Pricing and reimbursement mechanisms for advanced therapy medicinal products in 20 countries

Introduction: Advanced Therapy Medicinal Products are a type of therapies that, in some cases, hold great potential for patients without an effective current therapeutic approach but they also present multiple challenges to payers. While there are many theoretical papers on pricing and reimbursement (P&R) options, original empirical research is very scarce. This paper aims to provide a comprehensive international review of regulatory and P&R decisions taken for all ATMPs with centralized European marketing authorization in March 2022.Methods: A survey was distributed in July 2022 to representatives of 46 countries.Results: Responses were received from 20 countries out of 46 (43.5%). 14 countries reimbursed at least one ATMP. Six countries in this survey reimbursed no ATMPs.Conclusion: Access to ATMPs is uneven across the countries included in this study. This arises from regulatory differences, commercial decisions by marketing authorization holders, and the divergent assessment processes and criteria applied by payers. Moving towards greater equality of access will require cooperation between countries and stakeholders, for example, through the WHO Regional Office for Europe’s Access to Novel Medicines Platform

How innovation can be defined, evaluated and rewarded in health technology assessment

This study has received support from researchproject PID2019.105597RA.I00 financed by the Spanish Ministry of Science and Innovation/National Research Agency MCIN/AEI/10.13039/501100011033. The funders had no role in the study.Background: What constitutes innovation in health technologies can be defined and measured in a number of ways and it has been widely researched and published about. However, while many countries mention it as a criterion for pricing or reimbursement of health technologies, countries differ widely in how they define and operationalise it. Methods: We performed a literature review, using a snowballing search. In this paper, we explore how innovation has been defined in the literature in relation to health technology assessment. We also describe how a selection of countries (England, France, Italy, Spain and Japan) take account of innovation in their health technology assessment frameworks and explore the key methodologies that can capture it as a dimension of value in a new health technology. We propose a way of coming to, and incorporating into health technology assessment systems, a definition of innovation for health technologies that is independent of other dimensions of value that they already account for in their systems, such as clinical benefit. We use Spain as an illustrative example of how innovation might be operationalised as a criterion for decision making in health technology assessment. Results: The countries analysed here can be divided into 2 groups with respect to how they define innovation. France, Japan and Italy use features such as severity, unmet need and therapeutic added value as indicators of the degree of innovation of a health technology, while England, Spain consider the degree of innovation as a separate and additional criterion from others. In the case of Spain, a notion of innovation might be constructed around concepts of `step-change’, `convenience’, `strength of evidence base’ and `impact on future research & development’. Conclusions: If innovation is to be used as operational criteria for adoption, pricing and reimbursement of health technologies, the concept must be clearly defined, and it ought to be independent from other value dimensions already captured in their health technology assessment systems.Spanish Ministry of Science and Innovation/National Research Agency PID2019.105597RA.I00MCIN/AEI/10.13039/50110001103

The efficiency of increased HCV testing and treatment strategies in Spain to achieve elimination goals

In 2015, Spain launched a national eradication strategy for hepatitis C virus (HCV), resulting in the highest treatment rate in Europe and substantial reductions in HCV prevalence. However, to achieve the goal of HCV elimination, it is necessary to scale-up the diagnosis, treatment, and management of HCV infection. Objective: Our aim was to assess the prevalence, incidence, and cost effectiveness of scaling-up compared with status quo scenarios. A compartmental dynamic transmission model was developed comprising of a cascade of care and a liver progression module. Cost and quality-of-life inputs were sourced from the literature. Key outcomes were the prevalence and incidence of HCV and the incremental cost per quality-adjusted life-year (QALY) and per life-year (LY). Outcomes for a hypothetical elimination strategy were compared with the status quo. The base-case analysis found that scaling-up testing and treatment reduced both the prevalence and incidence of HCV over time, resulting in incremental costs per QALY and LY of €13,291 and €12,285 respectively, compared with the status quo. The main drivers of the cost-effectiveness results included cost of diagnosis, cost of treatment, proportion of people who are unaware, percentage of population who inject drugs, and calibration parameters related to HCV infection prevalence. This analysis demonstrated that scaling-up testing and treatment with direct-acting antivirals may be an efficient strategy for reducing the incidence and prevalence of HCV and may help achieve HCV elimination goals in Spai

The use of nonrandomized evidence to estimate treatment effects in health technology assessment

Health technology assessment (HTA) is increasingly informed by non-randomised studies but there is limited guidance from HTA bodies on expectations around evidence quality and study conduct. We developed recommendations to support the appropriate use of such evidence based on a pragmatic literature review and a workshop involving 16 experts from 8 countries as part of the European Union’s Horizon-2020 IMPACT-HTA programme (work package 6). To ensure HTA processes remain rigorous and robust, HTA bodies should demand clear, extensive, and structured reporting of non-randomised studies, including an in-depth assessment of the risk of bias. In recognition of the additional uncertainty imparted by non-randomised designs in estimates of treatment effects, HTA bodies should strengthen early scientific advice and engage in collaborative efforts to improve use of real-world data

Implementing Outcomes-Based Managed Entry Agreements for Rare Disease Treatments:Nusinersen and Tisagenlecleucel

Enthusiasm for the use of outcomes-based managed entry agreements (OBMEAs) to manage uncertainties apparent at the time of appraisal/pricing and reimbursement of new medicines has waned over the past decade, as challenges in establishment, implementation and re-appraisal have been identified. With the recent advent of innovative treatments for rare diseases that have uncertainties in the clinical evidence base, but which could meet a high unmet need, there has been renewed interest in the potential of OBMEAs. The objective of this research was to review the implementation of OBMEAs for two case studies across countries in the European Union, Australia and Canada, to identify good practices that could inform development of tools to support implementation of OBMEAs. To investigate how OBMEAs are being implemented with rare disease treatments, we collected information from health technology assessment/payer experts in countries that had implemented OBMEAs for either nusinersen in spinal muscular atrophy or tisagenlecleucel in two cancer indications. Operational characteristics of the OBMEAs that were publicly available were documented. Then, the experts discussed issues in implementing these OBMEAs and specific approaches taken to overcome challenges. The OBMEAs identified were based on individual outcomes to ensure appropriate use, manage continuation of treatment and in two cases linked to payment schedules, or they were population based, coverage with evidence development. For nusinersen, population-based OBMEAs are documented in Belgium, England and the Netherlands and individual-based schemes in Bulgaria, Ireland, Italy and Lithuania. For tisagenlecleucel, there were population-based schemes in Australia, Belgium, England and France and individual-based schemes in Italy and Spain. Comparison of the OBMEA constructs showed some clear published frameworks and clarity of the uncertainties to be addressed that were similar across countries. Agreements were generally made between the marketing authorisation holder and the payer with involvement of expert physicians. Only England and the Netherlands involved patients. Italy used its long-established, national, web-based, treatment-specific data collection system linked to reimbursement and Spain has just developed such a national treatment registry system. Other countries relied on a variety of data collection systems (including clinical registries) and administrative data. Durations of agreements varied for these treatments as did processes for interim reporting. The processes to ensure data quality, completeness and sufficiency for re-analysis after coverage with evidence development were not always clear, neither were analysis plans. These case studies have shown that important information about the constructs of OBMEAs for rare disease treatments are publicly available, and for some jurisdictions, interim reports of progress. Outcomes-based managed entry agreements can play an important role not only in reimbursement, but also in treatment optimisation. However, they are complex to implement and should be the exception and not the rule. More recent OBMEAs have developed document covenants among stakeholders or electronic systems to provide assurances about data sufficiency. For coverage with evidence development, there is an opportunity for greater collaboration among jurisdictions to share processes, develop common data collection agreements, and share interim and final reports. The establishment of an international public portal to host such reports would be particularly valuable for rare disease treatments

First GPS Baseline Results from the North Andes

The CASA UNO GPS (Global Positioning System) experiment (January-February 1988) has provided the first epoch baseline measurements for the study of plate motions and crustal deformation in and around the North Andes. Two dimensional horizontal baseline repeatabilities are as good as 5 parts in 108 for short baselines (100-1000km), and better than3 parts in 108 for long baselines (\u3e1000km). Vertical repeatabilities are typically 4 -6 cm, with a weak dependence on baseline length. The expected rate of plate convergence across the Colombia Trench is 6-8 cm/yr, which should be detectable by the repeat experiment planned for 1991. Expected deformation rates within the North Andes are of the order of 1 cm/yr, which may be detectable with the 1991 experiment

Multiple criteria decision analysis for HTA across four EU member states: piloting the Advance Value Framework

Multiple Criteria Decision Analysis (MCDA) has emerged as a methodology for Health Technology Assessment (HTA). However, limited empirical evidence is available on its use by decision-makers; where available, it only comes from single-setting exercises, while cross-country comparative studies are unavailable. This study applies the Advance Value Framework (AVF), an MCDA methodology for HTA based on multi-attribute value theory, through a series of case studies with decision-makers in four countries, to explore its feasibility and compare decision-makers' value preferences and results. The AVF was applied in the evaluation of three drugs for metastatic, castrate resistant, prostate cancer (abiraterone, cabazitaxel and enzalutamide) in the post-chemotherapy indication. Decision conferences were organised in four European countries in collaboration with their HTA or health insurance organisations by involving relevant assessors and experts: Sweden (TLV), Andalusia/Spain (AETSA), Poland (AOTMiT) and Belgium (INAMI-RIZIV). Participants' value preferences, including performance scoring and criteria weighting, were elicited through a facilitated decision-analysis modelling approach using the MACBETH technique. Between 6 and 11 criteria were included in each jurisdiction's value model, allocated across four criteria domains; Therapeutic Benefit criteria consistently ranked first in relative importance across all countries. Consistent drug rankings were observed in all settings, with enzalutamide generating the highest overall weighted preference value (WPV) score, followed by abiraterone and cabazitaxel. Dividing drugs' overall WPV scores by their costs produced the lowest “cost per unit of value” for enzalutamide, followed by abiraterone and cabazitaxel. These results come in contrast with the actual country HTA recommendations and pricing decisions. Overall, although some differences in value preferences were observed between countries, drug rankings remained the same. The MCDA methodology employed could act as a decision support tool in HTA, due to the transparency in the construction of value preferences in a collaborative manner

Distância anogenital das mulheres e a relação com a exposição pré-natal da mãe

Anogenital distance (AGD) is a genital development marker which is a sexually dimorphic trait in mammals. Different experimental studies have shown that AGD at birth reflects the androgen exposure of the fetus during its in-utero development. The object of our study was to examine the relation between maternal prenatal exposures to different substances and compounds used on a daily basis during pregnancy and AGD of their daughters as an indirect marker of the intrauterine hormonal environment. This is a cross-sectional study of 100 healthy female undergraduates of ages ranging from 18 to 23. Every participant was subjected to a full gynecological examination, where two AGD variants were measured: AGDAC (anus-clitoris) and AGDAF (anus-fourchette). Both the young women and their mothers completed an epidemiological questionnaire on lifestyles, including prenatal exposure to products and gynecological history. Multiple linear and logistic regression analysis was used to study the relation between the mothers’ exposure to products and their daughters’ AGD. A longer AGDAF in the daughters was significantly associated with a higher prenatal exposure of their mothers to insecticides/pesticides and solvents/degreasers (aOR: 3.9; IC 95%: 1.2, 12.7 and 3.8; IC 95%: 1.1-12.6, respectively). Our results show that certain prenatal environmental exposures of mothers might be associated with significant variations of their daughters’ AGD, a sensitive biomarker that reflects androgen fetal exposure during in-utero development.La distancia anogenital (DAG) es un marcador de desarrollo genital que presenta un dimorfismo sexual en mamíferos. Diversos estudios experimentales han mostrado que la DAG al nacimiento refleja la exposición androgénica a la que el feto ha estado expuesto durante su desarrollo intraútero. El objetivo de nuestro estudio fue explorar la relación entre exposiciones prenatales (maternas) a distintos productos o sustancias de uso cotidiano durante el embarazo y la DAG de sus hijas como marcador indirecto del ambiente hormonal intrauterino. Se trata de un estudio transversal que incluyó 100 jóvenes universitarias sanas entre 18 y 23 años. A cada participante se le realizó un examen ginecológico completo y se midieron dos variantes de DAG: ano-clítoris (DAGAC) y ano-horquilla vulvar (DAGAH). Tanto las jóvenes como sus madres completaron un cuestionario epidemiológico sobre estilos de vida, incluyendo exposición a productos prenatales e historia ginecológica. Las asociaciones entre la exposición a productos prenatales y las DAG de las hijas se realizaron mediante análisis de regresión lineal y logística múltiple. Una mayor exposición materna a insecticidas/plaguicidas y disolventes/desengrasantes se asoció significativamente con una DAGAH alargada en las hijas (ORa: 3,9; IC 95 % 1,2,- 12,7 y 3,8; IC 95 % 1,1 - 12,6, respectivamente). Nuestros resultados respaldan que ciertas exposiciones prenatales maternas ambientales podrían estar asociadas con variaciones significativas de las DAG en sus hijas, un biomarcador que refleja la exposición androgénica fetal durante el desarrollo intraútero.Distância anogenital (AGD) é um traço de dimorfismo sexual em mamíferos. Diversos estudos experimentais em animais sugerem que a AGD ao nascer reflete as concentrações de andrógenos a que o feto terá sido exposto durante o desenvolvimento uterino. O objetivo deste estudo é analisar as associações entre a exposição pré-natal da mãe a diferentes substâncias e compostos de uso quotidiano durante a gravidez e a AGD das suas filhas, como um marcador indireto do ambiente hormonal durante o desenvolvimento no útero. É um estudo transversal efetuado a 100 voluntárias, saudáveis, em idade universitária (18-23 anos) no sul da Espanha. Realizou-se um exame ginecológico completo a cada participante, tendo-se medido as diferenças da AGD: ânus- clitóris (AGDAC) e ânus-freio dos pequenos lábios (AGDAF). Foi também aplicado um questionário epidemiológico, tanto às jovens participantes como as suas mães, acerca dos estilos de vida, história ginecológica, incluindo a exposição a produtos na fase pré- natal. Para verificar a associação entre os produtos pré-natais e as AGD das filhas, foi usada a análise de regressão linear múltipla e a análise de regressão logística. Uma maior exposição materna a inseticidas/pesticidas e solventes teve uma associação significativa com uma AGDAF alargada nas filhas (ORa: 3,9; IC 95 % 1,2, 12,7 e 3,8; IC 95 % 1,1, 12,6, respetivamente). Os nossos resultados sugerem que determinadas exposições ambientais da mãe na fase pré-natal podem estar associadas com variações significativas das AGD das filhas, um biomarcador que reflete as concentrações de andrógenos durante o desenvolvimento uterino

Budget impact analysis of Dalbavancin in the treatment of acute bacterial skin and skin structure infections in three European countries

Background and Objective: Acute bacterial skin and skin structure infections (ABSSSIs) have been defined by the US Food and Drug Administration (FDA) in 2013 to include a subset of complicated skin and skin structure infections commonly treated with parenteral antibiotic therapy. Inpatient treatment of ABSSSIs involves a significant economic burden on the healthcare system. This study aimed to evaluate the economic impact on the National Health System associated with the management of non-severe ABSSSIs treated in hospitals with innovative long-acting dalbavancin compared to standard antibiotic therapy in Italy, Spain, and Austria. Methods: A budget impact analysis was developed to evaluate the direct costs associated with the management of ABSSSI from the national public health system perspective. The model considered the possibility of early discharge of patients directly from the Emergency Department (ED), after 1 night in the hospital, or after two or three nights in the hospital. A scenario with Standard of Care was compared with a dalbavancin scenario, where patients had the possibility of being discharged early. The epidemiological and cost parameters were extrapolated from national administrative databases and from a systematic literature review for each country. The analysis was conducted in a 3-year time horizon. A one-way deterministic sensitivity analysis was conducted to examine the robustness of the results. Results: The model estimated an average annual number of patients with non-severe ABSSSI in Italy, Spain, and Austria equal to 5396, 7884, and 1788, respectively. A total annual expenditure of about €9.9 million, €13.5 million, and €3.4 million was estimated for treating the full set of ABSSSI patients in Italy, Spain, and Austria, respectively. Dalbavancin reduced the in-hospital length of stay in each country. In the first year of its introduction, dalbavancin significantly reduced the total economic burden in Italy and Spain (− €352,252 and − €233,991, respectively), while it increased the total economic burden in Austria (€80,769, 0.7% of the total expenditure for these patients); in the third year of its introduction, dalbavancin reduced the total economic burden in each Country (− €1.1 million, − €810,650, and − €70,269, respectively). Conclusions: The introduction of dalbavancin in a new patient pathway to treat non-severe ABSSSI could generate a significant reduction in hospitalized patients and the overall patient length of stay in hospital

Priorities for health economic methodological research: Results of an expert consultation

Background: The importance of economic evaluation in decision making is growing with increasing budgetary pressures on health systems. Diverse economic evidence is available for a range of interventions across national contexts within Europe, but little attention has been given to identifying evidence gaps that, if filled, could contribute to more efficient allocation of resources. One objective of the Research Agenda for Health Economic Evaluation project is to determine the most important methodological evidence gaps for the ten highest burden conditions in the European Union (EU), and to suggest ways of filling these gaps. Methods: The highest burden conditions in the EU by Disability Adjusted Life Years were determined using the Global Burden of Disease study. Clinical interventions were identified for each condition based on published guidelines, and economic evaluations indexed in MEDLINE were mapped to each intervention. A panel of public health and health economics experts discussed the evidence during a workshop and identified evidence gaps. Results: The literature analysis contributed to identifying cross-cutting methodological and technical issues, which were considered by the expert panel to derive methodological research priorities. Conclusions: The panel suggests a research agenda for health economics which incorporates the use of real-world evidence in the assessment of new and existing interventions; increased understanding of cost-effectiveness according to patient characteristics beyond the “-omics” approach to inform both investment and disinvestment decisions; methods for assessment of complex interventions; improved cross-talk between economic evaluations from health and other sectors; early health technology assessment; and standardized, transferable approaches to economic modeling