Differences in Evidentiary Requirements Between European Medicines Agency and European Health Technology Assessment of Oncology Drugs—Can Alignment Be Enhanced?

ObjectivesNational health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies’ evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences.MethodsInterviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted.ResultsAcceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements.ConclusionsDifferences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed.     

Health technology assessment: decentralized and fragmented in the US compared to other countries

This paper presents the results of the first comprehensive international survey to catalogue health technology assessment (HTA) activities. By 1995, there were formal HTA programs in 24 countries established mostly in the late 1980s and early 1990s. European countries generally have one or two federal or provincial HTA programs each, Canada has an extensive network of federal and regional organizations coordinated by a central body and the US has 53 HTA organizations, the vast majority of which are in the private sector. While the commitment of the US government to HTA has been erratic, the private sector has been witness to an expansion of HTA activities by insurance companies, hospitals, medical/device manufacturers, consulting firms and health professional societies. In contrast to other developed countries, the current state of technology assessment in the US is decentralized, fragmented and duplicative. We conclude by discussing the importance of a US HTA agency at the national level.     

Review of Relative effectiveness assessments (REAs) of pharmaceuticals at the European network for health technology assessment (EUnetHTA): A first step towards a consolidated European perspective on comparative effectiveness & safety?

ObjectivesREAs from Joint Action (JA1−3) were reviewed and compared versus Health Technology Assessments (HTA) in France, Germany, UK, Italy.MethodsEUnetHTA REAs published until end of 2019 were identified. Leveraging information derived from the HTA bodies’ website key process (population; timing; national HTA bodies involved) and content characteristics (evidence base; comparative therapy, endpoints, subgroups) were determined and compared against national appraisals.ResultsAll twelve pharmaceutical EUnetHTA assessment finalized until end of 2019 were included with Ustekinumab being the most recent (October 2019) and Pazopanib the first assessment (September 2012). In all but three assessments EUnetHTA’s assessment did not cover the full EMA indication. Since JA3 time intervals between EMA approval and EUnetHTA assessment were < 80 days. Number of (co-)authoring HTA bodies ranged between 2 (in 6 REAs) and > 10 (Pazopanib). EUnetHTA did consider non – RCT evidence in 7 procedures; take a rather inclusive approach regarding appropriate comparative treatments; approach endpoints less restrictively than e.g. the German IQWiG/GBA; not apply a predetermined set of subgroups analyses. In seven REAs, national appraisal showed inhomogeneities across the 4 countries. National appraisals for Sotagliflozin and Ustekinumab were not yet available.ConclusionsA joint European HTA assessment has the potential to address the challenge of heterogeneity across the various national European HTA bodies and to determine joint European clinical development data standards that are aligned with regulatory requirements.     

Reported Challenges in Health Technology Assessment of Complex Health Technologies

ObjectivesWith complex health technologies entering the market, methods for health technology assessment (HTA) may require changes. This study aimed to identify challenges in HTA of complex health technologies.MethodsA survey was sent to European HTA organizations participating in European Network for HTA (EUnetHTA). The survey contained open questions and used predefined potentially complex health technologies and 7 case studies to identify types of complex health technologies and challenges faced during HTA. The survey was validated, tested for reliability by an expert panel, and pilot tested before dissemination.ResultsA total of 22 HTA organizations completed the survey (67%). Advanced therapeutic medicinal products (ATMPs) and histology-independent therapies were considered most challenging based on the predefined complex health technologies and case studies. For the case studies, more than half of the reported challenges were “methodological,” equal in relative effectiveness assessments as in cost-effectiveness assessments. Through the open questions, we found that most of these challenges actually rooted in data unavailability. Data were reported as “absent,” “insufficient,” “immature,” or “low quality” by 18 of 20 organizations (90%), in particular data on quality of life. Policy and organizational challenges and challenges because of societal or political pressure were reported by 8 (40%) and 4 organizations (20%), respectively. Modeling issues were reported least often (n = 2, 4%).ConclusionsMost challenges in HTA of complex health technologies root in data insufficiencies rather than in the complexity of health technologies itself. As the number of complex technologies grows, the urgency for new methods and policies to guide HTA decision making increases.     

Divergent evidence requirements for authorization and reimbursement of high-risk medical devices – The European situation

BackgroundUnsafe and dangerous medical devices have entered the European market during the last decade, raising public awareness. Consequently, regulatory processes and their requirements for evidence are under discussion.ObjectiveThis research aims to explore the authorization and reimbursement processes and associated evidence requirements for high-risk medical devices in four regions: Europe, the United States, Australia and Canada.MethodsA literature search in PubMed about the authorization and reimbursement processes in the four regions was performed. Seven high-risk medical devices were selected as examples, and their authorization and reimbursement status were analyzed. Information was extracted from publicly available summaries of the authorization agencies of the regions, from the Controlled Clinical Trial Database, supplemented by information from HTA and reimbursement organizations.ResultsThe evidence required for the authorization and reimbursement processes differs strongly in the four regions regarding the levels of methodology and scrutiny. All seven devices have been authorized in Europe, three in Australia, one in the USA, and one in Canada. Currently none of the devices is recommended for reimbursement in the regions except one, in the USA. Devices that have been authorized in more than one region show that authorization has been two to three years earlier in Europe.ConclusionHuge differences and gaps in the evidence required for market authorization and for reimbursement were observed, especially between the two processes (authorization and reimbursement) in Europe. To ensure the high quality and safe provision of medical devices, harmonization of requirements and transparency in processes are needed.     

The Perioperative Surgical Home (PSH): A Comprehensive Review of US and Non‐US Studies Shows Predominantly Positive Quality and Cost Outcomes

Context

The evolving concept of more rigorously coordinated and integrated perioperative management, often referred to as the perioperative surgical home (PSH), parallels the well-known concept of a patient-centered medical home (PCMH), as they share a vision of improved clinical outcomes and reductions in cost of care through patient engagement and care coordination. Elements of the PSH and similar surgical care coordination models have been studied in the United States and other countries.

Methods

This comprehensive review of peer-reviewed literature investigates the history and evolution of PSH and PSH-like models and summarizes the results of studies of PSH elements in the United States and in other countries. We reviewed more than 250 potentially relevant studies. At the conclusion of the selection process, our search had yielded a total of 152 peer-reviewed articles published between 1980 and 2013.

Findings

The literature reports consistent and significant positive findings related to PSH initiatives. Both US and non-US studies stress the role of anesthesiologists in perioperative patient management. The PSH may have the greatest impact on preparing patients for surgery and ensuring their safe and effective transition to home or other postoperative rehabilitation. There appear to be some subtle differences between US and non-US research on the PSH. The literature in non-US settings seems to focus strictly on the comparison of outcomes from changing policies or practices, whereas US research seems to be more focused on the discovery of innovative practice models and other less direct changes, for example, information technology, that may be contributing to the evolution toward the PSH model.

Conclusions

The PSH model may have significant implications for policymakers, payers, administrators, clinicians, and patients. The potential for policy-relevant cost savings and quality improvement is apparent across the perioperative continuum of care, especially for integrated care organizations, bundled payment, and value-based purchasing.     

Comparison of Recommendations and Use of Cardiovascular Risk Equations by Health Technology Assessment Agencies and Clinical Guidelines

Objectives

To identify risk equations for cardiovascular diseases (CVDs) in primary and secondary prevention settings that are used or recommended by health technology assessment (HTA) organizations and in clinical guidelines (CGs).

Ranking the Criteria Used in the Appraisal of Drugs for Reimbursement: A Stated Preferences Elicitation With Health Technology Assessment Stakeholders Across Jurisdictional Contexts

ObjectivesOur goal was to estimate the relative importance assigned to health technology assessment (HTA) criteria by stakeholders involved in the HTA process. HTA is an increasingly common framework used in the appraisal of drugs for public reimbursement. It identifies clinical, economic, social, and organizational criteria to be considered. The criteria can vary across jurisdictions and are typically appraised by multidisciplinary expert committees. Guidance on the relative weighing of criteria is often absent.MethodsWe elicited stakeholders’ preferences using a single-scenario discrete choice experiment and a best-worst scaling model with conviction scores to assess the weights assigned to selected criteria by HTA stakeholders. We recruited 111 HTA stakeholders across multiple jurisdictions, including members of expert committees, clinical and economic experts, patients, and public payer representatives. Each judged twelve hypothetical cancer drug profiles for suitability for public funding and identified which characteristics were best and worst. In addition to standard discrete choice experiment and best-worst scaling models, we estimated a hybrid model to obtain a ranking of criteria by importance they played in the appraisal.ResultsA strong clinical benefit proved the most important criterion, followed by cost considerations, presence of adverse events, and availability of other treatments. The importance of clinical benefit was moderated by unmet need, adverse events, and number of patients.ConclusionPolicymakers might want to consider providing an explicit weighing scheme, or moving to a 2-stage selection process with an assessment of the quality of clinical evidence as a gatekeeping step for a full HTA review.     

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

ObjectivesHealth 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).MethodsREQueST 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.ResultsHaute 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.ConclusionsThe 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.     

Variation in market access decisions for cell and gene therapies across the United States,Canada, and Europe

Transformative cell and gene therapies have now launched worldwide, and many potentially curative cell and gene therapies are in development, offering the prospect of significant health gains for patients. Access to these therapies depend on decisions made by health technology assessment (HTA) and payer organizations. We sought to describe the emerging cell and gene therapies market access landscape by analyzing 17 US commercial payer medical policies, and HTA reports from five European countries and Canada. We found that some US health plans applied coverage restrictions more often than others (four plans applied restrictions in all decisions, while four plans applied restrictions in <30% of decisions). The European and Canadian HTA bodies recommend access to fewer therapies than US health plans, reflecting a more stringent approach in the context of limited evidence and high scientific uncertainty that is commonly associated with these treatments. Our findings suggest that patient access to approved cell and gene therapies is restricted in all regions studied, though the nature of these restrictions differs between US health plans and the European/Canada HTA recommendations. Payers, HTA groups, pharmaceutical companies, and other stakeholders should collaborate to more clearly define the “uncertainties” and develop market access policies that balance benefits of early access with ongoing data collection to close evidence gaps over time.     

A Review of Current Approaches to Defining and Valuing Innovation in Health Technology Assessment

ObjectivesThe growing focus on the value of new drugs for patients and society has led to a more differentiated notion of innovation in the context of pharmaceutical products. The goal of this article is to provide an overview of the current debate about the definition and assessment of innovation and how innovation is considered in reimbursement and pricing decisions.MethodsTo compile the relevant literature, we followed a 2-step approach. First, we searched for peer-reviewed literature that deals with the definition of pharmaceutical innovation. Second, we reviewed health technology assessment (HTA) guidelines of 11 selected countries (Australia, Belgium, Canada, England, France, Germany, Italy, Japan, Norway, Sweden, and The Netherlands) regarding aspects of innovation that are currently considered as relevant by the respective HTA bodies.ResultsAll countries in our sample use 1 of 2 types of reward mechanism for novel drugs that they consider provide some sort of benefit. Generally, the focus is on the therapeutic benefit of a drug, whereas, depending on the exact arrangement, other aspects can also be taken into account. A reduction in side effects and aspects of treatment convenience can be invoked in some of the countries. Mostly, however, they are not considered unless they are already captured in the clinical outcomes used to measure the therapeutic benefit.ConclusionOur review shows that although the health economic literature discusses a range of aspects on how innovation may generate value even without providing an immediate added therapeutic benefit (or on top of it), these are only selectively considered in the reviewed HTA guidelines. For most part, only the added therapeutic value is crucial when it comes to pricing and reimbursement decisions.     

Key Considerations in the Health Technology Assessment of Advanced Therapy Medicinal Products in Scotland,The Netherlands,and England

ObjectivesAdvanced therapy medicinal products (ATMPs) are highly innovative therapies. Their costs and uncertain value claims have raised concerns among health technology assessment (HTA) bodies and payers. Little is known about how underlying considerations in HTA of ATMPs shape assessment and reimbursement recommendations. We aim to identify and assess key considerations that played a role in HTA of ATMPs underlying reimbursement recommendations.MethodsA review of HTA reports was conducted of all authorized ATMPs in Scotland, The Netherlands, and England. Considerations were extracted and categorized into EUnetHTA Core Model domains. Per jurisdiction, considerations were aggregated and key considerations identified (defined as occurring in >1/assessment per jurisdiction). A narrative analysis was conducted comparing key considerations between jurisdictions and different reimbursement recommendations.ResultsWe identified 15 ATMPs and 18 HTA reports. In The Netherlands and England most key considerations were identified in clinical effectiveness (EFF) and cost- and economic effectiveness (ECO) domains. In Scotland, the social aspects domain yielded most key considerations, followed by ECO and EFF. More uncertainty in evidence and assessment outcomes was accepted when orphan or end-of-life criteria were applied. A higher percentage of considerations supporting recommendations were identified for products with positive recommendations compared with restricted and negative recommendations.ConclusionsThis is the first empirical review of HTA’s using the EUnetHTA Core Model to identify and structure key considerations retrospectively. It provides insights in supporting and opposing considerations for reimbursement of individual products and differences between jurisdictions. Besides the EFF and ECO domain, the social, ethical, and legal domains seem to bear considerable weight in assessment of ATMPs.     

Value assessment of disease-modifying therapies for Relapsing-Remitting Multiple Sclerosis: HTA evidence from seven OECD countries

This study systematically compares HTA recommendations on a number of disease–modifying therapies for patients with Relapsing-Remitting Multiple Sclerosis. We analysed publicly available HTA reports for nine medicine-indication pairs across seven OECD countries using a methodological framework enabling systematic analysis of HTA recommendations. The analysis was conducted based on a number of value dimensions, including clinical and economic variables, as well as several other dimensions of value beyond cost-effectiveness. The material was qualitatively and quantitatively coded following the different stages of HTA decision-making process. Fifty-seven medicine-indication pairs were assessed across the study countries. Of those, eight medicine indication-pairs reported diverging HTA recommendations. Although HTA recommendations were based on the same evidence submitted in most cases, significant variations were identified in interpretation and acceptance of evidence resulting in different uncertainties raised and different ways of addressing them. Uncertainties arose both in terms of the clinical and the economic evidence, including the design of key trials or the data quality in economic models. Beyond costs and effects, additional dimensions of value had an impact in the direction of recommendations, however with different magnitude across countries. We show that there is heterogeneity across countries in HTA for evaluating DMTs for RRMS with a lack of standardised methods in evaluating clinical and economic evidence and the use of social value judgments to inform decision-making.     

Do Reimbursement Recommendations by the Canadian Agency for Drugs and Technology in Health Translate Into Coverage Decisions for Orphan Drugs in the Canadian Province of Ontario?

ObjectivesUnlike other high-income countries, Canada has no national policy for drugs treating rare diseases (orphan drugs). Nevertheless, in 2022, the Canadian government committed to creating a national strategy to make access to these drugs more consistent. Our aim was to study whether recommendations made by the Canadian Agency for Drugs and Technology in Health (CADTH) translated into coverage decisions for orphan drugs in Ontario, the largest Canadian province. This study is the first to look at this question for orphan drugs, which are at the center of policy attention.MethodsWe included 155 orphan drug-indication pairs approved and marketed in Canada between October 2002 and April 2022. Cohen’s kappa was used to test the agreement across health technology assessment (HTA) recommendations and coverage decisions in Ontario. Logistic regression was used to test which factors, relevant to decision-makers, might be associated with funding in Ontario.ResultsWe found only fair agreement between CADTH’s recommendations and coverage decisions in Ontario. Although a positive and statistically significant association between favorable HTA recommendations and coverage was found, more than half of the drugs with a negative HTA recommendation were available in Ontario, predominately through specialized funds. Successful pan-Canadian pricing negotiations were a strong predictor of coverage in Ontario.ConclusionsDespite efforts to harmonize access to drugs across Canada, considerable room for improvement remains. Introducing a national strategy for orphan drugs could help increase transparency, consistency, promote collaborations, and make access to orphan drugs a national priority.     

An International Survey of the Public Engagement Practices of Health Technology Assessment Organizations

ObjectivesMany jurisdictions are moving toward greater public involvement in health technology assessment (HTA) processes. This study aims to provide a broad, cross-sectional indication of the extent and methods of public engagement in HTA, with a focus on which public are engaged, by what mechanisms, and the purpose of public engagement.MethodsAn international Web-based survey of 217 organizations involved in HTA was undertaken. Contact e-mail addresses for targeted organizations were identified from the Internet.ResultsIndividuals from 39 (18%) of the contacted organizations completed a survey. The majority (67%) of responding HTA organizations undertake public engagement activities, predominantly involving lay representatives of organized groups (81%), and to a lesser extent individual patients/consumers (54%) or citizens/community members (54%). For organizations undertaking public engagement, mechanisms based on communication or consultation were the most common, although some organizations have used or intend to use participatory approaches, particularly the Citizens’ Jury (8%) or Consensus Council (20%) methods. Respondents identified with a number of rationales and barriers for undertaking public engagement.ConclusionsThis survey provides further insight into the public engagement approaches that are used by HTA organizations in practice. In particular, it suggests a limited adoption of participatory methods to date, and interest in the use of social media. Study findings require further confirmation, due to limitations related to survey response. There is considerable opportunity for further research into pragmatic, robust, and meaningful approaches to public engagement to strengthen HTA policy and decision-making frameworks. An agenda for future research evolving from the survey responses is proposed.     

Testing a new taxonomic model for the assessment of medical devices: Is it plausible and applicable? Insights from HTA reports and interviews with HTA institutions in Europe

Objective

Medical devices (MDs) encompass a broad and heterogeneous range of technologies. While practices vary considerably across countries, MDs often find application in patient care with little or no evaluation of their effectiveness and safety following market approval. A recently proposed taxonomy of MDs considered devices from the viewpoint of Health Technology Assessment (HTA). The aim of the work presented here was to test its plausibility and applicability by considering real-world HTA practices.

Health technology assessment use and dissemination by patient and consumer groups: why and how?

OBJECTIVES: Although increasing effort is being devoted to developing strategies to increase knowledge transfer and the uptake of health technology assessment (HTA) by various stakeholders, very little is known about the utilization and dissemination of HTA findings by patient and consumer organizations. The goal of this study is to understand how and why patient and consumer organizations use HTA findings within their organizations, and what factors influence how and when they communicate their findings to members or other organizations. METHODS: We examined the use and dissemination of four controversial HTA reports by sixteen patient and consumer organizations in Ontario and Quebec. We gathered data from semistructured interviews conducted between December 2006 and April 2007. RESULTS: Although HTA findings are often used by the patient and consumer organizations, key differences were observed in exactly how the four HTA reports were used. Three types of use (instrumental, conceptual, and symbolic) are reported and illustrated. We highlight the importance of the organization's mission and knowledge base in explaining the types of use observed. CONCLUSIONS: We contend that the use and dissemination of HTA reports by specific groups could help in widening the debate around controversial health technologies. The implications and opportunities for HTA agencies relate to the following: (i) identification of "lay" organizations that could help in disseminating results; (ii) acknowledgement of a "lay" audience for HTA findings; (iii) strategic inclusion of advocacy groups during the assessment process for highly controversial technologies; and (iv) contribution of these organizations to the push efforts of knowledge transfer.     

An overview of critical decision-points in the medical product lifecycle: Where to include patient preference information in the decision-making process?

BackgroundPatient preference (PP) information is not effectively integrated in decision-making throughout the medical product lifecycle (MPLC), despite having the potential to improve patients’ healthcare options. A first step requires an understanding of existing processes and decision-points to know how to incorporate PP information in order to improve patient-centric decision-making.ObjectivesThe aims were to: 1) identify the decision-making processes and decision-points throughout the MPLC for industry, regulatory authorities, and reimbursement/HTA, and 2) determine which decision-points can potentially include PP information.MethodsA scoping literature review was conducted using five scientific databases. Semi-structured interviews were conducted with representatives from seven European countries and the US, including industry (n = 24), regulatory authorities (n = 23), reimbursement/HTA (n = 23). Finally, validation meetings with key stakeholders (n = 11) were conducted.ResultsSix critical decision-points were identified for industry decision-making, three for regulatory decision-making, and six for reimbursement/HTA decision-making. Stakeholder groups agreed that PP information is not systematically integrated, either as obligatory information or pre-set criteria, but would benefit all the listed decision-points in the future.ConclusionCurrently, PP information is not considered as obligatory information to submit for any of the MPLC decision-points. However, PP information is considered an important component by most stakeholders to inform future decision-making across the MPLC. The integration of PP information into 15 identified decision-points needs continued discussion and collaboration between stakeholders.     

“It all depends”: Conceptualizing public involvement in the context of health technology assessment agencies

There have been calls in recent years for greater public involvement in health technology assessment (HTA). Yet the concept of public involvement is poorly articulated and little attention has been paid to the context of HTA agencies. This article investigates how public involvement is conceptualized in the HTA agency environment. Using qualitative concept analysis methods, we reviewed the HTA literature and the websites of HTA agencies and conducted semi-structured interviews with informants in Canada, Denmark, and the United Kingdom. Our analysis reveals that HTA agencies' role as bridges or boundary organizations situated at the frontier of research and policymaking causes the agencies to struggle with the idea of public involvement. The HTA community is concerned with conceptualizing public involvement in such a way as to meet scientific and methodological standards without neglecting its responsibilities to healthcare policymakers. We offer a conceptual tool for analyzing the nature of public involvement across agencies, characterizing different domains, levels of involvement, and types of publics.