Potential impact on cost-effectiveness estimates of using immature survival data: a case study based on transcatheter edge-to-edge repair (TEER) used for patients with severe mitral regurgitation at high surgical risk.

OBJECTIVE: To review the survival modelling used in cost-effectiveness studies evaluating an interventional procedure and to discuss implications for decision-makers. DESIGN: A case study of three economic evaluations that each used immature data from the EVEREST II High Surgical Risk (HSR) Study of transcatheter edge-to-edge repair (TEER) for patients with severe mitral regurgitation (MR) who were at high risk of surgery. SETTING: Estimation of patient survival in cost-effectiveness studies. PARTICIPANTS: The EVEREST II HSR Study included 78 patients who had TEER of the mitral valve using the MitraClip device and a retrospectively identified control group of 36 patients who received medical management and were followed up for 12 months. Observed survival (TEER arm only) was updated at 5 years. RESULTS: Two studies used 12-month observed mortality from EVEREST II HSR to model survival over lifetime horizons. Observed and modelled survival were associated with considerable uncertainty due to short follow-up and small numbers of participants. Modelling control patients' survival required an approximate 10-fold extrapolation based on 12-month observation of only 38 patients. Observed 5-year survival in the TEER group differed from that less mature follow-up suggesting that survival modelling based on shorter follow-up was unsatisfactory. No public domain data for the control group are available beyond 12-month follow-up so meaningful estimates using mature data for both arms are currently not possible. A third study developed survival models using incompletely reported transitions between MR grades in EVEREST II HSR and mortality rates observed for different MR grades derived from a study in an unrelated population. CONCLUSIONS: Modelling survival in such small samples followed up for only 12 months is associated with great uncertainty, and cost-effectiveness results based on these analyses should be viewed as premature and used cautiously in reimbursement decisions.

Impact of updated trial data on the cost-effectiveness of percutaneous mitral repair.

When updated clinical trial data becomes available reassessing the cost-effectiveness of technologies may modify estimates and influence decision-making. We investigated the impact of updated trial outcomes on the cost-effectiveness of percutaneous mitral repair (PR) for secondary mitral regurgitation. We updated our previous three-state time-varying Markov model to assess the cost-effectiveness of PR + guideline directed medical treatment (GDMT) versus GDMT alone. Key clinical inputs (overall survival (OS) and heart failure hospitalisations (HFH)) were obtained using the 3-year trial findings from the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy) RCT. We calculated incremental cost-effectiveness ratios (ICER) and report how these differ between analyses based on early (2-year) and updated (3-year) evidence. Updated trial data showed an increase in mortality in the intervention arm between two and three years follow-up that was not seen in the control arm. Deterministic and multivariate cost-effectiveness modelling yielded incremental cost effectiveness ratios ICERs of €38,123 and €31,227 /QALY. Compared to our 2-year based estimate (€21,918 / QALY) these results imply an approximate 1.5-fold increase in ICER. The availability of updated survival analyses from the COAPT pivotal trial suggests previous estimates based on 2-year trial findings were over optimistic for the intervention.

Is the assumption of waning of treatment effect applied consistently across NICE technology appraisals? A case-study focusing on disease-modifying therapies for treatment of multiple sclerosis.

OBJECTIVES: Whether the effects of therapies may wane over time is a matter of debate, especially when considering their long-term cost-effectiveness. Here, we examined how the assumption of the waning of treatment effect was applied across the National Institute for Health and Care Excellence (NICE) appraisals for disease-modifying therapies (DMTs) used in multiple sclerosis. METHODS: We undertook a document analysis following a search of the NICE website. The inclusion criteria of the study were as follows: all publicly available documents related to completed appraisals for DMTs (period: January 2000 to July 2021). The exclusion criteria of the study were as follows: all documents that did not meet the inclusion criteria, especially pertaining to drugs used in other disease areas. We extracted information about the waning of treatment effect assumption as considered by companies, assessment groups, and appraisal committees, and we analyzed trends over time. RESULTS: We reviewed fifteen appraisals that reported guidance on sixteen DMTs. Irrespective of the drugs' mechanism of action or their pharmaceutical nature, there was substantial variation in the modalities when the assumption of waning was implemented. We noted the recent preference to use all-cause discontinuation as a proxy. This heterogeneity did not appear to affect acceptance of the DMTs (all but one were recommended for use across the National Health System (NHS)). CONCLUSIONS: Modeling the long-term effect of therapies is challenging, especially given the limited follow-up duration of related trials. This generates recurrent debates on the presence of waning of treatment efficacy and heterogeneity across appraisals. More refined recommendations obtained by consensus among stakeholders could help to achieve greater consistency in decision making.

Cost-effectiveness of testing for latent tuberculosis infection in people with HIV.

OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of screening strategies for predicting LTBI that progresses to active tuberculosis (TB) in people with HIV. DESIGN: We developed a decision-analytical model that constituted a decision tree covering diagnosis of LTBI and a Markov model covering progression to active TB. The model represents the lifetime experience following testing for LTBI, and discounting costs, and benefits at 3.5% per annum in line with UK standards. We undertook probabilistic and one-way sensitivity analyses. SETTING: UK National Health Service and Personal Social Service perspective in a primary care setting. PARTICIPANTS: Hypothetical cohort of adults recently diagnosed with HIV. INTERVENTIONS: Interferon-gamma release assays and tuberculin skin test. MAIN OUTCOME MEASURE: Cost per quality-adjusted life year (QALY). RESULTS: All strategies except T-SPOT.TB were cost-effective at identifying LTBI, with the QFT-GIT-negative followed by TST5mm strategy being the most costly and effective. Results indicated that there was little preference between strategies at a willingness-to-pay threshold of £20 000. At thresholds above £40 000 per QALY, there was a clear preference for the QFT-GIT-negative followed by TST5mm, with a probability of 0.41 of being cost-effective. Results showed that specificity for QFT-GIT and TST5mm were the main drivers of the economic model. CONCLUSION: Screening for LTBI has important public health and clinical benefits. Most of the strategies are cost-effective. These results should be interpreted with caution because of the paucity of studies included in the meta-analysis of test accuracy studies. Additional high-quality primary studies are needed to have a definitive answer about, which strategy is the most effective.

Testing strategies for Lynch syndrome in people with endometrial cancer: systematic reviews and economic evaluation.

BACKGROUND: Lynch syndrome is an inherited genetic condition that is associated with an increased risk of certain cancers. The National Institute for Health and Care Excellence has recommended that people with colorectal cancer are tested for Lynch syndrome. Routine testing for Lynch syndrome among people with endometrial cancer is not currently conducted. OBJECTIVES: To systematically review the evidence on the test accuracy of immunohistochemistry- and microsatellite instability-based strategies to detect Lynch syndrome among people who have endometrial cancer, and the clinical effectiveness and the cost-effectiveness of testing for Lynch syndrome among people who have been diagnosed with endometrial cancer. DATA SOURCES: Searches were conducted in the following databases, from inception to August 2019 - MEDLINE ALL, EMBASE (both via Ovid), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (both via Wiley Online Library), Database of Abstracts of Reviews of Effects, Health Technology Assessment Database (both via the Centre for Reviews and Dissemination), Science Citation Index, Conference Proceedings Citation Index - Science (both via Web of Science), PROSPERO international prospective register of systematic reviews (via the Centre for Reviews and Dissemination), NHS Economic Evaluation Database, Cost-Effectiveness Analysis Registry, EconPapers (Research Papers in Economics) and School of Health and Related Research Health Utilities Database. The references of included studies and relevant systematic reviews were also checked and experts on the team were consulted. REVIEW METHODS: Eligible studies included people with endometrial cancer who were tested for Lynch syndrome using immunohistochemistry- and/or microsatellite instability-based testing [with or without mutL homologue 1 (MLH1) promoter hypermethylation testing], with Lynch syndrome diagnosis being established though germline testing of normal (non-tumour) tissue for constitutional mutations in mismatch repair. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, the Consolidated Health Economic Reporting Standards and the Philips' checklist. Two reviewers independently conducted each stage of the review. A meta-analysis of test accuracy was not possible because of the number and heterogeneity of studies. A narrative summary of test accuracy results was provided, reporting test accuracy estimates and presenting forest plots. The economic model constituted a decision tree followed by Markov models for the impact of colorectal and endometrial surveillance, and aspirin prophylaxis with a lifetime time horizon. RESULTS: The clinical effectiveness search identified 3308 studies; 38 studies of test accuracy were included. (No studies of clinical effectiveness of endometrial cancer surveillance met the inclusion criteria.) Four test accuracy studies compared microsatellite instability with immunohistochemistry. No clear difference in accuracy between immunohistochemistry and microsatellite instability was observed. There was some evidence that specificity of immunohistochemistry could be improved with the addition of methylation testing. There was high concordance between immunohistochemistry and microsatellite instability. The economic model indicated that all testing strategies, compared with no testing, were cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Immunohistochemistry with MLH1 promoter hypermethylation testing was the most cost-effective strategy, with an incremental cost-effectiveness ratio of £9420 per quality-adjusted life-year. The second most cost-effective strategy was immunohistochemistry testing alone, but incremental analysis produced an incremental cost-effectiveness ratio exceeding £130,000. Results were robust across all scenario analyses. Incremental cost-effectiveness ratios ranged from £5690 to £20,740; only removing the benefits of colorectal cancer surveillance produced an incremental cost-effectiveness ratio in excess of the £20,000 willingness-to-pay threshold. A sensitivity analysis identified the main cost drivers of the incremental cost-effectiveness ratio as percentage of relatives accepting counselling and prevalence of Lynch syndrome in the population. A probabilistic sensitivity analysis showed, at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year, a 0.93 probability that immunohistochemistry with MLH1 promoter hypermethylation testing is cost-effective, compared with no testing. LIMITATIONS: The systematic review excluded grey literature, studies written in non-English languages and studies for which the reference standard could not be established. Studies were included when Lynch syndrome was diagnosed by genetic confirmation of constitutional variants in the four mismatch repair genes (i.e. MLH1, mutS homologue 2, mutS homologue 6 and postmeiotic segregation increased 2). Variants of uncertain significance were reported as per the studies. There were limitations in the economic model around uncertainty in the model parameters and a lack of modelling of the potential harms of gynaecological surveillance and specific pathway modelling of genetic testing for somatic mismatch repair mutations. CONCLUSION: The economic model suggests that testing women with endometrial cancer for Lynch syndrome is cost-effective, but that results should be treated with caution because of uncertain model inputs. FUTURE WORK: Randomised controlled trials could provide evidence on the effect of earlier intervention on outcomes and the balance of benefits and harms of gynaecological cancer surveillance. Follow-up of negative cases through disease registers could be used to determine false negative cases. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019147185. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 42. See the NIHR Journals Library website for further project information.

Lynch syndrome is an inherited condition that is caused by a problem in the genes. People who have Lynch syndrome have a higher risk of some types of cancer (such as bowel and womb cancers) than people who do not have it. Identifying Lynch syndrome could stop cancers developing, lead to earlier treatment for cancers and help to find other family members who might have it. Currently, the National Institute for Health and Care Excellence guidance recommends testing for Lynch syndrome in people who have bowel cancer. Our aim was to investigate whether or not we should test for Lynch syndrome in women with womb cancer, and their relatives. We investigated two main tests: immunohistochemistry and microsatellite instability. There was no clear evidence that one of these tests is better than the other. There is some evidence that both tests are reasonably accurate. There was no good-quality evidence about whether or not treating women with Lynch syndrome with extra cancer screening and aspirin improves their outcomes. We used the best evidence available in our economic model, but it was at high risk of bias. The economic model suggested that testing women with endometrial cancer for Lynch syndrome is cost-effective. The best test in the model was immunohistochemistry followed by methylation testing. We are unsure of these results because of the low quality of evidence available.

Cost-effectiveness of community health systems strengthening: quality improvement interventions at community level to realise maternal and child health gains in Kenya.

INTRODUCTION: Improvements in maternal and infant health outcomes are policy priorities in Kenya. Achieving these outcomes depends on early identification of pregnancy and quality of primary healthcare. Quality improvement interventions have been shown to contribute to increases in identification, referral and follow-up of pregnant women by community health workers. In this study, we evaluate the cost-effectiveness of using quality improvement at community level to reduce maternal and infant mortality in Kenya. METHODS: We estimated the cost-effectiveness of quality improvement compared with standard of care treatment for antenatal and delivering mothers using a decision tree model and taking a health system perspective. We used both process (antenatal initiation in first trimester and skilled delivery) and health outcomes (maternal and infant deaths averted, as well as disability-adjusted life years (DALYs)) as our effectiveness measures and actual implementation costs, discounting costs only. We conducted deterministic and probabilistic sensitivity analyses. RESULTS: We found that the community quality improvement intervention was more cost-effective compared with standard community healthcare, with incremental cost per DALY averted of $249 under the deterministic analysis and 76% likelihood of cost-effectiveness under the probabilistic sensitivity analysis using a standard threshold. The deterministic estimate of incremental cost per additional skilled delivery was US$10, per additional early antenatal care presentation US$155, per maternal death averted US$5654 and per infant death averted US$37 536 (2017 dollars). CONCLUSIONS: This analysis shows that the community quality improvement intervention was cost-effective compared with the standard community healthcare in Kenya due to improvements in antenatal care uptake and skilled delivery. It is likely that quality improvement interventions are a good investment and may also yield benefits in other health areas.

A comparison of published time invariant Markov models with Partitioned Survival models for cost effectiveness estimation; three case studies of treatments for glioblastoma multiforme.

BACKGROUND: Cost-effectiveness analyses of treatments for glioblastoma multiforme (GBM) have mostly used state transition Markov models with time invariant transition probabilities (TIMMs). In three case studies of GBM treatments, we compared Partitioned Survival model (PSM) results with published outputs from TIMMs. METHODS: PSMs used the same RCT data sources, utility values, time horizons, cycle times and annual discounting used in published TIMMs. Reported overall survival and progression-free survival plots were digitised and fitted with a range of parametric models. Economic model outputs were generated in the same form as reported for the TIMMs. PSM output uncertainty was explored in univariate and in multivariate sensitivity analyses. RESULTS: PSMs generated incremental cost-effectiveness ratios that were different to the published TIMMs. The magnitude of difference was substantial in two cases. The PSMs were reasonably robust and in sensitivity analyses were sensitive to variations in the same model inputs as were the TIMMs. When compared to the RCT data, the TIMMs tended to generate underestimates of the likely overall survival gain. TIMM estimates for depletion of individuals from the stable disease state and for accumulation in the dead state had relatively poor resemblance to the source RCT data. CONCLUSION: TIMMs delivered different cost-effectiveness estimates to PSMs; in two cases, TIMMs produced substantially lower ICER values than PSMs. Model output differences appear attributable to less realistic cost-and-benefit estimates generated in TIMMs due to rapid depletion from the stable disease state and/or accumulation in the dead state.

Conflicting findings between the Mitra-Fr and the Coapt trials: Implications regarding the cost-effectiveness of percutaneous repair for heart failure patients with severe secondary mitral regurgitation.

PURPOSE: Two randomized controlled trials (RCTs), Mitra-Fr and Coapt, evaluating the benefit of percutaneous repair (PR) for heart failure (HF) patients with severe mitral regurgitation, have led to conflicting results. We aimed to evaluate the impact of these trial results on the cost-effectiveness of PR using effectiveness inputs from the two RCTs. METHODS: We developed a time varying Markov type model with three mutually exclusive health states: alive without HF hospitalisation, alive with HF hospitalisation, and dead. Clinically plausible extrapolations beyond observed data were obtained by developing parametric modelling for overall survival and HF hospitalisations using published data from each trial. We adopted the perspective of the French Health System and used a 30-year time horizon. Results were expressed as € / quality-adjusted life year (QALY) gained using utility inputs from literature. FINDINGS: Results are presented using treatment efficacy measures from Mitra-F and Coapt trials respectively. With the Mitra-Fr data, after annual discounting, the base case model generated an incremental 0.00387 QALY at a cost of €25,010, yielding an incremental cost effectiveness ratio (ICER) of €6,467,032 / QALY. The model was sensitive to changes made to model inputs. There was no potential of PR being cost-effective. With the Coapt data, the model generated 1.19 QALY gain at a cost of €26,130 yielding an ICER of €21,918 / QALY and at a threshold of >€50,000/QALY PR had a probability of 1 of being cost-effective. IMPLICATIONS: Cost effectiveness results were conflicting; reconciling differences between trials is a priority and could promote optimal cost effectiveness analyses and resource allocation.

Will the US$5 million onasemnogene abeparvosec treatment for spinal muscular atrophy represent 'value for money' for the NHS? A rapid inquiry into suggestions that it may be cost-effective.

OBJECTIVES: Nusinersen (Spinraza®, Biogen) and onasemnogene abeparvosec (Zolgensma®, Novartis) are novel gene-based therapies for the orphan disease Spinal Muscular Atrophy. Onasemnogene abeparvosec has been allocated an acquisition cost of up to US$5 million per patient. We undertook a rapid inquiry to evaluate if onasemnogene abeparvosec is likely to be cost-effective for the UK NHS. METHODS: We used publicly available cost-effectiveness data and recommended methodology to perform cost-utility evaluation of onasemnogene abeparvosec versus best supportive care and nusinersen. RESULTS: Our evaluations highlight wide variations in cost and benefit estimates of nusinersen and indicate that onasemnogene abeparvosec is unlikely to represent value for money according to current standards of reimbursement. Results are discussed in the context of reimbursement decisions for orphan diseases. CONCLUSION: Commonly implemented commercial confidentiality practices combined with uncertain data obscure scrutiny and justification of past and present reimbursement decisions for orphan drugs. Future cutting edge expensive therapies will be numerous, they will entail very substantial economic strains. We conclude that there is an urgent and increasing need for the development of improved procedures that can lead to equitable, consistent, and transparent decision-making.

Ocrelizumab for Treating Patients with Primary Progressive Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Ocrelizumab is indicated for relapsing remitting and primary progressive multiple sclerosis (RRMS and PPMS, respectively). In an appraisal undertaken by the National Institute for Health and Care Excellence (NICE), the company Roche presented the evidence for ocrelizumab used in patients with PPMS, which came from one single randomised controlled trial (RCT) comparing ocrelizumab versus placebo. Based on results from this trial, the licensed indication was restricted to patients with early PPMS in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity. Overall, the Evidence Review Group (ERG) found that the RCT had a low risk of bias. In the post-hoc defined magnetic resonance imaging (MRI) active subgroup, matching the label indication, the risk of confirmed disability progression sustained for 12 weeks (CDP-12) was significantly delayed in the ocrelizumab group compared to placebo. However, considering the same risk with progression sustained for 24 weeks (CDP-24), which was deemed the most clinically relevant, the benefit from ocrelizumab did not reach statistical significance. In the same MRI active subgroup, benefits from ocrelizumab on functional outcomes and on health-related quality of life were not clearly demonstrated. A de novo Markov model was used to estimate the cost-effectiveness of ocrelizumab versus best supportive care (BSC) for treating patients with PPMS. Health states were defined by the Expanded Disability Status Scale (EDSS), ranging from 0 to 9. Disability progression was based on the MSBase natural history cohort that exhibited disease progression in the absence of disease-modifying therapy. Treatment with ocrelizumab delayed disability progression, with evidence of its clinical effectiveness obtained from the RCT. The economic analysis was undertaken from the National Health Service and Personal Social Services perspective, and the outcomes were reported in terms of life years gained and quality-adjusted life years (QALYs), with the overall results reported in terms of an incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained over a 50-year time horizon. Both costs and effects were discounted at 3.5% per annum. The company undertook deterministic one-way sensitivity analyses and scenario analyses, including probabilistic sensitivity analysis (PSA). The ERG raised several concerns, which were discussed at the appraisal committee meetings, resulting in the committee's preferences being applied and a revised economic analysis from the company. Under an approved patient access scheme with appraisal committee preferences applied, analyses yielded an ICER of approximately £78,300 per QALY. Sensitivity analysis results indicated that the treatment effect on CDP-12 had the greatest impact. Results for the PSA showed that at a willingness-to-pay threshold of £30,000 per QALY gained, ocrelizumab versus BSC had a zero probability of being cost-effective. Following new analyses submitted by the company, with a revised confidential patient access scheme, NICE recommended ocrelizumab in the treatment of early PPMS in adults with imaging features characteristic of inflammatory activity.

A Systematic Review of Economic Evaluations Assessing the Cost-Effectiveness of Licensed Drugs Used for Previously Treated Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) Negative Advanced/Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers. There are many published studies of cost-effectiveness analyses of licensed treatments, but no study has compared these studies or their approaches simultaneously. OBJECTIVE: To investigate the methodology used in published economic analyses of licensed interventions for previously treated advanced/metastatic NSCLC in patients without anaplastic lymphoma kinase or epidermal growth factor receptor expression. METHODS: A systematic review was performed, including a systematic search of key databases (e.g. MEDLINE, EMBASE, Web of Knowledge, Cost-effectiveness Registry) limited to the period from 01 January 2001 to 26 July 2019. Two reviewers independently screened, extracted data and quality appraised identified studies. The reporting quality of the studies was assessed by using the Consolidated Health Economic Evaluation Reporting Standards and the Philips' checklists. RESULTS: Thirty-one published records met the inclusion criteria, which corresponded to 30 individual cost-effectiveness analyses. Analytical approaches included partitioned survival models (n = 14), state-transition models (n = 7) and retrospective analyses of new or published data (n = 8). Model structure was generally consistent, with pre-progression, post-progression and death health states used most commonly. Other characteristics varied more widely, including the perspective of analysis, discounting, time horizon, usually to align with the country that the analysis was set in. CONCLUSIONS: There are a wide range of approaches in the modelling of treatments for advanced NSCLC; however, the model structures are consistent. There is variation in the exploration of sensitivity analyses, with considerable uncertainty remaining in most evaluations. Improved reporting is necessary to ensure transparency in future analyses.

Cost-effectiveness of tumor-treating fields added to maintenance temozolomide in patients with glioblastoma: an updated evaluation using a partitioned survival model.

PURPOSE: A first cost-effectiveness analysis has raised a strong concern regarding the cost of tumor treatment fields (TTF) added to maintenance temozolomide for patients with glioblastoma. This evaluation was based on effectiveness outcomes from an interim analysis of the pivotal trial, moreover it used a "standard" Markov model. Our objective was to update the cost-effectiveness evaluation using the more flexible potential of the "partitioned survival" model design and using the latest effectiveness data. METHODS: We developed the model with three mutually exclusive health states: stable disease, progressive disease, and dead. Good fit parametric models were developed for overall survival and progression free survival and these generated clinically plausible extrapolations beyond the observed data. We adopted the perspective of the French national health insurance and used a 20-year time horizon. Results were expressed as cost/life-years (LY) gained (LYG). RESULTS: The base case model generated incremental benefit of 0.604 LY at a cost of €453,848 which, after 4% annual discounting of benefits and costs, yielded an incremental cost effectiveness ratio (ICER) of €510,273/LYG. Using sensitivity analyses and bootstrapping methods results were found to be relatively robust and were only sensitive to TTF device costs and the modelling of overall survival. To achieve an ICER below €100,000/LYG would require a reduction in TTF device cost of approximately 85%. CONCLUSIONS: Using a different type of model and updated survival outcomes, our results show TTF remains an intervention that is not cost-effective, which greatly restrains its diffusion to potentially eligible patients.

How Do Pharmaceutical Companies Model Survival of Cancer Patients? A Review of NICE Single Technology Appraisals in 2017.

OBJECTIVES: Before an intervention is publicly funded within the United Kingdom, the cost-effectiveness is assessed by the National Institute of Health and Care Excellence (NICE). The efficacy of an intervention across the patients' lifetime is often influential of the cost-effectiveness analyses, but is associated with large uncertainties. We reviewed committee documents containing company submissions and evidence review group (ERG) reports to establish the methods used when extrapolating survival data, whether these adhered to NICE Technical Support Document (TSD) 14, and how uncertainty was addressed. METHODS: A systematic search was completed on the NHS Evidence Search webpage limited to single technology appraisals of cancer interventions published in 2017, with information obtained from the NICE Web site. RESULTS: Twenty-eight appraisals were identified, covering twenty-two interventions across eighteen diseases. Every economic model used parametric curves to model survival. All submissions used goodness-of-fit statistics and plausibility of extrapolations when selecting a parametric curve. Twenty-five submissions considered alternate parametric curves in scenario analyses. Six submissions reported including the parameters of the survival curves in the probabilistic sensitivity analysis. ERGs agreed with the company's choice of parametric curve in nine appraisals, and agreed with all major survival-related assumptions in two appraisals. CONCLUSIONS: TSD 14 on survival extrapolation was followed in all appraisals. Despite this, the choice of parametric curve remains subjective. Recent developments in Bayesian approaches to extrapolation are not implemented. More precise guidance on the selection of curves and modelling of uncertainty may reduce subjectivity, accelerating the appraisal process.

Pembrolizumab for Previously Treated Advanced or Metastatic Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pembrolizumab is an intravenously administered monoclonal antibody licensed for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. This summary presents the perspective of Warwick Evidence, the Evidence Review Group (ERG) appointed by the National Institute of Health and Care Excellence (NICE) for the single technology appraisal of pembrolizumab for this indication. Pembrolizumab is manufactured by Merck, Sharp and Dohme (MSD). The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician's choice of docetaxel, paclitaxel or vinflunine as a second-line treatment. No indirect treatment comparison was performed. The clinical effectiveness was assessed using hazard ratios for overall survival (OS) and progression-free survival (PFS) of the intention-to-treat (ITT) population, together with the subpopulations positive for programmed cell death 1 ligand 1 (PD-L1) expression (combined positive score [CPS] ≥ 1%) and strongly positive for PD-L1 expression (CPS ≥ 10%). In the ITT population, OS improved with pembrolizumab (HR 0.73, 95% CI 0.59-0.91) while PFS outcomes showed no difference (HR 0.98, 95% CI 0.81-1.19). Pembrolizumab demonstrated a better safety profile than its combined comparators, with fewer patients experiencing adverse events (60.9 vs 90.2%). Similar results were observed in populations expressing PD-L1. MSD estimated the cost effectiveness of pembrolizumab using a de novo partitioned survival model. The model had three health states: pre-progression, post-progression and death, where OS and PFS estimates excluded patients who received vinflunine. The largest uncertainty was over the selection of the parametric models used to extrapolate OS and PFS and the time point for when to begin their extrapolation. The company preferences for extrapolation were not well supported and the ERG disagreed with their selection for OS. Utility values were also contentious, with the company preferring to use pooled time-to-death-based utilities pooled across treatment arms, whilst the ERG preferred pooled progression-based utilities. The company preferred to use data from patients receiving vinflunine when calculating the utility values, which the ERG disagreed with as this is not recommended treatment within the UK. The company assumed a lifetime treatment effect for their model; however, the lack of evidence made it difficult to confidently provide a realistic estimate of treatment effect duration. Various durations were explored (3, 5 and 10 years). The first appraisal committee meeting concluded that pembrolizumab was not cost effective, largely due to uncertainty in the OS and PFS extrapolations. The company's second submission included an additional 4 months follow-up to survival data. The company in this new submission maintained their original assumptions in their base-case analysis, changing only the choice of parametric curve for PFS. This change resulted in the OS and PFS curves intersecting at 6 years in the pembrolizumab arm, at which point PFS identically followed OS. This resulted in no patients in the post-progression health state beyond this time point, and therefore, the majority of pembrolizumab's benefit came from pre-progression survival. Given the unclear PFS benefit, the ERG found this implausible and maintained their original base-case model assumptions. Considerable uncertainty remained over the specification of the extrapolations and the duration of treatment effect. Based on a new-value proposition submitted by the company, the appraisal committee concluded that pembrolizumab had plausible potential to be cost effective. Pembrolizumab was referred for funding through the Cancer Drugs Fund, so that further data could be collected with the aim of diminishing the outstanding uncertainties pertaining to its clinical effectiveness.

Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages.

BACKGROUND: We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-ß) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs' recommended dosages. METHODS: We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-ß and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis. RESULTS: We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs. CONCLUSIONS: Meta-analyses confirmed that IFN-ß and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear 'winner' across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness. REVIEW REGISTRATION: PROSPERO CRD42016043278 .

Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation.

BACKGROUND: At the time of publication of the most recent National Institute for Health and Care Excellence (NICE) guidance [technology appraisal (TA) 32] in 2002 on beta-interferon (IFN-ß) and glatiramer acetate (GA) for multiple sclerosis, there was insufficient evidence of their clinical effectiveness and cost-effectiveness. OBJECTIVES: To undertake (1) systematic reviews of the clinical effectiveness and cost-effectiveness of IFN-ß and GA in relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome (CIS) compared with best supportive care (BSC) and each other, investigating annualised relapse rate (ARR) and time to disability progression confirmed at 3 months and 6 months and (2) cost-effectiveness assessments of disease-modifying therapies (DMTs) for CIS and RRMS compared with BSC and each other. REVIEW METHODS: Searches were undertaken in January and February 2016 in databases including The Cochrane Library, MEDLINE and the Science Citation Index. We limited some database searches to specific start dates based on previous, relevant systematic reviews. Two reviewers screened titles and abstracts with recourse to a third when needed. The Cochrane tool and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and Philips checklists were used for appraisal. Narrative synthesis and, when possible, random-effects meta-analysis and network meta-analysis (NMA) were performed. Cost-effectiveness analysis used published literature, findings from the Department of Health's risk-sharing scheme (RSS) and expert opinion. A de novo economic model was built for CIS. The base case used updated RSS data, a NHS and Personal Social Services perspective, a 50-year time horizon, 2014/15 prices and a discount rate of 3.5%. Outcomes are reported as incremental cost-effectiveness ratios (ICERs). We undertook probabilistic sensitivity analysis. RESULTS: In total, 6420 publications were identified, of which 63 relating to 35 randomised controlled trials (RCTs) were included. In total, 86% had a high risk of bias. There was very little difference between drugs in reducing moderate or severe relapse rates in RRMS. All were beneficial compared with BSC, giving a pooled rate ratio of 0.65 [95% confidence interval (CI) 0.56 to 0.76] for ARR and a hazard ratio of 0.70 (95% CI, 0.55 to 0.87) for time to disability progression confirmed at 3 months. NMA suggested that 20 mg of GA given subcutaneously had the highest probability of being the best at reducing ARR. Three separate cost-effectiveness searches identified > 2500 publications, with 26 included studies informing the narrative synthesis and model inputs. In the base case using a modified RSS the mean incremental cost was £31,900 for pooled DMTs compared with BSC and the mean incremental quality-adjusted life-years (QALYs) were 0.943, giving an ICER of £33,800 per QALY gained for people with RRMS. In probabilistic sensitivity analysis the ICER was £34,000 per QALY gained. In sensitivity analysis, using the assessment group inputs gave an ICER of £12,800 per QALY gained for pooled DMTs compared with BSC. Pegylated IFN-ß-1 (125 µg) was the most cost-effective option of the individual DMTs compared with BSC (ICER £7000 per QALY gained); GA (20 mg) was the most cost-effective treatment for CIS (ICER £16,500 per QALY gained). LIMITATIONS: Although we built a de novo model for CIS that incorporated evidence from our systematic review of clinical effectiveness, our findings relied on a population diagnosed with CIS before implementation of the revised 2010 McDonald criteria. CONCLUSIONS: DMTs were clinically effective for RRMS and CIS but cost-effective only for CIS. Both RCT evidence and RSS data are at high risk of bias. Research priorities include comparative studies with longer follow-up and systematic review and meta-synthesis of qualitative studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016043278. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Test accuracy of drug and antibody assays for predicting response to antitumour necrosis factor treatment in Crohn's disease: a systematic review and meta-analysis.

OBJECTIVE: To present meta-analytic test accuracy estimates of levels of antitumour necrosis factor (anti-TNF) and antibodies to anti-TNF to predict loss of response or lack of regaining response in patients with anti-TNF managed Crohn's disease. METHODS: MEDLINE, Embase, the Cochrane Library and Science Citation Index were searched from inception to October/November 2014 to identify studies which reported 2×2 table data of the association between levels of anti-TNF or its antibodies and clinical status. Hierarchical/bivariate meta-analysis was undertaken with the user-written 'metandi' package of Harbord and Whiting using Stata V.11 software, for infliximab, adalimumab,anti-infliximab and anti-adalimumab levels as predictors of loss of response. Prevalence of Crohn's disease in included studies was meta-analysed using a random effects model in MetaAnalyst software to calculate positive and negative predictive values. The search was updated in January 2017. RESULTS: 31 studies were included in the review. Studies were heterogeneous with respect to the type of test used, criteria for establishing response and loss of response, population examined and results. Meta-analytic summary point estimates for sensitivity and specificity were 65.7% and 80.6% for infliximab trough levels and 56% and 79% for antibodies to infliximab, respectively. Pooled results for adalimumab trough levels and antibodies to adalimumab were similar. Pooled positive and negative predictive values ranged between 70% and 80% implying that between 20% and 30% of both positive and negative test results may be incorrect in predicting loss of response. CONCLUSION: The available evidence suggests that these tests have modest predictive accuracy for clinical status; direct test accuracy comparisons in the same population are needed. More clinical trial evidence from test-treat studies is required before the clinical utility of the tests can be reliably evaluated.

Comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis.

BACKGROUND: Timely and accurate identification of people with latent tuberculosis infection (LTBI) is important for controlling Mycobacterium tuberculosis (TB). There is no gold standard for diagnosis of LTBI. Screening tests such as interferon gamma release assays (IGRAs) and tuberculin skin test (TST) provide indirect and imperfect information. This systematic review compared two types of IGRAs QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and T-SPOT.TB with TST for identification of LTBI by predicting progression to a diagnosis of active TB in three subgroups: children, immunocompromised people, and those recently arrived from countries with high TB burden. METHODS: Cohort studies were eligible for inclusion. We searched MEDLINE, EMBASE, the Cochrane Library and other databases from December 2009 to June 2015. One reviewer screened studies, extracted data, and assessed risk of bias with cross checking by a second reviewer. Strength of association between test results and incidence of TB was summarised using cumulative incidence ratios (CIRs with 95% CIs). Summary effect measures: the ratio of CIRs (R-CIR) with 95% CIs. R-CIRs, were pooled using a random-effects model. Heterogeneity was assessed using Chi-squared and I2 statistics. RESULTS: Seventeen studies, mostly of moderate or high risk of bias (five in children, 10 in immunocompromised people, and two in those recently arrived) were included. In children, while in two studies, there was no significant difference between QFT-GIT and TST (≥5 mm) (pooled R-CIR = 1.11, 95% CI: 0.71, 1.74), two other studies showed QFT-GIT to outperform TST (≥10 mm) in identifying LTBI. In immunocompromised people, IGRA (T-SPOT.TB) was not significant different from TST (≥10 mm) for identifying LTBI, (pooled R-CIR = 1.01, 95% CI: 0.65, 1.58). The forest plot of two studies in recently arrived people from countries with high TB burden demonstrated inconsistent findings (high heterogeneity; I2 = 92%). CONCLUSIONS: Prospective studies comparing IGRA testing against TST on the progression from LTBI to TB were sparse, and these results should be interpreted with caution due to uncertainty, risk of bias, and unexplained heterogeneity. Population-based studies with adequate sample size and follow-up are required to adequately compare the performance of IGRA with TST in people at high risk of TB.

Diabetic retinopathy and the use of laser photocoagulation: is it cost-effective to treat early?

BACKGROUND/AIMS: The aim of the study was to explore whether it would be cost-effective to apply panretinal photocoagulation (PRP) at the severe non-proliferative diabetic retinopathy (NPDR) (early treatment) stage, compared with waiting until high-risk proliferative diabetic retinopathy (HR-PDR) characteristics (deferred treatment) developed. METHODS: A Markov model with a 30-year time horizon was developed, in which patients presenting with moderate NPDR could progress through all stages of DR (severe NPDR>early PDR>HR-PDR>severe PDR) to severe vision loss and blindness (and to death). A National Health Service and personal social services perspective was adopted. Transition probabilities were mainly derived from the Early Treatment Diabetic Retinopathy Study. Health state utilities, costs and complications were based on information from the literature, supplemented by expert opinion. Costs and outcomes were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Administering PRP at the severe NPDR stage could be more effective and less costly than waiting until HR-PDR developed. Sensitivity analyses gave similar results, with early treatment continuing to dominate deferred treatment. The probabilistic sensitivity analysis suggests that at willingness-to-pay threshold of £20-£30 000 per quality-adjusted life year, the probability of early treatment being cost-effective is 60%. CONCLUSION: PRP administered at the severe NPDR stage is likely to be cost-effective compared with delaying photocoagulation until HR-PDR develops. However, given the limitations of the evidence, these results need to be interpreted with caution. A trial of early versus deferred laser therapy is needed to provide better data based on modern treatments.

Clinical effectiveness and cost-effectiveness of use of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits, TNF-α-Blocker ELISA kits and Promonitor® ELISA kits] versus standard care in patients with Crohn's disease: systematic reviews and economic modelling.

BACKGROUND AND OBJECTIVES: Systematic reviews and economic modelling of clinical effectiveness and cost-effectiveness of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [using LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits (Theradiag, Marne La Vallee, France, or Alpha Laboratories, Heriot, UK), TNF-α-Blocker ELISA kits (Immundiagnostik AG, Bensheim, Germany) and Promonitor® ELISA kits (Proteomika, Progenika Biopharma, Bizkaia, Spain)] versus standard care for Crohn's disease (CD). METHODS: Multiple electronic databases were searched from inception to December 2014 in order to identify primary studies and meta-analyses. POPULATION: Patients with moderate to severe active CD treated with infliximab (IFX) (Remicade®, Merck Sharp & Dohme Ltd, Kenilworth, NJ, USA) or adalimumab (ADA) (Humira®, AbbVie Inc., North Chicago, IL, USA). INTERVENTION: Monitoring of serum anti-TNF-α (IFX or ADA) and/or of anti-drug antibody levels using test assays with a test-treatment algorithm. COMPARATOR: Standard care. OUTCOMES: Any patient-related outcome, test agreement and cost-effectiveness estimates. The quality assessments used recognised checklists (Quality Assessment of Diagnostic Accuracy Studies-2, Cochrane, Philips and Consolidated Health Economic Evaluation Reporting Standards). Evidence was synthesised using narrative review and meta-analysis. A Markov model was built in TreeAge Pro 2013 (TreeAge Software, Inc., Williamstown, MA, USA). The model had a 4-week cycle and a 10-year time horizon, adopted a NHS and Personal Social Services perspective and used a linked evidence approach. Costs were adjusted to 2013/14 prices and discounted at 3.5%. RESULTS: We included 68 out of 2434 and 4 out of 2466 studies for the clinical effectiveness and cost-effectiveness reviews, respectively. Twenty-three studies comparing test methods were identified. Evidence on test concordance was sparse and contradictory, offering scant data for a linked evidence approach. Three studies [two randomised controlled trials (RCTs) and one retrospective observational study] investigated outcomes following implementation of a test algorithm. None used the specified commercial ELISA immunoassay test kits. Neither of the two RCTs demonstrated clinical benefit of a test-treatment regimen. A meta-analysis of 31 studies to estimate test accuracy for predicting clinical status indicated that 20-30% of test results are likely to be inaccurate. The four cost-effectiveness studies suggested that testing results in small cost reductions. In the economic analysis the base-case analysis showed that standard practice (no testing/therapeutic monitoring with the intervention tests) was more costly and more effective than testing for IFX. Sensitivity and scenario analyses gave similar results. The probabilistic sensitivity analysis indicated a 92% likelihood that the 'no-testing' strategy was cost-effective at a willingness to pay of £20,000 per quality-adjusted life-year. STRENGTHS AND LIMITATIONS: Rigorous systematic reviews were undertaken; however, the underlying evidence base was poor or lacking. There was uncertainty about a linked evidence approach and a lack of gold standard for assay comparison. The only comparative evidence available for economic evaluation was for assays other than the intervention assays. CONCLUSIONS: Our finding that testing is not cost-effective for IFX should be viewed cautiously in view of the limited evidence. Clinicians should be mindful of variation in performance of different assays and of the absence of standardised approaches to patient assessment and treatment algorithms. FUTURE WORK RECOMMENDATIONS: There is substantial variation in the underlying treatment pathways and uncertainty in the relative effectiveness of assay- and test-based treatment algorithms, which requires further investigation. There is very little research evidence on ADA or on drug monitoring in children with CD, and conclusions on cost-effectiveness could not be reached for these. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014015278. FUNDING: The National Institute for Health Research Health Technology Assessment programme.