Variations in cell therapy reimbursement across the Big5EU

Variations in cell therapy reimbursement across the Big5EU Jesper Jorgensen and Panos Kefalas May 2015 Catapult is an Innovate UK programme.

Overview This presentation describes how pricing and reimbursement (P&R) frameworks for cell therapies vary by: A. Geography across the Big5EU (France, Germany, Italy, Spain and UK) B. Therapy features: We focus on: magnitude of incremental benefit vs alternative therapeutic approaches size of target population regulatory status The hospital setting (in- and out-patient) The public payers

Licensed ATMP category

Pricing of innovative licensed therapies in Big5EU has shifted towards value-based models What is it? Examples Comments Cost-based Competitor-based Value-based Price based on costs, expected sales and margins Cost-plus pricing Becoming obsolete Exception: unlicensed ATMPs Price driven by competition Penetration pricing Reference group pricing Enforced for undifferentiated products Price based on evidence of therapeutic /economic value to the customer Value-based pricing Typical approach for differentiated products 4

Value-based assessments link price potential to the magnitude of the novel therapy s added-value over the standard of care (SOC) PRINCIPLES OF VALUE-BASED ASSESSMENTS V = RV + PDV - NDV Differentiating Value Includes: PDV Negative differentiation value (NDV) Positive differentiation value NDV Clinical effectiveness Economic effectiveness: budget impact, costminimisation, cost-effectiveness, cost-utility, costconsequence Comparative data against the SOC/BSC per country is required: V Gold-standard: H2H RCT RV Reference value (SOC) Indirect comparisons (NMA) can be leveraged when H2H not available Comparisons should be based on balanced data Data manipulation via regression: Observational vs RCT For a given indication, V varies depending on therapeutic positioning 5

QoL (utility score) ATMP In the UK the incremental cost-effectiveness ratio (ICER) is widely used to inform price potential Cost B Cost A ICER = QALY B QALY A QALYs = Life expectancy (life years) x Quality of life (QoL) utility Costs Utility ranges from 0 (death) to 1 (full health) NHS and PSS costs (wider societal costs excluded ICER thresholds for non-rare diseases (operated by UK HTA bodies: NICE, SMC,AWMSG) 20-30K/QALY; exact figure depends on: certainty on QoL and ICER; degree of innovation For end-of-life treatments and for small populations a higher threshold can be considered 1.0 0.5 Treatment A Treatment B EXCEPTIONS! Very small patient populations Willingness-to-pay increases as : disease burden increases 0 1 2 Life Years QALYs gained (B vs A) target population decreases 6

ATMP The ICER calculation is based on a therapy -specific model that captures health states, time-dependent transitions, outcomes and uncertainty Model Type e.g. decision tree, state transition Markov model, DES, transmission model Analysis: Cohort simulation (lack of IPD), Microsimulation Time horizon: Up to 100 yearly cycles Discount rate: 3.5% Health States (and transitions): as per disease trajectory Pay-offs: cost, utility and life years Model uncertainty is addressed through sensitivity analysis Deterministic: univariate / multivariate Probabilistic: parametric / non-parametric (bootstrapping) Structural

ATMP Given a certain level of uncertainty in model variables, a health economically justified price results in the majority of ICER values falling below the ICER threshold ICER scatterplot generated through a Monte Carlo simulation Software: TreeAge Pro 2014 8

ATMP Unlike UK, in Germany ICER thresholds are not in use; clinical benefit, budget impact and international price referencing are the key drivers of reimbursed price potential A clinical benefit assessment (by the Joint Federal Committee [G-BA] and the Institute for Quality and Efficiency in Healthcare [IQWiG]) is the starting point for reimbursement for the majority of novel therapies launching The early benefit assessment rates the incremental clinical effectiveness of the novel therapy vs a relevant comparator in Germany The National Association of Statutory Health Insurance Funds (GKV Spitzenverband) negotiate price based on the clinical benefit assessment and budget impact considerations Therapies with no additional benefit are included in price referencing groups (if available) International price referencing (based on a basket of 15 EU countries) is applied by arbitration in cases where an additional benefit is recognised, but no agreement is reached on price Free pricing applies for therapies with annual revenue < 1M, or for hospital-only products covered through existing DRG tariffs Benefit assessment (AMNOG) Price referencing Price negotiation Level of added benefit No (fehlt) Not quantifiable Minor/ marginal (gering) Considerable benefit (beträchtlich) Significant/ major (erheblich)

Benefit ATMP Under certain circumstances cost-benefit analysis may also be a driver in determining price CBA: Efficiency Frontier 3 2 E 1 D B A Net costs / Patient C Manufacturers can request a costbenefit-analysis (CBA) to be conducted by IQWiG in two scenarios: The benefit assessment finds no additional benefit, but the product cannot be included in a reference price group (e.g. new mechanism of action), or The manufacturer rejects the international price-referencing to EU15 Numbers 1-3 represent three hypothetical therapies The blue line, the efficiency frontier, represents the willingness to pay (needed to access the more expensive but more efficient therapies Rectangles A, B, C represent therapies of negative efficiency, i.e. more expensive and less beneficial than existing options (not reimbursed) Triangles D, E represent therapies that are not inefficient, but less efficient than the frontier New treatments exceeding the existing cost and benefit levels can be considered acceptable if they are above the extension of the existing willingness to pay

EU4* price corridor ATMP In France, the magnitude of incremental clinical benefit (ASMR) drives the choice of the pricing framework applied ASMR Definition Impact on pricing I II III Therapeutic breakthrough Important improvement Modest improvement Based on prices in EU4 (Germany, Italy, Spain and UK) and supporting cost-effectiveness data IV Minor improvement Parity or small premium over comparator V No/ weak improvement Discount to comparator Price ILLUSTRATIVE The national authority for health (HAS) assesses the added clinical benefit (ASMR) of new treatments vs SOC The pricing committee of the MoH (CEPS) negotiates price based on ASMR score, expected sales volumes, and, for treatments with ASMR I-III, cost-effectiveness No explicit ICER thresholds apply Similar to Germany, free pricing applies for hospital-only products covered sufficiently by existing DRG tariffs Price/volume agreements are commonly used to limit budget impact uncertainty; price is discounted stepwise at confidential volume thresholds Price below the EU4 corridor if HE evidence is inadequate and inconclusive ASMR III ASMR II ASMR I Added benefit

ATMP The Italian pricing committee of the National Medicines Agency (AIFA) leverages several factors in price negotiations List price Improved QoL Improved efficacy CONCEPTUAL Budget Impact Disease severity and availability of options Contribution to GDP; lobbying and political relations EU prices* Added benefits AIFA determines whether a new therapy is classified as innovative, based on clinical effectiveness and disease burden It sets the price and the conditions for reimbursement Being innovative helps escape existing pricing benchmarks however: Funding and use is restricted to certain centres, and patient outcomes must be recorded in product-specific AIFA registries Establishing registries for new product can be a hurdle and delay actual adoption An annual fee of 30,000 is levied by the AIFA for each registry Whereas the 21 regions normally have the final say on whether to provide certain treatments, all innovative products must be provided across Italy Mandatory and negotiated (confidential) national, regional and local level discounts are the norm which can result in considerable differences in net price across the country Payment-for-performance is also common for innovative treatments Rebates may be linked to achieving / not achieving pre-specified clinical outcomes (payment by results) and/or exceeding pre-specified budget caps * Typically France, Germany, Spain and the UK

ATMP Cost-effectiveness may be accounted for, but no formal requirements exist; budget impact is key A. Cost-effectiveness National level Cost effectiveness analysis is not mandatory in P&R decisions, and although AIFA considers the evidence submitted, it applies no standard requirements for methodology or threshold values Regional level Some Regions e.g. Veneto, Emilia Romagna, Tuscany have their own independent HTA capabilities, however they can also reference HTAs done in other countries (typically England and Scotland) Therefore, regional and local funding decisions in Italy may be negatively affected by negative reimbursement recommendations in the UK Local level Hospitals typically focus on cost offsets e.g. reductions in length of stay and hospitalization costs, as well as the impact on the drug budget B. The main economic value driver across all levels is budget impact The main focus for budget impact analyses is one-year horizon which limits the value proposition for treatments with long-term benefits 13

ATMP Spain is a highly decentralised market where P&R decisions are made at national, regional and local level Internal price referencing Novel therapy is benchmarked against existing therapeutic alternatives in Spain International price referencing Pricing authorities commonly reference the cheapest available prices in the Euro zone Tight budget constraints have increased decision-makers price-sensitivity A ceiling price for reimbursement is determined at national level Authorities reference comparator drugs and EU countries with lowest prices Impact on GDP (e.g. through industry presence in Spain) is considered Pricing is shifting towards value-based, however budget control is priority Value-based pricing tends to be applied in conjunction with risk-sharing agreements e.g. ChondroCelect: (100% refund if failure at year one; 75% if yr2, and 50% if yr3) The 17 regions make decisions on conditions for inclusion in regional formularies, and negotiate prices below national ceiling price Hospitals decide on formulary inclusion and negotiate prices further

ATMP HE considerations are mainly driven by BI; CE is compulsory, but given the budgetary constraints, it is of uncertain impact on pricing and reimbursement Budget impact (BI) is the main analysis employed by decision-makers Cost-effectiveness (CE) can be employed but plays a less defined role: Nationally: P&R authorities request CE analysis by manufacturers: The pricing benchmark ultimately applied by authorities may be different from the comparator used in the CE analysis No explicitly defined threshold; implicit threshold is 30,000 per QALY Regionally: Only six out of the 17 regions have HTA agencies that may conduct CE analysis (Catalonia being the most advanced) Regions without HTA capability may rely on assessments conducted elsewhere Locally: The GENESIS group provides a framework for assessment methodologies at hospital level (including CE, cost minimisation and number needed to treat) It also commonly references evaluations performed in other countries, e.g. NICE (England and Wales), CADTH (Canada), SMC (Scotland), NPS-RADAR (Australia)

ATMP Across Big5EU additional funding mechanisms exist to address funding gaps from DRG tariffs Innovative therapies with a favourable reimbursement decision (at national/ regional level) are typically funded through one of the following mechanisms: Revise/ update existing DRG (diagnosis-related group) tariff Create new DRG and tariff Provide supplementary funding Country France Supplementary funding for hospital products Hors T2A funding restricted to high-cost therapies with: ASMR I-III, or Germany Italy Spain UK ASMR IV-V against a comparator with ASMR I-III Temporary funding (NUB), negotiated between individual hospitals and sickness funds; different tariffs apply across hospitals Permanent funding (ZE); tariffs set nationally File F funding for hospital products, decided by individual regions DRGs not widely used; regions rarely agree to supplementary funding; hospitals have to absorb costs (impacting uptake) DRG exclusions/top-up payments, decided by NHS Monitor Cancer Drugs Fund ( 340M p.a.) available for those not approved by NICE (England)

ATMP The size of the target population has P&R implications Willingness to pay is generally higher in very rare diseases due to budget impact and disease burden considerations In payer negotiations, the definition of rarity is not explicit, and at the discretion of decision-makers, (unlike regulatory definitions of orphan, and ultra-orphan*) Country France Germany Italy Spain UK Impacts price/volume agreement Size of target population Forecasted sales determine P&R (abbreviated P&R submission for < 50M p.a., free pricing for < 1M p.a.) Budget impact is central to P&R NICE HSTE relevant to chronic treatments that target <500 patients/ provides greater flexibility with ICER thresholds For NHS Specialised Services ICER thresholds less relevant e.g. Cerezyme commissioned for the treatment of Gaucher s (prevalence 270) at an ICER of 391,244 <20 patients p.a: individual funding requests (rather than formal assessments) *Orphan is defined by prevalence <5/10,000 ; Ultra orphan is defined by prevalence <1/50,000

ATMP Only UK provides clear HTA guidance on how long-term claims can be substantiated through extrapolations To bridge the gap between short-term data and long-term claims a regression framework is applied Specified parametric and semi-parametric models are fitted Optimal model selected based on statistical considerations and biological plausibility Fitted survivor function (using example trial data) NICE Decision Support Unit Technical Support Document 14: Survival analysis for economic evaluations alongside clinical trials extrapolation with patient-level data, March 2013

ATMP Innovative pricing agreements are used across the Big5EU to address clinical and economic uncertainties EU Payers are increasingly resistant to budget uncertainties Uncertainties arise from: Inconclusive clinical and cost effectiveness data at launch Variation in individual patient needs for dosing and length of treatment Types of pricing agreements in operation: Financially-based (most common due to lower administrative burden) Discounts or rebates Outcomes-based, e.g. If value is proven, the negotiated price remains (if not, it decreases) Risk-sharing on individual patient basis e.g. ChondroCelect in Spain: 100% refund if failure at year one 75% refund if failure at year two 50% refund if failure at year three Post-launch evidence generation required 19

Other categories: Minimally Manipulated Cell Therapies Hospital Exemptions Compassionate Use

Depending on the market, certain regulatory categories of cell therapies can bypass formal P&R assessments Minimally manipulated cell therapies (MMCs) In France, Germany and UK similar P&R assessments apply to MMCs and ATMPs In Italy and Spain, MMCs can bypass national/regional P&R assessments and be assessed by hospitals only Hospital exemptions / Specials Price often determined on a cost-plus basis (rather than value-based) Exception Spain: Need to be supplied on a not-for-profit basis Compassionate use In Germany the manufacturer has to provide treatment free of charge In the other 4 markets price is set freely In France, free-pricing can be penalised through post-launch rebates (ATU) 21

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