Since the FDA began publishing its rejections of drug approval filings in July last year, companies have become more forthcoming about the details of agency decisions in their own disclosures, according to biopharma and regulatory analysts.
More than a year into the FDA’s “radical transparency” agenda, experts say the decision to publish complete response letters has led to a shift in how companies communicate regulatory rejections. The policy has reduced the scope for companies’ explanations to diverge from the agency’s position, analysts report; yet gaps remain as redactions and the ongoing privacy of meeting minutes cut observers off from a key resource.
“Portions of the CRLs can be redacted, which could lead to some amount of varying interpretation of the information provided,” TD Cowen analyst Joe Thome told BioSpace via email.
Last July, the agency published more than 200 complete response letters (CRLs) covering approval applications submitted from 2020 to 2024. The FDA has continued to add to two repositories of rejection letters, one for drugs that are now approved and another for products that have yet to come to market. Officials have shared archived CRLs reaching as far back as the FDA’s 2002 rejection of depression drug gepirone, which Fabre-Kramer ultimately won approval for in 2023. The FDA has also published recent rejections, including its February dismissal of Disc Medicine’s request for authorization.
The archived CRLs offered a closer look at historical FDA rejections and issues around clinical trial conduct, safety and efficacy and manufacturing that can sink filings. For analysts, such as TD Cowen’s Ritu Baral, the recent CRLs have made a bigger impact by ending their reliance on sponsors for details of FDA rejections.
“The reception from the investment community has been unanimously positive,” Baral told BioSpace. “Frankly, I think it brings a level of accountability and professionalism to a sector that is far from mature. There are smaller companies with less experienced management teams, and this gives communication some guardrails.”
Preventing misrepresentation
Lacking the guardrails provided by public CRLs, biotechs could previously provide incomplete or misleading pictures of why the FDA rejected their medicines without fear of contradiction, Baral said. She recounted a company that, in the era when CRLs were private, kept insisting that it needed more clarity on what the FDA wanted and why its drug was rejected.
The meeting minutes and CRL told another story when Baral managed to get hold of them, revealing that the FDA’s position was clear and consistent across the files. The reasons for the rejection were never disclosed to the investment community, Baral said.
Baral’s anecdote is consistent with a 2015 analysis by the FDA, which found companies frequently failed to disclose the agency’s concerns and requests for new clinical trials. Based on the study, the FDA said sponsors often misrepresent the rationale for rejections.
Today, a company that misrepresented the FDA’s rationale would quickly be contradicted by the CRL’s release on the agency’s openFDA server. While Baral has yet to see a formal quantitative analysis of the impact of the new publication policy, she said her personal feeling is that companies are providing more details in their disclosures about FDA rejections.
Disc, for example, published its CRL alongside its announcement of the rejection of rare disease drug bitopertin in February. Disc’s transparency diverged from how biotechs have typically handled CRL disclosures in the past, Thome said.
Disc CEO John Quisel appears to be in favor of the new policy.
“It’s remarkable, actually, to see this level of transparency,” he said during a February call with investors regarding the CRL. “I think it’s a new standard in the availability of these complete response letters to the public, and we’re actually proud to be part of that.”
Thome said the release of CRLs has been particularly useful where there is “a less well-trodden approval path to understand how the agencies and companies work together to define a clinical package and regulatory path.”
Protecting IP
Currently, the FDA redacts public CRLs, which leaves wiggle room for companies planning their communications around rejections. Thome also noted cases of the FDA changing regulatory policy, particularly over the past 12 months. When that happens, Thome said a CRL might fail to fully encapsulate years of agency interactions and communications.
Some of the interactions are documented in the minutes of meetings between drug developers and the FDA, but those documents remain private. Baral said companies are “completely loath to publicly release meeting minutes.” The reticence reflects their belief that details such as how they pose questions to the FDA and the feedback they receive are “extremely proprietary,” she said.
Such concerns echo the historical debate about CRL transparency. When the FDA proposed publishing rejection letters in 2010, Bausch+Lomb warned that the policy could jeopardize innovative research by revealing confidential information about clinical trial design. On the other hand, some companies were already more open to sharing CRLs, with GSK voicing qualified support for the policy. GSK issued a caveat, however: that its support was “contingent upon continued strong protection from disclosure of discrete information when such disclosure truly would cause substantial harm to the sponsor’s competitive position.”
While there is a long history of resistance to CRL transparency, regulatory consultant Steven Grossman said he sees no reason why the policy will or should be a long-term issue for companies or the FDA now that the agency is publishing the letters. Rather, Grossman told BioSpace via email that he expects all parties to adapt quickly to the new normal.
“Knowing that CRLs will become public, companies will start writing their submissions differently. In turn, [the] FDA, knowing their CRLs will become public, will be writing them differently,” Grossman said. “There may be a mismatch in the short term, but an equilibrium will be achieved in the mid- to long-term. Two years from now, stakeholders will have forgotten why they thought this was a big deal.”
