Single Arm Trials and External Control Arms as Pivotal Evidence for ATMPs in HTA Submissions in Germany, France, and UK: A Targeted Review

OBJECTIVES: The gold standard for clinical evidence submissions to health technology assessment (HTA) authorities across Europe is randomised controlled trials (RCTs). However, developing treatments for rare and orphan diseases, such as advanced therapy medicinal products (ATMPs), often poses methodological and ethical challenges in the conduct of RCTs. Developers may use single arm trials (SAT) with an external control arm (ECA) to demonstrate comparative efficacy and safety indirectly. This research aims to understand the acceptability of such methods in HTA submissions for ATMPs in rare and orphan diseases in France, Germany, and UK.

METHODS: A targeted literature review was conducted to answer research questions on SATs and ECAs. The search focused on products meeting these criteria:

• ATMPs marketed within the last 5 years
• Non-paediatric indications
• Marketed in France, Germany, and UK

RESULTS: Eight products meeting the inclusion criteria were identified, four of which were within the oncology space, and all of which gained regulatory approval based on Phase Ib/II/III open-label SATs. The findings highlight differences in decision-making between HTA authorities in scope markets. Favourable HTA outcomes with SAT/ECA submissions relied on robust evidence, justified unfeasibility of RCTs, study designs mimicking RCTs, and pre-defined ECAs. UK (NICE) appears to be more accepting of such analyses submitted as pivotal evidence when compared to France and Germany.

CONCLUSIONS: Consideration of SAT/ECA evidence in reimbursement requests by manufacturers focusing on innovative modalities is increasing. While EU and national methods guides are evolving in the consideration of such study approaches, the level of acceptance at national level varies between the countries considered.