Jean Hamilton

Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia: an evidence review group perspective of a NICE single technology appraisal

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of evolocumab (Amgen) to submit evidence on the clinical and cost effectiveness of evolocumab. The appraisal assessed evolocumab as monotherapy or in combination with a statin with or without ezetimibe, or in combination with ezetimibe (without statin therapy), in adult patients with primary hypercholesterolaemia (which includes mixed dyslipidaemia), for whom statins do not provide optimal control of their low-density lipoprotein cholesterol (LDL-C) levels and/or for whom statins are contraindicated or not tolerated. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based on the company’s submission to NICE. The evidence was derived mainly from four randomised controlled trials comparing evolocumab with either ezetimibe or placebo in adults with primary familial or non-familial hypercholesterolaemia, who were either able to take statins or who were statin intolerant. The clinical-effectiveness review found that evolocumab is efficacious at lowering LDL-C but that there was uncertainty regarding its impact on cardiovascular disease (CVD) outcomes. In response to the ERG’s critique of the submitted health economic model, the company submitted an amended model, which also included a patient access scheme (PAS). Based on this, the deterministic incremental cost-effectiveness ratios (ICERs) for evolocumab against ezetimibe were above £74,000 and £45,000 per quality-adjusted life-year (QALY) gained within the non-familial primary and secondary prevention populations, respectively, whilst the ICER within the heterozygous familial hypercholesterolaemia (HeFH) population was approximately £23,000 per QALY gained. The final determination was that evolocumab would be a clinically and cost-effective use of UK NHS resource in certain patient subgroups.

Complex-Valued Wavelet Lifting and Applications

ABSTRACT Signals with irregular sampling structures arise naturally in many fields. In applications such as spectral decomposition and nonparametric regression, classical methods often assume a regular sampling pattern, thus cannot be applied without prior data processing. This work proposes new complex-valued analysis techniques based on the wavelet lifting scheme that removes “one coefficient at a time.” Our proposed lifting transform can be applied directly to irregularly sampled data and is able to adapt to the signal(s)’ characteristics. As our new lifting scheme produces complex-valued wavelet coefficients, it provides an alternative to the Fourier transform for irregular designs, allowing phase or directional information to be represented. We discuss applications in bivariate time series analysis, where the complex-valued lifting construction allows for coherence and phase quantification. We also demonstrate the potential of this flexible methodology over real-valued analysis in the nonparametric regression context. Supplementary materials for this article are available online.

Understanding the alcohol harm paradox: an analysis of sex- and condition-specific hospital admissions by socioeconomic group for alcohol-associated conditions in England.

Background and Aims In many countries, conflicting gradients in alcohol consumption and alcohol‐associated mortality have been observed. To understand this ‘alcohol harm paradox’ we analysed the socio‐economic gradient in alcohol‐associated hospital admissions to test whether it was greater in conditions which were: (1) chronic (associated with long‐term drinking) and partially alcohol‐attributable, (2) chronic and wholly alcohol‐attributable, (3) acute (associated with intoxication) and partially alcohol‐attributable and (4) acute and wholly alcohol‐attributable. Our aim was to clarify how (1) drinking patterns (e.g. intoxication linked to acute admissions or dependence linked to chronic conditions) and (2) non‐alcohol causes (e.g. smoking and poor diet which are risks for partially alcohol‐attributable conditions) contribute to the paradox. Design Regression analysis testing the modifying effects of condition‐group (1–4 above) and sex on the relationship between area‐based deprivation and admissions. Setting England, April 2010–March 2013. Participants A total of 9 239 629 English hospital admissions where a primary or secondary cause was one of 36 alcohol‐associated conditions. Measurements Admissions by condition and deciles of Index of Multiple Deprivation (IMD). Socio‐economic gradient measured as the relative index of inequality (RII, the slope of a linear regression of IMD on admissions adjusted for overall admission rate). Conditions were categorized by ICD‐10 code. Findings A socio‐economic gradient in hospitalizations was seen for all conditions, except partially attributable chronic conditions. The gradient was significantly steeper for conditions which were wholly attributable to alcohol and for acute conditions than for conditions partially alcohol‐attributable and for chronic conditions. Gradients were steeper for men than for women in cases of wholly alcohol attributable conditions. Conclusions There is a socio‐economic gradient in English hospital admission for most alcohol‐associated conditions. The greatest inequalities are in conditions associated with alcohol dependence, such as liver disease and mental and behavioural conditions, and in acute conditions, such as alcohol poisoning and assault. Socio‐economic differences in harmful drinking patterns (dependence and intoxication) may contribute to the ‘alcohol harm paradox’.

Pirfenidone for Treating Idiopathic Pulmonary Fibrosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

The National Institute for Health and Care Excellence (NICE) published guidance on the use of pirfenidone (Esbriet®, Roche) for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in 2013. NICE decided to review existing guidance following publication of an additional clinical trial, and invited the manufacturer of pirfenidone to submit evidence of its clinical and cost effectiveness for the treatment of mild to moderate IPF when compared with best supportive care (BSC) or nintedanib; nintedanib was a comparator only for moderate IPF. An independent Evidence Review Group (ERG) critiqued the company submission and this paper summarises their report and subsequent NICE guidance. The key clinical effectiveness evidence was based on three randomised controlled trials (RCTs) and an open-label extension study. Supportive data were provided from two additional RCTs conducted in Japan, while one additional open-label study was included for safety outcomes. Meta-analysis of the three key RCTs found pirfenidone to be effective at reducing disease progression compared with placebo, but statistically significant differences were not identified in all of the RCTs. A statistically significant reduction in all-cause mortality was only demonstrated when pooling data across studies. The treatment effects of pirfenidone and nintedanib were broadly similar, based on an indirect comparison using network meta-analysis, although they have slightly different adverse event profiles. There remains considerable uncertainty in the cost-effectiveness estimates for pirfenidone versus BSC, particularly due to uncertainty regarding the duration of treatment effect and the method used to implement the stopping rule within the economic model.

Ponatinib for Treating Acute Lymphoblastic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (Incyte Corporation) of ponatinib (Inclusig®) to submit evidence of its clinical and cost effectiveness for previously treated Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and chronic myeloid leukaemia. This paper focusses on Ph+ ALL. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). This article presents the critical review of the company’s submission by the ERG and the outcome of the NICE guidance. The clinical-effectiveness evidence in the company’s submission was derived from a phase II, single-arm, open-label, non-comparative study. Given the lack of comparative evidence, a naïve indirect comparison was performed against re-induction chemotherapy comparing major cytogenetic response and complete remission. Best supportive care (BSC) was assumed to produce no disease response. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment for patients with Ph+ ALL. The company submitted a state transition model that analysed the incremental cost effectiveness of ponatinib versus re-induction therapy and BSC for the treatment of Ph+ ALL in patients whose disease is resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or who have the threonine-315-isoleucine mutation. This population was further subdivided into those who were suitable for allogeneic stem cell transplant (allo-SCT) and those who were not. The company’s revised economic evaluation, following the clarification process, estimated incremental cost-effectiveness ratios (ICERs) in those suitable for allo-SCT of £31,123 per quality-adjusted life-year (QALY) gained for ponatinib compared with re-induction chemotherapy and £26,624 per QALY gained compared with BSC. For those for whom allo-SCT was unsuitable, the company-estimated ICER compared with BSC was £33,954 per QALY gained. Following a critique of the model, the ERG undertook exploratory analyses that, when combined, produced a range in ICERs (due to uncertainty of the most appropriate overall survival function) of dominant (being less expensive and providing more QALYs) to £11,727 per QALY gained compared with re-induction chemotherapy and between £7892 and £31,696 per QALY gained compared with BSC for those in whom allo-SCT was suitable. For those in whom allo-SCT was not suitable, the ERG estimated that ponatinib was dominant. During the consultation period, the company agreed a revised patient access scheme (PAS) that reduced the ICER ranges to £7156 to £29,995 per QALY gained versus BSC and to less than £5000 per QALY gained versus re-induction chemotherapy. In people for whom allo-SCT was unsuitable, ponatinib dominated BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of UK NHS resources in the considered population, subject to the company providing the agreed discount in the PAS.

Ibrutinib for Treating Relapsed or Refractory Mantle Cell Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its Single Technology Appraisal process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of ibrutinib (Janssen) to submit evidence on the clinical effectiveness and cost effectiveness of ibrutinib for the treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL). The School of Health and Related Research Technology Assessment Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company’s submission to NICE. The clinical effectiveness evidence for ibrutinib included one randomised controlled trial comparing ibrutinib and temsirolimus and two single-arm studies. The company’s indirect comparison of ibrutinib versus rituximab plus chemotherapy (R-chemo) produced a hazard ratio (HR) for progression-free survival (PFS) of 0.28. The ERG’s random effects network meta-analysis (NMA) indicated that the treatment effect on PFS was highly uncertain (HR 0.27; 95% credible interval (CrI) 0.06–1.26). The company’s Markov model assessed the cost effectiveness of ibrutinib versus R-chemo for the treatment of R/R MCL from the perspective of the National Health Service (NHS) and Personal Social Services over a lifetime horizon. Based on a re-run of the company’s model by the ERG, the incremental cost-effectiveness ratio (ICER) for ibrutinib versus R-chemo [including the company’s original patient access scheme (PAS)] was expected to be £76,014 per quality-adjusted life-year (QALY) gained. The ERG had several concerns regarding the company’s model structure and the evidence used to inform its parameters. The ERG’s preferred analysis, which used the ERG’s NMA and the observed Kaplan–Meier curve for time to ibrutinib discontinuation and excluded long-term disutilities for R-chemo, produced ICERs of £63,340 per QALY gained for the overall R/R MCL population and of £44,711 per QALY gained for patients with one prior treatment. Following an updated PAS and consideration of evidence from a later data-cut of the RAY trial, the appraisal committee concluded that the most plausible ICER for the one prior treatment subgroup was likely to be lower than the company’s estimate of £49,848 per QALY gained. The company’s ICER for the overall R/R MCL population was higher, at £62,650 per QALY gained. The committee recommended ibrutinib as an option for treating R/R MCL in adults only if they have received only one previous line of therapy and the company provides ibrutinib with the discount agreed in the commercial access agreement with NHS England.

Rapid diagnostic test for antenatal syphilis screening in low-income and middle-income countries: a systematic review and meta-analysis

Objectives To undertake a systematic review and meta-analysis to evaluate the test performance including sensitivity and specificity of rapid immunochromatographic syphilis (ICS) point-of-care (POC) tests at antenatal clinics compared with reference standard tests (non-treponemal (TP) and TP tests) for active syphilis in pregnant women. Methods Five electronic databases were searched (PubMed, EMBASE, CRD, Cochrane Library and LILACS) to March 2016 for diagnostic accuracy studies of ICS test and standard reference tests for syphilis in pregnant women. Methodological quality was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies). A bivariate meta-analysis was undertaken to generate pooled estimates of diagnostic parameters. Results were presented using a coupled forest plot of sensitivity and specificity and a scatter plot. Results The methodological quality of the five included studies with regards to risk of bias and applicability concern judgements was either low or unclear. One study was judged as high risk of bias for patient selection due to exclusion of pregnant women with a previous history of syphilis, and one study was judged at high risk of bias for study flow and timing as not all patients were included in the analysis. Five studies contributed to the meta-analysis, providing a pooled sensitivity and specificity for ICS of 0.85 (95% CrI: 0.73 to 0.92) and 0.98 (95% CrI: 0.95 to 0.99), respectively. Conclusions This review and meta-analysis observed that rapid ICS POC tests have a high sensitivity and specificity when performed in pregnant women at antenatal clinics. However, the methodological quality of the existing evidence base should be taken into consideration when interpreting these results. PROSPERO registration number CRD42016036335.

A systematic review and economic evaluation of adalimumab and dexamethasone for treating non-infectious intermediate uveitis, posterior uveitis or panuveitis in adults

BACKGROUND Non-infectious intermediate uveitis, posterior uveitis and panuveitis are a heterogeneous group of inflammatory eye disorders. Management includes local and systemic corticosteroids, immunosuppressants and biological drugs. OBJECTIVES To evaluate the clinical effectiveness and cost-effectiveness of subcutaneous adalimumab (Humira®; AbbVie Ltd, Maidenhead, UK) and a dexamethasone intravitreal implant (Ozurdex®; Allergan Ltd, Marlow, UK) in adults with non-infectious intermediate uveitis, posterior uveitis or panuveitis. DATA SOURCES Electronic databases and clinical trials registries including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and the World Health Organizations International Clinical Trials Registry Platform were searched to June 2016, with an update search carried out in October 2016. REVIEW METHODS Review methods followed published guidelines. A Markov model was developed to assess the cost-effectiveness of dexamethasone and adalimumab, each compared with current practice, from a NHS and Personal Social Services (PSS) perspective over a lifetime horizon, parameterised with published evidence. Costs and benefits were discounted at 3.5%. Substantial sensitivity analyses were undertaken. RESULTS Of the 134 full-text articles screened, three studies (four articles) were included in the clinical effectiveness review. Two randomised controlled trials (RCTs) [VISUAL I (active uveitis) and VISUAL II (inactive uveitis)] compared adalimumab with placebo, with limited standard care also provided in both arms. Time to treatment failure (reduced visual acuity, intraocular inflammation, new vascular lesions) was longer in the adalimumab group than in the placebo group, with a hazard ratio of 0.50 [95% confidence interval (CI) 0.36 to 0.70; p < 0.001] in the VISUAL I trial and 0.57 (95% CI 0.39 to 0.84; p = 0.004) in the VISUAL II trial. The adalimumab group showed a significantly greater improvement than the placebo group in the 25-item Visual Function Questionnaire (VFQ-25) composite score in the VISUAL I trial (mean difference 4.20; p = 0.010) but not the VISUAL II trial (mean difference 2.12; p = 0.16). Some systemic adverse effects occurred more frequently with adalimumab than with placebo. One RCT [HURON (active uveitis)] compared a single 0.7-mg dexamethasone implant against a sham procedure, with limited standard care also provided in both arms. Dexamethasone provided significant benefits over the sham procedure at 8 and 26 weeks in the percentage of patients with a vitreous haze score of zero (p < 0.014), the mean best corrected visual acuity improvement (p ≤ 0.002) and the percentage of patients with a ≥ 5-point improvement in VFQ-25 score (p < 0.05). Raised intraocular pressure and cataracts occurred more frequently with dexamethasone than with the sham procedure. The incremental cost-effectiveness ratio (ICER) for one dexamethasone implant in one eye for a combination of patients with unilateral and bilateral uveitis compared with limited current practice, as per the HURON trial, was estimated to be £19,509 per quality-adjusted life-year (QALY) gained. The ICER of adalimumab for patients with mainly bilateral uveitis compared with limited current practice, as per the VISUAL trials, was estimated to be £94,523 and £317,547 per QALY gained in active and inactive uveitis respectively. Sensitivity analyses suggested that the rate of blindness has the biggest impact on the model results. The interventions may be more cost-effective in populations in which there is a greater risk of blindness. LIMITATIONS The clinical trials did not fully reflect clinical practice. Thirteen additional studies of clinically relevant comparator treatments were identified; however, network meta-analysis was not feasible. The model results are highly uncertain because of the limited evidence base. CONCLUSIONS Two RCTs of systemic adalimumab and one RCT of a unilateral, single dexamethasone implant showed significant benefits over placebo or a sham procedure. The ICERs for adalimumab were estimated to be above generally accepted thresholds for cost-effectiveness. The cost-effectiveness of dexamethasone was estimated to fall below standard thresholds. However, there is substantial uncertainty around the model assumptions. In future work, primary research should compare dexamethasone and adalimumab with current treatments over the long term and in important subgroups and consider how short-term improvements relate to long-term effects on vision. STUDY REGISTRATION This study is registered as PROSPERO CRD42016041799. FUNDING The National Institute for Health Research Health Technology Assessment programme.