September 12, 2023
Docket No. FDA-2023-D-0559
We appreciate the opportunity to comment on the Food and Drug Administration (FDA) proposed guidance: Postmarketing Studies and Clinical Trials: Determining Good Cause for Noncompliance with Section 505(o)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act Guidance for Industry.
We are a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
Noncompliance with required post-market studies (PMRs) is a serious problem that undermines FDA’s authority and the public trust in FDA decision-making. We support FDA’s efforts to ensure clarity and transparency regarding situations when noncompliance with postmarket requirements is acceptable. These situations should be rare; the more exceptions that are made, the more noncompliance becomes harmful to patients and unfair to companies that comply.
The PMRs that are the focus of this draft guidance are typically required following adverse events that have been reported to the FDA resulting in a serious enough event to warrant further examination into the safety and effectiveness of the drug. Any delay in this process places patients at undue risk and it is FDA’s responsibility to ensure that applicants avoid delays.
We understand this guidance document is specifically referencing non-compliance of PMRs which are not required as a condition of accelerated approval. However, we strongly recommend issuing similar guidance for applicants using this pathway.
We agree that applicants should continue to report regular updates to the FDA throughout the completion of the PMRs. The timelines and milestones established are agreed to by both the applicant and the FDA and should be adhered to. We appreciate the detail provided by FDA in the draft guidance stressing the importance of maintaining regular updates and providing multiple opportunities for applicants to inform the agency of missed milestones. These details, along with specific examples of what would or would not be considered good cause for non-compliance, should minimize overall non-compliance with the regulations. Documentation of delays is not sufficient to justify noncompliance, especially if the delays were foreseeable and avoidable and could suggest inadequate efforts to complete the study as was agreed to.
We support the process described in the guidance for applicants to correct circumstances that led to non-compliance with the agreed upon PMRs; however, we urge that the description of the actions taken by the applicant to address these issues be more explicit and less subjective. The guidance document states that the “FDA considers an applicant to have undertaken appropriate action if the applicant promptly develops and implements a reasonable plan to correct the underlying circumstance(s) leading to the PMR noncompliance” (emphasis added). The guidance document describes the term “promptly” as something the FDA will determine on a case-by-case basis. This is too vague; the FDA should clearly define the agency’s standards by providing examples of what could be considered inappropriate delays that will warrant escalation of actions taken by the agency. We also strongly urge that the FDA take into consideration if a company has a track record of delays in satisfying PMRs, regardless of whether the company’s justifications for those delays seem reasonable. The FDA should scrutinize the reasons given to determine if a company’s track record of delays show a pattern of making commitments to the FDA that the company has shown it is unlikely to meet. This would indicate that what might individually seem like justifiable delays may instead be based on a pattern of foreseeable and preventable delays.
As noted above PMRs which are required as a condition of accelerated approval warrant similar guidance. There have been unacceptable delays in postmarket trials for drugs granted accelerated approval status. More than 280 drug applications have been awarded accelerated approval since the program began; at least 100 of those applications still have incomplete confirmatory trials.1 Approximately 35 percent have at least one trial past its original planned completion date.1 A recently published journal article pointed out that Exondys 51, for Duchenne Muscular Dystrophy, was granted accelerated approval in 2016 with the PMR results required in 2020. Instead, that post-market study was not started until 2020 and FDA granted an extension until 2024, while also granting accelerated approval to 3 other drugs made by the same company, none of which have yet submitted their post-market studies.2 As a result of these delays, patients, insurance companies, and the Medicaid program have paid billions of dollars for treatments that have never been proven to work. This is unfair to patients and their families and threatens the financial integrity of Medicaid programs in States that have been subject to these expenses. We strongly urge that the FDA issue guidance about compliance with PMR for drugs granted accelerated approval before the end of 2023.
1.U.S. Department of Health and Human Services: Office of Inspector General. (2022). Delays in Confirmatory Trials for Drug Applications Granted FDA’s Accelerated Approval Raise Concerns. https://oig.hhs.gov/oei/reports/OEI-01-21-00401.asp#:~:text=WHAT%20WE%20FOUND,104%20have%20incomplete%20confirmatory%20trials.
2. Liam Bendicksen, Diana M. Zuckerman, Jerry Avorn, et al. (2023). The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence. Ann Intern Med. doi:10.7326/M23-1073