FDA clinical site inspections should focus on recruitment tactics as well as data integrity, the HHS Office of the Inspector General suggests in a report on clinical trial recruitment released June 12.

While FDA's inspections tend to focus on sites where data integrity questions have been raised, "the agency could address many of the concerns about recruiting methods and raise questions about how human subjects were recruited," the report states.

"Inspectors could consider assessing the range in number of subjects enrolled across sites," the report continues.

"If, for example, one site enrolled significantly more subjects than other sites or financial incentives were offered by sponsors, inspectors could probe to understand how these subjects were enrolled and why the high-enrolling site was able to recruit when others were unsuccessful," the IG said.

"Also, at these high-enrolling sites, inspectors could examine more closely whether enrolled subjects were truly eligible," the report says.

The report on clinical recruitment practices is a follow-up to a 1998 report on the Institutional Review Board process. IG previously identified clinical trial recruitment practices as an area for further investigation (¹ Also see "Clinical Trial Recruitment Ad Review To Be Included In IG Study" - Pink Sheet, 17 May, 1999.).

Public attention to the clinical trial process has been heightened by the high-profile investigation of problems in some gene therapy trials. The broader issue of human subject protections will likely receive attention over the summer in the context of hearings on legislation to reform the IRB process (² Also see "IG Clinical Trial Report Stresses Commercial Pressure To Speed Enrollment" - Pink Sheet, 19 June, 2000.).

At the end of May, HHS Secretary Donna Shalala announced a series of proposals designed to improve the clinical trial research process, including the ability to assess civil money penalties for violations of good clinical practices.

HHS was noncommittal about the suggested changes in FDA's inspection focus. "During the last several years, FDA has stepped up its on-site inspection process significantly," HHS said. "FDA will continue to refine and expand its inspection system as resources allow."

A companion IG report focusing on FDA's oversight of clinical investigators indicates the agency already inspects high-enrolling sites more regularly than low-enrolling sites. The report is based on interviews with FDA staff in the drugs, biologics and devices fields and a study of enforcement actions against investigators.

"Bioresearch monitoring staff at all three centers agree that the primary consideration in selecting clinical investigators for inspection is the size of the subject population at the sites," the report states. "Staff at all centers agreed that in general three clinical investigators are inspected per application."

The investigators interviewed by IG "noted some concern that clinical investigators with small numbers of subjects never get visited. Under a data validation focus this is appropriate, as smaller sites contribute proportionally less to the overall data." However, IG observed there is no reason to believe smaller sites are going to perform better in terms of human subject protection than larger sites.

IG recommends FDA "define cross-center goals for the bioresearch monitoring program and develop criteria to determine whether the program is achieving those goals." The agency should "clarify how long the process should take from the conclusion of the investigation and submission of the report until a decision is made on the results of the inspection and issuance of any agency actions," the report says.

FDA should "clarify the criteria for selection of clinical investigators for inspection including looking at smaller sites and previous inspection history and compliance," the report continues.

IG also recommends FDA "develop internal guidance on the thresholds that violations must meet to justify disqualifying a clinical investigator."

In the report, IG reviewed 189 official FDA actions resulting from clinical site inspections from fiscal 1994 through 1999, including warning letters, "Notice of Initiation of Disqualification Proceedings and Opportunity to Explain" letters, and disqualification notices. Fifty-eight of the actions were taken by the Center for Drug Evaluation & Research.

According to the IG analysis, the most common findings in the letters related to documentation, protocol violations and reporting procedures. Human subject protection violations were cited in 71% of CDER actions, IG found.

FDA Clinical Site Inspections Should Look At Recruitment Tactics - IG Report

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