News & Events
Efforts to Protect Human Research Subjects
William F. Raub, Ph.D
Deputy Assistant Secretary for Science Policy
Office of the Assistant Secretary for Planning and Evaluation
Office of the Secretary
Department oh Health and Human Services
the Subcommittee on Criminal Justice
House Committee on Government Reform
May 3, 2000
Good afternoon, Mr. Chairman and members of the Subcommittee. I am William Raub, Deputy Assistant Secretary for Science Policy at the Department of Health and Human Services (HHS). Thank you for this opportunity to discuss HHS efforts to protect human research subjects and to comment on the related findings and recommendations of the HHS Office of the Inspector General (OIG).
HHS LEADERSHIP IN PROTECTING HUMAN RESEARCH SUBJECTS
For more than fifty years, HHS and its predecessors have led the nation and the world in the conduct, support, and oversight of clinical research aimed at improving human health. Clinical research, by definition, involves experiments. If we knew the outcome in advance, we wouldn’t have to do the studies. Recognizing the risks and benefits of clinical research, HHS has extended its leadership role to protecting human research subjects from inappropriate risks.
This HHS role came about primarily because, in the years immediately following World War II, the federal government determined that the national interest would be served by investing substantial amounts of public funds in biomedical research through the then-fledgling National Institutes of Health (NIH); the investment strategy encompassed not only the direct operation of government laboratories but also awards to extramural entities such as medical schools, other institutions of higher education, and not-for-profit research institutes. In addition, the Food and Drug Administration (FDA) was assigned statutory responsibility to regulate clinical research associated with bringing drugs, vaccines and other biologics, and medical devices to market. Thus, protection of human research subjects long has been an integral part of HHS efforts to conduct, sponsor, and regulate biomedical research.
Public funding for biomedical research has been a high priority for both the Congress and the Executive Branch for the last half-century; and, during the same period, the pharmaceutical, biotechnology, and medical device industries also have been funding increasing amounts of clinical research to bring new or improved products into the health-care milieu. This ever-increasing investment by both the public and private sectors is yielding an ever-increasing fund of knowledge that, in turn, is yielding a stream of significant advances in our ability to diagnose, treat, and prevent disease.
Accompanying this series of highly productive investments has been the ever-increasing challenge to ensure that human research subjects are protected from unreasonable risks, participate of their own free will, and make their decisions only after they have been informed fully about the potential risks and possible benefits, if any, of their participation. This challenge flows directly from the Nuremburg Code -- whose principles have been adopted, reinforced, and built upon over the years in a succession of policies culminating in the current federal regulations for protection of human research subjects. HHS led the way in developing the core of these regulations -- the so-called Common Rule, which has been promulgated by 17 different Departments and Independent Agencies. Moreover, for its own programs, HHS has supplemented the Common Rule with companion requirements that address specific protections pertaining to research involving fetuses, pregnant women, and human in vitro fertilization; prisoners; and children; and FDA has promulgated its own rules, consistent to the extent practical with the Common Rule, governing clinical research associated with the products it regulates.
The primary foci for implementing these regulations and promoting compliance with them are the Institutional Review Boards (IRBs). IRBs are responsible for reviewing proposed research protocols and associated informed consent statements before subjects are recruited and clinical research begins; no project that falls under the Common Rule or FDA regulations may commence without IRB approval. Further, IRBs are responsible for continuing review -- that is, oversight of approved research projects throughout their life cycle. If, in the course of continuing review, the responsible IRB were to find cause for concern regarding the safety and well-being of research subjects, the IRB could halt the project temporarily or permanently or otherwise require the investigators to take whatever protective or corrective actions it deems appropriate.
Many IRBs are established and operated by universities, hospitals, and other institutions that receive research awards from the federal government or other sponsors. These IRBs are composed primarily of faculty and staff members who serve voluntarily and without special compensation for their IRB service; in addition, each IRB is required to have at least one member who is not a scientist and one member from outside the institution. These awardee-operated IRBs usually oversee all the clinical research conducted at their institutions -- irrespective of whether the funding for the research comes from government, foundations, or industry. In particular, most privately sponsored clinical research (e.g., drug trials sponsored by the pharmaceutical industry) is subject to review by awardee-based IRBs because much of this research is carried out in academic health centers. Research awards are the primary revenue stream available to institutions for IRB costs; many institutions receive significant funding to cover IRB operating costs by charging sponsors a fee to review privately funded research.
A small minority of IRBs operate independently -- that is, as private entities. Independent IRBs usually provide reviews for industry-sponsored projects conducted outside a university or hospital setting -- e.g., in physicians’ private offices or clinics. These IRBs typically comprise paid expert consultants, operate on a fee-for-service basis, and are overseen by FDA in the same manner that FDA oversees IRBs operated by research institutions.
Two HHS components share responsibility for overseeing IRBs: the NIH Office for Protection from Research Risks (OPRR) and the FDA. OPRR oversees IRBs operated by HHS awardee institutions. FDA oversees IRBs that review clinical research related to products it regulates, irrespective of whether that research is ongoing at HHS awardee institutions or other sites.
GENERAL COMMENTS ON THE OIG FINDINGS AND RECOMMENDATIONS
HHS is very concerned that the effectiveness of IRBs is in jeopardy. Although the OIG investigation did not reveal either significant instances of actual harm to research subjects or evidence for any widespread pattern of outright IRB failure, we must not let that be cause for complacency. Many IRBs face unacceptably large workloads with too little time and too few resources to do everything necessary to meet the letter and spirit of the applicable regulations. The fact that instances of actual harm to research subjects have been few and far between is a credit to the extraordinary dedication and prudent decision-making of IRB members and the commitment of investigators to the integrity of their work. We must strengthen the protections now before more -- and more serious -- failures ensue.
Recent reports of several gene transfer trials with insufficient patient protections have underscored the urgency of this effort and illustrated the new pressures facing biomedical scientists, research institutions, and IRBs. For example, the line between publically funded research (primarily funded by NIH and governed by the Common Rule and other applicable regulations) and industry-funded research (aimed at bringing a product to market and governed by FDA regulations) is becoming increasingly blurred. University scientists not only may be receiving public and private funding simultaneously for related lines of research but also may be stockholders in or corporate officers of pharmaceutical, biotechnology, or medical device companies.
In the wake of the June, 1998 reports, the OPRR and the FDA stepped up the pace of their inspections of human subjects protection activities at research institutions within their respective areas of cognizance. Taken together, the findings from these inspections reinforced the OIG conclusion that the IRB system is under considerable strain. Moreover, for several institutions, the OPRR and FDA inspections led to partial or complete suspension of clinical research at those sites until the institutions’ deficiencies were corrected -- often only after major revamping of the IRB structure and commitment of substantial additional resources by the research institutions. The experiences with these cited institutions suggest that HHS and the research community have considerably more work to do and that those efforts warrant a sense of urgency.
An imminent organizational change within HHS will do much to facilitate our intensified efforts to protect human research subjects. Last year, acting on the results of a study commissioned by the Director of the NIH, Secretary Shalala determined that the human subjects component of the OPRR should be elevated to the Office of Public Health and Science within the Office of the Secretary; this action also was consistent with the results of a similar study undertaken independently by the National Bioethics Advisory Commission. Further, the Secretary allocated a Senior Executive Service slot for the directorship of the new office (the Office for Human Research Protection -- OHRP), directed the Assistant Secretary for Health to carry out a national search to fill the position while also assessing the resource requirements for the new office, and authorized the creation of a public advisory committee to help guide the OHRP specifically and the Department overall. We agree with the OIG that the creation of OHRP and its associated advisory committee presents "a new opportunity to exert Federal leadership in protecting human subjects".
At the same time, we urge research institutions to strengthen their local efforts to protect human research subjects in accord with the framework of recommendations presented by the OIG. In particular, we urge research institutions to give their IRBs the standing and resources they need to do their job properly. Human subjects protection is a shared responsibility among the federal government, research institutions, IRBs, investigators, and sponsors. HHS is committed to doing its part; and we will continue to expect others to do theirs.
We recognize that, for many research institutions, the gap between what is being done to protect research subjects and what should be done is wide and that remedial actions may be costly; but we also recognize that federal research awards already provide a substantial revenue stream that can be applied toward this end. Approximately one third of the typical research grant is available to reimburse awardees’ expenditures for the indirect costs of research -- often referred to in the vernacular as "overhead"; and approximately half of these "overhead" payments are available to reimburse expenditures in the "administration" category, which includes essentially all of the costs of operating IRBs -- among other expenses. Thus, while we recognize that many different activities legitimately claim high priority when institutions allocate their resources, we are hard-pressed to identify any activities that are of greater importance than human subjects protection.
HHS ACTIONS RELATED TO OIG FINDINGS AND RECOMMENDATIONS
Since the OIG issued its June, 1998 reports on the IRB system, HHS agencies have taken substantial steps in each of the six action categories recommended by the OIG. I am pleased to highlight some of these ongoing or planned actions for the Subcommittee’s consideration. We view these steps as a strong beginning but concur with the OIG that much more remains to be done.
Recast Federal Requirements
In consultation with its Regulatory Burden Advisory Group, NIH developed a new policy for "just-in-time" IRB review of research proposals; the new policy will go into effect this summer. Current policy requires that the applicant institution provide NIH with results of the IRB review for each new and competing renewal clinical research grant application at or soon after the time that the institution submits the application. This means that a substantial fraction of IRB members’ time and energy is expended doing reviews of proposed projects that are not likely to be funded by NIH and thus not likely to be activated. The new policy will allow the applicant investigator to defer submission of his/her proposal to the IRB until the application has undergone the first phase of the NIH peer review process and NIH has provided the applicant investigator with the result. If, on the basis of this information, the applicant investigator determines that funding by NIH is unlikely, the institution may elect not to invoke IRB review--thereby allowing the IRB to direct more of its attention to proposed projects that have a reasonable chance of being funded as well as projects that are ongoing as a result of approval and funding at an earlier time.
Complementing the "just-in-time" initiative, OPRR has consulted with awardee institutions to streamline the assurance process -- that is, to reduce the time and documentation required for an institution to provide satisfactory evidence of its intent to comply with requirements for the protection of human research subjects. Such assurance statements generally cover a three-year period initially and then must be renewed every five years thereafter. HHS will not fund clinical research at any institution that has not provided such an assurance; moreover, failure to fulfill the terms of the assurance is grounds for enforcement action against the institution -- such as suspension of some or all its HHS-funded clinical research. The streamlined assurance process is ready to go and is slated to be introduced in the near future. This will allow both OPRR and the awardee institutions to redirect some resources to other areas, such as increased inspections and enhanced educational efforts directed toward investigators and IRB members.
Strengthen Continuing Protections
Another result of NIH consultations with its Regulatory Burden Advisory Group is a new requirement that Data and Safety Monitoring Boards (DSMBs) provide the responsible IRBs with summary reports of analyses of adverse events observed during clinical trials. This provides important assistance to IRBs in their continuing review of projects because DSMBs focus on their assigned trials throughout their course in more detail than an IRB realistically could do and often have expertise that is not represented on the responsible IRB. Since 1979, NIH has required that all clinical trials have some form of data and safety monitoring. In 1998, NIH reaffirmed policy by requiring that Phase III clinical trials (i.e., large-scale assessments of the safety and efficacy of a clinical intervention) have a DSMB. NIH now is developing further guidance for smaller scale clinical trials (i.e., Phase I and Phase II trials).
In a similar vein, FDA modified the Privacy Act Systems Notice to allow FDA to send sponsors and IRBs copies of correspondence to clinical investigators regarding violations of FDA regulations. Also, an FDA working group is assessing approaches to help ensure that adverse event reports associated with FDA-regulated trials are shared with the responsible IRBs in a useful manner; and another FDA working group is assessing issues related to DSMBs -- including guidelines for membership, management, quality control, value in protecting human subjects, and whether regulation is needed. All these efforts should enhance the effectiveness of IRBs’ continuing review.
In March, FDA announced new protections oriented specifically to subjects participating in gene transfer trials. FDA will require that sponsors of such trials routinely submit their monitoring plans for FDA review; FDA also will perform surveillance and "for cause" inspections of clinical trials to assess whether the plans are being followed and whether monitoring has been adequate to identify and correct critical problems. At the same time, NIH and FDA also announced their plans for a series of gene transfer safety symposia; these public forums are intended to enhance the safety of research subjects by fostering broad sharing and analysis of medical and scientific data from gene transfer research.
Enact Educational Requirements
Although neither NIH nor FDA has promulgated specific requirements for education, both agencies have worked assiduously to make informative materials more readily available to the research community than heretofore. For example, in March, 1999, FDA convened a national meeting that featured a presentation on the June, 1998 OIG reports. In addition, OPRR and FDA continued their series of widely acclaimed regional meetings to promote understanding of and compliance with the requirements for human subject protection; these sessions routinely are well attended by IRB members, investigators, and officials of research institutions. Further, OPRR increased its education staff, technical assistance to research institutions, and guidance documents while maintaining a web site replete with materials relevant to human subjects protection; and FDA is updating its Information Sheets, which are an important sources of guidance for IRBs and clinical investigators. We expect that the OHRP will continue and build upon the initiatives of OPRR and FDA in this regard.
In 1999, NIH established a web site called "Bioethics Resources on the Web" (http://www.nih.gov/sigs/bioethics). It provides information about bioethics initiatives at NIH and other government agencies as well as access to publications, reports, guidelines, and regulations related to bioethics.
In 1997 and 1999, NIH issued two solicitations for grant applications related to bioethics. One initiative provides funding for short courses in research ethics. This has led to 15 awards; as a result, hundreds of investigators are taking specific bioethics courses, and many more are accessing these courses through the Internet. The other provides funding for developing scientists to enhance their knowledge and experience regarding bioethics with a view to assuming leadership roles in this area later in their careers. In addition, NIH developed and disseminated widely a template for writing easy-to-understand informed consent documents; increased its support for investigators conducting research on the informed consent process; and, in specific response to the June, 1998 OIG reports, solicited research proposals involving the development and evaluation of outcome measures to help IRBs monitor protocol review.
Within its intramural program, NIH instituted computer-based training that is mandatory for its research staff and extramural program managers who have responsibility for clinical research. The training aims to help NIH staff understand better the requirements associated with research involving human subjects. The experience here could contribute to development of an effective national web-based training effort.
Help Insulate IRBs from Conflicts That Threaten Their Independence
Financial conflicts of interest on the part of IRB members warrant continuing attention. The Common Rule prohibits IRB members from participating in any matter in which they have a conflict. Moreover, the potential for financial conflicts of interest to threaten objectivity is not limited to them. Similar concerns obtain for investigators and institutions as a whole, for financial relationships related to clinical research have grown progressively more complex over the past two decades following the enactment of statutes promoting commercialization of the results of publically funded research.
The Public Health Service (PHS) and the FDA have promulgated regulations dealing with financial conflicts of interest. The PHS regulation, issued in 1994, provides for review and appropriate attention to any financial involvements of investigators that might impair their objectivity in conducting research. The FDA regulation, which became effective in 1999, requires that investigators report their financial interests to the sponsor, who, in turn, is required to report them to FDA for consideration in the course of review of marketing applications.
Recognize Workload Pressures
Initiatives to reduce workload pressures already have been mentioned in the context of recasting federal requirements; and we will continue to seek new means to relieve these pressures -- thus enhancing IRBs’ abilities to provide adequate human subjects protection. However, HHS recognizes that, even with streamlined processes and the substantial recent increases in funding to research institutions via the NIH for the direct and indirect cost of research, some IRBs may not receive the resources they need to fulfill their responsibilities. HHS is prepared to work with the leaders of research institutions to address IRB functions and to understand their resource implications.
Reengineer Federal Oversight Process
Several initiatives to reengineer the oversight process have been mentioned in the context of recasting federal requirements. In addition, HHS welcomes the recent interest within the research community in the concept of accreditation of IRBs. We are eager to explore this prospect and, with it, the associated issues of registration of IRBs and the credentialing of investigators. Also, we note that the National Bioethics Advisory Commission is conducting a wholesale assessment of the current system for protection of research subjects; and we look forward with having the benefits of its analysis and recommendations.
In developing the HHS’ proposed rules on the privacy of individually identifiable health information, we realized that the Common Rule may not contain all of the safeguards necessary to protect the privacy of research subjects. Thus, in addition to addressing the OIG’s recommendations, we also plan to begin a review of the privacy and confidentiality protections afforded by the Common Rule specifically as they relate to the subjects of records-based research.
HHS reaffirms its commitment to protecting human research subjects and will work actively with the research community to achieve that end. We believe that the OIG has provided a timely wake-up call for everyone involved.
(Updated by tg 2000-JUN-30)