The Impasse on Overall Survival in Oncology Reimbursement Decision-Making: How Can We Resolve This?

Mature overall survival (OS) data are often unavailable at the time of regulatory and reimbursement decisions for a new cancer treatment. For patients with early-stage cancers treated with potentially curative treatments, demonstrating an OS benefit may take years and may be confounded by subsequent lines of therapy or crossover to the investigational treatment. For patients with advanced-stage cancers, mature OS data may be available but difficult to interpret for similar reasons. There are strong opinions about approval and reimbursement in the absence of mature OS data, with concerns over delay in patient access set against concerns about uncertainty in long-term benefit. This position paper reflects our individual views as patient advocate, clinician or health economist on one aspect of this debate. We look at payer decisions in the absence of mature OS data, considering when and how non-OS trial outcomes could inform decision-making and how uncertainty can be addressed beyond the trial, supporting these views with evidence from the literature. We consider when it is reasonable for payers to expect or not expect mature OS data at the initial reimbursement decision (based on criteria such as cancer stage and treatment efficacy) acknowledging that there are settings in which mature OS data are expected. We propose flexible strategies for generating and appraising patient-relevant evidence, including context-relevant endpoints and quality of life measures, when survival rates are good and mature OS data are not expected. We note that fair reimbursement is important; this means valuing patient benefit as shown through prespecified endpoints and reappraising if there is ongoing uncertainty or failure to show a sustained benefit. We suggest that reimbursement systems continue to evolve to align with scientific advances, because innovation is only meaningful if readily accessible to patients. The proposed strategies have the potential to promote thorough assessment of potential benefit to patients and lead to timely access to effective medicines.

Cost-effectiveness modeling for neuropathic pain treatments: investigating the relative importance of parameters using an open-source model.

AIMS: The study objective was to develop an open-source replicate of a cost-effectiveness model developed by National Institute for Health and Care (NICE), in order to explore uncertainties in health economic modeling of novel pharmacological neuropathic pain treatments. MATERIALS AND METHODS: The NICE model, consisting of a decision tree with branches for discrete levels of pain relief and adverse event (AE) severities, was replicated using R, and used to compare a hypothetical neuropathic pain drug to pregabalin. Model parameters were sourced from NICE's clinical guidelines and associated with probability distributions to account for underlying uncertainty. A simulation-based scenario analysis was conducted to assess how uncertainty in efficacy and AEs affected the net monetary benefit (NMB) for the hypothetical treatment at a cost-effectiveness threshold of £20,000 per QALY. RESULTS: Relative to pregabalin, an increase in efficacy was associated with greater NMB than an improvement in tolerability. A greater NMB was observed when efficacy was marginally higher than that of pregabalin, while maintaining the same level of AEs than when efficacy was equivalent to pregabalin, but with a more substantial reduction in AEs. In the latter scenario, the NMB was only positive at a low cost-effectiveness threshold. LIMITATIONS: The replicate model shares the limitations described in the NICE guidelines. There is a lack of support in scientific literature for the assumption that increased efficacy is associated with a greater reduction in tolerability. The replicate model also included a single comparator, unlike the NICE model. CONCLUSIONS: Pain relief is a stronger driver of NMB than tolerability, at a cost-effectiveness threshold of £20,000 per QALY. Health technology assessment decisions which are influenced by NICE's model may reward efficacy gains, even if they are associated with more severe AEs. This contrasts with recommendations from clinical guidelines for neuropathic pain, which place more equal weighting on improvements in efficacy and tolerability as value drivers.

Cost-utility analysis of an intervention designed to reduce the critical handling error of insufficient inspiratory effort.

OBJECTIVES: Up to 70-80% of patients use inhalers incorrectly. Dry-powder inhalers (DPIs) require forceful inhalation for optimal delivery, and approximately 40% of Global Initiative for Asthma (GINA)-defined Step-3+ patients inhale corticosteroid and long-acting beta-agonist through DPIs. The CRITIKAL study (Price et al. in J Allergy Clin Immunol Pract 5:1071-e9-1081-e9, 2017) found a statistically significant association between 'insufficient inspiratory effort' error and increased risk of uncontrolled asthma and hospitalisation-requiring exacerbations. This paper explores the cost-effectiveness of an error-targeted intervention. METHODS: A probabilistic Markov cost-utility model simulated patients transitioning between controlled and uncontrolled health states over one year. Odds ratios (ORs, from the CRITIKAL study) of a patient having uncontrolled asthma conditional on making the error were applied to baseline transition probabilities sourced from the literature, both indirectly via an adjustment formula (Zhang et al. in JAMA 280:1690-1691, 1998) and directly by assuming OR approximates relative risk (RR). The analysis explored complete/partial eradication of the error when the intervention was priced to match comparators, as well as impact of indirect costs based on lost/reduced productivity. RESULTS: The intervention dominated both DPI comparators over one year, with direct cost savings of £45/£86 with 0.0053/0.0102 additional quality-adjusted life years (QALYs), and had the highest probability of being cost-effective at a £20,000/QALY threshold. Key factors driving variance were weekly utilities per state and RR of moving to an uncontrolled state. CONCLUSION: The analysis demonstrated the economic and societal costs of 'insufficient inspiratory effort' and potential economic benefits of introducing an effective intervention to reduce/eradicate this error. Further research should assess the economic impact of other handling errors.

Cost-Effectiveness of Take-Home Naloxone for the Prevention of Overdose Fatalities among Heroin Users in the United Kingdom.

BACKGROUND: Heroin overdose is a major cause of premature death. Naloxone is an opioid antagonist that is effective for the reversal of heroin overdose in emergency situations and can be used by nonmedical responders. OBJECTIVE: Our aim was to assess the cost-effectiveness of distributing naloxone to adults at risk of heroin overdose for use by nonmedical responders compared with no naloxone distribution in a European healthcare setting (United Kingdom). METHODS: A Markov model with an integrated decision tree was developed based on an existing model, using UK data where available. We evaluated an intramuscular naloxone distribution reaching 30% of heroin users. Costs and effects were evaluated over a lifetime and discounted at 3.5%. The results were assessed using deterministic and probabilistic sensitivity analyses. RESULTS: The model estimated that distribution of intramuscular naloxone, would decrease overdose deaths by around 6.6%. In a population of 200,000 heroin users this equates to the prevention of 2,500 premature deaths at an incremental cost per quality-adjusted life year (QALY) gained of £899. The sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: Our evaluation suggests that the distribution of take-home naloxone decreased overdose deaths by around 6.6% and was cost-effective with an incremental cost per QALY gained well below a £20,000 willingness-to-pay threshold set by UK decision-makers. The model code has been made available to aid future research. Further study is warranted on the impact of different formulations of naloxone on cost-effectiveness and the impact take-home naloxone has on the wider society.

Innovative pharmaceutical pricing agreements in five European markets: A survey of stakeholder attitudes and experience.

BACKGROUND: Innovative pricing agreements for medicines have been used in European markets for more than 20 years, and offer an opportunity for payers and pharmaceutical companies to align on value, optimise speed to patients, and share risk. Developing successful agreements requires alignment between key stakeholders, yet there is a lack of summative data on how current innovative agreements are used in the real-world (e.g. the level of realised access to medicines, and rebates and discounts, which are often non-transparent). METHODS: This research used a web-based survey of payer stakeholders to determine what kinds of innovative agreements are currently used, anticipated future usage, attitudes, and drivers of adoption. Participants included national and regional payers (or former payers) and hospital-level decision makers. RESULTS: Sixty-six payers completed the survey. Respondents expected that the use of innovative pricing agreements will remain the same or increase in the future. Overall, they felt there is a positive attitude towards new schemes, and that innovative agreements are likely to be used when they reduce total costs or reduce uncertainty. CONCLUSIONS: Given payer expectations, pharmaceutical companies should continue to take a role in ensuring that they have sufficient capacity to support payers in the design and implementation of innovative pricing agreements.

When Science is Not Enough: A Framework Towards More Customer-Focused Drug Development.

INTRODUCTION: The purpose of this study was to identify the key barriers to a customer-focused drug development process and develop a comprehensive framework to overcome them. METHODS: The paper draws on existing literature, both academic and practitioner, across a range of disciplines (innovation management, marketing, organizational behavior, behavioral economics, health economics, industry reports). On the basis of this extensive review, a conceptual framework is developed that offers concrete suggestions on how organizations can overcome the barriers and enable a more customer-focused development process. RESULTS: The barriers to collaboration are organized into three distinct categories (economic, behavioral, organizational), and within each category, a one-to-one mapping between barriers and solutions is developed. CONCLUSION: The framework is specifically designed with the objective of offering actionable and practical advice to executives who face these challenges in their organizations. The paper provides a unique theoretical contribution by synthesizing findings from several academic disciplines with concrete examples from the pharmaceutical industry. FUNDING: Mundipharma International Limited.

Use of opioid substitution therapies in the treatment of opioid use disorder: results of a UK cost-effectiveness modelling study.

AIMS: This study investigated the cost-effectiveness of buprenorphine maintenance treatment (BMT) and methadone maintenance treatment (MMT) vs no opioid substitution therapy (OST) for the treatment of opioid use disorder, from the UK National Health Service (NHS)/personal social services (PSS) and societal perspectives over 1 year. METHODS: Cost-effectiveness of OST vs no OST was evaluated by first replicating and then expanding an existing UK health technology assessment model. The expanded model included the impact of OST on infection rates of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. RESULTS: Versus no OST, incremental cost-effectiveness ratios (ICERs) for BMT and MMT were £13,923 and £14,206 per quality-adjusted life year (QALY), respectively, from a NHS/PSS perspective. When total costs (NHS/PSS and societal) are considered, there are substantial savings associated with adopting OST; these savings are in excess of £14,032 for BMT vs no OST and £17,174 for MMT vs no OST over 1 year. This is primarily driven by a reduction in victim costs. OST treatment also impacted other aspects of criminality and healthcare resource use. LIMITATIONS: The model's 1-year timeframe means long-term costs and benefits, and the influence of changes over time are not captured. CONCLUSIONS: OST can be considered cost-effective vs no OST from the UK NHS/PSS perspective, with a cost per QALY well below the UK's willingness-to-pay threshold. There were only small differences between BMT and MMT. The availability of two or more cost-effective options is beneficial to retaining patients in OST programs. From a societal perspective, OST is estimated to save over £14,032 and £17,174 per year for BMT and MMT vs no OST, respectively, due to savings in victim costs. Further work is required to fully quantify the clinical and health economic impacts of different OST formulations and their societal impact over the long-term.

A systematic review of health economic models of opioid agonist therapies in maintenance treatment of non-prescription opioid dependence.

BACKGROUND: Opioid dependence is a chronic condition with substantial health, economic and social costs. The study objective was to conduct a systematic review of published health-economic models of opioid agonist therapy for non-prescription opioid dependence, to review the different modelling approaches identified, and to inform future modelling studies. METHODS: Literature searches were conducted in March 2015 in eight electronic databases, supplemented by hand-searching reference lists and searches on six National Health Technology Assessment Agency websites. Studies were included if they: investigated populations that were dependent on non-prescription opioids and were receiving opioid agonist or maintenance therapy; compared any pharmacological maintenance intervention with any other maintenance regimen (including placebo or no treatment); and were health-economic models of any type. RESULTS: A total of 18 unique models were included. These used a range of modelling approaches, including Markov models (n = 4), decision tree with Monte Carlo simulations (n = 3), decision analysis (n = 3), dynamic transmission models (n = 3), decision tree (n = 1), cohort simulation (n = 1), Bayesian (n = 1), and Monte Carlo simulations (n = 2). Time horizons ranged from 6 months to lifetime. The most common evaluation was cost-utility analysis reporting cost per quality-adjusted life-year (n = 11), followed by cost-effectiveness analysis (n = 4), budget-impact analysis/cost comparison (n = 2) and cost-benefit analysis (n = 1). Most studies took the healthcare provider's perspective. Only a few models included some wider societal costs, such as productivity loss or costs of drug-related crime, disorder and antisocial behaviour. Costs to individuals and impacts on family and social networks were not included in any model. CONCLUSION: A relatively small number of studies of varying quality were found. Strengths and weaknesses relating to model structure, inputs and approach were identified across all the studies. There was no indication of a single standard emerging as a preferred approach. Most studies omitted societal costs, an important issue since the implications of drug abuse extend widely beyond healthcare services. Nevertheless, elements from previous models could together form a framework for future economic evaluations in opioid agonist therapy including all relevant costs and outcomes. This could more adequately support decision-making and policy development for treatment of non-prescription opioid dependence.

BEACON: A Summary Framework to Overcome Potential Reimbursement Hurdles.

OBJECTIVE: To provide a framework for addressing payers' criteria during the development of pharmaceuticals. METHODS: A conceptual framework was presented to an international health economic expert panel for discussion. A structured literature search (from 2010 to May 2015), using the following databases in Ovid: Medline(®) and Medline(®) In-Process (PubMed), Embase (Ovid), EconLit (EBSCOhost) and the National Health Service Economic Evaluation Database (NHS EED), and a 'grey literature' search, were conducted to identify existing criteria from the payer perspective. The criteria assessed by existing frameworks and guidelines were collated; the most commonly reported criteria were considered for inclusion in the framework. A mnemonic was conceived as a memory aide to summarise these criteria. RESULTS: Overall, 41 publications were identified as potentially relevant to the objective. Following further screening, 26 were excluded upon full-text review on the basis of no framework presented (n = 13), redundancy (n = 11) or abstract only (n = 2). Frameworks that captured criteria developed for or utilised by the pharmaceutical industry (n = 5) and reimbursement guidance (n = 10) were reviewed. The most commonly identified criteria-unmet need/patient burden, safety, efficacy, quality-of-life outcomes, environment, evidence quality, budget impact and comparator-were incorporated into the summary framework. For ease of communication, the following mnemonic was developed: BEACON (Burden/target population, Environment, Affordability/value, Comparator, Outcomes, Number of studies/quality of evidence). CONCLUSIONS: The BEACON framework aims to capture the 'essence' of payer requirements by addressing the most commonly described criteria requested by payers regarding the introduction of a new pharmaceutical.

Examining the association between pain severity and quality-of-life, work-productivity loss, and healthcare resource use among European adults diagnosed with pain.

OBJECTIVE: The goal of this research was to quantify the association between pain severity and several health outcomes in a large sample of patients diagnosed with some form of pain. METHODS: Responses from patients who had been diagnosed with some form of pain (n = 14,459) were drawn from the 2013 EU National Health and Wellness Survey (NHWS; n = 62,000). Respondents reported their subjective pain severity in the past week on a numerical rating scale (0-10) as well as the Medical Outcomes Study Short Form (SF-36), Work Productivity and Activity Impairment Questionnaire (WPAI), and healthcare resource utilization in the past 6 months (healthcare professional (HCP) visits, emergency room (ER) visits, and hospitalizations). Associations between pain severity and health outcomes were examined via a series of regression models controlling for a set of demographic and health-related covariates. RESULTS: After controlling for demographics and comorbidities, pain severity in the past week was shown to be significantly negatively associated with Health Utilities (b = -0.022, p < 0.001) and positively associated with overall WPAI scores (b = 0.18, p < 0.001) and healthcare resource use (Hospitalizations: b = 0.13, p < 0.001; ER Visits: b = 0.14, p < 0.001; HCP Visits: b = 0.08, p < 0.001). The nature of these relationships (linear, curvilinear, etc.) is also explored. LIMITATIONS: This study was a self-report cross-sectional study which may have biased the results and does not allow for causal inferences to be made. Finally, the regression models run were limited to available covariates and, hence, some potentially important covariates may not have been included in these models. CONCLUSIONS: The findings suggest that reducing pain severity could result in an increase in patients' quality-of-life and work productivity, and a decrease in healthcare resource use. The equations, linking pain and outcomes, were presented in an accessible format so they could be readily applied in healthcare decision-making.

The Suitability of End Point Designs for Health Technology Assessment in Chronic Pain Studies.

OBJECTIVES: To identify the pain instruments and study end points most commonly used in clinical trial settings and to provide insight into the extent to which outcome measures in clinical studies are meeting payer needs. METHODS: A literature review was conducted to identify published clinical studies and ongoing/recently completed registered trials in chronic pain. Inclusion criteria were interventional study, chronic pain in adults, and pain measured within the primary end point. RESULTS: Of 1256 PubMed citations and 3006 clinical trial registry entries, 356 reported large clinical studies in pain populations (e.g., malignant, neuropathic, functional, and musculoskeletal). Studies were designed for superiority in 28% of PubMed citations and 8% of registry entries. The primary end points of most studies were single-dimension pain instruments, such as the numerical rating scale (n = 131) and the visual analogue scale (n = 69). In cases in which multidimensional pain end points were used, this was most commonly the Brief Pain Inventory (n = 37). Payer-relevant end points were typically limited to secondary end points, and were limited and/or reported inconsistently in published studies and ongoing/recently completed studies: preference-weighted quality of life (36% and 42%), resource use (2% and 8%), physical function (28% and 39%), and psychological function (25% and 24%). CONCLUSIONS: Most pain trials were not designed to show superiority to an active comparator, and they used single-dimension pain scales as their primary end point in combination with a broader selection of secondary end points. The inclusion of payer-relevant end points among clinical trials was inconsistent.

Estimating the health care burden of prescription opioid abuse in five European countries.

BACKGROUND: Opioid abuse, including abuse of prescription opioids ("RxOs") and illicit substances like heroin, is a serious public health issue in Europe. Currently, there is limited data on the magnitude of RxO abuse in Europe, despite increasing public and scientific interest in the issue. The purpose of this study was to use the best-available data to derive comparable estimates of the health care burden of RxO abuse in France, Germany, Italy, Spain, and the United Kingdom (EU5). METHODS: Published data on the prevalence of problem opioid use and the share of opioid abuse patients reporting misuse of non-heroin opioids were used to estimate the prevalence of RxO abuse in the EU5 countries. The costs of RxO abuse were calculated by applying published estimates of the incremental health care costs of opioid abuse to country-specific estimates of the costs of chronic pain conditions. These estimates were input into an economic model that quantified the health care burden of RxO abuse in each of the EU5 countries. Sensitivity analyses examined key assumptions. RESULTS: Based on best-available current data, prevalence estimates of RxO abuse ranged from 0.7 to 13.7 per 10,000 individuals across the EU5 countries. Estimates of the incremental health care costs of RxO abuse ranged from €900 to €2,551 per patient per year. The annual health care cost burden of RxO abuse ranged from €6,264 to €279,927 per 100,000 individuals across the EU5 countries. CONCLUSION: This study suggests that RxO abuse imposes a cost burden on health systems in the five largest European countries. The extent of RxO abuse in Europe should be monitored given the potential for change over time. Continued efforts should be made to collect reliable data on the prevalence and costs of RxO abuse in Europe to facilitate an accurate characterization of the extent of this potentially growing problem.

The Budget Impact of Biosimilar Infliximab (Remsima®) for the Treatment of Autoimmune Diseases in Five European Countries.

INTRODUCTION: Inflammatory autoimmune diseases (rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, and psoriatic arthritis) have a considerable impact on patients' quality of life and healthcare budgets. Biosimilar infliximab (Remsima(®)) has been authorized by the European Medicines Agency for the management of inflammatory autoimmune diseases based on a data package demonstrating efficacy, safety, and quality comparable to the reference infliximab product (Remicade(®)). This analysis aims to estimate the 1-year budget impact of the introduction of Remsima in five European countries. METHODS: A budget impact model for the introduction of Remsima in Germany, the UK, Italy, the Netherlands, and Belgium was developed over a 1-year time horizon. Infliximab-naïve and switch patient groups were considered. Only direct drug costs were included. The model used the drug-acquisition cost of Remicade. The list price of Remsima was not known at the time of the analysis, and was assumed to be 10-30% less than that of Remicade. Key variables were tested in the sensitivity analysis. RESULTS: The annual cost savings resulting from the introduction of Remsima were projected to range from €2.89 million (Belgium, 10% discount) to €33.80 million (Germany, 30% discount). If any such savings made were used to treat additional patients with Remsima, 250 (Belgium, 10% discount) to 2602 (Germany, 30% discount) additional patients could be treated. The cumulative cost savings across the five included countries and the six licensed disease areas were projected to range from €25.79 million (10% discount) to €77.37 million (30% discount). Sensitivity analyses showed the number of patients treated with infliximab to be directly correlated with projected cost savings, with disease prevalence and patient weight having a smaller impact, and incidence the least impact. CONCLUSION: The introduction of Remsima could lead to considerable drug cost-related savings across the six licensed disease areas in the five European countries. FUNDING: Mundipharma International Ltd.