Sponsors, Regulators Cautious About Risk-Based Oversight of Clinical Trials

Jill Wechsler

Despite the high cost and extensive resources involved in monitoring the conduct of and data produced by clinical trials, the research community has been slow to embrace strategies for reducing on-site oversight to reflect risk. Sponsors appear willing to spend more to ensure that results meet regulatory expectations and avoid raising issues that could delay the review and approval of a market application. FDA and other regulators are responding with support for more flexible monitoring of clinical investigators and review of study records in order to limit study monitoring to situations where less oversight raises clear difficulties for investigators, participants, and data integrity.

To this end, FDA has encouraged sponsors to focus on risk in monitoring clinical trials, similar to agency initiatives to modify pharmaceutical plant inspections and pre-approval of product changes to situations likely to compromise product quality and safety. Instead of using on-site monitoring for every clinical site to verify study data and conduct, FDA advises sponsors to limit oversight to the most critical data elements, procedures, and processes, as outlined in guidance issued in 2013 and updated earlier this year. Such situations can be described in risk-based monitoring (RBM) strategies laid out in RBM plans.

Despite these efforts, biopharma companies have been slow to adopt RBM approaches, as seen at a public workshop in July organized by the Margolis Center for Health Policy at Duke University to gain more feedback from stakeholders on the challenges and barriers influencing the adoption of RBM. Jacqueline Corrigan-Curay, director of the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER), opened the meeting by emphasizing the importance of leveraging tools and methods to improve the efficiency and reliability of clinical trials. FDA wants to make risk-based monitoring “a reality for everyone,” she said, and is reviewing comments from the recent draft guidance to move forward.

The process begins with risk assessment to help shape the resulting clinical research protocol, explained David Burrow, director of the Office of Scientific Investigations (OSI) in CDER’s Office of Compliance. An RBM plan then can be built to support product approval and reduce errors “that matter,” he commented. An analysis of 334 OSI clinical investigation summaries over three years reveals relatively few “active recommendations” that raise questions about application quality likely to delay approval. The vast majority of clinical inspections find appropriate compliance with requirements.

Similar efforts by the European Medicines Agency (EMA) support risk-based approaches to clinical trial monitoring to ensure that studies generate reliable information, while protecting study subjects, commented Camelia Mihaescu, of the EMA Committees and Inspections Department. Risk-based approaches, she noted, should reflect trial-specific issues.

Yet, regional differences in monitoring practices, inspection procedures, and acceptance of RBM by regulatory agencies create barriers to wider adoption of RBM, observed Tim Rolfe, director of research-based monitoring at GlaxoSmithKline. Sponsors have concerns about ensuring quality data at multiple study sites that follow a range of research methods, with large, complex trials raising issues that differ with very small studies. He advised FDA to update its inspection guide for clinical sites and to train inspectors in RBM expectations through case examples. Research sites experience “general discomfort” with RBM approaches, according to a study by the Society for Clinical Research Sites, and often feel left out of planning for RBM approaches, which vary notably with each sponsor.

Burrow of OSI was optimistic that recent changes in FDA’s Office of Regional Affairs (ORA) to create specialized teams of clinical site inspectors may address some inspection issues. But OSI still finds problems with initial RBM efforts, particularly with record sampling and source-data verification, and limited coordination between sponsors and CROs can be a problem. FDA officials advise sponsors to involve all stakeholders in the RBM process, which should be adaptable and promote human subject protection and data integrity.

Jill Wechsler is the Washington Correspondent for Applied Clinical Trials