Emulations of Oncology Trials Using Real-World Data: A Systematic Literature Review.

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.

Calibrating Observational Health Record Data Against a Randomized Trial.

Importance: The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this. Objective: To pilot an emulation of the KEYNOTE-189 RCT using a commercially available electronic health record (EHR) data source. Design, Setting, and Participants: This retrospective cohort study used an EHR database spanning from April 2007 to February 2023. Follow-up began on treatment initiation and proceeded until an outcome event, loss to follow-up, end of data, or end of study period (640 days). The population-based cohort was ascertained from EHRs provided by 52 health systems across the US. Eligibility criteria were defined as closely as possible to the benchmark RCT. Patients with non-small cell lung cancer initiating first-line treatment for metastatic disease were included. Patients with evidence of squamous non-small cell lung cancer, primary nonlung malignant neoplasms, or identified EGFR/ALK variations were excluded. Data were analyzed from June to October 2023. Exposures: Initiation of first-line pembrolizumab and chemotherapy and chemotherapy alone. Chemotherapy in both groups was defined as a combination of pemetrexed and platinum-based (carboplatin or cisplatin) therapy. Main Outcomes and Measures: Outcomes of interest were 12-month survival probability and mortality hazard ratio (HR). Results: A total of 1854 patients (mean [SD] age, 63.7 [9.6] years; 971 [52.4%] men) were eligible, including 589 patients who initiated pembrolizumab and chemotherapy and 1265 patients who initiated chemotherapy only. The cohort included 364 Black patients (19.6%) and 1445 White patients (77.9%). The 12-month survival probabilities were 0.60 (95% CI, 0.54-0.65) in the pembrolizumab group and 0.58 (95% CI, 0.55-0.62) in the chemotherapy-only group, compared with 0.69 (95% CI, 0.64-0.74) in the KEYNOTE-189 pembrolizumab group and 0.49 (95% CI, 0.42-0.56) in the KEYNOTE-189 chemotherapy-only group. The mortality HR was 0.95 (95% CI, 0.78-1.16), compared with 0.49 (95% CI, 0.38-0.64) in the KEYNOTE-189 RCT. Conclusions and Relevance: In this cohort study piloting an RCT emulation, results were incongruous with the benchmark trial. Differences in patient treatment and data capture between the RCT and EHR populations, confounding by indication, treatment crossover, and accuracy of captured diagnoses may explain these findings. Future feasibility assessments will require data sources to have important oncology-specific measures curated.

The Aetion Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation Initiative: Oncology.

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.