Use of External Comparators for Health Technology Assessment Submissions Based on Single-Arm Trials

BackgroundSingle-arm trial (SAT) data is increasingly reviewed for drug approvals by regulators and Health Technology Assessment (HTA) bodies. Supplementary data in the form of external comparators (ECs) can be used to provide clinical context to support these drug evaluations. In this study we characterized HTAs for SAT-based submissions, the use of supplementary EC data and outcomes from HTA review.MethodsHTA Accelerator database was used to describe SAT-based HTA submissions with decisions (2011-2019).ResultsA total of 433 SAT-based HTA submissions were identified between 2011 and 2019 with a 13-fold increase during this period. Around 65%(283/433) were in oncology or hem-oncology. Around 52%(226/433) of submissions contained some type of EC data, including prior clinical trials (24%, 104) and real-world data (RWD) (20%, 87), but 40%(175) contained no EC data. The overall acceptance rate for SAT-based submissions was 48% and with RWD EC data acceptance was 59%. In the latest 5-year period (2015-2019), use of RWD ECs increased 22% as a proportion of submissions per year, whereas, prior trial ECs decreased (–14%) and use of no EC remained stable (–2%). Between 2015 to 2017 and 2018 to 2019, acceptance rate for RWD ECs increased by 20% (41% in 2015-2017 to 61% in 2018-2019) whereas prior trial EC use decreased by 10% and no EC submissions decreased 16%. Of 226 submissions using ECs, only 29%(66) used an adjusted indirect treatment comparison method.ConclusionsSAT-based submissions to HTA bodies are rapidly evolving in terms of composition and acceptance. Types of EC and methodological approach used are important determinants of positive outcomes.     

Health Technology Assessment (HTA) Case Studies: Factors Influencing Divergent HTA Reimbursement Recommendations in Australia,Canada, England,and Scotland

Objectives

To evaluate the national regulatory, health technology assessment (HTA), and reimbursement pathways for public health care in Australia, Canada, England, and Scotland, to compare initial Canadian national HTA recommendations with the initial decisions of the other HTA agencies, and to identify factors for differing national HTA recommendations between the four HTA agencies.

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.     

Can Observational Analyses of Routinely Collected Data Emulate Randomized Trials? Design and Feasibility of the Observational Patient Evidence for Regulatory Approval Science and Understanding Disease Project

ObjectivesThe Observational Patient Evidence for Regulatory Approval Science and Understanding Disease (OPERAND) project examines whether real-world data (RWD) can be used to inform regulatory decision making.MethodsOPERAND evaluates whether observational analyses using RWD to emulate index trials can produce effect estimates similar to those of the trials and examines the impact of relaxing the eligibility criteria of the observational analyses to obtain samples that more closely match the real-world populations receiving the treatments. In OPERAND, 2 research teams independently attempt to emulate the ROCKET Atrial Fibrillation and LEAD-2 trials using OptumLabs data. This article describes the design of the project, summarizes the approaches of the 2 research teams, and presents feasibility results for 2 emulations using new-user designs.ResultsThere were differences in the teams’ conceptualizations of the emulation, design decisions for cohort identification, and resulting RWD cohorts. These differences occurred even though both teams were guided by the same index trials and had access to the same source of RWD.ConclusionsReasonable alternative design and analysis approaches may be taken to answer the same research question, even when attempting to emulate the same index trial. Researcher decision making is an understudied and potentially important source of variability across RWD analyses.     

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.     

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.     

Policies for Use of Real-World Data in Health Technology Assessment (HTA): A Comparative Study of Six HTA Agencies

Background

Randomized controlled trials provide robust data on the efficacy of interventions rather than on effectiveness. Health technology assessment (HTA) agencies worldwide are thus exploring whether real-world data (RWD) may provide alternative sources of data on effectiveness of interventions. Presently, an overview of HTA agencies’ policies for RWD use in relative effectiveness assessments (REA) is lacking.

Evaluation of new medicines in Spain and comparison with other European countries

ObjectiveTo compare the use of health technology assessment (HTA) as a tool to support pricing and reimbursement (P&R) of new medicines in Spain with England, Sweden, France and Germany.MethodFor each country, the literature is used to identify the purpose and timing of the P&R decision, the HTA and decision-making procedures used to generate evidence, and the criteria used to make decisions.ResultsResults are presented as a summary of the HTA landscape for P&R of new medicines in each country. Comparisons are made between Spain and other countries regarding the procedure and implementation of HTA.ConclusionsBased on these assessments, we made recommendations for how HTA might develop in Spain with the aim of improving governance and efficiency. Spain has made considerable progress in recent years, but still falls short of international standards in terms of independence of the HTA agencies and decision-making committees from political influence and industrial policy, the setting of prices of medicines in relation to health gain, improve the transparency of the process and results of the evaluation, and promote the participation of stakeholders. In common with other countries, Spain needs to clarify the role of cost-effectiveness criteria. Further progress needs to be made to coordinate effort across the various agencies, strengthen technical staff, and ensure equitable access to medicines between regions.     

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.     

Sample size importantly limits the usefulness of instrumental variable methods,depending on instrument strength and level of confounding

ObjectivesInstrumental variable (IV) analysis is promising for estimation of therapeutic effects from observational data as it can circumvent unmeasured confounding. However, even if IV assumptions hold, IV analyses will not necessarily provide an estimate closer to the true effect than conventional analyses as this depends on the estimates' bias and variance. We investigated how estimates from standard regression (ordinary least squares [OLS]) and IV (two-stage least squares) regression compare on mean squared error (MSE).Study DesignWe derived an equation for approximation of the threshold sample size, above which IV estimates have a smaller MSE than OLS estimates. Next, we performed simulations, varying sample size, instrument strength, and level of unmeasured confounding. IV assumptions were fulfilled by design.ResultsAlthough biased, OLS estimates were closer on average to the true effect than IV estimates at small sample sizes because of their smaller variance. The threshold sample size above which IV analysis outperforms OLS regression depends on instrument strength and strength of unmeasured confounding but will usually be large given the typical moderate instrument strength in medical research.ConclusionIV methods are of most value in large studies if considerable unmeasured confounding is likely and a strong and plausible instrument is available.     

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.     

The role of health technology assessment on pharmaceutical reimbursement in selected middle-income countries

ObjectiveMiddle-income countries are often referred to as developing or emerging economies and face multiple challenges of severe financial stresses in their health care sectors, and high disease burden. The objective of this study is to provide an overview of how health technology assessment (HTA) is used and organized in selected middle-income countries and its role in the process of pharmaceutical coverage.MethodsWe selected middle-income countries where HTA activities are evident: Argentina, Brazil, China, Colombia, Israel, Mexico, Philippines, Korea, Taiwan, Thailand, and Turkey. We collected and reviewed relevant information to describe the health care and reimbursement systems and how HTA relates to coverage decision-making of pharmaceuticals. This was supplemented by information from a structured survey among professionals working in public and private health insurance, industry, regulatory authorities, ministries of health, academic units or HTA.ResultsAll countries require market authorization for pharmaceuticals to be sold and most countries have a national plan defining which pharmaceuticals can be reimbursed. However, the use of HTA in reimbursement decisions is still in its early stages with varying levels of HTA guidance implementation.ConclusionsThe study provides evidence of the development of HTA in coverage decision-making in middle-income countries. Increased health care spending and the resulting access to modern technology give a strong impetus to HTA. However, HTA is developing with uneven speed in middle-income countries and many countries are building on the organisational and methodological experience from established HTA agencies.     

Health technology assessment. The pharmaceutical industry perspective

Increasingly, health technology assessment (HTA) is used to aid decisions on the reimbursement of pharmaceuticals or recommendations for their use. The pharmaceutical industry seeks to work in partnership with HTA agencies; however, this presents a number of challenges. Clinical trials will need to include appropriate measures that capture economic and patient benefits as well as relevant clinical endpoints, and the industry will want to seek international harmonization of the many guidelines for economic evaluation. The problem of demonstrating cost-effectiveness of a product before it is available for use must be addressed, possibly by conditional reimbursement to allow collection of real world evidence. It is also important that reimbursement decision makers minimize bias, play fair, and adhere to the written rules they issue. If the industry fairly demonstrates the value of a product using the best available evidence, HTA agencies should be transparent in the rationale for their recommendations.     

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.     

Establishing a national HTA program for medical devices in Italy: Overhauling a fragmented system to ensure value and equal access to new medical technologies

Differing contexts have greatly influenced HTA development in various countries, with considerable effort recently made by international HTA networks (e.g., EUnetHTA) and the European Union (EU) to make HTA a more coherent, equal, and efficient process. Medical devices (MDs) present particular challenges for HTA because of frequent, rapid innovation, outcomes influenced by end-user competence, dynamic pricing and often low-quality scientific evidence. Our objective is to describe the development, structure and governance of a National HTA Program for MDs (PNHTADM) in Italy, a highly participatory, stakeholder-engaged, evidence-based process to reform a fragmented system of appraisal and approval. Based largely on EUnetHTA methods, the resulting process delineates a standardized system for proposing MDs by any stakeholders, accrediting HTA producers, setting criteria for prioritization and appraisals, and innovatively linking recommendations with coverage, reimbursement and procurement of MDs. Expected benefits include reduced disparities in pricing and reimbursement policies and improved access to new technologies across 21 regional healthcare systems in Italy's decentralized, universal system, complete with provisions to require additional evidence collection and centrally monitor diffusion. Though devised for Italy, the design, resources and underlying analysis provide a framework for other nations seeking to consolidate HTA initiatives, particularly in light of new EU regulation.     

Why do health technology assessment coverage recommendations for the same drugs differ across settings? Applying a mixed methods framework to systematically compare orphan drug decisions in four European countries

Purpose

Health technology assessment (HTA) coverage recommendations differ across countries for the same drugs. Unlike previous studies, this study adopts a mixed methods research design to investigate, in a systematic manner, these differences.

Methods

HTA recommendations for ten orphan drugs appraised in England (NICE), Scotland (SMC), Sweden (TLV) and France (HAS) (N = 35) were compared using a validated methodological framework that breaks down these complex decision processes into stages facilitating their understanding, analysis and comparison, namely: (1) the clinical/cost-effectiveness evidence, (2) its interpretation (e.g. part of the deliberative process) and (3) influence on the final decision. This allowed qualitative and quantitative identification of the criteria driving recommendations and highlighted cross-country differences.

Results

Six out of ten drugs received diverging HTA recommendations. Reasons for cross-country differences included heterogeneity in the evidence appraised, in the interpretation of the same evidence, and in the different ways of dealing with the same uncertainty. These may have been influenced by agency-specific evidentiary, risk and value preferences, or stakeholder input. “Other considerations” (e.g. severity, orphan status) and other decision modulators (e.g. patient access schemes, lower discount rates, restrictions, re-assessments) also rendered uncertainty and cost-effectiveness estimates more acceptable. The different HTA approaches (clinical versus cost-effectiveness) and ways identified of dealing with orphan drug particularities also had implications on the final decisions.

Conclusions

This research contributes to better understanding the drivers of these complex decisions and why countries make different decisions. It also contributed to identifying those factors beyond the standard clinical and cost-effectiveness tools used in HTA, and their role in shaping these decisions.