Why Cell and Gene Therapy Products Fail to Perform Post-Approval? A Matched-Pair analysis of Regulatory Submissions among Biologicals in the EU

Abstract Advanced therapy medicinal products (ATMPs), comprising cell therapy products, gene therapy products, and tissue-engineered products, offer a multitude of novel therapeutic approaches to a wide range of severe and debilitating diseases. To date, several advanced therapies have received marketing authorization for a variety of indications. However, some products showed disappointing market performance leading to their withdrawal. The available evidence for product quality, safety and efficacy at product launch can play a crucial rule in the success of the product throughout its life cycle. To evaluate the sufficiency of evidence in advanced therapies submissions for marketing authorization and to identify their unique characteristics, we conducted a retrospective; head-to-head, nearest neighbor matched comparison of the submissions between ATMPs and other biologicals. We applied a quantitative assessment of the regulatory objections and explored the impact of regulatory flexibility as indicators of the sufficiency of evidence in both cohorts. Our results indicated that product manufacturing was challenging for all biologicals. Advanced therapies displayed critical issues in the sufficiency of the submitted clinical data. The submitted non-clinical data packages benefited the most from regulatory flexibility. Additionally, ATMP developers need to comply with more commitments in the post-approval phase, which might add pressure on market performance.