FDA, EMA See Differences in Cell and Gene Therapy Trial Data

Cell and gene therapy (CGT) developers regularly submit different clinical trial data to U.S. and European regulators, potentially complicating the approval process for these treatments, a new study shows.

The research, published in JAMA Internal Medicine, found only 20% of trials submitted to both agencies had matching evidence. The study examined 15 cell and gene therapy products submitted to the FDA and European Medicines Agency (EMA) through October 2023.

Magdi Elsallab, M.D., Ph.D.

“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,” wrote the study authors, led by Magdi Elsallab, M.D., Ph.D., of Harvard Medical School.

Among the 20 trials reported to both agencies, 13 showed different sample sizes, with eight differing by more than 10%. The EMA received larger sample sizes for six of these trials. The findings also revealed 13 of 19 trials with comparable endpoints reported different efficacy outcomes between FDA and EMA applications, with six showing differences exceeding 10%.

In one example, a trial for Hemgenix (etranacogene dezaparvovec), a gene therapy for hemophilia B, reported a 22% higher annual bleeding rate to the FDA compared with the EMA, despite having matching trial sample sizes.

Most applications in the study were for gene therapies targeting rare diseases, with oncology being the most common therapeutic area. While some variance in reported clinical efficacy across applications may stem from different regulatory requirements or submission timing, the study authors suggest better understanding of factors causing large outcome differences is needed.

The FDA and EMA have already initiated efforts to improve alignment through programs like the Collaboration on Gene Therapies Global Pilot, which began last year and seeks to coordinate evidence requirements across global agencies. This pilot was announced by Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research (CBER) in January 2024 at the Alliance for Regenerative Medicine’s Cell & Gene State of the Industry Briefing. He said then that the goal was increase the efficiency of the regulatory process and reduce time and cost for regulators and companies.

The FDA also launched the Support for clinical Trials Advancing Rare Disease Therapeutics (START) pilot program, which asked for feedback about the challenges of developing cellular and gene therapies for diseases with small patient populations.

As of December 2024, the FDA had approved 43 cell and gene therapies, including hematopoetic stem cells and adult and embryonic stem cells.

The findings from the JAMA Internal Medicine study come as global regulators push for more standardized approaches to cell and gene therapy development. Researchers said that uniform evidence standards and reporting requirements could help speed patient access to these treatments while ensuring thorough safety and efficacy evaluation.

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

The authors said one limitation was that they did not have information on sponsor interactions with regulatory agencies, which may have led to the differences they saw.