German HTA Outcomes for Rare Disease Drugs When Orphan Designation Does Not Legally Determine Added Benefit
Author(s)
Jörg Tomeczkowski, PhD1, Paul Bussilliat, MASc2, Kirsten Heike Herrmann, BSc, MSc, PhD3, Tanja Heidbrede, PharmD4, Ulrike Osowski, PhD5, Friedhelm Leverkus, MSc6, Charalabos-Markos Dintsios, MA, MPH, MSc, RPh, PhD7.
1Evidence-generating Data Evaluation, Dormagen, Germany, 2vfa, Berlin, Germany, 3Pharming Group N.V., Ottobrunn, Germany, 4UCB Pharma GmbH, Monheim, NW, Germany, 5Merck Healthcare Germany, Darmstadt, Germany, 6Evidence-generating Data Evaluation, Berlin, Germany, 7Bayer Vital GmbH, Leverkusen, Germany.
1Evidence-generating Data Evaluation, Dormagen, Germany, 2vfa, Berlin, Germany, 3Pharming Group N.V., Ottobrunn, Germany, 4UCB Pharma GmbH, Monheim, NW, Germany, 5Merck Healthcare Germany, Darmstadt, Germany, 6Evidence-generating Data Evaluation, Berlin, Germany, 7Bayer Vital GmbH, Leverkusen, Germany.
OBJECTIVES: For Germany's HTA the AMNOG legislation originally intended to grant automatic added benefit status to rare disease therapies affecting 500 to 1,000 individuals, recognizing the challenges of generating comparative evidence and frequent absence of therapeutic alternatives. However, this protection requires formal orphan drug (OD) designation but not all drugs targeting small populations receive OD designation or the G-BA customize target population, or the protection is lost when a specific revenue exceeds a threshold. This study evaluated the proportion of drugs meeting orphan drug criteria but lacking formal OD designation or having lost OD protection and analyzed the reasons why an added benefit was not confirmed.
METHODS: We retrospectively analyzed 1,373 drug subpopulations evaluated by G-BA and IQWiG through June 2025. Outcomes were classified as: added benefit confirmed; no added benefit (accepted evidence but insufficient clinical relevance, evidence rejected, or no evidence submitted). Results were stratified by population size (≤1000 vs >1000 patients to consider smallest populations within rare disease drugs) and therapeutic alternative availability.
RESULTS: Added benefit was confirmed in 27.6% of all cases. Among the 72.4% without confirmed added benefit, data were accepted but clinically irrelevant in 27.0%. Data were rejected in 39.8%, and no data were submitted in 33.2%. Added benefit confirmation dropped to 21.7% in very small populations (≤1000 patients) but increased significantly to 53.1% in cases lacking alternative therapies. However, notably, the rate of no data submission rose from 33.2% to approximately 50% in subgroups without available alternatives.
CONCLUSIONS: Current AMNOG implementation fails to address evidence generation challenges for small patient populations, particularly those without OD protection. While benefit recognition improves when alternatives are unavailable, paradoxically high non-submission rates in these vulnerable populations suggest systematic barriers. The absence of automatic benefit pathways for rare disease therapies without formal OD status contradicts AMNOG's original patient-centered objectives and requires policy reconsideration.
METHODS: We retrospectively analyzed 1,373 drug subpopulations evaluated by G-BA and IQWiG through June 2025. Outcomes were classified as: added benefit confirmed; no added benefit (accepted evidence but insufficient clinical relevance, evidence rejected, or no evidence submitted). Results were stratified by population size (≤1000 vs >1000 patients to consider smallest populations within rare disease drugs) and therapeutic alternative availability.
RESULTS: Added benefit was confirmed in 27.6% of all cases. Among the 72.4% without confirmed added benefit, data were accepted but clinically irrelevant in 27.0%. Data were rejected in 39.8%, and no data were submitted in 33.2%. Added benefit confirmation dropped to 21.7% in very small populations (≤1000 patients) but increased significantly to 53.1% in cases lacking alternative therapies. However, notably, the rate of no data submission rose from 33.2% to approximately 50% in subgroups without available alternatives.
CONCLUSIONS: Current AMNOG implementation fails to address evidence generation challenges for small patient populations, particularly those without OD protection. While benefit recognition improves when alternatives are unavailable, paradoxically high non-submission rates in these vulnerable populations suggest systematic barriers. The absence of automatic benefit pathways for rare disease therapies without formal OD status contradicts AMNOG's original patient-centered objectives and requires policy reconsideration.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
HTA162
Topic
Health Technology Assessment, Methodological & Statistical Research
Topic Subcategory
Value Frameworks & Dossier Format
Disease
Rare & Orphan Diseases