ARE RARE DISEASE CLINICAL TRIALS READY FOR EU JOINT CLINICAL ASSESSMENT (JCA)?
Author(s)
Mojgan Gitimoghaddam, PhD, MD1, Gaurang Nazar, PhD, MD1, Mir-Masoud Pourrahmat, MSc.1, Massoud Toussi, MBA2, Mir Sohail Fazeli, PhD, MD1.
1Evidinno Outcomes Research Inc., Vancouver, BC, Canada, 2United BioSource LLC., Paris, France.
1Evidinno Outcomes Research Inc., Vancouver, BC, Canada, 2United BioSource LLC., Paris, France.
OBJECTIVES: The EU JCA emphasizes comparative effectiveness versus relevant comparators, patient-relevant endpoints, and mature evidence for HTA decision-making. Rare disease development programs rely on single-arm designs, surrogate endpoints, and limited long-term evidence due to small populations. We assessed alignment of rare disease pivotal trials with JCA evidence expectations.
METHODS: A targeted review (January 2015-March 2025) of PubMed, ClinicalTrials.gov, and EMA European Public Assessment Reports (EPARs) identified pivotal trials in rare diseases. Search terms included “rare diseases,” “orphan diseases,” “pivotal trial,” “clinical trial,” “comparative study,” and “patient-reported outcomes.” Data were extracted on study design, comparator, primary endpoint, PRO/HRQoL inclusion, and evidence maturity. Alignment with JCA evidence expectations was assessed descriptively.
RESULTS: Among 312 screened records, 22 pivotal trials were included, primarily in neuromuscular and hematologic rare diseases. Twelve (55%) were randomized controlled trials (RCTs), while 10 (45%) were non-randomized, including 6 single-arm and 4 externally controlled studies. Comparative evidence remained limited: 10 trials (45%) used active or standard-of-care comparators, whereas 12 (55%) relied on placebo, historical controls, or no comparator. Endpoints varied across trials: functional and surrogate endpoints were commonly used in 13 trials (59%), including motor function and bleeding rate outcomes, while definitive clinical outcomes were less frequent, which may increase uncertainty in comparative assessments. PRO/HRQoL measures were included in 9 trials (41%) but consistently reported in only 6 (27%). Evidence maturity was limited, with only 8 trials (36%) reporting long-term follow-up beyond 2 years. These characteristics may increase uncertainty for JCA comparative assessments, particularly regarding comparator selection, endpoints, and long-term evidence.
CONCLUSIONS: Rare disease trials frequently exhibit characteristics that may increase uncertainty in JCA assessments. While reflecting inherent rare disease constraints, these may pose challenges for EU HTA. Earlier integration of comparator strategies, patient-centered endpoints, and mature evidence will be critical for future access and reimbursement in rare diseases.
METHODS: A targeted review (January 2015-March 2025) of PubMed, ClinicalTrials.gov, and EMA European Public Assessment Reports (EPARs) identified pivotal trials in rare diseases. Search terms included “rare diseases,” “orphan diseases,” “pivotal trial,” “clinical trial,” “comparative study,” and “patient-reported outcomes.” Data were extracted on study design, comparator, primary endpoint, PRO/HRQoL inclusion, and evidence maturity. Alignment with JCA evidence expectations was assessed descriptively.
RESULTS: Among 312 screened records, 22 pivotal trials were included, primarily in neuromuscular and hematologic rare diseases. Twelve (55%) were randomized controlled trials (RCTs), while 10 (45%) were non-randomized, including 6 single-arm and 4 externally controlled studies. Comparative evidence remained limited: 10 trials (45%) used active or standard-of-care comparators, whereas 12 (55%) relied on placebo, historical controls, or no comparator. Endpoints varied across trials: functional and surrogate endpoints were commonly used in 13 trials (59%), including motor function and bleeding rate outcomes, while definitive clinical outcomes were less frequent, which may increase uncertainty in comparative assessments. PRO/HRQoL measures were included in 9 trials (41%) but consistently reported in only 6 (27%). Evidence maturity was limited, with only 8 trials (36%) reporting long-term follow-up beyond 2 years. These characteristics may increase uncertainty for JCA comparative assessments, particularly regarding comparator selection, endpoints, and long-term evidence.
CONCLUSIONS: Rare disease trials frequently exhibit characteristics that may increase uncertainty in JCA assessments. While reflecting inherent rare disease constraints, these may pose challenges for EU HTA. Earlier integration of comparator strategies, patient-centered endpoints, and mature evidence will be critical for future access and reimbursement in rare diseases.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
HTA365
Topic
Health Technology Assessment
Topic Subcategory
Value Frameworks & Dossier Format
Disease
No Additional Disease & Conditions/Specialized Treatment Areas, Rare & Orphan Diseases