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Key Takeaways
- FDA publishes over 200 complete response letters (CRLs): The agency released CRLs from 2020 to 2024 to improve transparency and regulatory predictability in drug development.
- Common issues identified: 48% of CRLs cited both safety and efficacy deficiencies, emphasizing the need for strong data and well-executed trial design.
- Industry-wide learning opportunity: Public access to CRLs may help developers avoid repeated mistakes and align submissions more closely with FDA expectations.
The FDA has published over 200 complete response letters (CRLs) issued between 2020 and 2024 in response to drug and biologic applications, aiming to increase transparency and enhance regulatory predictability, the agency stated in a press release.
Previously, CRLs were shared only with product sponsors, limiting broader industry visibility into the specific deficiencies that prevented approval. By releasing these letters to the public, the FDA said it hopes to reduce repeated submission errors and foster a more informed and efficient drug development landscape.1
“For far too long, drug developers have been playing a guessing game when navigating the FDA,” said Marty Makary, MD, MPH, FDA Commissioner, in a press release.
What is a CRL?
A CRL is a notice sent out by the FDA stating that a potential drug will not be approved in its current formation. However, it is important to note that a CRL is not an all-out rejection of an application.
The main goal of a CRL is to serve as the FDA’s mechanism for outlining necessary changes or additional data needed for potential approval in a future review cycle. Receiving a CRL is also fairly common in the drug development process.
Between 2018 and 2022, 37% of biologics license applications (BLAs) and new drug applications (NDAs) were issued a CRL.2 Common reasons for a CRL include safety concerns, trial design flaws, and manufacturing gaps.
Transparency Gaps Have Long Impacted Industry Learning
According to the FDA, limited access to CRLs in the past has allowed sponsors to downplay or omit the agency’s concerns. A 2015 analysis found that 85% of safety and efficacy issues cited in CRLs were not publicly disclosed by sponsors.
Additionally, in roughly 40% of cases in which the FDA requested new clinical trials to address safety or efficacy concerns, that critical information was not communicated in press releases. This lack of transparency has prevented industry-wide learning, leading many companies to unknowingly repeat similar mistakes.1
Key Findings from Published CRLs
The same analysis found that 48% of CRLs cited deficiencies in both safety and efficacy domains, while only 13% cited neither. Furthermore, 18% of CRLs were not accompanied by a press release and 21% of press releases issued contained no statements that aligned with the CRLs. In total, just 14% of statements in CRLs were reflected in public announcements, which includes 16% of efficacy-related and 15% of safety-related comments.
Of the 32 CRLs that called for new clinical trials for safety or efficacy, only 59% had press releases that acknowledged those requirements. Notably, among seven CRLs citing increased mortality in treated participants, only one corresponding press release disclosed this outcome.3
What Comes Next for the FDA’s Transparency Initiative?
The initial batch of publicly released CRLs—all associated with applications that were eventually approved—are now available through the openFDA platform. These documents have been redacted to exclude trade secrets and confidential commercial information. The FDA stated that it plans to continue releasing additional CRLs from its archives and will maintain efforts to increase visibility into its regulatory decision-making process.1
“Drug developers and capital markets alike want predictability,” continued Makary, in the press release. “So today, we’re one step closer to delivering it to them, with an ultimate goal of bringing cures and meaningful treatments to patients faster.”
References
- FDA Embraces Radical Transparency by Publishing Complete Response Letters. FDA. July 10, 2025. Accessed July 11, 2025. https://www.fda.gov/news-events/press-announcements/fda-embraces-radical-transparency-publishing-complete-response-letters
- Complete Response Letters: Implications for Product Access. Avalere Health. November 30, 2023. Accessed July 11, 2025. https://advisory.avalerehealth.com/insights/what-is-a-complete-response-letter
- Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study. The BMJ. Accessed July 11, 2025. https://www.bmj.com/content/350/bmj.h2758