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Trial Does Not Meet the Primary Endpoint? No Worries, FDA Still Might Approve
(Thursday, April 6, 2023) About 10% of new drugs approved by the FDA between 2018-2021 failed their primary endpoints in one of more pivotal clinical trial but were still approved based on success in at least 1 other pivotal study, positive findings from secondary or exploratory end points in the pivotal study, or favorable post hoc analysis. Before we jump to conclusions, it is important to review the fine print of these approval decisions by the FDA. Approval of a new drug should be based on the unambiguous conclusion of the benefit over risk as determined independently by the FDA. But many times, it is not easy to address the ambiguity. In those cases, the regulators need to rely on alternate logic. A generic analysis of the publicly available information on FDA’s rationale for the approval decision shows that all the 21 drugs approved in such fashion were unique drugs indicated either for rare diseases or diseases with no or severely inadequate treatment options. There was no significant regulatory trend. Just like all drugs approved by the FDA, about half of these 21 drugs were orphan designated, about two-thirds had expedited approval designations, and about half were first-in-class. Interestingly, only 2 of the 21 drugs approved with limited or alternate data were designed as breakthrough therapies indicating that most of these drugs did not exhibit early preliminary clinical data for benefit. Also, these were spread over multiple therapeutic areas indicating that this FDA practice is wide-spread across the agency and is an agency-wide policy and not an exception. This is good and bad. It is good because it indicates flexibility to review the wholistic picture of benefits of a drug rather than basing the outcome on one or few studies. That FDA can consider secondary endpoints, surrogate markers, and post-hoc analysis for a positive decision, should be heartening to the sponsors fretting over a trial considered failed due to the primary endpoints. Also, it would be encouraging for the sponsors that FDA can lower the weight of the data from a clinical trial if there are other trials with positive outcomes. But it also indicates the subjectivity of the regulatory process whereby FDA makes decisions based on less defined parameters on a case-by-case basis. Such non-transparency on FDA’s part creates controversy about its decisions and the related lack of trust in FDA by the patients and physicians. In some cases, such as that for the Alzheimer’s drug Aduhelm, the payors decided to either not cover the FDA approved drug or put strict limitations on the coverage. It is a tough no-win situation for the FDA where it has been trying to be more flexible for certain situations than others, apparently swayed by the patients’ perspectives, but at the same time creating negative publicity for the products it approved. Sponsors should be prepared to deal with this ambiguity of the regulatory review process, but the final outcome is not guaranteed. 
AUTHOR
Dr. Mukesh Kumar Founder & CEO, FDAMap Email: [email protected] Linkedin: Mukesh Kumar, PhD, RAC Instagram: mukeshkumarrac Twitter: @FDA_MAP Youtube: MukeshKumarFDAMap |
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