Uniform Global Standards, Processes Could Accelerate CGT Approvals, Access

Global initiatives to harmonize regulations for cell and gene therapies (CGTs)—including evidence standards, reporting requirements, and regulatory processes—could facilitate more timely access to innovative therapies, according to a research letter published in JAMA Internal Medicine. The study found that just 20% of trials submitted to both the FDA and European Medicines Agency (EMA) had matching evidence.

Initiatives such as the Collaboration on Gene Therapies Global Pilot, which was launched by the FDA and EMA last year,² aim to harmonize the evaluation and regulation of CGT products and allow for more efficient clinical development. Another FDA initiative, the Support for Clinical Trials Advancing Rare Disease Therapeutics Pilot Program, aims to speed up the development of novel drug and biologic products that would address unmet needs for rare diseases.³ The study’s findings emphasize the importance of these efforts and highlight inconsistencies in reported outcomes.¹

“Our comparative analysis of CGT product submissions to the FDA and EMA supports the crucial need for harmonization efforts in CGT product development, including improved standardization of trial design and reporting,” the authors wrote. “While some variance in clinical efficacy reported across applications may be expected due to differences in regulatory requirements, risk tolerance, and submission timing, a better understanding of factors resulting in large differences in outcomes is needed to ensure that regulatory decisions are based on robust and consistent evidence.”

The study included 15 CGT products approved by both the FDA and EMA as of October 2023, with a total of 20 original and supplemental applications submitted to both agencies. Data from a total of 24 trials were presented in the 20 applications, with 1 clinical trial per application submitted to both agencies. Regarding evidence reporting, just 4 of the 20 trials (20%) submitted the same trial evidence to both the FDA and EMA.

Of the 20 trials submitted to both agencies, 13 (65%) reported different sample sizes to each agency, and 8 of the reported sample sizes differed by more than 10%. In 6 of those trials, a larger sample size was presented to the EMA, which included 2 that were submitted to the EMA prior to FDA submission. In 12 trials (60%), the sample sizes listed on ClinicalTrials.gov matched sample sizes from data submitted to either agency.

In 16 of the trials (80%), the comparator used in the efficacy assessment matched. In the remaining 4 trials that were discordant, EMA submissions included a comparator, while the FDA and ClinicalTrials.gov trial reports did not include comparators.

In 13 (68.4%) out of 19 trials with comparable end points, the values reported differed between the FDA and EMA applications. In 6 of those trials, the difference was greater than 10%. With etranacogene dezaparvovec, for instance, the annualized bleeding rate reported to the FDA was 21.7% higher than the rate reported to the EMA, although the sample sizes were the same. Just 7 of the reports on ClinicalTrials.gov had aligned efficacy values compared with FDA or EMA submissions.

The study authors acknowledged that the research was limited by a lack of information on sponsor interactions with the FDA and EMA, which could explain certain differences seen in the study.

“These findings highlight the importance of emerging initiatives for global harmonization of regulations for CGTs, which may also apply to other product categories,” the authors concluded. “Uniform evidence standards and reporting requirements, combined with harmonized regulatory processes and reviews, may accelerate patient access to innovative and rigorously assessed therapies.”

References

1. Elsallab M, Gillner S, Bourgeois FT. Comparison of Clinical Evidence Submitted to the FDA and EMA for Cell and Gene Therapies. JAMA Intern Med. Published online February 3, 2025. doi:10.1001/jamainternmed.2024.7569

2. Marks P. CY 2023 report from the director. FDA. January 31, 2025. Accessed March 12, 2025. https://www.fda.gov/vaccines-blood-biologics/cy-2023-report-director

3. Roth LK. Support for Clinical Trials Advancing Rare Disease Therapeutics Pilot Program; program announcement. Federal Register. October 2, 2023. Accessed March 12, 2025. https://www.federalregister.gov/documents/2023/10/02/2023-21235/support-for-clinical-trials-advancing-rare-disease-therapeutics-pilot-program-program-announcement