Health Policy Analysis - Contents lists available at sciencedirect.com Journal homepage: www.elsevier.com/locate/jval Financing and Reimbursement of Approved Advanced Therapies in Several European Countries Carolina Iglesias-López, PhD, Antònia Agustí, MD, PhD, Antoni Vallano, MD, PhD, Mercè Obach, PhD A B S T R A C T Objectives: The uncertainty in the cost-benefit of advanced therapy medicinal products (ATMPs) is a current challenge for their reimbursement in health systems. This study aimed to provide a comparative analysis of the National Health Authorities (NHAs) reimbursement recommendations issued in different European countries. Methods: The NHA reimbursement recommendations for the approved ATMPs were compared among 8 European Union (EU) Countries (EU8: Ireland, England/Wales, Scotland, The Netherlands, France, Germany, Spain, and Italy). The search was carried out until December 31, 2021. Results: A total of 19 approved ATMPs and 76 appraisal reports were analyzed. The majority of the ATMPs were reimbursed, although with uncertainty in added therapeutic value. No relationship between the type of the European Medicines Agency approval and reimbursement was found. Managed entry agreements, such as payment by results, were necessary to ensure market access. The main issue during the evaluation was to base the cost-effectiveness analyses on assumptions because of the limited long-term data. The estimated incremental cost-effectiveness ratio among countries reveals high variability. Overall, the median time to NHA recommendation for the EU8 is in the range of 9 to 17 months. Conclusions: Transparent, harmonized, and systematic assessments across the EU NHAs in terms of cost-effectiveness, added therapeutic value, and grade of innovativeness are needed. This could lead to a more aligned access, increasing the EU market attractiveness and raising public fairness in terms of patient access and pricing. Keywords: added therapeutic value, advanced medicinal products, financing government, health technology assessment, market access. VALUE HEALTH. 2023; 26(6):841–853 Introduction perform a relative efficacy and safety assessment, giving recom- mendations on whether a product should be considered for Advanced therapy medicinal products (ATMPs) are innovative reimbursement and under what conditions, if necessary.4 These drugs, based on genes, cells, and tissues, offering potentially NHAs appraisals usually consider several criteria to make their curative treatment options for a range of diseases. ATMPs are recommendations, such as the burden and severity of the target associated with high costs and, for some of them, uncertain effi- indication, the relative effectiveness and safety of the new product cacy claims, which is being a current setback for the market access compared with the standard of care (SoC) or best supportive care, of these drugs.1 This is accentuated by the fact that an increased the cost and economical effectiveness, as well as ethical, social, number of ATMPs are expected to enter the market in the coming and patient aspects.5 decade, covering indications with higher prevalence rather than The aim of our research was (1) to provide a comparative orphan diseases.2,3 Once the European Commission (EC) approves analysis of NHAs recommendations issued by 8 different European an ATMP, the access to treatment depends on the inclusion of the countries, (2) to analyze if there was any relationship between the product in the public healthcare funding. Each European Member type of the European Medicines Agency (EMA) approval (condi- State has its own authority over the market access of new prod- tional approval or under exceptional conditions vs standard ucts and its reimbursement agreements, which are conditioned by approval) that could affect the reimbursement decision, and (3) to the respective healthcare resources. With this purpose, the Na- provide insights of the key considerations that played a role in the tional Health Authorities (NHAs) of European Member States NHA reimbursement recommendations. 1098-3015/Copyright ª 2023, International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 842 VALUE IN HEALTH JUNE 2023 Methods reimbursement final decision were classified according to the prespecified domains. In addition, these considerations were An analysis of NHAs reports of authorized ATMPs in 8 Euro- classified according to the ATMP type: gene therapies (chimeric pean Union (EU) countries (EU8) has been conducted using the antigen receptor T cell [CAR-T] products), gene therapies that following approach: consist of viral vector–delivered or cell-based therapies and cell- and tissue-engineered products. Data extraction and analysis Search Strategy were conducted by one author, and a second author validated it. Inconsistencies were discussed until consensus was reached. Data collection was primarily extracted from available NHAs reports, such as health technology assessments (HTAs) and other Statistical Analysis official national reports of the EU8, that is, Ireland, England/Wales, Scotland, The Netherlands, France, Germany, Spain, and Italy. The A descriptive statistical analysis was performed using means, inclusion of countries was according to the largest European median, and range (minimum and maximum). The relationship countries and HTA report availability written in a language un- between the type of EMA approval and the reimbursement deci- derstood by the researchers. The search was carried out until sion was assessed by a chi-square statistic test with Yates December 31, 2021. In addition, a search for related publications correction. A P value , .05 was considered statistically significant. was performed for pricing (ie, gray literature: open search and non–peer review journals). Results Eligibility Criteria The analyzed products and the type of approval granted by the Only products classified as ATMPs according to the EMA EMA are listed in Table 1. A total of 19 approved ATMPs were criteria6,7 and authorized under centralized procedure in the EU included for 20 indications, 7 of those were authorized under have been considered for the analysis. conditional or exceptional circumstances. In addition, 7 ATMPs were withdrawn from the market. A total of 76 NHAs appraisal Data Extraction and Collected Variables reports or summaries among the analyzed countries were avail- The authors designed specific data extraction forms using able and analyzed. Excel 2019 (Microsoft Corporation, Redmond, WA) to collect in- formation. A review of NHAs reports of approved ATMPs pub- Recommendations of Reimbursement and Type of lished by national bodies in each country was conducted. The Reimbursement Schemes national bodies and the type of HTA reports analyzed for each The majority of the ATMPs were initially reimbursed in most country are reported in Supplemental Material found at https:// EU8, except in the case of Ireland (Table 2). Germany reimbursed doi.org/10.1016/j.jval.2022.12.014. all the 13 ATMPs for 14 indications, as well as The Netherlands (6 For each ATMP/indication and NHA body, the following vari- ATMPs were reimbursed except for 1 indication of 1 product). ables were collected: type of EMA approval, reimbursement England and Wales agreed for the reimbursement of 11 out of 12 recommendation, financing conditions, drug comparator used for assessed ATMPs, similar to France with 10 out of 14 and Italy with the cost-effectiveness analysis and incremental cost-effectiveness 7 out of 8 products. Ireland did not reimburse any of the 5 ratio (ICER), reported price of the product (notified price or ap- assessed ATMPs at an initial stage but did it later after reassess- plicants requested price), date of publication of technology ment with CAR-T products. appraisal guidance, and the date of recommendation imple- England and Wales, Scotland, The Netherlands, France, and mentation. Only reports describing the initial assessments were Spain narrowed the authorized indication for the reimbursement included, excluding resubmissions. For the ICERs, the base case of some ATMPs. Germany did not restrict any ATMP to specific accepted by the agency after corrections was chosen. Time from conditions within the authorized indication. EMA approval to NHA recommendation in their appraisal reports Most countries established some types of reimbursement and time from EMA approval to implementation (ie, product schemes, but the specific type of schemes is divergent among the available to the patients) were analyzed. EU8. Managed entry agreements (MEAs) or patient access It was assessed if there was any relationship between the type schemes are regularly used in Scotland and England, deter- of EMA approval (conditional approval or under exceptional con- mining specific conditions for reimbursement, usually in a ditions vs standard approval) that could affect the reimbursement confidential manner. Payment based on outcomes are more decision, given that less comprehensive data might be available. frequently used in The Netherlands, Spain, and Italy where The key considerations that played a role in or might have financing is linked to the achievement of certain clinical out- influenced the NHA reimbursement recommendation or final comes. This risk-sharing reimbursement approach might allow decision were collected for those products with an available NHA discounts and rebates. assessment report (in which these considerations could be The type of EMA approval did not have an influence on the extracted). After identification of all HTA reports of authorized reimbursement decision (chi-square 0.4742; P = .492). ATMPs, considerations that had an influence on reimbursement were extracted—a consideration was defined as follows: “a value Determination of a Product’s Added Therapeutic Value judgement of the HTA-body during the assessment.” These key considerations were classified according to the 5 European The determination of a product’s added therapeutic value Network for Health Technology Assessement HTA Core Model (ATV) has different implications in terms of recommendations, (version 3) domains and the HTA Core Model for Rapid Relative reimbursement negotiations, and granting the drug innovative- Effectiveness Assessments domains (version 4.2).8,9 A review ness status. In Supplemental Material found at https://doi.org/1 was conducted for the published reports of approved ATMPs to 0.1016/j.jval.2022.12.014, these implications are further dis- compare the aforementioned variables of the ATMP assessments cussed by country. There is not a harmonized or defined standard across the 8 NHA bodies. The items or considerations included in for ATV classification, and the assessment criteria is different in the NHAs reports that might have had an influence on the each country. In France, Italy, and Germany, the ATV is assessed HEALTH POLICY ANALYSIS 843 Table 1. Analyzed ATMP approved in the European Union. Type of ATMP Brand name INN Pharmacotherapeutic Orphan Type of group drug authorization designation and current status GTMP Glybera Alipogen tiparvovec Lipid modifying agents Yes Exceptional circumstances. Withdrawn Imlygic Talimogene laherparepvec Antineoplastic agent No Standard Kymriah (DLBCL) Tisagenlecleucel Antineoplastic agent Yes Standard Kymriah (ALL) Tisagenlecleucel Antineoplastic agent Yes Standard Yescarta Axicabtagene ciloleucel Antineoplastic agent Yes Standard Tecartus Autologous peripheral blood T Antineoplastic agent Yes Conditional cells CD4 and CD8 selected and CD3 and CD28 activated transduced with retroviral vector expressing anti-CD19 CD28/CD3- zeta chimeric antigen receptor and cultured Strimvelis Autologous CD341 enriched cell Immunostimulants Yes Standard fraction that contains CD341 cells transduced with retroviral vector that encodes for the human ADA cDNA sequence Luxturna Voretigene neparvovec Ophthalmologicals Yes Standard  Zynteglo Betibeglogene autotemcel Other hematological agents Yes Conditional. Withdrawn Zolgensma Onasemnogene abeparvovec Other drugs for disorders of the Yes Conditional musculoskeletal system Libmeldy Atidarsagene autotemcel Other nervous system drugs Yes Standard Abecma Idecabtagene vicleucel Antineoplastic agent Yes Conditional Skysona Elivaldogene autotemcel Other nervous system drugs Yes Standard. Withdrawn SCTMP Provenge Autologous peripheral-blood Other immunostimulants No Standard. mononuclear cells activated with Withdrawn prostatic acid phosphatase granulocyte-macrophage colony-stimulating factor (Sipuleucel-T) Zalmoxis Allogeneic T cells genetically Antineoplastic agents Yes Conditional. modified with a retroviral vector Withdrawn encoding for a truncated form of the human low affinity nerve growth factor receptor (DLNGFR) and the herpes simplex I virus thymidine kinase (HSV-TK Mut2) Alofisel Darvadstrocel Immunosuppressants Yes Standard  TEP Chondrocelect Characterized viable autologous Other drugs for disorders of the No Standard. cartilage cells expanded ex vivo musculoskeletal system Withdrawn expressing specific marker proteins MACI Matrix-applied characterized Other drugs for disorders of the No Standard. autologous cultured musculoskeletal system Withdrawn chondrocytes Spherox Spheroids of human autologous Other drugs for disorders of the No Standard matrix-associated chondrocytes musculoskeletal system Holoclar Ex vivo expanded autologous Ophthalmologicals Yes Conditional human corneal epithelial cells containing stem cells ADA indicates adenosine deaminase; ALL, B-cell acute lymphoblastic leukemia; ATMP, advanced therapy medicinal product; cDNA, complementary DNA; DLBCL, diffuse large B-cell lymphoma; GTMP, gene therapy medicinal product; INN, international nonproprietary name; SCTMP, somatic-cell therapy medicinal product; TEP, tissue- engineered medicinal product. 844 VALUE IN HEALTH JUNE 2023 Table 2. Overview of initial reimbursement recommendations and financing conditions of approved advanced therapy medicinal products in the Europe Union (December 2021). Product/indication Scotland Ireland England The Italy Spain France Germany and Wales Netherlands GTMP Glybera ‡ *  † ‡ Imlygic MEA * Kymriah (DLBCL) MEA/OEP* *ODM§ MEA* ‡ PBO* PBO† * * Kymriah (ALL) MEA/OEP* *ODM§ MEA* OEP* PBO* PBO† * *  ‡ † Yescarta MEA/OEP* MEA* MEA* PBO* PBO * * Tecartus MEA/OEP* MEA* * * Strimvelis * PBO*  † ‡ Luxturna MEA/OEP MEA* PBO/OEP* * PBO* * * Zynteglo PBO/OEP* † * Zolgensma MEA/OEP† ‡ MEA† PBO† † † *  † Libmeldy * Abecma SCTMP Provenge *  ‡ Zalmoxis * * Alofisel OEP‡ ‡ ‡ ‡ PBO† † * TEP Chondrocelect † † ‡ MACI MEA†  † ‡ Spherox Holoclar OEP† † PBO* ‡ † * Available 20 8 6 13 7 9 7 14 14 reports/ indication ALL indicates B-cell acute lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; GTMP, gene therapy medicinal product; MEA, managed entry agreement; ODM, Oncology Drug Management System; OEP, ultraorphan or end-of-life process; PBO, payment based on outcomes; SCTMP, somatic-cell therapy medicinal product; TEP, tissue-engineered medicinal product. *Positive recommendation. † Positive recommendation with restricted indication. ‡ Negative recommendation. § Initial negative recommendation and finally, reimbursement following confidential price negotiations on July 2021. as a separate parameter according to several ranks and scales, these drugs, but there are differences in how the magnitude of this whereas in Scotland, Ireland, and Spain, there is no publicly benefit is considered among countries (Supplemental Material defined ATV classification, and it seems to be a part of their found at https://doi.org/10.1016/j.jval.2022.12.014). clinical effectiveness assessment. The Netherlands uses a binary categorical classification system, classifying whether a product Special Funding Process That Affects Reimbursement has ATV or not, which is called “established medical science and Decision medical practice.”10 Most countries have special funding processes regarding the Table 3 compares the ATV assigned per product in France, Italy, reimbursement decisions related to orphan drugs, drugs that are Germany, and The Netherlands. In Italy, of the 6 indications (5 targeted to treat patients in their last months of life (also called ATMPs) in which innovativeness was assessed, 4 indications ob- end-of-life medicine), the disease severity, or to cover an unmet tained the innovative status, and 2 were denied. For those prod- medical need. In Supplemental Material found at https://doi.org/1 ucts, the ATV was graded as “important” for 4 indications, as 0.1016/j.jval.2022.12.014, the considerations for special funding “moderate” for 1, and as “low” for 1. In Germany, of the 14 in- processes are further discussed by country. dications (13 ATMPs) approved, 3 were classified as having the Of the 7 ATMPs assessed in Scotland, all were submitted under “added benefit not proven,” 7 were classified as “hint for a non- the orphan or end-of-life processes. In England and Wales, 3 quantifiable additional benefit” because the scientific data does ATMPs (Kymriah in diffuse large B-cell lymphoma indication, not permit quantification, 1 product was classified as “hint for a Yescarta, and Tecartus) met the criteria for life-extending considerable additional benefit,” and 2 products were not subject treatments, but Kymriah in acute lymphocytic leukemia indica- to the scope of the benefit assessment. From the 7 available HTA tion did not. From 13 analyzed drugs, 4 were assessed under the reports in The Netherlands, 5 assessed indications were consid- Highly Specialized Technology procedure (Strimvelis, Luxturna, ered “substitutable” or with similar therapeutic value, 1 was Zolgensma, and Libmeldy). In The Netherlands, 3 ATMPs were considered to be equal as SoC, and 1 was concluded to provide reported to have an orphan drug agreement. In Germany, 3 of the insufficient evidence of its intended effects. In France, most ATMPs 7 analyzed and approved drugs obtained an orphan drug agree- had a minor or moderate ATV. Overall, there is a benefit found in ment to guarantee patient access. HEALTH POLICY ANALYSIS 845 Table 3. Product ATV and innovativeness status. Product/indication Italy France Germany The Netherlands  GTMP Glybera Insufficient clinical No added benefit proven benefit Imlygic No added benefit proven Kymriah INV/important added CAV IV: minor added Nonquantifiable added benefit Does not comply with (DLBCL) value value established medical science and medical practice: insufficient evidence of the intended effects* Kymriah (ALL) INV/ important added CAV III: moderate added Nonquantifiable added benefit Meets the statutory criterion value value of “established medical science and medical practice” Yescarta INV/important added CAV III: moderate added Nonquantifiable added benefit Meets the statutory criterion value value of “established medical science and medical practice” Tecartus CAV III: moderate added Nonquantifiable added benefit value Luxturna INV/important added CAV II: substantial added Hint for a considerable additional Meets the “current state of value value benefit science and practice” criterion, but with great uncertainties on long-term effects and the cost- effectiveness Zynteglo CAV III: moderate added Nonquantifiable added benefit Meets the “current state of value science and practice” criterion, but with great uncertainties on long-term effects and the cost- effectiveness Zolgensma INV/important added CAV III: moderate added No added benefit proven Meets the “current state of value value science and practice” criterion but the scientific data does not permit quantification of added value with the comparator Libmeldy CAV III: moderate added Nonquantifiable added benefit value SCTMP Zalmoxis Non-INV/moderate - Nonquantifiable added benefit added value Provenge Nonquantifiable added benefit Alofisel Non-INV/minor added CAV IV: minor added Nonquantifiable added benefit value value TEP Holoclar Unknown CAV IV: minor added † value ChondroCelect Insufficient clinical Therapeutic value equal to benefit comparator Italy: the 5 categories of ATV are as follows: maximum (the drug has proven larger efficacy than any possible existing alternatives to the point of cure or significantly alter its natural history), important (the drug has a proven larger efficacy measured on clinically relevant endpoints, decreases the risk of invalidating or fatal complications, avoids highly dangerous clinical procedures or has more favorable risk/benefit ratio than any available alternatives), moderate (the drug has a larger efficacy than any available alternatives, but it is only moderate or only proven in some subsets of patients, with limited impact on the quality of life), poor (the drug has either a limited improvement of efficacy or has been proven on endpoints which are not clinically relevant, minor advantages, eg, more acceptable administration route), absent (the drug has no relevant benefit when compared with other available treatments). France: the CAV categories are: major (CAV level I), substantial (CAV level II), moderate (CAV level III), minor (CAV level IV) or no improvement (CAV level V), with the latter level corresponding to no therapeutic progress. Germany: the 6 categories of ATV are as follows: major, considerable, minor, and nonquantifiable added benefit; no added benefit proven; the benefit of the drug under assessment is less than the benefit of the appropriate comparator therapy. The Netherlands: “established medical science and medical practice”: product leads to relevant (added) value for the patient in comparison with the standard or usual treatment; “net benefit” of the intervention being assessed is a relevant and sufficiently large benefit in comparison with all existing care. ALL indicates B-cell acute lymphocytic leukemia; ATV, added therapeutic value; CAV, clinical added value; DLBCL, diffuse large B-cell lymphoma; GTMP, gene therapy medicinal product; INV, innovative status granted; Non-INV, innovative status not granted; SCTMP, somatic-cell therapy medicinal product; TEP, tissue-engineered medicinal product. *In a reassessment performed in January 2022, it was concluded that Kymriah meets the legal criterion of “established medical science and medical practice” in patients with r/r DLBCL. † Ex vivo expanded autologous human corneal epithelial cells containing stem cells are therefore not included in the scope of the benefit assessment according to Section 35a Social Code Book V. 846 VALUE IN HEALTH JUNE 2023 Table 4. Time (months) from EC approval to the NHA recommendation and product market access. Type of ATMPs EC approval HTA HTA Implementation HTA Implementation date recommendation recommendation recommendation Scotland Ireland England and Wales GTMP Glybera October 25, 2012 Imlygic December 16, 16 2 9 12 2015 Strimvelis May 26, 2016 20 23  ‡ Kymriah August 22, 2018 12 12 34 6 8 (DLBCL) Kymriah August 22, 2018 5 18 34‡ 3 5 (ALL) Yescarta August 23, 2018 13 5 7 Luxturna November 22, 14 21 10 13 2018 Zynteglo May 29, 2019 Tecartus 14-December 14, 7 2 4 2020 Zolgensma May 18, 2020 9 10 13 16 Libmeldy December 17,2020 SCTMP Provenge September 6, 2013 Zalmoxis August 18, 2016 Alofisel March 23, 2018 15 18 9  TEP Holoclar February 17, 2015 66 30 33 Spherox July 10, 2017 7 10 Median, months 13 15 34 9 11 Range Max, months 66 21 - 30 33 Range Min, months 5 2 - 2 4 Note. NHA recommendation: time (months) from EC approval to the date of publication of technology appraisal recommendation. Implementation: time (months) from EC approval to date of implementation of NHA recommendation. When information is not publicly available, there is a blank gap. There is no information published for Abecma and Skysona as of December 31, 2021. MACI and Holoclar were evaluated via the medical procedure in Germany and not as a medicine, which undergoes the benefit assessment procedure. ALL indicates B-cell acute lymphocytic leukemia; ANSM, National Agency for the Safety of Medicines and Health Products; ATU, Authorization of Use; DLBCL, diffuse large B-cell lymphoma; EC, European Commission; GTMP, gene therapy medicinal product; HTA, Health Technology Assessment; Max, maximum; Min, minimum; NHA, National Health Authority; SCTMP, somatic-cell therapy medicinal product; TEP, tissue-engineered medicinal product. * Cohort temporary ATU granted in France. † Received nominative ATUs in France from June 2019 and a cohort ATU granted by the ANSM on May 15, 2020 in the marketing authorization indication. ‡ Finally, reimbursement following confidential price negotiations on July 2021. § Early access scheme. Time to Market Access cohort ATU later in the marketing authorization indication (Zolgensma). This allowed that once the Committee for Medici- The time from EC approval to the national NHA recommen- nal Products for Human Use opinion was positive the patients dation on financing decision and product market access is sum- could already have access to the medicine without the need of marized in Table 4. Overall, the median time to NHA waiting for EC Decision and the HTA full evaluation period. During recommendation for the EU8 is in the range of 9 to 17 months, the the ATU validity, the company can set a free price before the time to implementation being the same as the time to NHA negotiation, but subsequently, the ASMR category will be a driver recommendation in Germany and 12 or 13 months in England. for price negotiation. The data generated during this period are For the other countries that were analyzed, the time to imple- used in addition to the clinical data from pivotal trials to inform mentation could not be determined due to limited data. the subsequent HTA and reimbursement determination at the In France, products can be reimbursed before central authori- time of marketing authorisation.12,13 zation via the Temporary Authorization of Use (ATU) on a named In Scotland, the “interim acceptance decision” was introduced patient basis (nominal ATU) or for all patients for a given indica- in 2018, which also allows that the SMC should have the option to tion (cohort ATU).11,12 From 10 analyzed products in France, 4 accept a medicine for use, which is subject to ongoing evaluation received ATU; 3 products received cohort ATU (Kymriah, Yes- and future reassessment for those drugs with a conditional mar- carta, and Luxturna) and 1 received nominative ATU and a keting authorization by the EMA or Medicines and Healthcare HEALTH POLICY ANALYSIS 847 Table 4. Continued HTA HTA HTA HTA HTA recommendation Implementation recomm recomm Implementation recommendation recommendation Implementation endation endation The Netherlands Italy Spain France Germany 27 30 26 11 11 6 15 4 4 6* 24 24 3 15 4 4 6* 24 24 6 20 21 10 10 6* 8 8 14 29 29 6* 10 10 25 9 11 11 4 7 8 11 13 7† 17 17 § 10 10 10 18 18 30 22 22 17 17 11 7 7 18 23 - - 35 8.5 20 15 17 10 9 11 11 25 - 21 29 29 35 27 30 3 - 13 4 4 4 7 7 products Regulatory Agency early access to medicines scheme or Supplemental Material found at https://doi.org/10.1016/j.jval.2 innovative licensing and access pathway.14 Tecartus and Hol- 022.12.014 according to ATMP product. A total of 33 reports oclar were accepted in the interim for use in National Healht were analyzed from Scotland, Ireland, England, and The Sevice Scotland. Netherlands NHA bodies: 3 CAR-Ts for 4 indications (14 reports in total), 5 viral vector gene therapies (13 reports in total), and 3 cell Comparators Used for the Cost-Effectiveness Analysis, therapies (6 reports in total). Several factors within European Notified Prices, and ICER Network for Health Technology Assessement domains were considered (Supplemental Material found at https://doi.org/10.1 The ICER thresholds varied depending on the country 016/j.jval.2022.12.014). (Supplemental Material found at https://doi.org/10.1016/j.jval.2 022.12.014). Appendix Table 1 in Supplemental Material found at https://doi.org/10.1016/j.jval.2022.12.014 shows the comparators used to determine the cost-effectiveness analysis of the analyzed Discussion ATMPs. The comparators used in the analyzed countries consist of Although the majority of the ATMPs were reimbursed in most similar SoC or best supportive care. This information was not EU8, the decisions are heterogeneous among these European available for Spain for any product. Most of the therapies are above countries based on how HTA agencies interpret evidence and the the set thresholds ranging from V45 000 per quality-adjusted life- associated uncertainties. Whereas most of the approved ATMPs year (QALY) to less than V100 000 per QALY (Table 5). The esti- were reimbursed in Germany, none of them were initially mated ICER for each product in each country and between coun- financed in Ireland, mainly because of the high uncertainty of tries reveals high variability. The notified prices are aligned across efficacy evaluation. Although Germany had the highest approval all the EU8 (Table 6). rate, this was mostly achieved with an unquantifiable benefit. Nevertheless, this is not only the case for ATMP and is common Key Considerations That Influenced the Reimbursement and depends on how the appraisal is conducted. For other Decision countries, there is a substantial tendency to issue a positive The key considerations that might have influenced the reim- recommendation but restricting the approved indication. The bursement decision are summarized in Appendix Table 2 in type of EMA approval does not seem to have an influence on the 848 VALUE IN HEALTH JUNE 2023 Table 5. Reported ICER for the approved ATMPs in the European Union Type of Scotland Ireland England and Wales The Netherlands Italy France ATMPs Imlygic  £23 900/QALY vs dacarbazine  £24 100/QALY vs BSC Kymriah (ALL) £25 238/QALY  V75 748/  £44 299/QALY vs Estimated added costs V32 543 80/  V90 029/QALY vs vs salvage QALY-V116 blinatumomab vs blinatumomab QALY vs salvage chemotherapy chemotherapy 506/QALY vs  £74 322 per QALY vs ranging V1.8-V2.1 salvage as reference and blina- blinatumomab salvage million and V1.8 chemotherapy tumomab over a lifetime  V75 990/ chemotherapy million allogenic bone horizon QALY-V107 marrow transplant*  V189 822/QALY vs 163/QALY vs rescue chemotherapy FLA-IDA baseline and blinatumo- mab over a 10-year time horizon Kymriah  £44 330-48  V1 035 700/ £42 991-£55 403/QALY V60 680 63/ V294 381/QALY over 10 (DLBCL) 116/QALY vs QALY vs (with the discount QALY vs years [R-] Gem-Ox; SCHOLAR-1 agreed) salvage  £44 151-47  V734 534/ chemotherapy 903/QALY vs QALY vs [R-] GDP CORAL exten- sion studies Yescarta £49 136/QALY V87 957/QALY £50 000/QALY vs V46 048/QALY-V600 V54 699/QALY V97 015/QALY (V84 766/ salvage chemotherapy 262/QALY vs SoC* vs BSC QALY before the technical exchange) Tecartus £49 711/QALY £46 898-£72 920/QALY V111 649/QALY vs SoC Strimvelis £494 255-£170 668 incremental costs when compared with an HSCT from a MUD and a haploidentical donor respectively Luxturna £89 871/QALY V189 037/QALY £60 908-£86 118/QALY V191 811/QALY vs BSC vs BSC vs BSC (a (do not include the over a time horizon of 85 discount rate of company’s commercial years (lifetime) 4% on costs and arrangement) outcomes is applied) Zynteglo V90 000 per QALY V 151 003/QALY vs better supportive care (transfusions 1 iron chelators), a price of 215% results in an RDCR of 106 175 V/QALY Zolgensma £59 996-£74 V298 469/QALY ICERs cannot be V263 389/QALY vs V51 690/QALY from V576 000/QALY-V2.6 000/QALY vs vs Nusinersen reported Nusinersen vs Nusinersen million/QALY over a time BSC V387 717/QALY horizon of 10 years and vs BSC V212 226/QALY-V1.5 million/QALY over a lifetime time horizon depending on the data source chosen Alofisel £20 930/QALY V109 058-V248 £23 176/QALY darvastrocel vs 548/QALY surgical examination 6 seton placement plus curettage Chondrocelect £14 000/QALY continued on next page HEALTH POLICY ANALYSIS 849 Table 5. Continued Type of Scotland Ireland England and Wales The Netherlands Italy France ATMPs Spherox  £4360/QALY vs microfracture  Lower than £20 000/ QALY vs BSC Holoclar £3483/QALY vs  £42 139/QALY vs BSC conjunctival limbal allograft from a living related donor  £30 415/QALY vs keratolimbal allo- graft £6948/QALY vs BSC Note. ICER is the difference in the change in mean costs in the population of interest divided by the difference in the change in mean outcomes in the population of interest. One QALY is equal to 1 year of life in perfect health. QALYs are calculated by estimating the years of life remaining for a patient following a particular treatment or intervention and weighting each year with a quality of life score (on a 0 to 1 scale). It is often measured in terms of the person’s ability to carry out the activities of daily life and freedom from pain and mental disturbance. The indicated costs of the table are per patient and QALY gained. ALL indicates B-cell acute lymphocytic leukemia; ATMP, advanced therapy medicinal product; BSC, best supportive care; DLBCL, diffuse large B-cell lymphoma; FLA-IDA, fludarabine, cytarabine and idarubicin; GDP, gross domestic product; HSCT, hematopoietic stem cell transplantation; ICER, incremental cost-effectiveness ratio; MUD, matched unrelated donor; NICE, National Institute for Health and Care Excellence; QALY, quality-adjusted life-year; RDCR, ratio différentiel coût-résultat; SoC, standard of care. *No cost-effectiveness analysis was not carried out. For Yescarta, comments on cost-utility analysis from NICE were considered. No economic analysis was performed; Information for Glyebra, Libmeldy, Abecma, Provenge, Zalmoxis, and MACI is not available. reimbursement decision, probably because of the type of in- different jurisdictions, making it challenging for the sponsor and dications targeted, that is, rare, last lines of treatment (in which inefficient in terms of sharing of outcomes data across jurisdic- there is an unmet need), or serious conditions. Our results tions, which could facilitate more robust evidence for reap- showed that the potential benefit of these therapies was praisal.21 In those countries where payment by results are not acknowledged, but overall, the high degree of uncertainty asso- used, a continuous reassessment could be an approach to manage ciated with the magnitude of clinical efficacy and safety the decision uncertainties associated with these therapies (eg, hampered the decision and made the evaluation complex. Some based on cohort data from a combination of follow-up from the studies have confirmed that single-arm study, short-duration, pivotal trials and real-world evidence).12,13 Broad principles for and indirect comparison were reported as a major efficacy un- innovative payment models for high-cost innovative medicines certainty, and it is suggested that the access to these therapies is have already been addressed by the EC.22 On the industry side, a lower in the EU than in the United States.15 We found that concrete list of recommendations has been proposed, which in- considerations that might have influenced the decision could go cludes payment models that distribute costs over time.23 It is still beyond the 3 common core domains (clinical effectiveness, uncertain how, with the expansion of ATMPs to high-prevalent safety, and cost-effectiveness) and include items related to the diseases, patients will have rapid access to innovation while “health problem and current use of technology” and “patient and keeping health systems financially sustainable. Value-based pric- social aspects” domains, because most therapies are targeting ing methodologies are suggested to be an option to cope with the orphan or end-of-life conditions. Other studies have suggested specific challenges of ATMPs.24 that the incorporation of additional “social value judgements” For the NHAs, the ATV of a new drug compared with the best (beyond clinical benefit assessment) and economic evaluations available treatment options is one of the key points to make their could help explain heterogeneity in coverage recommendations recommendation on reimbursement. Although no major signif- and decision making.16 Budget impact, gross domestic product, icant differences have been found when the ATV for approved involvement of patient advocacy groups, equity considerations, ATMPs has been compared among countries, a comparable and and different economic evaluations performed among European unified criterion was not used. Other studies have reported low countries could also contribute to this heterogeneity. rates of agreement on the ATV of ATMP and non-ATMP drugs In terms of the type of reimbursement scheme applied, the compared with the SoC among Germany, Italy, and France.25,26 trends are divergent among the EU8—different in each country The main reasons for the inconsistency were found to be with different special funding processes but with an extended use related to a different appreciation of the subgroup analysis of of MEAs. It has been recognized that a single payment model is efficacy data, the appropriateness of comparators, the surrogate unlikely in the case of ATMPs.17 The use of MEAs, which are mainly endpoints, methodological differences, and the benefit/risk negotiated when there is uncertainty regarding the drug clinical criteria that were used.26 A study has already been performed benefit, allows the introduction of new products with potential with the aim to investigate the feasibility of a harmonized EU benefit, but it is not seen as a solution to address high prices and approach concerning the assessment of the ATV of medicines in uncertainties associated with the ATMPs.18,19 The introduction of the EU.27 In this report, it is suggested that the ATV should be the 2 initial CAR-T products, Kymriah and Yescarta, constituted measured on an ordinal scale, as well as by a multidisciplinary the first examples of national reimbursement schemes involving team of trained experts independent from the committees in outcomes-based, staged payments for innovative therapies in charge of determining the reimbursement and product price. A Germany, Italy, and Spain.12,13,20 Nevertheless, the implementation harmonized definition of ATV would clarify the expected bene- of these agreements is not always easy, because the burden of fits of a new drug, set rewards for higher therapeutic added value monitoring this process is challenging, and can differ among and promote the innovation.27 In contrast, it is also under dis- countries. Different agreements arise for the same treatment in cussion how the ATV of ATMPs, in particular, should be assessed. 850 VALUE IN HEALTH JUNE 2023 Table 6. Notified prices reported for the approved ATMPs in the European Union. Type of Scotland Ireland England and Wales The Italy Spain Germany ATMPs Netherlands Glybera V1 321 139 (26 vials per patient) Imlygic £1670 per vial Annual therapy costs V72 287 80- V289 151 20 Kymriah (ALL) £282 000 per Total cost including £282 000 per infusion The total cost V320 000 V320 000 Annual infusion rebate is V301 762; VAT (company submission). of V320 000 (excluding (excluding therapy costs is not applicable Commercial arrangement per patient VAT) VAT) V282 419 28- and per V283 244 95 treatment Kymriah £282 000 per Total cost including £282 000 per infusion V320 000 V327 000 Annual (DLBCL) infusion rebate is V301 762; VAT (company submission). (excluding (excluding therapy costs is not applicable Commercial arrangement VAT) VAT) per patient V283 062 13- V291 815 14 Yescarta £282 451 per The total cost including Price submitted as V327 000 per V327 000 2 single infusion rebate and VAT is commercial in confidence infusion (excluding infusion bag V384 225 (including VAT) V389 130 conditioning chemotherapy) Tecartus £316 118 per Price submitted as 1 single infusion commercial in confidence infusion bag V360 000 Strimvelis £505 000 (excluding VAT; V594 000 V355 000 company’s evidence per vial submission) Luxturna £658 946 (in V690 000 (for 2 single- £613 410 per patient V690 000 (for V321 000 (for each eye) use packs, 1 for each (excluding VAT; company 2 single-use both eyes) eye) submission); commercial packs, 1 for arrangement each eye) Zynteglo V1 929 926 88- V1 936 134 22 Zolgensma £1 795 000 Price to wholesaler £1 795 000 (excluding VAT; V2 155 124 V1 945 000 V2 314 550 single V1 945 000, V2 285 375 company 65 infusion (including 23% VAT) submission). Commercial (excluding arrangement VAT) Libmeldy £2 875 000 (excluding VAT; V2 875 000 company submission) Provenge Annual therapy costs per V79 952 58 Zalmoxis V149 000 V60 000 Annual therapy costs per patient: V189 474 78- V757 899 12 Alofisel The cost per patient per £13 500 per vial. One course V71 400 00 year to the HSE of treatment (4 vials) costs (incorporating VAT and £54 000 (company mandatory 5.5% rebate) submission). Commercial is V70 500 arrangement Chondrocelect £16 000 (company submission) MACI £16 226 per implant (price excluding VAT). Negotiated discounts continued on next page HEALTH POLICY ANALYSIS 851 Table 6. Continued Type of Scotland Ireland England and Wales The Italy Spain Germany ATMPs Netherlands Spherox £10 000 per culture per patient, including cell costs and transportation Holoclar £80 000 (1 £80 000 excluding VAT for 1 V95 000 treatment eye. Commercial per limbal arrangement stem cell transplant) Note. No information for Abecma is available yet. ALL indicates B-cell acute lymphocytic leukemia; ATMP, advanced therapy medicinal product; DLBCL, diffuse large B-cell lymphoma; HSE, health service executive; VAT, value-added tax. The challenges of the standard value and price assessment comprise a unique group of products, usually administered at an methods in the evaluation of ATMPs have already been analyzed, early age and expected to last for the patient’s entire life. The and new elements to define their value have been proposed. economic burden at long-term of these type of diseases with the These new elements are more focused on societal perspective current SoC might be underestimated and some studies suggest and not only on comparative clinical benefit and economical that efforts are needed to reduce costs through improved aspects, for example, value of hope, real option value, and sci- drugs.36 Similar analyses have been performed with CAR-T entific spillovers.28,49 It has been reported that the assessments products.37 For this group of products, these increased ICERs of additional values beyond QALY are often based on “delibera- and prices have been justified and the “willingness to pay” levels tive decision making,” which is criticized for the lack of a clear were exceeded on the assumption of improving long-term clin- framework and transparency, as well as potential risks of double ical outcomes and patient and caregiver quality of life. With counting of additional values that are already included as part of these type of drugs, long-term payment with risk-sharing HTA reports.29 It is important to mention that in January 2018, models and a price without the premium addition have been the EC proposed a new regulation with the aim to promote more proposed to help with the affordability, patient access, and the alignment in terms of HTA assessments, which was approved in given uncertainty on effect durability.38 The partnership and December 2021. This regulation aims to replace the current joint assessments across several countries to make the medicines system of cooperation between Member States on HTAs with a more accessible to patients have already been applied for some permanent framework for joint work, allowing a harmonized approved ATMPs, as was the case of Zolgensma and Zynteglo approach to clinical assessment of new medicines across EU through the Beneluxa Initiative,39,40 which led to a successful Member States. With this new regulation that will be mandatory reimbursement recommendation and an aligned agreement on from 2025, transparency and more alignment in terms of pricing the price. Other cross-country collaborations aim to negotiate is also foreseen. Above all, it is fairly defined in a consistent way affordable and sustainable prices for new and innovative drugs.41 among the EU Member States to reflect the added value that the In contrast, it should be noted that the gross domestic product, as product can bring to patients.30 well as the purchasing power of the population is not homoge- Drugs to treat orphan conditions, end-of-life medicines, and neous among the different European countries. Therefore, it the disease severity and unmet medical needs are factors that would also be necessary to adjust the prices for each country have an influence in terms of a higher price, which is the critical according to its gross domestic product.42 feature of ATMPs that restrain the market access. It is generally Additionally, the lack of transparency of the information on recognized that drugs in these categories are unlikely to meet the NHA decision-making process and pricing (because the “real” the preexisting cost-effectiveness threshold,31 as well as a higher prices are often unknown because of agreed confidential dis- degree of uncertainty in evidence and assessment outcomes counts) has been extensively discussed. The need for a more being accepted.32 These type of applications are increasing ac- harmonized, systematic, and reproducible assessment process cess to drugs for end-of-life and rare conditions in Scotland, has already been discussed at the EC level.43 Transparency and whereas they might not otherwise have been accepted.33 It was more alignment in terms of pricing is also foreseen, and above all also suggested that, in England, medicines for rare diseases not it is fairly defined in a consistent way among the EU Member evaluated under the Highly Specialized Technology framework States to reflect the added value that the product can bring to or with an appropriate modifier in the appraisal process are patients. subject to disadvantages.34 Cost-effectiveness analysis and ICER The limitation of this study is the small sample size given the are variable among EU8, because most of ATMPs are above ICER limited number of ATMPs approved. In addition, for the latest thresholds set by the different countries, with a notified price approved products, the public reports are not yet available given that range comprising between V2 00 000 and V2 million. Moreover, the evaluations are still ongoing, which also reduces the sample size. concerns in addition to the price are the additional costs of Although 8 EU countries were evaluated, the lack of publicly available treating and managing these patients, which are the clinical information and the lack of transparency for some countries led to infrastructure and skills of the clinical staff. The pre-evaluation of believe that the study could not cover these 8 EU countries for some the organizational impact of ATMPs and the need for healthcare of the analyzed points. The conclusions cannot be generalized to centers with the necessary resources are suggested requirements other than the EU countries analyzed. 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