Table 3.

OBMEAs for tisagenlecleucel

Country Organisation (respondent if not from organisation)	Australia Medical Services Advisory Committee (Pharmaceutical Benefits Advisory Committee)	Belgium INAMI	England NICE
P&R indication sought	ALL, DLBCL	ALL, DLBCL as per SPC indication	ALL, DLBCL as per SPC indication
P&R date	April 2019	1/6/19	ALL, 16/11/18; DLBCL, 1/2/19
P&R special process	None	Conditional, Chapter IV of positive list	Cancer Drugs Fund
OBMEA population	ALL indication as per regulation (DLBCL reimbursed November 2019)	ALL, DLBCL as per SPC indication	ALL, DLBCL, SPC indication with extensive eligibility criteria (Electronic Supplementary Material)
OBMEA duration	2 years	2 years (could be extended up to 3 years)	ALL: 4 years 7 months; DLBCL: 4 years
Purpose of OBMEA	Manage clinical, economic and financial uncertainties in the March 2019 submission for ALL, particularly - Patient not successfully infused - Patient receives second dose - Patient numbers overestimated - Durability of response - Proportion receiving SCT - Need for ongoing IVIG (Co 3 years, vs 6 years from MoH) CED	Resolve uncertainties relating to efficacy/safety (particularly longer term), therapeutic added value - Success rate of production and turn-around time - Optimal selection of patients (high chance of response, low risk of severe toxicity) - Number of patients treated in real life - OS, PFS 6, 12 and 20 months (DLBCL only) - Number who had SCT without disease progression (i.e. Bridge-to-transplant) - Medical resource utilisation - Number receiving tocilizumab and duration - Number not infused and reason - Is capacity of accredited centres sufficient? CED	Resolve clinical uncertainties ALL: - Immaturity of data that do not fully support the curative nature of tisagenlecleucel - Rate of subsequent sct - Need for IVIG and duration of treatment DLBCL: - Immaturity of data (OS) to support the curative nature of tisagenlecleucel - Need for IVIG and duration of treatment CED
Use in re-appraisal	Re-appraisal of clinical and cost effectiveness and budget impact	Re-appraisal for price re-negotiations or alteration in eligibility and other criteria	Re-appraisal of clinical and cost effectiveness after data collection period (no extension of OBMEA permitted)
Stakeholders involved	- MAH, MSAC, MoH - Highly specialised tertiary centres - Australian BMT Registry	- INAMI Commission for Reimbursement proposed OBMEA to MAH, who accepted and developed OBMEA with MoH and INAMI MEA taskforce - Clinicians - Clinical centres accredited by MAH	- Signatories: MAH, NICE, NHSE&I, PHEa - Non-signatory: BSBMTCTb - Phased approach in accredited centres with national clinical panel to judge eligibility against eligibility criteria
Data sources	Completion of ongoing trial Health service data Australian BMT Registry	Completion of ongoing trials Clinician completed forms INAMI reimbursement data	MAH: ongoing phase II open-label trials and phase I study of lymphomas BSBMTCT registry NHS SACT dataset
Data collected	Minimum dataset: - Indication for use of CAR-T - PFS - Complications, use of high-cost medications, late-onset aes, saes - Use and duration of IVIG - Reinfusion with any CAR-T Sub-group analyses of patients infused with non-optimal cell numbers	To resolve stated uncertainties, details confidential	From clinical trials: OS; and for DLBCL also PFS and IVIG use From BMT register (if data sharing is possible) ALL, nNumber and time to stem cell transplant From NHS datasets (including SACT and other data) DLBCL: OS, IVIG use (if possible)
Data analysis plan	?	Confidential	- Data analysis plan specified in data collection agreement - Methodologies for analyses from NHS SACT database are publishedc
Frequency of data collection	Registry enters info for each patient as treated, including those unsuccessfully or not infused	Yearly (allowing for delay in data collection, thus end of 2021, end of 2022)	- Clinical trials, as per protocol - SACT data uploaded 2-monthly by NHS trusts - Registry data uploaded after patient has transplant and gives consent
Interim data reviews	No	No	- MAH asked for updates on clinical trials - SACT and BSBMTCT aggregated data reviews (with MAH, NICE, NHSE&I, PHE) at 9 and 12 months and annually of OS
Data quality process	?	None	- Clinical trial standard processes - NHS systems map local data to SACT information standard based on NHS data dictionaryd. PHE employ data liaison officers to review data and chase trusts for missing/erroneous data for CDF data reports. All CDF reports are subject to a review by NICE, NHSE&I and PHE prior to sharing externally or publication - BSBMTCT perform regular checks and validation tests on registry
Funder for data collection	MAH	Insurance funds (MAH for their bespoke analyses)	- MAH funds ongoing clinical trial - NHSE&I, SACT, Blueteq, registry
Funder for data processing	MAH	MAH	- MAH funds analysis of clinical trials - NHSE&I fund analysis of SACT, Blueteq, registry data

Country Organisation (respondent if not from organisation)	France Haute Autorité de Santé (partnere, HAS reportsf,g)	Italy AIFA (EX, formerly AIFA)	Spain MoH (JE, Jorgensen 2020)
P&R indication sought	ALL, DLBCL as per SPC indication	ALL, DLBCL as per SPC indication	ALL: DLBCL as per SPC indication
P&R date	July 2019	13/8/19	January 2019
P&R special process	No	Fund for innovative oncological drugs (Law 232, 2016), fully innovative (Innovation status valid 13/08/2019–12/08/2022—with innovativeness confirmation in July 2020)	No
OBMEA population	ALL, DLBCL as per SPC indication	ALL, DLBCL with clear eligibility criteria (Electronic Supplementary Material)	ALL: DLBCL with extensive eligibility criteria stated in national clinical assessment (Electronic Supplementary Material)
OBMEA duration	Unknown	Linked to P&R contract (18 months)	Confidential
Purpose of OBMEA	Resolve uncertainties about efficacy, safety and complexity of treatment process CED	Manage clinical uncertainty based on outcome metrics Individual: “payment at result” (staged payments) 3 payments at baseline, 6 months, 12 months	- Ensure equitable, safe and efficient use and monitor patients - Provide long-term evaluation of outcomes in clinical practice to resolve uncertainties that remain after clinical trials Individual: outcomes-based staged payments
Use in re-appraisal	Annual HTAs to reassess improvement in the clinical benefit (SMR/ASMR rating)	Ongoing, part of the regular P&R contract reviews	P&R renegotiations
Stakeholders involved	HAS Hospitals Registry holder MAH	- AIFA hosts national medicines registry, for PaR, MAH accesses anonymised individual data to verify the payment - Pharmacists responsible for payments in case of PaR. - Regions authorise centres and health managers authorise clinicians and pharmacists (dispensing dependent on registry entry by clinician)	MoH National Pricing Committee outline data to be collected by Regions with agreement from MAH Designated hospitals responsible for administering CAR-T
Data sources	- National CAR-T registry data platform hosted by Lymphoma Academic Research Organisation (LYSARC) - Ongoing clinical trials and PAES - Patients who received treatment through early access ATU scheme	AIFA national web-based registry for medicines, data collection determined from AIFA Technical Scientific Committee report and produces reports based on anonymised data	VALTERMED national web-based registry system launched in November 2019 to pilot the CAR-Ts, but not fully functioning by early 2021, hence MAH organising data collection
Data collected	(On all patients eligible for treatment, not only those actually treated) Patient characteristics Time from failure of last treatment to apheresis Tisagenlecleucel production time Therapeutic strategies before and after injection (e.g. tocilizumab, IVIG) Key outcomes at 28 days, 100 days, 6 months and then 6 monthly - Survival - Remission status - Disease progression - AEs Reasons for treatment failure and subsequent management including re-injection	ALL: Diagnosis: information on relapse, first diagnosis date, genetic risk factors Treatment: leukapheresis date, expected infusion date, weight, infusion (or reason for not infusing), reason for delay of administration Immediate follow-up: chemotherapy regimen, need for bridging therapy Follow-up: disease response status, other ALL treatments, AEs End of follow-up: various outcomes about cause including death DLBCL: Diagnosis: stage, International Prognostic Index, first diagnosis date Treatment: leukapheresis date, expected infusion date, date of infusion (or reason for not infusing), reasons for delay of administration Immediate follow-up: chemotherapy regime, need for bridging therapy Follow-up: disease response, other anti-lymphoma treatments, AEs End of follow-up: various outcomes about cause including death (Electronic Supplementary Material)	Patient characteristics Disease characterisation Leukapheresis, CAR-T production Administration of tisagenlecleucel Post-infusion and long-term safety monitoring Disease relapse/progression Response evaluation (ALL), complete response with early negative residual disease maintained for at least 18 months due exclusively to treatment with tisagenlecleucel
Data analysis plan	Part of HTA process	Confidential	Unknown
Frequency of data collection	Data reported by hospitals quarterly	Continuum in clinical practice	Continuum in clinical practice
Interim data reviews	Quarterly reports from the LYSARC registry	Depends on duration of contracts for P&R (18 months) and innovation status (12 months)	On VALTERMED, regions intended to have access to their own aggregated data for review. National reports on utilisation
Data quality process	Within registry platform	Probably, but process unclear	Intended registry platform, built-in Currently MAH responsible
Funder for data collection	MAH	MAH	Regional authorities/hospitals
Funder for data processing	Registry holder/MAH	AIFA	MoH

AE adverse event, AIFA Italian Medicines Agency, ALL acute lymphoblastic leukaemia, AOTMiT Agency for Health Technology Assessment and Tariff System, ATU authorisation for temporary use, BMT bone marrow transplant, BSBMTCT British Society of Blood and Marrow Transplantation and Cellular Therapy, CED coverage with evidence development, DLBCL diffuse large B-cell lymphoma, HAS Haute Autorité de Santé, INAMI National Insurance for Health and Disability Insurance, IVIG intravenous immunoglobulin, LYSARC Lymphoma Academic Research Organisation, MAH marketing authorisation holder, MoH Ministry of Health, MSAC Medical Services Advisory Committee, NHIF National Health Insurance Fund, NHSE&I NHS England&Improvement, NICE National Institute for Health and Care Excellence, OBMEA outcomes-based managed entry agreement, OS overall survival, PAES post-authorisation efficacy study, P&R pricing and reimbursement, PFS progression-free survival, PHE Public Health England, PRO patient-reported outcomes, SACT systemic anti-cancer therapy, SAE serious adverse event, SCT stem cell transplant, SPC Summary of Product Characteristics, VALTERMED VALor TERapeutico en la Practica Clinica Real de los MEDicamentos de Alto Impacto Sanitario y Economico

^aDLBCL only

^bALL only

^chttp://www.chemodataset.nhs.uk/nhse_partnership

^dSystemic Anti-Cancer Therapy Data Set (datadictionary.nhs.uk)dSystemic Anti-Cancer Therapy Data Set (http://www.datadictionary.nhs.uk)

^eHospinomics IMPACT HTA Partner, member of HAS CEESP

^fhttps://www.has-sante.fr/upload/docs/application/pdf/2018-12/kymriah_ldgcb_pic_ins_avis3_ct17238.pdf

^gKYMRIAH_LAL_12122018_AVIS_CT17202 (has-sante.fr)