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EMA Describes Considerations for Single-Arm Studies for Oncology Drugs
(Thursday, April 27, 2023) More than half of the cancer drugs are approved by the FDA based on non-randomized single-arm trials using surrogate endpoints. Also, many drugs for ultra-rare diseases with few or no options are approved based on open-label studies since including a placebo or a standard of care control arm is not feasible or ethical in those trials. However, use of such trials for supporting efficacy claims raises several statistical challenges. The European Medicines Agency (EMA) published a “Reflection Paper” describing the various challenges and proposed solutions to the design and conduct of single-arm open-label trials. The key criteria for the validity of a single-arm study as a pivotal study is the availability of a clear and measurable primary endpoint that is relevant to the patient population and that is based on objective measures. The primary endpoint must be validated in exploratory trials which also form the basis for the sample size calculation. Other critical criteria are the justification for the inclusion and exclusion criteria for the participants, the treatment regimen and dose used in such pivotal trials. Additional to the pivotal trial using single-arm design, sponsors must collect robust alternate supporting information non-clinical studies and exploratory trials. Ideally, the sponsor should conduct more than one pivotal clinical trial with the single-arm design to support reproducibility of the results but as has been evident from the multiple approvals based on one single-arm study, the regulators are willing to accept one trial data if adequately supported. Detailed statistical analysis plans and presentation of complete data adds to the comfort of the regulatory authorities. While double-blind, randomized, controlled clinical trials remain the gold standard for scientific validity of the claims for a new drug, regulators acknowledge that such may not be feasible in the most desperate of cases and they are willing to compromise. While the Reflection Paper represents, the thought process at the EMA, these principles are very true for the FDA as well. 
AUTHOR
Dr. Mukesh Kumar Founder & CEO, FDAMap Email: mkumar@fdamap.com Linkedin: Mukesh Kumar, PhD, RAC Instagram: mukeshkumarrac Twitter: @FDA_MAP Youtube: MukeshKumarFDAMap |
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