The FDA today announced a plan to publicly release complete response letters at the same time they are issued to sponsoring companies, part of what the agency calls a push toward “radical transparency.”
At the same time, the FDA released 89 new CRLs, adding to the more than 200 that were previously made public in July and shedding more light on the agency's often-opaque review process. That earlier document dump, though, only included rejection letters for drugs that were eventually approved. Now, for the first time, the agency is releasing CRLs for non-approved drug candidates.
From now on, the regulator says it will release CRLs in real time as they are issued.
Further, when an application for a new medicine is approved, the agency plans to release all associated CRLs. The FDA also plans to go back and release CRLs from withdrawn or abandoned applications, the agency said.
All response letters will be redacted to “remove confidential commercial information, trade secrets and personal private information,” according to the release. The real-time nature of the new policy mimics the agency’s recently announced plan to update the FDA Adverse Event Reporting System on a daily basis.
“This is a milestone day for the agency,” FDA Commissioner Dr. Marty Makary, M.D., said in the release. “By embracing radical transparency—one of the guiding principles of this administration—we’re giving invaluable insights to help speed therapies and cures to market, providing complete context to investors and shareholders, and above all, restoring public trust.”
The fresh batch of 89 CRLs includes some recent high-profile rejections, including Ultragenyx’s gene therapy for Sanfilippo syndrome type A, Capricor Therapeutics’ Duchenne muscular dystrophy cell therapy and Replimune’s melanoma drug RP1 (vusolimogene oderparepvec).
At the time of its July 22 failure to obtain accelerated approval, Replimune said the FDA concluded that the biotech’s phase 1/2 Ignyte trial “cannot be adequately interpreted due to the heterogeneity of the patient population." The regulator further decided the trial is not “an adequate and well-controlled clinical investigation that provides substantial evidence of effectiveness," the company shared at the time.
These quotes from Replimune are found essentially verbatim in the now-public, but partially redacted, complete response letter. But, in its letter, the FDA also made mention of Replimune’s ongoing phase 3 trial of RP1, writing that the agency has identified “several issues that must be addressed” with the study.
“The study design may not isolate the contribution of vusolimogene oderparepvec due to the inclusion of single-agent chemotherapy options in the investigator’s choice control arm,” the FDA wrote. “There also is inadequate data to support the statistical assumption of a 6-month improvement in the primary endpoint of overall survival.”
The agency called on Replimune to submit a revised study protocol addressing these concerns; the biotech announced Sept. 2 that it has scheduled a meeting with the FDA to discuss the CRL and address the comments on the phase 3 trial.
In Replimune's phase 1/2 trial, patients with anti-PD1 failed melanoma were treated with a combination of RP1 and Bristol Myers Squibb’s Opdivo (nivolumab). The combination therapy led to an overall response rate (ORR) of 33.6% and a complete response rate of 15%, Replimune reported in November 2024. The company subsequently secured a breakthrough therapy designation from the FDA, enabling a submission for accelerated approval.
In its rejection letter, the FDA acknowledged that the trial's response rate "appears numerically higher compared to the proposed historical control rate from literature reports." But the agency said that due to patient variability and the trial's design, RP1's "specific contribution to the observed ORR cannot be determined." Replimune's submission was for RP1's use in combination with Opdivo, not alone.
The issues raised in the CRL "should have been apparent at the time Replimune received breakthrough-therapy designation in November 2024," analysts from William Blair wrote in a Sept. 4 note. "It does therefore support many investor views and journalist reports that higher-ups may have overruled the reviewers on the decision." Aug. 4, Stat reported that the FDA's top oncology regulator, Richard Pazdur, M.D., played a key role in the Replimune rejection.
Replimune’s rejection sent shock waves throughout the biotech world, causing Krystal Biotech to discontinue development of a similar melanoma asset and prompting The Wall Street Journal’s editorial board to write a scathing piece that claimed “therapies for rare and deadly disease are dying in Marty Makary’s shop.”
Massachusetts-based Replimune’s stock plummeted by 76% after the rejection to less than $3 per share. The company’s share price sat at $5.71 per share as of 12:30 p.m. ET on Sept. 4.
Editor's note: This story was updated at 2:45 p.m. ET on Sept. 4 to include information from an analyst report, and at 11:15 a.m. ET on Sept. 5 to clarify that the FDA is now for the first time releasing rejection letters for drugs that have not yet been approved.