Clinical and Translational Oncology https://doi.org/10.1007/s12094-021-02757-9 REVIEW ARTICLE A strategic reflection for the management and implementation of CAR‑T therapy in Spain: an expert consensus paper N. Zozaya1,2 · J. Villaseca1 · F. Abdalla1 · M. A. Calleja3 · J. L. Díez‑Martín4,5 · J. Estévez6 · R. García‑Sanz7 · J. Martínez‑López8 · J. Sierra9 · R. Vera10 · A. Hidalgo‑Vega11,12 Received: 15 October 2021 / Accepted: 9 December 2021 © The Author(s) 2022 Abstract CAR-T cell therapy represents a therapeutic revolution in the prognosis and treatment of patients with certain types of hema- tological cancer. However, they also pose new challenges in the healthcare, regulatory and financial fields. The aim of the RET-A project was to undertake a strategic reflection on the management of CAR-T therapies within the Spanish National Health System, to agree on recommendations that will help to better deal with the new context introduced by these cell therapies in the present and in the future. This think tank involved 40 key agents and opinion leaders. The experts identified three great challenges for implementing advanced therapies in Spain: therapeutic individualisation, with a multidisciplinary approach; acceleration of access times, by minimizing bureaucracy; and increase in the number of centers qualified to man- age the CAR-T therapies in the NHS. The experts agreed on the ideal criteria for designating those qualified centers. They also agreed on a comprehensive CAR-T care pathway with the timings and roles which would ideally be involved in each part of the process. Keywords Advanced therapies · CAR-T therapy · National health system · Spain Introduction represents a therapeutic revolution in the prognosis and life expectancy of patients with certain types of cancer. However, In the past decade, advances in cellular and molecular research this therapy also poses new challenges in the healthcare, regu- have led to the development of CAR T-cell therapy (chimeric latory and financial fields, which it is necessary to know to antigen receptor T-cell therapy), also known as CAR-T. It anticipate them and optimize their approach in the healthcare is a new generation of personalized immunotherapy which system. 7 * N. Zozaya Hematology Service, CIBERONC, and Salamanca Cancer neboa.zozaya@weber.org.es Research Centre‑IBMCC (USAL‑CSIC), University Hospital of Salamanca (HUS/IBSAL), Salamanca, Spain 1 Health Economics Department, Weber Economía y Salud, C/ 8 Hematology Department, Hospital Universitario, 12 de Moreto 17, 5D, 28014 Madrid, Spain Octubre, Complutense University of Madrid, CNIO, 2 Department of Quantitative Methods in Economics CIBERONC, Madrid, Spain and Management, University of Las Palmas de Gran Canaria, 9 Hematology Department and Sant Pau Biomedical Research Las Palmas, Spain Institute (IIB‑SP), Hospital de la Santa Creu i Sant Pau, 3 Pharmacy Department, Hospital Universitario Virgen Univarsitat Autonoma of Barcelona, Barcelona, Spain Macarena, Seville, Spain 10 Medical Oncology Service, Navarra Hospital Complex, 4 Hematology Department, Hospital GU Gregorio Marañón, Navarra Hospital, Pamplona, Navarra, Spain Gregorio Marañón Health Research Institute, Madrid, Spain 11 Weber Foundation, Madrid, Spain 5 Department of Medicine, Complutense University of Madrid, 12 Department of Economic Analysis and Finance, University Madrid, Spain of Castilla-La Mancha, Toledo, Spain 6 The Spanish Society of Health Executives, Sociedad Española de Directivos de La Salud (SEDISA), Madrid, Spain 13 Vol.:(0123456789) Clinical and Translational Oncology The aim of this study is to detail the RET-A project, ‘A Stra- was the allogeneic hematopoietic cell transplant (allo- tegic Reflection for the management and implementation of TPH), whose overall survival rate at 5 years was 20–45% the new Advanced Therapies in Spain’, which gathered experts [8, 9]. In cases of relapse after an allo-TPH, there was no together to reflect about the main challenges, opportunities and standard treatment, and the palliative treatments had an strengths of the Spanish NHS regarding CAR-T and to agree average survival period of less than 8 months [10, 11]. on recommendations to better deal with this new scenario in However, there is uncertainty about the real, long-term the present and the future. effectiveness of these advanced therapies that are tailor- made for each patient, require a multidisciplinary approach Methodology [12–14], as well as certain conditions for the caring capac- ity, and availability of human and technical resources in As a think tank on CAR-T therapies, the RET-A project the medical centers to ensure that their administration is brought together the multidisciplinary work of 40 key agents reliable and safe [15]. Moreover, these therapies are costly, of the Spanish NHS. RET-A was set in motion by an advisory so different financing schemes were set to promote their committee (the CORE group), which provided the overview, access [16–20]. For all these reasons, the management of design and scope of the project, as well the subjects to be dealt CAR-T therapy is different from that of drugs aimed at with by each working group, and the composition of those therapeutic targets and requires a more complex care pro- groups. cedure [12]. Four thematic multidisciplinary working groups (WG-1, WG-2, WG-3 and WG-4) (Table 1) were constituted. Face- to-face meetings were held among the different WG to share The Spanish Ministry of Health’s plan for advanced experiences and opinions about concrete important aspects of therapies the CAR-T therapies, to obtain reflections and recommenda- tions for improvement in each area. In 2018, the Spanish Ministry of Health approved, within To prepare the meetings, a detailed review of information the precision medicine strategy, the ‘Plan for Approaching about the different subjects connected with the CAR-T therapy Advanced Therapies in the National Health System: CAR was performed. It included, among other issues, a description Medicines’, aimed to organize in a planned, equitable, safe of CAR-T therapies, the Spanish Ministry of Health’s plan for and efficient way the use of these therapies [12]. Different advanced therapies, the evaluation and financing of CAR-T stakeholders participated in its design and development. therapies, and follow-up mechanisms. The project was led by The plan proposed an organizational model comprising Weber (a center for Research and Consulting in Health Eco- a network of qualified centers for the use and administra- nomics), who dealt with the search for information, the review tion of CAR medicines—currently, 14-, based on certain of the literature, as well as the organization and moderation of criteria [21, 22]. These centers, located in six Autono- each group of experts. mous Communities, have to attend all patients on equal terms regardless of their place of residence, provide care in a multidisciplinary team, guarantee continuity in care Relevant aspects in CAR‑T therapies: between stages of the patient's life and between levels of literature review care, evaluate the results and train other professionals. The plan also considered the creation of a committee at the A description of CAR‑T therapies national level to quickly assess the requests made by NHS specialists, whose favorable report will be mandatory for In 2018, the European Medicines Agency (EMA) and the the use of the medicine. U.S. Food and Drug Administration (FDA) authorized the The strategy of the Ministry of Health in advanced marketing of the first two industrially produced drugs with therapies had a dynamic character to evaluate and moni- CAR T-cells (tisagenlecleucel and axicabtagene ciloleu- tor the plan, identifying points to improve. And it will use cel) [1–4]. They provided promising clinical results to sat- horizon scanning to identify the CAR-T therapies that are isfy unmet therapeutic needs among patients with B-cell being incorporated in the medium / long term and the needs acute lymphoblastic leukemia (B-cell ALL) and diffuse to be satisfied [23]. To date, three follow-up reports have large B-cell lymphoma (DLBCL), with relapse or who had been published [24–26]. Some Autonomous Communities not responded to the available alternative treatments after have also tried to standardize and streamline the process of two or more lines of therapy [5–7]. CAR-T therapy [27–30]. Before these therapies were approved, only palliative or experimental treatments were applied. In patients with refractory B-cell ALL, the only potentially curative option 13 Table 1  Composition of the working groups participating in the RET-A project Working groups CORE group and WG-1 WG-2 WG-3 WG-4 Joaquín Estévez Lucas. President of the Span- Ana Lozano Blázquez. Director of the Unit Antoni Gilabert Perramón. Director of the Bernat Soria Escoms. Researcher at the ish Society of Health Directors (SEDISA) of Clinical Pharmacy Management, Central Pharmacy and Medicine Area of the Health Bioengineering Institute and Professor at the Joaquín Martínez López. Head of the Hema- University Hospital, Asturias and Social Consortium of Catalonia Faculty of Medicine of ‘Miguel Hernández’ tology Department, ‘12 October’ University Anna Sureda Balari. Head of the Clinical Francisco Javier López Jiménez. Head of University Hospital, Madrid Hematology Department, Catalan Institute the Hematology-Hemotherapy Depart- Carlos Solano Vercet. Head of the Hematology Clinical and Translational Oncology José Luis Díez Martín. Head of the Hema- of Oncology ment. ‘Ramón y Cajal’ University Hospital, and Hemotherapy Department, University tology Department, ‘Gregorio Marañón’ Ana Rodríguez Cala. Director of Strategy and Madrid Clinic Hospital, Valencia University General Hospital, Madrid Corporate Social Responsibility, Catalan Francisco Ayala de la Peña. Head of Section César Pascual Fernández. Head of the Health- Jordi Sierra Gil. Head of the Hematology Institute of Oncology of Medical Oncology, ‘Morales Meseguer’ care Quality Department, User Service and Department, ‘Santa Creu i Sant Pau’ Hospi- Antonio Pérez-Martínez. Head of the Pediatric University General Hospital, Murcia Evaluation of Information, Cantabrian Health tal, Barcelona Hemato-Oncology Department, ‘La Paz’ José Francisco Soto Banel. Manager Director, Service Miguel A. Calleja Hernández. President of University Hospital, Madrid ‘San Carlos’ University Clinic Hospital, Cristina Avendaño Solá. Physician specialist the Spanish Society of Hospital Pharmacy Begoña Barragán García. President of the Madrid in Clinical Pharmacology, ‘Puerta de Hierro’ (SEFH), and Head of the Pharmacy Depart- Spanish Group of Patients with Cancer José Luis Poveda Andrés. Head of the Phar- Hospital, Majadahonda, Madrid ment of ‘Virgen Macarena’ University (GEPAC), and the Spanish Association of macy Department, ‘Universitari i Politècnic Enrique Castellón Leal. President of ‘Cross Hospital, Sevilla Patients with Lymphoma, Myeloma and la Fe’ Hospital, Valencia Road Biotech Inversiones Biotecnológicas’ Ramón García Sanz. President-elect of the Leukemia (AEAL) Juan Oliva Moreno. Associate Professor, Felipe Prósper Cardoso. Director of the Cell Spanish Society of Hematology and Hemo- Emilio Vargas Castrillón. Head of the Clinical Economic Analysis Department, Castilla-La Therapy Area and Co-Director of the Clini- therapy (SEHH); and hematologist at the Pharmacology Department, ‘San Carlos’ Mancha University cal Hematology Department, University of University Hospital, Salamanca University Clinic Hospital, Madrid María Antonia Mangues Bafalluy. Director Navarra Ruth Vera García. President of the Spanish Fermín Schez-Guijo Martín. Head of Cell of the Pharmacy Department, ‘Santa Creu i Francesc Bosch Albareda. Principal Researcher Society of Medical Oncology (SEOM); and Therapy of the Hematology Department, Sant Pau’ Hospital, Barcelona of the Experimental Hematology Group of the Head of the Oncology Department, Hospital University Hospital, Salamanca M. Ángel Casado Gómez. General Director VHIO and Head of the Department of Hema- Complex, Navarra Jaime Masjuan Vallejo. Head of the Neurol- of PORIB tology, ‘Vall d’Hebron’ University Hospital, ogy Department, ‘Ramón y Cajal’ Univer- Pedro Gómez Pajuelo. General Secretary, Barcelona sity Hospital, Madrid Spanish National Transplant Organization Josep Torrent-Farnell. Deputy Physician and Luis de la Cruz Merino. Vice-president of Sandra Flores Moreno. Hospital Pharmacist, Co-ordinator of Minority Diseases and GETICA, and Head of the Medical Oncol- ‘Virgen del Rocío’ Hospital, Sevilla Orphan Drugs, ‘Santa Creu i Sant Pau’ Hospi- ogy Department, ‘Virgen de la Macarena’ tal, Barcelona University Hospital, Sevilla Julio Sánchez Fierro. Lawyer and Doctor of Patricia Muñoz García. Head of Section in Health Sciences the Infectious Diseases and Microbiology María Victoria Mateos Manteca. Hematologist, Department, ‘Gregorio Marañón’ University University Clinic Hospital, Salamanca General Hospital, Madrid Natacha Bolaños Fernández. Regional Manager Pedro Castro Rebollo. Consultant in the for Lymphoma Coalition in Europe Intensive Surveillance Area, Clinic Hospital, *Guests from the CORE group: Jordi Sierra and Barcelona Miguel Ángel Calleja Sonia García de San José. Deputy Managing Director, ‘Gregorio Marañón’ University General Hospital, Madrid WG working group *WG4 was composed of 11 experts, and 2 experts of the CORE Group also attended the meeting as guests 13 Clinical and Translational Oncology Assessment and price reimbursement of CAR‑T and will be subsequently refunded by the Health Cohesion therapies Fund [42, 43]. The current assessment of the overall value associated with Follow‑up mechanisms most innovative healthcare technologies, including advanced therapies, has to deal with the difficulty of producing, at the The management of CAR-T therapies requires long-term time of commercialization, plausible evidence to reach the follow-up of results in terms of effectiveness and adverse standards required to obtain national reimbursement [31]. effects, involving the compiling of data from Real World Besides the possibility of curing the patients, the benefits Evidence (RWE). These data also allow the compilation associated with the CAR-T therapies also reach the patients’ of information about the quality of life associated with the carers, their relatives and society in general [32]. Much of health of the treated patients, and the healthcare resources their value can derive from savings due to treatments and used to implement the therapy. EMA lays down, as a con- procedures avoided, and from improvements in patients’ dition of the authorization to market the CAR-T therapies, quality of life and productivity at work, throughout their the need for keeping a detailed record of the clinical data of lives. the candidate patients and of those who have received the The two first industrial CAR-T therapies have been rap- drug [44]. idly and positively evaluated by several agencies for Health There are several European initiatives for harmonizing Technology Assessment (HTA), although the decisions and optimizing the RWE’s records on advanced therapies, were not always unanimous [33]. The UK recommended including recommendations for improvements such as those the two CAR-T therapies for all their indications (B-cell proposed by the Alliance for Regenerative Medicine [31], ALL, DLBCL), through the ‘Cancer Drugs Fund’ [34–36]. EMA [45] and European Network for Health Technology Scotland recommended the use of tisagenlecleucel for B-cell Assessment (EUnetHTA) [46]. ALL, but not for DLBCL, whereas it did recommend axi- In Spain, the Ministry’s Plan envisaged the use of the new cabtagene ciloleucel for DLBCL [37–39]. France assessed VALTERMED (Valor Terapéutico del Medicamento: Thera- the degree of innovation of tisagenlecleucel for B-cell ALL peutic Value of Medicines) information system to determine as grade III. For DLBCL, France awarded a lower grade (IV) the therapeutic value, in actual clinical practice, of some to tisagenlecleucel than to axicabtagene ciloleucel (III) [33]. drugs, including those used in CAR-T therapies, that have The approval of treatments that are potentially curative, a high impact on healthcare and finances within the NHS. such as the CAR-T therapies, gives rise to more challenges for healthcare systems because the payment of the associated costs has to be made at the beginning of the therapy (which Reflections and recommendations is administered only once), whereas the greatest benefits are from the RET‑A project obtained in the long term. This situation is, therefore, very different from that of other oncological therapies which are Working group 1 (WG‑1): strategic starting map administered over a prolonged period. There is, therefore, an obvious need for new approaches which offer payers a WG1—composed of seven experts from the clinical and system that reduces the complications associated with the managerial fields and from four scientific societies, who financing of these therapies, at the same time facilitating also composed the CORE Group—reflected on the current rapid access to patients who need them, and also ensuring situation of the CAR-T therapies in Spain, and proposed, that the system is sustainable. based on the Ministry’s Plan on CAR-T, strategic actions for CAR-T therapies are costly, due not only to the costs improvement in the short and long terms. of research and development but also to the complexity of the processes of manufacturing and administration. There- Reflections fore, the national authorities of several countries, including Spain, have linked CAR-T therapies to systems of payment The group reviewed the strategic starting point, including by results. Besides, some countries have provided funds spe- the Plan’s strengths and possibilities for improvement. The cifically for these or other innovative therapies, such as the RET-A experts agreed that the Ministry’s plan was very ‘Cancer Drugs Fund’ of the United Kingdom [40] or the necessary, well designed, and had well-justified objectives. fund for innovative oncological medicines in Italy [41]. In They praised that it tried to anticipate real clinical practice, Spain, the drug’s costs are borne in full by the patient’s local involving many of the agents of the system. In addition, they hospital, and the costs of care are advanced by the Autono- enhanced its dynamic character, which will make it easier mous Community in which the treatment will take place, for it to be updated over time. 13 Clinical and Translational Oncology Moreover, the WG reflected upon the ideal criteria for Recommendations designating centers qualified to manage the CAR-T thera- pies in the NHS, versus the official ones contained in the The experts proposed the following recommendations: Ministry’s plan (Table 2). In this sense, for the administra- tion of commercial CAR-T, some specific aspects could be – It would be desirable to extend the number of CAR-T ignored, such as the capacity for cell production in situ or qualified centers to move from the actual 14 centers the availability of a specific CAR-T committee. Similarly, to 17 in the short term and 32 centers in the medium they mentioned that the activity in complex allogeneic trans- term (Fig. 1). Speeding up of the procedures needed to plants could be assessed, although the need for it to be a approve CAR-T treatments, simplifying the stages and requirement was not seen as necessary. In addition, some of committees involved at the ministerial, regional and hos- the experts noted that the follow items could be assessed as pital levels. additional but mandatory merits; having JACIE accredita- – To streamline the process, the CAR-T evaluation com- tion, promoting territorial equity (qualification in a region mittees should be unified. without a designated center), and evaluating the capacity of – The management of the CAR-T therapies is going to the hospital pharmacy of the center. foster a cultural change, as it involves multidisciplinary Another aim of this group was to outline the possible work. Common standards are needed, to avoid excessive locations of additional qualified centers to manage the prominence of individuals and to encourage teamwork. CAR-T therapies in the NHS, in the short and long term. The – The healthcare managers have to be involved in the experts considered the following premises: (1) In general, process and need to have the ability to give appropriate one center will be necessary for every 2 million inhabitants; financial and legal advice. They need to be facilitators, (2) For the short-term target population, the two indications coordinators and evaluators, with a fundamental role already approved for industrial CAR-T therapy were con- in the re-organization of hospital procedures and in sidered: about 200 patients per year with B-cell ALL and impelling the training of the clinicians. The healthcare about 800 per year with DLBCL. (3) The target population managers also need to receive training (and updates). at 5 years was estimated at about 1500 patients per year, – It would be advisable that the center of origin of the based on oncohematological indications for CAR-T therapy patient establishes an order of priority when choosing that have already been approved, as well as new CAR-T for the centers that will administer the CAR-T therapies. other oncohematological diseases and solid tumors. When – Information should flow as smoothly as possible preparing the maps, consideration was given to the popu- between the qualified hospitals and the others, as well lation of each Autonomous Community, the distance from as between the Autonomous Communities, the Ministe- other regions, the centers where allogeneic and/or autolo- rial committees, and the reference centers. gous transplants were performed, the centers’ capacity for – It will be necessary to insist on strategic co-ordination caring, and the current and future target populations. nationally, and hence among the Autonomous Com- Table 2  Possible lines of advance in the ‘Plan for Approaching Advanced Therapies in the National Health System: CAR Medicines’ Current criteria Alternative proposal of criteria Total activity of allogeneic hematopoietic stem cell transplants in the Total activity of allogeneic transplants of stem cells, including complex past 3 years ones, in the past 3 years Total activity of complex allogeneic hematopoietic stem cell trans- Previous clinical and preclinical experience with CAR-T medicines, plants in the past 3 years with the same weight for both types To have the JACIE-CAT-ONT accreditation Total apheresis activity of stem cells To have accreditation as CSUR for pediatric units To have a cell therapy unit or multi-disciplinary units (they do not need Known/demonstrable complex cell processing activity to be created for this purpose, nor do they need to be specific for To have a Cell Therapy Unit/Area or multi-disciplinary units created CAR-T). The ideal would be to spend the same day of the unit meet- for this purpose ing to do 2 parts: first for the diagnosis of new patients and then for Previous clinical or preclinical experience with CAR-T medicines the treated cases Capacity to manufacture own CAR-T medicines: authorization from As an additional merit: the AEMPS for manufacture “in house” To have JACIE-CAT-ONT accreditation (laboratory and clinic) or to Total apheresis activity of stem cells have requested it and be still in the approval process Provision of a clinical-pathological and multidisciplinary committee Territorial/population equity to review candidate cases for CAR-T therapies, as well as experts in Hospital pharmacy capacity: 24-h accessibility, experience with the pathologies for which it is indicated advanced therapies AEMPS (Agencia Española de Medicamentos y Productos Sanitarios): Spanish Agency for Medicines and Health Products. CSUR: Reference Centers, Departments and Units 13 Clinical and Translational Oncology Fig. 1  Maps of current and ideal locations of qualified CAR-T centers in the short term (17 centers) and medium/long term (32 centers) munities, to make interoperability viable and to ensure – As soon as the drug is approved, the industry must study that data are shared instead of being kept in niches in purchasing proposals which make it viable to introduce each hospital. it into the healthcare system. – Degrees of training and commitment differ among – In Spain, there should be a SIFCO (Information System hospitals. There needs to be adequate training of the of the Health Cohesion Fund) specifically for CAR-T, or staff who manage the CAR-T therapies (the ‘CAR-T- a similar fund, providing financing commensurate with ologists’) and of everyone involved in the treatment and the cost of the therapy. the follow-up. – The triple reporting of data should be simplified by – The different CAR-T therapies are not equally effective, means of a unified tool which could be used for the dif- so we must not equate them to one another or take their ferent databases. contributions for granted. Instead, we must evaluate the results actually achieved. 13 Clinical and Translational Oncology – The authorities should make an effort to transfer the cent- – Create an accreditation system that is common to all the ers of production of CAR-T to Spain, based on the exam- centers. ple of France and the UK. Recommendations: ‘Training, Communication Working group 2 (WG‑2): the comprehensive care and Co‑ordination’ process The experts focused their discussion on recommendations WG-2—composed of 12 experts from the clinical, car- regarding training, communication and co-ordination. It ing and managerial fields and a patients’ representative— would be desirable to: reflected on the need to give comprehensive consideration to the care process in the CAR-T therapies within the NHS. The – Improve the training of the multidisciplinary team that group held discussions in relation to ‘Roles and resources’ manages these therapies, including nurses and managers. and ‘Training, Communication, Co-ordination’ to propose a – Maintain a regular training of the leaders who teach other comprehensive care pathway with ideal timings. specialists, with international references, by means of congresses, research, visits to foreign centers, etc. Reflections: ‘Roles and resources’ – Candidate patients for CAR-T therapy, and their relatives, should also receive training. In the reflection on ‘Roles and resources’, this group of – Improve the training of the media professionals, so that experts considered that there was a need for a multidisci- scientific journalism is of high quality. plinary team including specialists in Hematology, Pediatric – Improve intra-hospital co-ordination. To achieve that, it Oncohematology (in cases of children), Oncology (in onco- would be necessary to identify all the agents involved logical patients), Intensive Medicine, Neurology, Clinical (the multidisciplinary team), to define their responsibili- Pharmacology, Immunology, Infectology, Radiology, Hos- ties, and to provide them with information about the pro- pital Pharmacy, Clinical Research, Pathology, Nursing and cedures to be followed. Medical Management, as well as other social or healthcare – Improve co-ordination among hospitals. experts and the patient’s relatives. – Streamline bureaucratic procedures and avoid errors. – Have standards of quality and patients’ safety in place, Recommendations: ‘Roles and resources’ with specific indicators. For this, the figure of the ‘data manager’ is required. The data collected should also be They also proposed the following recommendations: used for research, for improving the care process, and for accounting. – Determine who should lead the multidisciplinary group. – Provide the patients with adequate information. – Create the figure of the ‘case manager’ in CAR-T; this – Set up a system (perhaps telephonic) for knowing, in real role could be assumed by nursing or other social/health- time, what options can be given to the patient: and, if the care personnel. The patients could rely on this person as patient is a candidate for CAR-T therapy, which centers a source of information and orientation about the care are accredited for caring for that patient and what clinical process. trials are available in Spain at that time. – Create the figure of the ‘data manager’. A lot of informa- – Improve transparency and accountability to society. tion is generated about this therapy (through the entry of – Improve co-ordination between the NHS and the phar- data into company platforms, collection of clinical data, maceutical industry. etc.), and having a specialized data manager available would allow healthcare workers to lighten their work- Finally, as an output to the discussion held, a detailed loads. comprehensive care pathway was recommended (Fig. 2 and – Define and standardize the way to perform necropsies on Table 3). WG-2 also reviewed the current situation and the patients who have died while undergoing treatment with timings that would be desirable in the different stages of a CAR-T therapy. the care pathway of the CAR-T therapies (Fig. 3). Although – Adequately plan the structural resources so that the pro- there was considerable heterogeneity between centers, the cess is well integrated within the hospital. patient must wait up to 6.1 weeks from the moment when – Create cellular production units. This would ensure a he/she is identified as a candidate for these therapies until return on the investment. apheresis is finally performed (or 10 weeks if his/her center – Standardize the information systems, using a single data- of origin is not qualified). The times required by the differ- base to avoid the duplication of data. ent phases of the CAR-T care pathway were still far from the optimum that could be achieved. It was estimated that 13 Clinical and Translational Oncology Fig. 2  Comprehensive care circuit for CAR-T therapy proposed by Working Group 2 of RET-A (more detailed information in Table 3) there was a margin of improvement of 42% in qualified cent- ascertained. Raising civil society’s awareness, by means ers and of 52% in unqualified ones, since the total times of of a scientifically validated methodology, should allow all the process (between the identification of the patient and of us to limit the effort that needs to be made in relation to their discharge from hospital) could be reduced by 8.1 and these therapies and the results that we expect from them. 11.9 weeks, respectively. They also pointed out that the financing, together with the results, is the first point to be considered in the Working group 3 (WG‑3): innovative models approach to these therapies, and is irrevocably linked to for appraisal and financing the quality of the follow-up of the process. Failing in oper- ations as simple as the collection of data could jeopardize WG-3—composed of ten experts in the financial, clinical, all advances in innovative financing schemes. Therefore, academic and managerial fields—reflected on the innova- an intelligent and rigorous approach to the monitoring of tive models needed for the evaluation and financing of the health results is the cornerstone of the financing and CAR-T therapies. The experts’ objective was to make rec- follow-up of these therapies. ommendations for improvement in the processes of eco- nomic evaluation, financing and follow-up of the CAR-T Recommendations therapies in Spain, to better prepare the system for the personalized therapies to come. The group proposed the following actions: – Requirement to carry out economic evaluations of Reflections advanced therapies, based on a clear methodology, to inform financing decisions and drug pricing. According to the experts, when taking decisions, one – Economic evaluations using the public payer perspective should not disregard economic evaluations. If the actual and, secondly, the social perspective. results are evaluated using simple variables, the benefit for – Payments by results must be made in accordance with patients and the amount that has to be paid for it can be clear and transparent criteria. 13 Clinical and Translational Oncology Table 3  Agents of oncohematological indications involved in each activity within the CAR-T comprehensive care circuit (proposed by working group 2 of the RET-A project, represented in Fig. 2 of the article) No. Activity Agents involved (1) Patient identification Hematologist/oncologist/pediatric oncohematologist (2) Form Hematologist/oncologist/pediatric oncohematologist (3) To inform the patient Hematologist /pediatric oncohematologist; patient; relatives; Nursing (4) Evaluation of the request Group of experts in CAR-T from Hospital/Autonomous Communities/Committee of experts of Ministry (5) CAR-T approval Committee of experts of Ministry (6) Informed consent Hematologist /pediatric oncohematologist; patient; relatives; Nursing (7) Rejection of financing Committee of experts of Ministry (8) Referral of the patient Non-designated center: hematologist/pediatric oncohematologist; medical management. Designated Center: CAR-T Hospital (9) Assessment of the patient Hospital group of experts in CAR-T: hematologist, oncologist, intensivist, pediatric oncohematologist, infectologist, neurologist, radiologist, immunologist, pharmacologist, clinician, clinical investigator, and other specialists as required; medical management; hospital pharmacy; Nursing. social worker, psychologist (10) Formalities Patient; relatives; social worker, psychologist (11) Maintenance treatment Hematologist/pediatric oncohematologist/oncologist; Nursing; clinical pharmacologist; hospital phar- macy (12) Apheresis Blood Bank/Cell Therapy Unit; Nursing; hospital pharmacy; case manager; data manager (13) Logistics Blood Bank/Cell Therapy Unit; Nursing; hospital pharmacy; case manager; data manager (14) Production process Laboratory/Pharmaceutical Industry; Cell production units (15) Lymphodepletion (if required) Hematologist/pediatric oncohematologist/oncologist; Nursing; clinical pharmacologist; hospital phar- macy (16) Infusion Blood Bank/Cell Therapy Unit; Nursing; hospital pharmacy; case manager; data manager (17) Death of the patient Pathology; clinical researcher; relatives (18) Clinical follow-up CAR-T Hospital group of experts: hematologist, oncologist, intensivist, pediatric oncohematologist, infectologist, neurologist, radiologist, immunologist, pharmacologist, clinician, clinical investigator, and other specialists as required; hospital pharmacy; Nursing; medical management; case manager; data manager (19) Surveillance/Clinical follow-up CAR-T Hospital Expert Group: hematologist; oncologist; intensivist, pediatric oncohematologist, infectologist, neurologist, radiologist, immunologist, clinical pharmacologist, clinical investigator and other specialists as required; hospital pharmacy; Nursing; medical management (20) Hospital discharge Hematologist/pediatric oncohematologist; patient; relatives (21) Response evaluation Hematologist/pediatric oncohematologist; case manager; data manager. The times for evaluating the response to therapy depend on the indication. In lymphoma: quarterly follow-up in the first year, semi- annually in the second, and annually thereafter. In ALL: bi-weekly follow-up until the third month, monthly until the sixth month, and bi-monthly until the first year Fig. 3  Real versus ideal times at each stage of the CAR-T in Spanish care management circuit 13 Clinical and Translational Oncology – Create, in the medium term, several pre-designed models The future of CAR-T therapies is promising and exciting, of agreements for payment by results and by indication. but we need to be agile when incorporating innovation and – It is necessary to inform society about and involve it in all prioritizing reassessment. In the future, to serve many spe- the aspects which the new therapies represent for health- cialties, CAR-T services have to be a central service as the care. transfusion or blood analysis services are now. Changes are – Possibility of identifying a potential specific finalist fund needed in the development model, prioritizing active pub- for emerging therapies. lic–private collaboration in research, caring and resources. – Harmonize the health and economic impact variables of We also have to invest in relevant tools, such as artificial the national registry with the EBMT. intelligence. – Enhance the quality and credibility of the data collected in the clinical history, with automatic information cap- ture systems. Discussion and conclusion – Improve the EBMT registry, starting with disease work- ing groups. RET-A is a pioneering project in Spain, conceived as a forum – Systematic representation of patients to design what data, for strategic debate on CAR-T therapies. It is an opportunity including PRO, it would be advisable to collect. Acces- to optimize the management of these advanced therapies and sibility to the registration systems by patients should also to learn from the experts with the most experience in this be improved. field. The National Plan is a good and needed first step to – Creation of the figure of the data manager. adapt the management of the therapies to real needs, speed- – The professional should be made more involved in the ing up times and focusing knowledge in a reduced number achievements, receiving feedback of comparative data. of qualified centers of CAR-T in Spain. However, following the approval of the first industrial Working group 4 (WG‑4): reflection on the future CAR-T’s in oncohematology, further approvals are expected projection in the future in other indications, as well as in solid tumors and even other non-oncological diseases [47, 48]. Therefore, WG-4—composed of 11 experts from the clinical, mana- it is important to prepare the system to face the future. This gerial, political and technological fields, complemented, as need was exacerbated during 2020 due to the COVID-19 guests, by two experts from the CORE group—reflected on pandemic that affected the continuity of essential routine the future, in an attempt to predict the way in which the healthcare services and procedures [49]. CAR-T therapies will evolve, and their needs in the medium The current structure of qualified centers for the man- and long terms. The group evaluated the scalability of the agement of CAR-T within the NHS has made it possible current structure, processes, models and systems, based on to concentrate efforts and experiences in a reduced number the therapies which are still to come in hematology, oncol- of centers of excellence. However, for reasons of territo- ogy and other specialties. rial equality, it will be necessary to rethink the dimension- The group focused on the following aspects: the patient’s ing of the current healthcare structure, and possibly extend perspective, the care process, the regulation and financ- the management of CAR-T to a greater number of centers, ing, the information systems, and the research. The group especially in those regions geographically far from qualified also performed a SWOT analysis (strengths, weaknesses, centers. opportunities, and threats) of the way in which the NHS will Combining equity and territorial equality with agility in accommodate these therapies in the future. patient access is also an important challenge, for which it According to the experts, new therapies, and in particular will be key to minimize bureaucracy, automate processes CAR-T, are a factor that contributes to the transformation of as much as possible, and enhance communication. In this the NHS, which needs a complete review. CAR-T must be an changing reality, we must learn from the mistakes and opportunity for the NHS to really re-orientate itself towards successes of others, shortening times and optimizing the its fundamental goals, which are equity and efficiency. In selection and referral phases of patients. In addition, the this sense, CAR-T therapy is an opportunity for patients, patient must be more clearly involved in all stages of the health professionals and society to improve healthcare pro- process, from their adequate informed consent to the col- cesses, increasing their effectiveness and efficiency, and lection of data on their reported health outcomes. promoting a culture of evaluation of results. This therapy is The management of CAR-T must necessarily be mul- promising but requires further collaboration, consolidation tidisciplinary, with a process that, placing the patient at and adaptation to innovation. We are facing a new paradigm; the center of the system, allows interaction between the a new opportunity to re-launch clinical research and caring. different medical specialties, as well as the hospital phar- macy, nursing and medical management, among others. 13 Clinical and Translational Oncology For this, the processes must be optimized, with joint train- Informed consent Informed consent was obtained from all individual ing efforts—which must be individualized and continu- participants included in the study. ous—and communication, seeking the involvement of all the parties involved. Open Access This article is licensed under a Creative Commons Attri- CAR-Ts are very promising treatments for patients who bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long lack therapeutic alternatives. However, it is convenient to as you give appropriate credit to the original author(s) and the source, differentiate the therapies based on their efficacy, safety, provide a link to the Creative Commons licence, and indicate if changes uncertainty, and cost-effectiveness. In general, it is nec- were made. The images or other third party material in this article are essary to associate its commercialization with financing included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in schemes based on the results obtained in real life, with a the article's Creative Commons licence and your intended use is not longer-term vision of traditional annual budgets. The sub- permitted by statutory regulation or exceeds the permitted use, you will sequent evaluation of the results obtained from the infor- need to obtain permission directly from the copyright holder. To view a mation systems will be essential for the reimbursement of copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. the therapies and to be able to continue making decisions based on evidence and value. The challenge in this regard lies in making the professional a part of the achievements, without adding a substantial burden. For this, it will be References key to harmonize and simplify the information systems, 1. U.S. Food and Drug Administration (FDA). ­Kymriah® (tisagen- seeking for the interoperability of the different databases. lecleucel) FDA. 2017. https://​www.​fda.​gov/​vacci​nes-​blood-​biolo​ Maximum use, both of current therapies and those yet gics/​cellu​lar-​gene-​thera​py-​produ​cts/​kymri​ah-​tisag​enlec​leucel. to come, must come from public–private collaboration. All Accessed 15 Apr 2021. parties must accept this binomial scenario without enter- 2. U.S. Food and Drug Administration (FDA). ­Yescarta® (axicabta- gene ciloleucel). 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