USE OF REAL-WORLD EVIDENCE IN PRE-APPROVAL ASSESSMENTS FOR RARE AND ULTRA-RARE DISEASE THERAPIES IN UK, GERMANY, FRANCE, AND THE UNITED STATES
Author(s)
Sandra Milev, MSc1, Casey Cabot, BSc2, Theia Kwong, MSc2, Anne Heyes, MBA3, Isobel Owens-Smith, MSc2, Mitun Patel, BSc, MSc2, Stephen Deitch, PharmD2, Monique Martin, MBA, MSc, PharmD3;
1Red Nucleus, Integrated HEOR & RWE Solutions, Yardley, PA, USA, 2Red Nucleus, Integrated Access Solutions, London, United Kingdom, 3Red Nucleus, Integrated HEOR & RWE Solutions, London, United Kingdom
1Red Nucleus, Integrated HEOR & RWE Solutions, Yardley, PA, USA, 2Red Nucleus, Integrated Access Solutions, London, United Kingdom, 3Red Nucleus, Integrated HEOR & RWE Solutions, London, United Kingdom
OBJECTIVES: To characterize how real-world evidence (RWE) has been used pre-approval for therapies targeting rare and ultra-rare diseases across the UK, Germany, France, and the United States.
METHODS: A systematic review was conducted of 30 products appraised through the NICE Highly Specialised Technologies (HST) pathway. For each product-indication, corresponding health technology assessments in France (HAS) and Germany (IQWiG/G-BA), and regulatory documentation from the US Food and Drug Administration (FDA), were reviewed where submissions existed. RWE was categorized by purpose as: (1) comparative effectiveness evidence, including natural history cohorts and external comparator arms; (2) long-term clinical outcomes, including open-label extensions, managed access programs, and post-approval registries; and (3) real-world safety and tolerability.
RESULTS: Of the 30 products assessed, 28 were submitted to HAS, 28 to IQWiG/G-BA, and 24 to FDA. Use of pre-approval RWE varied by jurisdiction: UK 63% (19/30), France 43% (12/28), US 25% (6/24), and Germany 11% (3/28). Germany’s low aggregate RWE use primarily reflects the simplified orphan drug pathway, under which most products bypass comparative efficacy assessment. Among fully assessed products, Germany’s acceptance rate (67%) approaches the UK’s (63%), but requires large effect sizes robust to plausible confounding. When RWE was used, it most commonly informed natural history cohorts (UK 84%, US 83%). Among 11 products submitting RWE to multiple jurisdictions, 10 achieved acceptance across all submitted jurisdictions; the single rejection cited insufficient confounder control. France demonstrated greater diversity in RWE application, with 50% natural history, 25% long-term clinical outcomes, and 17% real-world safety data.
CONCLUSIONS: Pre-approval RWE use varies substantially by jurisdiction and is shaped by local assessment pathways. While RWE is most consistently used to generate natural history cohorts, acceptance of comparative and long-term RWE depends on structural context and effect size magnitude. Early, jurisdiction-tailored RWE planning incorporating effect size expectations may improve alignment across regulatory and HTA submissions.
METHODS: A systematic review was conducted of 30 products appraised through the NICE Highly Specialised Technologies (HST) pathway. For each product-indication, corresponding health technology assessments in France (HAS) and Germany (IQWiG/G-BA), and regulatory documentation from the US Food and Drug Administration (FDA), were reviewed where submissions existed. RWE was categorized by purpose as: (1) comparative effectiveness evidence, including natural history cohorts and external comparator arms; (2) long-term clinical outcomes, including open-label extensions, managed access programs, and post-approval registries; and (3) real-world safety and tolerability.
RESULTS: Of the 30 products assessed, 28 were submitted to HAS, 28 to IQWiG/G-BA, and 24 to FDA. Use of pre-approval RWE varied by jurisdiction: UK 63% (19/30), France 43% (12/28), US 25% (6/24), and Germany 11% (3/28). Germany’s low aggregate RWE use primarily reflects the simplified orphan drug pathway, under which most products bypass comparative efficacy assessment. Among fully assessed products, Germany’s acceptance rate (67%) approaches the UK’s (63%), but requires large effect sizes robust to plausible confounding. When RWE was used, it most commonly informed natural history cohorts (UK 84%, US 83%). Among 11 products submitting RWE to multiple jurisdictions, 10 achieved acceptance across all submitted jurisdictions; the single rejection cited insufficient confounder control. France demonstrated greater diversity in RWE application, with 50% natural history, 25% long-term clinical outcomes, and 17% real-world safety data.
CONCLUSIONS: Pre-approval RWE use varies substantially by jurisdiction and is shaped by local assessment pathways. While RWE is most consistently used to generate natural history cohorts, acceptance of comparative and long-term RWE depends on structural context and effect size magnitude. Early, jurisdiction-tailored RWE planning incorporating effect size expectations may improve alignment across regulatory and HTA submissions.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
PT18
Topic
Health Technology Assessment
Topic Subcategory
Systems & Structure
Disease
No Additional Disease & Conditions/Specialized Treatment Areas, SDC: Rare & Orphan Diseases