Only 20% of clinical trials submitted for cell and gene therapy approvals reported identical data to both the U.S. Food and Drug Administration and the European Medicines Agency.

Researchers conducted a cross-sectional study to compare clinical evidence submitted to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for cell and gene therapies (CGTs). The study, led by Magdi Elsallab of Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, and colleagues, analyzed discrepancies in regulatory submissions to assess the need for harmonization.

They identified original and supplemental CGT applications approved by both agencies as of October 3, 2023. Applications were matched by treatment indication, and clinical trial data—including sample size, primary endpoints, comparator types, and efficacy outcomes—were extracted from agency submissions and ClinicalTrials.gov.

Published as a research letter in JAMA Internal Medicine, the study included 15 CGT products, corresponding to 20 applications submitted to both regulatory agencies. These applications presented data from 24 clinical trials, with 20 trials submitted to both agencies. Among the 20 trials, only 4 (20.0%) reported identical clinical trial evidence across both FDA and EMA submissions.

Sample size discrepancies were identified in 13 trials (65%), with 8 differing by more than 10%. The EMA was presented with a larger sample size in six trials, including two submitted to the EMA before the FDA. Sample size data from ClinicalTrials.gov matched 12 trials (60%) reported by either agency.

Comparators used in efficacy assessments were consistent in 16 trials (80%), whereas the remaining four trials included a comparator in EMA submissions but not in FDA or ClinicalTrials.gov reports. Among 19 trials with comparable endpoints, 13 (68.4%) reported different efficacy outcome values across regulatory submissions, with six differing by more than 10%. For etranacogene dezaparvovec, the FDA submission reported a 21.7% higher annualized bleeding rate despite identical sample sizes.

The study identified discrepancies in CGT regulatory submissions, documenting variations in trial data reporting between regulatory agencies. Variability in data submission may be influenced by expected differences in regulatory requirements, risk tolerance, and submission timing.

The study was limited by the absence of data on sponsor interactions with regulatory agencies. However, the results align with ongoing efforts to harmonize regulatory standards to ensure more consistent and rigorous regulatory decision-making.

The researchers reported no conflicts of interest.