Joint Clinical Assessment in the EU HTA Regulation – Would Drugs Supported by Single-Arm Trials Fit Under Evaluation?

The Joint Clinical Assessment (JCA) evaluates the relative effectiveness (RE) of 4 interventions over comparators. While randomized control trials (RCTs) are considered 5 the gold standard, single-arm trials (SATs) require an external control for accurate RE 6 estimation. This study reviewed Health Technology Assessment (HTA) opinions for 7 medicinal products supported by SATs in France, Germany, Poland, and Spain, and 8 simulated the JCA assessment for these products based on evidence submitted in France. 9 Among HTA opinions published in France in 2019-2024, 16% were SAT-driven, and 5.6% 10 of them included external controls. SAT-supported drugs had a high reimbursement 11 approval rate (74%) and showed better HTA outcomes when controls were used. In 12 Germany, 64% of SAT-based opinions indicated no added benefit and 30% - non- 13 quatifiable benefit. In Poland and Spain, 63% and 72% opinions recommending 14 reimbursement, respectively. Despite wide acceptance by Member States, experts 15 determined that 94% of SAT-supported products would not qualify for JCA review due 16 to insufficient evidence. Only 6% would qualify for JCA for a likely limited number of 17 PICOs (Population-Intervention-Comparator-Outcome), but the certainty rating would be 18 low. These findings suggest that SATs, as primary evidence, may not be suitable for JCA, 19 potentially undermining HTA assessments in EU Member States.