Involvement of Patients and Medical Professionals in the Assessment of Relative Effectiveness: A Need for Closer Cooperation

ObjectivesInvolvement of patients and medical professionals in assessment of relative effectiveness (relative effectiveness assessment) contributes to an efficient and effective health technology assessment (HTA) process and supports acceptance and implementation of the outcome. This study aimed to analyze stakeholder involvement in assessing relative effectiveness and how the parties involved value this collaboration.MethodsThis is a document analysis of all drug assessments completed in 2019 (20) by the public HTA agency of The Netherlands, enriched with semistructured interviews with employees of the HTA agency (18) and representatives of patient (5) and medical (11) associations involved in these assessments. Data were analyzed, coded, and categorized.ResultsIn almost half of the assessments, there was no coordination with the medical associations at the start of the relative effectiveness assessment and no patient associations involved in this phase. During the assessment procedure, patient and medical associations were always asked to comment on the draft report. Nevertheless, the strict 5-day deadline that the HTA agency uses as a response period often hampered a proper response and involvement. According to interviewees of the HTA agency, this leads to a great diversity in the substantive quality of their input. Patient and medical associations indicated that the HTA agency relies too much on “paper knowledge,” which leads to a (perceived) lack of alignment with clinical practice.ConclusionsThe limited involvement results in a lack of coordination and mutual trust. Optimizing involvement of patients and medical professionals in HTA practice requires effort from all parties involved. Procedural adjustments and better coordination, especially at the start of the assessment, would probably improve cooperation.     

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.     

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.     

A Conceptual Framework for Life-Cycle Health Technology Assessment

ObjectivesHealth technology assessment (HTA) uses evidence appraisal and synthesis with economic evaluation to inform adoption decisions. Standard HTA processes sometimes struggle to (1) support decisions that involve significant uncertainty and (2) encourage continued generation of and adaptation to new evidence. We propose the life-cycle (LC)-HTA framework, addressing these challenges by providing additional tools to decision makers and improving outcomes for all stakeholders.MethodsUnder the LC-HTA framework, HTA processes align to LC management. LC-HTA introduces changes in HTA methods to minimize analytic time while optimizing decision certainty. Where decision uncertainty exists, we recommend risk-based pricing and research-oriented managed access (ROMA). Contractual procurement agreements define the terms of reassessment and provide additional decision options to HTA agencies. LC-HTA extends value-of-information methods to inform ROMA agreements, leveraging routine, administrative data, and registries to reduce uncertainty.ResultsLC-HTA enables the adoption of high-value high-risk innovations while improving health system sustainability through risk-sharing and reducing uncertainty. Responsiveness to evolving evidence is improved through contractually embedded decision rules to simplify reassessment. ROMA allows conditional adoption to obtain additional information, with confidence that the net value of that adoption decision is positive.ConclusionsThe LC-HTA framework improves outcomes for patients, sponsors, and payers. Patients benefit through earlier access to new technologies. Payers increase the value of the technologies they invest in and gain mechanisms to review investments. Sponsors benefit through greater certainty in outcomes related to their investment, swifter access to markets, and greater opportunities to demonstrate value.     

Challenges of Health Technology Assessment in Pluralistic Healthcare Systems: An ISPOR Council Report

Health technology assessment (HTA) has been growing in use over the past 40 years, especially in its impact on decisions regarding the reimbursement, adoption, and use of new drugs, devices, and procedures. In countries or jurisdictions with “pluralistic” healthcare systems, there are multiple payers or sectors, each of which could potentially benefit from HTA. Nevertheless, a single HTA, conducted centrally, may not meet the needs of these different actors, who may have different budgets, current standards of care, populations to serve, or decision-making processes.This article reports on the research conducted by an ISPOR Health Technology Assessment Council Working Group established to examine the specific challenges of conducting and using HTA in countries with pluralistic healthcare systems. The Group used its own knowledge and expertise, supplemented by a narrative literature review and survey of US payers, to identify existing challenges and any initiatives taken to address them. We recommend that countries with pluralistic healthcare systems establish a national focus for HTA, develop a uniform set of HTA methods guidelines, ensure that HTAs are produced in a timely fashion, facilitate the use of HTA in the local setting, and develop a framework to encourage transparency in HTA. These efforts can be enhanced by the development of good practice guidance from ISPOR or similar groups and increased training to facilitate local use of HTA.     

Differences in Health Technology Assessment Recommendations Among European Jurisdictions: The Role of Practice Variations

BackgroundHealth technology assessment (HTA) plays an important role in reimbursement decision-making in many countries, but recommendations vary widely throughout jurisdictions, even for the same drug. This variation may be due to differences in the weighing of evidence or differences in the processes or procedures, which are known as HTA practices.ObjectiveTo provide insight into the effects of differences in practices on interpretation of intercountry differences in HTA recommendations for conditionally approved drugs.MethodsHTA recommendations for conditionally approved drugs (N = 27) up until June 2017 from England/Wales, France, Germany, the Netherlands, and Scotland were included. Recommendations and practice characteristics were extracted from these five jurisdictions and this data was validated. The effect of nonsubmissions, resubmissions, and reassessments; cost-effectiveness assessments; and price negotiations on changes in the percentage of negative recommendations and the interpretation of intercountry differences in HTA outcomes were analyzed using Fisher exact tests.ResultsThe inclusion of cost-effectiveness assessments led to significant increases in the proportion of negative recommendations in England/Wales (from 4% to 50%, P<.01) and Scotland (from 21% to 71%, P<.01). The subsequent inclusion of price negotiations led to significant reductions in the proportion of negative recommendations in England/Wales (from 50% to 14%, P<.01), France (from 31% to 3%, P=.012), and Germany (from 34% to 0%, P<.01). Results indicated that the inclusion of nonsubmissions and resubmissions might affect Scottish negative HTA recommendations (from 7% to 21%), but this effect was not significant. No significant effects were observed in the Netherlands, possibly owing to sample size.ConclusionVariations in HTA practices between international jurisdictions can have a substantial and significant impact on conclusions about recommendations by HTA bodies, as exemplified in this cohort of conditionally approved products. Studies comparing international HTA recommendations should carefully consider possible practice variations between jurisdictions.     

Emulating Target Trials With Real-World Data to Inform Health Technology Assessment: Findings and Lessons From an Application to Emergency Surgery

ObjectivesInternational health technology assessment (HTA) agencies recommend that real-world data (RWD) are used in some circumstances to add to the evidence base about the effectiveness and cost-effectiveness of health interventions. The target trial framework applies the design principles of randomized-controlled trials to RWD and can help alleviate inevitable concerns about bias and design flaws with nonrandomized studies. This article aimed to tackle the lack of guidance and exemplar applications on how this methodology can be applied to RWD to inform HTA decision making.MethodsWe use Hospital Episode Statistics data from England on emergency hospital admissions from 2010 to 2019 to evaluate the cost-effectiveness of emergency surgery for 2 acute gastrointestinal conditions. We draw on the case study to describe the main challenges in applying the target trial framework alongside RWD and provide recommendations for how these can be addressed in practice.ResultsThe 4 main challenges when applying the target trial framework to RWD are (1) defining the study population, (2) defining the treatment strategies, (3) establishing time zero (baseline), and (4) adjusting for unmeasured confounding. The recommendations for how to address these challenges, mainly around the incorporation of expert judgment and use of appropriate methods for handling unmeasured confounding, are illustrated within the case study.ConclusionsThe recommendations outlined in this study could help future studies seeking to inform HTA decision processes. These recommendations can complement checklists for economic evaluations and design tools for estimating treatment effectiveness in nonrandomized studies.     

A Systematic Review of Health Technology Assessments of Chimeric Antigen Receptor T-Cell Therapies in Young Compared With Older Patients

ObjectivesThe objective of this review was to identify sources of variability in cost-effectiveness analyses of chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel and axicabtagene ciloleucel, evaluated by health technology assessment (HTA) agencies, focusing on young compared with older patients.MethodsHTA evaluations in pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma (DLBCL) were included from Australia, Canada, England, Norway, and the United States. Key clinical evidence, economic approach, and outcomes (costs, quality-adjusted life-years [QALYs] and incremental cost-effectiveness ratios) were summarized.ResultsFourteen HTA evaluations were identified (5 ALL, 9 DLBCL [4 tisagenlecleucel, 5 axicabtagene]). Analyses were naive comparisons of prospective single-arm studies for the CAR-Ts with retrospective cohort studies for the comparators. Key clinical evidence and economic model approaches were generally consistent by CAR-T and indication, although outcomes varied. Notably, incremental QALYs varied substantially in ALL (3.67-10.6 QALYs gained), whereas variation in DLBCL was less (1.21-1.97 [tisagenlecleucel], 1.97-3.40 [axicabtagene]). Discounting of costs and outcomes varied, with the highest QALYs generated for tisagenlecleucel in ALL (10.95) associated with the lowest discount rate (1.5%) and vice versa (4.97 QALYs; 5% discount rate). The approach to extrapolation of overall survival data varied, even where the same empirical data were used.ConclusionModeled, long-term treatment benefit in young patients may be associated with greater uncertainty compared with adults because of potential life-long benefits with cell and gene therapies. This reflects the methodological challenges identified by HTA agencies associated with single-arm, short-term studies.     

Do Cost-Effectiveness Analyses Account for Drug Genericization? A Literature Review and Assessment of Implications

ObjectivesWe investigated how health technology assessment (HTA) organizations around the world have handled drug genericization (an allowance for future generic drug entry and subsequent drug price declines) in their guidelines for cost-effectiveness analyses (CEAs). We also analyzed a large sample of published CEAs to examine prevailing practices in the field.MethodsWe reviewed 43 HTA guidelines to determine whether and how they addressed drug genericization in their CEAs. We also selected a sample of 270 US-based CEAs from the Tufts Medical Center’s CEA Registry, restricting the sample to studies on pharmaceuticals published from 1991 to 2019 and to analyses taking a lifetime time horizon. We determined whether each CEA examined genericization (and if so, whether in base case or sensitivity analyses), and how inclusion of genericization influenced the estimated incremental cost-effectiveness ratios.ResultsFourteen (33%) of the 43 HTA guidelines mention genericization for CEAs and 4 (9%) recommend that base case analyses include assumptions about future drug price changes due to genericization. Most published CEAs (95%) do not include assumptions about future generic prices for intervention drugs. Only 2% include such assumptions about comparator drugs. Most studies (72%) conduct sensitivity analyses on drug prices unrelated to genericization.ConclusionsThe omission of assumptions about genericization means that CEAs may misrepresent the long run opportunity costs for drugs. The field needs clearer guidance for when CEAs should account for genericization, and for the inclusion of other price dynamics that might influence a drug’s cost-effectiveness.     

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.     

Americans’ Health Priorities During the COVID-19 Pandemic

ObjectivesThis study aimed to examine how Americans’ opinions of the seriousness of various health-related problems have changed over time and to quantify the public’s preferences for research prioritization.MethodsWe conducted a survey that asked respondents to rate the seriousness of 80 health-related problems on a 4-point Likert scale (“very serious problem,” “somewhat serious problem,” “not too serious of a problem,” or “not a problem at all”). Results were compared with past surveys from 2001 and 2013 that examined the same set of health-related problems (with the exception of COVID-19). The survey also included best-worst scaling questions that asked respondents to select, from 20 health problems, those they considered most and least important for research funding. Respondents were recruited from the KnowledgePanel, a nationally representative sample of American households.ResultsA total of 768 adults completed the survey between September 3, 2020, and September 14, 2020. The health-related problems that Americans consider to be “very serious” generally align with the leading causes of death and noncommunicable diseases such as heart disease, diabetes, and mental health; nevertheless, several social determinants of health are also identified. COVID-19 was an unsurprising top priority, whereas cancer remains the highest and a persistent priority for research funding.ConclusionsAmericans consider a diverse set of health-related problems to be “very serious,” with recognition of social determinants of health rising. Our findings offer guidance as to the disease areas for which the public would value further public and private investment in treatment innovations.     

The Emerging Social Science Literature on Health Technology Assessment: A Narrative Review

BackgroundSocial scientists have paid increasing attention to health technology assessment (HTA). This paper provides an overview of existing social scientific literature on HTA, with a focus on sociology and political science and their subfields.MethodsNarrative review of key pieces in English.ResultsThree broad themes recur in the emerging social science literature on HTA: the drivers of the establishment and concrete institutional designs of HTA bodies; the effects of institutionalized HTA on pricing and reimbursement systems and the broader society; and the social and political influences on HTA decisions.ConclusionSocial scientists bring a focus on institutions and social actors involved in HTA, using primarily small-N research designs and qualitative methods. They provide valuable critical perspectives on HTA, at times challenging its otherwise unquestioned assumptions. However, they often leave aside questions important to the HTA practitioner community, including the role of culture and values. Closer collaboration could be beneficial to tackle new relevant questions pertaining to HTA.     

“Stick or Twist?” Negotiating Price and Data in an Era of Conditional Approval

BackgroundChanges in the regulatory context enable faster approval of transformative medicines. They also lead to health technology assessment (HTA) agencies having to make decisions with less evidence. In response, HTA agencies have also initiated forms of conditional approval. When the evidence base for a new oncology treatment leaves substantial uncertainty, the new Cancer Drugs Fund allows the National Institute for Heath and Care Excellence to give the manufacturer two options: (1) offer a low price based on conservative assumptions and obtain immediate approval (“stick”) or (2) wait until the evidence base has further matured before finalizing a potentially higher agreed price (“twist”).ObjectivesThe purpose of this article is to explain how, using the theoretical framework of the expected value of sample information, simulation methods can help inform a manufacturer’s decisions when faced with the option to stick or twist.MethodsWe first summarize a general model to help frame the manufacturer’s negotiating strategy. We then use a motivating case study, based on a hypothetical immunotherapy, to illustrate how manufacturers can use simulation methods to robustly characterize the uncertainty inherent to further data collection and incorporate this uncertainty within their decision making.ResultsOur approach allows us to estimate the commercial value of generating additional data (the difference between the estimated net present value of stick and twist). We test the sensitivity of the results to different assumptions via scenario analyses.ConclusionsThis article shows that simulation methods can be used to help pharmaceutical managers make informed strategic decisions in contexts of uncertainty.     

Formal Implementation of Cost-Effectiveness Evaluations in Japan: A Unique Health Technology Assessment System

In April 2019, Japan formally introduced health technology assessment (HTA) and, more specifically, a cost-effectiveness analysis, to inform healthcare decision making, mainly when it comes to the pricing of new technologies. This article provides an overview of this new policy, which was implemented formally after a pilot program. In the fiscal year (FY) 2012, discussions on cost-effectiveness assessments were initiated in Japan. After 7 years of deliberations, a cost-effectiveness assessment was implemented formally in April 2019. In Japan, the cost-effectiveness analysis has been used to inform price adjustments of healthcare technologies, although it has not yet been used for decision making on insurance coverage. Selection criteria were established because not all drugs and medical devices could be evaluated owing to a shortage of experts. Exclusion criteria have also been applied to prevent access restriction. The scope of the evaluation’s price adjustment target is limited to part of the product price. If the cost per quality-adjusted life-year (QALY) threshold falls below ¥5 million per QALY, the price adjustment rate changes stepwise according to the cost per QALY. In addition to price reduction, a price-raising scheme has also been implemented for scenarios where products are evaluated to be highly cost-effective and innovative. This article describes the first formally implemented HTA system in Japan. Although it is too early to make any conclusions about its effect, the Japan-specific context makes this system unique. To fully understand the opportunities and challenges of the new system, it is vital that Japan accumulates experience with this system and develops human resources in health economic evaluation.     

Mapping to Obtain EQ-5D Utility Values for Use in NICE Health Technology Assessments

Quality-adjusted life-years (QALYs) are widely used as an outcome for the economic evaluation of health interventions. However, preference-based measures used to obtain health-related utility values to produce QALY estimates are not always included in key clinical studies. Furthermore, organizations responsible for reviewing or producing health technology assessments (HTAs) may have preferred instruments for obtaining utility estimates for QALY calculations. Where data using a preference-based measure or the preferred instrument have not been collected, it may be possible to “map” or “crosswalk” from other measures of health outcomes. The aims of this study were 1) to provide an overview of how mapping is currently used as reported in the published literature and in an HTA policy-making context, specifically at the National Institute for Health and Clinical Excellence in the United Kingdom, and 2) to comment on best current practice on the use of mapping for HTA more generally. The review of the National Institute for Health and Clinical Excellence guidance found that mapping has been used since first established but that reporting of the models used to map has been poor. Recommendations for mapping in HTA include an explicit consideration of the generalizability of the mapping function to the target sample, reporting of standard econometric and statistical tests including the degree of error in the mapping model across subsets of the range of utility values, and validation of the model(s). Mapping can provide a route for linking outcomes data collected in a trial or observational study to the specific preferred instrument for obtaining utility values. In most cases, however, it is still advantageous to directly collect data by using the preferred utility-based instrument and mapping should usually be viewed as a “second-best” solution.     

Oral Health Among Older Adults With Complex Needs Living in the Community and in Aged Residential Care Facilities within New Zealand

ObjectivesTo describe the oral health status and dental service use of older adults with complex needs living within the community and aged residential care (ARC) facility settings, and to determine associations between dental service utilization and sociodemographic variables.DesignSecondary analysis of 2 continuously recruited national cohorts.Setting and ParticipantsAdults aged ≥65 years having standardized assessments between July 1, 2012, and May 31, 2018, within New Zealand and who provided consent.MethodsAll community-living older people with complex needs undergo a standardized assessment, using the Home Care International Residential Assessment Instrument (interRAI-HC), whereas all ARC facility residents undergo Long Term Care Facilities assessments (interRAI-LTCF). Anonymized data from consenting participants were extracted. Cross-sectional analyses of oral health status and dental service use variables employed logistic regression models, whereas longitudinal analysis of factors influencing dental service utilization employed binary generalized estimating equation models.ResultsOverall, 144,380 interRAI-HC assessments from 97,229 participants, and 195,549 interRAI-LTCF assessments from 62,798 participants were eligible. At first assessment, their average age was 81.9 years (range: 65-109 years) and 84.4 years (range: 65-110 years), respectively. Approximately 65% of the participants wore dentures; 9% had broken, fragmented, loose, or otherwise nonintact natural teeth; and 10% reported difficulties chewing. Overall, only 25.3% of community-dwelling older adults and 17.5% of ARC residents had a dental examination within the previous year. Stark inequalities were observed with, for example, Māori participants having adjusted odds 3.14 [95% confidence interval (CI): 2.88, 3.42] and 2.08 (95% CI: 1.81, 2.39) of not having a dental examination in community and ARC facility settings compared with their New Zealand European counterparts.Conclusions and ImplicationsHeavy and unequal oral health burdens were observed among older adults with complex needs, together with low dental service uptake. New Zealand needs an oral health policy for older adults.     

Challenges in Research and Health Technology Assessment of Rare Disease Technologies: Report of the ISPOR Rare Disease Special Interest Group

Background

Successful development of new treatments for rare diseases (RDs) and their sustainable patient access require overcoming a series of challenges related to research and health technology assessment (HTA). These impediments, which may be unique to RDs or also apply to common diseases but are particularly pertinent in RDs, are diverse and interrelated.

European collaboration on relative effectiveness assessments: What is needed to be successful?

ObjectiveThe objective of this study is to identify the possible barriers and critical success factors for the implementation of European collaboration in the field of relative effectiveness assessment (REA) of drugs.MethodsData were gathered through semi-structured interviews with representatives from eight European health technology assessment (HTA) organisations involved in assessment of drugs for coverage decision-making (AAZ, AIFA, AHTAPol, HAS, HVB, IQWIG, NICE and ZiN).ResultsPotential barriers identified mainly relate to methodology, resources and challenges with implementation in the respective national processes (e.g. legal restrictions). The most critical success factors for production of cross-border assessments were the continuous cooperation of competent partners, and the quality and timely availability of the assessment.ConclusionFurther adaptation of the process and methods is required for optimal collaboration. In the near future it can be expected that cross-border assessments will meet in particular the needs of smaller/middle-sized European countries and also European countries with less developed HTA systems as the potential efficiency/quality gains are the highest for these countries. Therefore, national implementation of cross-border assessments is especially likely in these countries in the coming years. Once more experience is gained with cross-border assessments, and successes become more evident, efficiency/quality gains may also be likely for some larger countries with well established processes.