Correction to: Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The title of the article should read.

Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancer: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ceritinib (Zykadia®, Novartis) to submit evidence on the clinical and cost effectiveness of the drug, as a first-line treatment for adults with anaplastic lymphoma kinase (ALK)-positive (+) advanced non-small-cell lung cancer (NSCLC), as part of the Institute's single technology appraisal (STA) process. The CRD (Centre for Reviews and Dissemination) and CHE (Centre for Health Economics) Technology Assessment Group at the University of York was commissioned to act as the Evidence Review Group (ERG). This paper describes the Company's submission (CS), the ERG review and NICE's subsequent decisions. The evidence submitted in support of ceritinib, as the first-line treatment in ALK+ advanced NSCLC, was a phase III, international, multicentre, open-label randomised controlled trial (RCT) comparing ceritinib with pemetrexed/cisplatin plus pemetrexed maintenance therapy (chemotherapy [CT] group). The results indicated that ceritinib prolonged progression-free survival (PFS) compared with CT. The only comparator considered in the CS was crizotinib. The evidence selected in support of crizotinib was PROFILE 1014, an open-label RCT of crizotinib, compared with pemetrexed/cisplatin CT (without maintenance therapy), in previously untreated advanced or metastatic ALK+ NSCLC. The design and population of PROFILE 1014 was similar to that of ASCEND-4, though there were some differences between the trials. The Company considered it not possible to perform an 'anchor-based' analysis of first-line ceritinib and crizotinib, and presented a Matching-Adjusted Indirect Comparison (MAIC) of ceritinib and crizotinib using only the ALK inhibitor arm of ASCEND-4 and PROFILE 1014. The indirect comparison suggests that ceritinib may be more effective in prolonging PFS than crizotinib. The ERG agreed that an indirect comparison using only the ALK inhibitor arm of the trials was the only option available in the present assessment; however, a number of limitations and potential bias were identified in this analysis. The Company's model estimated that ceritinib was cost effective when compared with crizotinib. However, the ERG highlighted several concerns with the Company's analysis; the ERG's preferred base case estimated an incremental cost-effectiveness ratio of £69,255 per quality-adjusted life-year (no patient access scheme [PAS] included). The ERG considered the economic analysis to be sensitive to changes in assumption used, partly due to the due to the immaturity of the overall survival data from trials, which leads to uncertainty around the extrapolation used. The NICE Appraisal Committee concluded that ceritinib is recommended, within its marketing authorisation, as an option for untreated ALK+ advanced NSCLC in adults, if the Company provides it with the discount agreed in the PAS.

Strimvelis® for Treating Severe Combined Immunodeficiency Caused by Adenosine Deaminase Deficiency: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Evaluation.

The Centre for Reviews and Dissemination and Centre for Health Economics Technology Assessment Group at the University of York was commissioned by the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) programme to act as the independent Evidence Review Group (ERG) for an appraisal of Strimvelis®, a gene therapy treatment for adenosine deaminase deficiency-severe combined immunodeficiency (ADA-SCID). This paper describes the manufacturing company's submission of clinical and economic evidence, the ERG's review and the resulting NICE guidance. For Strimvelis® compared with haematopoietic stem cell transplant (HSCT) from a matched unrelated donor (MUD) and HSCT from a haploidentical donor, the company base-case deterministic incremental cost-effectiveness ratios (ICERs) were £36,360 and £14,645 per quality-adjusted life-year (QALY) gained, respectively (using a discount rate of 1.5%). Although overall survival in patients receiving Strimvelis® was substantially higher than historical comparator data on HSCT from a MUD or haploidentical donor, the ERG was concerned that the estimated treatment benefit remained highly uncertain. The ERG critiqued some assumptions in the cost-effectiveness model, including that all patients return to general population mortality and morbidity after a successful procedure; that all patients receive a matched sibling donor following an unsuccessful engraftment; and that differences in wait times exist between the treatments. Incorporating a number of changes to the model, the ERG's base-case ICERs were £86,815 per QALY gained for Strimvelis® compared with HSCT from a MUD and £16,704 per QALY gained compared with HSCT from a haploidentical donor (using a discount rate of 1.5%). The ICER for Strimvelis® compared with HSCT from a MUD was highly sensitive to the difference in procedural mortality and could exceed NICE's £100,000 per QALY gained threshold for HSTs, if HSCT survival rates have improved since the most recent data. The evaluation committee concluded that the most plausible ICERs were lower than £100,000 per QALY gained and that Strimvelis® should be recommended for treatment of ADA-SCID where a matched related donor is unavailable.

Ustekinumab for Treating Moderately to Severely Active Crohn's Disease after Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Janssen to submit evidence on the clinical and cost effectiveness of their drug ustekinumab, an interleukin-12/23 inhibitor, for treating moderate-to-severe active Crohn's disease (CD). The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the Company's submission, the ERG's critical review of submitted evidence, and the resulting NICE guidance. The main supporting clinical evidence was derived from four well conducted, randomised controlled trials, comparing ustekinumab with placebo in two sub-populations (conventional care failure and anti-TNFα failure patients) of adults with moderate-to-severe CD. Three trials assessed treatment induction over 8 weeks, while the fourth recruited successfully induced patients into a maintenance trial for 1 year. These trials showed ustekinumab to be more effective than placebo in terms of its ability to induce and maintain clinical response and remission. In the absence of any direct head-to-head data, the Company conducted a network meta-analysis (NMA), which synthesised induction trial data on ustekinumab and relevant comparators (vedolizumab, adalimumab and infliximab) using placebo data as a common comparator. This analysis found ustekinumab to be of comparable efficacy to previously approved biologics in treatment induction. A 'treatment sequence analysis' compared long-term treatment efficacy, finding ustekinumab to be comparable in maintaining treatment response and remission to the three other biologic therapies. However, the ERG had identified many limitations and potential bias in this analysis, and urged caution when interpreting the results. The Company's economic model estimated ustekinumab to be dominant in both sub-populations compared with conventional care; however, the ERG's preferred base-case estimated an incremental cost-effectiveness ratio of £109,279 in the conventional care failure sub-population, and £110,967 in the anti-TNFα failure sub-population when compared with conventional care. However, the ERG identified significant failings in both the model structure and data inputs, which could not be addressed without complete restructuring. The ERG considered that the economic analysis presented by the Company failed to adequately address the decision problem specified in NICE's scope. The NICE Appraisal Committee recommended ustekinumab within its market authorisation, on the grounds of sufficiently similar efficacy and costs to previously recommended biologic therapies. However, the ERG's analyses demonstrated that all currently recommended biologics are unlikely to be cost effective relative to conventional care, raising broader questions regarding the appropriateness of cost-comparison exercises for decision making.

Certolizumab pegol and secukinumab for treating active psoriatic arthritis following inadequate response to disease-modifying antirheumatic drugs: a systematic review and economic evaluation.

BACKGROUND: Several biologic therapies are approved by the National Institute for Health and Care Excellence (NICE) for psoriatic arthritis (PsA) patients who have had an inadequate response to two or more synthetic disease-modifying antirheumatic drugs (DMARDs). NICE does not specifically recommend switching from one biologic to another, and only ustekinumab (UST; STELARA®, Janssen Pharmaceuticals, Inc., Horsham, PA, USA) is recommended after anti-tumour necrosis factor failure. Secukinumab (SEC; COSENTYX®, Novartis International AG, Basel, Switzerland) and certolizumab pegol (CZP; CIMZIA®, UCB Pharma, Brussels, Belgium) have not previously been appraised by NICE. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of CZP and SEC for treating active PsA in adults in whom DMARDs have been inadequately effective. DESIGN: Systematic review and economic model. DATA SOURCES: Fourteen databases (including MEDLINE and EMBASE) were searched for relevant studies from inception to April 2016 for CZP and SEC studies; update searches were run to identify new comparator studies. REVIEW METHODS: Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis (NMA) methods to investigate the relative efficacy of SEC and CZP compared with comparator therapies. A de novo model was developed to assess the cost-effectiveness of SEC and CZP compared with the other relevant comparators. The model was specified for three subpopulations, in accordance with the NICE scope (patients who have taken one prior DMARD, patients who have taken two or more prior DMARDs and biologic-experienced patients). The models were further classified according to the level of concomitant psoriasis. RESULTS: Nineteen eligible RCTs were included in the systematic review of short-term efficacy. Most studies were well conducted and were rated as being at low risk of bias. Trials of SEC and CZP demonstrated clinically important efficacy in all key clinical outcomes. At 3 months, patients taking 150 mg of SEC [relative risk (RR) 6.27, 95% confidence interval (CI) 2.55 to 15.43] or CZP (RR 3.29, 95% CI 1.94 to 5.56) were more likely to be responders than patients taking placebo. The NMA results for the biologic-naive subpopulations indicated that the effectiveness of SEC and CZP relative to other biologics and each other was uncertain. Limited data were available for the biologic-experienced subpopulation. Longer-term evidence suggested that these newer biologics reduced disease progression, with the benefits being similar to those seen for older biologics. The de novo model generated incremental cost-effectiveness ratios (ICERs) for three subpopulations and three psoriasis subgroups. In subpopulation 1 (biologic-naive patients who had taken one prior DMARD), CZP was the optimal treatment in the moderate-severe psoriasis subgroup and 150 mg of SEC was optimal in the subgroups of patients with mild-moderate psoriasis or no concomitant psoriasis. In subpopulation 2 (biologic-naive patients who had taken two or more prior DMARDs), etanercept (ETN; ENBREL®, Pfizer Inc., New York City, NY, USA) is likely to be the optimal treatment in all subgroups. The ICERs for SEC and CZP versus best supportive care are in the region of £20,000-30,000 per quality-adjusted life-year (QALY). In subpopulation 3 (biologic-experienced patients or patients in whom biologics are contraindicated), UST is likely to be the optimal treatment (ICERs are in the region of £21,000-27,000 per QALY). The optimal treatment in subpopulation 2 was sensitive to the choice of evidence synthesis model. In subpopulations 2 and 3, results were sensitive to the algorithm for Health Assessment Questionnaire-Disability Index costs. The optimal treatment is not sensitive to the use of biosimilar prices for ETN and infliximab (REMICADE®, Merck Sharp & Dohme, Kenilworth, NJ, USA). CONCLUSIONS: SEC and CZP may be an effective use of NHS resources, depending on the subpopulation and subgroup of psoriasis severity. There are a number of limitations to this assessment, driven mainly by data availability. FUTURE WORK: Trials are needed to inform effectiveness of biologics in biologic-experienced populations. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033357. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) commissioned a 'mock technology appraisal' to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal. METHODS: Our research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia. RESULTS: An assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the 'curative' and 'bridging to stem-cell transplantation' treatment approaches separately. Within each TPP, three 'hypothetical' evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision. CONCLUSIONS: It is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than £50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis of OS and assumptions made regarding the duration of therapy. The ERG exploratory re-analysis of the OS data relaxed the assumption of proportional hazards made in the company submission, which demonstrated significant uncertainty regarding the OS gains from crizotinib. The ERG reconfigured the economic model so that duration of therapy was based on the area under the curve analysis of the PROFILE 1014 trial, dramatically increasing the cost associated with implementing crizotinib and consequently, substantially increasing the ICER. At the first appraisal meeting, the NICE Appraisal Committee concluded that crizotinib, while clinically effective, was not sufficiently cost effective for use in the UK NHS. Following the consultation, the company offered a revised PAS and conducted extensive re-analysis, resulting in a revised base-case ICER of £47,291 per QALY gained. The NICE Appraisal Committee concluded that crizotinib was likely to be a cost-effective use of NHS resources, despite the uncertainty that persisted around a number of factors, namely the long-term survival benefit of crizotinib. Crizotinib was therefore recommended as an option for untreated ALK-positive advanced NSCLC in adults.

A Review of Ruxolitinib for the Treatment of Myelofibrosis: A Critique of the Evidence.

As part of the National Institute for Health and Care Excellence's (NICE) Single Technology Appraisal (STA) process, ruxolitinib was assessed to determine the clinical and cost effectiveness of its use in the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib had previously been assessed as part of the STA process and was not recommended in NICE guidance issued in June 2013 (TA289). A review of TA289 was commissioned following the availability of new longer-term survival data; a price discount patient access scheme (PAS) was also introduced. The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a summary of the manufacturer or sponsor of the technology's (referred to as the company) submission, the ERG review and the resulting NICE guidance issued in March 2016. The main clinical effectiveness data were derived from two good-quality multicentre randomised controlled trials (RCTs): COMFORT-II compared ruxolitinib with best available therapy (BAT) and COMFORT-I compared ruxolitinib with placebo. Both RCTs demonstrated a statistically significant reduction in splenomegaly and its associated symptoms in intermediate-2 and high-risk myelofibrosis patients. Overall survival was statistically significantly improved with ruxolitinib compared with BAT at 3.5 years of follow-up in the COMFORT-II trial (hazard ratio 0.58, 95 % CI 0.36-0.93). Grade 3-4 adverse events were more frequent in the ruxolitinib group than in the BAT group; 42 % compared with 25 %. Evidence relating to patients with lower-risk disease or low platelet counts (50-100 × 109/L) was less robust. The company's economic model was well-presented and had an appropriate model structure. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be around £45,000 per quality-adjusted life-year (QALY) gained (including the PAS discount). Extensive sensitivity and scenario analyses were presented, demonstrating that the estimated ICER was robust to a range of input values and assumptions made in the model. Alternative scenarios presented by the ERG showed only modest increases in the estimated ICER, primarily as a result of including an element of drug wastage within the model. Alternative scenarios resulted in estimated ICERs ranging from around £45,000 to £49,000 per QALY gained (including the PAS discount). At the first appraisal meeting, the NICE Appraisal Committee concluded that ruxolitinib was clinically effective and was a cost effective use of National Health Service (NHS) resources for patients with high-risk myelofibrosis who meet NICE's end-of-life criteria. Following the consultation, the company offered a revised PAS, resulting in a revised base-case ICER of £31,229 per QALY gained. The company also presented new evidence on the cost effectiveness of ruxolitinib in intermediate-2 and high-risk subgroups and a revised version of the model. The NICE Appraisal Committee considered the new evidence and recommended ruxolitinib for the treatment of patients with intermediate-2-risk disease as well as patients with high-risk disease, based on International Prognostic Scoring System (IPSS) prognostic factors.

Issues Related to the Frequency of Exploratory Analyses by Evidence Review Groups in the NICE Single Technology Appraisal Process.

BACKGROUND: Evidence Review Groups (ERGs) critically appraise company submissions as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process. As part of their critique of the evidence submitted by companies, the ERGs undertake exploratory analyses to explore uncertainties in the company's model. The aim of this study was to explore pre-defined factors that might influence or predict the extent of ERG exploratory analyses. OBJECTIVE: The aim of this study was to explore predefined factors that might influence or predict the extent of ERG exploratory analyses. METHODS: We undertook content analysis of over 400 documents, including ERG reports and related documentation for the 100 most recent STAs (2009-2014) for which guidance has been published. Relevant data were extracted from the documents and narrative synthesis was used to summarise the extracted data. All data were extracted and checked by two researchers. RESULTS: Forty different companies submitted documents as part of the NICE STA process. The most common disease area covered by the STAs was cancer (44%), and most ERG reports (n = 93) contained at least one exploratory analysis. The incidence and frequency of ERG exploratory analyses does not appear to be related to any developments in the appraisal process, the disease area covered by the STA, or the company's base-case incremental cost-effectiveness ratio (ICER). However, there does appear to be a pattern in the mean number of analyses conducted by particular ERGs, but the reasons for this are unclear and potentially complex. CONCLUSIONS: No clear patterns were identified regarding the presence or frequency of exploratory analyses, apart from the mean number conducted by individual ERGs. More research is needed to understand this relationship.

The Clinical and Cost Effectiveness of Apremilast for Treating Active Psoriatic Arthritis: A Critique of the Evidence.

As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of apremilast was invited to submit evidence for its clinical and cost effectiveness for the treatment of active psoriatic arthritis (PsA) for whom disease-modifying anti-rheumatic drugs (DMARDs) have been inadequately effective, not tolerated or contraindicated. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This paper provides a description of the ERG review of the company's submission, the ERG report and submission and summarises the NICE Appraisal Committee's subsequent guidance (December 2015). In the company's initial submission, the base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £14,683 per quality-adjusted life-year (QALY) gained for the sequence including apremilast (positioned before tumour necrosis factor [TNF]-α inhibitors) versus a comparator sequence without apremilast. However, the ERG considered that the base-case sequence proposed by the company represented a limited set of potentially relevant treatment sequences and positions for apremilast. The company's base-case results were therefore not a sufficient basis to inform the most efficient use and position of apremilast. The exploratory ERG analyses indicated that apremilast is more effective (i.e. produces higher health gains) when positioned after TNF-α inhibitor therapies. Furthermore, assumptions made regarding a potential beneficial effect of apremilast on long-term Health Assessment Questionnaire (HAQ) progression, which cannot be substantiated, have a very significant impact on results. The NICE Appraisal Committee (AC), when taking into account their preferred assumptions for HAQ progression for patients on treatment with apremilast, placebo response and monitoring costs for apremilast, concluded that the addition of apremilast resulted in cost savings but also a QALY loss. These cost savings were not high enough to compensate for the clinical effectiveness that would be lost. The AC thus decided that apremilast alone or in combination with DMARD therapy is not recommended for treating adults with active PsA that has not responded to prior DMARD therapy, or where such therapy is not tolerated.

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

BACKGROUND: Tumour 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. OBJECTIVE: To 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). DESIGN: Systematic review and economic model. DATA SOURCES: Fifteen databases were searched for relevant studies in July 2014. REVIEW METHODS: Clinical 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. RESULTS: In 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. CONCLUSIONS: In 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 RECOMMENDATIONS: Randomised trials are needed to identify the nr-AxSpA population who will benefit the most from anti-TNFs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014010182. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Thigh length versus knee length antiembolism stockings for the prevention of deep vein thrombosis in postoperative surgical patients; a systematic review and network meta-analysis.

OBJECTIVES: To assess the clinical effectiveness of thigh length versus knee length antiembolism stockings for the prevention of deep vein thrombosis (DVT) in surgical patients. DESIGN: Systematic review and meta-analysis using direct methods and network meta-analysis. METHODS: Previous systematic reviews and electronic databases were searched to February 2014 for randomised controlled trials (RCTs) of thigh length or knee length antiembolism stockings in surgical patients. Study quality was assessed using the Cochrane Risk of Bias Tool. The primary outcome was incidence of DVT. Analysis of the DVT data was performed using ORs along with 95% CIs. The I(2) statistic was used to quantify statistical heterogeneity. RESULTS: 23 RCTs were included; there was substantial variation between the trials and many were poorly reported with an unclear risk of bias. Five RCTs directly comparing thigh length versus knee length stockings were pooled and the summary estimate of effect favouring thigh length stockings was not statistically significant (OR 1.48, 95% CI 0.80 to 2.73). 13 RCTs were included in the network meta-analysis; thigh length stockings with pharmacological prophylaxis were more effective than knee length stockings with pharmacological prophylaxis, but again results were not statistically significant (OR 1.76, 95% credible intervals 0.82 to 3.53). CONCLUSIONS: Thigh length stockings may be more effective than knee length stockings, but results did not reach statistical significance and the evidence base is weak. Further research to confirm this finding is unlikely to be worthwhile. While thigh length stockings appear to have superior efficacy, practical issues such as patient acceptability may prevent their wide use in clinical practice. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42014007202.

The Clinical and Cost Effectiveness of Ustekinumab for the Treatment of Psoriatic Arthritis: A Critique of the Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of ustekinumab (Janssen) to submit evidence for the clinical and cost effectiveness of ustekinumab for the treatment of active psoriatic arthritis (PsA) as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics Technology Appraisal Group at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the ERG review of the manufacturer's evidence submission, and summarises the NICE Appraisal Committee's final guidance (TA340) issued in June 2015. The manufacturer presented evidence on ustekinumab for two patient populations: (1) a tumour necrosis factor-α (TNFα)-inhibitor-naïve population who had not previously received any TNFα inhibitors (biologics); and (2) a TNFα-inhibitor-exposed population who had previously received at least one TNFα inhibitor. The clinical evidence for ustekinumab was derived from two randomised controlled trials (PSUMMIT 1 and 2), in which a total of 927 patients who had not responded to previous disease-modifying antirheumatic drug therapies received ustekinumab 45 mg, ustekinumab 90 mg, or placebo. These data suggested that ustekinumab is more effective than placebo over 16-24 weeks in terms of both joint and skin response. In the absence of head-to-head comparisons between different biologics (ustekinumab, golimumab, etanercept, adalimumab and infliximab), the manufacturer conducted a network meta-analysis to estimate the relative efficacy of treatments for the TNFα-inhibitor-naïve population. Results of this analysis were marked as academic in confidence and are therefore not reported. For the TNFα-inhibitor-exposed population, the clinical analysis was limited to ustekinumab versus conventional management only, and was based on a subgroup of 180 patients from the PSUMMIT 2 trial. The ERG raised concerns relating to the lack of data on the long-term efficacy of ustekinumab, the limited data available for the exposed population, and the lack of consideration of the sequential use of treatments. Based on the manufacturer's original model, the ERG found ustekinumab to be dominated by golimumab in the anti-TNF-inhibitor-naïve population, and had an incremental cost-effectiveness ratio (ICER) of £29,843/quality-adjusted life-years versus conventional management in the exposed population. The ERG's analyses highlighted the fact that there is significant uncertainty around the model results. In addition, the ERG's exploratory cost-effectiveness analysis, which incorporated the sequential use of TNFα inhibitors, suggested that ustekinumab would not be cost effective if it were used as second-line treatment. The initial NICE recommendations asserted that ustekinumab was not recommended for treating active PsA. However, the manufacturer submitted a post-consultation model that included a Patient Access Scheme (PAS), halving the unit cost of ustekinumab 90 mg to £2147 (the same as a 45 mg dose). The NICE final recommendations were that, dependent on the inclusion of the PAS, ustekinumab is recommended as an option, along or in combination with methotrexate, for treating active PsA in adults only when treatment with TNFα inhibitors is contraindicated but would otherwise be considered, or the person has previously had treatment with one or more TNFα inhibitors, which has failed.

The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis.

BACKGROUND: It is uncertain which simple measures of childhood obesity are best for predicting future obesity-related health problems and the persistence of obesity into adolescence and adulthood. OBJECTIVES: To investigate the ability of simple measures, such as body mass index (BMI), to predict the persistence of obesity from childhood into adulthood and to predict obesity-related adult morbidities. To investigate how accurately simple measures diagnose obesity in children, and how acceptable these measures are to children, carers and health professionals. DATA SOURCES: Multiple sources including MEDLINE, EMBASE and The Cochrane Library were searched from 2008 to 2013. METHODS: Systematic reviews and a meta-analysis were carried out of large cohort studies on the association between childhood obesity and adult obesity; the association between childhood obesity and obesity-related morbidities in adulthood; and the diagnostic accuracy of simple childhood obesity measures. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and a modified version of the Quality in Prognosis Studies (QUIPS) tool. A systematic review and an elicitation exercise were conducted on the acceptability of the simple measures. RESULTS: Thirty-seven studies (22 cohorts) were included in the review of prediction of adult morbidities. Twenty-three studies (16 cohorts) were included in the tracking review. All studies included BMI. There were very few studies of other measures. There was a strong positive association between high childhood BMI and adult obesity [odds ratio 5.21, 95% confidence interval (CI) 4.50 to 6.02]. A positive association was found between high childhood BMI and adult coronary heart disease, diabetes and a range of cancers, but not stroke or breast cancer. The predictive accuracy of childhood BMI to predict any adult morbidity was very low, with most morbidities occurring in adults who were of healthy weight in childhood. Predictive accuracy of childhood obesity was moderate for predicting adult obesity, with a sensitivity of 30% and a specificity of 98%. Persistence of obesity from adolescence to adulthood was high. Thirty-four studies were included in the diagnostic accuracy review. Most of the studies used the least reliable reference standard (dual-energy X-ray absorptiometry); only 24% of studies were of high quality. The sensitivity of BMI for diagnosing obesity and overweight varied considerably; specificity was less variable. Pooled sensitivity of BMI was 74% (95% CI 64.2% to 81.8%) and pooled specificity was 95% (95% CI 92.2% to 96.4%). The acceptability to children and their carers of BMI or other common simple measures was generally good. LIMITATIONS: Little evidence was available regarding childhood measures other than BMI. No individual-level analysis could be performed. CONCLUSIONS: Childhood BMI is not a good predictor of adult obesity or adult disease; the majority of obese adults were not obese as children and most obesity-related adult morbidity occurs in adults who had a healthy childhood weight. However, obesity (as measured using BMI) was found to persist from childhood to adulthood, with most obese adolescents also being obese in adulthood. BMI was found to be reasonably good for diagnosing obesity during childhood. There is no convincing evidence suggesting that any simple measure is better than BMI for diagnosing obesity in childhood or predicting adult obesity and morbidity. Further research on obesity measures other than BMI is needed to determine which is the best tool for diagnosing childhood obesity, and new cohort studies are needed to investigate the impact of contemporary childhood obesity on adult obesity and obesity-related morbidities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005711. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The Clinical and Cost Effectiveness of Aflibercept in Combination with Irinotecan and Fluorouracil-Based Therapy (FOLFIRI) for the Treatment of Metastatic Colorectal Cancer Which has Progressed Following Prior Oxaliplatin-Based Chemotherapy: a Critique of the Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of aflibercept (Sanofi) to submit clinical and cost-effectiveness evidence for aflibercept in combination with irinotecan and fluorouracil-based therapy [irinotecan/5-fluorouracil/folinic acid (FOLFIRI)] for the treatment of metastatic colorectal cancer which has progressed following prior oxaliplatin-based chemotherapy, as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA307 issued in March 2014. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The clinical effectiveness data were derived from one good-quality double-blind randomised controlled trial (RCT), the VELOUR trial, which compared aflibercept plus FOLFIRI with placebo plus FOLFIRI. This RCT found a small but statistically significant increase in overall survival (OS); the difference in median OS was 1.44 months (13.5 months in the aflibercept group and 12.06 months in the placebo group). There was also a statistically significant increase in progression-free survival (PFS) with aflibercept; the difference in median PFS was 2.23 months (6.9 months in the aflibercept group and 4.67 months in the placebo group). However, grade 3-4 adverse events were more frequent in the aflibercept group than the placebo group: 83.5% compared with 62.5%. Treatment-emergent adverse events led to permanent discontinuation of treatment in 26.8% of patients in the aflibercept group and 12.1% of patients in the placebo group. The manufacturer's submission included an estimation of mean OS benefit based on extrapolation of the data, which was considerably longer than the median OS benefit reported (4.7 vs. 1.44 months). The ERG considered this to be an over estimate. The base-case incremental cost-effectiveness ratio (ICER) for the overall population was reported by the manufacturer to be £36,294 per quality-adjusted life-year (QALY). After correcting the model programming and updating the model to include the ERG's preferred parameter estimates, the ICER from the ERG's alternative base case was £54,368 per QALY. The extrapolation of the OS curves was the key cost-effectiveness driver and a major source of uncertainty in the model. Additional scenarios related to the extrapolation of OS undertaken by the ERG resulted in ICERs between £62,894 and £92,089 per QALY. After consideration of the manufacturer's submission and the ERG's critique, and submissions from other stakeholders, the NICE Appraisal Committee concluded that aflibercept in combination with irinotecan and fluorouracil-based therapy could not be considered a cost effective use of National Health Service resources for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended for the treatment of metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen in NICE guidance TA307.

The added clinical and economic value of diagnostic testing for epilepsy surgery.

The costs, benefits and risks associated with diagnostic imaging investigations for epilepsy surgery necessitate the identification of an optimal pathway in the pre-surgical workup. In order to assess the added value of additional investigations a full cost-effectiveness evaluation should be conducted, taking into account all of the life-time costs and benefits associated with undertaking additional investigations. This paper considers and applies the appropriate framework against which a full evaluation should be assessed. We conducted a systematic review to evaluate the progression of the literature through this framework, finding that only isolated elements of added value have been appropriately evaluated. The results from applying the full added value framework are also presented, identifying an optimal strategy for pre-surgical evaluation for temporal lobe epilepsy surgery. Our results suggest that additional FDG-PET and invasive EEG investigations after an initially discordant MRI and video-EEG appears cost-effective, and that the value of subsequent invasive-EEGs is closely linked to the maintenance of longer-term benefits after surgery. It is integral to the evaluation of imaging technologies in the work-up for epilepsy surgery that the impact of the use of these technologies on clinical decision-making, and on further treatment decisions, is considered fully when informing cost-effectiveness.

Ruxolitinib for the treatment of myelofibrosis: a NICE single technology appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of ruxolitinib (Novartis) to submit clinical and cost-effectiveness evidence for ruxolitinib within its licensed indication (the treatment of disease-related splenomegaly or symptoms in adult patients with myelofibrosis), according to the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA289 issued in June 2013. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The main clinical effectiveness data were derived from two phase III, multicentre, randomised controlled trials (RCTs): Controlled myelofibrosis study with oral JAK inhibitor treatment (COMFORT)-II compared ruxolitinib with best available therapy (BAT), and COMFORT-I compared ruxolitinib with placebo. These RCTs demonstrated that ruxolitinib confers significant benefits in terms of spleen size reduction and improvement in symptom burden. In the COMFORT-II trial, a reduction in spleen volume of ≥35 % was achieved in 28 % of ruxolitinib-treated patients compared with 0 % of patients in the BAT group (p < 0.001) at 48 weeks, and there was a mean change in spleen volume of -30.1 versus +7.3 % (p < 0.001). Ruxolitinib also provided significant improvements in myelofibrosis-associated symptoms and health-related quality-of-life compared with BAT and placebo. The ERG concluded that ruxolitinib appears to reduce splenomegaly and its associated symptoms, but that there was considerable uncertainty surrounding the manufacturer's cost-effectiveness estimates due to limitations in the manufacturer's model. The manufacturer's model did not allow for disease progression, did not accurately capture symptomatic relief, had several implausible or unjustified assumptions, and there were several parameter choices that the ERG found sub-optimal. ERG sensitivity analyses found that nearly all plausible adjustments to the model reduced the cost effectiveness of ruxolitinib. It is very likely that the base-case incremental cost-effectiveness ratio of £73,980/quality-adjusted life-year presented by the manufacturer represents a best-case scenario. The NICE Appraisal Committee concluded that ruxolitinib was clinically effective, but could not be considered a cost effective use of National Health Service (NHS) resources for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib is not recommended for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis in NICE TA289.

The EOS 2D/3D X-ray imaging system: a cost-effectiveness analysis quantifying the health benefits from reduced radiation exposure.

OBJECTIVES: To evaluate the cost-effectiveness of the EOS(®) 2D/3D X-ray imaging system compared with standard X-ray for the diagnosis and monitoring of orthopaedic conditions. MATERIALS AND METHODS: A decision analytic model was developed to quantify the long-term costs and health outcomes, expressed as quality-adjusted life years (QALYs) from the UK health service perspective. Input parameters were obtained from medical literature, previously developed cancer models and expert advice. Threshold analysis was used to quantify the additional health benefits required, over and above those associated with radiation-induced cancers, for EOS(®) to be considered cost-effective. RESULTS: Standard X-ray is associated with a maximum health loss of 0.001 QALYs, approximately 0.4 of a day in full health, while the loss with EOS(®) is a maximum of 0.00015 QALYs, or 0.05 of a day in full health. On a per patient basis, EOS(®) is more expensive than standard X-ray by between £10.66 and £224.74 depending on the assumptions employed. The results suggest that EOS(®) is not cost-effective for any indication. Health benefits over and above those obtained from lower radiation would need to double for EOS to be considered cost-effective. CONCLUSION: No evidence currently exists on whether there are health benefits associated with imaging improvements from the use of EOS(®). The health benefits from radiation dose reductions are very small. Unless EOS(®) can generate additional health benefits as a consequence of the nature and quality of the image, comparative patient throughput with X-ray will be the major determinant of cost-effectiveness.

Dilemmas in the interpretation of diagnostic accuracy studies on presurgical workup for epilepsy surgery.

We conducted a systematic review to determine which noninvasive technologies should be used in the workup for epilepsy surgery to identify structural or functional abnormalities to help locate the site of seizure onset. The review focused on patients where there was insufficient confidence, in either the decision to go to surgery or the site at which surgery should be conducted, after the initial clinical examination. The majority of the studies identified were single-gate diagnostic accuracy studies; none were randomized controlled trials, and only one reported the effect of the test results on the decision making process. It became apparent that the data derived from diagnostic accuracy studies could not be used to answer the review question. This article focuses on the methods used to extract data from the diagnostic accuracy studies, the difficulties interpreting the resulting data, why such studies are not an appropriate study design in this setting, and how the evidence-base can be improved.