FDA Enables Instant Access to CRLs—Insights for Drug Discovery and Manufacturing

Silver Spring, MD, USA - June 25, 2022: The FDA White Oak Campus, headquarters of the United States Food and Drug Administration, a federal agency of the Department of Health and Human Services (HHS). | Image Credit: © Tada Images - stock.adobe.com

After saying in July 2025 that it would embrace “radical transparency” by publishing complete response letters (CRLs) issued in response to drug approval applications, FDA said on Sept. 4, 2025 that it would further advance that policy by releasing future CRLs “promptly” after being issued to sponsors (1,2). The agency immediately released 89 previously unpublished CRLs, issued from 2024 to present, dealing with pending or withdrawn applications (2).

“This is a milestone day for the agency,” FDA Commissioner Marty Makary, MD, MPH, said in an agency press release (2). “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.”

Are companies responding, and how?

One newly published CRL that attracted immediate attention was addressed to Lykos Therapeutics, for an 3,4-Methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of post-traumatic stress disorder (PTSD). The nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS) commended FDA for its transparency, but dissented with the decision expressed in this particular CRL.

“Let’s be clear: the CRL reveals a devastating truth—FDA moved the goalposts,” Rick Doblin, PhD, MAPS founder and president, said in a statement (3). “Thirteen million Americans live with PTSD today. Every year of delay means more will die by suicide and more remain trapped in cycles of trauma and despair. They deserve better ... Lykos will continue negotiations with FDA.”

Following FDA’s initial disclosure of transparency regarding CRLs, Pharmaceutical Technology® covered the responses of Capricor Therapeutics, for an experimental treatment (deramiocel) for cardiomyopathy associated with Duchenne muscular dystrophy, and Replimune, for RP1 (vusolimogene oderparepvec) in combination with nivolumab for the treatment of advanced melanoma (4).

“I wonder if part of the problem is that many biotechs do not have sufficient experience in-house, and rely on contract organizations,” Pharmaceutical Technology® Editorial Advisory Board member Chris Moreton, PhD, VP, Pharmaceutical Sciences, FinnBrit Consulting, said at the time, speaking from his perspective as a consultant for various industry companies (4). “However, the contract staff may not be sufficiently familiar with the details of the project they are working on. Thus, things fall between the cracks, so to speak.”

What does this mean for drug discovery, development, and manufacturing?

This policy shift ostensibly gives developers, including those in discovery, preclinical, and clinical domains, much earlier access to FDA feedback on safety and effectiveness issues detailed in CRLs (2). Access to these real-time communications enables sponsors to detect recurring deficiencies and better align their study design and regulatory strategies with the agency’s expectations.

Also, CRLs often cite detailed chemistry, manufacturing, and controls (CMC) deficiencies. With immediate public access to these letters—albeit redacted for trade secrets and proprietary information—developers gain indirect insight into the most common CMC pitfalls flagged by FDA. This heightened awareness may allow for more proactive quality assurance and process control planning.

On the other hand, although FDA has committed to “prompt” publication and redaction of confidential information such as trade secrets and personal identifiers, precise timing as it relates to CRL issuance remains unspecified (2). Additionally, the policy currently covers human drug and biologic applications; direction on other application types has not been clarified.

FDA’s searchable database of CRLs can be accessed at this link.

References

1. FDA. FDA Embraces Radical Transparency by Publishing Complete Response Letters. Press Release. July 10, 2025.
2. FDA. FDA Announces Real-Time Release of Complete Response Letters, Posts Previously Unpublished Batch of 89. Press Release. Sept. 4, 2025.
3. MAPS. MAPS Statement on FDA’s Public Release of Complete Response Letter for MDMA-Assisted Therapy. Press Release. Sept. 4, 2025.
4. Cole, C. CMC and Analytical Gaps in CRLs: Why They Persist Despite FDA Guidance and How You Can Position Yourself for Success. PharmTech.com, July 25, 2025.