FDA Publishes CRLs for Past Drug, Biological Product Applications

The US Food and Drug Administration (FDA) has announced the publication of > 200 Complete Response Letters (CRLs) issued in response to applications submitted to the Agency for approval of drugs or biological products between 2020 and 2024.1

According to a July 10, 2025, release from the FDA, the initial batch of published decision letters are associated with since-approved applications. The Agency describes the availability of the CRLs as marking a significant step in its broader initiatives to modernize and increase transparency, providing the public with greater insight into the FDA’s decision-making and the most common deficiencies cited that sponsors must address before their application is approved.1

“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 statement.1 “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.”

As described in the press release, CRLs are issued directly to product sponsors when the FDA completes its review cycle and determines it cannot grant an approval of an application in its current form. The Agency most frequently issues CRLs for safety and efficacy concerns, manufacturing deficiencies, and bioequivalence issues. Such deficiencies are detailed in the letter and may also include recommendations for addressing them.1

Recent notable CRLs issued by the FDA include Unicycive Therapeutics’ New Drug Application (NDA) for oxylanthanum carbonate for the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis; Regeneron’s supplemental Biologic License Application for an extended 24-week dosing duration for aflibercept 8 mg (EYLEA HD) in the treatment of wet age-related macular degeneration, diabetic macular edema, and diabetic retinopathy; Aldeyra Therapeutics’ resubmission of an NDA for reproxalap for dry eye disease, and Milestone Pharmaceutical's application for etripamil nasal spray (Cardamyst) in the treatment of paroxysmal supraventricular tachycardia.2,3,4,5

Historically, the FDA has refrained from publishing CRLs for pending applications, leading sponsors to often misrepresent the rationale behind FDA’s decision to their stakeholders and the public. According to a 2015 analysis conducted by FDA researchers, sponsors avoided mentioning 85% of the FDA’s concerns about safety and efficacy when publicly announcing their application was not approved. Additionally, when the Agency calls for a new clinical trial for safety or efficacy, that information is not disclosed approximately 40% of the time.1

The FDA also noted lessons learned from non-approvals are also not shared within the industry, leading companies to repeatedly make similar mistakes.1

This initial batch of published decision letters associated with since-approved applications is accessible to the public at openFDA, the first ever centralized database of past CRLs, and includes > 200 documents. Of note, the CRLs were redacted for trade secrets and confidential commercial information, and the Agency is in the process of publishing additional CRLs from its archives.1

References

1. US Food and Drug Administration. FDA Embraces Radical Transparency by Publishing Complete Response Letters. July 10, 2025. Accessed July 10, 2025. https://www.fda.gov/news-events/press-announcements/fda-embraces-radical-transparency-publishing-complete-response-letters

2. Brooks A. FDA Issues CRL to Oxylanthanum Carbonate for Hyperphosphatemia in CKD, Dialysis. HCPLive. June 30, 2025. Accessed July 10, 2025. https://www.hcplive.com/view/fda-issues-crl-oxylanthanum-carbonate-hyperphosphatemia-ckd-dialysis

3. Livingston R. FDA Issues Complete Response Letter to Aflibercept 8 mg for Extended Dosing. HCPLive. April 18, 2025. Accessed July 10, 2025. https://www.hcplive.com/view/fda-issues-complete-response-letter-to-aflibercept-8-mg-for-extended-dosing

4. Livingston R. FDA Issues Complete Response Letter to Reproxalap for Dry Eye Disease. HCPLive. April 3, 2025. Accessed July 10, 2025. https://www.hcplive.com/view/fda-issues-complete-response-letter-to-reproxalap-for-dry-eye-disease

5. Campbell C. FDA Issues CRL for Etripamil Nasal Spray (Cardamyst) in PSVT. HCPLive. March 28, 2025. Accessed July 10, 2025. https://www.hcplive.com/view/fda-issues-crl-for-etripamil-nasal-spray-cardamyst-in-psvt