ABSTRACT Purpose: Gene therapy brings opportunities to discover cures for diseases for which there are no adequate treatments. As most gene therapies target rare diseases, several challenges are associated with their clinical development, such as limited population size, lack of established clinical pathways for development, and sometimes the absence of validated endpoints. The objective of this study was to systematically review and evaluate the methodology and design of European clinical trials (CTs) utilising gene therapy medicinal products (GTMPs). Methods: A systematic search of online CT databases was performed using keywords to identify CTs conducted with GTMPs in Europe, published from 1 January 1995 to 31 July 2019. Results: The search identified 1571 CTs, of which 199 were identified as published articles. A total of 159 CTs remained following the elimination of duplicated CTs, non-gene therapy trials, and those conducted outside Europe. Of these, only nine CTs were randomised, double-blind, with or without parallel groups, and placebo-controlled. Conclusions: The analysed randomised CTs were conducted in accordance with Good clinical practice with low risk of bias across domains. Only one CT was identified with some concerns of bias due to lack of information regarding the randomisation process and changes in protocol.

BACKGROUND: In recent years there is a growing interest in public beliefs about mental disorders. Numerous representative population-based studies have been conducted around the globe, also in European countries bordering on the Mediterranean Sea. However, relatively little is known about public beliefs in countries in Northern Africa. OBJECTIVE: To fill this gap by comparing public beliefs about mental disorders in Tunisia and Germany, focusing on causal beliefs, help-seeking recommendations and treatment preferences. METHODS: Representative national population-based surveys have been conducted in Tunisia in 2012 (N = 811) and in Germany in 2011 (N = 1852), using the same interview mode and the same fully structured interview starting with a vignette depicting a person suffering from either schizophrenia or depression. RESULTS: In Tunisia, the public was more likely to adopt psychosocial and to reject biogenetic explanations than in Germany. Correspondingly, psychological treatments were more frequently recommended and biological ones more frequently advised against. There was also a strong inclination to share religious beliefs and to recommend seeking religious advice. Tunisians tended much more than Germans to hold moralistic views and to blame the afflicted person for his or her illness. In Tunisia, the public tended less to differentiate between schizophrenia and depression than in Germany. CONCLUSION: Marked differences between Tunisia and Germany exist in public beliefs about the causes of mental disorders and their treatment, which correspond to differences in cultural orientations prevailing in these countries. Mental health professionals need to be sensitive to the particular cultural context in which they operate, in order to be able to reach those they intend to care for.

Real-world evidence (RWE) provides external validity, supplementing and enhancing the randomized controlled trial (RCT) data with valuable information on patient behaviours and outcomes, turning efficacy and safety results into real-world effectiveness and risks, but the use of RWE is associated with challenges.The objectives of this communication were to (1) summarise all guidance on how to conduct an RWE meta-analysis (MA) and how to develop an RWE cost-effectiveness model, (2) to describe our experience, challenges faced and solutions identified, (3) to provide recommendations on how to conduct such analyses.No formal guidelines on how to conduct an RWE MA or to develop an RWE cost-effectiveness model were identified. Using the context of non-vitamin K antagonist oral anticoagulants (NOACs) in stroke prevention in atrial fibrillation, we conducted an RWE MA, after having identified sources of uncertainty. We then implemented the results in an RWE cost-effectiveness model, defined as a model where all inputs come from RWE, including all parameters related to treatment effect. Based on challenges faced, our first recommendation relates to the necessity of conducting sensitivity analyses, either based on clinical or methodological considerations. Our second recommendation is the need for extensive collaboration with a wide range of experts, during the development of the analyses protocols, the implementation of the analyses and the interpretation of the results.RWE may address a number of gaps related to the treatment effect, and RWE economic evaluations for the treatment effect can provide extremely valuable insights into real-world economic value of interventions. As the increased recognition of the value of RWE could influence health technology assessment decision, and current practices, this communication supports the urgent need of more formal guidelines.

BACKGROUND: Despite the burden of varicella, there is no universal varicella vaccination (UVV) programme in the United Kingdom (UK) due to concerns this could increase herpes zoster (HZ) incidence. This study assessed the cost-utility of a first-dose monovalent (V) or quadrivalent (MMRV) followed by a second-dose quadrivalent (MMRV) UVV programmes. GSK and MSD varicella-containing vaccines (VCVs) were considered. METHODS: A dynamic transmission and cost-effectiveness models were adapted to the UK. Outcomes measured included varicella and HZ incidences, the incremental cost-utility ratio (ICURs) over a lifetime horizon. The payer and societal perspectives were evaluated. RESULTS: The impact of V-MMRV and MMRV-MMRV UVV programmes on varicella incidence was comparable between both VCVs at equilibrium. HZ incidence increased by 1.6%-1.7% over seven years after UVV start, regardless of the strategies, then decreased by >95% at equilibrium. ICURs ranged from £5,665 (100 years) to £18,513 (20 years) per quality-adjusted life year (QALY) gained with V-MMRV; and from £9,220 to £27,101 per QALY gained with MMRV-MMRV (payer perspective). MMRV-MMRV was cost-effective in medium- and long-terms with GSK VCV, and only cost-effective at long-term with MSD VCV at £20,000 per QALY gained threshold. Without the exogenous boosting hypothesis, HZ incidence decreased through UVV implementation. ICURs were most sensitive to discount rates and MMRV price. CONCLUSIONS: A 2-dose UVV was demonstrated to be a cost-effective alternative to no vaccination. With comparable effectiveness as MSD VCV at lower costs, GSK VCV may offer higher value for money.

ABSTRACT Background Morbidity and mortality associated with non-valvular atrial fibrillation (NVAF) imposes a substantial economic burden on the UK healthcare system. Objectives An existing Markov model was adapted to assess the real-world cost-effectiveness of rivaroxaban and apixaban, each compared with a vitamin K antagonist (VKA), for stroke prevention in patients with NVAF from the National Health Service (NHS) and personal and social services (PSS) perspective. Methods The model considered a cycle length of 3 months over a lifetime horizon. All inputs were drawn from real-world evidence (RWE): baseline patient characteristics, clinical event and persistence rates, treatment effect (meta-analysis of RWE studies), utility values and resource use. Deterministic and probabilistic sensitivity analyses were performed. Results The incremental cost per quality-adjusted life year was £14,437 for rivaroxaban, and £20,101 for apixaban, compared with VKA. The probabilities to be cost-effective compared with VKA were 90% and 81%, respectively for rivaroxaban and apixaban, considering a £20,000 threshold. In both comparisons, the results were most sensitive to clinical event rates. Conclusions These results suggest that rivaroxaban and apixaban are cost-effective vs VKA, based on RWE, considering a £20,000 threshold, from the NHS and PSS perspective in the UK for stroke prevention in patients with NVAF. This economic evaluation may provide valuable information for decision-makers, in a context where RWE is more accessible and its value more acknowledged.

OBJECTIVES: Doctor shopping, double doctoring, and overlapping prescriptions are often used as synonyms for multiple physician appointments in the same disease episode. Such behaviours translate into poor patient satisfaction and patient-doctor communication as well as abuse or misuse of drugs, increasing health care costs and resulting in negative health consequences. This systematic review of the literature was conducted to identify factors that drive doctor-shopping behaviour in children’s caregivers. METHODS: The search was conducted in PubMed and grey literature and was based on the following search terms: included doctor or physician shopping, drug seeking, double doctoring, children, and combinations of those. Overall, 500 records were identified, of which 11 were selected for qualitative synthesis. Data extracted considered definitions of doctor shopping, co-morbidities, and target population characteristics. RESULTS: Definitions of doctor shopping were inconsistent. The frequency of doctor shopping was high for acute illnesses and ranged from 53% in children with a fever in Hong Kong to 18% at an emergency department in Canada. The incidence of this phenomenon was low when taking into account addictive drugs and was rated at 0.02% to 0.3% in the full paediatric population. This phenomenon was more prevalent in children younger than 1 year, in children with attention-deficit hyperactivity disorder (ADHD) and co-morbid psychiatric conditions, and in those whose caregivers themselves had psychiatric conditions. It was more frequent in cases with an acute disease (eg, fever, gastroenteritis, and urinary tract infection) than a chronic disease (eg, asthma). CONCLUSIONS: The knowledge about doctor shopping by children’s caregivers is limited, despite that this is a frequent behaviour. There is a need for further research covering a broader range of diseases. The causes and consequences of doctor shopping should be sought as well to investigate its relation to health care regulations and possibility to reduce unnecessary medical resource utilization.

Objectives: Inclusion of patient preference (PP) data in decision making has been largely discussed in recent years. Healthcare decision makers-regulatory and health technology assessment (HTA)-are more and more conscious of the need for a patient-centered approach to decide on optimal allocation of scarce money, time, and technological resources. This literature review aims to examine the use of and recommendations for the integration of PP in decision making. Methods: A literature search was conducted through PubMed/Medline in May 2019 to identify publications on PP studies used to inform benefit-risk assessments (BRAs) and HTAs and patient-centered projects and guidelines related to the inclusion of PPs in health policy decision making. After title and abstract screening and full-text review, selected publications were analyzed to retrieve data related to the collection, use, and/or submission of PPs informing BRA or HTA as well as attempts and initiatives in recommendations for PPs integration in decision-making processes. Results: Forty-nine articles were included: 24 attempts and pilot project discussions and 25 PP elicitation studies. Quantitative approaches, particularly discrete choice experiments, were the most used (24 quantitative elicitation studies and 1 qualitative study). The objective of assessing PPs was to prioritize outcome-specific information, to value important treatment characteristics, to provide patient-focused benefit-risk trade-offs, and to appraise the patients’ willingness to pay for new technologies. Moreover, attempts and pilot projects to integrate PPs in BRAs and HTAs were identified at the European level and across countries, but no clear recommendations have been issued yet. No less than seven public and/or private initiatives have been undertaken by governmental agencies and independent organizations to set guidance targeting improvement of patients’ involvement in decision making. Conclusion: Despite the initiatives undertaken, the pace of progress remains slow. The use of PPs remains poorly implemented, and evidence of proper use of these data in decision making is lacking. Guidelines and recommendations formalizing the purpose of collecting PPs, what methodology should be adopted and how, and who should be responsible for generating these data throughout the decision-making processes are needed to improve and empower integration of PPs in BRA and HTA.

INTRODUCTION: Currently, 15-20% of individuals with coronary artery disease (chronic coronary syndrome [CCS]) or peripheral artery disease (PAD) receiving routine treatment experience cardiovascular events (CVEs) within 3-4 years. Using PICOSTEPS (Patients-Intervention-Comparators-Outcomes-Setting-Time-Effects-Perspective-Sensitivity analysis) reporting, we evaluated the cost-effectiveness of recently approved rivaroxaban 2.5 mg twice daily in combination with acetylsalicylic acid 100 mg daily (RIV + ASA) for the prevention of CVEs among Finns with CCS or symptomatic PAD. METHODS: Myocardial infarction, ischemic stroke, intracranial hemorrhage, acute limb ischemia, amputations, major extracranial bleeding, venous thromboembolism, and cardiovascular deaths were modeled in a Markov model examining a cohort of patients with CCS or symptomatic PAD. Relative effects of the intervention (RIV + ASA) and comparator (ASA) were based on the COMPASS trial. The primary outcome was 3%/year discounted incremental cost-effectiveness ratio (ICER), defined as cost (2019 euros) per quality-adjusted life year (QALY) gained in the Finnish setting over a lifetime horizon. In addition to nonfatal and fatal CVEs, the effects factored Finnish non-CVE mortality, quality of life, and direct costs from a public payer perspective. Disaggregated costs and QALYs, costs per life year gained (LYG), and ischemic strokes avoided, net monetary benefit (NMB), expected value of perfect information (EVPI), economic value-added (EVA), cost-effectiveness table, and acceptability frontier were examined. Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: In the deterministic comparison with ASA over a lifetime horizon, RIV + ASA resulted in a benefit of 0.404 QALYs and 0.474 LYGs for an additional cost of €3241, resulting in an ICER of €8031/QALY. The probabilistic ICER was €4313/QALY (EVPI €1829/patient). RIV + ASA had positive NMB (€8791/patient), low EVPI (€88/patient), high EVA (€8703/patient), and 91% probability of cost-effectiveness using the willingness-to-pay of €25,254/QALY. The primary result was conservative and robust for RIV + ASA. CONCLUSION: RIV + ASA was a cost-effective treatment alternative compared with ASA in patients with CCS or symptomatic PAD in Finland.
Finland lacks published evidence on the cost-effectiveness of approved interventions for the prevention of cardiovascular events among individuals with chronic coronary syndrome (stable coronary artery disease) or symptomatic peripheral artery disease at risk of cardiovascular complications. Rivaroxaban 2.5 mg twice daily plus acetylsalicylic acid 100 mg once daily is indicated and reimbursed in Finland for the prevention of cardiovascular events for patients with stable coronary artery disease or symptomatic peripheral artery disease. We assessed the effectiveness and costs of treatment with rivaroxaban plus acetylsalicylic acid in comparison with treatment with acetylsalicylic acid. That is, we examined whether rivaroxaban is cost-effective when prescribed in combination with acetylsalicylic acid.Cardiovascular events with their associated costs and impact on quality of life were modeled over the lifetime of patients. The main effectiveness outcome was quality-adjusted life years (modeled survival multiplied by the expected quality of life), and costs included those relevant to the Finnish public payer in 2019. Extensive sensitivity analyses were carried out to evaluate the impacts of different model inputs and rationale.Rivaroxaban plus acetylsalicylic acid had high probability of being cost-effective, compared with acetylsalicylic acid. By valuing quality-of-life benefit with a plausible willingness-to-pay, net cost savings of €8791 per patient could be gained or economic value added by €8703 per patient if rivaroxaban was used.
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ABSTRACTObjective Advanced Therapy Medicinal Products (ATMPs) present significant therapeutic advantages for inherited rare diseases. However, the development of orphan ATMPs is challenging due to their complexity and unpredictable biological activity. This study aims to comprehensively describe the current state of orphan ATMPs in Europe.Methods Orphan drugs (ODs) granted by European Commission until March 2020 were investigated. The characteristic of diseases and ATMPs were extracted from the public summary reports of ODs from Committee for Orphan Medicinal Products. The methodology for the pivotal studies of ATMPs was extracted.Results A total of 274 ATMPs were identified, covering 116 rare diseases, with metabolic, optical, and oncologic diseases being the most targeted. A total of 158 ATMPs were indicated for life-threatening diseases, 129 ATMPs targeted diseases currently lacking authorized or satisfactory treatment available. Twenty-eight ATMPs are being investigated in the phase II/IIII or phase III studies. The median patient size of pivotal studies was 127, 15 were open-label studies, 8 were single-arm trials, and 14 reported surrogate outcomes.Conclusion There are rapid growths in developing ATMPs for life-threatening diseases with high unmet clinical needs. Optimizing the study methodology and exploring innovative design to facilitate the market access is paramount.