Human Research Oversight Expands

While Health and Human Services builds a comprehensive program to ensure the safety of human subjects, Congress weighs proposals to stiffen the rules.

When the Office for Human Research Protections shut down clinical studies at Johns Hopkins University in July, one objective was to send a strong message that OHRP will not tolerate lax oversight of human research by even the most eminent medical institution. Since it was established in June 2000, the Office for Human Research Protections in the Department of Health and Human Services has gained visibility for waving a big stick at noncompliant research organizations, while expanding the governments capacity for setting policy, monitoring studies, and educating all segments of the research community. OHRP director Greg Koski is leading the charge, working with other government agencies to build an aggressive oversight program.

OHRP is working closely with the Food and Drug Administration, which has established an agency-wide office to coordinate oversight of clinical trials and ensure that studies provide unbiased and sound data to support market applications. FDAs good clinical practice staff (which may be renamed Office for Human Research Trials) in the Commissioners Office of Science Coordination and Communication now oversees FDA bioresearch monitoring programs, in coordination with the Office of Regulatory Affairs and individual product centers. David Lepay, senior advisor for clinical science, heads the GCP staff; he represents FDA in meetings with other federal agencies and at external policy forums. Stan Woollen has moved from the Division of Scientific Investigations (DSI) in the Center for Drug Evaluation and Research (CDER) to assist Lepay, prompting CDER to name Martin Cohen, medical officer in CDERs Division of Oncology, to head up DSI on an acting basis. Health issues analyst Bonnie Lee rounds out Lepays GCP staff. The group plans to revise FDA Information Sheets for investigators and Institutional Review Boards (IRBs) along with other policy initiatives.

Congress weighs in
Administration efforts to step up oversight of clinical research may be encouraged by action on Capitol Hill. In August, the House International Relations Committee approved a measure that aims to protect individuals participating in clinical trials overseas. If finalized, this amendment to the Export Administration Act could require pharmaceutical companies to obtain approval from a U.S. IRB and from federal regulators to sponsor clinical studies in developing nations.

Members of Congress also are weighing new legislation to expand federal oversight of human research studies and to impose penalties on noncompliant researchers. Representative Diana DeGette (Democrat, Colorado) leads efforts in the House to enact legislation to codify certain human research protections for both private and publicly funded studies. Senator Ted Kennedy (Democrat, Massachusetts), chairman of the Senate Health, Education, Labor and Pensions Committee, may go further and offer legislation to establish a central federal clinical research agency, as recommended by the National Bioethics Advisory Commission. Kennedy also supports giving FDA and NIH the authority to levy fines on researchers who violate the rules, as an alternative to shutting down research activities altogether. Academic research institutions and industry sponsors are leery of added mandates and penalties. But the research community may encourage Congress to signal its support for stronger research oversight by increasing funds for OHRP and FDA to expand educational efforts and boost inspections of clinical study sites and IRBs.

Setting the agenda
Other than funding initiatives, Congress may hold off making major changes in human research policy until the Institute of Medicine (IOM) completes a broad assessment of the nations system for overseeing human research. The same IOM panel (headed by Daniel Federman of the Harvard Medical School) that issued recommendations for accreditation standards for research organizations in April (View from Washington, June 2001) has launched this broader project, due to be completed in the fall of 2002. OHRP requested this IOM review. The panel held meetings in May and August, and another is planned for November. One objective is to identify ways to measure system effectiveness in order to establish models for improvement.

During the August session, the panel examined the role of private-sector organizations in protecting human research participants. David Lepay described FDA policies and procedures for regulating commercial clinical trials. Bert Spilker (senior vice president, Pharmaceutical Research and Manufacturers of America, or PhRMA) described the role of industry sponsors, and Helen Wyn Davies (senior vice president, Quintiles) explained how large contract research organizations (CROs) operate. Davies noted that too often examinations of the biomedical research system focus on federal agencies, research institutions, and investigatorsleaving out sponsors and CROs. Increased outsourcing of clinical trials, she explained, has transformed CROs from subject recruitment and support providers to full partners in drug development that are well positioned to ensure the safe treatment of study subjects and maintain quality research programs.

Another group examining the research enterprise is the Human Subjects Research Subcommittee of the White House Office of Science Technology Policy. This government-wide panel chaired by Koski evaluates specific issuessuch as international research policiesas well as big-picture initiatives. For example, its SUEE task force on simplification, uniformity, efficiency, and effectiveness will meet in November to discuss ways to make government oversight more efficient. The subcommittee also plans to form a think tank to explore ways that a new, high-tech system could be designed to capture information in real time and prevent harm to research subjects.

And moving onto the stage is the White House Council on Bioethics, which President Bush announced in August as part of his program to permit limited government funding for stem cell research. The new panel will monitor studies of embryonic stem cells while also addressing broader biomedical issues. It may replace the National Bioethics Advisory Commission, which was scheduled to go out of business in October 2001. Bush raised some eyebrows by naming University of Chicago bioethicist Leon Kass to chair the council. Kass opposes cloning human embryos to derive stem cells, but supports adult stem cell research and is considered fair-minded and well-versed in the issues.

Key initiatives
Meanwhile, Congresss General Accounting Office is assessing how well government agencies have improved research oversight since the death of Jesse Gelsinger, the first recorded gene therapy fatality, in fall 1999. These issues were discussed at the July meeting of the National Human Research Protections Advisory Committee, which advises Health and Human Services (HHS) and OHRP on specific policies. Participants at the meeting outlined a number of initiatives by OHRP, FDA, and the research community to address public concerns.

Improve IRB operations. OHRP and FDA have launched an online program to register all IRBs in order to facilitate oversight and enhance communication with IRB officials. All organizations that receive government research funding will have to register an IRB. FDA is developing a rule that would require registration of all IRBs regulated by the agency and hopes to issue it by year-end. In addition, an NIH Regulatory Burden Working Group is studying IRB operations to better assess resource needs.

Develop central IRBs. To improve the review and monitoring of multicenter trials, academic institutions and PhRMA are promoting increased reliance on accredited central IRBs. These bodies will demonstrate expertise in overseeing complex research studies and compliance with good IRB practices, which are being developed by a joint government/private-sector panel. FDA and OHRP would encourage this system by instructing all IRBs that an expedited review will suffice for a component of a multicenter trial that has been approved by an accredited IRB.

Improve trial monitoring. To help IRBs oversee ongoing studies, OHRP and FDA are encouraging research institutions and sponsors to make greater use of data and safety monitoring boards (DSMBs) to monitor research and evaluate adverse event reports. NIH has issued guidance supporting DSMB review of adverse events for certain multisite and high-risk studies, and FDA is developing additional guidance on DSMB use.

Separately, the Center for Biologics Evaluation and Research (CBER), which is responsible for regulating gene therapy research studies, is weighing new policies to improve clinical trials monitoring. CBER has formed a working group to evaluate the need for earlier agency review of sponsor monitoring plans to make sponsor oversight requirements clearer and more specific.

Clarify conflict-of-interest standards. HHS has issued a draft interim guidance on financial relationships involving investigators and institutions, largely to help IRBs and researchers evaluate proposals and programs. Academic institutions have complained that the agency is going too far in micromanaging research arrangements, and HHS is reviewing these comments.

Promote accreditation. HHS is pilot testing accreditation programs by nongovernmental organizations, as recommended by the IOM April report mentioned above. This initiative should be spurred by the August release of final accreditation standards by the Department of Veterans Affairs and the National Committee for Quality Assurance for VA-sponsored research.

Promote investigator training. HHS now requires investigators applying for NIH grants to meet educational requirements on human subject protections. A national educational summit in August recommended forming a national council to promote educational efforts.

Update informed consent policies. A main goal for OHRP is to reshape informed consent from a system that documents subject consent to one that promotes understanding of the research process as a prelude to voluntary participation. NIH is conducting studies on how well individuals can understand risks and benefits in research, and FDA is reviewing these issues.

Enhance adverse event reporting. HHS and FDA are working to reduce differences between their AE reporting requirements to make it easier for investigators to understand and comply with the rules.

Building infrastructure
To carry out these multiple assignments, Koski has organized OHRPs staff into units that reflect the agencys roles and responsibilities.Education. This division, headed by Jeffrey Cohen, provides training programs for professional societies, IRBs, and other government agencies on research policies and ethics. It co-sponsors workshops for investigators with organizations such as PRIM&R, and plans a series of town meetings to explain research practices and policies to the public.

Assurance and quality improvement. An important OHRP initiative under George Gasparis is streamlining the process for NIH grantee institutions to provide the required assurance that they will comply with research regulations. The online assurance system has approved about 800 federal-wide assurances, with 3000 expected in the long run. This division also is testing a quality self-assessment tool for human research protection programs that could lead to a site visit by the agency. OHRP aims to conduct 60 quality improvement interactions with research organizations each month, reaching all 125 accredited medical schools in the coming year.

Oversight. Kristina Borror leads OHRPs Division of Compliance, which investigates research institutions, primarily after receiving a complaint or learning of a potential problem. In addition, the agency is beginning to conduct not-for-cause site visits, which eventually will mesh with a voluntary accreditation program. A goal for Koski is to shift the perception of compliance from an administrative burden to an opportunity to learn about policies and how to fulfill responsibilities appropriately.

International policies. With human research increasingly global in scope, OHRP has established a small international affairs office headed by Melody Lin. OHRP is playing a lead role in developing federal policies related to the conduct of clinical trials overseas, including non-biomedical research.

Policies and planning. OHRPs policy office under Irene Stith-Coleman helps to assess and develop proposals related to a broad range of research issues, such as studies involving prisoners and children.

Koski acknowledges that OHRP cannot regulate some 5000 IRBs and hundreds of research organizations with a staff of fewer than 50 people. He regards the oversight of biomedical research as a distributed system with many key players, including Congress, the White House, and other federal agencies, along with public and private research organizations. The goal is a network of outstanding research organizations that use quality improvement tools to meet voluntary accreditation standards that ensure compliance with educational and oversight requirements.