FDA regulators have long thought about ways to make Complete Response Letters more transparently available to both the public and industry. Now, interest in developing treatments for COVID-19 as quickly as possible may make that transparency more important than ever before.
By Aaron Badida, JD
Before the FDA can approve a medical product, a company must first submit an application to the agency seeking its approval. For drugs and biologics, these applications are known as New Drug Applications (NDAs) and Biologics License Applications (BLAs), respectively.
Then, the FDA must figure out what to do with that application. Specifically: Is the application worthy of approval, or does it have issues which preclude the FDA from granting an approval decision?
If the FDA decides not to approve a drug, it can broadly take either of two actions. First, the agency may issue a Refuse to File (21 CFR 314.101(d)) notice. A Refuse to File outlines ways in which the application is incomplete, which means that the agency would not have enough information at its disposal to come to an approval decision, regardless of the remaining data. According to a 2017 guidance document on the subject, bases of refusal include issues with the content or format of the application, legal issues, and incomplete applications.
Second, the agency may refuse to approve an application (21 CFR 314.125). This process has changed in the past decade, however. Prior to 2008, the agency issued “approvable” and “not approvable” letters in response to NDAs. Under this design, the agency had two versions of an “approvable” letter—with and without changes—and one “not approvable” letter.
In 2008, to align its processes between CDER and CBER, the FDA migrated to a single type of non-approval response known as a “Complete Response Letter” (CRL) (21 CFR 314.110). While this alignment was helpful for regulators, it unfortunately also served to deprive the public of information about a drug’s chances for approval.
While the outcome of a CRL is the same – an application is not approval – the content and purpose of CRLs vary widely.
The letters may contain the FDA’s assessment of substantive issues on methods of manufacturing, processing or storage issues; inadequate safety and efficacy tests or results; and a lack of evidence of intended effect. According to a British Medical Journal study, CRLs most often are issued regarding issues associated with the efficacy and safety of a drug, and least often about manufacturing and labeling.
Once a company has received a CRL, FDA regulations stipulate that the recipient may request an administrative hearing with the CDER Associate Director of Policy upon receiving a decision not to approve. They can also address the CRL’s findings and resubmit. Resubmissions following the correction of an issue identified in the CRL will trigger a new 2-month review cycle. Resubmissions are categorized into class I and class II resubmissions, with class I submissions requiring a new 2-month review cycle and class II submissions requiring a new 6-month review cycle.
Current Challenges With CRLs
Though the existence of a CRL may be made public by a company, the FDA is limited in what it may share with the public.
“The contents of an approvable letter and a complete response letter are considered proprietary, and the FDA does not divulge the contents of such letters, nor does it issue a press release,” explained Mark Senak, a healthcare consultant and lawyer, in 2008. “Rather, it is in the purview of the sponsoring drug company to release as much information as it wants, with as much specificity as it wishes.”
This secrecy is due to federal law and FDA regulations. The FDA is bound to keep much of the information it obtains in an NDA protected from the public under 21 CFR 20.61. In that regulation, trade secrets are as “any commercially valuable plan, formula, process, or device that is used for the making, preparing, compounding, or processing of trade commodities and that can be said to be the end product of either innovation or substantial effort.”
Even the existence of an NDA is typically kept secret unless the FDA holds an advisory committee meeting to discuss an application. This process primarily exists to allow companies to develop products without fear of their competitors knowing when a new product is likely to launch. However, many drugs—even those developed by private companies—are known based on other public data, such as from ClinicalTrials.gov, patent filings and company statements.
Under current practice, the recipient of a CRL may share the existence of that letter, or even make it public. However, the FDA is not itself permitted to make it publicly available (or at least not without significant redactions).
Public companies must share the existence—but not the content—of CRL letters with shareholders, since the severity of the citation can significantly influence the trajectory of an investment in research, development, testing and manufacturing in the billions. CRLs are a decisional marker and constitute “agency action,” which can affect investor confidence.
Spinning the CRL
The result of this secrecy is that most CRLs are never revealed to the public in any meaningful way. The majority of CRLs remain veiled, depriving the public of potentially useful information.
While certain filings with the SEC are required by law in order to prevent securities fraud, companies maintain the ability to control the public narrative about what the FDA discloses in a CRL. This can often result in a portrayal that is more commercially favorable than it is accurate.
A study of CRLs published in the British Medical Journal compared the full CRLs with press releases by the companies to which the CRLs were issued (the authors, who were FDA staffers, had access to both). The study concluded:
“FDA generally issued complete response letters to sponsors for multiple substantive reasons, most commonly related to safety and/or efficacy deficiencies. In many cases, press releases were not issued in response to those letters and, when they were, omitted most of the statements in the complete response letters. Press releases are incomplete substitutes for the detailed information contained in complete response letters.”
These findings suggest that companies are cherry-picking what to disclose when the FDA doesn’t approve a drug or biologic outright.
Even with high profile drugs that have demonstrated safety and efficacy and are likely to ultimately gain approval, drugmakers can downplay or remain opaque about the contours of the CRL.
For patients (or trial participants) who are following a drug’s progress, CRLs may contain information that can help them make informed decisions about their willingness to try the drug if approved or seek expanded access or right-to-try use prior to the drug’s approval. In the event a once-promising drug begins to seem out of reach due to resubmission delays, patients may also wish to consider other options or wait for a new drug.
For other drug companies, the inability to know what sorts of issues the FDA is flagging—particularly for a type of drug or biologic other companies are developing—can result in inefficiencies, added costs and avoidable delays as developers make the same mistakes as their competitors.
Opening the Blackbox
Recognizing the potential value of sharing this information, in 2018 then-FDA Commissioner Scott Gottlieb committed to evaluating “whether there is a subset of the complete response letters where there are especially important public health reasons to redact and release these letters.” He acknowledged that making every CRL publicly available would be “administratively burdensome,” but saw the value to patient safety and clinical practice.
The exploratory approach was a step back from Gottlieb’s position during confirmation hearings, in which he leaned in favor of making CRLs categorically available. Not much appears to have been changed during Gottlieb’s tenure on this front.
The FDA Transparency Working Group—a collaboration between Yale, Johns Hopkins and Harvard researchers—published a series of similar recommendations in the Journal of Law, Medicine and Ethics. This report specifically advocated for CRL disclosure in the biosimilar industry, highlighting how it could generate an infusion of knowledge and accelerate growth:
“Doing so would permit policymakers, patients, researchers, and others to understand why products were not approved and accelerate learning in the generic industry about key challenges and solutions. It would require redaction by FDA of trade secret information and a corresponding recognition that the Agency would not be disclosing problems related to the manufacturing process.
Biologic products are high-cost products, but can also provide innovative and effective new therapies. The filing of biosimilar licensing applications presents a compelling case for disclosure. Information on FDA’s assessment of biosimilarity will also be valuable for the more rapid development of other biosimilar products. Here, too, it must be recognized that FDA will not disclose information on the manufacturing process, which might be a major reason for non-approval of biosimilars.”
There are several ways in which the FDA could choose to increase the transparency of CRLs if it decided to do so.
One possibility would be an annual summary in which the FDA would offer high-level details and reporting about CRLs issued during a particular year. The FDA has analogs for this approach in its release of quality manufacturing data. While not identifying specific firms or causes for inspection citations, annual summaries give a sense of where systemic problems exist. Annual summaries can also provide aggregate insight into the most common manufacturing issues and locations. The FDA has on occasion done this for other topic areas, including Refuse to File letters for generics drug submission.
A similar approach could be taken to aggregate the causes for issuing a CRL. For example, the Agency could generally outline trends around the primary reason for not granting approval in broad categories like manufacturing issues, safety issues, data integrity problems and more.
The agency could also craft general statements that are publicly available, but that do not violate any confidentiality clauses, or find a method of redaction that would not be too administratively burdensome.
Finally, the agency could issue guidance to help companies avoid common mistakes that lead to CRLs, especially if those mistakes can be quickly remedied and expedite the approvals process. For example, the FDA could issue a Q&A-style guidance with a running list of common issues cited in CRLs, or release case studies of common problems. It has previously made us of the case study model for trial analysis, and has often made use of the Q&A guidance approach.
The agency also could draw from the approach of international regulators, such as the EMA, which issues general insights into why they decided not to approve a drug (e.g., Refusal of Marketing for a drug).
Recipients of the CRL in its current form certainly benefit most from the secrecy, but even incrementally more transparency could help create a broader “culture of quality” in the pharmaceutical industry—an idea which comes up frequently in forward-looking initiatives for improving drug quality manufacturing standards.
CRL Transparency and COVID-19
The use of the CRL can be a barrier to transparency. It benefits the developer in the discrete instance of the refusal to approve a particular product, but potentially at the cost of public health and safety and the accumulation of industry intelligence and experience.
As many companies now begin to enter late-stage testing for products intended to treat or prevent COVID-19, the FDA may begin to see significant interest in the content of those CRLs. Regulators and legislators may therefore feel pressure to reform how information about CRLs are made available to the public, or at least ensure that the public understands the purpose of CRLs.
The risk of CRLs is especially acute given the speed at which companies are seeking market access for their products. Without adequate testing of their products safety or efficacy, and with the potential for concerns about the quality of a product due to its manufacturing, the FDA may have reason not to approve many products.
Consider one potential scenario in which a frontrunner developing a new vaccine receives a CRL, and the sponsor fails to disclose the FDA’s reasoning—or releases a rosier-than-accurate portrayal of the reasons for rejection. Without knowing why a vaccine wasn’t approved, the public could become skeptical about the safety or efficacy of a vaccine—or lose trust in the FDA as an institution.
The agency should consider how a single CRL for a closely watched COVID-19 drug or vaccine could undermine agency credibility and hamper efforts to implement global inoculation programs. At best, the public will be eager to know why a product wasn’t approved. At worst, people could engage in rampant speculation, and lose faith in both the FDA and become less likely to become vaccinated in the future. Public health officials are already deeply concerned about vaccine hesitancy and its impact on managing the pandemic. A nonspecific CRL for a vaccine or therapeutic could exacerbate public distrust and reduce vaccine uptake, rendering immunity less valuable and effective in the long-term fight against the coronavirus pandemic.
Implementing greater transparency need not be particularly burdensome, and the value to consumers, industry and a widespread culture of quality could be significant. But even Gottlieb—who favored greater transparency—found it difficult to disclose additional information about them during his time at the agency’s helm.
Now, FDA Commissioner Stephen Hahn has an opportunity to leverage the concerns hovering around COVID-19 to drive forward significant advances in transparency. The FDA is breaking records for speed, but every efficiency may introduce new opportunities for issues that could lead to an initial refusal to approve. The stakes for safety are extraordinarily high.
Key Documents and Dates
- British Medical Journal: Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study
- American Health and Drug Benefits: Potayto—Potahto? The Meaning of the FDA’s “Complete Response” Letters
- Journal of Law, Medicine and Ethics: Recommendations to Advance the Development of Safe and Effective Medical Products
- FDA Draft Guidance: Refuse to File: NDA and BLA Submissions to CDER Guidance for Industry