By: Pharmacally Medical News Desk
Key points
- The U.S. FDA has announced, it will begin publishing future Complete Response Letters (CRLs) in real time after they are issued to sponsors.
- The agency has already released earlier batches of CRLs from recent years and says more historical letters will follow.
- Real‑time publication is intended to improve transparency around why an application is not approvable in its current form.
- Sponsors should prepare for immediate public scrutiny, investor questions, and media coverage following a CRL.
What is a Complete Response Letter?
A Complete Response Letter is the FDA’s formal notice that it has completed the review of a drug or biologic application and cannot approve it in its current form. CRLs explain the specific deficiencies that must be addressed before approval is possible. Common reasons include:
- Insufficient evidence of efficacy or safety
- Problems with trial design, endpoints, or data integrity
- Chemistry, Manufacturing, and Controls (CMC) or facility inspection findings
- Issues related to bioequivalence or labeling
Historically, CRLs were sent only to the sponsor and were not routinely made public.
What changed?
In mid‑2025, FDA began posting previously confidential CRLs to a central database and later announced a shift to publishing future CRLs promptly after issuance. The goal is to enhance clarity around negative decisions and reduce misinformation about why applications are rejected or deferred.
Notable points:
Initial publication wave: FDA posted a large part of historic CRLs from the past few years. Examines of that dataset suggested that manufacturing and quality problems were a leading cause of non‑approval.
Second wave and policy update: The agency followed with another batch of CRLs and confirmed that, going forward, it will release CRLs in near real time and continue adding older letters when feasible.
Scope: The commitment applies to CRLs for NDAs and BLAs. Device and generic pathways may be addressed separately by their respective centers.
What will be made public?
- The CRL text, with confidential commercial information redacted.
- A central searchable database with basic metadata (sponsor, product, application type, date, therapeutic area).
- Where appropriate, linking to related approval packages if the product is later approved.
What will remain Protected?
- Trade secrets, proprietary manufacturing details, and certain personal privacy information.
- Confidential aspects of ongoing inspections or enforcement matters.
Why this matters
For patients and clinicians
- Faster visibility into the FDA’s scientific reasoning when an anticipated therapy does not get approved.
- Clearer signal on what evidence gaps remain for a therapy to reach the market.
For sponsors
- Public CRLs can immediately affect company valuation and partnerships.
- Messaging must be accurate and aligned with the publicly posted letter.
- Programs with known CMC or trial‑design risks may face tougher scrutiny from investors and investigators.
For investors and media
- Access to the primary document reduces reliance on selective company statements.
- Enables more consistent comparisons across applications and therapeutic areas.
What we are seeing in the letters
Although each application is unique, recurring themes include:
- Manufacturing and quality deficiencies such as process control, stability, and facility observations.
- Clinical evidence gaps including lack of robust pivotal data or failure on key endpoints.
- Statistical and data‑integrity issues such as missing data plans or invalidated analysis.
- Labeling and risk‑management questions that require additional study or REMS changes.
Recent High Profile CRLS includes
In the latest batch of 89 publicly released CRLs, the FDA highlighted several high-profile denials that underscored both clinical and manufacturing concerns. Notable among them
- Replimune – RP1 (vusolimogene oderparepvec) + nivolumab for advanced melanoma; trial heterogeneity and confirmatory study design issues
- Capricor Therapeutics – Deramiocel for Duchenne muscular dystrophy–related cardiomyopathy; insufficient clinical evidence
- Ultragenyx – Gene therapy for Sanfilippo syndrome type A; manufacturing deficiencies
Glossary
- CRL: Complete Response Letter. A formal notification that an application is not approvable in its current form. It lists deficiencies and may suggest paths to resolution.
- CMC: Chemistry, Manufacturing and Controls. The set of data and processes that ensure product quality and consistency.
- NDA/BLA: New Drug Application / Biologics License Application.
- REMS: Risk Evaluation and Mitigation Strategy.
Quick summary:
FDA will begin publishing future Complete Response Letters (CRLs) shortly after issuing them to sponsors, framing this as a shift toward “radical transparency.” On the same day, the agency posted an additional batch of previously unpublished CRLs.
Earlier this summer, FDA published more than 200 historical CRLs and launched a centralized, searchable database; analyses of that tranche showed a large share of rejections tied to manufacturing and quality issues.
In the new update (Sep 4, 2025), FDA said it released 80+ more letters and will move to near real-time posting going forward. Trade coverage highlighted examples like Replimune to illustrate what the public letters look like.
References
FDA Announces Real-Time Release of Complete Response Letters, Posts Previously Unpublished Batch of 89, 04 September 2025, https://www.fda.gov/news-events/press-announcements/fda-announces-real-time-release-complete-response-letters-posts-previously-unpublished-batch-89
FDA Embraces Radical Transparency by Publishing Complete Response Letters, 10 July 2025, https://www.fda.gov/news-events/press-announcements/fda-embraces-radical-transparency-publishing-complete-response-letters
CRLs made public: What FDA’s new policy means for the drug industry, 11 August 2025, DLA Piper, https://www.dlapiper.com/en/insights/publications/2025/08/crls-made-public
FDA moves to publish drug rejection letters in real time, releases new batch including Replimune’s high profile snub, 04 September 2025, Fierce Biotech, https://www.fiercebiotech.com/biotech/fda-announces-plan-publish-drug-rejection-letters-real-time-releases-new-batch-including