Pivotal Studies for Rare Diseases: Will They Better Support Market Access?

OBJECTIVES: High prices request and limited clinical evidence at market launch are considered barriers to the assessment, appraisal and market access of drugs for rare indications. Our aim is analyzing the pivotal studies of these drugs and detecting the opinion of Italian experts on actions improving their market access.

METHODS: Rare indications, expected to be appraised for the price and reimbursement status in Italy by 2026, and the relevant pivotal studies were retrieved from the Biomedtracker Database, US and European Clinical Trial Databases and Datamonitor Reports. The opinion of 78 Italian experts (HTA authorities, payers, industry, patient representatives) was gathered through a structured and validated questionnaire.

RESULTS: We identified 154 new rare indications. Hematology and onco-hematology account for the majority of trials. 77% of indications have orphan designation and 8% are ultra-rare drugs. More than 80% of pivotal trials are Phase III studies. Single-arm accounts for 36% of trials. Almost 50% of RCTs are designed using an active comparator for control arms and 61% are double-blinded. Primary endpoints are mostly (82%) surrogate. 59% of studies include PROMs among secondary endpoints. Experts highlighted the importance of a more structured criteria to identify alternative treatments, a selective use of outcome-based managed entry agreements, and a structured early dialogue between the industry and AIFA (Italian Medicines Agency) to discuss uncertainties on the available evidence.

CONCLUSIONS: Our findings were partially expected (extensive use of surrogate endpoints) and partially not (many RCTs with an active comparator in control arms). Having more head-to-head studies may reduce the uncertainty on evidence at market launch, but different issues persist, including the still limited role of PROMs and the quality of the pivotal studies, which was not investigated. Hence, despite the evidence on drugs for rare diseases has been strengthening, experts suggestions are still valid.