Table 2.

OBMEAs for nusinersen: individual agreements

Country Organisation (respondent if not from organisation)	Bulgaria National Health Insurance Fund (TB, Founding President of National Council on Prices and Reimbursement of Medicinal Products)	Ireland Health Service Executive (HSE) (AOL, NCPE)	Italy Italian Medicines Agency (AIFA) (EX, formerly AIFA)
P&R indication sought	5q SMA	Children aged < 18 years with genetically confirmed SMA types I, II or III	5q SMA types I–III No age limitation
P&R date	29/9/19, inclusion in NHIF list 1/1/20	December 2017 following HTA not deemed to be cost effective and further pricing negotiations	28/9/17
P&R special process	Prescription for individual patients according to protocol approved by special commission in NHIF	Ultra-rare Conditional reimbursement according to protocol published by MoH	Fund for innovative drugs achieved “full” innovation score valid for 3 years (28/09/2017–17/09/2020), with P&R contract re-negotiations annually http://www.aifa.gov.it/sites/default/files/6-Spinraza_v1.0.pdf
OBMEA population	Children with 5q SMA aged < 18 years excluding those with - Anamnesis of peripheral or CNS disease - Severe scoliosis - Coagulation disorders - Hypersensitivity with manifestations of severe anaphylactic reactions to active substance or excipients - Those in a clinical trial for SMA Patients cannot receive treatment with other drugs paid by NHIF for the same indication, which are not included in the protocol	National Drugs Management Protocol states: Children aged < 18 years with genetically confirmed SMA types I, II or III excluding those with contraindications and - Patients with other life-limiting conditions - SMA type 0 - Clinical and genetic diagnosis of SMA not fulfilled - Current participation in a clinical trial with an investigational gene therapy for SMA - Comorbidities that might preclude lumbar puncture Patients prioritised on the basis of clinical need and the potential for treatment benefit	Genetically confirmed 5q SMA types I–III with no more than 4 copies of SMN2 gene. SMN1 for naive patients
OBMEA duration	3 years	28 months? Planned to start in August 2019, but some delays in execution	1 year and reviewed annually, often beyond innovation status, for many years 1st PR negotiation 28/09/17 https://www.aifa.gov.it/sites/default/files/Determina_1611-2017_Spinraza.pdf PR re-negotiation 29/9/18 https://www.gazzettaufficiale.it/eli/id/2018/09/27/18A06132/sg
Purpose of OBMEA	Obligatory requirement for some form of MEA as condition for positive drug list This OBMEA to ensure appropriate use and treatment discontinuation	Resolve uncertainties about long-term benefit by ensuring appropriate use including treatment discontinuation	Manage clinical uncertainty by ensuring appropriate use including treatment discontinuation
Use in re-appraisal	(OB)MEAs valid for 3 years until reimbursement re-negotiation	As defined in protocol, originally planned for review in November 2021	Part of the annual review of P&R contract
Stakeholders involved	NHIF and MAH	- Healthcare payer: primary care eligibility and reimbursement service - HSE medicines management programme (HSE MMP) to review individual applications for treatment against protocol (developed with clinicians)	- AIFA establishes registry for use by hospitals, can access anonymised data to produce reports - MAH funds registry - Regions: authorise prescribing centres - Health managers authorise clinicians and pharmacists - Clinicians/pharmacists: dispensing and access depends on entries into the registry for initiating and continuing treatment
Treatment stopping criteria	Assessment of performance status according to HFMSE, CHOP INTEND and HINE for SMA type 1 and RULM for SMA type 2 and re-evaluation of exclusion criteriaa	Differentiated for SMA types, based on motor/mobility scales, respiratory and patient/clinician viewsb	None
Data sources	Hospitals	Hospital clinicians (paper based), submitted to HSE-MMP for review	Drug-specific national web-based registry
Data collected	Confidential	As outlined in protocolb: - Baseline patient characteristics - Treatment information - Outcomes at 12 months to determine treatment continuation, different for each SMA type	Baseline patient characteristics Inclusion criteria: Patient with a genetically confirmed diagnosis of SMA 5q (mutations in the SMN1 gene), alleged SMA phenotype (types 1, 2, 3a or 3b) For patients diagnosed with SMA type 2, the forced vital capacity measurement to be collected Tests: CHOP INTEND, Motor milestones HINE, or HFMSE Information about whether patient has already been treated and appears in early access registry (as for all the AIFA registries) Date of nusinersen administration and dose First assessments after the loading dose and each four months of treatment - Clinician overall assessment - % change in score (CHOP INTEND, motor milestones HINE or HFMSE) - Disease progression, patient death, drug toxicity Treatment continuation decision End of treatment, date, reason, end-points (Electronic Supplementary Material)
Data analysis plan	NHIF	HSE-MMP	AIFA https://www.aifa.gov.it/en/-/attivazione-del-registro-spinraza-12-12-2017-
Frequency of data collection	Confidential	Annually	Continuum in clinical practice (medicine cannot be dispensed for any visit until data entered)
Interim data reviews	Depends on OBMEA	Not stipulated	Annually, and specifically after end of innovation status
Data quality process	Confidential	Not stipulated	Standard summary graphs and charts can be produced and sent to stakeholders for review
Funder for data collection	No special funding	Not funded	MAH
Funder for data processing	Confidential	Not funded	AIFA

Country Organisation (respondent if not from organisation)	Latvia NHS of Latvia (payer) [unvalidated]	Lithuania National Health Insurance Fund (AV, prior head of HTA)	Poland MoH/National Health Fund (AZ, AOTMiT) (unclear if OBMEA proposals implemented)
P&R indication sought	5q SMA as per SPC indication	5q SMA as per SPC indication	5q SMA as per SPC indication
P&R date	May 2019	First case reimbursed July 2017	January 2019
P&R special process	Special state programme for OMPs	Special process for reimbursement of OMP and medicines for treatment of very rare conditions is regulated by special order of Minister of Health. The order specifies decision making body (Very Rare Conditions Committee) and the process flow	Positive drugs list, drug programme B.102
OBMEA population	Genetically confirmed diagnosis of SMA: - Pre-symptomatic genetically confirmed SMA, 2/3 SMN2 gene copies - SMA I, 2 copies of SMN2 gene, up to 6 months old - SMA I, 3 copies of SMN2 gene, up to 8 months old - SMA II/III, SMN2 gene copy number ≥ 2, up to 12 years old Excluding those: - Who need breathing support (including CPAP or supplemental oxygen) to provide spo2 > 95% - With significant contractures that would prevent full use of motor function rating scale - With severe scoliosis (radiographic Cobb angle > 40°) Patient or guardian understands start/stop treatment criteria and agrees with treatment and multidisciplinary state of health evaluation regimec	Excluded non-ambulant SMA type 3 Then, based on individual case submission	Pre-symptomatic and symptomatic patients with diagnosed SMA 5q confirmed by genetic testing. Patients are approved by the coordinating team in the SMA treatment programme Most important exclusion criteria: - Scoliosis, which makes intrathecal injection impossible - Deterioration (different level in various scales) in the scale appropriately selected for age and type of sma (chop intend, hine or hfmse) - Drainage of the cerebrospinal fluid - Pregnancy
OBMEA duration	Confidential	3 years	2 years in line with P&R contract
Purpose of OBMEA	Appropriate use and discontinuation of treatment	Appropriate use: hospital justifies to NHIF for each treatment cycle of each patient that there is no disease worsening since the previous treatment cycle	Proposal from AOTMiT to evaluate uncertainty in clinical efficacy, especially long term (no data for SMA 0, IV and lack of randomised research for asymptomatic patients) with appropriateness and continuation criteria
Use in re-appraisal	In reimbursement re-negotiations, particularly evaluating number of patients treated	P&R renegotiation at 3 years or earlier if utilisation cap exceeded	Unknown
Stakeholders involved	- NHS develops criteria for the agreement and performs analysis - Childrens’ University Hospital	- NHIF may develop OBMEA with advice from clinical experts about how to assess effectiveness - Hospital: submit information for each patient before each maintenance cycle with physician’s conciliumd about patient response based on HFMSE	- AOTMiT Transparency Council can recommend OBMEA to MoH - MoH Economic Commission, which includes experts from the NHFe, negotiates with MAH and the P&R contract may include and OBMEA but this is confidential
Treatment stopping criteria	By decision of multidisciplinary team at any time if any of the following criteria are met: 1. Reduction in age-appropriate motor function rating compared with baseline; at 1 year, then every 6 months 2. Invasive or non-invasive ventilation > 16 h per day, for 21 consecutive days, without acute infectious disease 3. Contraindications to lumbar puncture or technically impossible to perform 4. Patient monitoring and international SMA care standards are not followed appropriately 5. Lack of equality between patients and patients’ relatives (non-adherence or insufficient patient nutrition provided) 6. Significant adverse drug reactions 7. Patient or carer requests to discontinue Criteria for starting and stopping treatment can be updated at any time according to latest scientific evidence	Physicians’ concilium in treating hospital: if individual’s disease is worsening, treatment should be discontinued (opinion, data not shared)	AOTMiT proposition was to discontinue if no improvement from baseline by at least 1 point on CHOP INTEND, HINE or HFMSE on 2 assessments taken 4 months apart
Data sources	Childrens’ University Hospital	NHIF from hospital	Clinicians
Data collected	Medicine utilisation data	Information about starting and stopping of treatment for each patient as supplied by hospital (data and opinion from physicians’ concilium)	Patient data to inform eligibility and treatment continuation decisions
Data analysis plan	None	None	None
Frequency of data collection	After 1 year, then every 6 months	Before each maintenance cycle (4-monthly)	Proposed before each maintenance cycle (4-monthly)
Interim data reviews	Unknown	NHIF produces annual report on budget expenditure for ultra-rare conditions by therapeutic area	Unknown
Data quality process	Unknown	NHIF has routine checks on data quality	Unknown
Funder for data collection	NHS	NHIF	Unknown
Funder for data processing	NHS	NHIF	Unknown

AIFA Italian Medicines Agency, AOTMiT Agency for Health Technology Assessment and Tariff System, CHOP INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, CNS central nervous system, CPAP HFMSE Hammersmith Functional Motor Scale Expanded, HINE Hammersmith Infant Neurological Examination, HSE MMP Health Services Executive Medicines Management Programme, MEA , MAH marketing authorisation holder, MoH Ministry of Health, NHIF National Health Insurance Fund, NHS National Health Service, OBMEA outcomes-based managed entry agreement, P&R pricing and reimbursement, RULM revised upper limb module, SMA spinal muscular atrophy

^aNHIF requirements: Section B on page 4: https://www.nhif.bg/get_file?uuid=9AECFAA6771D62DBE05400144FFB42AE (Bulgarian)

^bhttps://www.hse.ie/eng/about/who/acute-hospitals-division/drugs-management-programme/protocols/hse-nusinersen-spinraza-protocol.pdf

^chttp://www.vmnvd.gov.lv/uploads/files/5d0a2aa94a54d.pdf and http://www.vmnvd.gov.lv/lv/veselibas-aprupes-pakalpojumi/retas-slimibas

^dConvocation of 3 or more physicians to give advice

^eNarodowy Fundusz Zdrowia