OP380 A Review Of The Methodology Used To Synthesize Continuous And Time-To-Event Outcomes For Clinical And Cost-Effectiveness

2020 ◽  
Vol 36 (S1) ◽  
pp. 7-7
Author(s):  
Suzanne Freeman ◽  
Alex Sutton ◽  
Nicola Cooper
Keyword(s):  
Cost Effectiveness ◽  
Decision Model ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Clinical Effectiveness ◽  
Evidence Base ◽  
Synthesis Methods ◽  
Time To Event ◽  
Health Technologies ◽  
Treatment Comparison

IntroductionSynthesis of continuous and time-to-event outcomes is often complicated by the use of multiple outcome scales and heterogeneous reporting of outcomes across trials. Simple methods of evidence synthesis for clinical effectiveness can fail to account for these issues and result in a reduction of the evidence base, which can be further reduced at the cost-effectiveness stage as common outcome measures, such as standardized mean differences, cannot easily be incorporated into the economic decision model. Recent methodological advances for synthesizing continuous and time-to-event outcomes aim to include a greater proportion of the available evidence base within a single coherent analysis.MethodsTo assess the statistical methods commonly used in health technology assessment (HTA) and establish whether recent advances in synthesis methods have been adopted in practice, we conducted a review of HTA reports and guidelines published in the United Kingdom (UK) between 1 April 2018 and 31 March 2019 reporting a quantitative meta-analysis (MA), network meta-analysis (NMA) or indirect treatment comparison (ITC) of at least one continuous or time-to-event outcome.ResultsForty-seven articles were considered eligible for this review. Fifty-one percent of eligible articles reported at least one continuous outcome and 55 percent at least one time-to-event outcome. Twenty-nine articles reported NMA or ITC and twenty-seven reported MA of a continuous or time-to-event outcome. Forty articles included a decision model, of which twenty-seven incorporated evidence from a synthesis of a continuous or time-to-event outcome with eleven informed by a single trial (despite synthesis being conducted).ConclusionsUptake of methods to include a greater proportion of the available evidence base within a single coherent analysis in UK HTA reports has been slow. Evaluating health technologies using an evidence-based approach often results in better outcomes for patients. Therefore, HTA analysts and decision modelers must be aware of the expanding literature for synthesis of continuous and time-to-event outcomes and appreciate the limitations of simpler approaches.

OP236 Evidence Synthesis Of Time-To-Event Outcomes In The Presence Of Non-Proportional Hazards

2021 ◽  
Vol 37 (S1) ◽  
pp. 8-8
Author(s):  
Suzanne Freeman ◽  
Nicola Cooper ◽  
Alex Sutton ◽  
Michael Crowther ◽  
James Carpenter ◽  
...  
Keyword(s):  
Survival Time ◽  
Simulation Study ◽  
Proportional Hazards ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Clinical Effectiveness ◽  
Time To Event ◽  
Mean Survival Time ◽  
Restricted Mean Survival Time

IntroductionSynthesis of clinical effectiveness is a well-established component of health technology assessment (HTA) combining data from multiple trials to obtain an overall pooled estimate of clinical effectiveness, which may inform an associated economic evaluation. Time-to-event outcomes are often synthesized using effect measures from Cox proportional hazards models assuming a constant hazard ratio over time. However, where treatment effects vary over time an assumption of proportional hazards is not always valid. Several methods have been proposed for synthesizing time-to-event outcomes in the presence of non-proportional hazards. However, guidance on choosing between these methods and the implications for HTA is lacking.MethodsWe applied five methods for estimating treatment effects from time-to-event outcomes, which relax the proportional hazards assumption to a network of melanoma trials, reporting overall survival: restricted mean survival time, an accelerated failure time generalized gamma model, piecewise exponential, fractional polynomial and Royston-Parmar models. We conducted a simulation study to compare these five methods. Simulated individual patient data was generated from a mixture Weibull distribution assuming a treatment-time interaction. Each simulated meta-analysis consisted of five trials with varying numbers of patients and length of follow-up across trials. For each model fitted to each dataset, we calculated the restricted mean survival time at the end of observed follow-up and following extrapolation to a 20-year time horizon.ResultsAll models fitted the melanoma data reasonably well with some variation in the treatment rankings and differences in the survival curves. The simulation study demonstrated the potential for different conclusions from different modelling approaches.ConclusionsThe restricted mean survival time, generalized gamma, piecewise exponential, fractional polynomial and Royston-Parmar models can all accommodate non-proportional hazards and differing lengths of trial follow-up within an evidence synthesis of time-to-event outcomes. Further work is needed in this area to extend the simulation study to the network meta-analysis setting and provide guidance on the key considerations for informing model choice for the purposes of HTA.

scholarly journals Tumour necrosis factor-α inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation

2016 ◽  
Vol 20 (9) ◽  
pp. 1-334 ◽  
Author(s):  
Mark Corbett ◽  
Marta Soares ◽  
Gurleen Jhuti ◽  
Stephen Rice ◽  
Eldon Spackman ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cost Effectiveness ◽  
Decision Model ◽  
Axial Spondyloarthritis ◽  
De Novo ◽  
Meta Analysis ◽  
Clinical Effectiveness ◽  
Necrosis Factor ◽  
Quality Adjusted Life

BackgroundTumour necrosis factor (TNF)-α inhibitors (anti-TNFs) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-AxSpA) have not responded adequately to conventional therapy. Current National Institute for Health and Care Excellence (NICE) guidance recommends treatment with adalimumab, etanercept and golimumab in adults with active (severe) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS. Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE.ObjectiveTo determine the clinical effectiveness, safety and cost-effectiveness within the NHS of adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, within their licensed indications, for the treatment of severe active AS or severe nr-AxSpA (but with objective signs of inflammation).DesignSystematic review and economic model.Data sourcesFifteen databases were searched for relevant studies in July 2014.Review methodsClinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis methods. Results from other studies were summarised narratively. Only full economic evaluations that compared two or more options and considered both costs and consequences were included in the systematic review of cost-effectiveness studies. The differences in the approaches and assumptions used across the studies, and also those in the manufacturer’s submissions, were examined in order to explain any discrepancies in the findings and to identify key areas of uncertainty. A de novo decision model was developed with a generalised framework for evidence synthesis that pooled change in disease activity (BASDAI and BASDAI 50) and simultaneously synthesised information on function (BASFI) to determine the long-term quality-adjusted life-year and cost burden of the disease in the economic model. The decision model was developed in accordance with the NICE reference case. The model has a lifetime horizon (60 years) and considers costs from the perspective of the NHS and personal social services. Health effects were expressed in terms of quality-adjusted life-years.ResultsIn total, 28 eligible RCTs were identified and 26 were placebo controlled (mostly up to 12 weeks); 17 extended into open-label active treatment-only phases. Most RCTs were judged to have a low risk of bias overall. In both AS and nr-AxSpA populations, anti-TNFs produced clinically important benefits to patients in terms of improving function and reducing disease activity; for AS, the relative risks for ASAS 40 ranged from 2.53 to 3.42. The efficacy estimates were consistently slightly smaller for nr-AxSpA than for AS. Statistical (and clinical) heterogeneity was more apparent in the nr-AxSpA analyses than in the AS analyses; both the reliability of the nr-AxSpA meta-analysis results and their true relevance to patients seen in clinical practice are questionable. In AS, anti-TNFs are approximately equally effective. Effectiveness appears to be maintained over time, with around 50% of patients still responding at 2 years. Evidence for an effect of anti-TNFs delaying disease progression was limited; results from ongoing long-term studies should help to clarify this issue. Sequential treatment with anti-TNFs can be worthwhile but the drug survival response rates and benefits are reduced with second and third anti-TNFs. The de novo model, which addressed many of the issues of earlier evaluations, generated incremental cost-effectiveness ratios ranging from £19,240 to £66,529 depending on anti-TNF and modelling assumptions.ConclusionsIn both AS and nr-AxSpA populations anti-TNFs are clinically effective, although more so in AS than in nr-AxSpA. Anti-TNFs may be an effective use of NHS resources depending on which assumptions are considered appropriate.Future work recommendationsRandomised trials are needed to identify the nr-AxSpA population who will benefit the most from anti-TNFs.Study registrationThis study is registered as PROSPERO CRD42014010182.FundingThe National Institute for Health Research Health Technology Assessment programme.

OP179 Quantitative Evidence Synthesis Methods For Assessing The Effectiveness Of Treatment Sequences For Clinical And Economic Decision-Making: Methodology Review

2021 ◽  
Vol 37 (S1) ◽  
pp. 4-4
Author(s):  
Ruth Lewis ◽  
Dyfrig Hughes ◽  
Alex Sutton ◽  
Clare Wilkinson
Keyword(s):  
Decision Making ◽  
Chronic Conditions ◽  
Evidence Synthesis ◽  
Policy Decision ◽  
Clinical Effectiveness ◽  
Synthesis Methods ◽  
Economic Decision Making ◽  
Treatment Sequencing ◽  
Policy Decision Making ◽  
Treatment Sequences

IntroductionThe sequential use of alternative treatments for chronic conditions represents a complex, dynamic intervention pathway; previous treatment and patient characteristics affect both choice and effectiveness of subsequent treatments. Evidence synthesis methods that produce the least biased estimates of treatment-sequencing effects are required to inform reliable clinical and policy decision-making. A comprehensive review was conducted to establish what existing methods are available, outline the assumptions they make, and identify their shortcomings.MethodsThe review encompassed both meta-analytic techniques and decision-analytic modelling, any disease condition, and any type of treatment sequence, but not diagnostic tests, screening, or treatment monitoring. It focused on the estimation of clinical effectiveness and did not consider the impact of treatment sequencing on the estimation of costs or utility values.ResultsThe review included ninety-one studies. Treatment-sequencing is usually dealt with at the decision-modelling stage and is rarely addressed using evidence synthesis methodology for clinical effectiveness. Most meta-analyses are of discrete treatments, sometimes stratified by line of therapy. Prospective sequencing trials are scarce. In their absence, there is no single best way to evaluate treatment sequences, rather there is a range of approaches, each of which has advantages and disadvantages and is influenced by the evidence available and the decision problem. Due to the scarcity of data on sequential treatments, modelling studies generally apply simplifying assumptions to data on discrete treatments. A taxonomy for all possible assumptions was developed, providing a unique resource to aid the critique of decision-analytic models.ConclusionsThe evolution of network meta-analysis in HTA demonstrates that clinical and policy decision-making should account for the multiple treatments available for many chronic conditions. However, treatment-sequencing has yet to be accounted for within clinical evaluations. Economic modelling is often based on the simplifying assumption of treatment independence. This can lead to misrepresentation of the true level of uncertainty, potential bias in estimating the effectiveness and cost effectiveness of treatments and, eventually, the wrong decision.

scholarly journals Identifying stroke therapeutics from preclinical models: A protocol for a novel application of network meta-analysis

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 11 ◽  
Author(s):  
Manoj M. Lalu ◽  
Dean A. Fergusson ◽  
Wei Cheng ◽  
Marc T. Avey ◽  
Dale Corbett ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Burden Of Illness ◽  
Evidence Synthesis ◽  
Meta Analysis ◽  
Synthesis Methods ◽  
Preclinical Models ◽  
Ovid Medline ◽  
Scientific Meetings ◽  
Ischemia Testing

Introduction: Globally, stroke is the second leading cause of death. Despite the burden of illness and death, few acute interventions are available to patients with ischemic stroke. Over 1,000 potential neuroprotective therapeutics have been evaluated in preclinical models. It is important to use robust evidence synthesis methods to appropriately assess which therapies should be translated to the clinical setting for evaluation in human studies. This protocol details planned methods to conduct a systematic review to identify and appraise eligible studies and to use a network meta-analysis to synthesize available evidence to answer the following questions: in preclinical in vivo models of focal ischemic stroke, what are the relative benefits of competing therapies tested in combination with the gold standard treatment alteplase in (i) reducing cerebral infarction size, and (ii) improving neurobehavioural outcomes? Methods: We will search Ovid Medline and Embase for articles on the effects of combination therapies with alteplase. Controlled comparison studies of preclinical in vivo models of experimentally induced focal ischemia testing the efficacy of therapies with alteplase versus alteplase alone will be identified. Outcomes to be extracted include infarct size (primary outcome) and neurobehavioural measures. Risk of bias and construct validity will be assessed using tools appropriate for preclinical studies. Here we describe steps undertaken to perform preclinical network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. This will be a novel use of this evidence synthesis approach in stroke medicine to assess pre-clinical therapeutics. Combining all evidence to simultaneously compare mutliple therapuetics tested preclinically may provide a rationale for the clinical translation of therapeutics for patients with ischemic stroke.  Dissemination: Review findings will be submitted to a peer-reviewed journal and presented at relevant scientific meetings to promote knowledge transfer. Registration: PROSPERO number to be submitted following peer review.

scholarly journals Clinical Effectiveness and Cost-Effectiveness of Oral-Health Promotion in Dental Caries Prevention among Children: Systematic Review and Meta-Analysis

2019 ◽  
Vol 16 (15) ◽  
pp. 2668 ◽  
Author(s):  
Nadine Fraihat ◽  
Saba Madae’en ◽  
Zsuzsa Bencze ◽  
Adrienn Herczeg ◽  
Orsolya Varga
Keyword(s):  
Health Promotion ◽  
Cost Effectiveness ◽  
Oral Health ◽  
Financial Burden ◽  
Meta Analysis ◽  
Age Groups ◽  
Clinical Effectiveness ◽  
Oral Health Promotion ◽  
Health Institutions ◽  
Reduction Effect

The objective of this study was to evaluate the clinical effectiveness and cost-effectiveness of oral-health promotion programs (OHPPs) aiming to improve children’s knowledge of favorable oral health behavior to lower decayed/-missing/-filled teeth (DMFT) while reducing the financial cost on health institutions. An electronic search was performed in seven databases. Studies were restricted to human interventions published in English. The search study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and the risk of bias was assessed based on the Drummonds Checklist. A total of 1072 references were found. Among these, 19 full texts were included. Most studies had a strong quality. The overall pooled impact of OHPPs estimates children suffering from DMFT/S to have 81% lower odds of participating in OHPP (95% CI 61–90%, I2: 98.3%, p = 0). Furthermore, the program was shown to be effective at lowering the cost in 97 out of 100 OHPPs (95% CI 89–99%, I2: 99%, p = 0). Three subgroups analyses (age groups, study countries, studies of the last five years) were performed to evaluate the influence modification on the pooled effect. A comprehensive analysis of the OHPPs confirmed a reduction effect on child DMFT, hence, lowering the financial burden of dental-care treatment on health institutions.

scholarly journals Challenges in synthesising cost-effectiveness estimates

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Gemma E. Shields ◽  
Jamie Elvidge
Keyword(s):  
Cost Effectiveness ◽  
Systematic Reviews ◽  
Meta Analysis ◽  
Cost Effective ◽  
Evidence Base ◽  
Decision Makers ◽  
Economic Evaluations ◽  
Quality Adjusted Life Years ◽  
Life Years ◽  
Study Designs

AbstractEconomic evaluations help decision-makers faced with tough decisions on how to allocate resources. Systematic reviews of economic evaluations are useful as they allow readers to assess whether interventions have been demonstrated to be cost effective, the uncertainty in the evidence base, and key limitations or gaps in the evidence base. The synthesis of systematic reviews of economic evaluations commonly takes a narrative approach whereas a meta-analysis is common step for reviews of clinical evidence (e.g. effectiveness or adverse event outcomes). As they are common objectives in other reviews, readers may query why a synthesis has not been attempted for economic outcomes. However, a meta-analysis of incremental cost-effectiveness ratios, costs, or health benefits (including quality-adjusted life years) is fraught with issues largely due to heterogeneity across study designs and methods and further practical challenges. Therefore, meta-analysis is rarely feasible or robust. This commentary outlines these issues, supported by examples from the literature, to support researchers and reviewers considering systematic review of economic evidence.

scholarly journals Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation

2018 ◽  
Vol 22 (69) ◽  
pp. 1-276 ◽  
Author(s):  
Tristan Snowsill ◽  
Huiqin Yang ◽  
Ed Griffin ◽  
Linda Long ◽  
Jo Varley-Campbell ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cost Effectiveness ◽  
Usual Care ◽  
Cancer Mortality ◽  
Meta Analysis ◽  
Lung Cancer Screening ◽  
Lung Cancer Mortality ◽  
Clinical Effectiveness ◽  
Cost Effective ◽  
Cochrane Library

BackgroundDiagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early.ObjectivesTo estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations.Data sourcesBibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library.MethodsClinical effectiveness – a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness – an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm.ResultsClinical effectiveness – 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with ≤ 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost-effectiveness – screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60–75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in only a minority of analyses.LimitationsClinical effectiveness – the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness – a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included.ConclusionsLDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits.Future workClinical effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs [particularly the NEderlands Leuvens Longkanker Screenings ONderzoek (NELSON) screening trial].Study registrationThis study is registered as PROSPERO CRD42016048530.FundingThe National Institute for Health Research Health Technology Assessment programme.

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