FDA Refines Inspection Process for Clinical Sites

An increase in the number of clinical research sites per clinical trial, along with a steady rise in foreign research activity, is prompting FDA bioresearch monitoring (BIMO) staffs to update and refine systems for targeting inspections to key study sites. Tight resources limit agency inspections to only one percent of investigators listed in new drug applications, making it critical for the agency to identify those sites with the greatest risk to subject protection or that raise concerns about data integrity.

Last year, the Center for Drug Evaluation and Research (CDER) conducted more than 1000 inspections related to research operations, including bioequivalence studies, institutional review boards, test laboratories. That total includes inspections of more than 400 clinical investigators; another 200 sites were visited involved in biologics and medical devices, according to FDA officials participating in the DIA forum on regulatory submissions, information and document management in early February. Two-thirds of these investigator inspections involve U.S. sites, while one-third are overseas. For drugs, this program is managed by the Office of Scientific Investigations (OSI) in CDER’s Office of Compliance. The Office of Compliance and Biologics Quality (OCBQ) in the Center for Biologics Evaluation and Research (CBER) oversees clinical site inspections related to vaccines, blood products and cellular and gene therapies. The main aim of site inspections is to ensure adequate protection of trial participants and that data submitted in applications is reliable.

Consumer safety officer Bhanu Kannon in CBER’s OCBQ outlined the importance of complete and accurate study data collection from clinical trials and sound sponsor monitoring programs to avoid inspections that uncover data quality and integrity issues. She advised sponsors to carefully organize study records and to retain these records for up to five years, as FDA may need to visit a site long after a trial concludes.

Jean Mulinde, senior policy advisor in OSI’s division of clinical compliance evaluation, explained how CDER is trying to deal with site inspection challenges through further development of its Clinical Investigator Site Selection Tool (CISST). This program aims to rank sites according to risk characteristics, including data irregularities, outliers, inspection history, investigator experience, regional and country-specific information, and comparison of variables across treatment arms.

This analysis is based on sponsor submission of a full “Clinsite” dataset, including complete information on sponsor(s), clinical trial design, investigators, and the specific site. The latter includes site enrollment, adverse events, protocol violations, financial disclosures, and efficacy data.

The aim is to identify sites for inspection earlier during the application review process, especially any sites with a history of non-compliance with good clinical practices, a process that has improved in the past two years. OSI now selects sites in less than 30 days for priority review applications, but continues to struggle to meet a 45-day goal for identifying sites listed in standard submissions.

An added benefit of the CISST program is to obtain more data on clinical investigators and trial enrollment in other regions of the world, Mulinde noted, which can help FDA improve how it assigns inspectors globally. She looks to improve how FDA evaluates clinical site attributes and risk algorithms with the development of new CISST standards through a PhUSE working group and CDISC, and to issue updated guidance to clarify policy and program changes.