7-year FDA review finds improved GCP compliance

A study of routine good clinical practice (GCP) inspections between 2017 and 2023 found a declining number of Form 483s flagging violations at clinical trial sites and a very low number requiring official action (0.3%), US Food and Drug Administration (FDA) officials report.

During the seven-year period, there were 2,386 inspections of clinical trials requested as part of reviews of Center for Drug Evaluation and Research (CDER) marketing applications, according to the retrospective study, which was published in Therapeutic Innovation & Regulatory Science on 19 July.

After an inspection, the agency issues a Form FDA 483 if there are potential regulatory violations, then allows sponsors time to respond.

The proportion of inspections triggering a Form FDA 483 decreased over time from 23.5% in 2017, to 10.4% in 2023, the lowest of all years in the review period, reported the study authors, who are officials at the GCP Assessment Branch, Office of Scientific Investigations (OSI) Office of Compliance (OC) at CDER.

“We are encouraged by the analysis of the GCP inspection outcomes for marketing applications,” Courtney McGuire, senior physician, and colleagues wrote. “We hope disseminating regulatory and GCP findings such as these may help raise awareness of GCP inspection expectations, and most importantly, strengthen human subject protections and improve clinical trial data quality and integrity.”

The decline could reflect better compliance at inspected facilities, with the implementation of electronic systems in trial operations and central and remote monitoring, the authors suggested. Such advances could be helping facilities detect and correct errors in real time.

“While the recent release of multiple FDA guidances reflect the increased use of eSystems, further research is required to evaluate the connection of these eSystems and the incidence of Form FDA 483s,” the authors explained. “Other factors which may have resulted in improved GCP compliance during this timeframe include the publication of harmonized GCP Guidelines in 2018 and associated GCP training programs.”

The study evaluated outcomes of inspections related to new drug applications (71%), biologics license applications (28.6%) and emergency use authorizations (0.4%). Researchers queried several FDA databases, including the Document Archiving Reporting & Regulatory Tracking System (DARRTS) and the Compliance Program Information System (COMPLIS), and then examined trends in outcomes of review-based GCP inspections between 2017 and 2023.

The OII conducts inspections and then the OSI reviews inspection results and facility responses, where applicable, and sets the final classification: no action indicated (NAI), voluntary action indicated (VAI) or official action indicated (OAI). Of the total 2,386 inspections, the final classifications were 81.2% NAI, 18.5% VAI, and 0.3% were OAI.

Common deficiency areas were related to adherence to trial protocols and adequacy of records.

“Nearly all (99.7%) inspections were classified as either NAI or VAI during the study period and recommended and final classifications remained highly congruent,” the authors noted.

However, there were some notable changes in inspection outcomes trends related to the coronavirus pandemic during the study period. The largest number of inspections were carried out in 2017 (527) and the lowest in 2020 (282). In early 2020, FDA issued guidance acknowledging that some aspects of GCP would be difficult to comply with due to pandemic control measures.

The number of ‘voluntary action indicated’ downgraded to ‘no action indicated’ increased in 2020, 2021 and 2022.

Sites run by clinical investigators and sponsors had similar outcomes, and contract research organizations (CROs) performed best, with over 90% of inspections requiring no FDA action, the authors reported.

The findings about CROs and the impact of the pandemic, when it was difficult to travel, are not surprising, but the proportion requiring no official action appears to be very low and that is a bit unexpected, commented Beth Weinman, a member of Ropes & Gray’s life sciences regulatory and compliance practice group.

One might expect to see a higher number of violations as more research moves into community settings, Weinman explained in an interview. People trained primarily as physicians and not necessarily researchers don’t always understand key differences in treatment versus research and that can lead to problematic decision-making and record-keeping, explained Weinman, who is a former Associate Chief Counsel at FDA.

Also, she noted that there have been staffing changes, such as retirements of experienced officials, at FDA, raising the question of whether there is less scrutiny during inspections, but the study didn’t examine inspection numbers and outcomes before 2017 to allow a comparison.

On the other hand, it could be that training has improved or that sponsors are doing a better job at vetting sites in reaction to high-profile clinical trial fraud cases, she said.

“You can look at this data and say, ‘Oh, this is great – it seems like people are better at compliance with GCP.’ And maybe that's what the trend shows,” Weinman said.

“I'm not prepared at this time to draw that conclusion,” she added. “I think it may have more to do with a reduced number of inspections and a less experienced investigator corps, but I guess we have to look and see what happens in the next couple of years.”

7-year FDA review finds improved GCP compliance

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