Accelerated approval is a privilege that every applicant desires. Not only can you expedite market entry, but you can also temporarily bypass the time-consuming process of obtaining data for conventional endpoints by leveraging surrogate endpoints to achieve this goal. Once it goes on the market, it means that R&D investment can be recovered, regardless of whether the drug is really effective and safe. As for when to submit post-marketing confirmatory research data, you only need to make a time commitment to FDA, and then you can take your time to make money by listing your products while collecting data for the FDA to see. What should be done in case of exceeding the time limit? You can apply for an extension and continue working. After all, this drug may already have a large patient population, especially for those indications with no other options, and the FDA is likely to be in a dilemma because of its fear of harming the patient. For example, the cancer drug Folotyn (Pralatrexate) received accelerated approval from FDA 15 years ago for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL), but 15 years later, FDA still has no conclusive evidence for the effectiveness of this expensive drug. What's more, Folotyn has changed hands several times in the post-marketing process, but the data is still pending. And its previous and current owners have pushed back deadlines for post-marketing research at least 10 times. According to GoodRx, the annual cost of Folotyn is approximately USD 900,000, and the drug has undergone four price increases since January 2022. And such examples are everywhere in the United States.
But that is a bygone era of yore. The FDA has woken up.
On December 29, 2022, President Biden signed the Consolidated Appropriations Act, 2023, which includes the Food and Drug Omnibus Reform Act (FDORA). In the face of certain developers employing stalling tactics in the post-marketing confirmatory research, two provisions of the newly enacted FDORA law warrant attention. First, FDA is allowed to require pharmaceutical companies to conduct confirmatory research at the same time as obtaining accelerated approval. Otherwise, FDA will have the power to reject the application even if the data is perfect. Regeneron became the first "tester" of this regulation. On March 25, 2024, Regeneron's two applications for CD20xCD3 bispecific antibody odronextamab for relapsed/refractory follicular lymphoma (FL) and relapsed/refractory diffuse large B-cell lymphoma (DLBCL) were rejected by FDA. The issues emphasized in the FDA's complete response letter regarding the confirmatory research of odronextamab do not pertain to efficacy and safety, clinical design, or CMC. Rather, the concern lies in the timeline of the confirmatory tests for odrone xtamab, which did not demonstrate that the confirmatory research was "underway" concurrently with its sBLA application. The CRL received by Regeneron may be the first time in the history of FDA to be issued due to "post-marketing research timetable issues". This phenomenon clearly sent a signal that FDA was tightening its accelerated approval regulatory policy, and also verified the previous commitment of Richard Pazdur, director of FDA's Oncology Center of Excellence, to take a tougher stance on the confirmatory test requirements for new anti-cancer drugs before accelerated approval.
The second major power granted to FDA by FDORA is to simplify the withdrawal procedure, allowing it to withdraw approval directly without holding a public hearing. The first to try this approach was Oncopeptides' multiple myeloma drug Pepaxto (Melphalan flufenamide). Pepaxto received accelerated approval from FDA on February 26, 2021. After confirming the new test, FDA voted (14: 2) against the drug's benefit-risk profile at an advisory committee meeting in September 2022. In July 2023, FDA proposed that Oncopeptides withdraw its drug from the market of the United States. In August, Oncopeptides appealed the FDA's fast withdrawal proposal. In February 2024, FDA officially withdrew its accelerated approval decision for Pepaxto. FDA took7 months from the proposed withdrawal to the formal withdrawal, setting a record for the ...
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