IRBs in the Spotlight

Government efforts to protect the rights and safety of participants in clinical trials are focusing more attention on the activities and roles of institutional review boards. Increased funding of research by the National Institutes of Health and by the pharmaceutical industry continues to expand IRB work loads. New government policies are adding to these assignments. Such developments raise concerns about the ability of these panels to provide timely and informed review of research programs.

The Department of Health and Human Services (HHS) is responding with more guidance to improve institutional review board (IRB) operations. The Food and Drug Administration has proposed new policies to help IRBs do their jobs. The HHS Office of the Inspector General (OIG) is keeping its eye on IRB policies following its major 1998 report that was highly critical of IRB performance. The OIG acknowledges that HHS and the research community have implemented many of its recommendations for improving the medical research process, but notes that more remains to be done.

More oversight?
IRBs have become such a key element for ensuring research integrity that policy makers are wrestling over the need for more intense regulatory oversight of these entities. Senator Edward Kennedy (Democrat, Massachusetts), who chairs the Senate Health Committee, is considering legislation that would mandate accreditation of all IRBs. Last spring, Kennedy circulated a proposal requiring IRBs accredited by the HHS Office of Human Research Protection (OHRP) to approve all human subject research regulated or funded by the federal government. Such a mandate would involve establishing more detailed national standards for human subject research.

HHS officials, including OHRP director Greg Koski, prefer a voluntary accreditation program for IRBs and research institutions. Similarly, a legislative proposal in the U.S. House of Representatives advocates voluntary accreditation by private organizations, an effort now getting under way. To build support for the voluntary approach, OHRP is working with FDA, accrediting organizations, and the research community to improve and expand OHRPs quality improvement program for all institutions involved in human research protection.

One OHRP initiative is to help IRBs improve operations. OHRP issued a guidance in July advising IRBs how to develop written procedures to better inform outside observers about the way they handle research plan reviews. HHS requires IRBs to establish written procedures for their oversight activities, including how to hold board meetings, assemble materials needed to conduct a review, conduct reviews in emergency situations, and maintain records and meeting minutes.

Another OHRP guidance describes appropriate IRB procedures for carrying out continuing review of long-term clinical research programs. The guidance defines what constitutes substantive and meaningful continuing review, how to set a continuing review schedule, continuing review of multicenter trials, expedited continuing review procedures, and dealing with lapses in continuing review.

Avoiding clinical holds
FDA also is encouraging accreditation of IRBs that oversee clinical trials regulated by the agency, a move that reflects the steadily expanding role of IRBs in ensuring research integrity. A new FDA guidance indicates that failure of an investigator to obtain IRB approval of significant protocol changes is one reason for the agency to put a clinical trial on hold. An August 2002 Draft Guidance for Industry and Clinical Investigators on the Use of Clinical Holds Following Clinical Investigator Misconduct (www.fda.gov/OHRMS/DOCKETS/98f/ 082702f.htm) says that if FDA finds that an investigators actions pose a significant risk to study subjects and should be halted immediately, it will go the clinical hold route. FDA emphasizes that it wont close down a study merely for record-keeping violations or failure of an investigator to disclose certain types of financial interests. But agency officials say that shutting down a trial is warranted in serious cases because it usually takes months or years for the agency to bring charges to disqualify an unethical investigator from involvement in FDA-regulated studies (see sidebar on Grounds for Disqualification).

Those significant violations most likely to prompt FDA to suspend a trial include:

• failure to report serious or life-threatening adverse events.
• serious protocol violations, such as enrolling ineligible subjects in a study that could put them at risk.
• repeat or deliberate failure to obtain adequate informed consent, including falsification of consent forms or failure to disclose serious risks of the investigational drug.
• falsification of study safety data.
• failure to obtain IRB review and approval for significant protocol changes.

FDA says it will meet with a sponsor to discuss such problems before imposing a clinical hold, unless the agency finds that subjects are being exposed to immediate and serious risk. The agency also indicates that it may lift a clinical hold if a sponsor replaces the violative investigator or hires a monitor to oversee the trial. FDA is accepting comments on the clinical hold proposal until the end of November.

Keeping IRBs informed
Another FDA proposal requires sponsors and clinical investigators to inform IRBs of any prior reviews of a protocol by another IRB. The aim of this draft proposal, issued March 2002, is to discourage IRB shopping by sponsors who run into opposition to a research plan from one review board and then look for another panel likely to regard their plan more favorably. The FDA proposal responds to the OIG 1998 report that cited IRB shopping as a problem for adequately protecting clinical trial participants.

In June, PhRMA (Pharmaceutical Research and Manufacturers of America) filed comments objecting to the requirement as likely to delay IRB decision making, particularly for trials at multiple sites or in foreign countries. Sponsors fear that the requirement will add to the heavy volume of information already overwhelming IRBs and would require researchers to track the status of different site studies more closely. Some sponsors and research institutions indicated, though, that mandatory disclosure of important safety issues raised by another IRB might be justified.

Protecting privacy
In addition to these and other new requirements, IRBs and privacy boards will play a central role in a vast new program for ensuring that biomedical researchers take steps to protect the privacy of participants in clinical and health care studies. HHS issued its final Standards for Privacy of Individually Identifiable Health Information on 14 August 2002, establishing a federal policy to protect the privacy of individual health information, as required by the Health Insurance Portability and Accountability Act of 1996 (HIPAA). The privacy rule regulates how health plans and providers may use and disclose identifiable health information to treat patients, pay for medical services, conduct health research, and other purposes.

Researchers repeatedly have raised concerns about the privacy rule because its requirements are likely to make it difficult for them to access important patient health information (see ACT View from Washington, June 2002). The final rule addresses some of these objections, but not all. One important revision is to permit more patient identifiers, including zip code and birthdate, in the prescribed limited data set that would be available to researchers, health care providers, and public health officials. Researchers must agree to keep the information secure and use it only for permitted purposes, a requirement that many fear will be difficult to carry out and may delay or kill certain research projects.

The final rule also streamlines procedures for researchers to obtain individual consent to access personal medical information. However, considerable uncertainty remains about what criteria are needed to obtain a waiver from an IRB to use patient data for research without individual authorization. HHS says it will issue a guidance on waiver criteria to address this difficulty, including how an IRB should determine that the research use of the information poses no more than a minimal risk to an individuals privacy. A guidance will further define what steps a research entity should take to ensure privacy protection, how long a researcher may retain individual data, and whether restrictions on data retention would compromise data reanalysis and other later studies.

The highly complex rule poses even greater difficulties for health plans and providers. Many health care organizations continue to press HHS for further delay in full implementation of the policy, but it now is scheduled to become effective for most entities April 2003.

SIDEBAR: Clinical Trial Control and Conduct
In June, PhRMA approved a set of principles for the conduct of clinical trials in June that calls for IRBs or ethics committees to review all clinical study proposals before the studies begin. The code also recommends that sponsors conduct all clinical trials in accordance with applicable laws and regulations and follow good clinical practice (GCP). While these policies raise little controversy, the code also addresses more tricky issues involving control and publication of research results. Here is a summary of some of the more interesting statements:

• Study results involving marketed products should be reported in an objective and timely manner. However, studies that are exploratory in nature or involve a product that is not marketed may be highly proprietary. Sponsors do not commit to publish the results of every exploratory study or to make clinical trial protocol designs publicly available at inception.
• Sponsors are the owners of a study database and are responsible for receipt and verification of data from all study sites. Sponsors thus have discretion to determine who will have access to the database. Individual investigators in multisite trials will have access to data on their own research participants as well as a summary of study results from the sponsor. Investigators also should be able to review relevant statistical tables and to examine reports on the entire study at the sponsors facilities or other agreeable location.
• Only individuals who are involved in the conception or design of a study, in data acquisition and interpretation, and in writing the manuscript should be recognized as authors or contributors to a manuscript. All authors should be given the relevant statistical tables, figures, and reports needed to support the planned publication. Companies may have staff help analyze and interpret data and produce manuscripts and presentations, and their contributions should be recognized appropriately.
• Sponsors have the right to review any manuscripts, presentations, or abstracts originating from their studies prior to publication. Sponsors will review such material in a timely manner and will not suppress or veto publication, although publication delay may be necessary in some cases to protect intellectual property.
• While clinical investigators should be independent, it is reasonable to compensate researchers for their work. However, such compensation should not be stock in the sponsor company, and payments should not be tied to the outcome of a trial.
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SIDEBAR: Grounds for Disqualification
FDA may take enforcement action to disqualify an investigator from conducting future studies regulated by the agency if the individual commits offenses likely to put a study on clinical hold, according to its draft guidance on clinical holds issued in August. This process begins when an FDA Center issues a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) letter. In addition to taking enforcement action for the above violations, FDA may send such a letter to an investigator who repeatedly and deliberately:

• fails to obtain or document informed consent, which may involve inadequate description of serious risks associated with an experimental therapy or failing to provide informed consent in language understandable to the subject.
• administers the investigational product to ineligible individuals.
• fails to comply with conditions placed on the study by the IRB, sponsor, or FDA or fails to follow the signed investigator statement or protocol.
• fails to maintain accurate study records or submit required adverse event reports to the sponsor.
• falsifies or conceals study records, possibly by substituting erroneous biological samples or by fabricating subjects.
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