Процедура селекции ридж-регрессионных моделей

Исследована эффективность процедуры селекции регрессионных моделей в случае неопределённости структуры модели, аппроксимируемой ридж-регрессией.Досліджена ефективність процедури селекції регресійних моделей в разі невизначеності структури моделі, що апроксимується рідж-регресією.Efficiency of procedure of selection of regressive models is investigational in the case of vagueness of model structure, by the approximated ridge-regression

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

Alignment of European Regulatory and Health Technology Assessments: A Review of Licensed Products for Alzheimer's Disease

Aims: To facilitate regulatory learning, we evaluated similarities and differences in evidence requirements between regulatory and health technology assessment (HTA) bodies of Alzheimer's disease (AD) approved products.Methods: The European marketing authorisation application dossiers and European public assessment reports (EPARs) of the licensed AD drugs were screened to identify the phase III randomised controlled trials (RCTs) and outcomes used. We also screened the assessment reports of the National Institute of Health and Care Excellence (NICE, England) and the National Health Care Institute (ZiN, the Netherlands) to identify the studies and outcomes used in HTA assessments.Results: The application dossiers of donepezil, galantamine, rivastigmine, and memantine contained 16 phase III RCTs in total. These trials were also included in HTA assessments except that NICE excluded studies that were not published (n = 2) or trials that included patients with other types of dementia (n = 3). In the regulatory assessments the focus was on cognitive and global outcomes, and to some extent on function. In the HTA assessments of clinical effectiveness other domains were also covered including: function, behaviour and mood, and, occasionally, quality of life. In the economic analyses of NICE the domains cognition, function, and quality of life were included.Conclusion: There was a large overlap in inclusion of trials in regulatory and HTA assessments, although the focus on specific outcomes slightly differed. Understanding the methods and perceptions of both authorities can stimulate regulatory and HTA cross-talk and further alignment, and therefore more rapid patient access to new treatments

Managed Entry Agreements for Pharmaceuticals in the Context of Adaptive Pathways in Europe

As per the EMA definition, adaptive pathways is a scientific concept for the development of medicines which seeks to facilitate patient access to promising medicines addressing high unmet need through a prospectively planned approach in a sustainable way. This review reports the findings of activities undertaken by the ADAPT-SMART consortium to identify enablers and explore the suitability of managed entry agreements for adaptive pathways products in Europe. We found that during 2006–2016 outcomes-based managed entry agreements were not commonly used for products with a conditional marketing authorization or authorized under exceptional circumstances. The barriers and enablers to develop workable managed entry agreements models for adaptive pathways products were discussed through interviews and a multi-stakeholder workshop with a number of recommendations made in this paper

Epidemiology of Adverse Drug Reactions in Europe: A Review of Recent Observational Studies

Adverse drug reactions (ADRs) cause considerable mortality and morbidity but no recent reviews are currently available for the European region. Therefore, we performed a review of all epidemiological studies quantifying ADRs in a European setting that were published between 1 January 2000 and 3 September 2014. Included studies assessed the number of patients who were admitted to hospital due to an ADR, studies that assessed the number of patients who developed an ADR during hospitalization, and studies that measured ADRs in the outpatient setting. In total, 47 articles were included in the final review. The median percentage of hospital admissions due to an ADR was 3.5 %, based on 22 studies, and the median percentage of patients who experienced an ADR during hospitalization was 10.1 %, based on 13 studies. Only five studies were found that assessed ADRs occurring in the outpatient setting. These results indicate that the occurrence of ADRs in the European hospital setting—both ADRs that result in hospitalization and ADRs that occur during the hospital stay—is significant. Furthermore, the limited number of studies that were performed in the outpatient setting identify a lack of information regarding the epidemiology of ADRs in this setting

Registries in European post-marketing surveillance : a retrospective analysis of centrally approved products, 2005-2013

Purpose: Regulatory agencies and other stakeholders increasingly rely on data collected through registries to support their decision-making. Data from registries are a cornerstone of post-marketing surveillance for monitoring the use of medicines in clinical practice. This study was aimed at gaining further insight into the European Medicines Agency's (EMA) requests for new registries and registry studies using existing registries and to review the experience gained in their conduct. Methods: European Public Assessment Reports were consulted to identify products for which a request for a registry was made as a condition of the marketing authorisation. All centrally authorised products that received a positive opinion of the EMA Committee for Medicinal Products for Human Use between 1 January 2005 and 31 December 2013 were included. Data regarding registry design and experiences were collected from EMA electronic record keeping systems. Results: Of 392 products that received a positive Committee for Medicinal Products for Human Use opinion during 2005-2013, 31 registries were requested for 30 products in total. Sixty-five percent were product registries whereas 35% were disease registries and 71% of the registries had a primary safety objective. Most commonly reported issues with registries were delayed time to start and low patient accrual rates. Conclusions: The delays found in getting new registries up and running support the need to improve the timeliness of data collection in the post-marketing setting. Methodological challenges met in conducting this study highlighted the need for a clarification of definitions and epidemiological concepts around patient registries. The results will inform the EMA Patient Registry initiative to support use of existing patient registries for the post-authorisation benefit-risk monitoring of medicinal products

Registries in European post-marketing surveillance : a retrospective analysis of centrally approved products, 2005-2013

Purpose: Regulatory agencies and other stakeholders increasingly rely on data collected through registries to support their decision-making. Data from registries are a cornerstone of post-marketing surveillance for monitoring the use of medicines in clinical practice. This study was aimed at gaining further insight into the European Medicines Agency's (EMA) requests for new registries and registry studies using existing registries and to review the experience gained in their conduct. Methods: European Public Assessment Reports were consulted to identify products for which a request for a registry was made as a condition of the marketing authorisation. All centrally authorised products that received a positive opinion of the EMA Committee for Medicinal Products for Human Use between 1 January 2005 and 31 December 2013 were included. Data regarding registry design and experiences were collected from EMA electronic record keeping systems. Results: Of 392 products that received a positive Committee for Medicinal Products for Human Use opinion during 2005-2013, 31 registries were requested for 30 products in total. Sixty-five percent were product registries whereas 35% were disease registries and 71% of the registries had a primary safety objective. Most commonly reported issues with registries were delayed time to start and low patient accrual rates. Conclusions: The delays found in getting new registries up and running support the need to improve the timeliness of data collection in the post-marketing setting. Methodological challenges met in conducting this study highlighted the need for a clarification of definitions and epidemiological concepts around patient registries. The results will inform the EMA Patient Registry initiative to support use of existing patient registries for the post-authorisation benefit-risk monitoring of medicinal products

Weighing of Evidence by Health Technology Assessment Bodies: Retrospective Study of Reimbursement Recommendations for Conditionally Approved Drugs

This study assessed whether five Health Technology Assessment (HTA) bodies in Europe were more negative about drugs with a Conditional Marketing Authorization (CMA) that are approved without controlled studies compared to CMA drugs that are approved based on controlled studies. The HTA recommendations were categorized into positive, restricted, and negative. A total of 92 HTA recommendations were available for 27 drugs. Thirty of 62 (48%) and 17 of 30 (57%) of the recommendations were negative for drugs with and without controlled studies, respectively. Overall, only 12 (13%) recommendations were positive. In all jurisdictions, recommendations between drugs with and drugs without controlled data were comparable, which suggests that the presence of controlled data is not decisive in HTA evaluations. The small proportion of unrestricted positive recommendations highlights difficulties with recommending the drugs in this cohort, which may be caused by scientific uncertainty or other factors. Earlier collaboration between stakeholders is advised in order to improve patient access

Weighing of Evidence by Health Technology Assessment Bodies : Retrospective Study of Reimbursement Recommendations for Conditionally Approved Drugs

This study assessed whether five Health Technology Assessment (HTA) bodies in Europe were more negative about drugs with a Conditional Marketing Authorization (CMA) that are approved without controlled studies compared to CMA drugs that are approved based on controlled studies. The HTA recommendations were categorized into positive, restricted, and negative. A total of 92 HTA recommendations were available for 27 drugs. Thirty of 62 (48%) and 17 of 30 (57%) of the recommendations were negative for drugs with and without controlled studies, respectively. Overall, only 12 (13%) recommendations were positive. In all jurisdictions, recommendations between drugs with and drugs without controlled data were comparable, which suggests that the presence of controlled data is not decisive in HTA evaluations. The small proportion of unrestricted positive recommendations highlights difficulties with recommending the drugs in this cohort, which may be caused by scientific uncertainty or other factors. Earlier collaboration between stakeholders is advised in order to improve patient access

Developing a Framework for the Health Technology Assessment of Histology-independent Precision Oncology Therapies

The arrival of precision oncology is challenging the evidence standards under which technologies are evaluated for regulatory approval as well as for health technology assessment (HTA) purposes. Several key concepts are discussed to highlight the source of the challenges in evaluating these products, particularly those impacting the HTA of histology-independent therapies. These include the basket trial design, high uncertainty in (potentially substantial) benefits for histology-independent therapies, and the inability to identify and quantify benefits of standard of care in daily practice when the biomarker is not currently used in practice. There is little precedent for a technology with the unique mixture of challenges for HTA of histology-independent therapies and they will be evaluated using standard HTA, as there currently is no evidence suggesting the standard HTA framework is not appropriate. A number of questions proposed to help guide HTA bodies when assessing the appropriateness of local processes to optimally evaluate histology-independent therapies. Pragmatic solutions are further proposed to decrease uncertainty in the benefits of histology independent therapies as well as fill gaps in comparative evidence. The proposed solutions ensure a consistent and streamlined approach to evaluation across histology-independent products, although with varying strengths and limitations. Alongside these solutions, sponsors should engage early with HTA bodies/payers and regulatory agencies through parallel/joint scientific advice to facilitate the integration of both regulatory and HTA perspectives into one clinical development programme, potentially reconciling evidence requirements