Abstract
Randomized controlled trials (RCTs) that assess overall survival are considered the “gold standard” when evaluating the efficacy and safety of a new oncology intervention. However, single-arm trials that use surrogate endpoints (e.g., objective response rate or duration of response) to evaluate clinical benefit have become the basis for accelerated or breakthrough regulatory approval of precision oncology drugs for cases where the target and research populations are relatively small. Interpretation of efficacy in single-arm trials can be challenging because such studies lack a standard-of-care comparator arm. Although an external control group can be based on data from other clinical trials, using an external control group based on data collected outside of a trial may not only offer an alternative to both RCTs and uncontrolled single-arm trials, but it may also help improve decision-making by study sponsors or regulatory authorities. Hence, leveraging real-world data (RWD) to construct external control arms in clinical trials that investigate the efficacy and safety of drug interventions in oncology has become a topic of interest. Herein, we review the benefits and challenges associated with the use of RWD to construct external control groups, and the relevance of RWD to early oncology drug development.
Highlights
Randomized controlled trials (RCTs) are considered the most reliable study method for providing data on the effects of a therapeutic intervention [1]
This review considers the use of external controls as a comparator arm to clinical trials, and we consider the relevance and limitations of real-world data (RWD)-based external controls in early oncology drug development
When designing a singlearm phase Ib expansion study in a specific population, an external control group could be constructed from RWD in the same population to create a real-world benchmark and to provide objective thresholds for deciding whether to advance or stop the development of drug candidates based on the eventual study result observed
Summary
Randomized controlled trials (RCTs) are considered the most reliable study method for providing data on the effects of a therapeutic intervention [1]. One example is the approval of blinatumomab (Blincyto) by the FDA for relapsed/refractory acute lymphoblastic leukemia in 2014 (described in case 2 below) [23] In this case, the single-arm trial of blinatumomab was supported by historical control group data that were extracted from chart review of patients from US and European study sites who were treated with standard-of-care salvage chemotherapy [23, 24]. The FDA granted lutetium Lu 177 dotatate (a radiolabeled somatostatin analog) orphan drug designation for the treatment of somatostatin receptor-positive (SSTR-positive) gastroenteropancreatic neuroendocrine tumors on the basis of data from a randomized, open-label, active controlled trial (NETTER-1) and supporting RWE from a retrospective, investigator-sponsored, open-label, single-arm, expanded access study (ERASMUS) of patients with SSTR-positive neuroendocring tumors [22, 25]. Other regulatory agencies, such as the European Medicines Agency (EMA) and Japanese Pharmaceuticals Medical Devices Agency (PMDA), have expressed interest in using RWD to support regulatory decisions or postmarketing obligations [27,28,29]
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