Functional, Fatiguability and Quality of Life (QoL) Endpoints for Spinal Muscular Atrophy (SMA) Clinical Trials: Perception by Health Technology Assessment (HTA) Bodies and Regulators and Validation Status
Author(s)
SYED RAZA, MBA, MSc1, Noemi Hummel, PhD2, Katarzyna Lasota, MS3, Roeland Vanhauwaert, PhD4, Flavia Menezes, MD5, Jamie Aldridge, PhD5, Glenn A. Phillips, PhD5;
1Argenx, Global HEOR Director, Milton Keynes, United Kingdom, 2Certara, Lorrach, Germany, 3Certara, Cracow, Poland, 4argenx, Ghent, Belgium, 5argenx, US, MA, USA
1Argenx, Global HEOR Director, Milton Keynes, United Kingdom, 2Certara, Lorrach, Germany, 3Certara, Cracow, Poland, 4argenx, Ghent, Belgium, 5argenx, US, MA, USA
OBJECTIVES: To explore how HTA bodies and the Food and Drug Administration (FDA) appraise the applicability of endpoints to measure muscle strength, fatigue/fatiguability and QoL in SMA clinical trials.
METHODS: Appraisals of SMA and analogue disease treatments by the UK (National Institute for Health and Care Excellence, NICE), France (Haute Autorité de Santé, HAS), Germany (Federal Joint Committee, G-BA), Canada’s Drug Agency (CDA) were assessed to evaluate their acceptance of the Revised Hammersmith Scale (RHS), Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), 6-Minute Walk Test (6MWT), 32-item Motor Function Measure (MFM-32), Pediatric Quality of Life Inventory (PedsQL) and further QoL and fatiguability endpoints. Ad hoc searches on validation and minimal clinically important difference (MCID) were performed.
RESULTS: Most endpoints were validated. MCIDs were identified for HFMSE (SMA type 2: 1.5; type 3: 2.4), RULM (2.9- 4.3) and 6MWT (30-70m). HFMSE was considered validated (G-BA, HAS, CDA) and appropriate for advanced SMA with limited mobility (CDA). G-BA rejected the MCID provided. RULM was considered appropriate for individuals ≥24 (CDA) or ≥30 (HAS) months. G-BA rejected evidence on its validation and considered it less relevant than HFMSE. 6MWT was found relevant in SMA analogue diseases, however, its MCID was not accepted (G-BA), and impact of external factors could lead to bias (FDA). MFM-32 offered sufficient gradation to assess functional abilities (NICE), but longer trial duration was recommended (FDA). PedsQL was considered validated (G-BA) and correlated with mobility status (CDA). Other endpoints were not mentioned in the evaluations.
CONCLUSIONS: HTA and regulatory bodies generally found functional endpoints to be relevant and validated, though their perception varied by country. The applicability of functional endpoints also depended on the age and mobility status of the target population. Consideration of fatigability and other QoL endpoints was lacking, MCIDs were not available, and validation was limited.
METHODS: Appraisals of SMA and analogue disease treatments by the UK (National Institute for Health and Care Excellence, NICE), France (Haute Autorité de Santé, HAS), Germany (Federal Joint Committee, G-BA), Canada’s Drug Agency (CDA) were assessed to evaluate their acceptance of the Revised Hammersmith Scale (RHS), Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), 6-Minute Walk Test (6MWT), 32-item Motor Function Measure (MFM-32), Pediatric Quality of Life Inventory (PedsQL) and further QoL and fatiguability endpoints. Ad hoc searches on validation and minimal clinically important difference (MCID) were performed.
RESULTS: Most endpoints were validated. MCIDs were identified for HFMSE (SMA type 2: 1.5; type 3: 2.4), RULM (2.9- 4.3) and 6MWT (30-70m). HFMSE was considered validated (G-BA, HAS, CDA) and appropriate for advanced SMA with limited mobility (CDA). G-BA rejected the MCID provided. RULM was considered appropriate for individuals ≥24 (CDA) or ≥30 (HAS) months. G-BA rejected evidence on its validation and considered it less relevant than HFMSE. 6MWT was found relevant in SMA analogue diseases, however, its MCID was not accepted (G-BA), and impact of external factors could lead to bias (FDA). MFM-32 offered sufficient gradation to assess functional abilities (NICE), but longer trial duration was recommended (FDA). PedsQL was considered validated (G-BA) and correlated with mobility status (CDA). Other endpoints were not mentioned in the evaluations.
CONCLUSIONS: HTA and regulatory bodies generally found functional endpoints to be relevant and validated, though their perception varied by country. The applicability of functional endpoints also depended on the age and mobility status of the target population. Consideration of fatigability and other QoL endpoints was lacking, MCIDs were not available, and validation was limited.
Conference/Value in Health Info
2025-05, ISPOR 2025, Montréal, Quebec, CA
Value in Health, Volume 28, Issue S1
Code
CO159
Topic
Clinical Outcomes
Topic Subcategory
Clinical Outcomes Assessment
Disease
SDC: Musculoskeletal Disorders (Arthritis, Bone Disorders, Osteoporosis, Other Musculoskeletal)