The R&D of innovative drugs is characterized within the sector as an odyssey "towards vitality from the verge of demise," attributable to the substantial financial requisites, protracted development durations, and elevated incidence of failure. The minority that secure endorsement from global regulatory bodies indeed epitomize rarity. Nonetheless, certain entities, despite securing initial authorization, may witness their approvals rescinded if their post-market performance is suboptimal, if they fail to fulfill the regulatory mandates for subsequent research undertakings, or if the research outcomes are deemed deficient. This document endeavors to compile and elucidate data pertaining to instances where the U.S. FDA, in recent years, has rescinded market approval for pharmaceuticals previously sanctioned.
Part One: The Sombre Chronicle of Pepaxto's Endorsement and Subsequent Market Withdrawal
On February 23, 2024, the FDA disseminated its conclusive verdict to retract the authorization of Pepaxto (melphalan flufenamide). This pronouncement, articulated by Peter Marks, the Director of the FDA's CBER, signifies the inaugural application of the 2023 amended accelerated approval revocation process, as stipulated in the Food and Drug Omnibus Reform Act of 2022 (FDORA). The rationale for the market withdrawal of Pepaxto encompasses: (1) the failure of the confirmatory study, mandated as a condition of the accelerated approval, to corroborate Pepaxto's clinical advantage, and (2) the prevailing evidence indicating that Pepaxto has not been substantiated as safe or efficacious under its prescribed conditions of utilization (Figure 1).
The Withdrawal Process of Pepaxto
Pepaxto, a product of Oncopeptides' innovation targeting aminopeptidase and heralded as the FDA's inaugural endorsement of an anticancer peptide-drug conjugate (PDC), was accorded accelerated approval on February 26, 2021. It was intended for usage in tandem with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (R/R MM). Concurrent with its approval, the FDA mandated Oncopeptides to execute a confirmatory Phase III OCEAN trial. Subsequent to this, the OCEAN trial elucidated disheartening findings, not achieving the clinical endpoint for overall survival (OS) and recording a higher mortality rate in the Pepaxto treatment group as opposed to the control group (overall survival hazard ratio of 1.104). Consequently, the FDA suspended the trial of Pepaxto, issued a safety notification, and resolved to convene a session of the Oncologic Drugs Advisory Committee (ODAC) on October 28, 2021, for the evaluation of Pepaxto's safety profile.
Prior to the assembly of the FDA's expert panel, Oncopeptides announced on October 22, 2021, its volitional withdrawal of Pepaxto from the market. Nevertheless, in January 2022, Oncopeptides retracted its market withdrawal application for Pepaxto, with intentions to "engage in close dialogue with the FDA and reassess the clinical data." Despite these efforts, the American regulatory authority did not align with Oncopeptides' renewed analysis, maintaining that Pepaxto required further evaluation. On July 20, 2022, the FDA once more convened the ODAC to deliberate on the benefit/risk assessment of Pepaxto.
Adhering to the advisory panel's counsel, the FDA officially decreed the revocation of accelerated approval for Pepaxto on December 7, 2022, thus forbidding its commercial distribution. In August 2023, Oncopeptides lodged an appeal against the FDA's decision to withdraw. The decree issued on February 23 is the FDA's response to this appeal. In accordance with the revised protocols for accelerated approval revocation, the FDA issued to Oncopeptides a notice of intended withdrawal, an explanation thereof, an opportunity for a hearing, and a provision for submitting a written appeal to the Commissioner (or an appointed delegate). Following the submission of a written appeal, Oncopeptides engaged in a consultation with an appointed delegate of the Commissioner.
Part Two: Narratives of Pharmaceuticals Accorded Authorization Subsequently Revoked in the United States Market
The Accelerated Approval (AA) protocol was inaugurated by the FDA in 1992, primarily to address the exigencies of the HIV/AIDS pandemic. Post its codification wi...
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