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Abstract Background: Third-generation aromatase inhibitors (letrozole, anastrozole) have shown superior efficacy in early and advanced breast cancer compared with tamoxifen. For HR+, HER2+ MBC, combination of an AI with an anti-HER2 agent (lapatinib or trastuzumab) has shown clinical benefit. Methods: Six databases were searched until January 2009 for randomized controlled clinical trials, assessing the safety and efficacy of first-line treatments for postmenopausal women with HR+ and HER2 (ErbB2) positive MBC, who have not received prior therapy for advanced or metastatic disease. Relevant interventions were lapatinib, aromatase inhibitors, tamoxifen, and trastuzumab. Outcomes included overall survival (OS), progression-free-survival (PFS), time-to-progression (TTP), and objective response rate (ORR). Results: Eighteen studies (62 papers) were included. Lapatinib + letrozole was significantly superior to letrozole alone based on a direct head-to-head study in terms of PFS/TTP and ORR. Using a network meta-analysis, compared with lapatinib + letrozole, tamoxifen (HR = 0.45 (95% CI: 0.32, 0.65) and anastrozole (HR = 0.53 (0.36, 0.80)) scored significantly worse in terms of PFS/TTP and ORR (tamoxifen: OR = 0.25 (0.12, 0.53), anastrozole: OR = 0.27 (0.12, 0.58). The combination also seemed significantly superior to exemestane in terms of PFS/TTP (HR = 0.52 (0.34, 0.79)). Lapatinib + letrozole also seemed better, although not significantly, in terms of OS versus tamoxifen: HR = 0.74 (0.49, 1.12), anastrozole: HR = 0.71 (0.45, 1.14) and exemestane: HR = 0.65 (0.39, 1.11). When compared with trastuzumab + anastrozole, lapatinib + letrozole seemed to be better in terms of OS (HR = 0.85 (0.47, 1.54)), PFS/TTP (HR = 0.89 (0.54, 1.47)) and ORR (OR = 0.92 (0.24, 3.48)), although, none of these results were significant. Discussion: Lapatinib + letrozole was significantly superior to letrozole in terms of PFS/TTP and ORR based on a direct head-to-head study. Indirect comparisons appeared to favor lapatinib + letrozole versus other first-line treatments used in this patient population in terms of three main outcomes: OS, PFS/TTP and ORR. Indirect comparison results are based on a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with caution. [ABSTRACT FROM AUTHOR]

Abstract Objective: To systematically assess efficacy and safety of buprenorphine patch versus fentanyl patch in patients with chronic moderate to severe pain. Methods: Fifteen databases were searched up to December 2010. Randomised and quasi-randomised trials assessing the efficacy in patients with chronic pain were included. Quantitative methods for data synthesis were used and two network meta-analyses were conducted. Results: Fourteen unique trials (17 publications) were included. No head-to-head randomised trials of buprenorphine patch compared with fentanyl patch were identified. Therefore, less robust evidence from indirect comparisons was used. Results from a network meta-analysis of non-enriched designs (eight trials), using trials versus placebo and trials versus morphine for indirect comparisons, indicated that transdermal fentanyl, in comparison with transdermal buprenorphine, showed significantly more nausea (odds ratio [OR] 4.66, 95% confidence interval (CI) 1.07 to 20.39), a significantly higher number of treatment discontinuations due to adverse events (OR 5.94, 95% CI 1.78 to 19.87), and non-significant differences on all other outcomes, including pain measures. In comparison with morphine, transdermal buprenorphine had a significantly higher decrease of pain intensity (MD [mean difference] -16.20, 95% CI -28.92 to -3.48) while morphine caused more cases of constipation (OR 7.50, 95% CI 1.45 to 38.85) and a significantly higher number of treatment discontinuations due to adverse events (OR 5.80, 95% CI 1.68 to 20.11). All other outcomes showed non-significant differences between transdermal buprenorphine and morphine. The results were similar when also including six trials using enriched designs with the exception of more cases of vomiting for fentanyl (OR 17.32, 95% CI 4.43 to 67.71) and morphine (OR 15.85, 95% CI 3.92 to 64.13) compared to buprenorphine. Conclusions: The findings indicate comparability of transdermal buprenorphine and transdermal fentanyl for pain measures with significantly fewer adverse events (nausea and treatment discontinuation due to adverse events) caused by transdermal buprenorphine. [ABSTRACT FROM AUTHOR]

DUTCH-AIMS2, a Dutch version of AIMS2 and successor to DUTCH-AIMS, is an instrument to assess health status among patients with rheumatic diseases. It provides measurements of 12 areas of health status on scales for health status proper, satisfaction, attribution and arthritis impact. We assessed the reliability of its scales in terms of internal consistency and their validity according to both internal standards and external standards. Correctly completed questionnaires were returned by 231 RA patients and 131 controls. Internal consistency coefficients for the health status scales ranged from 0.66 and 0.89, but most exceeded 0.80. Within-scale factor analyses produced single factors in all composite health status scales for both patients and controls, with only two exceptions. Factor analysis also identified a physical, social and psychological dimension among 11 areas of health. External validity was established by strong correlations between DUTCH-AIMS2 health status scales and functional class, laboratory parameters, and self-assessments of fatigue, loneliness, pain, functional disability and social support. DUTCH-AIMS2 is acceptably reliable and valid for use in a variety of settings. [ABSTRACT FROM PUBLISHER]

Abstract Background To undertake a systematic review of the available data for oral and intravenous topotecan in adults with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first line regimen is not considered appropriate. Methods We searched six databases from 1980 up to March 2009 for relevant trials regardless of language or publication status. Relevant studies included any randomised trial of any chemotherapeutic treatment against any comparator in this licensed indication. Where possible we used apposite quantitative methods. Where meta-analysis was considered unsuitable for some or all of the data, we employed a narrative synthesis method. For indirect comparisons we used the method of Bucher et al., where available data allowed it, otherwise we used narrative descriptions. Results Seven unique studies met the inclusion criteria, four of which could be used in our analyses. These included one study comparing oral topotecan plus best supportive care (BSC) to BSC alone, one study comparing intravenous topotecan to cyclophosphamide, adriamycin and vincristine (CAV), and two studies comparing oral topotecan with intravenous topotecan. All four studies appear to be well conducted and with low risk of bias. Oral topotecan plus BSC has advantages over BSC alone in terms of survival (hazard ratio = 0.61; 95% CI, 0.43 to 0.87) and quality of life (EQ-5 D difference: 0.15; 95% CI, 0.05 to 0.25). Intravenous topotecan was at least as effective as CAV in the treatment of patients with recurrent small-cell lung cancer and resulted in improved quality-of-life with respect to several symptoms. CAV was associated with significantly less grade 4 thrombocytopenia compared with IV topotecan (risk ratio = 5.83; 95% CI, 2.35 to 14.42). Survival (hazard ratio = 0.98; 95% CI, 0.77 to 1.25) and response (pooled risk ratio = 1.04; 95% CI, 0.58 to 1.85) data were similar for the oral and IV topotecan groups. Symptom control was also very similar between the trials and between the oral and IV groups. Toxicity data showed a significant difference in favour of oral topotecan for neutropenia (pooled risk ratio = 0.65; 95% CI, 0.47 to 0.89). Indirect evidence showed that oral topotecan was at least as good as or better than CAV on all outcomes (survival, response rates, toxicities, and symptoms) that allowed indirect comparisons, with the only exception being grade four thrombocytopenia which occurred less often on CAV treatment. Conclusions Concerning topotecan both the oral and intravenous options have similar efficacy, and patient preference may be a decisive factor if the choice would be between the two formulations. The best trial evidence for decision making, because it was tested versus best supportive care, exists for oral topotecan. Indirectly, because we have two head-to-head comparisons of oral versus intravenous topotecan, and one comparison of intravenous topotecan versus CAV in similar patients as in the trial against best supportive care, one might infer that IV topotecan and CAV could also be superior to best supportive care, and that oral topotecan has similar effects to CAV with possibly better symptom control. From the evidence discussed above, it is evident that oral topotecan has similar efficacy to IV topotecan (direct comparison) and CAV (indirect comparison). There is no further evidence base of direct or possible indirect comparisons for other comparators than CAV of either oral or IV topotecan.

Abstract Background Amblyopia and amblyogenic factors like strabismus and refractive errors are the most common vision disorders in children. Although different studies suggest that preschool vision screening is associated with a reduced prevalence rate of amblyopia, the value of these programmes is the subject of a continuing scientific and health policy discussion. Therefore, this systematic review focuses on the question of whether screening for amblyopia in children up to the age of six years leads to better vision outcomes. Methods Ten bibliographic databases were searched for randomised controlled trials, non-randomised controlled trials and cohort studies with no limitations to a specific year of publication and language. The searches were supplemented by handsearching the bibliographies of included studies and reviews to identify articles not captured through our main search strategy. Results Five studies met the inclusion criteria. Of these, three studies suggested that screening is associated with an absolute reduction in the prevalence of amblyopia between 0.9% and 1.6% (relative reduction: between 45% and 62%). However, the studies showed weaknesses, limiting the validity and reliability of their findings. The main limitation was that studies with significant results considered only a proportion of the originally recruited children in their analysis. On the other hand, retrospective sample size calculation indicated that the power based on the cohort size was not sufficient to detect small changes between the groups. Outcome parameters such as quality of life or adverse effects of screening have not been adequately investigated in the literature currently available. Conclusion Population based preschool vision screening programmes cannot be sufficiently assessed by the literature currently available. However, it is most likely that the present systematic review contains the most detailed description of the main limitations in current available literature evaluating these programmes. Therefore, future research work should be guided by the findings of this publication.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (GlaxoSmithKline [GSK]) of Benlysta (belimumab) to submit evidence regarding its clinical and cost effectiveness, for the review and possible extension of a previously conditionally approved intravenous formulation of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee.This appraisal is different to the previous appraisal in three ways: (1). This appraisal expands its definition of 'high disease activity'. (2). In TA397, belimumab was approved, with a managed access arrangement (MAA), for adults only. This appraisal includes subjects aged 5 years or older. (3). The original appraisal included an intravenous formulation only, but the current appraisal also includes a new subcutaneous formulation in the form of a prefilled pen.The company was required to collect real-world data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR), including data on the efficacy, safety, and effect on health-related quality of life of belimumab versus rituximab. This appraisal considers these data as well as additional clinical trial evidence presented in the company's updated submission to address uncertainties identified during the original appraisal. The ERG identified three major concerns with the evidence presented on the clinical effectiveness in the current submission; namely, short follow-up in the main comparative trials (BLISS-SC, BLISS-52 and BLISS-76); using the propensity score-matching (PSM) analysis in calibrating the cost-effectiveness model can severely bias the results in favour of belimumab; and BILAG-BR data are not suitable for a comparison of belimumab with rituximab.The main issue in the economic analysis was the uncertainty about long-term disease activity progression and resulting organ damage. The company's approach of calibrating modelled organ damage to longer-term data analysed using the PSM analysis was methodologically inappropriate. The final analysis comparing belimumab with standard treatment for the intravenous formulation resulted in an incremental cost-effectiveness ratio of £12,335 per quality-adjusted life-year (QALY) gained and £30,278 per QALY gained in the company's and ERG's base-case analyses, respectively. For the subcutaneous formulation, the final analysis resulted in £8480 per QALY gained and £29,313 per QALY gained in the company's and ERG's base-case analyses, respectively. NICE recommended belimumab in both intravenous and subcutaneous formulations as an add-on treatment option for active autoantibody-positive SLE in the HDA-2 subgroup., (© 2022. The Author(s).)

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Gilead) of filgotinib (Jyseleca TM ), as part of the single technology appraisal process, to submit evidence for its clinical and cost effectiveness for the treatment of patients with moderate to severe rheumatoid arthritis (RA). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee. The evidence for filgotinib was based on two good-quality international randomised controlled trials. In FINCH 1, filgotinib was compared with placebo, and in FINCH 2, filgotinib was compared with adalimumab and placebo. As there was no head-to-head evidence with most active comparators, the company performed two separate network meta-analyses (NMAs), one for the conventional disease-modifying antirheumatic drugs-inadequate response population and one for the biological disease-modifying antirheumatic drugs-inadequate response population. The outcomes analysed were American College of Rheumatology response criteria at weeks 12 and 24, and European League Against Rheumatism response criteria at 24 weeks. The statistical methods used to perform the NMAs were valid and were in line with previous NICE appraisals. Results of the NMAs are confidential and cannot be reported here, but they were uncertain due to heterogeneity of the included studies. The economic analysis of the patient population with moderate RA suffered from limited evidence on the progression from moderate to severe health states. For the moderate RA population, the final analyses comparing filgotinib, with or without methotrexate, against standard of care resulted in incremental cost-effectiveness ratios of around £20,000 per quality-adjusted life-year gained in the company's and ERG's base-case and scenario analyses. NICE recommended filgotinib in combination with methotrexate or as monotherapy when methotrexate is contraindicated, or if people cannot tolerate it, for patients with moderate RA whose disease had responded inadequately to two or more conventional disease-modifying antirheumatic drugs (DMARDs). For the severe RA population, in view of the higher or similar net health benefits that filgotinib provided versus its comparators, NICE recommended filgotinib with or without methotrexate for patients whose disease had responded inadequately to two or more conventional DMARDs, who had been treated with one or more biological DMARDs, if rituximab was not an option, or after treatment with rituximab., (© 2021. The Author(s).)

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of lenalidomide (Revlimid ® ), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of lenalidomide in combination with rituximab (MabThera ® ), together referred to as R 2 , for the treatment of adults with treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included one relevant study, for the comparison of R 2 versus rituximab monotherapy (R-mono): the AUGMENT trial. In addition, the company performed an unanchored indirect comparison of R 2 versus rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and rituximab combined with cyclophosphamide, vincristine, and prednisolone (R-CVP), using data for R 2 from the AUGMENT trial and pooled data for R-CHOP/R-CVP from the Haematological Malignancy Research Network (HMRN) database. During the STA process, the company provided an addendum containing evidence on only the FL population, in line with the marketing authorisation obtained at that time, which did not include MZL. The probabilistic incremental cost-effectiveness ratios (ICERs) presented by the company were £27,768 per quality-adjusted life year (QALY) gained for R 2 versus R-CHOP, £41,602 per QALY gained for R 2 versus R-CVP, and £23,412 per QALY gained for R 2 versus R-mono. The ERG's concerns included the validity of the unanchored comparison, the unavailability of a state transition model to verify the outcomes of the partitioned survival model, substantial uncertainty in survival curves, and potential over-estimation of utility values. The revised ERG base case resulted in ICERs ranging from £16,874 to £44,888 per QALY gained for R 2 versus R-CHOP, from £23,135 to £59,810 per QALY gained for R 2 versus R-CVP, and from £18,779 to £27,156 per QALY gained for R 2 versus R-mono. Substantial uncertainty remained around these ranges. NICE recommended R 2 within its marketing authorisation, as an option for previously treated FL (grade 1-3A) in adults, contingent on the company providing lenalidomide according to the commercial arrangement.

The National Institute for Health and Care Excellence (NICE) invited Alimera Sciences, the company manufacturing fluocinolone acetonide intravitreal implant (FAc) 0.19 mg (tradename ILUVIEN ® ), to submit evidence on the clinical and cost-effectiveness of FAc for treating recurrent non-infectious uveitis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre + , was commissioned to act as the independent Evidence Review Group (ERG). This paper contains a summary of the clinical and cost-effectiveness evidence submitted by the company, the ERG's critique on the submitted evidence, and the guidance issued by the NICE Appraisal Committee (AC). The company submission (CS) was mainly informed by the PSV-FAI-001 trial in which FAc was compared with (limited) current practice [(L)CP], which was not considered to be representative of UK clinical practice by the ERG. There was no comparison of FAc to any treatment listed in the final scope, and especially to the dexamethasone intravitreal implant (dexamethasone), which was considered to be a relevant comparator by the AC. The primary outcome of the PSV-FAI-001 was recurrence of uveitis in the treated eye. Most of the events for the primary outcome were imputed during the PSV-FAI-001 trial, which probably led to an overestimation of the number of recurrences of disease, and a biased estimate of the relative effectiveness of FAc versus (L)CP. Finally, the place of FAc in the treatment pathway was not clearly defined by the company. Substantial uncertainty surrounded the cost-effectiveness results due to the shortcomings of the clinical evidence. Additionally, the quality of life of patients was not measured during the PSV-FAI-001 trial and long-term effectiveness data of FAc were lacking. The ERG adjusted several issues identified in the CS and added dexamethasone as a comparator in the decision analytic model. The ERG presented multiple analyses as base-cases because several elements of the assessment remained uncertain. The fully incremental ERG results ranged from dexamethasone (extendedly) dominating FAc (when assuming a hazard ratio of 1 or 0.7 for dexamethasone versus FAc) to an incremental cost-effectiveness ratio (ICER) of £30,153 per quality-adjusted life-year (QALY) gained for FAc versus (L)CP [when assuming a hazard ratio of 0.456 for dexamethasone versus (L)CP]. The ICER of FAc versus (L)CP ranged from £12,325 to £30,153 per QALY gained. After a second AC meeting where alternative company scenarios comparing FAc with dexamethasone were considered by the AC, the AC concluded that "the results of the company's analyses ranged from the fluocinolone acetonide implant being dominant (that is, it was more effective and costs less), to an ICER of £29,461 per QALY gained, and most of the ICERs were below £20,000 per QALY gained". Therefore, the AC recommended FAc as a cost-effective use of National Health Service (NHS) resources for treating recurrent non-infectious uveitis affecting the posterior segment of the eye in the final TA590 guidance (published July 2019).

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme; MSD) of pembrolizumab (Keytruda ® ) to submit evidence of its clinical and cost effectiveness for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma (RRcHL) who did not respond to treatment with brentuximab vedotin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. According to the NICE scope, pembrolizumab was compared with single or combination chemotherapy. Comparisons were undertaken in two populations: patients who did and did not receive prior autologous stem cell transplant (autoSCT; populations 1 and 2, respectively). Despite it having been recommended by NICE in population 1 at the time the ERG received the company submission, nivolumab was not included as a comparator. No studies directly comparing pembrolizumab and its comparators were identified. One ongoing, single-arm study of the efficacy and safety of pembrolizumab (KEYNOTE-087) and one comparative observational study (Cheah et al., 2016) were used to inform the comparative effectiveness of pembrolizumab and standard of care (SoC), using indirect comparisons in both populations. Almost all analyses showed significant PFS and overall response rate benefits for pembrolizumab versus SoC, but due to being based on indirect comparison, were likely to contain systematic error. The economic evaluation therefore suffered from substantial uncertainty in any estimates of cost effectiveness. Furthermore, there was a lack of evidence on the uptake and timing of allogeneic stem cell transplant, and alternative assumptions had a significant impact on cost effectiveness. Immature survival data from KEYNOTE-087 exacerbated this issue and necessitated the use of alternative data sources for longer-term extrapolation of survival. Some issues identified in the company's analyses were amended by the ERG. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's second Appraisal Consultation Document response for pembrolizumab versus SoC (with a commercial access agreement) for populations 1 and 2 were £54,325 and £62,527 per quality-adjusted life-year gained, respectively. There was substantial uncertainty around these ICERs, especially in population 2. NICE did not recommend pembrolizumab as an option for treating RRcHL in population 1, but recommended pembrolizumab for use within the Cancer Drugs Fund in population 2.

The National Institute for Health and Care Excellence (NICE), as part of the institute's single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1-3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was <£20,000 per quality-adjusted life-year (QALY) gained. Although the ERG concluded that the economic model met the NICE reference case to a reasonable extent, some errors were identified and several assumptions made by the company were challenged. A new base-case scenario produced by the ERG suggested an ICER that was higher than the company base case, but still below £30,000 per QALY gained. However, some ERG scenario analyses were close to or even above the threshold. This was the case in particular for assuming a treatment effect that did not extend beyond trial follow-up. These results led to an initial negative recommendation by the appraisal committee. Subsequently, the company submitted a revised base case focusing on patients at intermediate or high risk of premature mortality. Simultaneously, a further price discount for obinutuzumab was granted. In addition to the company's revised base case, the ERG suggested a restriction of the treatment effect to 5 years and implemented biosimilar uptake and cheaper prices for rituximab. All of these adjustments did not exceed £30,000 per QALY gained and therefore the use of obinutuzumab for patients with advanced FL and a Follicular Lymphoma International Predictive Index (FLIPI) score of two or more could be recommended.

The National Institute for Health and Care Excellence (NICE) invited Teva, the company manufacturing arsenic trioxide (ATO; tradename Trisenox ® ), to submit evidence for the clinical and cost effectiveness of ATO for untreated and relapsed or refractory acute promyelocytic leukaemia (APL). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG's critical review of the clinical and cost effectiveness evidence in the CS, key methodological considerations and the development of the NICE guidance by the Appraisal Committee (AC). The CS presented three randomized controlled trials (RCTs). Two of these were trials in newly diagnosed APL (APL0406 and AML17) and the third trial was in patients with relapsed APL. Results from APL0406 showed that more people having AATO [ATO plus all-trans retinoic acid (ATRA)] were alive at 50 months compared with people having AIDA (ATRA in combination with idarubicin) (99% vs. 93%; p = 0.007). There was also a statistically significant lower cumulative incidence of relapse with AATO compared with AIDA at 50 months (2% vs. 14%; p = 0.001). At 4 years, results from AML17 showed a significant difference in event-free survival (91% vs. 70%; p = 0.002) favouring AATO but not in overall survival (93% vs. 89%; p = 0.250). The only trial presented for relapsed/refractory patients compared AATO with ATO, which was not a relevant comparison according to the NICE scope. The AC concluded that AATO was effective for untreated APL while for relapsed or refractory APL the effectiveness of ATO was considered uncertain and the long-term safety remains unexplored. In the CS base-case, AATO was less expensive (£31,088 saved) and more effective (2.546 quality-adjusted life-years (QALYs) gained) than AIDA and thus the dominating strategy for newly diagnosed low- to intermediate-risk APL. However, the ERG's critical assessment highlighted a number of concerns, including deviations from the NICE reference case and a lack of detailed description and justification of parameters and assumptions related to (the extrapolation of) treatment effectiveness. However, it was reassuring that AATO for untreated APL remained dominant in the ERG base-case, and that the worst-case scenario produced by the ERG resulted in an incremental cost-effectiveness ratio (ICER) of £21,622. The AC concluded that although there was uncertainty in the model, it could recommend ATO for both untreated and relapsed or refractory APL.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Bristol-Myers Squibb) of nivolumab (Opdivo ® ) to submit evidence of its clinical and cost effectiveness for metastatic or unresectable urothelial cancer. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG), which produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. Nivolumab was compared with docetaxel, paclitaxel, best supportive care and retreatment with platinum-based chemotherapy (cisplatin plus gemcitabine, but only for patients whose disease has had an adequate response in first-line treatment). Two ongoing, phase I/II, single-arm studies for nivolumab were identified, but no studies directly compared nivolumab with any specified comparator. Evidence from directly examining the single arms of the trial data indicated little difference between the outcomes measured from the nivolumab and comparator studies. A simulated treatment comparison (STC) analysis was used in an attempt to reduce the bias induced by naïve comparison, but there was no clear evidence that risk of bias was reduced. Multiple limitations in the STC were identified and remained. The effect of an analysis based on different combinations of covariates in the prediction model remains unknown. The ERG's concerns regarding the economic analysis included the use of a non-established response-based survival analysis method, which introduced additional uncertainty. The use of time-dependent hazard ratios produced overfitting and was not represented in the probabilistic sensitivity analysis. The use of a treatment stopping rule to cap treatment cost left treatment effectiveness unaltered. A relevant comparator was excluded from the base-case analysis. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's Appraisal Consultation Document response were £58,791, £78,869 and £62,352 per quality-adjusted life-year gained versus paclitaxel, docetaxel and best supportive care, respectively. Nivolumab was dominated by cisplatin plus gemcitabine in the ERG base case. Substantial uncertainties about the relative treatment effectiveness comparing nivolumab against all comparators remained. NICE did not recommend nivolumab, within its marketing authorisation, as an option for treating locally advanced, unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy, and considered that nivolumab was not suitable for use within the Cancer Drugs Fund.

The National Institute for Health and Care Excellence, as part of the institute's single technology appraisal process, invited the manufacturer of ribociclib (Kisqali ® , Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer's decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3-not reached) vs. 14.7 months (95% confidence interval 13.0-16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft ® Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.

The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ramucirumab (Cyramza ® , Eli Lilly and Company) to submit evidence of the clinical and cost effectiveness of the drug administered alone (monotherapy) or with paclitaxel (combination therapy) for treating adults with advanced gastric cancer or gastro-oesophageal junction (GC/GOJ) adenocarcinoma that were previously treated with chemotherapy, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and NICE's subsequent decisions. Clinical effectiveness evidence for ramucirumab monotherapy (RAM), compared with best supportive care (BSC), was based on data from the REGARD trial. Clinical effectiveness evidence for ramucirumab combination therapy (RAM + PAC), compared with paclitaxel monotherapy (PAC), was based on data from the RAINBOW trial. In addition, the company undertook a network meta-analysis (NMA) to compare RAM + PAC with BSC and docetaxel. Cost-effectiveness evidence of monotherapy and combination therapy relied on partitioned survival, cost-utility models. The base-case incremental cost-effectiveness ratio (ICER) of the company was £188,640 (vs BSC) per quality-adjusted life-year (QALY) gained for monotherapy and £118,209 (vs BSC) per QALY gained for combination therapy. The ERG assessment indicated that the modelling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. The ERG provided a new base case, with ICERs (vs BSC) of £188,100 (monotherapy) per QALY gained and £129,400 (combination therapy) per QALY gained and conducted additional exploratory analyses. The NICE Appraisal Committee (AC), considered the company's decision problem was in line with the NICE scope, with the exception of the choice of comparators for the combination therapy model. The most plausible ICER for ramucirumab monotherapy compared with BSC was £188,100 per QALY gained. The Committee considered that the ERG's exploratory analysis in which RAM + PAC was compared with PAC by using the direct head-to-head data (including utilities) from the RAINBOW trial, provided the most plausible ICER (i.e. £408,200 per QALY gained) for ramucirumab combination therapy. The Committee concluded that end-of-life considerations cannot be applied for either case, since neither failed to offer an extension to life of at least 3 months. The company did not submit a patient access scheme (PAS). After consideration of the evidence, the Committee concluded that ramucirumab alone or with paclitaxel could not be considered a cost-effective use of National Health Service resources for treating advanced GC/GOJ patients that were previously treated with chemotherapy, and therefore its use could not be recommended. We might wonder if a complete STA process is necessary for treatments without a PAS, which are, according to the company's submission, already associated with ICERs far above the currently accepted threshold in all (base-case, sensitivity and scenario) analyses.

Background: Incontinence constitutes a major health problem affecting millions of people worldwide. The present study aims to assess cure rates from treating urinary (UI) or fecal incontinence (FI) and the number of people who may remain dependent on containment strategies., Methods: Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and PEDro were searched from January 2005 to June 2015. Supplementary searches included conference abstracts and trials registers (2013-2015). Included studies had patients ≥ 18 years with UI or FI, reported treatment cure or success rates, had ≥ 50 patients treated with any intervention recognized in international guideline algorithms, a follow-up ≥ 3 months, and were published from 2005 onwards. Title and abstract screening, full paper screening, data extraction and risk-of-bias assessment were performed independently by two reviewers. Disagreements were resolved through discussion or referral to a third reviewer where necessary. A narrative summary of included studies is presented., Results: Most evidence was found for UI: Surgical interventions for stress UI showed a median cure rate of 82.3% (interquartile range (IQR), 72-89.5%); people with urgency UI were mostly treated using medications (median cure rate for antimuscarinics = 49%; IQR, 35.6-58%). Pelvic floor muscle training and bulking agents showed lower cure rates for UI. Sacral neuromodulation for FI had a median cure rate of 38.6% (IQR, 35.6-40.6%)., Conclusions: Many individuals were not cured and hence may continue to rely on containment. No studies were found assessing success of containment strategies. There was a lack of data in the disabled and in those with neurological diseases, in the elderly and those with cognitive impairment. Surgical interventions were effective for stress UI. Other interventions for UI and FI showed lower cure rates. Many individuals are likely to be reliant on containment strategies., Prospero Registration: PROSPERO registration number: CRD42015023763 .

The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga ® ), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting (i.e. best supportive care [BSC]) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG report, subsequent addenda, and the development of the NICE guidance for the use of this drug in England and Wales by the Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of AAP based on the CS. An important question in this appraisal was, according to the ERG, whether AAP followed by docetaxel is more effective than BSC followed by docetaxel. In the COU-AA-302 trial, 239 of 546 (43.8 %) AAP patients and 304 of 542 (56.1 %) BSC patients received docetaxel as subsequent therapy, following AA or placebo. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here. The ERG's critical assessment of the company's economic evaluation highlighted a number of concerns, including (a) not using the intention-to-treat (ITT) population; (b) inconsistencies in estimating prediction equations; (c) not fully incorporating the impact of adverse events; (d) incorrectly incorporating the new patient access scheme (PAS); and (e) the assumption that AA non-compliance leads to recoverable drug costs. Although some of these issues were adjusted in the ERG base case, the ERG could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. With the exception of the ERG's preference for using the ITT population, the AC agreed with the approach taken in the ERG base case. The original company and ERG base-case incremental cost-effectiveness ratios (ICERs) were £46,722 and £57,688 per QALY gained, respectively; these changed to £28,563 and £38,061 per QALY gained, respectively, in the revised base cases applying a new PAS. Regarding the end-of-life criteria, after 24 months approximately 63 % of patients in the control group of the COU-AA-302 trial were still alive, and the median survival was 30.1 months (95 % CI 27.3-34.1). Therefore, it is unlikely that life expectancy would be less than 24 months. The AC stated that the most plausible ICER is likely between £28,600 and £32,800 per QALY gained, and concluded that AAP at this stage in the treatment pathway did not meet the end-of-life criterion for short life expectancy. Moreover, in March 2016, the AC produced the final guidance, stating that AAP is recommended, within its marketing authorisation, as an option for treating mCRPC., Competing Interests: Compliance with Ethical Standards Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme (see the HTA programme website for further project information [http://www.hta.ac.uk]). This summary of the ERG report was compiled after NICE issued the FAD. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of NICE or the Department of Health. Conflict of interest Bram Ramaekers, Rob Riemsma, Florian Tomini, Thea van Asselt, Sohan Deshpande, Steven Duffy, Nigel Armstrong, Johan Severens, Jos Kleijnen, and Manuela A. Joore have no conflicts of interest to declare. Contributions of authors All authors have commented on the submitted manuscript and have given their approval for the final version to be published. Rob Riemsma, Sohan Deshpande and Jos Kleijnen reviewed the clinical-effectiveness evidence; Steven Duffy reviewed the search methods; and Bram Ramaekers, Florian Tomini, Thea van Asselt, Nigel Armstrong, Johan Severens, and Manuela Joore reviewed the cost-effectiveness evidence. Bram Ramaekers acts as overall guarantor for the manuscript. This summary has not been externally peer reviewed by PharmacoEconomics.

Our aim was to establish the comparative effectiveness of rheumatoid arthritis (RA) biologics, using a systematic review and network meta-analysis. The systematic review used randomized controlled trials (RCTs) in adults with RA who failed treatment with conventional disease-modifying agents for rheumatoid disease (cDMARDs). We compared the effectiveness of abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, and rituximab to tocilizumab, a recent biologic with a different mechanism of action (anti-IL-6 receptor). A network meta-analysis (NMA) included the indirect and direct evidence previously selected. In total, 207 articles were included describing 68 RCTs. The NMA showed that tocilizumab monotherapy was superior to standard care (ACR20, OR 13.27, 95 % CrI [3.958, 43.98]; ACR50, 17.45 [10.18, 31.24]; ACR70, 37.77 [7.226, 216.3]; EULAR, 10.42 [1.963, 54.8]); and methotrexate (MTX; ACR50, OR 5.44 [4.142, 7.238]; ACR70, 7.364 [1.4, 30.83]; EULAR, 4.226 [1.184, 15.58]) at 26 weeks. Similarly, the combination of tocilizumab + MTX was significantly better than standard care/placebo and MTX alone for ACR20, ACR50, ACR70, and EULAR at 26 weeks (OR 18.63 [5.32, 66.81]; 24.27 [14.5, 41.91]; 46.13 [10.08, 277]; 14.23 [2.493, 84.02]; 4.169 [2.267, 7.871]; 5.44 [4.142, 7.238]; 8.731 [4.203, 19.29]; 7.306 [4.393, 13.04], respectively). At 52 weeks, compared to MTX alone, tocilizumab + MTX was significantly better for ACR20 and ACR50 response. Few significant differences were found between tocilizumab (alone or in combination) and any other biologics. Results must be considered in context with the limitations of the available evidence. This NMA suggests that tocilizumab was superior to cDMARDs and as effective as other biologics for RA.

Background: In recent years, meters for continuous monitoring of interstitial fluid glucose have been introduced to help people with type 1 diabetes mellitus (T1DM) to achieve better control of their disease., Objective: The objective of this project was to summarise the evidence on the clinical effectiveness and cost-effectiveness of the MiniMed(®) Paradigm™ Veo system (Medtronic Inc., Northridge, CA, USA) and the Vibe™ (Animas(®) Corporation, West Chester, PA, USA) and G4(®) PLATINUM CGM (continuous glucose monitoring) system (Dexcom Inc., San Diego, CA, USA) in comparison with multiple daily insulin injections (MDIs) or continuous subcutaneous insulin infusion (CSII), both with either self-monitoring of blood glucose (SMBG) or CGM, for the management of T1DM in adults and children., Data Sources: A systematic review was conducted in accordance with the principles of the Centre for Reviews and Dissemination guidance and the National Institute for Health and Care Excellence Diagnostic Assessment Programme manual. We searched 14 databases, three trial registries and two conference proceedings from study inception up to September 2014. In addition, reference lists of relevant systematic reviews were checked. In the absence of randomised controlled trials directly comparing Veo or an integrated CSII + CGM system, such as Vibe, with comparator interventions, indirect treatment comparisons were performed if possible., Methods: A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), was used for this assessment. This model is an internet-based, interactive simulation model that predicts the long-term health outcomes and costs associated with the management of T1DM and type 2 diabetes. The model consists of 15 submodels designed to simulate diabetes-related complications, non-specific mortality and costs over time. As the model simulates individual patients over time, it updates risk factors and complications to account for disease progression., Results: Fifty-four publications resulting from 19 studies were included in the review. Overall, the evidence suggests that the Veo system reduces hypoglycaemic events more than other treatments, without any differences in other outcomes, including glycated haemoglobin (HbA1c) levels. We also found significant results in favour of the integrated CSII + CGM system over MDIs with SMBG with regard to HbA1c levels and quality of life. However, the evidence base was poor. The quality of the included studies was generally low, often with only one study comparing treatments in a specific population at a specific follow-up time. In particular, there was only one study comparing Veo with an integrated CSII + CGM system and only one study comparing Veo with a CSII + SMBG system in a mixed population. Cost-effectiveness analyses indicated that MDI + SMBG is the option most likely to be cost-effective, given the current threshold of £30,000 per quality-adjusted life-year gained, whereas integrated CSII + CGM systems and Veo are dominated and extendedly dominated, respectively, by stand-alone, non-integrated CSII with CGM. Scenario analyses did not alter these conclusions. No cost-effectiveness modelling was conducted for children or pregnant women., Conclusions: The Veo system does appear to be better than the other systems considered at reducing hypoglycaemic events. However, in adults, it is unlikely to be cost-effective. Integrated systems are also generally unlikely to be cost-effective given that stand-alone systems are cheaper and, possibly, no less effective. However, evidence in this regard is generally lacking, in particular for children. Future trials in specific child, adolescent and adult populations should include longer term follow-up and ratings on the European Quality of Life-5 Dimensions scale at various time points with a view to informing improved cost-effectiveness modelling., Study Registration: PROSPERO Registration Number CRD42014013764., Funding: The National Institute for Health Research Health Technology Assessment programme.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of lenalidomide (Celgene) to submit evidence of the clinical and cost effectiveness of the drug for treating adults with myelodysplastic syndromes (MDS) associated with deletion 5q cytogenetic abnormality, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and the NICE's subsequent decisions. The ERG reviewed the evidence for clinical and cost effectiveness of the technology, as submitted by the manufacturer to the NICE. The ERG searched for relevant additional evidence and validated the manufacturer's decision analytic model to examine the robustness of the cost-effectiveness results. Clinical effectiveness was obtained from a three-arm, European, randomized, phase III trial among red blood cell (RBC) transfusion-dependent patients with low-/intermediate-1-risk del5q31 MDS. The primary endpoint was RBC independence for ≥26 weeks, and was reached by a higher proportion of patients in the lenalidomide 10 and 5 mg groups compared with placebo (56.1 and 42.6 vs 5.9 %, respectively; both p < 0.001). The option of dose adjustments after 16 weeks due to dose-limiting toxicities or lack of response made long-term effectiveness estimates unreliable, e.g. overall survival (OS). The de novo model of the manufacturer included a Markov state-transition cost-utility model implemented in Microsoft Excel. The base-case incremental cost-effectiveness ratio (ICER) of the manufacturer was £56,965. The ERG assessment indicated that the modeling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. In response to the appraisal documentation, the company revised the economic model, which increased the ICER to £68,125 per quality-adjusted life-year. The NICE Appraisal Committee (AC) did not recommend lenalidomide as a cost-effective treatment. Subsequently, the manufacturer submitted a Patient Access Scheme (PAS) that provided lenalidomide free of charge for patients who remained on treatment after 26 cycles. This PAS improved the ICER to £25,300, although the AC considered the proportion of patients who received treatment beyond 26 cycles, and hence the ICER, to be uncertain. Nevertheless, the AC accepted a commitment from the manufacturer to publish, once available, data on the proportion of patients eligible for the PAS, and believed this provided reassurance that lenalidomide was a cost-effective treatment for low- or intermediate-1-risk MDS patients.

Background: Patients with large abdominal aortic aneurysms (AAAs) are usually offered reparative treatment given the high mortality risk. There is uncertainty about how to treat juxtarenal AAAs (JRAAAs) or thoracoabdominal aortic aneurysms (TAAAs). Endovascular repair of an abdominal aortic aneurysm (EVAR) is often seen as safer and easier than open surgical repair (OSR). However, endovascular treatment of JRAAAs or TAAAs requires specially manufactured stent grafts, with openings to allow blood to reach branches of the aorta. Commissioners are receiving increasing requests for fenestrated EVAR (fEVAR) and branched EVAR (bEVAR), but it is unclear whether or not the extra cost of fEVAR or bEVAR is justified by advantages for patients., Objective(s): To assess the clinical effectiveness, safety and cost-effectiveness of fEVAR and bEVAR in comparison with conventional treatment (i.e. no surgery) or OSR for two populations: JRAAAs and TAAAs., Data Sources: Resources were searched from inception to October 2013, including MEDLINE (OvidSP), EMBASE (OvidSP) and the Cochrane Central Register of Controlled Trials (Wiley) and, additionally, for cost-effectiveness, NHS Economic Evaluation Database (NHS EED; Wiley) and EconLit (EBSCOhost). Conference abstracts were also searched., Review Methods: Studies were included based on an intervention of either fEVAR or bEVAR and a comparator of either OSR or no surgery. For clinical effectiveness, observational studies were excluded only if they were not comparative, i.e. explicitly selected on the basis of prognosis., Results: For clinical effectiveness, searches retrieved 5253 records before deduplication. Owing to overlap between the databases, 1985 duplicate records were removed. Of the remaining 3268 records, based on titles and abstracts, 3244 records were excluded, leaving 24 publications to be ordered. All 24 studies were excluded as none of them satisfied the inclusion criteria. Sixteen studies were excluded on study design, six on intervention and two on comparator. Five out of 16 studies excluded on study design reported a comparison. However, all of the studies acknowledged that they had groups that were not comparable at baseline given that they had selectively assigned younger, fitter patients to OSR. Therefore, these studies were considered 'non-comparative'. For cost-effectiveness, searches identified 104 references before deduplication. Owing to overlap between the databases, 34 duplicate records were removed. Of the remaining 70 records, seven were included for the full assessment based on initial screening. After a full-text review, no studies were included. Because of the lack of clinical effectiveness evidence and difficulty in estimating costs given the rapidly changing and variable technology, a cost-effectiveness analysis (CEA) was not performed. Instead a detailed description of modelling methods was provided., Conclusions: Despite a thorough search, no studies could be found that met the inclusion criteria. All studies that compared either fEVAR or bEVAR with either OSR or no surgery explicitly selected patients based on prognosis, i.e. essentially the populations for each comparator were not the same. Despite not being able to conduct a CEA, we have provided detailed methods for the conduct if data becomes available., Future Work: We recommend at least one clinical trial to provide an unbiased estimate of effect for fEVAR/bEVAR compared with OSR or no surgery. This trial should also collect data for a CEA., Study Registration: This study is registered as PROSPERO CRD42013006051., Funding: The National Institute for Health Research Health Technology Assessment programme.

As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the Evidence Review Group (ERG) produced a report to comment on the clinical and cost effectiveness of golimumab (Simponi(®), Merck Sharp & Dohme) for the treatment of ankylosing spondylitis (AS) relative to other comparators as presented in the manufacturer's submission (MS) to NICE. The population was those with active disease who had not responded to conventional therapy. The specified comparators were conventional care and two other tumour necrosis factor alpha (TNF-α) inhibitors (adalimumab and etanercept). Outcomes to be considered were disease activity, functional capacity, disease progression, adverse effects of treatment and health-related quality of life (HR-QOL). There were no head-to-head trials comparing TNF-α inhibitors. The submission included one trial of golimumab versus placebo (the GO-RAISE trial) and additionally seven placebo-controlled randomized controlled trials (RCTs) of other TNF-α inhibitor agents (five with etanercept, and two with adalimumab). The results of these trials were generally a statistically significant improvement from each of the TNF-α inhibitors. A Bayesian mixed treatment comparison (MTC) showed there was generally overlap in the 95 % credible intervals (CrIs) between the TNF-α inhibitors. Exceptions included a greater risk of discontinuation of treatment for golimumab than for etanercept (relative risk [RR] 4.30; 95 % CrI 1.01-18.50). The cost-effectiveness analysis (CEA) compared all of these TNF-α inhibitors. Relative effectiveness was informed only by RR of response (proportion achieving at least a 50 % improvement in Bath AS Disease Activity Index [BASDAI] score; BASDAI50) from the MTC. In the base-case analysis, the incremental cost-effectiveness ratio (ICER) of golimumab versus conventional care was £26,597 and adalimumab and etanercept were extendedly dominated by golimumab. The manufacturer concluded that golimumab is a cost-effective treatment option. Generally, the ERG agreed with the MTC analyses. The main problem was that the MS used data from one trial, which included a period of cross-over. The ERG found some problems with the CEA model, mainly that it did not allow for comparison of TNF-α inhibitor sequences and did not use MTC estimates for treatment discontinuation or adverse events (AEs). The ERG could not correct the sequencing problem, but re-ran the CEA with discontinuations and AEs estimated from the MTC and using the correct trial data. The results of the ERG analysis were that golimumab was extendedly dominated by etanercept, and the preferred treatment was either conventional treatment or etanercept, depending on the ICER threshold. Uncertainty was also substantial. NICE issued guidance (technology appraisal [TA] 233), which recommended golimumab according to the indications described in TA143 for etanercept and adalimumab, i.e. as first-line therapy among the TNF-α inhibitors unless patients are intolerant to one or both alternatives. Given the factors cited by NICE for their decision, the ERG recommends that there should be greater clarity in the NICE methods guidance on handling uncertainty in CEAs as well as the incorporation of benefit from process of care.

Objectives: To develop explicit and transparent recommendations on controversial asthma management issues in children and to illustrate the usefulness of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach in rating the quality of evidence and strength of recommendations., Methods: Health care questions were formulated for 3 controversies in clinical practice: what is the most effective treatment in asthma not under control with standard-dose inhaled corticosteroids (ICS; step 3), the use of leukotriene receptor antagonist for viral wheeze, and the role of extra fine particle aerosols. GRADE was used to rate the quality of evidence and strength of recommendations after performing systematic literature searches. We provide evidence profiles and considerations about benefit and harm, preferences and values, and resource use, all of which played a role in formulating final recommendations., Results: By applying GRADE and focusing on outcomes that are important to patients and explicit other considerations, our recommendations differ from those in other international guidelines. We prefer to double the dose of ICS instead of adding a long-acting β-agonist in step 3; ICS instead of leukotriene receptor antagonist are the first choice in preschool wheeze, and extra fine particle ICS formulations are not first-line treatment in children with asthma. Recommendations are weak and based on low-quality evidence for critical outcomes., Conclusions: We provide systematically and transparently developed recommendations about controversial asthma management options. Using GRADE for guideline development may change recommendations, enhance guideline implementation, and define remaining research gaps.

SUMMARY This systematic review compares convenience of administration, adverse events and tolerability of buprenorphine patch with fentanyl patch in patients with chronic pain. Methods of quantitative and qualitative research were combined. Seventeen databases were searched up to December 2010. A total of 49 unique trials (56 publications) were included. Patients regarded the use of patches, both transdermal buprenorphine and fentanyl, as easy and convenient. Compared with buprenorphine patch, fentanyl can cause more cases of constipation and could lead to a higher number of serious adverse events. There were no differences between buprenorphine patch and fentanyl patch regarding dizziness, somnolence, nausea and treatment discontinuation. Overall, transdermal administration of buprenorphine and fentanyl can be seen as an alternative pathway for delivering these drugs. Use of transdermal buprenorphine might be favorable in certain groups of patients, such as renally impaired, elderly and immunosuppressed patients.

Introduction. Estimates on the epidemiology of chronic pain vary widely throughout Europe. It is unclear whether this variation reflects true differences between populations or methodological factors. Information on the epidemiology of chronic pain can support decision makers in allocating adequate health care resources. Methods. In order to obtain epidemiological data on chronic pain in Denmark and Sweden, we conducted a literature review of epidemiological data primarily on chronic noncancer pain, prioritising studies of highest quality, recency, and validity by conducting a systematic search for relevant studies. Following quality assessment, data were summarised and assigned to the research questions. Results. The prevalence of moderate to severe noncancer pain was estimated at 16% in Denmark and 18% in Sweden. Chronic pain impacts negatively on perceived health status, quality of life and is associated with increased cost. Despite using pain medications, a large proportion of chronic pain sufferers have inadequate pain control. There was a lack of high-quality and low-bias studies with clear inclusion criteria. Conclusions. In both Denmark and Sweden, chronic pain is a common health problem which is potentially undertreated and warrants attention of health care workers, policy makers and researchers. Future research should utilise clear reporting guidelines to assist decision and policy makers, in this important area.