FDA Transparency Initiative Sheds Light on Drug Rejection Process

In a groundbreaking move towards transparency, the U.S. Food and Drug Administration (FDA) has released 200 complete response letters (CRLs) from the past decade, offering unprecedented insight into the drug approval process. This release, described as an act of "radical transparency," provides a detailed look at the reasons behind drug rejections, including those for high-profile treatments that eventually made it to market.

Key Rejections Revealed

Eli Lilly's Alzheimer's Drug Kisunla

Eli Lilly's Alzheimer's treatment Kisunla faced significant hurdles before its eventual approval in July 2024. The CRL, signed by then-director of the office of neuroscience Billy Dunn, rejected Lilly's application for accelerated approval. The FDA cited insufficient long-term safety data, with only 49 patients exposed to the drug for at least 12 months, far short of the agency's 100-patient requirement.

The FDA also raised concerns about the treatment protocol, which allowed patients to stop taking the drug once their amyloid plaques had declined to a certain level. This variable dosing schedule complicated the assessment of long-term safety profiles. Additionally, the agency noted that much of the six-month safety data came from open-label studies, further limiting its utility in the approval process.

Sarepta's Duchenne Muscular Dystrophy Treatment Vyondys 53

Sarepta Therapeutics' Vyondys 53, approved in December 2019 for Duchenne muscular dystrophy (DMD), initially received a rejection from the FDA. The CRL, signed by Ellis Unger, then-director of the Office of Drug Evaluation, highlighted concerns about the drug's efficacy and safety.

The FDA noted that the increase in truncated dystrophin produced by Vyondys 53 was small, suggesting that any clinical benefit would be "commensurately small." Moreover, the agency observed no correlation between physical performance and the amount of dystrophin produced in patients.

Safety concerns were paramount, with the FDA citing "serious infections related to delivery of the drug" and "renal toxicity" as potentially life-threatening side effects. These safety issues were particularly notable in light of recent deaths attributed to acute liver failure in patients treated with Sarepta's gene therapy Elevidys.

Manufacturing and Packaging Challenges

Gilead's HIV Drug Sunlenca

Gilead Sciences' long-acting HIV-1 capsid inhibitor, now marketed as Sunlenca, faced delays due to unexpected packaging issues. The FDA rejected the initial application in March 2022 due to concerns about the glass vials used to house the medicine.

The CRL, signed by Adam Sherwat, then-deputy director of the Office of Infectious Diseases, explained that Gilead's own data revealed incompatibility between the highly alkaline drug solution and the borosilicate glass vials commonly used in pharmaceutical packaging. Glass particles were found in clinical batches of the drug, prompting Gilead to propose using aluminosilicate glass as an alternative.

However, the FDA deemed the data supporting this change "incomplete and ambiguous," leading to a delay in approval until August 2022. This case highlights the importance of considering drug-packaging interactions in the development process.

The FDA's release of these CRLs marks a significant step towards transparency in the pharmaceutical industry, offering valuable insights into the complex process of drug approval and the challenges faced by even the most promising treatments.