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The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz ® ), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of £25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of £39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost-effectiveness ratio was within the range that could be considered a cost-effective use of National Health Service resources.

Objective: The aim was to evaluate the cost-effectiveness of Crohn's disease (CD) treatment with vedolizumab and ustekinumab after failure of therapy with tumor necrosis factor-α antagonists (anti-TNFs)., Methods: The Markov model incorporated the lifetime horizon, synthesis-based estimates of biologics' efficacy in relation to anti-TNF exposure, and administration of biologics reflecting clinical practice (e.g., sequence of biologics, retreatment, 12-month treatment). The utilities, non-medical costs and indirect costs were derived from a study of 200 adult patients with CD, while the healthcare costs were from a study of 1393 adults with CD who used biologics in Poland. The quality-adjusted life years (QALYs) and costs (the societal perspective) were discounted with the annual rates of 3.5 and 5%, respectively., Results: The addition of vedolizumab (ustekinumab) to the sequence of available anti-TNFs (after first-line infliximab or after second-line adalimumab) led to a gain of 0.364 (0.349) QALYs at an additional cost of €5600.24 (€6593.82). The incremental cost-effectiveness ratios (ICERs) were €15,369 [95% confidence interval (CI) 7496-61,354] and €18,878 (95% CI 9213-85,045) per QALY gained with vedolizumab and ustekinumab, respectively. Sensitivity analyses revealed a high impact on the ICERs of the relapse rate after discontinuation of biologic treatment. The highest value of vedolizumab/ustekinumab was estimated after the failure of therapies with both anti-TNFs., Conclusions: CD treatment with ustekinumab or vedolizumab after failure of anti-TNF therapy appears to be cost-effective at a threshold of €31,500. The replacement of the second-line anti-TNF with ustekinumab/vedolizumab and the course of the disease after discontinuation of biologics are influential drivers of the cost-effectiveness.

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.

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.