R WE ready for reimbursement? A round up of developments in real-world evidence relating to health technology assessment: part 15.

In this latest update we discuss real-world evidence (RWE) guidance from the leading oncology professional societies, the American Society of Clinical Oncology and the European Society for Medical Oncology, and the PRINCIPLED practical guide on the design and analysis of causal RWE studies.

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

OBJECTIVES: The 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. METHODS: HTA 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. RESULTS: Fourteen 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. CONCLUSION: Modeled, 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.

Implementation Barriers to Value of Information Analysis in Health Technology Decision Making: Results From a Process Evaluation.

OBJECTIVES: Value of information (VOI) analysis can support health technology assessment decision making, but it is a long way from being standard use. The objective of this study was to understand barriers to the implementation of VOI analysis and propose actions to overcome these. METHODS: We performed a process evaluation of VOI analysis use within decision making on tomosynthesis versus digital mammography for use in the Dutch breast cancer population screening. Based on steering committee meeting attendance and regular meetings with analysts, we developed a list of barriers to VOI use, which were analyzed using an established diffusion model. We proposed actions to address these barriers. Barriers and actions were discussed and validated in a workshop with stakeholders representing patients, clinicians, regulators, policy advisors, researchers, and the industry. RESULTS: Consensus was reached on groups of barriers, which included characteristics of VOI analysis itself, stakeholder's attitudes, analysts' and policy makers' skills and knowledge, system readiness, and implementation in the organization. Observed barriers did not only pertain to VOI analysis itself but also to formulating the objective of the assessment, economic modeling, and broader aspects of uncertainty assessment. Actions to overcome these barriers related to organizational changes, knowledge transfer, cultural change, and tools. CONCLUSIONS: This in-depth analysis of barriers to implementation of VOI analysis and resulting actions and tools may be useful to health technology assessment organizations that wish to implement VOI analysis in technology assessment and research prioritization. Further research should focus on application and evaluation of the proposed actions in real-world assessment processes.

Accounting for Heterogeneity in Resource Allocation Decisions: Methods and Practice in UK Cancer Technology Appraisals.

OBJECTIVES: The availability of novel, more efficacious and expensive cancer therapies is increasing, resulting in significant treatment effect heterogeneity and complicated treatment and disease pathways. The aim of this study is to review the extent to which UK cancer technology appraisals (TAs) consider the impact of patient and treatment effect heterogeneity. METHODS: A systematic search of National Institute for Health and Care Excellence TAs of colorectal, lung and ovarian cancer was undertaken for the period up to April 2020. For each TA, the pivotal clinical studies and economic evaluations were reviewed for considerations of patient and treatment effect heterogeneity. The study critically reviews the use of subgroup analysis and real-world translation in economic evaluations, alongside specific attributes of the economic modeling framework. RESULTS: The search identified 49 TAs including 49 economic models. In total, 804 subgroup analyses were reported across 69 clinical studies. The most common stratification factors were age, gender, and Eastern Cooperative Oncology Group performance score, with 15% (119 of 804) of analyses demonstrating significantly different clinical outcomes to the main population; economic subgroup analyses were undertaken in only 17 TAs. All economic models were cohort-level with the majority described as partitioned survival models (39) or Markov/semi-Markov models. The impact of real-world heterogeneity on disease progression estimates was only explored in 2 models. CONCLUSION: The ability of current modeling approaches to capture patient and treatment effect heterogeneity is constrained by their limited flexibility and simplistic nature. This study highlights a need for the use of more sophisticated modeling methods that enable greater consideration of real-world heterogeneity.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

The Use of Decision Analytic Modeling in the Evaluation of Surgical Innovations: A Scoping Review.

OBJECTIVES: The main objective of this review was to map how decision analytic models are used in surgical innovation (in which research phase, with what aim) and to understand how challenges related to the assessment of surgical interventions are incorporated. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library for studies published in 2018. We included original articles using a decision analytic model to compare surgical strategies. We included modeling studies of surgical innovations. General, innovation, and modeling characteristics were extracted, as were outcomes, recommendations, and handling of challenges related to the assessment of surgical interventions (learning curve, incremental innovation, dynamic pricing, quality variation, organizational impact). RESULTS: We included 46 studies. The number of studies increased with each research phase, from 4% (n = 2) in the preclinical phase to 40% (n = 20) in phase 3 studies. Eighty-one studies were excluded because they investigated established surgical procedures, indicating that modeling is predominantly applied after the innovation process. Regardless of the research stage, the aim to determine cost-effectiveness was most frequently identified (n = 40, 87%), whereas exploratory aims (eg, exploring when a strategy becomes cost-effective) were less common (n = 9, 20%). Most challenges related to the assessment of surgical interventions were rarely incorporated in models (eg, learning curve [n = 1, 2%], organizational impact [n = 2, 4%], and incremental innovation [n = 1, 2%]), except for dynamic pricing (n = 10, 22%) and quality variation (n = 6, 13%). CONCLUSIONS: In surgical innovation, modeling is predominantly used in later research stages to assess cost-effectiveness. The exploratory use of modeling seems still largely overlooked in surgery; therefore, the opportunity to inform research and development may not be optimally used.

Early technology assessment of using whole genome sequencing in personalized oncology.

Introduction: Personalized medicine-based treatments in advanced cancer hold the promise to offer substantial health benefits to genetic subgroups, but require efficient biomarker-based patient stratification to match the right treatment and may be expensive. Standard molecular diagnostics are currently very heterogeneous, and tests are often performed sequentially. The alternative to whole genome sequencing (WGS) i.e. simultaneously testing for all relevant DNA-based biomarkers thereby allowing immediate selection of the most optimal therapy, is more costly than current techniques. In the current implementation stage, it is important to explore the added value and cost-effectiveness of using WGS on a patient level and to assess optimal introduction of WGS on the level of the healthcare system.Areas covered: First, an overview of current worldwide initiatives concerning the use of WGS in clinical practice for cancer diagnostics is given. Second, a comprehensive, early health technology assessment (HTA) approach of evaluating WGS in the Netherlands is described, relating to the following aspects: diagnostic value, WGS-based treatment decisions, assessment of long-term health benefits and harms, early cost-effectiveness modeling, nation-wide organization, and Ethical, Legal and Societal Implications.Expert opinion: This study provides evidence to guide further development and implementation of WGS in clinical practice and the healthcare system.

Assessing the capacity of Ghana to introduce health technology assessment: a systematic review of economic evaluations conducted in Ghana.

OBJECTIVES: Ghana is in the process of formally introducing health technology assessment (HTA) for health decision making. Similar to other low- and middle-income countries, evidence suggests that the lack of data and human capacity is a major barrier to the conduct and use of HTA. This study assessed the current human and data capacity available in Ghana to undertake HTA. METHODS: As economic evaluation (EE) forms an integral part of HTA, a systematic review of EE studies undertaken in Ghana was conducted to identify the quality and number of studies available, methods and source of data used, and local persons involved. The literature search was undertaken in EMBASE (including MEDLINE), PUBMED, and Google Scholar. The quality of studies was evaluated using the Consolidated Health Economics Evaluation Reporting Standards. The number of local Ghanaians who contributed to authorship were used as a proxy for assessing human capacity for HTA. RESULTS: Thirty-one studies were included in the final review. Overall, studies were of good quality. Studies derived their effectiveness, resource utilization and cost data mainly from Ghana. The most common source of cost data was from the National Health Insurance Scheme pricing list for medicines and tariffs. Effectiveness data were mostly derived from either single study or intervention programs. Sixty out of 199 authors were Ghanaians (30 percent); these authors were mostly involved in data collection and study conceptualization. CONCLUSIONS: Human capacity for HTA in Ghana is limited. To introduce HTA successfully in Ghana, policy makers would need to develop more local capacity to undertake Ghanaian-specific HTA.

Cell-Free Circulating Tumour DNA Blood Testing to Detect EGFR T790M Mutation in People With Advanced Non-Small Cell Lung Cancer: A Health Technology Assessment.

BACKGROUND: Cell-free circulating tumour DNA blood testing (also called liquid biopsy) can determine if a person with advanced non-small cell lung cancer (NSCLC) whose disease is progressing has developed the epidermal growth factor receptor (EGFR) T790M resistance mutation. Identifying this resistance mutation can help physicians choose appropriate treatment (i.e., osimertinib if positive and chemotherapy if negative). Tissue biopsy is typically used to look for the resistance mutation, but this is an invasive test that might not be feasible if the patient is too ill. We conducted a health technology assessment of liquid biopsy for people with advanced NSCLC, which included an evaluation of the diagnostic accuracy, clinical utility, safety, cost-effectiveness, and the budget impact of publicly funding liquid biopsy, as well as an evaluation of patient preferences and values. METHODS: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using Risk of Bias in Systematic Reviews (ROBIS), Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2), Risk of Bias Among Non-randomized Studies (RoBANS), and the Cochrane risk of bias (ROB) tool and assessed quality of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted short-term and long-term cost-effectiveness and cost-utility analyses comparing liquid biopsy as a triage test, liquid biopsy alone, and tissue biopsy alone from a public payer perspective. We also analyzed the budget impact of publicly funding liquid biopsy for people in Ontario with advanced NSCLC. To assess the potential value of liquid biopsy, we spoke with people with lung cancer and people with an understanding of the process of liquid biopsy. RESULTS: We included 19 studies (within a published systematic review) to examine diagnostic test accuracy and 12 studies to examine clinical utility. In patients with advanced NSCLC, liquid biopsy to detect the EGFR T790M resistance mutation demonstrated a positive and negative predictive value of 89% and 61%, respectively, a sensitivity of 68%, and specificity of 86%. No studies examined the clinical utility of liquid biopsy as a triage test. When NSCLC was treated appropriately, progression-free survival was similar in patients with and without the resistance mutation, as ascertained by liquid biopsy.We estimated that it costs about $700 to conduct a liquid biopsy and $2,500 to conduct a tissue biopsy. Our analyses showed that, when considering costs and effects directly related to testing, liquid biopsy (as a triage test, which means patients who test negative undergo a follow-up tissue biopsy, or alone, which means using only liquid biopsy) was less costly than tissue biopsy alone and led to fewer tissue biopsies. Using liquid biopsy as a triage test produced the most correct treatment decisions and greatest number of people who were given osimertinib.When considering long-term costs (i.e., treatment and care) and effects (i.e., life-years and quality-adjusted life-years [QALYs]), liquid biopsy as a triage test was the most effective and most costly strategy followed by liquid biopsy alone. Tissue biopsy alone was the least effective and least costly strategy. The incremental cost-effectiveness ratios (ICERs) of liquid biopsy as a triage test compared with liquid biopsy alone and of liquid biopsy alone compared with tissue biopsy alone were greater than $100,000 per QALY. However, this result was largely driven by the cost of osimertinib, which was used more often when liquid biopsy was used as a triage test.We estimated that the total annual budget impact of publicly funding liquid biopsy as a triage test in Ontario over the next 5 years would range from approximateily $60,000 in year 1 to $3 million in year 5.People with lung cancer with whom we spoke said that liquid biopsy would likely be an appropriate test for people with NSCLC given their frail condition and because it would avoid the pain and anxiety associated with tissue biopsy. CONCLUSIONS: As a minimally invasive test, liquid biopsy identifies a high proportion of people with the EGFR T790M resistance mutation. This identification could better guide treatment for people with advanced NSCLC. However, its relatively low negative predictive value means it is best used as a triage test (i.e., followed by tissue biopsy if the liquid biopsy does not identify a resistance mutation). Liquid biopsy as a triage test is likely more effective than tissue biopsy alone. However, owing to the high cost of treatment, liquid biopsy may not be cost-effective. We estimated that publicly funding liquid biopsy as a triage test in Ontario would result in additional costs (related to more patients being treated) of between $0.06 million and $3 million over the next 5 years.

"Stick or Twist?" Negotiating Price and Data in an Era of Conditional Approval.

BACKGROUND: Changes 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"). OBJECTIVES: The 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. METHODS: We 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. RESULTS: Our 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. CONCLUSIONS: This article shows that simulation methods can be used to help pharmaceutical managers make informed strategic decisions in contexts of uncertainty.

Association Between the Use of Surrogate Measures in Pivotal Trials and Health Technology Assessment Decisions: A Retrospective Analysis of NICE and CADTH Reviews of Cancer Drugs.

OBJECTIVE: To assess whether using surrogate versus patient-relevant endpoints in pivotal trials of cancer drugs was associated with health technology assessment recommendations in England (National Institute for Health and Care Excellence [NICE]) and Canada (Canadian Agency for Drugs and Technologies in Health [CADTH]). METHODS: Cancer drug approvals from 2012 to 2016 were categorized by demonstrating benefit on overall survival (OS), progression-free survival, disease response, or having no comparator. Approvals were analyzed by benefit category and health technology assessment recommendation. The association between benefit (surrogate vs OS) and recommending a drug was examined using descriptive statistics and linear probability models controlling for unmet need, orphan designation, and cost-effectiveness. RESULTS: Of 42 cancer indications that NICE recommended, 15 (36%) demonstrated OS benefit. Cancer indications with OS benefit were less likely to receive a recommendation from NICE than those without (P = .04). In linear probability models, availability of OS benefit was no longer associated with a recommendation from NICE (P = .32). Cost-effective cancer drugs had a 55.6% (95% CI: 38.9%-72.3%) higher probability of receiving a recommendation from NICE than those that were not. In Canada, 15 of 37 (41%) cancer indications that were recommended showed OS benefit. There was no detectable association between surrogate measures and CADTH recommendations based on descriptive statistics (P = .62) or in linear probability models (P = .73). CONCLUSION: When cost-effectiveness was considered, pivotal trial endpoints were not associated with NICE recommendations. Pivotal trial endpoints, unmet need, orphan status, and cost-effectiveness did not explain CADTH recommendations.

Economic Evaluation of Systemic Treatments for Advanced Melanoma: A Systematic Review.

BACKGROUND: Many high cost treatments for advanced melanoma have become available in recent years. National health technology assessment agencies have raised concerns regarding uncertainty in their clinical and cost-effectiveness. OBJECTIVE: The aim of this systematic review is to identify economic evaluations of treatments for advanced melanoma and review model assumptions, outcomes, and quality as preparation for a health technology assessment. METHODS: A search of Embase, MEDLINE, EconLit, and the Cochrane Database was conducted. Only studies using decision-analytic models were included. Two authors independently completed full-text review and data extraction. RESULTS: Fifteen studies were identified. There were major differences in the structural assumptions underpinning the models. There was general agreement in study conclusions, although the predicted costs and quality-adjusted life years for each treatment varied. BRAF monotherapy (vemurafenib, dabrafenib) or BRAF/MEK combination therapy (BRAF monotherapy with cobimetinib or trametinib) has not been shown to be cost-effective in any jurisdiction. PD-1 inhibitors (pembrolizumab, nivolumab) are consistently found to be cost-effective compared with ipilimumab, although their cost-effectiveness compared with chemotherapy is not established. Combination therapy with nivolumab and ipilimumab is unlikely to be cost-effective in any setting. One study including all agents found that none of the new treatments were cost-effective relative to chemotherapy. Publication of the study in a health economics journal is associated with better reporting of and higher-quality assessment than those published in clinical journals. CONCLUSION: Despite differences in model structures and assumptions, the conclusions of most included studies were consistent. Health technology assessment has a key role in maximizing value from high-cost innovative treatments. Consideration should be given to divestment from BRAF/MEK inhibitors and ipilimumab in favor of reimbursement of PD-1 inhibitors.

Transferability of Economic Evaluations of Treatments for Advanced Melanoma.

BACKGROUND: Differing methodological requirements and decision-making criteria are recognised as barriers to transferability of cost-effectiveness analysis (CEA) across jurisdictions. OBJECTIVE: We assessed the generic and specific transferability of published CEAs of systemic treatments for advanced melanoma to the Irish setting. METHODS: CEAs of treatments for melanoma were identified by systematic review. Transferability to the Irish setting was assessed using the EUnetHTA transferability tool for Economic Evaluation. We present a narrative discussion comparing the differences in key parameter inputs and the likely impact of these differences on the model outcomes and the reimbursement recommendation. Transferability is considered within the context of the Irish cost-effectiveness threshold, using the net monetary benefit (NMB) framework. RESULTS: No published CEAs (n = 15) aligned with the Irish reference case for CEA. Changes to key parameters were unlikely to change the conclusions of the CEA when the cost-effectiveness threshold was considered. Ten studies (19 pairwise comparisons) were compared with findings by the National Centre for Pharmacoeconomics (NCPE) using NMB. Without accounting for differences in the cost-effectiveness threshold, there was alignment between the study conclusions and NCPE recommendations in 73.7% cases. When the Irish cost-effectiveness threshold was applied in the estimation of NMB, there was agreement in 89.5% of cases. CONCLUSIONS: Alignment in methodological requirements for CEA is important to facilitate joint health technology assessment (HTA) by regional collaborations in Europe. When parameter inputs are not exactly aligned, conclusions may still be comparable across jurisdictions. For international joint procurement initiatives, determining and implementing joint decision rules may be more important than trying to align rules regarding methodological and parameter inputs.

Influence of Modeling Choices on Value of Information Analysis: An Empirical Analysis from a Real-World Experiment.

BACKGROUND: Value of information (VOI) analysis often requires modeling to characterize and propagate uncertainty. In collaboration with a cancer clinical trial group, we integrated a VOI approach to assessing trial proposals. OBJECTIVE: This paper aims to explore the impact of modeling choices on VOI results and to share lessons learned from the experience. METHODS: After selecting two proposals (A: phase III, breast cancer; B: phase II, pancreatic cancer) for in-depth evaluations, we categorized key modeling choices relevant to trial decision makers (characterizing uncertainty of efficacy, evidence thresholds to change clinical practice, and sample size) and modelers (cycle length, survival distribution, simulation runs, and other choices). Using a $150,000 per quality-adjusted life-year (QALY) threshold, we calculated the patient-level expected value of sample information (EVSI) for each proposal and examined whether each modeling choice led to relative change of more than 10% from the averaged base-case estimate. We separately analyzed the impact of the effective time horizon. RESULTS: The base-case EVSI was $118,300 for Proposal A and $22,200 for Proposal B per patient. Characterizing uncertainty of efficacy was the most important choice in both proposals (e.g. Proposal A: $118,300 using historical data vs. $348,300 using expert survey), followed by the sample size and the choice of survival distribution. The assumed effective time horizon also had a substantial impact on the population-level EVSI. CONCLUSIONS: Modeling choices can have a substantial impact on VOI. Therefore, it is important for groups working to incorporate VOI into research prioritization to adhere to best practices, be clear in their reporting and justification for modeling choices, and to work closely with the relevant decision makers, with particular attention to modeling choices.

Supervisión de ensayos clínicos en hospitales del Seguro Social de Salud del Perú: enfoque administrativo y regulatorio / Supervision of clinical trials in Social Health Insurance at Peruvian Hospitals: administrative and regulatory approach

RESUMEN El objetivo del estudio fue describir las características de los ensayos clínicos (EC) supervisados por el Instituto de Evaluación de Tecnologías en Salud e Investigación en EsSalud entre el 2015 y 2018 y las principales observaciones de las supervisiones realizadas. Se realizó un estudio descriptivo de 82 ensayos clínicos supervisados entre 2015 y 2018. La mayoría de los ensayos clínicos fueron estudios de fase III (81,7%), la vía de administración más frecuente de los productos de estudio fue oral (47,6%) y la mayoría fueron patrocinados por la industria farmacéutica (96,3%). Las observaciones más frecuentes fueron las relacionadas al contrato de estudio (83,8%), al pago por concepto de overhead (57,3%) y a la falta de documentos regulatorios (47,6%). Estos hallazgos permiten la identificación de oportunidades de mejora en la regulación y gestión de la investigación.

ABSTRACT The objective of the study was to describe the characteristics of the Clinical Trials (CT) supervised by the Institute of Health Technology Assessment and Research carried out in EsSalud between 2015 and 2018 and the main observations of the supervisions completed. A descriptive study of 82 supervised clinical trials was conducted between 2015 and 2018. Most of the clinical trials were phase III studies (81.7%); the most frequent route of administration of the study products was oral (47.6%), and most were sponsored by the pharmaceutical industry (96.3%). The most frequent observations were those related to the study contract (83.8%), overhead payment (57.3%), and the lack of regulatory documents (47.6%). These findings allow the identification of opportunities for improvement in research regulation and management.

Modelling the lifetime cost-effectiveness of catheter ablation for atrial fibrillation with heart failure.

OBJECTIVES: Assessing the cost-effectiveness credentials of this intervention in patients with concomitant atrial fibrillation (AF) and heart failure (HF) compared with usual medical therapy. DESIGN: A Markov model comprising two health states (ie, alive or dead) was constructed. The transition probabilities were directly derived from published Kaplan-Meier curves of the pivotal randomised controlled trial and extrapolated over the cohort's lifetime using recommended methods. Costs of catheter ablation, outpatient consultations, hospitalisation, medications and examinations were included. Resource use and unit costs were sourced from government websites or published literature. A lifetime horizon and a healthcare system perspective were taken. All costs and benefits were discounted at 3% annually. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were run around the key model parameters to test the robustness of the base case results. PARTICIPANTS: A hypothetical Australian cohort of patients with concomitant AF and HF who are resistant to antiarrhythmic treatment. INTERVENTIONS: Catheter ablation versus medical therapy. RESULTS: The catheter ablation was associated with a cost of $A44 377 per person, in comparison to $A28 506 for the medical therapy alone over a lifetime. Catheter ablation contributed to 4.58 quality-adjusted life years (QALYs) and 6.99 LY gains compared with 4.30 QALYs and 6.53 LY gains, respectively, in the medical therapy arm. The incremental cost-effectiveness ratio was $A55 942/QALY or $A35 020/LY. The DSA showed that results were highly sensitive to costs of ablation and time horizon. The PSA yielded very consistent results with the base case. CONCLUSIONS: Offering catheter ablation procedure to patients with systematic paroxysmal or persistent AF who failed to respond to antiarrhythmic drugs was associated with higher costs, greater benefits. When compared with medical therapy alone, this intervention is not cost-effective from an Australia healthcare system perspective.

[The incorporation of nusinersen by the Brazilian Unified National Health System: critical thoughts on the institutionalization of health technology assessment in Brazil]. / A incorporação do nusinersena no Sistema Único de Saúde: uma reflexão crítica sobre a institucionalização da avaliação de tecnologias em saúde no Brasil.

In April 2019, a ruling was signed for the incorporation of the drug nusinersen by the Brazilian Unified National Health System (SUS). Nusinersen is the most expensive drug ever incorporated by the SUS and is used to treat type I 5q spinal muscular atrophy. The incorporation has been described as a milestone in decision-making on new technologies in the SUS, enabled through a risk-sharing agreement. The article discusses the process involved in the incorporation of nusinersen, highlighting the context, timing, and technical issues, in addition to possible consequences for the institutionalization of health technology assessment (HTA) in the SUS. The study used an exploratory method, reviewing public information produced by the Commission for Incorporation of Technologies in the SUS (CONITEC) and searches in government databanks on prices and purchases. A timeline was produced, describing the key points in the process of incorporation. There were two formal requests for the drug's incorporation. The first was submitted by the Division of Science, Technology, and Strategic Inputs (SCTIE) of the Brazilian Ministry of Health and was turned down unanimously in November 2018. This was followed by a petition by the head of the SCTIE to the Attorney General's Office (AGU) to overrule the recommendation by the CONITEC plenary. The AGU recommended a new submission, made by the drug's manufacturing company, which was approved unanimously in March 2019. The was no addition of new evidence or a price reduction to justify the change of decision. No elements were identified in the risk-sharing agreement. This suggests problems of transparency and accountability, as well as risks in the process of institutionalization of HTA that had been underway in the SUS.

Em abril de 2019, foi assinada a portaria de incorporação do medicamento nusinersena no Sistema Único de Saúde (SUS). É o medicamento mais caro já incorporado ao SUS, para uso no tratamento de atrofia muscular espinhal 5q tipo I. A incorporação é referida como um marco na tomada de decisão sobre novas tecnologias no SUS, a ser viabilizada por meio de acordo de partilha de risco. O trabalho discute o processo de incorporação do nusinersena, destacando aspectos contextuais, temporais e técnicos, além de possíveis consequências para a institucionalização da avaliação de tecnologias em saúde (ATS) no SUS. Seguiu método exploratório, com revisão de informações públicas produzidas pela Comissão de Incorporação de Tecnologias no SUS (CONITEC) e busca em bancos de dados governamentais de preços e compras. Foi produzida linha temporal descrevendo os pontos-chave do processo de incorporação. Houve dois pedidos de incorporação do medicamento. O primeiro, submetido pela Secretaria de Ciência, Tecnologia e Insumos Estratégicos (SCTIE) do Ministério da Saúde, negado por unanimidade, em novembro de 2018. Seguiu-se o pedido do Secretário da SCTIE à Advocacia-Geral da União (AGU), para que pudesse decidir de forma contrária à recomendação do plenário da CONITEC. A AGU recomendou uma nova submissão, feita pela empresa produtora e aprovada por unanimidade, em março de 2019. Não houve acréscimo de novas evidências ou redução de preço que justificassem a mudança de decisão. Não foram identificados os elementos constituintes do acordo de partilha de risco. São sinalizados problemas de transparência e accountability, bem como riscos ao processo de institucionalização da ATS que vinha em curso no SUS.

Resumen: En abril de 2019, se firmó el decreto de incorporación del medicamento nusinersén en el Sistema Único de Salud brasileño (SUS). Es el medicamento más caro que se ha incorporado al SUS para su uso en el tratamiento de la atrofia muscular espinal 5q tipo I. La incorporación del mismo está considerada como un marco de referencia en la toma de decisiones sobre nuevas tecnologías en el SUS, que puede ser viable mediante el acuerdo de distribución de riesgo. El trabajo discute el proceso de incorporación del nusinersén, destacando aspectos contextuales, temporales y técnicos, además de posibles consecuencias para la institucionalización de la evaluación de tecnologías en salud (ETS) en el SUS. El trabajo siguió el método exploratorio, con una revisión de la información pública, generada por la Comisión de Incorporación de Tecnologías en el SUS (CONITEC) y la búsqueda en bancos de datos gubernamentales de precios y compras. Se creó una línea temporal, describiendo los puntos-clave del proceso de incorporación. Hubo dos peticiones de incorporación del medicamento. La primera, sometida a la Secretaría de Ciencia, Tecnología e Insumos Estratégicos (SCTIE) del Ministerio de Salud, rechazada por unanimidad, en noviembre de 2018. A lo que le siguió la petición del Secretario de la SCTIE a la Abogacía-General de la Unión (AGU), para que pudiese decidir en otro sentido respecto a la recomendación del pleno de la CONITEC. La AGU recomendó una nueva remisión, realizada por la empresa productora y aprobada por unanimidad, en marzo de 2019. No se produjo un incremento de nuevas evidencias o una reducción del precio que justificasen el cambio de decisión. No se identificaron los elementos constituyentes del acuerdo de distribución de riesgo. Se señalaron los problemas de transparencia y rendición de cuentas, así como riesgos para el proceso de institucionalización de la ETS que estaba en curso en el SUS.

Health Technology Assessment Challenges in Oncology: 20 Years of Value in Health.

BACKGROUND: Oncology treatments have changed from chemotherapies to targeted therapies and more recently immuno-oncology. This has posed special challenges in the field of health technology assessment (HTA): capturing quality of life (QOL) associated with toxicity due to chemotherapy, crossover upon progression in targeted therapy trials, and survival extrapolation for immuno-oncology drugs. OBJECTIVES: To showcase 20 years of Value in Health (ViH) publications in oncology. METHODS: A review was undertaken of oncology articles published in ViH from May 1998 to August 2018. Full-length articles published in ViH with the keywords "oncology," "cancer," "h(a)ematology," and "malignancy" were included for review. Conference abstracts were excluded. RESULTS: Four major themes were identified: (1) QOL and the development of multiple functional assessment of cancer therapy tools and mapping instruments; (2) analysis of clinical evidence using indirect comparisons, network analyses, and adjustment for crossovers; (3) modeling, Markov models, partitioned survival models, and extrapolation methods; and (4) financial implications and how to deal with uncertainty, introduction of conditional reimbursement, managed entry, and risk share agreements. DISCUSSION: This review article highlights the important role ViH has played in disseminating HTA research in oncology. A few key issues loom on the horizon: precision medicine, further development and practical application of new QOL measures, methods for translating clinical evidence, and exploration of modeling techniques. For a better understanding of the complex interplay between access and financial risk management, ViH will no doubt continue to promote pioneering research in HTA and oncology.

To HTA or Not to HTA: Identifying the Factors Influencing the Rapid Review Outcome in Ireland.

OBJECTIVES: Reimbursement systems are evolving and endeavor to balance access and affordability. One such evolution in Ireland is the compulsory rapid review (RR) process, the outcome from which is a recommendation for a health technology assessment (HTA) or no HTA. For drugs that avoid an HTA, evaluation times are shorter, lengthy price negotiations are avoided, and access is faster. In the absence of formal decision-making criteria around the requirement of an HTA, this study examines the factors influencing the outcome of the RR process in Ireland. METHODS: A database was developed combining data from publicly available sources for drug evaluations conducted by the National Centre for PharmacoEconomics (NCPE) (January 2010-June 2017, n = 296). Because Irish cost data were not publicly available for all drugs, cost data from the Scottish Medicines Consortium were employed as a proxy. Employing logistic regressions, the factors influencing the RR outcome are revealed. RESULTS: After an RR, an HTA was recommended for 55% of drugs. The regression results revealed therapeutic area (endocrine, musculoskeletal, and neoplasm), first-in-class and orphan disease increased the probability of an HTA. Furthermore, when proxy costs were included, results revealed that every €1000 increase in annual drug costs per patient increased the probability of an HTA being required by 1% and that an HTA was more likely than no HTA when annual drug costs exceeded €15 000. CONCLUSION: Given the current focus on access and affordability, this study identifies the factors influencing the requirement of an HTA in Ireland.