By Lisa Seachrist

Washington Editor

WASHINGTON — The medical research enterprise's method for protecting the well-being of clinical trial participants is in jeopardy of failing its mandate, according to a wide-ranging investigation by the Health and Human Services Inspector General's Office.

In a series of four draft reports, Inspector General June Gibbs Brown describes a system that is cracking under the strain of an ever-increasing number of protocols, the proliferation of multisite studies, the commercialization of research and inadequate resources.

While claiming the Institutional Review Board (IRB) system remains free of widespread abuse of human research subjects, the reports warn that without measures to make IRBs more effective and accountable, the system could ultimately fail under the weight of current administration plans to increase the funding of biomedical research.

The Inspector General's (IG) reports and recommendations will serve as the centerpiece of a hearing Thursday by the House Committee on Government Reform and Oversight's Subcommittee on Human Resources, chaired by Rep. Christopher Shays (R-Conn.).

Requirements for IRBs were established in the National Research Act of 1974 and in the FDA regulations issued in 1981. Composed of local scientists and community representatives who serve on a voluntary basis, IRBs review and approve a research plan before the clinical trial is conducted. The primary function of the IRB as designed is to ensure that the risks of the research are warranted by the potential benefits and that study volunteers are adequately informed about the trial and its potential risks.

In addition, federal regulations require that IRBs provide continuing oversight of protocols, evaluate study amendments and follow reports of unexpected adverse events.

Unfortunately, this system was set up in an era when research on human subjects was characterized by a "single investigator working under government funding with a small cohort of human subjects in a university teaching hospital," the report notes.

The rapid expansion of clinical protocols funded by the federal government and by industry, as well as the proliferation of multisite studies, means IRBs typically review too much too quickly, and with too little expertise.

The IG report documents one IRB that handled 18 initial protocol reviews, nine expedited reviews, 43 protocol amendments and 21 adverse-event reports in a two-and-a-half hour meeting. Such a daunting workload means the IRB's oversight function is often hurried or performed perfunctorily in paperwork reviews.

The report notes many trial participants blur the distinction between research and treatment and don't fully understand the implications of the informed consents they sign. IRBs are charged with overseeing the informed consent documents used in clinical trials.

That mission may be failing. The IG reports, "Many IRBs strive to see that consent forms are as informative and clear as possible. But these efforts often run up against the grains as the forms become longer and more complex serving, it seems, more as documents to protect the institutions and the sponsors rather than the human subjects."

Because research funding serves as a significant source of income for universities and health centers, IRBs now find themselves under pressure to approve research that will bring funding to the institution, the report notes.

In addition, industry sponsors are under pressure to move quickly during drug and device development, increasing the pressure on IRBs to act quickly.

To aid in speeding review, independent IRBs have become more common. While noting that these entities can provide quick review and more complete oversight, especially when dealing with multisite trials, the IG said nothing prevents a sponsor from "shopping" for an IRB that will approve a protocol without ever notifying the group that a previous IRB turned it down.

To address these issues, the IG report calls for "strong and inevitably controversial actions." Because both the National Institutes of Health's Office of Protection from Research Risks (OPPR) and the FDA have jurisdiction over IRBs, the IG calls for the two organizations to coordinate activities and first eliminate unnecessary procedural requirements.

Many clinical trials employ data safety and monitoring boards (DSMBs) to review research conducted at multiple sites. The IG proposes that DSMBs be required in certain circumstances and that they share their information with IRBs. To prevent IRB shopping, the IG calls for investigators and sponsors to notify IRBs of any prior review of a research plan.

In order to keep members of IRBs up on the ethical standards they are trying to maintain, the report calls for education programs for IRB members, increased participation by persons not involved in research or affiliated with the research institution, and increased support staff resources.

Many institutions find it difficult to fund the administrative aspects of an IRB and to convince laypersons to serve on the board without compensation.

The report also calls for the federal government to step up its oversight of IRB activities. The IG describes the current oversight efforts as "procedural, compliance-focused reviews [that] reveal little about IRB effectiveness in protecting human subjects." *