Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States: A comparative study of accelerated approvals

Abstract

Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross-sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug-indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.

FIGURE 1

Flowchart of the regulatory status of cancer accelerated approvals in the European Union (EU) and Japan that were approved via the Food and Drug Administration (FDA's) accelerated approval pathway but subsequently withdrawn by the FDA. * Among the eight indications applied for two were through CMA pathway. One of the approved indications through CMA were withdrawn subsequently based on the result of the confirmatory trial (olaratumab for soft tissue sarcoma). ^†“Rejected” means that the sponsor's application was rejected by the regulatory authority. ^‡“Withdrawn” means that after the initial CMA, the market authorization was withdrawn by the regulatory authority.

FIGURE 2

Timeline of cancer accelerated approvals and subsequent withdrawals from the US market, and key regulatory events in the European Union (EU) and Japan. Fifteen cancer accelerated approvals that were withdrawn by the FDA and for which marketing authorization was sought either in the EU or Japan, or both regions. (a) EU. (b) Japan. AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; FAP, familial adenomatous polyposis; FL, follicular lymphoma; MM, multiple myeloma; NSCLC, non‐small cell lung cancer; PDL1, programmed death‐ligand 1; PTCL, peripheral T‐cell lymphoma; R/R, relapsed or refractory; TNBC, triple‐negative breast cancer; UC, urothelial carcinoma.