Study: Sponsors often submit different clinical evidence to FDA, EMA, for cell and gene therapies

Sponsors submitting applications for cell and gene therapy (CGT) products to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) tend to present data from the same clinical trials, but only a handful of trials showed the same clinical evidence across both agencies, according to a recent research letter published in JAMA Internal Medicine.

“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,” Magdi Elsallab, of the Harvard-MIT center for regulatory science at Harvard Medical School in Boston, and colleagues wrote.

Elsallab and colleagues performed a cross-sectional study of 15 original and supplemental CGT applications approved by FDA and EMA up to October 2023, as well as 20 original and supplemental applications submitted to FDA and EMA. The researchers analyzed characteristics of the clinical trials presented in each application, including primary endpoint, primary efficacy outcomes, sample size, and comparator type. They also evaluated the product type, disease area, use of an expedited pathway, and noted whether the product had an orphan designation.

Of the 15 CGT products approved by both agencies, there were 13 gene therapies (87%) and 2 cell-based therapies (13%). A majority of CGT products had an orphan designation with FDA (87%) and EMA (80%) and also used an expedited regulatory pathway such as FDA’s breakthrough designation (80%) and EMA’s PRIME designation (73%). Most of the products were related to oncology (53%), while other products were in disease areas involving blood and lymphatic system disorders (20%), disorders of musculoskeletal and connective tissue (13%), disorders of metabolism and nutrition (7%), or disorders of the eye (7%). The product characteristics were similar for the 20 applications submitted to both FDA and EMA.

Overall, 20 applications submitted to both agencies included 24 clinical trials; of these, there were 20 trials submitted to FDA and EMA, with 4 trials having the same clinical evidence across both agencies. For the other trials, 13 trials (65%) had differing sample sizes, and 8 trials had a difference of over 10% in sample size between agencies, and EMA submissions had the larger sample size for 6 trials. When checking FDA and EMA data against ClinicalTrials.gov, the researchers found 12 trials (60%) matched sample size data from either agency.

The researchers also examined efficacy assessments from trials presented to both agencies and found 16 trials (80%) matched the comparator. In the other cases, 4 trials submitted to EMA had a comparator, while the same trials submitted to FDA and ClinicalTrials.gov did not have a comparator.

Concerning endpoints, 13 of 19 trials (68.4%) had different values between FDA and EMA, with 6 trials having a difference of over 10%. When checking FDA and EMA submissions against ClinicalTrials.gov, 7 reports matched efficacy outcome values that were submitted to either agency, the researchers said.

“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,” Elsallab and colleagues said.

The researchers noted that they did not have access to the interactions the sponsors had with FDA and EMA, which may limit the findings and potentially explain the observed differences 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. Uniform evidence standards and reporting requirements, combined with harmonized regulatory processes and reviews, may accelerate patient access to innovative and rigorously assessed therapies,” Elsallab and colleagues concluded.

JAMA Intern Med Elsallab et al.

Study: Sponsors often submit different clinical evidence to FDA, EMA, for cell and gene therapies

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