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The randomised trial a company must run after an accelerated approval to prove the drug really helps patients live longer or better. If it fails or never finishes, the approval is supposed to be withdrawn.
Accelerated approvals rest on surrogate endpoints (response rate, pCR, MRD) from single-arm or early trials; the confirmatory trial tests overall survival, progression-free survival or another clinical benefit against a control. The 2022 FDORA law lets the FDA require the confirmatory trial to be under way at approval and streamlines withdrawal when it fails. Notable failures and withdrawals include PI3K inhibitors in lymphoma, several checkpoint-inhibitor indications ('dangling approvals' reviewed by ODAC in 2021), and melphalan flufenamide. Regulators increasingly scrutinise whether the confirmatory population matches the accelerated one (STARGLO complete response letter).
Shares Complete response letter (CRL), FDORA 2022 accelerated approval reforms, Indication withdrawal.
Shares Trial lifecycle: from protocol to label, Why trials fail: underpowered, wrong endpoint, control arm drift, subgroup fishing, crossover, Phase 1, 2 and 3 trials, KEYNOTE-522.
Shares Japan conditional early approval and time-limited approval, Conditional marketing authorisation (EU), Accelerated approval.
Shares Full (traditional, regular) approval, Trial lifecycle: from protocol to label, Accelerated approval.
Shares Complete response letter (CRL), Full (traditional, regular) approval, Trial lifecycle: from protocol to label, Pivotal (registrational) trial.
Shares Complete response letter (CRL), Japan conditional early approval and time-limited approval, Conditional marketing authorisation (EU), Trial lifecycle: from protocol to label.
Shares Full (traditional, regular) approval, Conditional marketing authorisation (EU), Indication withdrawal, Accelerated approval.
Shares Trial lifecycle: from protocol to label, Why trials fail: underpowered, wrong endpoint, control arm drift, subgroup fishing, crossover, Phase 1, 2 and 3 trials, KEYNOTE-522.