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Nov/Dec 2000
Vol. 3, No. 9, pp. 31, 33,

clinical trials track

A new broom?

From OPPR to OHRP–transforming human research protectionsOpening Art

Over the past several years, increasing problems in the conduct of clinical trials have led to significant administrative and congressional scrutiny of the way that the U.S. Department of Health and Human Services (HHS) monitors patient protections. (HHS is the federal home of both the FDA and the NIH.) The death of Jesse Gelsinger during a gene therapy trial late last year seemed to provide a particularly powerful catalyst for action. “The failure of oversight for gene therapy is notable . . . and relevant to human subject protection in other areas of human research,” according to Paul Kim, counsel for Rep. Henry Waxman (cosponsor with Dennis Kucinich of H.R. 3569, a bill that attempted to create an independent Office for Protection of Human Research Subjects that would report to the U.S. President rather than to HHS). As a result of the intense, broad-based concern for human subjects, earlier this year, HHS attempted to improve federal oversight of clinical trials.

The most substantial change involved the status of the NIH Office for Protection from Research Risks (OPRR). On Nov. 4, 1999, Donna E. Shalala, secretary of HHS, announced that after significant review (including recommendations from the NIH director’s advisory committee and an independent analysis by the National Bioethics Advisory Commission), the department had decided to relocate OPRR to the Office of the Secretary of HHS. On June 18, 2000, the office was officially upgraded and moved from the NIH administrative chain. It was renamed the Office for Human Research Protections (OHRP). The director of the newly organized OHRP reports to the Office of the Secretary of HHS, specifically to the Assistant Secretary for Health. Monitoring the treatment of experimental animals will remain in the NIH as part of a new Office of Laboratory Animal Welfare. These moves are intended to increase both the visibility and accountability of human research protections as monitored by the federal system. The OHRP will “provide leadership for all 17 federal agencies which carry out research involving human subjects under a regulation known as the Common Rule” (see box, “The Common Rule”).

The old system

In 1971, the OPRR was created as a part of the NIH to ensure the welfare of participants in HHS-sponsored research studies. In 1974, the regulations that would become the Common Rule were inaugurated. Historically, the OPRR has been responsible for the welfare of all human subjects who participate in HHS-sponsored research and for the humane care and use of animals in HHS-funded studies. This responsibility has included formal agreements with more than 4000 federally funded universities, hospitals, and medical and behavioral institutions in the United States and abroad. The agreements include establishing and regulating Institutional Review Boards (IRBs), which are the fundamental means of locally monitoring patient welfare in clinical trials. The OPRR had (and now the OHRP has) chief oversight authority through
The Common Rule
illustration of test tubesThe Common Rule is actually the set of Regulations for Protection of Human Subjects (45 CFR Part 46). These NIH regulations were originally established in 1974. Revised in 1991, the rule has since formed the basis for all OPRR—and now OHRP—oversight of federally monitored clinical trials and human experimentation. The rule addresses issues of IRBs, special protections for pregnant women, prisoners, and children in research, as well as the use of fetal tissues and in vitro fertilization. Changes to the rule require the concurrence of all 17 agencies involved. This, according to June Gibbs Brown, the inspector general of HHS, is a significant flaw that “inhibits a timely response to many of our recommendations and to the rapidly changing developments in the clinical research environment. In view of this reality, legislative change may well be necessary.”
“assurance” and inspection of IRBs. Institutions that conduct human-subject research under HHS jurisdiction must appoint an IRB of record by applying for and receiving an assurance from OHRP. Assurance is a document stating an institution’s commitment to uphold HHS human-subject protection regulations and listing the policies and procedures for meeting these regulations. Assurances must be renewed every five years after an initial period of three years.

In a June 1998 report, Institutional Review Boards: A Time for Reform, the inspector general of HHS warned that “the effectiveness of these boards was in jeopardy and presented numerous recommendations to NIH, its OPRR, and FDA.” A follow-up report in April 2000, Protecting Research Subjects: Status of Recommendations, detailed how both OPRR and the FDA had significantly increased their on-site inspections of institutions. Between April 1997 and May 1998, OPRR had conducted only one such inspection; between June 1998 and March 2000, it conducted 10 inspections. The FDA’s on-site inspections increased from 253 in FY 1998 to 336 in FY 1999. More importantly, the report pointed out, seven of the OPRR’s investigations resulted in a temporary suspension of federally funded research and sent a clear signal to the scientific community that things had changed. The report, quoted from the May 21, 1999, issue of Science, stated that “OPRR has put every federally funded U.S. research institution on notice that its right to conduct clinical research could be summarily yanked.”

But problems remained. Few of the inspector general’s recommended reforms had been enacted in the areas of flexibility and accountability for IRBs, oversight and protections (including continuing review of projects by IRBs rather than mere initial ratification of studies proposed), and education. Congress, for its part, held hearings on how the effectiveness of IRBs could be improved (particularly in light of the gene therapy scandal). Part of the goal of the new system is to address some of these problems. Accordingly, the inspector general’s report states bluntly: “We urge that the new office give significant attention to our prior recommendations and to those that will be forthcoming from the NBAC.”

The new system

The renaming and relocation of the OPRR outside of the NIH has created little external evidence of substantial changes beyond a moved home page and a confusion in using the OHRP acronym in place of OPRR (even in documents referring to regulations and incidents that happened before the creation of the OHRP—a nightmare for historians, to say the least). This is bound to be only an interim situation as the possibilities and potentials of the restructuring become apparent. The mood for change and a new regulatory climate is strong, as shown by continued congressional interest and the demands of the Office of the Inspector General.

The new OHRP must surely prove itself up to the task, or risk a more hands-on approach from Congress via legislation such as the Kucinich–Waxman bill introduced in 2000 and the 1997 Human Research Subject Protection Act introduced by Sen. John Glenn. Although neither bill was passed, they demonstrate continuing congressional concern with the issue, which can only be exacerbated if further problems surface similar to the recent gene therapy scandal.

The long-term goal of the new OHRP, according to David Satcher, the U.S. surgeon general and HHS assistant secretary for health, is to develop “new, stronger, and clearer patient protection policies, with an expanded focus on performance and prevention”. The change in organizati
A selection of HHS clinical trials-related information

OHRP home page:

The Common Rule (45 CFR Part 46):

HHS fact sheets/news:

Protecting Human Research Subjects: Status of Recommendations (PDF format):

on is intended to allow effective coordination across HHS and to provide a model for other federally and privately sponsored research.

Under the new structure, the FDA retains its traditional enforcement authority to ensure that researchers carrying out FDA-authorized clinical trials are complying with HHS human subject protection regulations and consent requirements. The OHRP functions as did the OPRR to ensure these requirements in HHS-sponsored research.

One significant change has been the establishment of a National Human Research Protections Advisory Committee (NHRPAC). According to the announcement in the June 19, 2000, Federal Register, NHRPAC “will serve as the Department’s principal advisory body on matters pertaining to human subjects protection. Members will be selected from individuals possessing demonstrated experience and expertise. . . . The Director, OHRP, shall serve as Executive Secretary of the committee.”

Greg Koski has been appointed the first director of OHRP. Koski served as director of human research affairs for Partners HealthCare System, Inc., in Boston, and as associate professor of anesthesia at Harvard Medical School.

As for the role of education, according to a May 23, 2000, HHS press release, the department is committed to an “aggressive effort to improve the education and training of clinical investigators, IRB members, and associated IRB and institutional staff.”

Given the current climate, the likelihood of increased oversight is high; to what extent these major changes in the structure of federal human-research protections will result in new regulatory procedures or further institutional changes remains to be seen.


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