Use of External Control Arms in Rare Disease: Are We Moving Towards an International Gold Standard and How Can We Facilitate Progress?

ISSUE: Historically, rare diseases (RD) have faced challenges generating gold-standard evidence through randomized controlled trials (RCT) due to limited population sizes and ethical issues. External control arms (ECA) emerged as an alternative and now play an important role in market authorization and reimbursement decisions for RD products.

While ECAs in RD have been accepted by the EMA as pivotal and sole comparative evidence instead of RCT, European HTA bodies and payers have proven more reluctant, arguing that evidence from ECAs present too much uncertainty for decision-making. This resulted in treatment access being delayed or denied. Despite the availability of case-by-case joint scientific advice and recent publications related to the generation of robust alternative evidence to RCTs, transparent eligibility criteria for ECA are still missing, preventing manufacturers from anticipating their acceptability. Constructive discussions between stakeholders to determine practical conditions of use for ECAs are thus necessary to pave a path forwards.

OVERVIEW: NICE was the first European HTA body to provide guidance for conducting ECAs in its 2022 RWE framework. HAS and CADTH released their recommendations in 2023 which shared conclusion as NICE. In parallel, the FDA released a draft guidance on ECAs while the EMA published a reflection paper on the use of single arm trials (SAT).

Jasdeep Hayre will kick-off the discussion by detailing the NICE position on ECA. Andrew Thomson, representing the EMA, will present the SAT reflection paper and its commonalities/differences with HTA bodies’ approaches. Finally, Amr Makady will represent the industry viewpoint and discuss the operational and strategic applicability of those guidances.

The discussion will be moderated by Carla Vossen who will identify areas of alignment/divergence across all parties and steer the discussion on the impact of the future EUnetHTA assessment on the global development of RD drugs and the continued challenge of generating internationally harmonized fit-for-purpose evidence.