Financing and Reimbursement of Approved Advanced Therapies in Several European Countries

Advanced medicinal products; Financing government; Health technology assessmentMedicamentos avanzados; Financiación del gobierno; Evaluación de tecnologías sanitariasMedicaments avançats; Finançament del govern; Avaluació de tecnologies sanitàriesObjectives 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

Regulatory framework for advanced therapy medicinal products in Europe and United States

Europe; United States Food and Drug Administration; Legislation and jurisprudenceEuropa; Administración de Alimentos y Medicamentos de los Estados Unidos; Legislación y jurisprudenciaEuropa; Administració d'Aliments i Medicaments dels Estats Units; Legislació i jurisprudènciaAdvanced therapy medicinal products (ATMPs) are a fast-growing field of innovative therapies. The European Union (EU) and the United States (US) are fostering their development. For both regions, ATMPs fall under the regulatory framework of biological products, which determines the legal basis for their development. Sub-classifications of advanced therapies are different between regions, while in EU, there are four major groups, i.e., gene therapy, somatic cell therapy, tissue-engineered therapies, and combined advanced therapies; in US, the sub-classification covers two major groups of products, i.e., gene therapy and cellular therapy. The inclusion criteria that define a gene therapy are equivalent in both regions, and the exclusion criteria are directly related to the indications of the product. In the EU, there is a clear differentiation between cell- and tissue-based products regarding their classification as advanced therapies or coverage by other legal frameworks, whereas in US, there is a broader classification about whether or not these products can be categorized as biologic products. Both in EU and in US, in order to classify a cell- or a tissue-based product as an advanced therapy, it must be ensured that the processing of the cells implies a manipulation that alters their biological characteristics, although the term of manipulation in US differentiates between structural and non-structural cells and tissues. The regulatory terminology used to define ATMPs and their sub-classification reveals some differences between EU and US

Methodological Characteristics of Clinical Trials Supporting the Marketing Authorisation of Advanced Therapies in the European Union

Advanced therapies; Clinical trials; Drug developmentTeràpies avançades; Assaigs clínics; Desenvolupament de fàrmacsTerapias avanzadas; Ensayos clínicos; Desarrollo de fármacosSeveral advanced therapy medicinal products (ATMPs) have been approved in the European Union (EU). The aim of this study is to analyse the methodological features of the clinical trials (CT) that supported the marketing authorization (MA) of the approved ATMPs in the EU. A systematic review of the characteristics of pivotal CT of ATMPs approved in the EU until January 31st, 2021 was carried out. A total of 17 ATMPs were approved and 23 CT were conducted to support the MA (median, 1, range, 1–3). Of those studies, 8 (34.78%) were non-controlled and 7 (30.43%) used historical controls. Only 7 (30.4%) were placebo or active-controlled studies. Among all CT, 21 (91.3%) were open-label and 13 (56.52%) had a single-arm design. To evaluate the primary endpoint, 18 (78.26%) studies used an intermediate and single variable. The median (IQR) number of patients enrolled in the studies was 75 (22–118). To date, ATMPs’ approval in the EU is mainly supported by uncontrolled, single-arm pivotal CT. Although there is a trend toward an adaptive or a life cycle approach, a switch to more robust clinical trial designs is expected to better define the benefit and the therapeutic added value of ATMPs

Medicina de precisión: de la población al individuo

Medicina de precisió; Farmacogenòmica; Teràpies avançades; NanomedicinaMedicina de precisión; Farmacogenómica; Terapias avanzadas; NanomedicinaPrecision medicine; Pharmacogenomics; Advanced therapies; NanomedicineLa medicina de precisió té com a repte utilitzar el medicament adequat, en la persona concreta i en el moment adequat, el que suposa un canvi d’enfocament en la medicina: d’una visió poblacional a una visió individual. La variabilitat interindividual de la resposta a un fàrmac pot implicar el fracàs terapèutic, fet que suposa una minva de la qualitat de vida dels pacients i un alt impacte econòmic per al sistema sanitari. La resposta a la teràpia farmacològica ve determinada en bona part pels factors genètics, els quals expliquen gran part de la variabilitat interindividual. La farmacogenòmica, les teràpies avançades o la nanomedicina són tres àrees que s’engloben dintre de la medicina de precisió. La farmacogenòmica permet la detecció de biomarcadors que ens poden predir la resposta o toxicitat d’un determinat tractament. Aquesta àrea és molt utilitzada en oncologia atesa la base genètica de les neoplàsies malignes. També s’utilitza en altres patologies, com en determinats fàrmacs per a la !brosi quística, l’ús de la codeïna per a la tos o en fàrmacs antidepressius. Les teràpies avançades són medicaments que es basen en la teràpia gènica, la teràpia de cèl·lules somàtiques, la teràpia d’enginyeria de teixits i els medicaments combinats de teràpies avançades per al maneig d’algunes malalties. El desenvolupament d’aquests medicaments és molt complex com a conseqüència de la pròpia naturalesa d’aquestes teràpies. Actualment a Espanya en tenim tres de comercialitzades. Per últim, la nanomedicina estudia i desenvolupa nanomaterials per a la prevenció, el diagnòstic o el tractament de la malaltia a escala cel·lular o molecular. Avui dia disposem de nanomaterials que s’utilitzen a la pràctica clínica diària, com són els biosensors de glucosa, i també de nanofàrmacs comercialitzats en el nostre país. Aquestes tres àrees han creat grans avenços que han permès millorar el diagnòstic i/o tractament de les malalties de forma “individual”, sobretot en l’àmbit de l’oncologia i de les malalties minoritàries.La medicina de precisión tiene como reto utilizar el medicamento adecuado, en la persona concreta y en el momento apropiado, lo que supone un cambio de enfoque en la medicina: de una visión poblacional a una visión individual. La variabilidad interindividual de la respuesta a un fármaco puede implicar el fracaso terapéutico, hecho que supone una disminución en la calidad de vida de los pacientes y un alto impacto económico para el sistema sanitario. La respuesta a la terapia farmacológica viene determinada en buena parte por los factores genéticos, los cuales explican gran parte de la variabilidad interindividual. La farmacogenómica, las terapias avanzadas o la nanomedicina son tres áreas que se engloban dentro de la medicina de precisión. La farmacogenómica permite la detección de biomarcadores que nos pueden predecir la respuesta o toxicidad de un determinado tratamiento. Esta área es muy utilizada en oncología dada la base genética de las neoplasias malignas. También se utiliza en otras patologías, como en determinados fármacos para la !brosis quística, el uso de la codeína para la tos o en fármacos antidepresivos. Las terapias avanzadas son medicamentos que se basan en la terapia génica, la terapia de células somáticas, la terapia de ingeniería de tejidos y los medicamentos combinados de terapias avanzadas para el manejo de determinadas enfermedades. El desarrollo de estos medicamentos es muy complejo como consecuencia de la propia naturaleza de estas terapias. Actualmente en España hay tres comercializadas. Por último, la nanomedicina estudia y desarrolla nanomateriales para la prevención, el diagnóstico o el tratamiento de los trastornos a escala celular o molecular. Hoy en día disponemos de nanomateriales que se utilizan en la práctica clínica diaria, como los biosensores de glucosa, y también de nanofármacos ya comercializados en nuestro país. Estas tres áreas han supuesto grandes avances que han permitido mejorar el diagnóstico y/o tratamiento de las enfermades de forma “individual”, sobre todo en el ámbito de la oncología y de las enfermedades minoritarias

Early Access to Medicines: Use of Multicriteria Decision Analysis (MCDA) as a Decision Tool in Catalonia (Spain)

Early access to medicines allows the prescription of a medicine before it is available in the public formulary to patients with severe or rare diseases with high unmet needs who have no authorised therapeutic alternatives available. In this context, consistent decision making is difficult, and a systematic assessment procedure could be useful to tackle complex situations and guarantee the equity of medicines' access. A multidisciplinary panel (MP) conducted four workshops to develop an early access framework based on a reflective multiple criteria decision analysis (MCDA). A set of 12 criteria was agreed: eight quantitative (severity of disease, urgency, efficacy, safety, internal and external validity, therapeutic benefit and plausibility) and four qualitative (therapeutic alternative, existence of precedents, management impact and costs). Quantitative criteria were weighted using a five-point scale. The relative importance of quantitative criteria had mean weights from 4.7 to 3.6, showing its relevance in the decisions. The framework was tested using two case studies, and reliability was assessed by re-test. The re-test revealed no statistical differences, indicating the consistency and replicability of the framework developed. MCDA may help to structure discussions for heterogeneous treatment requests, providing predictability and robustness in decision making involving sensitive and complex situations

Regulatory framework for advanced therapy medicinal products in Europe and United States

Advanced therapy medicinal products (ATMPs) are a fast-growing field of innovative therapies. The European Union (EU) and the United States (US) are fostering their development. For both regions, ATMPs fall under the regulatory framework of biological products, which determines the legal basis for their development. Sub-classifications of advanced therapies are different between regions, while in EU, there are four major groups, i.e., gene therapy, somatic cell therapy, tissue-engineered therapies, and combined advanced therapies; in US, the sub-classification covers two major groups of products, i.e., gene therapy and cellular therapy. The inclusion criteria that define a gene therapy are equivalent in both regions, and the exclusion criteria are directly related to the indications of the product. In the EU, there is a clear differentiation between cell- and tissue-based products regarding their classification as advanced therapies or coverage by other legal frameworks, whereas in US, there is a broader classification about whether or not these products can be categorized as biologic products. Both in EU and in US, in order to classify a cell- or a tissue-based product as an advanced therapy, it must be ensured that the processing of the cells implies a manipulation that alters their biological characteristics, although the term of manipulation in US differentiates between structural and non-structural cells and tissues. The regulatory terminology used to define ATMPs and their sub-classification reveals some differences between EU and US

Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut)

Catalan healthcare; Decision-making; Multi-criteria decision analysis; Orphan drugsSanitat catalana; Presa de decisions; Anàlisi de decisions multicriteri; Medicaments orfesSanidad catalana; Toma de decisiones; Análisis de decisiones multicriteria; Medicamentos huérfanosBACKGROUND: Orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut. METHODS: The assessment and decision-making process for orphan drugs in the Programa d'Harmonització Farmacoterapeutica (PHF) of CatSalut was prioritized to test the implementation of the reflective MCDA both a qualitative and quantitatively. A staged approach was used with the following main steps: selection and structuration of quantitative criteria (Core Model) and qualitative criteria (Contextual Tool), framework scoring and assessment of three orphan drug case studies. This proof-of-concept would grant a continued refinement of the methodology and, if and when validated, its potential integration to other therapeutic areas of the PHF. RESULTS: The final framework was composed by 10 quantitative criteria (Core Model) and 4 qualitative criteria (Contextual Tool) according to the PHF goals being the most important criteria "disease severity", "unmet need", "comparative effectiveness" and "comparative safety /tolerability". The matrix developed for the case studies served as a guide for the selection of the essential information that the decision-makers were expected to include in a framework. The reflective discussion was considered the most relevant phase of the approach to support inputs for health decision-making processes reflecting both drug value and place in therapy. CONCLUSIONS: The study showed that reflective MCDA methodology could be implemented to complement the decision-making process in CatSalut, as an aid to determine the clinical added value for orphan medicines. MCDA provided transparency and a structured discussion during the committee meetings, thus increasing transparency and predictability of the relevant items supporting the agreements adopted on orphan drugs access

Pautes per a l’harmonització dels tractaments farmacològics

Pautes del tractament farmacològic; Harmonització farmacoterapèutica; CronicitatPautas del tratamiento farmacológico; Armonización farmacoterapéutica; CronicidadGuidelines for pharmacological treatment; Pharmacotherapeutic Harmonization; ChronicityL’augment de l’esperança de vida i el consegüent envelliment de la població, juntament amb els avenços mèdics que transformen malalties agudes en patologies de llarga evolució (p. ex. VIH o càncer, entre d’altres), enllacen de forma ineludible amb la cronificació. L’existència de diferents visions terapèutiques en un entorn multidisciplinari, la falta de comunicació entre professionals i les diferents perspectives assistencials fan que en ocasions es prenguin decisions terapèutiques heterogènies, que afecten tant els resultats en salut com l’equitat en la utilització de recursos. L’objectiu de les pautes d’harmonització és l'’optimització de la prestació farmacoterapèutica en termes d’ús racional, de manera que permeti maximitzar el benefici i minimitzar els riscs de l’exposició individual i poblacional als medicaments, d’una manera sostenible pel sistema.El aumento de la esperanza de vida y el consiguiente envejecimiento de la población, junto con los avances médicos que transforman enfermedades agudas en patologías de larga evolución (p. Ej. VIH o cáncer, entre otros), enlazan de forma ineludible con la cronificación. La existencia de diferentes visiones terapéuticas en un entorno multidisciplinar, la falta de comunicación entre profesionales y las diferentes perspectivas asistenciales hacen que en ocasiones se tomen decisiones terapéuticas heterogéneas, que afectan tanto a los resultados en salud como la equidad en la utilización de recursos. El objetivo de las pautas de armonización es la optimización de la prestación farmacoterapéutica en términos de uso racional, de forma que permita maximizar el beneficio y minimizar los riesgos de la exposición individual y poblacional a los medicamentos, de una manera sostenible por el sistema.The increase in life expectancy and the consequent aging of the population, together with the medical advances that transform acute illnesses into long-standing pathologies (eg HIV or cancer, among others), are inextricably linked with the chronification The existence of different therapeutic visions in a multidisciplinary environment, the lack of communication between professionals and the different healthcare perspectives, sometimes lead to heterogeneous therapeutic decisions, which affect both health outcomes and equity in the use of resources. The goal of the harmonization guidelines is to optimize the pharmacotherapeutic benefit in terms of rational use, in order to maximize the benefit and minimize the risks of individual and population exposure to medication in a way sustainable by the system

Nonviral-Mediated Hepatic Expression of IGF-I Increases Treg Levels and Suppresses Autoimmune Diabetes in Mice

Altres ajuts: This work was supported by grants from Ministerio de Ciencia e Innovación (SAF2005-01262 and SAF2008-00962) and from the European Community (FP6 CLINIGENE, LSHB-CT-2006-018933). X.M.A., J.A., and A.R. were recipients of a predoctoral fellowship from Ministerio de Educación, Cultura y Deporte, and D.C. received a predoctoral fellowship from Instituto de Salud Carlos III, Spain. C.J.M.In type 1 diabetes, loss of tolerance to β-cell antigens results in T-cell-dependent autoimmune destruction of β cells. The abrogation of autoreactive T-cell responses is a prerequisite to achieve long-lasting correction of the disease. The liver has unique immunomodulatory properties and hepatic gene transfer results in tolerance induction and suppression of autoimmune diseases, in part by regulatory T-cell (Treg) activation. Hence, the liver could be manipulated to treat or prevent diabetes onset through expression of key genes. IGF-I may be an immunomodulatory candidate because it prevents autoimmune diabetes when expressed in β cells or subcutaneously injected. Here, we demonstrate that transient, plasmid-derived IGF-I expression in mouse liver suppressed autoimmune diabetes progression. Suppression was associated with decreased islet inflammation and β-cell apoptosis, increased β-cell replication, and normalized β-cell mass. Permanent protection depended on exogenous IGF-I expression in liver nonparenchymal cells and was associated with increased percentage of intrapancreatic Tregs. Importantly, Treg depletion completely abolished IGF-I-mediated protection confirming the therapeutic potential of these cells in autoimmune diabetes. This study demonstrates that a nonviral gene therapy combining the immunological properties of the liver and IGF-I could be beneficial in the treatment of the disease

Insulin-like growth factor 2 overexpression induces β-Cell dysfunction and increases beta-cell susceptibility to damage

The human insulin-like growth factor 2 (IGF2) and insulin genes are located within the same genomic region. Although human genomic studies have demonstrated associations between diabetes and the insulin/IGF2 locus or the IGF2 mRNA-binding protein 2 (IGF2BP2), the role of IGF2 in diabetes pathogenesis is not fully understood. We previously described that transgenic mice overexpressing IGF2 specifically in β-cells (Tg-IGF2) develop a pre-diabetic state. Here, we characterized the effects of IGF2 on β-cell functionality. Overexpression of IGF2 led to β-cell dedifferentiation and endoplasmic reticulum stress causing islet dysfunction in vivo. Both adenovirus-mediated overexpression of IGF2 and treatment of adult wild-type islets with recombinant IGF2 in vitro further confirmed the direct implication of IGF2 on β-cell dysfunction. Treatment of Tg-IGF2 mice with subdiabetogenic doses of streptozotocin or crossing these mice with a transgenic model of islet lymphocytic infiltration promoted the development of overt diabetes, suggesting that IGF2 makes islets more susceptible to β-cell damage and immune attack. These results indicate that increased local levels of IGF2 in pancreatic islets may predispose to the onset of diabetes. This study unravels an unprecedented role of IGF2 on β-cells function