Enhancing the Acceptance of Externally Controlled Trials (ECTs) in the German HTA System: Analysis of Guidance Documents From Other Countries

OBJECTIVES: With the rise of externally controlled trials (ECTs), regulatory and Health Technology Assessment (HTA) bodies have issued diverse guidelines. This review examines these guidelines, focusing on their application within the German HTA system to enhance the acceptance and integration of ECTs.

METHODS: Seven guidance documents from regulatory (FDA, EMA) and HTA agencies (EUnetHTA 21, IQWiG, HAS, NICE, CADTH) related to single-arm trials, real-world evidence (RWE), and/or external control arms were analyzed.

RESULTS: The analysis highlighted that most agencies recommend seeking early advice for ECTs before conducting the single-arm trial and/or the external control. When there is consensus that a randomized controlled trial (RCT) is not feasible or unethical, it is possible to conduct quantitative bias analysis, power for surrogate markers, plan for higher p-values under certain conditions, and adhere to diverse evidence levels. This contrasts with IQWiG's stricter criteria, suggesting a so-called dramatic effect with a shifted null (relative risk >10 and p < 0.01).

CONCLUSIONS: In situations where RCTs are impractical or unethical, accepting the inherent uncertainties of surrogate measures and higher p-values may be more beneficial than insisting on stringent criteria, as practiced by agencies like IQWiG and EUnetHTA 21, which could lead to the exclusion of potentially valuable interventions. By adopting methodologies from other agencies, the quality and acceptance of ECTs within the German HTA system could be significantly improved. This includes early consultations with the Federal Joint Committee (G-BA) for single-arm trials, the use of quantitative bias analysis, the inclusion of surrogate markers, acceptance of higher p-values under certain conditions, and introduction of a new evidence level to reflect the inherent uncertainties.