FDA Publishes 200+ Complete Response Letters in Historic Transparency Shift
The letters published on Thursday were issued in response to applications the FDA had received between 2020 and 2024. It said it's in the process of sharing additional letters.
The FDA made a groundbreaking move on July 10 by publishing over 200 Complete Response Letters (CRLs) in a centralized database on openFDA.
Read the news release here.
Most of these letters, which detail why the FDA rejected drug and biological product applications, were issued between 2020 and 2024 and relate to products that were eventually approved.
Following FDA review, a new drug application (NDA) or biologics license application (BLA) that does not meet statutory or regulatory standards for approval is issued a CRL, noting the deficiencies that preclude approval. These deficiencies can range from safety concerns and inadequate efficacy data to manufacturing or bioequivalence problems.
The FDA historically has not released CRLs at the time of issuance, instead publishing them as part of the approval package made publicly available after NDA or BLA approval. Many sponsors have historically kept these letters confidential, sometimes misrepresenting the reasons for rejection to stakeholders.
Why now?
The FDA's decision to publish these CRLs is characterized as part of Commissioner Makary's promise of "radical transparency" regarding approvals of drugs and biologics (and decisions not to approve). Commissioner Makary stated: "For far too long, drug developers have been playing a guessing game when navigating the FDA."
The numbers behind the decision
The FDA cited a few statistics that drove this transparency initiative:
According to a 2015 analysis conducted by FDA researchers, sponsors avoided mentioning 85% of the FDA's concerns about safety and efficacy when announcing publicly that their application was not approved.
When the FDA calls for a new clinical trial for safety or efficacy, that critical information is not disclosed approximately 40% of the time.
According to Avalere Health analysis, in the 2018–2022 cycle of the Prescription Drug User Fee Act (PDUFA), 37% of drugs and biologics received a CRL.
What's actually in the database
The published letters include:
CRLs for major pharmaceutical companies.
Some letters date back to at least 2007, despite the FDA's statement about the 2020-2024 timeframe.
The published CRLs all relate to since-approved applications, according to the FDA, and "were redacted for trade secrets and confidential commercial information."
Notable discrepancies
Several news outlets have noted inconsistencies:
Again, while the FDA stated the letters were from applications between 2020 and 2024, reporters found letters dating back to 2007.
A 2008 rejection for Kyowa Kirin's istradefylline—now sold as Nourianz—for Parkinson's disease "off" episodes was included, though the drug wasn't approved until 2019.
Many letters contain extensive redactions, with some covering multiple paragraphs.
Industry concerns and legal questions
The FDA's press release sheds no light on how the agency made determinations regarding redactions of "trade secrets and confidential commercial information." This raises several concerns. Even redacted, a CRL can contain hints, or even details, about an applicant's internal decision-making, intellectual property strategy, or technological hurdles. It’s not clear how or whether the FDA consulted with applicants in making the redactions and publishing the CRLs, or whether applicants will agree that their confidential information has been properly protected.
Potential litigation risks
Legal experts are already anticipating challenges. Health policy lawyer Paul Kim said "The policy justification that (the) FDA is offering will invite challenge by one or more sponsors (applicant companies) or possibly a trade association."
There may also be challenges raised about the adequacy of the FOIA staff's review and redaction of the CRLs.
We may also see an uptick in securities litigation brought by investors alleging information in the CRLs does not line up with previous company statements, or in product liability suits using newly disclosed information.
What this may mean going forward
A few things to start thinking about—both short- and long-term here:
More scrutiny of public comms: Companies will need to be more careful and transparent when communicating about CRLs to investors and the public, knowing that the FDA may eventually release the actual letters.
Competitive intel concerns: There’s considerable risk that third parties could use these breadcrumbs to advance their own interests, from companies developing competing products to shareholders or product liability plaintiffs seeking to bolster litigation claims against the sponsor.
Learning opportunities: The FDA hopes that "Lessons learned from non-approvals" will be shared within the industry, potentially reducing repeated mistakes and speeding up the approval process.
More coming: Calling this release an "initial batch," the FDA said it "is in the process of publishing additional CRLs from its archives." This suggests more releases are coming.
Standardization questions: Whether the FDA will standardize its redaction process and provide guidance to industry on what the agency plans to disclose moving forward remains unclear.
AI integration: It's also unclear whether the FDA employed the Elsa tool in publishing the CRLs or redacting information, and if Elsa will play a role in this process moving forward. The agency's new AI tool, Elsa, could potentially streamline future disclosures.
Strategic planning changes: Companies may need to:
Revise their regulatory submission strategies, knowing that deficiencies may become public.
Strengthen their crisis communication plans for when CRLs are issued.
Consider the long-term public disclosure implications when crafting responses to FDA feedback.
Implement more robust intellectual property protection strategies in their submissions.
Investor relations impact: Piper Sandler analyst Biren Amin said that the letters could help investors gain better insights into the FDA's review process. This could lead to more informed markets but also more pressure on companies to be transparent from the outset.
The bottom line
This move is a big shift in FDA transparency that will likely reshape how pharma companies approach both regulatory submissions and public communications. While the stated goal is to improve predictability and speed drug development, the industry must now navigate new challenges around confidentiality, competitive intelligence, and litigation risk.
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