FDA Publishes Hundreds of Complete Response Letters From First Half of the Decade

The FDA has published over 200 complete response letters (CRLs) from 2020 to 2024, providing the opportunity for consumers to have greater insights into the decisions behind the FDA’s drug approval process. Typically, the FDA has refrained from publishing CRLs for pending applications, marking a major shift in transparency initiatives under new leadership.¹

By publishing the trove of CRLs, the FDA is seeking to improve its transparency to the public. | Image Credit: © Sergei Elagin - stock.adobe.com

“For far too long, drug developers have been playing a guessing game when navigating the FDA,” FDA Commissioner Marty Makary, MD, MPH, said in a news release announcing the decision. “Drug developers and capital markets alike want predictability. 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.”¹

What Are CRLs?

CRLs are notices sent to drug manufacturers from the FDA indicating that an application for a drug will be approved in its current form. While the letter is not an explicit rejection of the drug, it indicates that the drug submission—whether it be a new drug application (NDA) or biologics license application (BLA)—was deemed inadequate and explains how the drug sponsor can properly remedy the noted issues.²

Although a CRL is not a rejection and not unusual, according to Avalere Health, 37% of BLAs and NDAs submitted during the 2018 to 2022 cycle of Prescription Drug User Fees received a CRL. Further, resubmitting an application in response to the letter will not guarantee a future approval. Once factors in the CRL are addressed, the FDA reevaluates the application and could indeed send another CRL to the drug sponsor if deemed necessary.²

Questions Surrounding Transparency on Behalf of Drug Sponsors

When a sponsor receives a CRL for their drug candidate, they are not mandated to reveal the exact reasons the FDA cites as reasons to not move forward with approval. Because of this, according to the FDA, “sponsors often misrepresent the rationale behind the FDA’s decision to their stakeholders and the public.”¹

A 2015 cross-sectional study conducted by researchers at the FDA’s Office of Public Health Strategy and Analysis aimed to compare the content of CRLs issued by the FDA with the content of subsequent news releases issued by the sponsors detailing the CRL. The analysis included 61 CRLs that were issued between 2008 and 2013.³

The authors found that, of the CRLs, 48% (29) cited deficiencies in both the safety and efficacy domains of a drug. Furthermore, 32 CRLs called for a new clinical trial of the specified drug due to safety or efficacy. In a concerning development, no news release was issued for 18% (11) of the total number of CRLs, while 21% (12) of the news releases did not match any statements from the CRLs. Perhaps most notable is that news releases from sponsors matched 93 of the 687 statements (14%), including 16% (30/191) of efficacy and 15% (22/150) of safety statements.³

For CRLs that called for a new clinical trial evaluating safety and efficacy, only 59% (19) had matching press release statements. For the 7 CRLs that reported higher mortality rates in treated patients, only 1 associated news release mentioned that aspect. Makary and current FDA officials echo the sentiments of these past investigators, who wrote in their conclusion that “press releases are incomplete substitutes for the detailed information contained in complete response letters.”^1,3

Implications for Sponsors and Providers

The batch of 200 CRLs from the last 5 years are associated with drugs that have since been approved. The FDA published the CRLs on their openFDA website for members of the public to download. Importantly, the FDA said it redacted from the CRL potential trade secrets and any confidential commercial information. Though many investors and some drug developers have clamored for the release of such CRLs to better inform them on the FDA’s decision-making process, the releasing of the CRLs could pose legal problems for sponsors who now have more information on their drugs out in the open.^1,4

For providers and pharmacists, having more information to give patients is always a plus, and patients will have access to the full breadth of information on how a drug they may be prescribed came to be approved. It could go a long way to improving hesitancy and fears regarding the safety of new drugs approved by the FDA and lead to more transparency initiatives in the future.

The FDA said it is continuing to publish additional CRLs from its archives.¹

REFERENCES

1. FDA. FDA embraces radical transparency by publishing complete response letters. News Release. Released July 10, 2025. Accessed July 10, 2025.

2. Avalere Health. Complete response letters: Implications for product access. Last Updated November 30, 2023. Accessed July 10, 2025. https://advisory.avalerehealth.com/insights/what-is-a-complete-response-letter

3. Lurie P, Chahal HS, Sigelman DW, Stacy S, Sclar J, Ddamulira B. Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study. BMJ. 2025;350:h2758. doi:10.1136/bmj.h2758

4. FDA. Complete Response Letters. openFDA. Uploaded July 10, 2025. Accessed July 10, 2025. https://open.fda.gov/apis/other/approved_CRLs/