluded that academic institutions' policies and procedures on financial conflicts of interest reflected a disturbing degree of variability in content and implementation. The report concluded that current federal regulations and oversight are limited in their promotion of research integrity and protection of human subjects, and recommended "that HHS undertake efforts to highlight and communicate best practices for institutions to identify and to manage investigator and institutional financial conflicts of interest...[and]...that HHS develop specific guidance or regulations to address institutional financial conflict of interest."

It was in this context that the Association of American Medical Colleges (AAMC) announced in October 2000 its intention to form a task force to recommend policy and guidance regarding academic medicine's management of financial conflicts of interest in human subjects research. AAMC was aware that the Association of American Universities (AAU) was forming a Task Force on Research Accountability (on which both authors have participated), and therefore chose to focus its efforts in the more circumscribed area of clinical research in which the AAMC's members are leading participants.

AAMC undertook this effort for two major reasons. First and foremost was the peril to academic medicine and public health of eroding public confidence in academic biomedical research. Second was growing concern that academic medicine has not been sufficiently responsive to the profound changes that have occurred during the past two decades in the ecology of academic biomedical research.

These changes have been driven by four major factors. First, the astonishing progress of biomedical science has afforded ever deeper and more powerful understandings of the molecular and genetic bases of human health and disease, and collapsed the timeline between fundamental discovery and commercial development. Second, the invention of recombinant DNA technology spawned a burgeoning biotechnology industry, the scientific agenda of which continues to be deeply intertwined with academic biomedical research and researchers. Third was the seminal holding of the U.S. Supreme Court in 1980 that a recombinant bacterium was patentable subject matter. By stating that "anything under the sun" made by humans was patentable, the decision deemed a vast expanse of fundamental biomedical research and technology eligible for intellectual property protection and, therefore, private appropriation. Fourth, the enactment of the Bayh-Dole Act, also in 1980, gave federal research awardees both the right to patent their discoveri es and the obligation to promote the commercialization of their federally funded research results.

As a consequence, the intensity of the interaction of academic medicine with industry has increased dramatically, as has the prevalence of faculty and institutional financial interests in academic biomedical research. Some alarmed observers have opined that academic medicine is facing a veritable pandemic of financial conflicts of interest, and a few have even suggested that academia is busily bartering its very soul for the prospects of material enrichment. At the same time, public discourse about these matters has been badly confounded by deep-seated conflict between the public's impatience to reap the benefits of biomedical research and its failure to appreciate that the pathway of commercial development in biomedicine is almost exclusively dependent on private investment, much of it involving venture capital and small business investment. The public increasingly recognizes and exhorts academic medical center s to serve as engines of regional socioeconomic development but at the same time remains intolerant of any tinge of suspicion that the academy's deepening engagement with industry might distort the conduct or color the reporting of research. This conflict of public expectations severely burdens the challenge faced by academic medicine to implement conflict of interest policies that are transparent and credible, while at the same time workable and sensible.

The AAMC Task Force was chaired by William Danforth, former chancellor, then chairman of the board of trustees of Washington University in St. Louis, and, to embrace all stakeholder communities in the process, included leaders of medical schools and teaching hospitals, clinical investigators experienced in the commercial development of research inventions, leaders from the pharmaceutical and biotechnology industries, general counsels, bioethicists, nationally recognized patient advocates and media representatives, and a former member of Congress. The task force was asked to explore territory beyond that defined by current federal regulations. Specifically, it was asked to consider "whether certain types of financial interests [in research on human subjects] should be prohibited" (none are prohibited categorically under existing Public Health Service [PHS] regulations) and "under what circumstances, if any, it is acceptable for institutions to invest in and sponsor faculty entrepreneurial activities involving human subjects" (PHS regulations do not address the topic of institutional conflict of interest).

The task force produced two reports. The first, issued in December 2001, offers policy and guidelines for the oversight of individual financial interests in research involving human subjects. The second, issued in October 2002, provides principles and recommendations demarcating the bounds and circumstances of appropriate conduct when an institution hosts research involving human subjects and the institution or its administrators have direct financial interests in the research. It is noteworthy that with a single exception (noted in the first report) this eclectic and strong-minded group of distinguished individuals with very different perspectives was able to achieve consensus on issues that are extraordinarily challenging and complicated.

Individual conflicts

While noting that most individual conflicts of interest are being managed through existing institutional policies and practices, the task force acknowledged that financial interests in human subjects research are distinct from other interests inherent in academic life that might impart bias or otherwise contaminate research objectivity. They may threaten scientific integrity by fostering real or apparent biases in study design, data collection and analysis, adverse event reporting, or the presentation and publication of research findings. The task force recognized the importance of the burgeoning partnership among industry, researchers, and universities, but noted that these interactions place new demands on institutions to be scrupulous in the enforcement of conflict of interest guidelines.

Moreover, existing federal financial disclosure regulations do not require a comprehensive system of disclosure and oversight of all significant financial interests in human subjects research, whether such research is federally funded or privately sponsored. Equally important, federal regulations do not acknowledge the unique obligations that attend research involving human beings. The task force asserted "academic medicine must look beyond the scope of current federal financial disclosure requirements and delineate more fully the bounds of acceptable conduct for those who conduct research with human subjects."

The task force identified several core principles to animate institutional policies concerning individual financial interests in such research, including:

Institutions should regard all significant financial interests in human subjects research as potentially problematic and requiring close scrutiny. Institutions should establish "a rebuttable presumption that an individual who holds a significant financial interest in research involving human subjects may not conduct such research." Though the task force did not believe that every financial interest jeopardized either the welfare of human subjects or the integrity of research, it was strongly committed to the notion that institutions should "limit the conduct of human subjects research by financially interested individuals to those situations in which the circumstances are compelling," regardless of the source of research funding, and wherever the research is carried out under institutional auspices.

In the event of compelling circumstances, an individual holding a significant financial interest in human subjects research may be permitted to conduct the research. Case-by-case analysis should determine whether the circumstances are deemed compelling, based on such factors as the nature of the science, the nature of the interest, how closely the interest is related to the research, the degree to which the interest may be affected by the research, and the extent to which the interest is amendable to effective oversight and management. By recommending that institutions specify the criteria that their conflicts committees would apply to determine whether sufficiently compelling circumstances exist to justify proceeding with research in the face of conflict, the task force communicated its sense that these circumstances be relatively uncommon, that they be clearly specified, and that records of such circumstances be maintained.

Institutional policies should require full prior reporting of each covered individual's significant financial interests that would reasonably appear to be affected by the individual's research, updated reporting where necessary, and review of any significant financial interest by the institution's conflict of interest committee prior to final IRB approval of the research. The task force's definitions of key terms included several significant departures designed to impel more stringent institutional practices than are required under current PHS regulations. Thus, a broad definition of "conducting research" reaches deeper into a research team, to include designing or directing research, serving as the principle investigator, enrolling research subjects (including determining eligibility or obtaining informed consent), analyzing or reporting research data, or submitting manuscripts describing the research for publication. "Significant financial interest" newly embraces in the task force's formulation equity inte rests, including stock options, in non-publicly traded financially interested companies regardless of value, royalty income or the right to receive future royalties under a patent license or copyright, non-royalty payments or entitlements to payments in connection with the research that are "not directly related to the reasonable costs of the research," and "bonus or milestone payments to the investigators in excess of reasonable costs incurred," no matter from whom received. Service as an officer, director, or in other fiduciary roles for a financially interested company, whether or not for remuneration, is considered to be a significant financial interest, unlike in the federal regulations.

Reflecting its core principle of individual accountability and responsibility, the task force endorsed a process of annual reporting to the institution, with prompt updating whenever necessary, as well as certification by investigators to institutional review boards (IRBs) that they have current conflict of interest information on file with the institution when they submit proposals to IRBs. In addition, the task force recommended that the conflicts committee review any significant financial interests that would be created by potential licensing agreements of university technology.

Institutional policy should require disclosure of the existence of significant individual financial interests in human subjects research to appropriate state and federal officials, to research funding providers and sponsors, to editors, to research subjects in the consent process, to participants in multi-center trials, and in other appropriate forums. The institution should prohibit "payments from the institution or the sponsor to a covered individual, if such payments are conditioned upon a particular research result or tied to successful research outcomes." Payments, including those for subject enrollment or referrals to research studies, are permissible only to the extent that they are reasonably related to costs incurred and reflect fair market value of the services performed.

Institutional policies on intellectual property, publication, and documentation of gifts must be affirmed. The special vulnerability of students and trainees should be acknowledged through prohibition of publication restrictions on activities of students or trainees or, failing that, the requirement that any agreements restricting publication be subjected to close scrutiny by the conflict of interest committee and fully disclosed to students and trainees prior to their involvement in any such activity.

Institutional conflicts

The massive growth of the federally sponsored academic research enterprise since World War II has occurred under a system of federal oversight of research conduct that is remarkably deferential to university autonomy. The linchpin in this system is the credibility with which universities demonstrate responsibility and accountability for managing their federally supported research portfolios, or, put differently, the trustworthiness of awardee institutions. Only recently has the matter of institutional financial conflicts of interest in clinical research come under close scrutiny, as the public has recognized the growing institutional investment in the commercialization of their faculties' research discoveries and the increasing prominence of equity holdings in startup companies and other small businesses founded on university technologies.

As the 2001 GAO report stated, "some collaborations have raised concerns that research ... institutions that have significant financial interests in the research may focus attention on the financial rewards of the research, compromising its integrity and the safety of human subjects." In addition, institutional officials sit on boards of major corporate interests, including interests whose work brings them into close association with universities. Suggesting that institutional financial interests "may color [an institution's] review, approval, or monitoring of research conducted under its auspices or its allocation of equipment, facilities, and staff for research," the report called on HHS to issue regulations or guidance to address institutional conflicts of interest.

In tackling this complex and largely uncharted issue, the AAMC task force did not provide exhaustive guidance, but rather established a conceptual framework for assessing institutional conflicts of interest and offered specific recommendations for the oversight of certain financial interests in human subjects research that merit special scrutiny. The task force's work complements and further develops the general recommendations issued on this subject by the AAU in its 2001 Report on Individual and Institutional Financial Conflicts of Interest, by presenting the first detailed formulation of principles by which institutional conflicts of interest should be evaluated and managed.

The task force recommended that the conflict between the institution's competing fiduciary responsibilities--on the one hand its legitimate interest in its own financial health and the economic viability of its academic and research missions and on the other its ethical obligations to protect human subjects and the integrity of its research--should be resolved by a clear declaration that the welfare of human subjects and the integrity of research must not be compromised or appear to be compromised by competing institutional financial interests.

Throughout its report, the task force returned repeatedly to the theme that separation of the functions of financial management and technology licensing from the functions relating to management and oversight of human subjects research represents the pillar of credible management of institutional conflicts of interest, whether achieved by external management or (with more difficulty) internal firewalls. However, in some circumstances, despite separation of function, the protection of human subjects is still not assured to be free from the fact or the appearance of conflict and therefore, absent compelling circumstances and careful management of the conflict, the research in question should not be conducted at or under the auspices of the conflicted institution.

The source of institutional financial conflicts is not confined to investments and income, but includes those instances in which officers and administrators face a conflict between their primary institutional responsibilities and their secondary and personal financial interests. Though such interests are normally governed by an institution's policies on individual conflicts of interest, the task force noted that "an official's position may convey an authority that is so pervasive or a responsibility for research programs or administration that is so direct that a conflict between the individual's financial interests and the institution's human subjects research should also be considered an institutional conflict of interest." Such circumstances require the disclosure of all relevant details to a superior, and if conflicts cannot be eliminated through recusal or managed effectively through a strategy approved by the institutional conflict committee, the research should not be conducted by the institution or u nder its auspices.

The heart of this report is found in its enumeration of the circumstances that ipso facto may create or appear to create institutional conflicts of interest in human subjects research, and must therefore receive close scrutiny:

* When the institution is entitled to receive royalties from the sale of the investigational product that is the subject of the research,

* When through technology licensing or investments related to technology licensing, the institution has obtained an equity interest or an entitlement to equity of any value in a non-publicly traded sponsor of human subjects research at the institution,

* When through technology licensing or investments related to licensing, the institution has obtained an ownership interest or entitlement to equity of greater than $100,000 in value...in a publicly traded sponsor of human subjects research at the institution, or

* When with respect to a specific research project, institutional officials with direct responsibility for human subjects research hold a significant financial interest in the commercial research sponsor or the investigational product. Significant financial interest is defined for this purpose essentially identically as in the report on individual conflicts of interest.

In addition to the relationships identified above that warrant close scrutiny, the task force believed that certain other relationships could also merit special attention, including:

* When an investigator or institutional official with research oversight participates materially in a procurement or purchasing decision involving major purchases from or supply contracts with a commercial entity that sponsors human subjects research, or

* When an institution has received substantial gifts from a potential commercial sponsor of human subjects research, taking into account the magnitude of the gift(s) over defined periods of time, whether the gift is held for the benefit of the institutional unit where the human subjects research is to be conducted, and whether any institutional officer who has authority over the administration of the research has been involved in solicitation of the gift.

The task force made clear that it did not intend to prevent institutions from accepting philanthropy from corporations that sponsor human subjects research. However, it affirmed the necessity of identifying circumstances in which the appearance of conflict is present and of establishing means to assure that inappropriate considerations do not jeopardize the welfare of human subjects or contaminate the objectivity and integrity of the research. The task force also affirmed the necessity of institutions' having clear policies to ensure that all gifts are appropriately accepted and recorded.

Oversight mechanisms

To evaluate institutional conflicts of interest, the task force recommended a standing institutional conflicts of interest committee, all members of which should be independent of the direct institutional line of authority for human subjects research. Though the choice is left to each institution, the task force urged institutions to consider the advantages of separate individual and institutional conflicts committees, in view of the complexity and sensitivity of the issues to be considered by the institutional committee, the need for participation by senior officials, and the strong recommendation that public members be included to increase the transparency and credibility of the committee's work

Linkages between the institution's office of technology licensing and the institutional conflicts committee should be forged, so that there would be a report to the committee when, as a result of a licensing agreement, the institution takes or intends to take an equity interest or any entitlement to an ownership interest in or royalty payments from a potential sponsor of human subjects research. Institutional conflicts, including those of institutional officials, must be reported to the IRB of record.

The task force recommended that in general human subjects research should not be conducted in the presence of any of the earlier enumerated financial interests that deserve special scrutiny. As in the case of individual conffict of interest, exceptions should be made only when the circumstances are compelling (as defined in the first report), and there is an effective management plan.

As with individual conflicts of interest, the task force was convinced that instances of potential institutional conflicts tend to be highly situational and that evaluation should be on a case-by-case basis, with the circumstances and context of each case fully considered in the oversight process. Establishing rules that permit exceptions allows universities and their academic medical centers to establish their own standards for how compelling the circumstances must be to support rebuttal of the presumption, but it was the clear intent of the task force that the bar be set high.

The task force made a number of additional recommendations concerning special research circumstances, including a recommendation that when the institution holds one of the financial interests creating an ipso facto conflict, it not conduct related human subjects research except as a non-primary and non-coordinating site in a multi-center trial. Again, required disclosure of institutional financial conflicts to the IRB of record, to research subjects, and in all publications constitutes the essential element of a transparent conflicts management process.

Recognizing that its recommendations on individual and especially institutional conflicts of interest extend beyond current legal requirements, as well as beyond standard institutional practices, the task force's intention was to assist the academic community in responding voluntarily and credibly to the emerging concern over institutional conflicts of interest in human subjects research. The AAMC intends to follow the fate of the task force's reports to determine how influential and effective they will be, whether any of the provisions prove unwieldy or unduly burdensome, and whether aspects of this complicated and sensitive set of issues merit further attention. The reports are stringent, and their widespread adoption would significantly raise the standards for oversight and management of individual and institutional financial conflicts of interest in human subjects research, as well as reduce the disturbing variability in institutional policies and practices highlighted in the recent literature.

The epilogue that ends the first report serves equally well the second. Its conclusion states: "The Task Force does not believe, and does not intend, that adoption of the recommended policy and guidelines by the academic medical community should interfere with healthy academic- industry relationships, or with the continued robust flow of academic biomedical invention into products that benefit the public. The Task Force does believe that these policies and guidance can help to ensure that these relationships remain principled and capable of withstanding intense public scrutiny."

Recommended Reading

Marcia Angell, "Is Academic Medicine for Sale?" New England Journal of Medicine, 342, 1516-18, 2000.

David Korn, "Industry, Academia, Investigator: Managing the Relationships," Academic Medicine, 77, 1089-1095, November 2002.

Task Force on Financial Conflicts of Interest in Clinical Research. Protecting Subjects, Preserving Trust, Promoting Progress: Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research (Washington, D.C.: AAMC, December 2001).

Task Force on Financial Conflicts of Interest in Clinical Research. Protecting Subjects, Preserving Trust, Promoting Progress II: Principles and Recommendations for Oversight of an Institution's Financial Interests in Human Subjects Research. Washington, D.C.: AAMC, October 2002.

Task Force on Research Accountability. Report on Individual and Institutional Financial Conflict of Interest. Washington, D.C.: Association of American Universities, October 2001.

U.S. General Accounting Office, Biomedical Research: HHS Direction Needed to Address Financial Conflicts of Interest (GAO-02-89). Washington, D.C.: U.S. Government Printing Office, November 2001.

Susan Ehringhaus ([e-mail]) is vice chancellor and general counsel of the University of North Carolina at Chapel Hill. David Korn ([e-mail]) is senior vice president for biomedical and health sciences research at the Association of American Medical Colleges in Washington, D.C.