The Evolving Nature of Health Technology Assessment: A Critical Appraisal of NICE's New Methods Manual.

OBJECTIVES: The National Institute for Health and Care Excellence (NICE) recently completed a review of its methods for health technology assessment, involving a 2-stage public consultation. We appraise proposed methodological changes and analyze key decisions. METHODS: We categorize all changes proposed in the first consultation as "critical," "moderate" or "limited" updates, considering the importance of the topic and the degree of change or the level of reinforcement. Proposals were followed through the review process, for their inclusion, exclusion, or amendment in the second consultation and the new manual. RESULTS: The end-of-life value modifier was replaced with a new "disease severity" modifier and other potential modifiers were rejected. The usefulness of a comprehensive evidence base was emphasized, clarifying when nonrandomized studies can be used, with further guidance on "real-world" evidence developed separately. A greater degree of uncertainty was accepted in circumstances when evidence generation raised challenges, in particular for children, rare diseases, and innovative technologies. For some topics, such as health inequality, discounting, unrelated healthcare costs, and value of information, significant changes were possibly warranted, but NICE decided not to make any revisions at present. CONCLUSION: Most of the changes to NICE's health technology assessment methods are appropriate and modest in impact. Nevertheless, some decisions were not well justified and further research is needed on several topics, including investigation of societal preferences. Ultimately, NICE's role of protecting National Health Services resources for valuable interventions that can contribute toward improving overall population health must be safeguarded, without accepting weaker evidence.

Funding Sources of Therapeutic and Vaccine Clinical Trials for COVID-19 vs Non-COVID-19 Indications, 2020-2021.

Importance: Effective COVID-19 vaccines and therapeutics reached the market within the first year of the pandemic. This rate of development and availability was an unprecedented achievement that required attention to numerous research and development, regulatory, and policy challenges. However, only limited evidence is currently available on the sources of funding for COVID-19 clinical trials. Objective: To compare the number and funding sources of clinical trials aimed at investigating therapeutics and vaccines for COVID-19 vs those for all non-COVID-19 indications. Design, Setting, and Participants: In this cross-sectional study, clinical trials in phase 1 to 3 that were registered to start between January 1, 2020, and August 31, 2021, were examined. All relevant data were collected from ClinicalTrials.gov. Main Outcomes and Measures: Number of clinical trials and their funding sources. Results: A total of 1977 clinical trials that addressed COVID-19 therapeutics and vaccines were registered worldwide with starting dates from January 1, 2020, to August 31, 2021. This cohort represented 13.9% of all trials (N = 14 274) during the same period. Most of the COVID-19 therapeutic and vaccine clinical trials were funded by public sources (1144 [57.9%]), followed by industry (540 [27.3%]) and public-private partnerships (293 [14.8%]). Most of these studies focused on the development of anti-COVID-19 therapeutics (1680 [85.0%]) rather than vaccines (297 [15.0%]). Conclusions and Relevance: The findings of this study suggest that publicly funded research and medical institutions played a leading role as funding sources for generating effective COVID-19 therapeutics and vaccines during the first 1.5 years of the pandemic and were most likely instrumental in their rapid development. It may be beneficial for the public sector to maintain the affordability and global access to these therapeutics and vaccines to ensure that they remain available for use worldwide.

Advancing structured decision-making in drug regulation at the FDA and EMA.

The recent benefit-risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit-risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit-risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators.

Recalibrating Health Technology Assessment Methods for Cell and Gene Therapies.

Recently licensed cell and gene therapies have promising but highly uncertain clinical benefits. They are entering the market at very high prices, with the latest entrants costing hundreds of thousands of dollars. The significant long-term uncertainty posed by these therapies has already complicated the use of conventional economic evaluation approaches such as cost-effectiveness and cost-utility analyses, which are widely used for assessing the value of new health interventions. Cell and gene therapies also risk jeopardising healthcare systems' financial sustainability. As a result, there is a need to recalibrate the current health technology assessment methods used to measure and compensate their value. In this paper, we outline a set of technical adaptations and methodological refinements to address key challenges in the appraisal of cell and gene therapies' value, including the assessment of efficiency and affordability. We also discuss the potential role of alternative financing mechanisms. Ultimately, uncertainties associated with cell and gene therapies can only be meaningfully addressed by improving the evidence base supporting their approval and adoption in healthcare systems.

ICER Value Framework 2020 Update: Recommendations on the Aggregation of Benefits and Contextual Considerations.

The Institute for Clinical and Economic Review (ICER) in the United States recently published a 2020 update to its value assessment framework. We are commenting on the method by which the benefits of health interventions are integrated, relating to contextual considerations and other factors relevant to an intervention's value. We start by discussing the theoretical foundations of decision analysis and its extension to multiple criteria decision analysis (MCDA). Then we provide a detailed, evidence-based response to some of the claims made by ICER with regard to the use of MCDA methods and stakeholder engagement. Finally, we provide a number of recommendations on the use of quantitative decision analysis and decision conferencing that could be of relevance to the ICER methodology. Overall, we agree that some of the proposed changes by ICER are moving in the right direction toward improving transparency in the value assessment process, but these changes are probably inadequate. We advocate that more serious attention should be paid to the use of quantitative decision analysis together with decision conferencing for the construction of value preferences via group processes for the integration of an intervention's various benefit components.

Early Health Technology Assessment during Nonalcoholic Steatohepatitis Drug Development: A Two-Round, Cross-Country, Multicriteria Decision Analysis.

Background. The assessment of value along the clinical development of new biopharmaceutical compounds is a challenging task. Complex and uncertain evidence has to be analyzed, considering a multitude of value preferences from different stakeholders. Objective. To investigate the use of multicriteria decision analysis (MCDA) to support decision making during drug development while considering payer and health technology assessment (HTA) value concerns, by applying the Advance Value Framework in nonalcoholic steatohepatitis (NASH) and testing for the consistency of the results. Design. A multiattribute value theory methodology was applied and 2 rounds of decision conferences (DCs) were organized in 3 countries (England, France, and Germany), with the participation of national key experts and stakeholders using the MACBETH questioning protocol and algorithm. A total of 51 health care professionals, patient advocates, and methodologists, including (ex-) committee members or assessors from national HTA bodies, participated in 6 DCs in the study countries. Target Population. NASH patients in fibrosis stages F2 to 3 were considered. Interventions. The value of a hypothetical product profile was assessed against 3 compounds under development using their phase 2 results. Outcome Measures. DC participants' value preferences were elicited involving criteria selection, options scoring, and criteria weighting. Results. Highly consistent valuation rankings were observed in all DCs, always favoring the same compound. Highly consistent rankings of criteria clusters were observed, favoring therapeutic benefit criteria, followed by safety profile and innovation level criteria. Limitations. There was a lack of comparative treatment effects, early evidence on surrogate endpoints was used, and stakeholder representativeness was limited in some DCs. Conclusions. The use of MCDA is promising in supporting early HTA, illustrating high consistency in results across countries and between study rounds.

Quantifying Preferences in Drug Benefit-Risk Decisions.

Benefit-risk assessment is used in various phases along the drug lifecycle, such as marketing authorization and surveillance, health technology assessment (HTA), and clinical decisions, to understand whether, and for which patients, a drug has a favorable or more valuable profile with reference to one or more comparators. Such assessments are inherently preference-based as several clinical and nonclinical outcomes of varying importance might act as evaluation criteria, and decision makers must establish acceptable trade-offs between these outcomes. Different healthcare stakeholder perspectives, such as those from patients and healthcare professionals, are key for informing benefit-risk trade-offs. However, the degree to which such preferences inform the decision is often unclear as formal preference-based evaluation frameworks are generally not used for regulatory decisions, and, if used, rarely communicated in HTA decisions. We argue that for better decisions, as well as for reasons of transparency, preferences in benefit-risk decisions should more often be quantified and communicated explicitly.

An EU-wide approach to HTA: An irrelevant development or an opportunity not to be missed?

An EU-wide cooperation on HTA has been proposed recently by the European Commission, focusing on relative effectiveness assessment (REA) for pharmaceuticals and medical devices. This cooperation is operationalised through a proposal for a regulation. While a good step in the right direction, this HTA cooperation framework needs to be more explicit and pragmatic about clinical value definition, what constitutes quality of evidence, how real-world evidence is handled, whether the same assessment requirements will apply for medical devices as they do for pharmaceuticals, and how to safeguard consistency in REA interpretation. If demand-rather than supply-driven, this initiative can deliver wider benefits: Europe can improve its power in global drug design and development, while Member States will have at their disposal more resources to assess performance of interventions in their healthcare systems.

Using health technology assessment to assess the value of new medicines: results of a systematic review and expert consultation across eight European countries.

BACKGROUND: Although health technology assessment (HTA) systems base their decision making process either on economic evaluations or comparative clinical benefit assessment, a central aim of recent approaches to value measurement, including value based assessment and pricing, points towards the incorporation of supplementary evidence and criteria that capture additional dimensions of value. OBJECTIVE: To study the practices, processes and policies of value-assessment for new medicines across eight European countries and the role of HTA beyond economic evaluation and clinical benefit assessment. METHODS: A systematic (peer review and grey) literature review was conducted using an analytical framework examining: (1) 'Responsibilities and structure of HTA agencies'; (2) 'Evidence and evaluation criteria considered in HTAs'; (3) 'Methods and techniques applied in HTAs'; and (4) 'Outcomes and implementation of HTAs'. Study countries were France, Germany, England, Sweden, Italy, Netherlands, Poland and Spain. Evidence from the literature was validated and updated through two rounds of feedback involving primary data collection from national experts. RESULTS: All countries assess similar types of evidence; however, the specific criteria/endpoints used, their level of provision and requirement, and the way they are incorporated (e.g. explicitly vs. implicitly) varies across countries, with their relative importance remaining generally unknown. Incorporation of additional 'social value judgements' (beyond clinical benefit assessment) and economic evaluation could help explain heterogeneity in coverage recommendations and decision-making. CONCLUSION: More comprehensive and systematic assessment procedures characterised by increased transparency, in terms of selection of evaluation criteria, their importance and intensity of use, could lead to more rational evidence-based decision-making, possibly improving efficiency in resource allocation, while also raising public confidence and fairness.

Evaluating the Benefits of New Drugs in Health Technology Assessment Using Multiple Criteria Decision Analysis: A Case Study on Metastatic Prostate Cancer With the Dental and Pharmaceuticals Benefits Agency (TLV) in Sweden.

Background. Multiple criteria decision analysis (MCDA) has been identified as a prospective methodology for assisting decision makers in evaluating the benefits of new medicines in health technology assessment (HTA); however, limited empirical evidence exists from real-world applications. Objective. To test in practice a recently developed MCDA methodological framework for HTA, the Advance Value Framework, in a proof-of-concept case study with decision makers. Methods. A multi-attribute value theory methodology was adopted applying the MACBETH questioning protocol through a facilitated decision-analysis modelling approach as part of a decision conference with four experts. Settings. The remit of the Swedish Dental and Pharmaceutical Benefits Agency (Tandvårds- och läkemedelsförmånsverket [TLV]) was adopted but in addition supplementary value dimensions were considered. Patients. Metastatic castrate-resistant prostate cancer patients were considered having received prior chemotherapy. Interventions. Abiraterone, cabazitaxel, and enzalutamide were evaluated as third-line treatments. Measurements. Participants' value preferences were elicited involving criteria selection, options scoring, criteria weighting, and their aggregation. Results. Eight criteria attributes were finally included in the model relating to therapeutic impact, safety profile, socioeconomic impact, and innovation level with relative importance weights 44.5%, 33.3%, 14.8%, and 7.4% per cluster, respectively. Enzalutamide scored the highest overall weighted preference value score, followed by abiraterone and cabazitaxel. Dividing treatments' overall weighted preference value scores by their costs derived "costs per unit of value" for ranking the treatments based on value-for-money grounds. Limitations. Study limitations included lack of comparative clinical effects across treatments and the small sample of participants. Conclusion. The Advance Value Framework has the prospects of facilitating the evaluation process in HTA and health care decision making; additional research is recommended to address technical challenges and optimize the use of MCDA for policy making.

Multiple criteria decision analysis in the context of health technology assessment: a simulation exercise on metastatic colorectal cancer with multiple stakeholders in the English setting.

BACKGROUND: Multiple criteria decision analysis (MCDA) has appeared as a methodology to address limitations of economic evaluation in health technology assessment (HTA), however there are limited empirical evidence from real world applications. The aim of this study is to test in practice a recently developed MCDA methodological framework known as Advance Value Framework (AVF) through a proof-of-concept case study engaging multiple stakeholders. METHODS: A multi-attribute value theory methodological process was adopted involving problem structuring, model building, model assessment and model appraisal phases. A facilitated decision analysis modelling approach was used as part of a decision conference with thirteen participants. An expanded scope of the National Institute for Health and Care Excellence (NICE) remit acted as the study setting with the use of supplementary value concerns. Second-line biological treatments were evaluated for metastatic colorectal cancer (mCRC) patients having received prior chemotherapy, including cetuximab monotherapy, panitumumab monotherapy and aflibercept in combination with FOLFIRI chemotherapy. Initially 18 criteria attributes were considered spanning four value domains relating to therapeutic impact, safety profile, innovation level and socioeconomic impact. RESULTS: Nine criteria attributes were finally included. Cetuximab scored the highest overall weighted preference value score of 45.7 out of 100, followed by panitumumab with 42.3, and aflibercept plus FOLFIRI with 14.4. The relative weights of the two most important criteria (overall survival and Grade 4 adverse events) added up to more than the relative weight of all other criteria together (52.1%). Main methodological limitation was the lack of comparative clinical effects across treatments and challenges included the selection of "lower" and "higher" reference levels on criteria attributes, eliciting preferences across attributes where participants had less experience, and ensuring that all attributes possess the right decision theory properties. CONCLUSIONS: This first application of AVF produced transparent rankings for three mCRC treatments based on their value, by assessing an explicit set of evaluation criteria while allowing for the elicitation and construction of participants' value preferences and their trade-offs. It proved it can aid the evaluation process and value communication of the alternative treatments for the group participants. Further research is needed to optimise its use as part of policy-making.

Multiple Criteria Decision Analysis (MCDA) for evaluating new medicines in Health Technology Assessment and beyond: The Advance Value Framework.

Escalating drug prices have catalysed the generation of numerous "value frameworks" with the aim of informing payers, clinicians and patients on the assessment and appraisal process of new medicines for the purpose of coverage and treatment selection decisions. Although this is an important step towards a more inclusive Value Based Assessment (VBA) approach, aspects of these frameworks are based on weak methodologies and could potentially result in misleading recommendations or decisions. In this paper, a Multiple Criteria Decision Analysis (MCDA) methodological process, based on Multi Attribute Value Theory (MAVT), is adopted for building a multi-criteria evaluation model. A five-stage model-building process is followed, using a top-down "value-focused thinking" approach, involving literature reviews and expert consultations. A generic value tree is structured capturing decision-makers' concerns for assessing the value of new medicines in the context of Health Technology Assessment (HTA) and in alignment with decision theory. The resulting value tree (Advance Value Tree) consists of three levels of criteria (top level criteria clusters, mid-level criteria, bottom level sub-criteria or attributes) relating to five key domains that can be explicitly measured and assessed: (a) burden of disease, (b) therapeutic impact, (c) safety profile (d) innovation level and (e) socioeconomic impact. A number of MAVT modelling techniques are introduced for operationalising (i.e. estimating) the model, for scoring the alternative treatment options, assigning relative weights of importance to the criteria, and combining scores and weights. Overall, the combination of these MCDA modelling techniques for the elicitation and construction of value preferences across the generic value tree provides a new value framework (Advance Value Framework) enabling the comprehensive measurement of value in a structured and transparent way. Given its flexibility to meet diverse requirements and become readily adaptable across different settings, the Advance Value Framework could be offered as a decision-support tool for evaluators and payers to aid coverage and reimbursement of new medicines.

PARS PLANA VITRECTOMY FOR DIABETIC MACULAR EDEMA: A Systematic Review, Meta-Analysis, and Synthesis of Safety Literature.

PURPOSE: To assess the risk and benefit of pars plana vitrectomy for diabetic macular edema. METHODS: The authors conducted a systematic literature review using PubMed, EMBASE, Web of Science, and Cochrane Central Database of Controlled Trials until September 2014. The population was patients with diabetic macular edema, intervention vitrectomy, comparator macular laser or observation, and efficacy outcome visual acuity and central retinal thickness. Safety outcomes were intraoperative and postoperative surgical complications. The efficacy meta-analysis included only randomized controlled trials. The safety analysis included prospective, retrospective, controlled, and uncontrolled studies. RESULTS: Five studies were eligible for the efficacy meta-analysis (n = 127 eyes) and 40 for the safety analysis (n = 1,562 eyes). Combining follow-up intervals from 6 to 12 months, the meta-analysis found a nonsignificant 2 letter visual acuity difference favoring vitrectomy, and a significant 102 µm greater reduction in central retinal thickness favoring vitrectomy, but a post hoc subgroup analysis found that a 6-month central retinal thickness benefit reversed by 12 months. The most frequent complications were retinal break (7.1%), elevated intraocular pressure (5.2%), epiretinal membrane (3.3%), and vitreous hemorrhage (2.4%). Cataract developed in 68.6% of 121 phakic eyes. CONCLUSION: Vitrectomy produces structural and functional improvements in select eyes with diabetic macular edema, but the visual gains are not significantly better than with laser or observation. No major safety concerns were identified.