Health technology assessment bodies like the National Institute for Health and Care Excellence (NICE) in the UK are interested in hard outcomes, like long-term overall survival (OS), which are not always available in oncology clinical trials. We reviewed the methods used by immuno-oncology (I-O) manufacturers to extrapolate OS in their economic evaluations, and the critiques of these methods highlighted by NICE. Technology appraisals of I-O therapies published between 2011 and 2020 were identified from the NICE website (excluding terminated appraisals), based on the Cancer Research Institute classification of immunotherapies. The methodology to extrapolate OS and NICE’s critiques of these methods were extracted from Final Appraisal Documents. OS extrapolation was included in the majority of appraisals (58/75). The most widely used extrapolation method was a standard parametric model (42/75), followed by spline models (6/75), external sources (3/75), cure models (3/75), only trial data (2/75), response-based analysis (1/75) and trial data/published sources (1/75). Where NICE rejected the extrapolation method (16/75), the main critiques asserted that OS estimates were implausible and inconsistent with the clinical trial evidence or the real-world data (5/16), followed by scepticism of assumptions implying future mortality rates of patients will be similar to or lower than those of the general population (4/16). Other issues flagged by NICE included long extrapolation used despite median survival not being met or short follow-up-data (2/16), improper application of the hazard function/relative risk in OS analysis (2/16), trial issues including censoring (1/16), use of parametric models instead of observed data (1/16) and disregard of covariates (1/16). The number of I-O therapies assessed by the NICE has increased exponentially in recent years. Uncertainty in the long-term OS impacts the cost-effectiveness of I-O treatments. Issues with plausibility and mortality risk assumptions can lead to a rejection of OS extrapolation methods by NICE.

Tralokinumab is approved for adults with moderate-to-severe atopic dermatitis at a 300mg maintenance dose every other week (Q2W). At prescriber's discretion, every fourth week (Q4W) dosing may be considered for patients responding to treatment after 16 weeks of administration. The proportion switching to Q4W dosing in clinical practice is uncertain. This study explored the impact of varying the proportion of patients on Q4W after 52 weeks on the budget impact of tralokinumab from a UK perspective over a five-year period.

To estimate the cost-effectiveness of vagus nerve stimulation (VNS) as an adjunctive therapy to anti-seizure medication (ASMs) when compared with a strategy of ASMs alone for the management of drug resistant epilepsy (DRE). A five health state cohort transition model was developed, with a 10-year time horizon, a 3-month cycle length and an English National Health Service perspective. Health states were defined by a percentage reduction in seizure frequency and aligned with randomised trial data informing the first cycle transition probabilities. Thereafter, non-VNS patients remained in state, while a systematic literature review informed further VNS patient transitions up to year 2, after which they remained in state (subject to death or device discontinuation). Extrapolation of registered VNS implant Kaplan-Meier data informed explantation and replacement probabilities. Health state utilities were age and gender adjusted. Published estimates, combined with trial data regarding mean seizure frequency, informed health state resource use. In addition to the base case analysis, scenarios, one-way deterministic and probabilistic sensitivity analyses were undertaken. Adjunctive VNS has an incremental cost-effectiveness ratio of £17,711 per quality-adjusted life year (QALY) when compared to a strategy of ASMs alone. Results were most sensitive to unit costs of inpatient care, with VNS expected to be dominant if the cost of a non-elective care admission exceeded £2,225. Using the UK National Institute of Health and Care Excellence threshold of £20,000 to £30,000 per QALY, VNS was cost-effective in the majority of scenarios evaluated, inclusive of varying the costs of device implantation, replacement and explantation by 15 percent. Management of DRE with VNS is a cost-effective option in comparison to ASM therapy alone. This finding is driven by a reduced seizure frequency with VNS, which is consequently expected to improve a patient's health-related quality of life and reduce downstream medical costs.

In recent years, immuno-oncology (I-O) therapies have emerged as effective treatment options for cancer. Their efficacy has been compared to chemotherapy and other treatments in Health Technology Assessment submissions, using indirect treatment comparisons (ITCs) when head-to-head trials were not available. We evaluated the appraisal of I-O ITCs by the National Institute for Health and Care Excellence (NICE) in the UK and summarised the different approaches and main critiques to their implementation. I-O appraisals published between 2011-2022 were identified from the NICE website based on the Cancer Research Institute classification (excluding terminated appraisals). ITC methods and Evidence Review Groups (ERGs) and NICE committees' critiques were extracted from Final Appraisal Documents. Of the 92 I-O appraisals identified, 64.1% (59/92) included an ITC, most commonly a network meta-analysis (NMA; 50.8%, 30/59). Matching-adjusted indirect comparisons (MAICs) were frequently included in I-O submissions (30.5%, 18/59), while naïve comparisons were also conducted (28.8%, 17/59), mostly alongside MAICs. Simulated treatment comparisons were rarely performed (5.1%, 3/59). Approximately half of the ITCs (49.2%, 29/59) were considered acceptable for decision-making by NICE; most of these treatments were then recommended for reimbursement (82.8%, 24/29). Substantially fewer treatments were reimbursed when an ITC was considered unsuitable for decision-making (43.3%, 13/30). The main criticism highlighted by the ERGs and NICE committees concerned the choice of ITC method (e.g. naïve comparison instead of MAIC), the comparator study selection (e.g. study design heterogeneity, patient cohort differences), the statistical analyses performed (e.g. choice of NMA model, insufficient matching of effect modifiers in MAICs), and the poor face validity of the results. Only half of the I-O ITCs were considered acceptable by NICE for reimbursement decision-making, with NMA being the most widely used and acknowledged method. Manufacturers should ensure methodological validity and clinical plausibility to increase their chances of I-O treatment approval.

Methods such as network meta-analysis (NMA) are used frequently by the National Institute for Health and Care Excellence (NICE; United Kingdom), to indirectly compare technologies' clinical effectiveness. NICE Decision Support Unit (DSU) Technical Support Documents (TSD) encourage the use of WinBUGS to conduct NMAs. We explored indirect comparison software trends within NICE Technology Appraisal (TA) submissions. We reviewed a random sample of 50% of NICE TAs submitted between March 2000 to May 2022 and recorded whether an indirect comparison was included, and which software was used. We excluded terminated TAs and TAs that did not assess investigational drugs. Main data sources included the company submission and Evidence Assessment Group critique. We included 299 TAs; 168 reported at least one indirect comparison. The most frequently reported analyses were NMA and mixed treatment comparison (MTC; 95/168), indirect treatment comparison (ITC; 51/168), and population-adjusted indirect comparison (PAIC; 33/168). Of those, 104 TAs reported what software was used, including 21 TAs that used more than one software. Of the TAs submitting an NMA/MTC, 81 reported the software used (BUGS: 62; R, either as standalone or as interface to another software: 21; JAGS: 9). ITCs were conducted using R, BUGS and SAS. TAs reporting PAIC methods were more likely to use R (7/13), followed by BUGS (4/13). Convergence issues were mentioned in approximately one-third of TAs, and 30% that used BUGS developed their own code. Use of R has increased within TAs since 2015 and use of JAGS has been reported from 2016 onwards. Our analyses show that NICE TA submissions often include indirect comparisons, for which BUGS is commonly used. However, the increased use of R and JAGS in recent years demonstrates the diversified use and acceptance of statistical software beyond those recommended by the NICE DSU.

Over the last decade, the rapid development of immuno-oncology (I-O) therapies has transformed the cancer treatment landscape. However, a thorough analysis of the rationale behind I-O reimbursement is yet to be provided. We evaluated the I-O treatment appraisal process by the National Institute for Health and Care Excellence (NICE) in the UK, to quantify their success rate and highlight the main reimbursement barriers. We used the Cancer Research Institute classification to identify I-O therapies published between 2011-2020 from the NICE website (excluding terminated appraisals). We then extracted approval determinants, including all NICE critiques of I-O treatment clinical and cost-effectiveness evidence, from Final Appraisal Documents. Of the 75 I-O appraisals identified, 62.6% (47/75) were recommended for reimbursement by the National Health Service, 22.7% (17/75) within the Cancer Drugs Fund (CDF), and 14.7% (11/75) were not recommended. Most NHS-recommended treatments (59.6%, 28/47) demonstrated significantly improved overall survival (OS) during clinical trials, as opposed to 35.3% (6/17) of CDF-recommended treatments, for which OS uncertainties were frequent. The majority of non-recommended treatment also improved OS (63.6%, 7/11); the main barrier to their reimbursement was their incremental cost-effectiveness ratio (ICER) exceeding the NICE accepted threshold. Notably, due to modest clinical effectiveness only 27.3% (3/11) of non-recommended treatments met NICE's end-of-life criteria (for which the accepted ICER threshold is substantially higher than treatments that do not meet these criteria) as opposed to 53.2% (25/47) of recommended treatments. Additional barriers to recommendation were OS data immaturity, leading to uncertainties in long-term survival extrapolations (3/11), and lack of survival benefit (3/11). Trial treatment regimen and choice of efficacy outcomes were also frequently criticised by NICE. Most I-O treatments receive positive recommendations by NICE. However, manufacturers should beware that high ICERs, not meeting end-of-life criteria and long-term survival benefit uncertainties can undermine I-O approval.

Immuno-oncology (I-O) therapies have emerged as an alternative approach to chemotherapy and other cancer treatments over the last decade. However, their reimbursement can be hindered by biological complexity and higher costs than other cancer therapies. We attempted to quantify the success rate of I-O treatments vs other cancer treatments appraised by the National Institute for Health and Care Excellence (NICE) in the UK. We identified oncology technology appraisals published by NICE between 2011-2020 and categorised I-O treatments based on the Cancer Research Institute classification. We defined success as the treatment being reimbursed by the National Health Service (NHS) or by the Cancer Drugs Fund (CDF). Of 400 NICE appraisals, 95/400 (23.7%) assessed I-O treatments (75 completed, 20 terminated), and 126/400 (31.5%) assessed other oncology treatments, including chemotherapy and targeted therapies (109 completed, 17 terminated). The number of appraisals per year increased from 4 (2011) to 18 (2020) for I-O, and from 6 to 14 for other oncology treatments. Recommended I-O therapies were less likely to be reimbursed within the NHS (47/75, 62.6% vs 82/109, 75.2%) and twice as likely to be reimbursed within the CDF (17/75, 22.7% vs 12/109, 11.0%) compared to other cancer therapies, possibly indicating a higher uncertainty of I-O effectiveness. The most appraised I-O treatments were checkpoint inhibitors, recommended in 30/32 appraisals (93.7%; 19 NHS, 11 CDF). Most non-I-O therapies were tyrosine kinase inhibitors, which received positive recommendations in 41/53 appraisals (77.4%; 37 NHS, 4 CDF). The rate of negative recommendations was similar for I-O and other cancer treatments (11/75, 14.7% vs 15/109, 13.8%, respectively). I-O treatments had a similar success rate as other cancer treatments (85.3% vs 86.2%, pooling NHS and CDF recommendations); however, a greater proportion of I-O treatments were funded under the CDF, potentially due to effectiveness uncertainties. . .

Insertable cardiac monitors (ICMs) are more likely than standard of care (SoC) intermittent external ECG monitors to detect atrial fibrillation (AF) in patients with cryptogenic stroke (CS). Anticoagulation is proven to decrease recurrent stroke risk in patients with documented AF. We aimed to evaluate the cost-effectiveness of immediate ICM at hospital discharge versus a 'short-to-long-term monitoring' (STLM) approach (7-day ECG monitor followed by ICM in patients remaining undiagnosed) and versus SoC, in a CS population. A lifetime Markov model assessed the cost-effectiveness of immediate ICM vs. STLM vs. SoC, from a US payer perspective. Patient characteristics and AF detection rates were based on the CRYSTAL-AF trial: three-year diagnostic yield was 30% with ICM and 3% in SoC; 1% of STLM patients are diagnosed with initial 7-day monitor. AF detection resulted in a change from aspirin to NOAC, unless precluded by prior bleeds. Subsequent risks of ischemic strokes and bleeding events were modeled based on published literature. Costs and effects were discounted at 3% annually. Immediate ICM was associated with a 0.20 quality-adjusted life year (QALY) gain compared to SoC (6.99 vs. 6.79) and $6,588 higher per-patient costs, resulting in an incremental cost-effectiveness ratio of $33,169 per QALY gained. ICM's expected value improved with increased recurrent stroke risk. Compared to STLM, immediate ICM was associated with lower costs ($54,480 vs. $54,665), and a modest benefit in outcomes (gain of 0.0011 QALYs) making it economically dominant for AF detection. In sensitivity analysis, the immediate ICM approach remained cost-saving when varying the duration of initial short-term monitor (1-, 2-, 21-, and 30-days). ICMs are a cost-effective diagnostic tool for the prevention of recurrent stroke in a US cryptogenic stroke population. Immediate ICM was cost-saving compared to STLM, due to the cost and low diagnostic yield of short-term monitoring and delay in AF detection.

Treatment-resistant depression (TRD) is a debilitating condition with a significant impact on patients and carers, and health care spending. Treatment resistance occurs in approximately 30% of individuals affected by Major Depressive Disorder. This analysis explored the potential cost-effectiveness of introducing vagus nerve stimulation (VNS) adjunctive to treatment as usual (TAU) for patients with TRD who have failed on ≥4 adequate anti-depressant treatments in England and Wales. A Markov model simulated patient transitions between health states defined by type of treatment, battery status and disease severity, as defined by Montgomery–Åsberg Depression Rating Scale score. Effectiveness was based on individual patient data from the D-21 dosing trial and the D-23 observational study assessing the effectiveness of VNS plus TAU compared to TAU alone. Hypothetical patients included those with moderate and severe depression at baseline, reflecting the population that would be eligible for VNS. The model had a 10-year time horizon and took a UK NHS perspective. Longer time horizons were also explored, as was a societal perspective. Costs and benefits were discounted at a rate of 3.5%. One-way deterministic, probabilistic and scenario analyses were undertaken to test various model inputs. When considering direct costs, the total cost of the VNS strategy was £42,589 compared to £29,928 for TAU. VNS generated 0.42 incremental quality-adjusted life-years (QALYs) compared to TAU, giving an incremental cost-effectiveness ratio (ICER) of £29,995 per QALY gained. When societal costs were considered, the VNS strategy dominated. In the probabilistic sensitivity analysis, VNS had a 50% probability of being cost-effective at a willingness-to-pay threshold of £30,000 per QALY. Extending the time horizon of the analysis to 20 years resulted in an ICER of £25,764. This analysis shows that VNS in addition to TAU could represent a cost-effective option for patients with TRD in the UK.

To estimate the cumulative incidence of colectomy for ulcerative colitis (UC) patients in the UK, and the risk of perioperative complications and mortality. A literature review was conducted using Medline. Search keywords included UC, terms for surgical interventions such as colectomy, proctocolectomy, ileal pouch anal anastomosis, ileoanal pouch, pouch surgery, ileorectal anastomosis, and ileostomy. Paediatric population studies were excluded. In addition, the review considered data from the UK inflammatory bowel disease (UK IBD) audits in 2012 and 2014. The Medline search identified 310 unique records. Nine studies reported data on UK patients. Five of them considered only emergency operations for the management of acute exacerbations. From the remaining four records, two publications reported data from large, population-based studies, with 15 and 20 years of patient follow-up. The evidence suggested a linear increase in the incidence after the first 5 years since diagnosis. The cumulative probability of colectomy ranged from 6.9% over 15 years in one study to 8.3% and 11.2% at 10 and 20 years since diagnosis in the second study. This cumulative risk was lower, but broadly within the range of colectomy incidence rates presented by other studies from Norway or a multi-country meta-analysis of population-based studies for surgery in inflammatory bowel diseases. The UK IBD reported complications among 32% and 35% of patients undergoing elective and non-elective surgery respectively, with wound infection being the most common event. The overall mortality was reported to be reduced by 19% between two consecutive versions of the audit: 0.92% (28/3049) in 2010-2012 and 0.75% (30/3987) in 2012-2014. Colectomy is still the last option for UC patients with an inadequate response to pharmacological treatments. The cumulative probability of colectomy, since diagnosis of UC, showed a steady increase but remained in comparable levels with other non-UK studies.

To compare the clinical efficacy and safety of tofacitinib, an orally administered small molecule therapy, with approved biologic therapies for the treatment of moderately to severe active ulcerative colitis (UC). A systematic review was conducted to identify randomised controlled trials (RCTs) reporting pre-defined efficacy and safety endpoints for tofacitinib or biological therapies (adalimumab, golimumab, infliximab and vedolizumab). Clinical response and clinical remission after a short-term induction phase (6-10 weeks) and at the end of a longer-term maintenance phase (52-60 weeks) were evaluated using a random effects Bayesian multinomial likelihood model with probit link. Patients with and without prior exposure to TNF inhibitor (TNFi) drugs were considered separately. Sensitivity analyses tested alternatives to the population inclusion criteria (TNFi-failure vs TNFi-exposure) and clinical endpoints (centrally versus locally assessed endoscopic sub-scores). Safety outcomes, including serious infections, were also explored. The network meta-analyses (NMA) adhered to NICE-recommended methods. Searches of Medline, Embase and Cochrane were last performed April 2019. Seventeen RCTs were included in the NMAs. No statistically significant differences between biological therapies and tofacitinib for either TNFi-naïve or TNFi-exposed patients were observed. In TNFi-naïve patients, all therapies were more efficacious than placebo, with infliximab, vedolizumab and tofacitinib ranked best in induction and tofacitinib, vedolizumab and golimumab ranked best in maintenance. In TNFi-exposed patients, only tofacitinib was significantly more efficacious than placebo as induction therapy, and only tofacitinib and vedolizumab were significantly more efficacious as maintenance therapies. Results of the NMA sensitivity analyses were consistent with the base case. There were no significant differences in serious infection rates among therapies. This study provides a contemporary and robust assessment of the relative efficacy and safety of targeted therapies for patients with UC, with specific regard for TNFi-naïve and TNFi-exposed subgroups. These results show that tofacitinib is efficacious in both populations.

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon which has a major impact on patients' health related quality of life and a substantial burden on health care budgets. The objective of this analysis was to evaluate the cost-effectiveness of tofacitinib and other approved biologic therapies for the treatment of moderately to severe active UC in the United Kingdom. A Markov model compared the lifetime costs and consequences of treatment with tofacitinib, adalimumab, golimumab, infliximab, vedolizumab and conventional therapy. The analysis took a National Health Service (NHS) perspective and measured benefits in quality-adjusted life years (QALYs). Patients transitioned between health states (defined by treatment and level of disease control) based on results of a network meta-analysis of clinical response and clinical remission. Utility values and estimates of resource use were sourced from systematic reviews of the published literature. Drug, disease monitoring, adverse event and colectomy costs were obtained from UK sources. Analyses were conducted separately for patients with and without prior TNF inhibitor (TNFi) exposure. Deterministic and probabilistic sensitivity analysis were undertaken. The incremental cost-effectiveness ratios for tofacitinib versus conventional therapy were £21,338 and £22,816 per QALY in the TNFi-naïve and TNFi-exposed populations, respectively. TNFi therapies were dominated or extendedly dominated in both populations. Compared with vedolizumab, tofacitinib generated a similar number of QALYs at a lower cost. Results were most sensitive to variation in response and remission rates and to costs of conventional therapy and serious infections. Probabilistic sensitivity analysis showed that tofacitinib had the highest likelihood of being cost effective at a threshold of £30,000 per QALY: 54% and 46% in in TNFi-naïve and TNFi-exposed patients, respectively. Tofacitinib is an efficacious treatment for moderately to severely active UC and is likely to be a cost-effective use of NHS resources.

Heart Failure: new targets for treatment / Health economics and policy to improve cardiovascular care and outcomes 645 Methods: Pressure overload in mice was induced via transverse aortic constriction (TAC) surgery leading to hypertrophic adaptation and finally heart failure.Mice underwent echocardiography 1 week (hypertrophy) and 8 weeks (heart failure) post TAC with subsequent isolation of the left ventricle (LV).Human samples were obtained from heart transplants.We analysed total RNA expression via next generation sequencing (NGS) and RNA methylation with a Methylated RNA Immunoprecipitation (MeRIP) prior to sequencing.Translation efficiency was analysed by polysomal profiling and subsequent NGS of polysomal fractions.Results: We could show, that ∼25% of all mRNAs are methylated in LV tissue from both, mouse and human.Furthermore we observed a RNA methylation pattern change from compensated hypertrophy to heart failure in the TAC mouse model.Interestingly, no correlation was seen between methylation and expression of genes in response to hypertrophic changes.Changes in methylation mainly occurred in the coding sequence (CDS) and the 3' untranslated region (3'UTR) of mRNAs.Similar results were obtained from human samples of patients with heart failure.Transcripts prevalently hyper methylated in the 5'UTR showed correlation with a higher expression level.Polysomal sequencing revealed a strong correlation between methylation of the CDS and expression efficiency.Conclusions: We conclude that m6A-methylation is a conserved mechanism playing an important role in the development of heart failure, even if the underlying mechanisms were not elucidated until now.Furthermore, especially 3'UTR methylation is of big interest as it contains miR binding sites, regulatory protein binding sites and silencer regions which can be influenced by a methylation change.This adds another layer of transcriptional and translational regulation via miR interactions, even more as miRs can be methylated themselves.A higher methylation of the 5'UTR and CDS enhances gene expression which suggests new insights into translation efficiency regulation by m6A methylation.

Atrial fibrillation (AF) is a major risk factor for stroke and is managed via oral anticoagulation (OAC) after a confirmed diagnosis. Continuous monitoring with an insertable cardiac monitor (ICM) in the REVEAL AF study demonstrated a high incidence of AF in high-risk patients where previous external monitoring (≥24 hours) was negative. Currently it is unknown whether ICM monitoring to detect AF is cost-effective in this population. A Markov model was designed to synthesise clinical evidence with costs and patient quality of life. The UK NHS perspective was used. The model input was based on a large, prospective, single-arm, multicenter study that included patients with an ICM (REVEAL AF). The diagnostic yield of alternative testing strategies was simulated from ICM data. The model included treatment with OAC after AF detection; the incidence of ischaemic strokes and major and minor bleeding events was based on published literature. One-way deterministic and probabilistic sensitivity analyses were undertaken to test key model inputs. For the average patient (aged 71.3 and with a virtual CHADS2 score of 2.94), the total cost for the ICM device was £2,891. When considering all costs, including treatment and downstream events, the total per-patient cost for an ICM-based strategy was £13,370, compared with £12,946 for an annual 24h Holter (Standard-of-Care, "SoC"). ICMs generated 6.51 QALYs vs. 6.31 for SoC, giving an incremental cost-effectiveness ratio of £7,128/QALY. In probabilistic sensitivity analysis, using a £20,000 willingness-to-pay threshold, the probability of ICMs being cost-effective was 78.4%. The model results were sensitive to the rate patients initiated and discontinued treatment after a diagnosis, the type of OAC used, and the intensity of monitoring methods assumed for SoC. The use of ICMs to identify AF in a high-risk population is cost-effective for the UK NHS.

To compare the clinical efficacy of brodalumab, an anti-IL 17RA human monoclonal antibody, with approved biologic therapies and apremilast for the treatment of moderate-to-severe psoriasis. A PRISMA-compliant systematic literature review identified RCTs reporting induction phase Psoriasis Area Severity Index (PASI) responses for therapies at European Medicines Agency approved doses. The primary analysis examined the proportion of patients achieving PASI 50, 75, 90 or 100 responses using a random effects Bayesian multinomial likelihood model with probit link, without and with an adjustment for study-level placebo responses. A second analysis assessed the number of patients with Physician Global Assessment (PGA) scores of 0 or 1. Effects of alternative inclusion criteria, such as including unlicensed therapies and introducing restrictions based on disease severity, were explored in a series of sensitivity analyses. The NMA adhered to NICE Decision Support Unit recommended methods. A total of 41 studies reporting PASI outcomes were included in the base case NMA. All active therapies were found to be significantly more efficacious than placebo at achieving all levels of PASI response. Based on PASI 100 response (complete clearance), the most efficacious therapies in the network were brodalumab and ixekizumab, followed by infliximab and secukinumab. Brodalumab was significantly more efficacious than adalimumab, apremilast, etanercept and ustekinumab. This ranking was consistent for PASI 50, 75 and 90 outcomes, as well as the PGA response analysis and all sensitivity analyses. Results of the NMA reflect the results from recent pivotal trials which found that high levels of complete clearance can be achieved with brodalumab. Based on currently available evidence, the induction-phase efficacy of brodalumab is similar to ixekizumab, secukinumab and infliximab and superior to other approved therapies, including adalimumab, apremilast, etanercept, and ustekinumab. Analysis of longer-term data is needed to understand the comparative efficacy biological therapies beyond induction.

Patients with moderate-to-severe psoriasis require long-term treatment, yet few clinical trials compare outcomes beyond a short-term induction period. To our knowledge, no network meta-analysis (NMA) of longer-term data has been performed. This NMA aimed to compare longer-term outcomes of currently approved biological therapies and apremilast. A systematic review (2000 to August 2016) identified studies reporting Psoriasis Area Severity Index (PASI) 75, 90 and 100 responses. Feasibility of an NMA on maintenance phase PASI endpoints was assessed and sources of heterogeneity considered. Data appropriate for analysis were modelled using a Bayesian multinomial likelihood model with probit link. Wherever possible, study data corresponding to an intention-to-treat approach with non-responder imputation was used. Twenty-two studies reporting outcomes at 40-60 weeks were included, but heterogeneity in study design led to use of a step-wise approach to the synthesis. Four 52-week RCTs were included in the primary indirect comparison, which found brodalumab to be significantly more efficacious than secukinumab (Risk ratio: 1.32 [95% Credible Interval: 1.06, 2.02]), ustekinumab (1.90 [1.26, 3.46]) and etanercept (3.31 [1.58, 10.00]) in terms of PASI 100 response. In secondary analyses, 18 additional studies and four more drugs were included in the network by comparing maintenance phase outcomes from active interventions to induction phase outcomes from placebo arms. For this it was assumed that, had placebo therapy been continued, no change in response would have been observed between end of induction and maintenance. Results were consistent with the main analysis: brodalumab appeared to be most effective, followed by ixekizumab, secukinumab, ustekinumab, infliximab, adalimumab, etanercept and apremilast. Results of this NMA suggest that brodalumab is associated with the highest likelihood of maintained PASI response after a year of treatment. Further long-term active-comparator RCT data is required to better assess relative efficacy across the range of currently approved therapies.

Background: No head-to-head trials have compared biologic treatments for early active RA (ERA).We evaluated the effectiveness of tocilizumab (TCZ) compared with other traditional and biologic DMARDs (tDMARDs and bDMARDs) in adult patients with moderateto-severe ERA naive to MTX or bDMARDs.Methods: A literature review identified randomized controlled trials (RCTs) of tDMARDs and bDMARDs in patients with ERA (duration <3 years) reporting efficacy outcomes (proportions of patients achieving ACR scores of 20, 50, 70 and 90; DAS for 28 joints (DAS28)-defined remission (DAS28 <2.6).Bayesian network meta-analysis was performed.For ACR response, data were analysed using a fixedeffects (FE) ordered probit model.For DAS remission, data were analysed with an FE binomial logit model.The analysis included only results for treatments at licenced doses.Sensitivity analyses were performed for treatment class and inclusion criteria.Results: 16 RCTs of tDMARDs (MTX, SSZ, HCQ), bDMARDs [abatacept (ABT), adalimumab (ADA), etanercept (ETN), infliximab (IFX), golimumab (GOL), TCZ), and tofacitinib (Tofa) were included.All bDMARDs plus MTX, triple tDMARD therapies, and TCZ and Tofa in monotherapy significantly increased response across all ACR categories versus MTX.Probabilities of ACR response to bDMARDs plus MTX were broadly similar, with no significant differences between agents.Probabilities of ACR response to bDMARDs in monotherapy were more varied, with a trend toward higher values for Tofa and TCZ than for ETN or ADA.Only a subset of studies reported DAS remission.Treatment with Tofa or any bDMARD (AEMTX), except ADA alone, improved the likelihood of DAS remission versus MTX.TCZ (AE MTX) generated the highest probability of remission among bDMARDs and was significantly more effective than all other bDMARDs (AEMTX) and Tofa.Results were robust to sensitivity analyses.Conclusion: Based on ACR response, the expected efficacy of bDMARDs plus MTX, Tofa and TCZ monotherapy, and triple tDMARD therapy appears comparable in early RA.TCZ and Tofa in monotherapy are more effective than ADA alone and are likely to be more effective than ETN alone.TCZ AE MTX is expected to have the highest probability of generating DAS remission.Disclosure statement: L.S. has acted as a consultant for Roche.

To assess the cost-utility of Tocilizumab (TCZ) in the treatment of methotrexate (MTX)-naïve adults with active rheumatoid arthritis (RA) in Slovakia. A decision tree model was developed to reflect the early management of MTX-naïve adult RA patients in Slovakia. Efficacy, DAS28 remission, for each treatment in the model was derived from a network meta-analysis (NMA) of randomised controlled trials (RCTs) [Sawyer et al. 2015]. Benefits were measured in Quality Adjusted Life years (QALYs) derived by mapping DAS28 scores onto EQ-5D utility weights. The analysis was conducted from the third-party payer perspective, and included direct medical costs (drugs, administration, monitoring). The time horizon is one year, in line with the maximum follow-up period from RCTs. Incremental costs and QALYs associated with TCZ±MTX were compared to anti-tumour necrosis factors (TNFs), including adalimumab (ADA), etanercept (ETN) and infliximab (IFX), within their licensed indications. Each treatment was also compared to MTX alone. Variables related to efficacy, cost and utility were tested in the sensitivity analysis. TCZ±MTX had a lower incremental cost-effectiveness ratio (ICER) than other TNFs ±MTX when compared to MTX alone in base case. When compared head-to-head with TNFs, TCZ was cost-effective, with ICERs range from €6,500 to €16,000 per QALY gained in monotherapy and from €10,000 to €24,000 per QALY gained in combination therapy. Furthermore, TCZ+MTX dominated IFX+MTX. The full incremental analysis showed that TCZ±MTX was the next most cost-effective strategy after MTX. Results of the sensitivity analysis showed the efficacy variables and the assumption on the utility mapping formula have an impact on the ICERs. The results suggest TCZ is a cost-effective alternative to the approved and reimbursed TNFs, used either as monotherapy or in combination with MTX in the treatment of MTX-naïve adult RA patients in Slovakia.