FDA Opens Access to Over 200 CRLs

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Today, the US Food and Drug Administration (FDA) published over 200 decision letters, known as Complete Response Letters (CRLs), in response to applications submitted for approval of drugs or biological products between 2020 and 2024. The agency says this marks a “significant step” in their broader initiatives to modernize and increase overall transparency.¹

“By making the CRLs available, the public now has significantly greater insight into the FDA’s decision-making and the most common deficiencies cited that sponsors must address before their application is approved,” the FDA said in a news release.

CRLs are issued when the FDA completes its review cycle and are sent directly to sponsors. They determine that an approval cannot be granted of an application in its current form. Recently in the world of dermatology, the FDA approved dupilumab for adolescents and adults with H1 Antihistamine-refractory chronic spontaneous urticaria (CSU), despite an October 2023 CRL stating that additional efficacy data were needed to support approval. In response to this CRL, Regeneron and Sanofi resubmitted the supplemental Biologics License Application (sBLA) including updated efficacy and safety data from a third phase 3 trial – ultimately leading to the long-awaited approval.²

The FDA can issue CRLs for various reason, most related to safety and efficacy concerns, manufacturing deficiencies, and bioequivalence issues. In the case of dupilumab for CSU, while additional efficacy data was requested the agency did not identify any concerns regarding safety or manufacturing. CRLs detail any deficiencies and may also include recommendations for addressing them.

In another case concerning prademagenezamikeracel (pz-cel) for the treatment of recessive dystrophic epidermolysis bullosa, the FDA issued a CRL noting the need for additional chemistry, manufacturing, and controls information, including validation for specific manufacturing and release testing methods stated during the pre-license inspection. Abeona Therapeutics later resubmitted its BLAforpz-cel, leading to the April 2025 approval of the gene therapy.^3-4

“For far too long, drug developers have been playing a guessing game when navigating the FDA,” said FDA Commissioner Marty Makary, MD, MPH, in the release. “Drug developers and capital markets alike want predictability. So today we’re 1 step closer to delivering it to them, with an ultimate goal of bringing cures and meaningful treatments to patients faster.”

The agency said that because the FDA has historically refrained from publishing CRLs for pending applications, it feels sponsors often misrepresent the rationale behind the FDA’s decision to their stakeholders and the public. According to a 2015 analysis conducted by FDA researchers, they stated sponsors avoided mentioning 85% of the FDA’s concerns about safety and efficacy when publicly announcing that their application was not approved. Moreover, the agency noted that when it calls for a new clinical trial for safety or efficacy, that critical information remains undisclosed around 40% of the time. Finally, the FDA stated that lessons learned from these non-approvals are not shared within the industry, ultimatly leading to companies repeatedly making similar mistakes.

The initial batch of published decision letters associated with since-approved applications is now accessible and open to the public at openFDA. In the release, the FDA noted that the CRLs were redacted for trade secrets and confidential commercial information. The agency stated it is in the process of publishing additional CRLs from its archives and is “continuously exploring ways of providing the public with greater transparency into its decision-making process.”

References

1. FDA embraces radical transparency by publishing complete response letters. News Release. US FDA. Published July 10, 2025. Accessed July 10, 2025. https://www.fda.gov/news-events/press-announcements/fda-embraces-radical-transparency-publishing-complete-response-letters?utm_medium=email&utm_source=govdelivery
2. Andrus E, Hebebrand M. FDA approves dupilumab for adolescents and adults with H1 antihistamine-refractory chronic spontaneous urticaria. News article. Dermatology Times. Published April 18, 2025. Accessed July 10, 2025. https://www.dermatologytimes.com/view/fda-approves-dupilumab-chronic-spontaneous-urticaria
3. Andrus E. FDA sets PDUFA date, accepts BLA submission for pz-cel in epidermolysis bullosa. News article. Dermatology Times. Published November 12, 2024. Accessed July 10, 2025. https://www.dermatologytimes.com/view/fda-sets-pfuda-date-accepts-bla-submission-for-pz-cel-in-epidermolysis-bullosa
4. Hebebrand M. FDA approves first gene therapy for RDEB. News article. Dermatology Times. Published April 29, 2025. Accessed July 10, 2025. https://www.dermatologytimes.com/view/fda-approves-first-gene-therapy-for-rdeb