Postlaunch evidence generation practices among health technology assessment bodies in Europe.

OBJECTIVES: The term Postlaunch Evidence Generation (PLEG) refers to evidence generated after the launch or licensing of a health technology. The aim of this paper is to provide an overview of the implementation of these practices in the European Union in order to explore cross-border cooperation opportunities. METHODS: In December 2019, a survey composed of nine closed-ended questions with multiple choice answers about the PLEG practices in each country was sent to all twenty-five dedicated work package (WP5B) partners of the European Network of Health Technology Assessment (EUnetHTA) Joint Action 3. In addition to the survey, the national practices were discussed during a face-to-face meeting with WP5B partners. RESULTS: Twelve Health TechnologyAssessment (HTA) bodies completed the survey. Of these, eleven reported procedures in place for official requests for PLEGs in their remit. In the large majority of cases, the requests are made at the time of the assessment/appraisal. Several agencies participate in the definition of the scope of the PLEG or review of its protocol. Data collection and analysis mainly lie with companies for pharmaceuticals, whereas it is more the responsibility of the HTA bodies for medical devices. Only one agency owns the data and is able to exchange them without asking permission. CONCLUSIONS: Most agencies recommend European collaboration on PLEG commence once the evidence gaps have been defined or during the production of the HTA report in the case of European joint assessment.

Development and Pilot Test of the Registry Evaluation and Quality Standards Tool: An Information Technology-Based Tool to Support and Review Registries.

OBJECTIVES: Health technology assessment (HTA) bodies are increasingly making use of real-world evidence and data. High-quality registries could be an asset for this; nevertheless, there is a lack of specified standards to assess the quality of data in the registry, or the registry itself. The European Network for Health Technology Assessment Joint Action 3 led the work to develop a tool for the evaluation of clinical registries: the "Registry Evaluation and Quality Standards Tool" (REQueST). METHODS: REQueST was developed in 4 steps: (1) A partnership between HTA bodies across Europe drafted the assessment criteria. (2) Multiple rounds of consultation across HTA bodies and the public domain developed an Excel version of REQueST. (3) This version was transformed into a web-based application. (4) An external pilot tested this REQueST tool with SMArtCARE and NeuroTransData registries. RESULTS: Haute Autorité de Santé, the National Institute for Health and Care Excellence, and the Croatian Institute of Public Health led the development of REQueST. Another 4 HTA bodies contributed regularly to development meetings, and all European Network for Health Technology Assessment partners were invited to contribute. Eight methodological, 12 essential, and 3 supplementary criteria were identified. Both pilot registries scored well, fulfilling the requirements for >70% of criteria, with none failed. Feedback by registry holders led to streamlining of the process and clarification of the criteria. CONCLUSIONS: The REQueST tool uses an iterative and collaborative methodology with registry holders. It has the potential to maximize the utility of registry data for decision making by regulatory and HTA bodies and provides a foundation for future research.

Early Dialogues for Pharmaceutical Products in European Network for Health Technology Assessment Joint Action 3: What Was Done and Where to Go in the Future.

OBJECTIVES: The aim of this article is to describe the process, results, and experiences of European Network for Health Technology Assessment (EUnetHTA) Joint Action 3's (JA3) Early Dialogue (ED) activities and to highlight opportunities for improving the processes. METHODS: A descriptive analysis of the steps of the EUnetHTA ED process and evaluation of the data from the EDs conducted by EU health technology assessment (HTA) bodies, published guidelines, and documents, as well as internal statistics. RESULTS: In JA3, an Early Dialogues Working Party (EDWP) was established, responsible for developing and improving processes and providing advice to pharmaceutical companies, supported by the ED Secretariat. From June 2017 to May 2021, 113 requests for pharmaceutical EDs were received and 38 conducted. The process was continuously optimized, and different approaches for involving patients were tested. Finally, a centralized procedure was chosen with the key documents produced by two responsible agencies and reviewed by the EDWP. Patient involvement was primarily done by interviewing a national patient representative to obtain general feedback on the disease and the planned study design. CONCLUSIONS: During JA3, EDs were established as an efficient, successful product. Pharmaceutical companies benefited not only from the positions of the individual agencies for the national HTA, but also from the recommendations that were common to all HTA authorities. In addition, regarding the European HTA Regulation, it will be important to conduct Joint Scientific Consultations with a view toward future Joint Clinical Assessments and to further develop processes aligned with the high demand for consultation.

Regulatory and health technology assessment advice on postlicensing and postlaunch evidence generation is a foundation for lifecycle data collection for medicines.

The understanding of the benefit risk profile, and relative effectiveness of a new medicinal product, are initially established in a circumscribed patient population through clinical trials. There may be uncertainties associated with the new medicinal product that cannot be, or do not need to be resolved before launch. Postlicensing or postlaunch evidence generation (PLEG) is a term for evidence generated after the licensure or launch of a medicinal product to address these remaining uncertainties. PLEG is thus part of the continuum of evidence development for a medicinal product, complementing earlier evidence, facilitating further elucidation of a product's benefit/risk profile, value proposition, and/or exploring broader aspects of disease management and provision of healthcare. PLEG plays a role in regulatory decision making, not only in the European Union but also in other jurisdictions including the USA and Japan. PLEG is also relevant for downstream decision-making by health technology assessment bodies and payers. PLEG comprises studies of different designs, based on data collected in observational or experimental settings. Experience to date in the European Union has indicated a need for improvements in PLEG. Improvements in design and research efficiency of PLEG could be addressed through more systematic pursuance of Scientific Advice on PLEG with single or multiple decision makers. To date, limited information has been available on the rationale, process or timing for seeking PLEG advice from regulators or health technology assessment bodies. This article sets out to address these issues and to encourage further uptake of PLEG advice.

Cost-effectiveness analysis of memantine for moderate-to-severe Alzheimer's disease in the Netherlands.

OBJECTIVE: The purpose of this study was to estimate the cost-effectiveness of memantine relative to standard care in patients with moderate-to-severe Alzheimer's disease in the Netherlands. METHODS: A country-adapted five-year Markov model simulated disease progression through a series of states, defined by dependency and disease severity. Transition probabilities were derived from trials, with utility and epidemiological data obtained from a longitudinal Dutch cohort. Cost-effectiveness was described in terms of quality-adjusted life years and time spent in a nondependent state or in a moderate severity state. RESULTS: Memantine monotherapy versus standard care led to 0.058 quality-adjusted life years gained (1.207 versus 1.265), longer time in a nondependent state (from 1.602 to 1.751 years) and in a moderate state (from 2.051 to 2.141 years), and no additional costs (€113,927 versus €110,097). Robustness of results was confirmed through sensitivity analyses. CONCLUSION: Memantine is dominant compared with standard care in the Netherlands. Results are consistent with similar economic evaluations in other countries.

Modeling stroke management: a qualitative review of cost-effectiveness analyses.

OBJECTIVE: To review recent economic analyses and determine if means of improving methodology used in modeling stroke management may exist. STUDY DESIGN AND SETTING: The Medline database was searched for pharmacoeconomic models of treatments or interventions in acute, non-transitory ischemic stroke. Search terms were: stroke, cost, cost-effectiveness, cost analysis, stroke management, model, modeling, and economic. All English-language articles published from January 1997 to January 2008 were reviewed. RESULTS: Ten Markov models and three decision analytical models were identified. All models had a societal perspective and all but one had lifetime horizons. They were all based on common patient states of disability, mortality and recurrence of stroke. Inputs used in the models were transparent and valid. Intracranial hemorrhage, cardiovascular events and data closely related to local settings were not systematically considered. One-way sensitivity analyses were the most common, but few parameters were tested and these varied between models. Consensus key drivers were therefore difficult to determine. CONCLUSION: The overall structure of the models reviewed was sound. However, they should include more systematically cardiovascular events and intracranial hemorrhage, as well as local epidemiological data. Further multi-way sensitivity analyses would help to identify key cost drivers with greater precision and robustness.

Cost-effectiveness of memantine compared with standard care in moderate-to-severe Alzheimer disease in Canada.

OBJECTIVE: To conduct a cost-effectiveness analysis comparing the addition of memantine to standard care (that is, without acetylcholinesterase inhibitors) with standard care alone in moderate-to-severe Alzheimer disease (AD) in Canada. METHODS: A 2-year Markov model estimated clinical effects in terms of quality-adjusted life years (QALYs) and time in complete dependence as well as societal costs in four 6-month cycles. Health states were defined by AD severity assessed with the Mini-Mental State Examination (moderate = 10 to 19; severe < 10), by level of dependence in activities of daily living, and by death. Transition probabilities were estimated by combining data of patients with moderate-to-severe AD from all relevant clinical trials. QALYs were estimated from a UK epidemiologic study. The initial distribution and use of medical and support services for each health state was obtained from the Canadian Study on Health and Aging with current estimates of frequency of use and unit prices applied. RESULTS: Compared with standard care, the memantine strategy saved more than 1 month of complete dependence and produced 0.03 additional QALYs, with no additional cost. Probabilistic sensitivity analyses give an 83.3% chance that memantine treatment is cost-neutral, an 89.5% chance of its being cost-effective if the decision maker is willing to pay $20 000 for a QALY, and a 96.2% chance with a willingness to pay $100 000 per QALY. Robustness of results was confirmed through 1-way and scenario-based sensitivity analyses. CONCLUSIONS: Our evaluation found that memantine monotherapy produced relevant health benefit, compared with standard care alone, with no additional costs. Results are consistent with other economic evaluations of memantine conducted in Europe and the United States.

New assessment of dependency in demented patients: impact on the quality of life in informal caregivers.

UNLABELLED: A qualitative tool was recently developed for evaluation of dependency in a demented population. This tool assesses the impact of cognitive impairment on functional status, taking into account disability in both the basic and the instrumental activities of daily living. The purpose of the present paper was to study the impact of dependency on informal caregivers who assist demented patients at home, with this new useful tool. METHODS: A cross-sectional analysis was undertaken of the subgroup of 145 demented patients of the National Dementia Economic Study, aged > or = 65 years, living in the community, with an available caregiver. A neuropsychological assessment of patients (Mini-Mental State Examination) and a comprehensive evaluation of caregivers (quality of life, Short Form Health Survey-36, depression, Sense of Competence) were recorded. A total of 32.4% were dependent, disabled in both basic and instrumental functions, 42.1% were non-dependent but with instrumental functional disabilities and 25.5% were non-dependent. Impact of dependency on the caregiver's experience was significant for different aspects (satisfaction with caregiving, subjective burden, quality of life, depression). Medical and non-medical costs increased with the severity of functional disability. Findings indicate that this tool is also useful to assess the impact of progression of functional disability in patients with dementia, on the caregiver issues. The consequences appeared both on personal feelings and on quality of life and financial involvement in management of the patient. Cognitive impairment appears to have more moderate repercussions in these areas.

Cost-effectiveness of memantine in community-based Alzheimer's disease patients: An adaptation in Spain.

Several clinical trials have demonstrated the efficacy and safety of the NMDA antagonist memantine in moderately severe to severe Alzheimer's disease (AD) patients. A 28-week pharmacoeconomic study conducted in the US also showed a reduction of total healthcare costs and informal care compared to placebo. Long-term implications of memantine treatment were modelled in the UK and Finland and revealed reductions in dependency, institutionalization and costs. However, these conclusions were not directly applicable to the Spanish setting where patients are mainly treated within the community. The objective of this study was to estimate the long-term implications in terms of costs and health benefits of memantine therapy compared to standard care using a Spanish adaptation of previous models over a 2-year time horizon. As in previous adaptations, Markov health states were defined as a combination of severity (mild-moderate, moderately severe, severe) and dependency plus death as the absorbing state. Spain-specific data (costs, mortality and epidemiological data) were obtained from local and recently published cohorts of AD patients. Data on the effectiveness of memantine were derived from a randomized double-blind placebo-controlled clinical trial of 252 moderately severe to severe AD patients. Effectiveness was measured as the time spent in a non-dependent health state. The evaluation was conducted over 2 years, while the efficacy of memantine was applied for 1 year only in order to ensure a conservative approach. The robustness of the model was tested by conducting stochastic analyses and various sensitivity analyses on the key assumptions. Patients receiving standard care were estimated to spend 6 months in a non-dependent state and to incur average total costs of Euro 24,700 over 2 years. The memantine strategy was associated with an additional 2.5 months in a non-dependent state and a Euro 700 cost reduction. Monte-Carlo simulations and sensitivity analyses supported these findings. Memantine appears to be cost-effective compared with standard care in moderately severe to severe AD patients in a Spanish setting. The prolonged independence provided by memantine treatment translated into cost reductions which offset drug costs and resulted in overall cost-savings.

Characteristics and health status change over 6 months in people with moderately severe to severe Alzheimer's disease in the U.K.

BACKGROUND AND OBJECTIVES: Until recently, attention and treatment strategies have focused mainly on patients in the early phases of Alzheimer's disease (AD). The objectives of this study were to collect information on moderately severe and severe AD patients (Mini-mental State Examination score < 15) in terms of epidemiological, clinical and economic characteristics and disease change in the later stages of AD, and to compare this specific AD population over 6 months with those in the earlier stages. METHODS: This descriptive analysis recruited institutionalized patients and patients living within the community from the city of London and the South-East region of the U.K. Subgroup analyses at baseline and 6 months were performed using the study population from the London and South-East Region Alzheimer's Disease (LASER-AD) Study. Data from a range of clinical scales, a quality of life (QOL) scale and a resource-utilization questionnaire were analyzed. RESULTS: People with moderately severe or severe AD are a heterogeneous group with varying QOL, cognitive and functional disabilities, neuropsychological symptoms and relatively low health care resource consumption. This patient group continued to decline but progression of the disease was observed only in some domains. CONCLUSION: Even at the later stages of AD, patients show varying rates of decline. Improved knowledge about the characteristics and progression of the disease reveals that moderately severe and severe patients cannot be regarded as beyond help and have the potential to experience varying and even high levels of QoL.

Cost effectiveness of memantine in Alzheimer's disease: an analysis based on a probabilistic Markov model from a UK perspective.

BACKGROUND: Clinical trials with memantine, an uncompetitive moderate-affinity NMDA antagonist, have shown improved clinical outcomes, increased independence and a trend towards delayed institutionalisation in patients with moderately severe-to-severe Alzheimer's disease. In a randomised double-blind, placebo-controlled, 28-week study conducted in the US, reductions in resource utilisation and total healthcare costs were noted with memantine relative to placebo. While these findings suggest that, compared with placebo, memantine provides cost savings, further analyses may help to quantify potential economic gains over a longer treatment period. OBJECTIVE: To evaluate the cost effectiveness of memantine therapy compared with no pharmacological treatment in patients with moderately severe-to-severe Alzheimer's disease over a 2-year period. METHODS: A Markov model was constructed to simulate patient progression through a series of health states related to severity, dependency (determined by patient scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL] inventory and residential status ('institutionalisation') with a time horizon of 2 years (each 6-month Markov cycle was repeated four times). Transition probabilities from one health state to another 6 months later were mainly derived from a 28-week, randomised, double-blind, placebo-controlled clinical trial. Inputs related to epidemiological and cost data were derived from a UK longitudinal epidemiological study, while data on quality-adjusted life-years (QALYs) were derived from a Danish longitudinal study. To ensure conservative estimates from the model, the base case analysis assumed drug effectiveness was limited to 12 months. Monte Carlo simulations were performed for each state parameter following definition of a priori distributions for the main variables of the model. Sensitivity analyses included worst case scenario in which memantine was effective for 6 months and one-way sensitivity analyses on key parameters. Finally, a subgroup analysis was performed to determine which patients were most likely to benefit from memantine. Informal care was not included in this model as the costs were considered from National Health Service and Personal Social Services perspective. RESULTS: The base case analysis found that, compared with no treatment, memantine was associated with lower costs and greater clinical effectiveness in terms of years of independence, years in the community and QALYs. Sensitivity analyses supported these findings. For each category of Alzheimer's disease patient examined, treatment with memantine was a cost-effective strategy. The greatest economic gain of memantine treatment was in independent patients with a Mini-Mental State Examination score of > or =10. CONCLUSION: This model suggests that memantine treatment is cost effective and provides cost savings compared with no pharmacological treatment. These benefits appear to result from prolonged patient independence and delayed institutionalisation for moderately severe and severe Alzheimer's disease patients on memantine compared with no pharmacological treatment.