Table 1.

OBMEAs for nusinersen: coverage with evidence development

Country Organisation	Belgium National Institute for Health and Disability Insurance (INAMI)	England National Institute for Health and Care Excellence (NICE)	The Netherlands Zorg Instituut (ZIN)
P&R indication sought	5q SMA	5q SMA Types I, II, III and pre-symptomatic patients genetically destined to develop SMA	5q SMA
P&R date	1/9/18	July 2019	1. ≤ 9.5 years old 1/8/18 (fully reimbursed) 2. > 9.5 years old 1/1/20 (conditional)
P&R special process	Conditional—Chapter IV of positive list (Joint negotiation in BENLUXA with Netherlands)	Conditional on OBMEA and commercial agreement organised by NHS England and Improvement (NHSE&I)	OBMEA possible for OMPs (Joint negotiation in BENLUXA with Netherlands) 1. Ultra-rare, financial agreement until 1/21, with extension, “informal OBMEA” initiated after formal CED for other sub-population 2. Conditional reimbursement with legal OBMEA
OBMEA population	5q SMA not needing permanent ventilation 1. ≤ 9.5 years old – 1st symptoms before 6 mos, disease < 26 weeks – 1st symptoms 6–20 mos, disease < 94 mos – Pre-symptomatic babies with genetic diagnosis and 2 or 3 SMN2 copies 2. > 9.5 years old	5q SMA Types I–III and pre-symptomatic excluding – Permanent ventilation/ tracheostomy – Intrathecal injection not feasible – Had spinal fusion surgery – Severe contractures that prohibit measurement of motor milestones – Who gained ability to ambulate independently, but are no longer able to (except children who lost independent ambulation in prior 12 mos)	1. ≤ 9.5 years old—informal OBMEA – 1st symptoms before 6 months, disease < 26 weeks – 1st symptoms 6–20 mos, disease < 94 mos – Pre-symptomatic babies with genetic diagnosis and 2 or 3 SMN2 copies 2. > 9.5 years old—Legal OBMEA Extensive exclusion criteria
OBMEA Duration	28 months (up to max of 3 years)	5 years, with minimum of 3 years’ data collection	1. Informal OBMEA planned to start—no end date 2. Legal OBMEA—7 years including HTA re-assessment (290 pats recruited in first 2 years)
Purpose of OBMEA	Resolve uncertainties – Number pats treated in real life number pats treated by SMA type – Age at symptom appearance – Disease duration at onset of Rx – Real-life efficacy/safety: mortality, ventilation, performance, discontinuation reasons – Long-term efficacy/safety – Evidence in populations with no determined added value to date	To resolve clinical uncertainties in NICE appraisal with – Clinical data collection – PRO data collection – Resource utilisation data collection	1. In reimbursed population (≤ 9.5 years old), informal OBMEA to evaluate real-life effectiveness, determine appropriate use and cost effectiveness 2. For conditional coverage (> 9.5 years old), CED, legal OBMEA to collect enough evidence to determine if it is clinically and cost effective compared to no use (historic registry data)
Use in re-appraisal	Re-appraisal for P&R re-negotiations to convert to standard reimbursement or change in target population etc or to extend OBMEA	– 1 year review for a specific population (type III, non-ambulant) – Reassessment in year 4 using at least 3 years of OBMEA data collection and any additional evidence from other sources. – Revised commercial agreement – Decision by year 5 to reimburse or not, no further OBMEA	1. Continuing process to refine start and stop criteria, collecting long-term follow up data and if it does not work as well as expected, reassessment can be initiated with potential to change advice to not reimburse or renegotiate price 2. Legal requirement for P&R re-negotiations
Stakeholders involved	– INAMI Commission for Reimbursement proposed OBMEA to MAH, who accepted and developed OBMEA with MoH and INAMI MEA taskforce – Clinicians	– NICE can propose OBMEA according to clear criteria, developed in collaboration with MAH, NHSE&I, registry holder, clinicians and patient groups – Patient groups liaise with patients to explain OBMEA, feedback issues, input to data monitoring discussions – Other members of the Managed Access Oversight Committee (MAOC) clinicians from 4 expert centres, academics responsible for development of PROM – National Clinical Panel assesses the patients included against the eligibility and continuation criteria on an annual basis and discuss other clinical issues that arise such as difficult cases requiring clinical judgement	– ZIN appraisal committee proposed both the informal and the legal OBMEAs to Minister of Health – Research group send application with research protocol to ZIN for review and approval this forms basis of legal agreement – Clinical expert centre, patient group, health insurers, bureau of university hospitals, pharmacists (and for legal OBMEA MoH)
Treatment stopping criteria	Permanent ventilation	– Permanent ventilation (≥ 16 h/day for 21 consecutive days in the absence of acute reversible infection) or requirement of insertion of permanent tracheostomy. – Total worsening in outcome score corroborated by two consecutive measurements. A scaled equivalent of these losses would apply if a domain was unmeasurable/not suitable: > 2 points on horizontal kick or 1 point on other HINE scores excluding voluntary grasp > 4 points on the CHOP INTEND scale > 3 points on the Revised Hammersmith scale – Inability to regain ambulation within 12 months of nusinersen initiation – Inability to give intrathecal administration because of spinal fusion surgery	1. 9.5 years old reimbursed population, informal OBMEA—not known yet, will be evaluated in the informal OBMEA 2. 9.5 years old CED, legal OBMEA– not stipulated, but important to establish if reimbursement is agreed after OBMEA
Data sources	– INAMI and Insurance Funds have established a bespoke registry with healthdata.be that links into the internationally coordinated SMA registry Data from the registry will be combined with INAMI reimbursement data – MAH can also collect data through other routes	– Completion of ongoing trials – SMA REACH registry (organised by leading children’s hospital) – NHS Blueteq (System for high-cost drugs) – PROMs being developed	1. Dutch registry 2. Dutch registry developed for use by clinicians in the expert centre and data will be compared with historical Dutch cohort
Data collected	To resolve stated uncertainties, details confidential	– Nusinersen (use, first dose, dose, combination therapy, parental perceived benefit) – Survival, need for ventilation (+ respiratory events) – Motor function (various measures) – Scoliosis – Fractures – Nasogastric tube, gastrostomy placement – For each group a “primary” endpoint is defined in the DCA and many other endpoints as well	1. ≤ 9.5 years old, reimbursed population, informal OBMEA (data collection still under development) 2. > 9.5 years old, CED, legal OBMEA A lot of data to assess clinical and cost effectiveness with specific research questions compared to historical control. Primary endpoints: If HFMSE score ≥ 5, decrease in HFMSE over 4 years follow-up. MCID—75% reduction in the average decrease compared to the historical cohort. (HFMSE decreases by an average of 0.8 points per year in historical cohort, so there is a clinically relevant difference if the HFMSE score decreases by an average of ≤ 0.2 points per year). IF HFMSE < 5, RULM is the primary outcome measure. Secondary efficacy measures: RULM, EQ-5D, SF-36, PedsQoL, SMA-FRS, fatigue (measured with the ES9HPT, ESBBT and ESWT), Safety: side effects, serious side effects Economics: budget impact and cost effectiveness.
Data Analysis Plan	?	Developed by MAH	1. Expert centre 2. Research group from expert centre
Frequency of data collection	Annually, with an initial delay: so 2020, 2021, 2022	Twice per year (at least 4 months apart) to coincide with 6-monthly follow-ups or 4-monthly administrations	1. ≤ 9.5 years old, informal OBMEA—not known yet 2. > 9.5 years old, legal OBMEA—every 3–6 months
Interim data reviews	None	SMA REACH (registry) 6-monthly – Summary reports to MAOC to monitor data completeness and case ascertainment. – Pseudo-anonymised individual reports to Clinical Panel to monitor eligibility and stopping rules MAH provides annual summary data At end of year 1 provide evidence submission to NICE re non-ambulant type III	1. Aggregated public data reported in ZIN annual report “monitoring orphan drugs in practice” 2. Group meets 6-monthly to review status of research—no. of patients treated, no. on waiting list, no. stopped treatment etc and reported in annual report about use of OMPs
Data quality process	No	– Mandatory fields to be completed – Registry holder undertakes site monitoring of data entry and remote monitoring of completeness. – MAOC checks case ascertainment figures from another NHS data source (Blueteq)	Organised by the research centre
Funder for data collection	INAMI for the new SMA registry MAH	MAH	1. No standard system for informal OBMEA 2. MAH
Funder for data processing	MAH	MAH and SMA REACH	1. No standard system for informal OBMEA 2. MAH

CED Coverage with Evidence Development, CHOP INTEND Children`s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, ES9HPT Endurance Shuttle Nine Hole Peg Test, ESBBT Endurance Shuttle Box and Block Test, ESWT Endurance Shuttle Walk Test, FRS Functional Rating Scale, HFMSE Hammersmith Functional Motor Scale Expanded, HINE Hammersmith Infant Neurological Examination, INAMI National Institute for Health and Disability Insurance, MAH Marketing Authorisation Holder, MAOC Managed Access Oversight Committee, mos months, MoH Ministry of Health, MCID minimum clinically important difference, NHIF National Health Insurance Fund, NHSE&I NHS England and Improvement, NICE National Institute for Health and Care Excellence, OBMEA Outcomes-Based Managed Entry Agreement, OMP orphan medicinal product, P&R pricing and reimbursement, PROM patient-reported outcome measure, Rx treatment, RULM revised upper limb module, SMA spinal muscular atrophy, ZIN Zorg Instituut