FDA inspectors are taking a closer look to confirm that quality management systems are being used in trials, experts say, citing the updated Bioresearch Monitoring Program (BIMO) inspection guide.

The latest revision to the BIMO manual shows that the agency’s Good Clinical Practice (GCP) inspections now place greater scrutiny on the selection and monitoring of clinical investigators, among other critical issues.

The manual also includes sections on outsourced services, safety oversight and data/safety monitoring boards/data monitoring committees, Crissy MacDonald, vice president of client delivery for WCG Avoca, said during a webinar last week. Risk-based quality management (RBQM) systems and standard operating procedures (SOP) that ensure proper documentation are essential to ensuring smooth inspections going forward.

Common inspection observations, including failure to comply with Form 1572 (Statement of Investigator) requirements and failure to report and/or record adverse events, among others, remain front and center, MacDonald said.

For example, on selecting and monitoring principal investigators (PI), FDA investigators will check whether PIs conducted any trials without an IND at a site outside of the U.S. and will look for assurance and documentation that GCP was followed in such trials. It’s also likely that they will request documentation on PIs conducting trials that have been placed on enrollment hold, including rationale and corrective and preventive actions (CAPA) that were taken before allowing them to re-enroll patients, MacDonald said.

Similarly, sponsors are expected to ensure that a list of any changes in PIs (and rationale for changes) is kept during a trial, as well as documentation showing that the process for selecting PIs includes a review of the FDA’s clinical investigator debarment list and any administrative or regulatory actions taken against a PI.

“It doesn’t necessarily mean that you can’t use [a PI] if they’ve had some administrative or regulatory actions [against them], but you do need to make sure that if you select a PI like that, there’s corresponding documentation that addresses the risk of using that PI,” she said.

The FDA expects to see a risk-based approach to monitoring procedures and activities, MacDonald explained. Historically, the agency has focused on reviewing SOPs and confirming that procedures were followed. With the BIMO update, the agency is also focusing on a trial’s written monitoring plan, where it was followed and if modifications had to be made, she said.

The agency has also shifted to account for the increased use of remote monitoring during the pandemic. Inspectors will now scrutinize the ways remote monitors access site files, including direct access to electronic medical records (EMR) and screen-sharing, and assessing whether the security and confidentiality of records were maintained.

In addition, the updated BIMO manual, released in September with little fanfare, specifies that FDA investigators will evaluate a trial’s data management plan and SOPs for collecting, handling and managing data. Audit trails in particular are “a big, big area that they’re looking at now” during inspections, not just for a specific document but for the entire trial, said Jamie Toth, global head of trial master files at Beigene, at the recent DIA Regulatory Submissions, Information and Document Management Forum.

On outsourcing services, the updated BIMO guide directs more attention to written agreements between sponsors and CROs, CRO qualifications and protocol-specific training given to the CRO, David Burrow, director of the FDA’s Office of Scientific Investigations, noted during a public BIMO webinar.

“You just can’t copy and paste parts of your trial risk management and operations from one trial to another outright, and I think to the extent that individual components might need to be uniquely tailored to the specific studies, those contractors and vendors would really need to be able to have full access to … quality-by-design analysis, risk assessments and mitigation strategies. They all feed into that trial design consideration and need to be incorporated into the downstream operations,” Burrow said.

Managing noncompliance in real time is also a focal point for the FDA. Creating an SOP for staff training doesn’t fix every problem, Chrissy Cochran, BIMO director, cautioned. Sponsors need to determine the root cause and ensure the corrective action actually fixes the problem at hand. Agency investigators confirm that sites and sponsors are truly fixing issues and testing their corrective actions, she said.

Safety oversight, one of the new sections in the manual, addresses how FDA investigators will look to see that the sponsor has established and is abiding by a risk management plan. To Burrow, the importance of RBQM, which sponsors are being pushed to adopt as the core of their trials, cannot be overstated.

“The FDA has a really critical interest in ensuring you have a robust ecosystem across all different domains of clinical research. RBQM is the beating heart of clinical research,” Burrow said.

Cochran noted during the BIMO webinar and confirmed to CenterWatch Weekly that, while the FDA is not ruling out further use of remote assessments for GCP inspections postpandemic, the agency is clear on one point: The bulk of its inspection activity will remain onsite even as more remote-based approaches catch on overseas.

“Within the U.S., our authority to inspect says we actually need to do an onsite inspection. We need to be there in person, and that’s not necessarily the case when you’re talking about the EU and the entities over there,” said Cochran.

The FDA does envision a possible “hybrid approach” that would allow sponsors and sites to send documents and information prior to an inspection to help make the actual onsite visit shorter. She noted that the logistics for this strategy to be implemented industrywide have not been hammered out and did not have a timeframe for when that might happen.

Remote assessments will be used when the FDA physically cannot do an onsite inspection, although the agency does not view these as equivalent to a real inspection, she said. The agency’s enforcement authority only applies to onsite inspections. But a remote assessment, which is voluntary, could lead to an onsite inspection if the FDA finds problems it wants to investigate.