The cost-effectiveness of a bimekizumab versus IL-17A inhibitors treatment-pathway in patients with active axial spondyloarthritis in Scotland.

OBJECTIVE: To estimate the cost-effectiveness of a treatment-pathway initiated with bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A, in patients with axial spondyloarthritis (axSpA) compared with IL-17Ai's, ixekizumab, and secukinumab, from the NHS Scotland perspective. METHODS: The axSpA treatment-pathway was modeled using a decision tree followed by a lifetime Markov model. The pathway included first- and second-line biologic disease-modifying antirheumatic drugs (bDMARD), followed by best supportive care (bDMARD, nonbiologic). Bimekizumab followed by any bDMARD ("BKZ") was compared with IL-17Ai's: secukinumab 150 mg followed by a blend ("SEC") of dose up-titration to secukinumab 300 mg and any bDMARD, or ixekizumab followed by any bDMARD ("IXE"). Transition to the next therapy was triggered by Bath Ankylosing Spondylitis Disease Activity Index-50% (BASDAI50) non-response or any-cause discontinuation. A published network meta-analysis provided efficacy data. EuroQoL-5-dimensions utilities were derived by mapping from Ankylosing Spondylitis Disease Activity Score. Costs included disease management (linked to functional limitations), biologics acquisition (list prices), administration and monitoring (NHS 2021/22). Discounting was 3.5%/year. Probabilistic results from patients with non-radiographic axSpA and ankylosing spondylitis were averaged to reflect the axSpA disease spectrum. Scenario and sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratio (ICER) of BKZ was £24,801/quality-adjusted life-year (QALY) vs. SEC (95% credible interval £24,163-£25,895). BKZ had similar costs (Δ -£385 [-£15,239-£14,468]) and QALYs (Δ 0.039 [-0.748-0.825]) to IXE, with £1,523 (£862-£2,222) net monetary benefit. Conclusions remained unchanged in most scenarios. Results' drivers included BASDAI50 response rate and disease management cost. LIMITATIONS: Results were based on list prices. Data concerning up-titration to secukinumab 300 mg was scarce. CONCLUSIONS: The bimekizumab treatment-pathway represents a cost-effective option across the axSpA disease spectrum in Scotland. Bimekizumab is cost-effective compared to a secukinumab-pathway that includes dose up-titration, and has similar costs and QALYs to an ixekizumab-pathway.

Etelcalcetide for Treating Secondary Hyperparathyroidism: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The manufacturer of the calcimimetic drug etelcalcetide was invited to make an evidence submission as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) programme. Within this submission, they reported evidence on the clinical and cost effectiveness of etelcalcetide for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) on haemodialysis. The Southampton Health Technology Assessments Centre (SHTAC), part of the Wessex Institute at the University of Southampton, was the independent Evidence Review Group (ERG) commissioned to appraise the company's submission. This article describes the ERG's review and critique of the company's submission and summarises the NICE Appraisal Committee's subsequent guidance (issued in June 2017). The clinical-effectiveness evidence submitted by the company consisted of two double-blind, randomised controlled trials (RCTs) comparing etelcalcetide with placebo, one RCT comparing etelcalcetide with cinacalcet, two single-arm extension studies of the above trials, and one single-arm study evaluating the effect of switching from cinacalcet to etelcalcetide. No study specifically examined the population specified in the NICE appraisal scope: patients refractory to standard therapy with phosphate binders and vitamin D (PBVD). None of these trials were designed to collect long-term efficacy data for outcomes such as mortality, bone fractures, cardiovascular events, or parathyroidectomies. Instead, biomarker data from the trials were mapped to long-term outcomes by an assumed linear relationship between the trial outcome, reduction of parathyroid hormone (PTH) by > 30%, and the log-hazard ratios for the occurrence of clinical events derived from a large, long-term RCT of cinacalcet (the EVOLVE trial). After submission of a confidential Patient Access Scheme (PAS) discount reducing etelcalcetide drug costs, the incremental cost-effectiveness ratio (ICER) for etelcalcetide versus cinacalcet was £14,778 per quality-adjusted life-year (QALY) gained in the company's base case. While this value is lower than the NICE threshold range of £20,000 and £30,000 per QALY gained, it was the opinion of the ERG that the ICER was highly uncertain due to efficacy data limitations for etelcalcetide, inadequate synthesis of clinical-effectiveness evidence, and strong assumptions connecting short-term biomarker data with long-term clinical outcomes. The ERG produced an alternative base case for etelcalcetide versus cinacalcet, with an ICER of £22,400 per QALY gained, also subject to uncertainty. The NICE Appraisal Committee recommended etelcalcetide as an option for the treatment of SHPT in adults with CKD only if treatment with a calcimimetic is indicated and cinacalcet is not suitable, subject to the company's provision of the agreed PAS discount.

Does Methodological Guidance Produce Consistency? A Review of Methodological Consistency in Breast Cancer Utility Value Measurement in NICE Single Technology Appraisals.

Since 2004, National Institute for Health and Care Excellence (NICE) methodological guidance for technology appraisals has emphasised a strong preference for using the validated EuroQol 5-Dimensions (EQ-5D) quality-of-life instrument, measuring patient health status from patients or carers, and using the general public's preference-based valuation of different health states when assessing health benefits in economic evaluations. The aim of this study was to review all NICE single technology appraisals (STAs) for breast cancer treatments to explore consistency in the use of utility scores in light of NICE methodological guidance. A review of all published breast cancer STAs was undertaken using all publicly available STA documents for each included assessment. Utility scores were assessed for consistency with NICE-preferred methods and original data sources. Furthermore, academic assessment group work undertaken during the STA process was examined to evaluate the emphasis of NICE-preferred quality-of-life measurement methods. Twelve breast cancer STAs were identified, and many STAs used evidence that did not follow NICE's preferred utility score measurement methods. Recent STA submissions show companies using EQ-5D and mapping. Academic assessment groups rarely emphasized NICE-preferred methods, and queries about preferred methods were rare. While there appears to be a trend in recent STA submissions towards following NICE methodological guidance, historically STA guidance in breast cancer has generally not used NICE's preferred methods. Future STAs in breast cancer and reviews of older guidance should ensure that utility measurement methods are consistent with the NICE reference case to help produce consistent, equitable decision making.

Reslizumab for Treating Asthma with Elevated Blood Eosinophils Inadequately Controlled by Inhaled Corticosteroids: 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 (STA) process, the manufacturer of reslizumab (Teva) submitted evidence for its clinical and cost effectiveness for the treatment of eosinophilic asthma inadequately controlled by inhaled corticosteroids. NICE commissioned Southampton Health Technology Assessments Centre (SHTAC) as an independent Evidence Review Group (ERG) to provide a critique of the manufacturer's submitted evidence. Reslizumab is compared with best standard of care and omalizumab, for a small 'overlap' population of patients who have both eosinophilic and IgE-mediated severe asthma. This paper provides a summary of the ERG's review of the manufacturer's submission, and summarises the NICE Appraisal Committee's subsequent guidance (issued in August 2017). The ERG considered that there were limitations in the approach proposed by the manufacturer for the exacerbation rate and the utility for severe exacerbation. The company amended their initial analysis, following comments from the ERG and the NICE committee, whereby the incremental cost effectiveness ratio was £29,870 per QALY gained for reslizumab compared with best standard care. The NICE Appraisal Committee (AC) concluded that reslizumab was recommended as an option for the treatment of severe eosinophilic asthma that is inadequately controlled in adults despite maintenance therapy with high-dose inhaled corticosteroids plus another drug, only if (1) the blood eosinophil count has been recorded as 400 cells per microlitre or more and (2) the patient has had three or more asthma exacerbations in the past 12 months, and (3) the company provides reslizumab with the discount agreed in the patient access scheme.

Virtual chromoendoscopy for the real-time assessment of colorectal polyps in vivo: a systematic review and economic evaluation.

BACKGROUND: Current clinical practice is to remove a colorectal polyp detected during colonoscopy and determine whether it is an adenoma or hyperplastic by histopathology. Identifying adenomas is important because they may eventually become cancerous if untreated, whereas hyperplastic polyps do not usually develop into cancer, and a surveillance interval is set based on the number and size of adenomas found. Virtual chromoendoscopy (VCE) (an electronic endoscopic imaging technique) could be used by the endoscopist under strictly controlled conditions for real-time optical diagnosis of diminutive (≤ 5 mm) colorectal polyps to replace histopathological diagnosis. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of the VCE technologies narrow-band imaging (NBI), flexible spectral imaging colour enhancement (FICE) and i-scan for the characterisation and management of diminutive (≤ 5 mm) colorectal polyps using high-definition (HD) systems without magnification. DESIGN: Systematic review and economic analysis. PARTICIPANTS: People undergoing colonoscopy for screening or surveillance or to investigate symptoms suggestive of colorectal cancer. INTERVENTIONS: NBI, FICE and i-scan. MAIN OUTCOME MEASURES: Diagnostic accuracy, recommended surveillance intervals, health-related quality of life (HRQoL), adverse effects, incidence of colorectal cancer, mortality and cost-effectiveness of VCE compared with histopathology. DATA SOURCES: Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and Database of Abstracts of Reviews of Effects were searched for published English-language studies from inception to June 2016. Bibliographies of related papers, systematic reviews and company information were screened and experts were contacted to identify additional evidence. REVIEW METHODS: Systematic reviews of test accuracy and economic evaluations were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were conducted, where possible, to inform the independent economic model. A cost-utility decision-analytic model was developed to estimate the cost-effectiveness of VCE compared with histopathology. The model used a decision tree for patients undergoing endoscopy, combined with estimates of long-term outcomes (e.g. incidence of colorectal cancer and subsequent morbidity and mortality) derived from University of Sheffield School of Health and Related Research's bowel cancer screening model. The model took a NHS perspective, with costs and benefits discounted at 3.5% over a lifetime horizon. There were limitations in the data on the distribution of adenomas across risk categories and recurrence rates post polypectomy. RESULTS: Thirty test accuracy studies were included: 24 for NBI, five for i-scan and three for FICE (two studies assessed two interventions). Polyp assessments made with high confidence were associated with higher sensitivity and endoscopists experienced in VCE achieved better results than those without experience. Two economic evaluations were included. NBI, i-scan and FICE are cost-saving strategies compared with histopathology and the number of quality-adjusted life-years gained was similar for histopathology and VCE. The correct surveillance interval would be given to 95% of patients with NBI, 94% of patients with FICE and 97% of patients with i-scan. LIMITATIONS: Limited evidence was available for i-scan and FICE and there was heterogeneity among the NBI studies. There is a lack of data on longer-term health outcomes of patients undergoing VCE for assessment of diminutive colorectal polyps. CONCLUSIONS: VCE technologies, using HD systems without magnification, could potentially be used for the real-time assessment of diminutive colorectal polyps, if endoscopists have adequate experience and training. FUTURE WORK: Future research priorities include head-to-head randomised controlled trials of all three VCE technologies; more research on the diagnostic accuracy of FICE and i-scan (when used without magnification); further studies evaluating the impact of endoscopist experience and training on outcomes; studies measuring adverse effects, HRQoL and anxiety; and longitudinal data on colorectal cancer incidence, HRQoL and mortality. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016037767. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The Type and Impact of Evidence Review Group Exploratory Analyses in the NICE Single Technology Appraisal Process.

BACKGROUND: As part of the UK National Institute for Health and Care Excellence (NICE) single technology appraisal process, independent evidence review groups (ERGs) critically appraise a company's submission relating to a specific technology and indication. OBJECTIVES: To explore the type of additional exploratory analyses conducted by ERGs and their impact on the recommendations made by NICE. METHODS: The 100 most recently completed single technology appraisals with published guidance were selected for inclusion. A content analysis of relevant documents was undertaken to identify and extract relevant data, and narrative synthesis was used to rationalize and present these data. RESULTS: The types of exploratory analysis conducted in relation to companies' models were fixing errors, addressing violations, addressing matters of judgment, and the provision of a new, ERG-preferred base case. Ninety-three of the 100 ERG reports contained at least one of these analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category "Matters of judgment," which was reported in 83 reports (89%). At least one of the exploratory analyses conducted and reported by an ERG is mentioned in 97% of NICE appraisal consultation documents and 94% of NICE final appraisal determinations, and had a clear influence on recommendations in 72% of appraisal consultation documents and 47% of final appraisal determinations. CONCLUSIONS: These results suggest that the additional analyses undertaken by ERGs in the appraisal of company submissions are highly influential in the policy-making and decision-making process.

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.

Placental growth factor (alone or in combination with soluble fms-like tyrosine kinase 1) as an aid to the assessment of women with suspected pre-eclampsia: systematic review and economic analysis.

BACKGROUND: Pre-eclampsia (PE) prediction based on blood pressure, presence of protein in the urine, symptoms and laboratory test abnormalities can result in false-positive diagnoses. This may lead to unnecessary antenatal admissions and preterm delivery. Blood tests that measure placental growth factor (PlGF) or the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to PlGF could aid prediction of PE if either were added to routine clinical assessment or used as a replacement for proteinuria testing. OBJECTIVES: To evaluate the diagnostic accuracy and cost-effectiveness of PlGF-based tests for patients referred to secondary care with suspected PE in weeks 20-37 of pregnancy. DESIGN: Systematic reviews and an economic analysis. DATA SOURCES: Bibliographic databases including MEDLINE, EMBASE, Web of Science and The Cochrane Library and Database of Abstracts of Reviews of Effects were searched up to July 2015 for English-language references. Conferences, websites, systematic reviews and confidential company submissions were also accessed. REVIEW METHODS: Systematic reviews of test accuracy and economic studies were conducted to inform an economic analysis. Test accuracy studies were required to include women with suspected PE and report quantitatively the accuracy of PlGF-based tests; their risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. The economic studies review had broad eligibility criteria to capture any types of economic analysis; critical appraisal employed standard checklists consistent with National Institute for Health and Care Excellence criteria. Study selection, critical appraisal and data extraction in both reviews were performed by two reviewers. ECONOMIC ANALYSIS: An independent economic analysis was conducted based on a decision tree model, using the best evidence available. The model evaluates costs (2014, GBP) from a NHS and Personal Social Services perspective. Given the short analysis time horizon, no discounting was undertaken. RESULTS: Four studies were included in the systematic review of test accuracy: two on Alere's Triage® PlGF test (Alere, Inc., San Diego, CA, USA) for predicting PE requiring delivery within a specified time and two on Roche Diagnostics' Elecsys® sFlt-1 to PlGF ratio test (Roche Diagnostics GmbH, Mannheim, Germany) for predicting PE within a specified time. Three studies were included in the systematic review of economic studies, and two confidential company economic analyses were assessed separately. Study heterogeneity precluded meta-analyses of test accuracy or cost-analysis outcomes, so narrative syntheses were conducted to inform the independent economic model. The model predicts that, when supplementing routine clinical assessment for rule-out and rule-in of PE, the two tests would be cost-saving in weeks 20-35 of gestation, and marginally cost-saving in weeks 35-37, but with minuscule impact on quality of life. Length of neonatal intensive care unit stay was the most influential parameter in sensitivity analyses. All other sensitivity analyses had negligible effects on results. LIMITATIONS: No head-to-head comparisons of the tests were identified. No studies investigated accuracy of PlGF-based tests when used as a replacement for proteinuria testing. Test accuracy studies were found to be at high risk of clinical review bias. CONCLUSIONS: The Triage and Elecsys tests would save money if added to routine clinical assessment for PE. The magnitude of savings is uncertain, but the tests remain cost-saving under worst-case assumptions. Further research is required to clarify how the test results would be interpreted and applied in clinical practice. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015017670. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and a limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of four biologic DMARDs [etanercept (Enbrel(®), Pfizer), abatacept (Orencia(®), Bristol-Myers Squibb), adalimumab (Humira(®), AbbVie) and tocilizumab (RoActemra(®), Roche) - with or without methotrexate where indicated] for the treatment of JIA (systemic or oligoarticular JIA are excluded). DATA SOURCES: Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and the Database of Abstracts of Reviews of Effects were searched for published studies from inception to May 2015 for English-language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence. REVIEW METHODS: Systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision-analytic model was developed to compare the estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base-case time horizon was 30 years and the model took a NHS perspective, with costs and benefits discounted at 3.5%. RESULTS: Four placebo-controlled randomised controlled trials (RCTs) met the inclusion criteria for the clinical effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi)-30 response to open-label lead-in treatment in order to be randomised. An exploratory adjusted indirect comparison suggests that the four biologic DMARDs are similar, with fewer disease flares and greater proportions of ACR Pedi-50 and -70 responses among participants randomised to continued biologic DMARDs. However, confidence intervals were wide, the number of trials was low and there was clinical heterogeneity between trials. Open-label extensions of the trials showed that, generally, ACR responses remained constant or even increased after the double-blind phase. The proportions of adverse events and serious adverse events were generally similar between the treatment and placebo groups. Four economic evaluations of biologic DMARDs for patients with JIA were identified but all had limitations. Two quality-of-life studies were included, one of which informed the cost-utility model. The incremental cost-effectiveness ratios (ICERs) for adalimumab, etanercept and tocilizumab versus methotrexate were £38,127, £32,526 and £38,656 per quality-adjusted life year (QALY), respectively. The ICER for abatacept versus methotrexate as a second-line biologic was £39,536 per QALY. LIMITATIONS: The model does not incorporate the natural history of JIA in terms of long-term disease progression, as the current evidence is limited. There are no head-to-head trials of biologic DMARDs, and clinical evidence for specific JIA subtypes is limited. CONCLUSIONS: Biologic DMARDs are superior to placebo (with methotrexate where permitted) in children with (predominantly) polyarticular course JIA who have had an insufficient response to previous treatment. Randomised comparisons of biologic DMARDs with long-term efficacy and safety follow-up are needed to establish comparative effectiveness. RCTs for JIA subtypes for which evidence is lacking are also required. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015016459. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The use of exploratory analyses within the National Institute for Health and Care Excellence single technology appraisal process: an evaluation and qualitative analysis.

BACKGROUND: As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) process, independent Evidence Review Groups (ERGs) critically appraise the company submission. During the critical appraisal process the ERG may undertake analyses to explore uncertainties around the company's model and their implications for decision-making. The ERG reports are a central component of the evidence considered by the NICE Technology Appraisal Committees (ACs) in their deliberations. OBJECTIVE: The aim of this research was to develop an understanding of the number and type of exploratory analyses undertaken by the ERGs within the STA process and to understand how these analyses are used by the NICE ACs in their decision-making. METHODS: The 100 most recently completed STAs with published guidance were selected for inclusion in the analysis. The documents considered were ERG reports, clarification letters, the first appraisal consultation document and the final appraisal determination. Over 400 documents were assessed in this study. The categories of types of exploratory analyses included fixing errors, fixing violations, addressing matters of judgement and the ERG-preferred base case. A content analysis of documents (documentary analysis) was undertaken to identify and extract relevant data, and narrative synthesis was then used to rationalise and present these data. RESULTS: The level and type of detail in ERG reports and clarification letters varied considerably. The vast majority (93%) of ERG reports reported one or more exploratory analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category 'matters of judgement', which was reported in 83 (89%) reports. The category 'ERG base-case/preferred analysis' was reported in 45 (48%) reports, the category 'fixing errors' was reported in 33 (35%) reports and the category 'fixing violations' was reported in 17 (18%) reports. The exploratory analyses performed were the result of issues raised by an ERG in its critique of the submitted economic evidence. These analyses had more influence on recommendations earlier in the STA process than later on in the process. LIMITATIONS: The descriptions of analyses undertaken were often highly specific to a particular STA and could be inconsistent across ERG reports and thus difficult to interpret. CONCLUSIONS: Evidence Review Groups frequently conduct exploratory analyses to test or improve the economic evaluations submitted by companies as part of the STA process. ERG exploratory analyses often have an influence on the recommendations produced by the ACs. FUTURE WORK: More in-depth analysis is needed to understand how ERGs make decisions regarding which exploratory analyses should be undertaken. More research is also needed to fully understand which types of exploratory analyses are most useful to ACs in their decision-making. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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.