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Statement on Protecting Human Subjects in Research: Are Current Safeguards Adequate?

Mr. Chairman and members of the Subcommittee, I am Bob Kelch, M.D., Dean of the University of Iowa's Roy J. and Lucille A. Carver College of Medicine. I also serve as the Chair of the Advisory Panel on Research for the Association of American Medical Colleges (AAMC). The AAMC represents the 125 accredited U.S. medical schools; the 16 accredited Canadian medical schools; some 400 major teaching hospitals, including 74 Veterans Administration medical centers; more than 105,000 faculty in 98 academic and scientific societies; and the nation's 66,000 medical students and 97,000 resident physicians. Our member institutions conduct a very large share of the biomedical and behavioral research performed in this country, and we have been the source of many of the dramatic breakthroughs that have revolutionized biology and are transforming medicine. My testimony today will focus on how the AAMC, on behalf of our members, has undertaken significant new initiatives aimed at strengthening the protection of the many thousands of human patients and volunteers who participate in medical research each year.

The AAMC commends the Subcommittee for convening this hearing to explore the issues surrounding the protection of human research participants. We recognize that academic medicine and the American public have forged a special relationship rooted in trust that is nowhere more evident - or more fragile - than in clinical research involving human participants. We are troubled by recent reports of lapses in the oversight of clinical research in some of our most prestigious members, reports that threaten public confidence in our nation's system for protecting research participants. And we are disturbed by allegations that the financial interests of faculty investigators or their institutions may have compromised their independence and credibility, and threatened the welfare of research participants as well as scientific integrity.

AAMC and its members are vitally concerned for the safety and well being of the patients and healthy individuals who participate in our research programs. We believe that their protection can be most reliably achieved and effectively sustained in settings that place a high priority on, and devote significant attention to, research ethics, as well as compliance with legal and regulatory requirements. We agree with OHRP Director, Dr. Greg Koski, that the most effective programs of protection of human research participants will occur in institutions that go beyond compliance to foster "a culture of conscience and responsibility" that lodges not just in Institutional Review Boards (IRBs), but in every principal investigator and all of those who engage in clinical research.

To assist our members to create and maintain such a desired culture of conscience and responsibility, and to achieve uniformly high standards of human research protections across the entire community of academic medicine, we have organized national research compliance conferences, and have worked jointly with the organization, Public Responsibility in Medicine and Research (PRIM&R), to sponsor focused regional educational programs for Institutional Review Board members and staff, faculty who conduct clinical research, and institutional officials responsible for its oversight in our member institutions. All of these efforts have been enthusiastically received and over-subscribed. A year ago the AAMC created a compliance web site (www.aamc.org/research/dbr/compliance/startcom.htm) to publicize and make accessible the most promising initiatives developed by our members to address the education and credentialing of clinical investigators. A number of attractive approaches were already in development by our members well before October 2000, when the NIH made such educational programs mandatory for its awardees. The credentialing of clinical investigators, an approach initiated by the University of Rochester Medical Center, is becoming widespread and will soon be a requirement. Visitors to the AAMC compliance site can locate a rich set of information related to federal regulations, model policies and procedures, and available educational resources.

During the remainder of my testimony, I will emphasize two major new initiatives in which the AAMC is heavily engaged: initiatives designed to ensure the safety and well being of the patients and healthy individuals who volunteer to participate in our research programs. First, we have worked to establish a system of voluntary accreditation of institutional programs of human research participant protections; second, we have developed and published our first report, including detailed guidelines to address the concerns that have been raised about financial conflicts of interests in clinical research.

Accreditation

Despite the existence for more than 25 years of an evolving code of federal regulations (since 1991 commonly dubbed "the Common Rule") and policies to protect the rights and welfare of human research participants, there has been increasing concern in recent years that the system for protecting these participants needs improvement. These concerns were dramatically underscored by the recent wave of federal suspensions of research at various institutions around the country, which indicated to many that systemic improvements in human research protection programs are necessary. While acknowledging that researchers and IRB members are generally adhering to the federal requirements for protecting human research participants, the Inspector General of the Department of Health and Human Services observed that the national system for protecting research subjects is currently under strain and facing increasing pressure in a rapidly changing research environment.

IRBs have a significant number of weighty responsibilities. Under the terms of the assurances their institutions provide to federal funding agencies, IRBs must make certain that the research they oversee is conducted in accordance with Federal policies and all applicable state and federal laws. To assure that the risks to human participants are minimized, IRBs must assess these risks in hundreds or even thousands of research protocols, while meeting exacting procedural requirements and maintaining detailed records. Moreover, even as the complexity of clinical research and the volume of research protocols are increasing, IRBS must respond to an ever-expanding array of federal and state requirements that, in the aggregate, have become procedurally onerous, and, some argue, distracting.

Given that within the academic community IRB members are almost always volunteers with major responsibilities in teaching, research, and often, patient care, it is not surprising that they are finding it difficult to accept progressively increasing new burdens of oversight, or finding the time and resources to undertake periodic self-assessment. The AAMC agrees with Dr. Koski that responsibility for ensuring the well being of human research participants in this rapidly changing environment of clinical research, can no longer be considered primarily to rest on IRBs, but must become the duty of all who are engaged in the enterprise. The British code of medical ethics speaks of a solemn "duty of care" that rests on every physician; the AAMC suggests that same ethical "duty of care" should rest on every physician-investigator who conducts research on human participants.

Universities, medical schools, and teaching hospitals must work to instill across their campuses, in all who engage in human participant research, a new sense of shared obligation and a new culture of individual responsibility. The AAMC believes, based on its long experience with many different kinds of academic accreditation programs, that establishing a mechanism of voluntary accreditation of human research protection programs would be very helpful to our members, as well as the broader academic community, in accomplishing the changes in faculty attitude and institutional culture that are necessary. The idea of creating such an accreditation mechanism had been debated within PRIM&R circles for several years. In May 1999 PRIM&R announced that it would develop a program of accreditation for human research protection programs, which it dubbed AAHRPP (Association for the Accreditation of Human Research Protection Programs), and formed a committee to begin to draft accreditation standards. Since that time, as I will describe, the AAMC has partnered with PRIM&R to bring this concept into existence in a way that is consonant with our traditional and uniquely American model of voluntary, peer-driven, educationally focused accreditation of academic institutions and their components.

The accreditation model, while necessarily conforming to all applicable statutory and regulatory requirements, is importantly different from the regulatory model, common in other countries, which focuses purely upon regulatory compliance. Accreditation fosters a process of self-examination and a culture of self-improvement that is stimulated and nurtured by the accreditation process itself. AAMC shares with PRIM&R the belief that such an accreditation process for human subjects protection programs should combine objective, outcome-oriented performance standards with on-site reviews involving collegial dialogue and education. An approach that is collaborative yet based upon clearly defined standards will encourage institutions to strive for ever higher levels of performance beyond the threshold of compliance. The ultimate objective of accreditation will be to foster a commitment to continuing quality improvement within each institution's system for the protection of human research participants.

The AAMC conceived of AAHRPP as a nonprofit Member corporation, in which the Members would be the large Washington-based associations representing America's universities (Association of American Universities and National Association of State Universities and Land-Grant Colleges), medical schools and teaching hospitals (AAMC), biomedical scientists (Federation of American Societies for Experimental Biology), behavioral and social scientists (Consortium of Social Science Associations), patient advocacy organizations (National Health Council), and IRB experts (the Boston based PRIM&R). AAMC took the lead in forging this alliance, securing funding, and bringing AAHRPP into existence; AAHRPP was incorporated in the state of Maryland on April 23, 2001. AAHRPP's mission is to provide a process of voluntary, peer-driven, educationally focused accreditation and continuing quality improvement for academic institutions and other organizations concerned with research involving human participants. AAHRPP's goal is to create and administer a highly respected program of accreditation that is viewed by the larger research enterprise, the federal government, and the public as safeguarding and improving the protection of human research participants. AAHRPP is now operational and a full slate of site visits is anticipated to be performed this year.

AAHRPP is governed by a 21 member Board of Directors that includes 5 public representatives and has full authority over the organization and its accreditation programs and activities. The founding Members serve in a Trustee role, with strictly circumscribed fiduciary responsibilities; the Members will have no role whatever in the operations of AAHRPP or its decision-making processes. The Executive Director of AAHRPP is Marjorie Speers, Ph.D. and the President is David Skorton, M.D., from the University of Iowa.

The AAMC is very pleased to have been able to play a major role in the creation of AAHRPP and is prepared to continue to do whatever it may be asked to ensure its success. We believe that AAHRPP will contribute in important ways to the change in culture of human participant research, which Dr. Koski has repeatedly called for, and to which our members and we unequivocally subscribe.

Conflicts of Interest

Following the reports of several tragic events that occurred in gene transfer experiments in which both faculty and their sponsoring institutions were perceived to have significant financial interests, the Administration, the Congress, and the media began to question the sufficiency of current federal conflict of interest guidelines, the credibility of institutional conflict of interest policies, and the dependability of academic institutions in complying with their own policies. Driving this concern was the fear that financial conflicts of interest may jeopardize the safety of research participants and the integrity of research data. This topic had last captured public attention in the 1980s, when congressional hearings cast a harsh light on several instances in which financial conflicts of interest seemed linked to scientific misconduct in clinical research.

More than a decade ago, the AAMC developed and published guidelines to aid its membership in addressing faculty conflicts of interest in research. These guidelines were a necessary response to the emerging paradigm of university/industry collaboration spurred by the Bayh-Dole Act, which in 1980 gave universities title to inventions arising from federally sponsored research. Bayh-Dole created fertile ground for nurturing the transfer of basic research findings to the developers of beneficial products, but also gave rise to new incentives for investigators and their institutions to pursue financial interests in the course of scientific research.

Although the AAMC guidelines have served as a useful model for conflict of interest policies developed by individual medical schools and teaching hospitals, recent studies have indicated that across the academic community approaches to identifying and managing individual financial conflicts of interest vary widely. Of particular concern is the absence of consensus regarding the proper management of related financial interests in clinical research that involves human participants. Moreover, neither the AAMC guidelines nor most institutional policies address the conflicts that may arise from the financial interests of the institutions themselves, which have increased substantially in the past decade from both royalty streams and equity holdings. Although conflicts of interest are ubiquitous and inevitable in academic life, as they are in all professions, the existence of related financial interests of either individual investigators or their institutions in research involving human participants raises special concerns. Yet, such interests have become particularly widespread in academic medicine, which has spawned a flourishing biotechnology industry, generated an insatiable public appetite and impatience for ever more wondrous treatments, and contributed importantly to the intense public and political interest in universities as sources of regional economic prosperity.

Our collective experience with the increasingly commercial nature of academic research and our obligation to be responsible compel a thorough reexamination of how the academic medical community manages financial interests in research involving human participants. The AAMC believes it imperative that our community take the initiative in reassuring the public and policy makers that neither institutional nor faculty financial interests will be permitted to compromise the safety of human participants or the integrity of biomedical research. AAMC President Jordan Cohen, M.D., made financial conflicts of interest the theme of his address at the AAMC 2000 Annual Meeting, where he announced the formation of a high level Task Force on Financial Conflicts of Interest in Clinical Research. The Association chose to focus the efforts of the Task Force upon financial conflicts of interest involving human participants, in part because we perceive an urgent need to rethink and revise our guidance in this area, and in part to complement the activities of an AAU Task Force on the Responsible Conduct of Research, which examined some of these same issues from the campus-wide perspective of university presidents. In composing our Task Force and developing its charge, we were particularly sensitive to the special relationship of trust that academic medicine enjoys with the American public. The work of the Task Force was guided by our commitment to sustain that trust in the context of the new, extraordinarily promising, and far more entrepreneurial environment in which we now conduct research.

Chaired by William Danforth, M.D., chancellor emeritus of Washington University, the task force published its recommendations in December 2001. An overview of our work was also published this January in the New England Journal of Medicine. The Task Force roster is contained in the final report, which is appended to this testimony, as is a copy of the summary article. We request that this material be entered into the record of this hearing. Among the 28 members of the AAMC Task Force on Financial Conflicts of Interest in Clinical Research are prominent representatives from the fields of academic medicine, law, industry, bioethics, patient advocacy, the media and politics.

The Task Force was charged with examining the appropriate limits of financial interests for faculty, students, and staff involved in the conduct of research with human participants, and whether certain types of financial interests should be prohibited. The Task Force considered the most effective means by which significant related financial interests in research involving human participants should be disclosed to the institution, the research participants, and to the public, and under what circumstances, if any, it is acceptable for institutions to invest in and sponsor faculty entrepreneurial activities involving human participants. For those circumstances that may be deemed acceptable, the Task Force proposed mechanisms to ensure that institutional oversight of faculty activities is responsible and credible.

Quoting from my summary article, the guidelines offered by the AAMC task force are based on some core principles. The first guideline makes it clear that the welfare of the patient is paramount. The second guideline addresses the circumstances under which researchers with financial conflicts might be allowed to participate in human research. The other guidelines define institutional responsibilities for the oversight and management of conflicts of interest, as well as the individual responsibilities of faculty members, staff members, and students. For example, the task force recommends that full initial and updated reporting of any relevant activity be required. Moreover, institutional policies should be comprehensive, unambiguous, well publicized, consistently applied, and enforced by means of effective sanctions. The document states that "Transparency must be the watchword for the oversight of financial interests" and that "transparency is achieved through full and ongoing internal reporting and external disclosure." The task force recognized that some conflicts pose little threat to the physician-patient relationship and may even advance its primacy; they therefore adopted, as part of the complex definition of "significant financial interest in research," the threshold established by the Public Health Service of $10,000 of total interest in companies related to the research in question for a conflict of interest in any given research project."

The report lists the requirements that must be met as institutions develop their own policies. For example, the key responsibilities of the committee that assesses conflicts of interest are identified. In addition, detailed guidance is provided on reporting requirements, the certification of investigators, disclosure practices, monitoring procedures, the protection of students and trainees, legal obligations, and sanctions. Advice is also provided on the implementation of such policies, including consideration of information flow, resources, written acknowledgment by those involved in clinical research that they have read and understood the policy, education and training of researchers, and accreditation of institutional research review processes.

The greatest challenge for the task force was reaching a consensus on the best way to ensure that the welfare of the patient remains the top priority. One sentence in the first guideline deserves further discussion; it states that, "institutional policies should establish the rebuttable presumption that an individual who holds a significant financial interest in research involving human subjects may not conduct such research." Some members of the task force and some research organizations, such as the American Society of Gene Therapy, believe that any financial conflict should preclude involvement in such research. The privilege of conducting research involving human subjects in cases which investigators have substantial financial conflicts of interest should be restricted to instances in which there are compelling reasons for an exception to be made. The AAMC task force recommended that it should be the responsibility of the researcher who has such a conflict to persuade an institutional committee that it is in the best interest of the subjects to allow the investigator to have direct involvement in the research.

Addressing investigator conflicts of interests is only part of the challenge. It is also necessary to address the management of institutional conflicts of interest. The AAMC's institutional conflict of interest task force is confronting this issue. The Task Force's complete report will provide detailed guidelines for the recognition and management of all institutional conflicts of interest.

The AAMC respectfully urges the Subcommittee to afford academic medicine the opportunity to demonstrate that we can - and will - take the actions necessary to sustain the public trust in our institutions, our investigators, and the integrity of biomedical research, while continuing to play a seminal role in translating the remarkable fruits of the "Golden Age of Biology" into public benefit.

To conclude, the AAMC and its members are firmly committed to the protection of the rights and welfare of every individual who elects to participate in human research, and we look forward to continue working with the members of this Subcommittee to achieve this goal.