FDA publishes 200 complete response letters in transparency effort

The US Food and Drug Administration (FDA) on Thursday published more than 200 complete response letters (CRLs) sent to drugmakers outlining the reasons for their products’ rejections in a centralized database. All of the letters pertain to products that were later approved, and most of the letters were previously published by FDA as part of each respective drug’s approval package.

The letters are now available on the agency’s openFDA resource; previously, the published letters were only available by navigating to a specific drug in the agency’s Drugs@FDA database and viewing the review documentation for that product. In a press release, FDA said the move is part of its embrace of “radical transparency,” and said it plans to publish additional CRLs in the future.

The agency primarily issues CRLs due to concerns about safety and efficacy, manufacturing deficiencies, and bioequivalence issues. CRLs outline these concerns and often include recommendations for addressing them. When the FDA issues a CRL, it indicates that sponsors must resolve the deficiencies listed in the letter before the product can receive approval.

Transparency advocates and researchers have long argued that complete response letters should be made public; however, it has been up to companies to disclose the reasons for their applications being rejected.

“For far too long, drug developers have been playing a guessing game when navigating the FDA,” said FDA Commissioner Marty Makary in a press release. The press release went on to say that “sponsors often misrepresent the rationale behind FDA’s decision to their stakeholders and the public.”

The agency referenced a 2015 analysis conducted by FDA staff, which revealed that 85% of companies did not mention safety and efficacy concerns in their communications about a CRL to investors. The agency also noted that when it mandates a new clinical trial to address safety or efficacy issues, this information goes undisclosed approximately 40% of the time.

The agency said the CRLs were issued in response to applications submitted for the approval of drugs or biological products between 2020 and 2024. However, Focus observed applications dating back to 2007 when reviewing the documents.

The archive includes letters issued to major pharmaceutical and biotech companies, such as Mylan Pharmaceuticals, which merged with Pfizer's Upjohn to form Viatris in 2020, as well as Sun Pharmaceutical Industries and Novo Nordisk, down to smaller pharmaceuticals and biotech companies.

FDA claimed that “by making the CRLs available, the public now has significantly greater insight into the FDA’s decision-making and the most common deficiencies cited that sponsors must address before their application is approved.”

“Lessons learned from non-approvals are also not shared within the industry, leading companies to repeatedly make similar mistakes,” the agency said.

According to an analysis by Avalere Health, in the 2018–2022 cycle of Prescription Drug User Fee Act (PDUFA), 37% of drugs and biologics received a CRL.

The idea of releasing CRLs is not new. In 2019, former FDA commissioner Scott Gottlieb explored making summaries of these CRLs public but then scuttled the idea. (RELATED: Time for FDA to Release Complete Response Letters? Debate Reignites, Regulatory Focus 23 August 2019)

Members of academia have also urged the FDA to be more transparent in its reasons for rejecting applications. In a 2018 article published in JAMA Internal Medicine, researchers explained how there’s a public health rationale for publicly disclosing CRLs. (RELATED: Viewpoint: FDA Should Release CRLs and Clinical Study Reports, Regulatory Focus 3 July 2018)

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FDA publishes 200 complete response letters in transparency effort

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