OBJECTIVES: The availability of diverse real-world data (RWD) or real-world evidence (RWE) emphasizes the use of external control arm (ECA) comparator when randomization is deemed infeasible/unethical in randomized controlled trials (RCTs), or when a single-arm trial design is elected. The growing interest in real-world external comparators (RWEC) in oncology and rare diseases accentuates the need for extended application of meta-analysis (MA) with advanced epidemiological methods for expanded use of RWD/RWE.

METHODS: A RWEC built from RWD includes patient-level characteristics with appropriate matching, allowing for direct-matching between patients in the external and index cohorts. The data from comparator are combined in the same research database as index-cohort patient data, allowing for direct comparisons. Matching-adjusted Indirect comparisons (MAIC) using Network meta-analysis (NMA) and propensity-score weighting can be used to develop an ECA from RWE and existing RCTs. In single-arm studies, aggregate level covariates are incorporated using a matched-arm of covariates in the dataset as a comparator or using the baseline odds of an event in a chosen matched trial from MA.

RESULTS: MAIC approach compared first-in-class immunotherapy agents and orphan medical products to existing therapies in rare diseases like relapsed/refractory diffuse large B-cell lymphoma, and mantle cell carcinoma (n=2). Similarly, MAIC and NMA have been used to generate ECA for single-arm studies comparing immunotherapy agents and combinations with existing lines of treatment for advanced cancers (e.g., hepatocellular carcinoma and melanoma; n=2). Recent regulatory approvals in immunotherapy by the USFDA and EMA, besides health technology assessors' guidelines for use of MAIC, point to an increase in the use of better fit-for-purpose ECA.

CONCLUSIONS: The underutilized advanced epidemiologic methods combined with MA approach can be used to generate relevant evidence, gain regulatory poise, and accelerate access to newer therapies with ECA developed from RWD/RWE/existing RCTs.