Pragmatic Randomized Clinical Trials: A Proposal to Enhance Evaluation of New Cancer Therapies with Early Signs of Exceptional Activity.

An analysis of oncology regulatory approvals since 2011 reveals that several new drugs demonstrate exceptional clinical activity in Phase 1 or Phase 2 trials. This has led to increased use of regulatory mechanisms that allow initial approval based on these early data. However, full regulatory approval is contingent upon subsequent verification of clinical benefit in confirmatory Phase 3 randomized controlled trials.There has been a growing interest in the systematic collection of real-world data to gain further insight into the impact of new drugs as they are introduced into clinical practice. Furthermore, payers, physicians, and patients increasingly require more data on alternative comparators, specific subgroups, patient-reported outcomes, and long-term toxicities – data that may be more appropriately collected in real-world studies than in separate confirmatory trials.We propose that for oncology drugs that demonstrate "exceptional activity" in early trials and receive accelerated/conditional approval and/or Breakthrough Therapy Designation, and for certain expanded indications, regulatory authorities should consider accepting data from prospectivelyagreed pragmatic randomized clinical trials (pRCTs) to grant full regulatory approval. The "exceptional activity" would be defined as (1) an objective response rate ≥50% to a single agent or (2) a hazard ratio of <0.5 in an early randomized study. In pRCTs, patients would be randomized to two or more interventions and then treated and followed up according to the investigators’ usual practice. Patients participating in pRCTs would be representative of the real-world population. pRCTs would provide data necessary for full regulatory approval and would address questions of the new drug’s value for reimbursement purposes.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

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