Increasingly regulatory approval for novel agents is sought following early phase single-arm trials. However, many countries’ governmental agencies require value assessment of new agents to determine reimbursement. The ESMO-MCBS provides an evaluation framework based on treatment efficacy, response duration, adverse events, quality of life, and phase 4 data scored from 1-5 with scores >4 indicating substantial benefit worthy of reimbursement.
INDs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2010 and April 2022 based on single-arm early phase 1 and/or 2 trials were reviewed. INDs were assessed using form 3 of the ESMO-MCBS from published data available at time of approval.
Among 94 approved IND, 34 (36%) were approved based on single arm trial data. INDs were 23 ( 68% ) targeted kinase inhibitors, 4 (12%) antibody directed cytotoxics, 5 (15%) immunotherapeutics, and 2 (6%) other. Alectinib, sonidegib, and crizotinib were the only INDs to meet the threshold for substantial benefit at the time of FDA/EMA approval (score=4). Whereas 12 (34%) had scores of 0 to 2 and the majority (n=19; 56%) had scores of 3. Results of patient reported outcomes (n=6; 17%) were uncommon at time of approval and only 1 (16%) illustrated an improved quality of life. 14/19 (74%) INDs which had published later phase trials achieved ESMO-MBCS score >4 subsequently in controlled studies. 28 of 34 FDA approved INDs (82%) were also approved by EMA. EMA approvals followed FDA approvals at a median of 10 months (range: 0 to 24). FDA and EMA approved INDs had median score of 3.0 vs 2.5 for INDs approved by FDA alone (p=0.5). 44% of INDs (n=15) provided a meaningful benefit with duration of response >12 months (n=9) and/or objective response rate >50% (n=12).
Only 3 early phase approvals met threshold for substantial benefit by ESMO-MBCS criteria despite clinical benefits seen in >40% of patents with INDs. Revision and recalibration of ESMO-MCBS is warranted to match the desires of patients, oncologists, and their governmental organizations to license effective drugs from early phase studies.
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V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/ Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to conduct Clinical trial: Eli Lilly/Loxo Oncology, Blueprint medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/ Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, Takeda; Financial Interests, Institutional, Invited Speaker, Research funding to conduct clinical trial: Shasqi; Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, I receive research funding from NCI: National Cancer Institute, USA. All other authors have declared no conflicts of interest.