Abstract
BACKGROUND: The Food and Drug Administration (FDA)'s Accelerated Approval (AA) pathway has increasingly used to authorize market approval of new drugs amid controversy. The present study aims to inform the most recent data on the strength of clinical evidence supporting such approvals. METHODS: Evidentiary characteristics of pre-approval pivotal clinical studies and regulator-required post-approval confirmatory studies supporting AAs between 2015 and 2022 were extracted from publicly available FDA documents. Descriptive analyses were conducted for each of the characteristic including study design, study phase, primary endpoint, number of participants, and magnitude of effect. Trends of these characteristics over time were documented and accounted for class of drugs, application type, novelty, orphan status, and oncology/non-oncology indications. RESULTS: During 2015-2022, 156 drug-indication pairs received AA. To support these AAs, 77% of pre-approval pivotal trials employed single-arm designs, and 22% were phase I trials, with a median of 92 participants (IQR, 45-125); 61% of post-approval confirmatory studies were required by FDA to use randomized controlled design, 25% to use clinical endpoints, and 33% specified the number of participants requirement. During the 8-year observation period, the pairs approved via AA pathway almost tripled from 20 (2015-2016) to 59 (2019-2020) and fell to 36 (2021-2022); the corresponding proportion to all new drug approvals showed the same trend. Single-arm pre-approval pivotal studies increased from 55% (2015-2016) to 91% (2019-2020) and fell to 69% (2021-2022), while the median number of participants decreased from 106 (2015-2016) to 59 (2019-2020) and rose to 106 (2021-2022). Randomized controlled post-approval confirmatory studies decreased from 75% (2015-2016) to 42% (2019-2020) and rebounded to 75% (2021-2022), while those using surrogate endpoints increased from 50% (2015-2016) to 72% (2021-2022). Analyses adjusting for drug class, application type, novelty, orphan status, and oncology/non-oncology showed similar results. CONCLUSIONS: The number of drug-indication pairs receiving AA increased sharply during 2015-2016 to 2019-2020 but fell in 2021-2022. Meanwhile, the strength of clinical evidence supporting FDA's AAs appeared to decline from 2015 to 2020 but seems to have improved in 2021-2022. Measures should be taken to further improve the strength of evidence in Accelerated Approvals.