METHODOLOGICAL DIFFERENCES IN PIVOTAL EVIDENCE FOR RARE AND NON-RARE DISEASE MEDICINES: A RETROSPECTIVE ANALYSIS IN ITALY
Author(s)
Claudio Jommi, MSc1, Daiana Mattoteia, PhD2, Martina Fardella, MSc2, Bonfanti Marzia, PhD2, Carlotta Galeone, ScD, PhD3, Pier Luigi Canonico, MD1, Patrizia Popoli, MD4, Chiara Lucchetti, MSc2.
1Università del Piemonte Orientale, Novara, Italy, 2Cencora, Milano, Italy, 3Università degli Studi di Milano Bicocca, Milano, Italy, 4Istituto Superiore di Sanità, Roma, Italy.
1Università del Piemonte Orientale, Novara, Italy, 2Cencora, Milano, Italy, 3Università degli Studi di Milano Bicocca, Milano, Italy, 4Istituto Superiore di Sanità, Roma, Italy.
OBJECTIVES: The uncertainty concerning regulatory and HTA evaluations of rare diseases medicines (RDMs) remains considerable, driven by limitations in clinical evidence robustness, including small sample sizes, reliance on surrogate endpoints, and heterogeneity in quality-of-life data. A recent publication highlighted an improvement of RDMs clinical trial design for HTA purposes, but this evidence was not compared with studies for non‑rare disease medicines (NRDMs). The objective of this study is to carry out this comparative analysis.
METHODS: A retrospective analysis was conducted on medicines reimbursed in Italy (2018-2024), including RMDs and NRMDs, based on available pivotal trial data. Study design, sample size, duration, endpoints, and Patient-Reported Outcome Measures (PROMs) use were examined, integrating regulatory and HTA sources. Comparative analyses were performed using descriptive and inferential approaches.
RESULTS: RDMs were supported by fewer pivotal studies and showed higher rates of innovativeness requests (55%vs28%, p<0.001), more often accepted (61%vs44%, p=0.014). Clinical evidence relied less on RCTs (74%vs90%, p<0.0001) and phase III studies (75%vs88%, p=0.0003), with greater use of open‑label (44%vs21%, p<0.0001) and cross‑over designs (9%vs2%, p=0.0016). Despite fewer primary endpoints on average (1.46vs1.96, p=0.0007), RDMs more frequently included clinical outcomes (54%vs36%, p<0.0001). PROMs were more commonly incorporated in RDM trials (70%vs56%, p=0.0015), mainly as secondary endpoints.
CONCLUSIONS: Pivotal evidence for RDMs differs significantly from that of NRDMs across multiple features, confirming a persistent level of uncertainty in rare diseases, despite the improvement reported by other contributions. Notwithstanding, RDMs more frequently incorporate clinical outcomes and show higher rates of innovativeness recognition. PROMs are used to a similar extent across both groups. However, they remain undervalued in HTA processes, perhaps depending on a suboptimal methodological strength of such measures and/or on a limited preparedness of HTA bodies to consider them in decision‑making.
METHODS: A retrospective analysis was conducted on medicines reimbursed in Italy (2018-2024), including RMDs and NRMDs, based on available pivotal trial data. Study design, sample size, duration, endpoints, and Patient-Reported Outcome Measures (PROMs) use were examined, integrating regulatory and HTA sources. Comparative analyses were performed using descriptive and inferential approaches.
RESULTS: RDMs were supported by fewer pivotal studies and showed higher rates of innovativeness requests (55%vs28%, p<0.001), more often accepted (61%vs44%, p=0.014). Clinical evidence relied less on RCTs (74%vs90%, p<0.0001) and phase III studies (75%vs88%, p=0.0003), with greater use of open‑label (44%vs21%, p<0.0001) and cross‑over designs (9%vs2%, p=0.0016). Despite fewer primary endpoints on average (1.46vs1.96, p=0.0007), RDMs more frequently included clinical outcomes (54%vs36%, p<0.0001). PROMs were more commonly incorporated in RDM trials (70%vs56%, p=0.0015), mainly as secondary endpoints.
CONCLUSIONS: Pivotal evidence for RDMs differs significantly from that of NRDMs across multiple features, confirming a persistent level of uncertainty in rare diseases, despite the improvement reported by other contributions. Notwithstanding, RDMs more frequently incorporate clinical outcomes and show higher rates of innovativeness recognition. PROMs are used to a similar extent across both groups. However, they remain undervalued in HTA processes, perhaps depending on a suboptimal methodological strength of such measures and/or on a limited preparedness of HTA bodies to consider them in decision‑making.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
CO78
Topic
Clinical Outcomes, Health Policy & Regulatory, Study Approaches
Topic Subcategory
Clinical Outcomes Assessment
Disease
No Additional Disease & Conditions/Specialized Treatment Areas, Rare & Orphan Diseases