OBJECTIVES: Randomised controlled trials (RCTs), while the gold standard, may not always be feasible. In this context, non-randomised evidence (NRE) can provide valuable insights. This study examines the application of NRE in regulatory and HTA decision-making through a series of case studies, and to demonstrate how NRE can complement RCTs to facilitate timely access to innovative treatments

METHODS: Four key themes were identified in which RCTs may not be feasible or practical. These were 1) unresolved uncertainty, 2) lack of a meaningful comparator, 3) small patient pool, and 4) practical, technical or ethical limitations. Products were selected based on the coverage of these topics within the review of the case. In the end, four products were selected to illustrate the use of NRE: Strimvelis for ADA-SCID, Zolgensma for Type 1 SMA, Blincyto for MRD+BCP ALL, and Libtayo for advanced CSCC. Each case was analyzed for the specific challenges that precluded the use of RCTs and the rationale for accepting NRE.

RESULTS: All four disease areas were in rare conditions with small patient populations that lacked meaningful comparators resulting in the submission of single-arm trials as primary evidence for regulatory approval. The types of NRE used for submissions across all cases included data from external control arms, disease registries, and administrative data. Practical, technical or ethical challenges included short untreated life expectancy, no existing treatments, and the potential lifetime benefit. All products were approved by regulators however, HTA approval varied across EU5 markets.

CONCLUSIONS: These case studies illustrate that NRE can be a critical component in HTA and regulatory decision-making, particularly when RCTs are not feasible. NRE can provide robust evidence to support the efficacy and safety of treatments, facilitating access to innovative therapies for patients with high unmet medical needs.