Extending Beyond Bagust and Beale: Fully Parametric Piecewise Exponential Models for Extrapolation of Survival Outcomes in Health Technology Assessment.

OBJECTIVES: When extrapolating time-to-event data the Bagust and Beale (B&B) approach uses the Kaplan-Meier survival function until a manually chosen time point, after which a constant hazard is assumed. This study demonstrates an objective statistical approach to estimate this time point. METHODS: We estimate piecewise exponential models (PEMs), whereby the hazard function is partitioned into segments each with constant hazards. The boundaries of these segments are known as change points. Our approach determines the location and number of change points in PEMs from which the hazard in the final segment is used to model long-term survival. We reviewed previous applications of the B&B approach in National Institute for Health and Care Excellence Technology Appraisals (TAs) completed between July 2011 and June 2017. The time points after which constant hazards were assumed were compared between PEMs and the B&B approaches. When further survival data were published following the original TA, we compared these updated estimates to predicted survival from the PEM and other parametric models adjusted for general population mortality. RESULTS: Six of the 59 TAs in this review considered the B&B approach. There was general agreement between the location of time points identified through the PEM and the B&B approaches. In 2 of the identified TAs the best fitting model to the data was a no-change-point model. Of the 3 TAs for which further survival data became available, PEM provided the closest prediction for survival outcomes in 2 TAs. CONCLUSIONS: PEMs are useful for survival extrapolation when a long-term constant hazard trend for the disease is clinically plausible.

Direct Incorporation of Expert Opinion into Parametric Survival Models to Inform Survival Extrapolation.

BACKGROUND: In decision modeling with time-to-event data, there are a variety of parametric models that can be used to extrapolate the survival function. Each model implies a different hazard function, and in situations in which there is moderate censoring, this can result in quite different survival projections. External information such as expert opinion on long-term survival can more accurately characterize the uncertainty in these extrapolations. OBJECTIVE: We present a general and easily implementable approach to incorporate various types of expert opinions into parametric survival models, focusing on opinions about survival at various landmark time points. METHODS: Expert opinion is incorporated into parametric survival models using Bayesian and frequentist approaches. In the Bayesian method, expert opinion is included through a loss function and in the frequentist approach by penalizing the likelihood function, although in both cases the core approach is the same. The issue of aggregating multiple expert opinions is also considered. RESULTS: We apply this method to data from a leukemia trial and use previously elicited expert opinion on survival probabilities for that particular trial population at years 4 and 5 to inform our analysis. We take a robust approach to modeling expert opinion by using pooled distributions and fit a broad class of parametric models to the data. We also assess statistical goodness of fit of the models to both the observed data and expert opinion. CONCLUSIONS: Expert opinions can be implemented in a straightforward manner using this novel approach; however, more work is required on the correct elicitation of these quantities. HIGHLIGHTS: Presentation of a novel and open-source method to incorporate expert opinion into decision modeling.Extends upon earlier work in that expert opinion can be incorporated into a wide range of parametric models.Provides methodological guidance for directly including expert opinion in decision modeling, which is a research focus area in NICE TSD 21.1.

Efficacy and Safety of Brolucizumab, Aflibercept, and Ranibizumab for the Treatment of Patients with Visual Impairment Due to Diabetic Macular Oedema: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Key clinical guidelines recommend anti-vascular endothelial growth factor (VEGF) therapy as first-line treatment for visual impairment due to diabetic macular oedema (DMO). A systematic literature review (SLR) and network meta-analysis (NMA) were conducted comparing the relative efficacy of the anti-VEGF brolucizumab with a focused network of the most relevant comparator dosing regimens approved in countries other than the USA (aflibercept, ranibizumab). The safety and tolerability of brolucizumab were also assessed. METHODS: A broad SLR was conducted to identify randomised controlled trials to ensure all relevant potential comparators were captured. Identified studies were refined to those appropriate for inclusion in the NMA. A Bayesian NMA was conducted comparing brolucizumab 6 mg (every 12 [Q12W]/every 8 weeks [Q8W]) with relevant aflibercept 2 mg and ranibizumab 0.5 mg regimens. RESULTS: Fourteen studies were included in the NMA. At 1-year follow-up, the various aflibercept 2 mg and ranibizumab 0.5 mg regimens were mostly comparable with brolucizumab 6 mg Q12W/Q8W across key visual and anatomical outcomes, except brolucizumab 6 mg was favoured over ranibizumab 0.5 mg every 4 weeks (Q4W) for the change from baseline (CFB) in best-corrected visual acuity (BCVA), and BCVA loss/gain of pre-specified numbers of letters, and over ranibizumab 0.5 mg pro re nata for CFB in diabetic retinopathy severity scale, and retinal thickness. At year 2, where data were available, brolucizumab 6 mg showed similar results across efficacy outcomes versus all other anti-VEGFs. In most cases, discontinuation rates (all cause, and due to adverse events [AE]) and serious and overall rates of AEs excluding ocular inflammatory events were similar (in unpooled and pooled-treatment analyses) versus comparators. CONCLUSION: Brolucizumab 6 mg Q12W/Q8W was comparable or superior to aflibercept 2 mg and ranibizumab 0.5 mg regimens for various visual and anatomical efficacy outcomes and discontinuation rates.

The views and experiences of people with type 2 diabetes being cared for by their community pharmacist: a cross-sectional patient survey.

Purpose: Community pharmacists are highly accessible healthcare providers and studies in several countries have demonstrated a role for community pharmacists in delivering enhanced care to people with type 2 diabetes. The aim of this study is to evaluate the views and experiences of people with type 2 diabetes attending community pharmacies in Ireland. Methods: A 13-item questionnaire, anchored on a 5-point Likert scale, was used. The study took place in seven pharmacies in the Munster region of Ireland. Participants were people attending a participating pharmacy who had type 2 diabetes and were aged ≥ 18 years. Results: The questionnaire was answered by 125 people with type 2 diabetes. Mean age of participants was 65.7 ± 12.4 years and 59.2% were male. The statement "I am totally satisfied with my visit to this pharmacist", was the item that participants most frequently agreed with (agree/strongly agree = 99.2%, mean score 4.9 ± 0.4). Over 80% of participants agreed or strongly agreed with the statement "It is easier to get to see the pharmacist than the doctor", (mean score 4.3 ± 1.1). Conclusion: In this population, people with type 2 diabetes were highly satisfied with the care provided to them by their community pharmacist. These data support the implementation of enhanced community pharmacy services for people with type 2 diabetes in Ireland.

Cost-Effectiveness Analysis of Ofatumumab for the Treatment of Relapsing-Remitting Multiple Sclerosis in Canada.

BACKGROUND: Ofatumumab is a high-efficacy disease-modifying therapy (DMT) approved for first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Canada. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of ofatumumab from a Canadian healthcare system perspective. METHODS: A Markov cohort model was run over 65 years using annual cycles, 1.5% annual discount rate, and 100% treatment discontinuation at 10 years. The British Columbia database informed natural history transition probabilities. Treatment efficacy for DMTs were sourced from a network meta-analysis. Clinical trial data were used to estimate probabilities for treatment-related adverse events. Health utilities and costs were obtained from Canadian sources (if available) and the literature. RESULTS: Among first-line indicated therapies for RRMS, ofatumumab was dominant (more effective, lower costs) over teriflunomide, interferons, dimethyl fumarate, and ocrelizumab. Compared with glatiramer acetate and best supportive care, ofatumumab resulted in incremental cost-effectiveness ratios (ICERs) of $24,189 Canadian dollars per quality-adjusted life-year (QALY) and $28,014/QALY, respectively. At a willingness-to-pay threshold of $50,000/QALY, ofatumumab had a 64.3% probability of being cost effective. Among second-line therapies (scenario analysis), ofatumumab dominated natalizumab and fingolimod and resulted in an ICER of $50,969 versus cladribine. CONCLUSIONS: Ofatumumab is cost effective against all comparators and dominant against all currently approved and reimbursed first-line DMTs for RRMS, except glatiramer acetate.

Cost-Effectiveness of Erenumab for the Preventive Treatment of Migraine in Patients with Prior Treatment Failures in Sweden.

BACKGROUND: Migraine is a common neurological disease that disproportionately affects females and has a peak incidence during productive years, resulting in significant burden. OBJECTIVE: The aim of the study was to determine the cost effectiveness of erenumab for the preventive treatment of migraine. METHODS: A hybrid decision-tree plus Markov model was developed to evaluate the cost effectiveness of erenumab as a migraine treatment compared with best supportive care only for patients experiencing at least 4 monthly migraine days for whom at least two prior preventive treatments had failed. Clinical efficacy data were based on results from four randomized controlled trials of erenumab against placebo. The primary outcomes were costs, migraine days, and quality-adjusted life-years (QALYs). An incremental cost-effectiveness ratio (ICER) was estimated as the cost per QALY gained. The cost per migraine day avoided was also estimated, as were disaggregated direct and indirect costs. The analysis was conducted from Swedish societal and healthcare system perspectives based on total migraine, chronic migraine and episodic migraine populations, using a discount rate of 3% applied to both costs and health benefits and using year 2019 values. RESULTS: In the base-case deterministic analyses, erenumab treatment resulted in ICERs of Swedish krona (SEK) 34,696 (€3310) and SEK301,565 (€28,769) per QALY gained in the total migraine and episodic migraine populations, respectively. Erenumab was dominant in the chronic migraine population. In the total migraine population, the use of erenumab resulted in a net benefit to society of SEK81,739 (€7773) per patient, assuming a willingness-to-pay threshold of SEK300,000 (€28,528) per QALY. CONCLUSIONS: Our analysis suggests that erenumab is a cost-effective treatment for migraine with a willingness-to-pay threshold of SEK300,000 per QALY.

Economic evaluations in migraine: systematic literature review and a novel approach.

Background: For novel migraine therapies, economic evaluations will be required to understand the trade-offs between additional health benefit and additional cost. The purpose of this study was to conduct a systematic literature review (SLR) to identify previous economic evaluations in migraine from the United Kingdom or Irish perspective to critically appraise these evaluations and to propose, if necessary, a novel modelling approach that can be used for future economic evaluations of migraine therapies.Methods: An SLR was conducted to identify previous economic evaluations of preventive migraine treatments. Key opinion leaders were consulted to determine the criteria for a robust migraine economic evaluation. Economic evaluations identified in the SLR were appraised against these criteria, and a novel cost-effectiveness model structure was then proposed.Results: Eight records reporting on published economic evaluations were identified and critically appraised for general quality. Expert consultation provided 6 recommendations on the ideal model structure for migraine that is both clinically and economically meaningful. A decision-tree plus Markov structure was then developed as a cost-effectiveness model for migraine therapies where each health state is associated with a patient distribution across monthly migraine day (MMD) frequencies.Conclusions: Future migraine economic evaluations should allow for assessments across the full spectrum of migraine, a response-based stopping rule, and the estimation of benefits and resource costs based on MMD frequency. The approach proposed in this paper captures all of the desired elements for an economic evaluation of migraine therapy and is suitable to assess new migraine therapies.