Access to Innovative Therapies in Rare Diseases—Evaluation Challenges of Single Arm Trials With External Control Arm: FDA Versus French Has Evaluations Between 2018 and 2024

OBJECTIVES:

Context : The need for innovative therapies is increasingly raising for rare diseases. Unfortunately, randomized controlled trials (RCTs) in orphan drug development programs, often face significant methodological challenges. That’s why licensing of new treatments could be based on evidence from phase II/III single arm trials (SAT) with external control arms (ECA).

Objective : Both FDA (American Food and Drug Administration) and HAS (French National Authority for Health) have published nonbonding recommendations concerning externally controlled trials. In the absence of a clearly defined framework, this analysis aims to understand the evaluation challenges of SAT with ECA in rare diseases between 2018 and 2024 and identify differences between these two agencies.

METHODS: A targeted search of rare condition (non-oncology) submissions was performed on PRISMACCESS database. From this list, only dossiers with a pivotal study based on SAT with an indirect treatment comparison (ITC) were selected. One last review was added to this list, after a search on HAS website.

RESULTS: A total of 12 SAT with ECA-based submissions were identified between 2018 and 2024 : 5 in metabolic diseases, 4 in neurology and 3 in hematology. Different ECA were used : 44% historical controls, 37% prior clinical trials, 13% real-world data and 6% comparison to baseline. 3 ITC were accepted by both agencies, 4 ITC refused by both agencies and 2 ITC accepted by the FDA but refused by the HAS. Both agencies tend to have similar methodological requirements as found in their recommendations, with a greater flexibility of FDA regarding the post hoc nature of the comparison.

CONCLUSIONS: Though SAT with ECA seem to be more suitable than RCTs in rare diseases, they have methodological weaknesses often criticized by HTA bodies. Collaboration to establish a validated framework would be crucial to increase the acceptability of those studies.