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By evaluating published emulations of oncology RCTs studies in which both the active and comparator groups are sourced from RWD and target trial results are available for benchmarking, this systematic review aims to gain insight into factors related to emulation performance. Thirteen oncology emulation studies using various types of RWD were identified through an online database search of PubMed through 2022. Based on the ROBINS-I tool, most studies (N=8) had a serious risk of overall bias driven by risk of bias from confounding. Approximately half of the studies (N=6) fully proxied the RCT entry criteria. Of 11 RWD studies that provided sufficient detail to quantify emulation performance, the emulation HR estimate fell within the 95% CI of the trial estimate in 9 of the studies. There were no clear trends between risk of bias or degree to which the entry criteria were proxied and emulation performance. Findings may have been influenced by publication bias and researcher degrees of freedom, as only one emulation study pre-registered its protocol. Tools for comprehensively characterizing factors that affect emulation performance, including the real-world clinical context as it relates to the RCT research question, are needed to evaluate the feasibility of a RCT emulation.

RESUMEN

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real-world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and regulatory decision making. In the oncology setting, studies leveraging RWD offer distinct advantages that are complementary to randomized controlled trials (RCTs). They also permit the conduct of investigations that may not be possible through prospective designs due to ethics or feasibility. Despite its promise, the use of RWD for the generation of clinical evidence remains controversial due to concerns of unmeasured confounding and other sources of bias that must be carefully addressed in the study design and analysis. To facilitate a better understanding of when RWD can provide reliable conclusions on drug effectiveness, we seek to conduct 10 RWD-based studies that emulate RCTs in oncology using a systematic, protocol-driven approach described herein. Results of this investigation will help inform clinical, scientific, and regulatory stakeholders on the applications of RWD in the context of product labeling expansion, drug safety, and comparative effectiveness in oncology.

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INTRODUCTION: New drug products are tested for safety and efficacy in clinical trials before being approved for use in medical practice. Clinical trial data are often misreported or underreported to ClinicalTrials.gov and in the medical literature. There is limited research on clinical trial characteristics for Food and Drug Administration (FDA) approved drugs, particularly examining differences in characteristics across different approval pathways or therapeutic indications. METHODS: Data from the Aggregate Analysis of ClinicalTrials.gov (AACT) were used to compare the characteristics of completed clinical trials for drugs approved by the FDA in 2015 and 2016 across different approval pathways (expedited vs. nonexpedited) and therapeutic indications (oncology vs. nononcology). RESULTS: There were 59 novel therapeutic drugs approved by the FDA in 2015 and 2016. A search of the AACT database yielded 955 studies that were associated with these 59 drugs. Median Phase 2 trial enrollment was smaller for drugs granted expedited approval compared with drugs without expedited approval (60 vs. 94; P=0.0079) and for oncology drugs compared with nononcology drugs (53 vs. 92; P<0.001). In general, trials across all phases were less likely to be blinded for drugs that received expedited approval compared with drugs without expedited approval and for oncology drugs compared with nononcology drugs. CONCLUSIONS: The characteristics of clinical trials differ across different approval pathways and therapeutic indications. More research is needed to determine whether the information from clinical trials of approved drugs is sufficient to adequately inform the public regarding their potential benefits and harms.

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