What Is the Evidence from Past National Institute of Health and Care Excellence Single-Technology Appraisals Regarding Company Submissions with Base-Case Incremental Cost-Effectiveness Ratios of Less Than £10,000/QALY?

BACKGROUND: The National Institute for Health and Care Excellence has recently proposed that company submissions with a base-case incremental cost-effectiveness ratio (ICER) of less than £10,000/quality-adjusted life-year (QALY) might be eligible for a "fast-track" appraisal. OBJECTIVES: To explore outcomes relating to previously conducted single-technology appraisals (STAs) with base-case ICERs of less than £10,000/QALY. METHODS: All STAs with published guidance from 2009 to 2016 were included; those with company base-case ICERs of less than £10,000/QALY were identified and analyzed. A secondary analysis was also conducted for those with a company base-case ICER of £10,000 to £15,000/QALY. Relevant data were extracted and presented in a narrative and in tables. RESULTS: In total, 15% (26 of 171) of STAs included a company submission with a base-case ICER of less than £10,000/QALY. Of these, 73% (19 of 26) were given positive recommendations after the first Appraisal Committee (AC) meeting, whereas 27% (7 of 26) were initially given a Minded No before receiving a positive recommendation in the final appraisal determination, albeit with restricted recommendations for three technologies. Five STAs had company base-case ICERs of £10,000 to £15,000/QALY and all received a positive recommendation after the first AC meeting. CONCLUSIONS: Most previous STAs with a company base-case ICER of £10,000 or even £15,000/QALY received a positive recommendation after the first AC meeting, but a number of them proved more complicated and required detailed appraisal, which influenced the final recommendation. This finding might have implications for the proposed fast-track process of the National Institute for Health and Care Excellence.

Nature and reporting characteristics of UK health technology assessment systematic reviews.

BACKGROUND: A recent study by Page et al. (PLoS Med. 2016;13(5):e1002028) claimed that increasing numbers of reviews are being published and many are poorly-conducted and reported. The aim of the present study was to assess how well reporting standards of systematic reviews produced in a Health Technology Assessment (HTA) context compare with reporting in Cochrane and other 'non-Cochrane' systematic reviews from the same years (2004 and 2014), as reported by Page et al. (PLoS Med. 2016;13(5):e1002028). METHODS: All relevant UK HTA programme systematic reviews published in 2004 and 2014 were identified. After piloting of the form, two reviewers each extracted relevant data on conduct and reporting from these reviews. These data were compared with data for Cochrane and "non-Cochrane" systematic reviews, as published by Page et al. (PLoS Med. 2016;13(5):e1002028). All data were tabulated and summarized. RESULTS: There were 30 UK HTA programme systematic reviews and 300 other systematic reviews, including Cochrane reviews (n = 45). The percentage of HTA reviews with required elements of conduct and reporting was frequently very similar to Cochrane and much higher than all other systematic reviews, e.g. availability of protocols (90, 98 and 16% respectively); the specification of study design criteria (100, 100, 79%); the reporting of outcomes (100, 100, 78%), quality assessment (100, 100, 70%); the searching of trial registries for unpublished data (70, 62, 19%); reporting of reasons for excluding studies (91, 91 and 70%) and reporting of authors' conflicts of interests (100, 100, 87%). HTA reviews only compared less favourably with Cochrane and other reviews in assessments of publication bias. CONCLUSIONS: UK HTA systematic reviews are often produced within a specific policy-making context. This context has implications for timelines, tools and resources. However, UK HTA systematic reviews still tend to present standards of conduct and reporting equivalent to "gold standard" Cochrane reviews and superior to systematic reviews more generally.

Patient-Reported Outcome Measures in Carotid Artery Revascularization: Systematic Review and Psychometric Analysis.

BACKGROUND: Patient-reported outcome measures (PROMs) provide a way to measure the impact of a disease and its associated treatments on the quality of life (QoL) from the patients' perspective. The aim of this review was to identify PROMs that have been developed and/or validated in patients with carotid artery stenosis (CAS) undergoing revascularization and to assess their psychometric properties and examine suitability for research and clinical use. METHODS: Eight electronic databases including MEDLINE and CINAHL were searched using a 2-stage search approach to identify studies reporting the development and/or validation of relevant PROMs in patients with CAS undergoing revascularization. Supplementary citation searching and hand-searching reference lists of included studies were also undertaken. The COnsensus-based Standards for the selection of health Measurement INstruments and Oxford criteria were used to assess the methodological quality of the included studies, and the psychometric properties of the PROMs were evaluated using established assessment criteria. RESULTS: Five studies reporting on 6 PROMs were included: 36-Item Short Form Health Survey (SF-36), Euro-QoL-5-Dimension Scale (EQ-5D), Hospital Anxiety and Depression Scale, Dizziness Handicap Inventory, QoL for carotid artery disease scale, and a disease-specific PROM for CAS. The rigor of the psychometric assessment of the PROMs was variable with most only attempting to assess a single psychometric criterion. No study reported evidence on construct validity and test-retest reliability. Evidence for acceptability for the use of SF-36, EQ-5D, and the disease-specific PROM was rated good in most studies. Only one study reported a Cronbach alpha score >0.70 as evidence of internal consistency. Overall, the psychometric evaluation of all included PROMs was rated as poor within the CAS population undergoing revascularization. CONCLUSIONS: This review highlighted a lack of evidence in validated PROMs used for patients undergoing carotid artery revascularization. As a result, the development and validation of a new PROM for this patient population is warranted to provide data which can supplement traditional clinical outcomes (stroke<30 days post-procedural, myocardial infarction, and death) and capture changes in health status and QoL to help inform treatment decisions.

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

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

The Relationship between Hospital or Surgeon Volume and Outcomes in Lower Limb Vascular Surgery in the United Kingdom and Europe.

BACKGROUND: Peripheral vascular disease is a major cause of death and disability. The extent to which volume influences outcome of lower limb (LL) vascular surgery remains unclear. This review evaluated the relationship between hospital/surgeon volume and outcome in LL surgery. METHODS: Electronic databases-MEDLINE, Embase, the Cochrane Library Databases, Science Citation Index, and CINAHL-proceedings from conferences, citations, and references of included studies were searched. Studies from Europe, of adults undergoing LL vascular surgery reporting outcomes by hospital or surgeon volume were included. The quality of studies was assessed using a modified Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions (Robins1) tool. The association between hospital/surgeon volume and outcome was summarized using tables. RESULTS: Nine studies from different European countries, comprising 67,445 patients who had undergone diverse LL surgeries were included. The increase in hospital/surgeon volume was associated with a decrease in post-operative amputations (hospital at 30 days [odds ratio {OR}: 0.20, 95% confidence interval {CI} 0.29-0.45, P = 0.01; OR: 0.67, 95% CI 0.44-0.9, P = 0.05; OR: 0.96, 95% CI 0.92-1.00, P = 0.06], at 1 year [OR: 0.96, 95% CI 0.93-0.98, P = 0.002; OR: 0.66, 95% CI 0.52-0.84, P < 0.001; OR: 2.05, 95% CI 1.24-3.42, P = 0.01], surgeon at 30 days [OR: 0.53, 95% CI 0.36-0.87, P = 0.01; OR: 0.40, 95% CI 0.18-0.91, P = 0.03; OR: 0.41, 95% CI 0.24-0.69, P = 0.0006]). The evidence on an association between hospital/surgeon volume and mortality was contradictory, but mortality and amputations may covary by hospital volume. There were an insufficient number of studies reporting on the other variables to draw firm conclusions, but their results suggest that high-volume hospitals may undertake more repeated surgeries/revascularizations and limb salvage. The impact of hospital/surgical volume on adverse events and length of hospitalization could not be determined. CONCLUSIONS: High-volume hospitals/surgeons may undertake fewer amputations and mortality and amputations may covary. The finding that hospital and surgeon volume affected the number of secondary amputations has implications on reorganization of vascular surgery services. However, due to the small number and poor quality of some of the included studies, decisions on reorganization of LL vascular surgery services should be supplemented by results from clinical audits. There is need for standardization of definition of volume stratification of outcomes by patient's clinical conditions.

The use of rapid review methods in health technology assessments: 3 case studies.

BACKGROUND: Rapid reviews are of increasing importance within health technology assessment due to time and resource constraints. There are many rapid review methods available although there is little guidance as to the most suitable methods. We present three case studies employing differing methods to suit the evidence base for each review and outline some issues to consider when selecting an appropriate method. METHODS: Three recently completed systematic review short reports produced for the UK National Institute for Health Research were examined. Different approaches to rapid review methods were used in the three reports which were undertaken to inform the commissioning of services within the NHS and to inform future trial design. We describe the methods used, the reasoning behind the choice of methods and explore the strengths and weaknesses of each method. RESULTS: Rapid review methods were chosen to meet the needs of the review and each review had distinctly different challenges such as heterogeneity in terms of populations, interventions, comparators and outcome measures (PICO) and/or large numbers of relevant trials. All reviews included at least 10 randomised controlled trials (RCTs), each with numerous included outcomes. For the first case study (sexual health interventions), very diverse studies in terms of PICO were included. P-values and summary information only were presented due to substantial heterogeneity between studies and outcomes measured. For the second case study (premature ejaculation treatments), there were over 100 RCTs but also several existing systematic reviews. Data for meta-analyses were extracted directly from existing systematic reviews with new RCT data added where available. For the final case study (cannabis cessation therapies), studies included a wide range of interventions and considerable variation in study populations and outcomes. A brief summary of the key findings for each study was presented and narrative synthesis used to summarise results for each pair of interventions compared. CONCLUSIONS: Rapid review methods need to be chosen to meet both the nature of the evidence base of a review and the challenges presented by the included studies. Appropriate methods should be chosen after an assessment of the evidence base.

Patient-reported outcome measures in patients with peripheral arterial disease: a systematic review of psychometric properties.

BACKGROUND: Peripheral arterial disease (PAD) is generally associated with considerable morbidity and reduced quality of life. Patient-reported outcome measures (PROMs) provide important information about the burden of disease and impact of treatment in affected patients. OBJECTIVES: The objective of the review was to identify and appraise studies reporting the psychometric evaluation of PROMs administered to a specified population of patients with PAD with a view to recommending suitable PROMs. METHODS: A systematic review of peer-reviewed English language articles was undertaken to identify primary studies reporting psychometric properties of PROMs in English-speaking patients with various stages of PAD. Comprehensive searches were completed up until January 2015. Study selection, data extraction and quality assessment were undertaken independently by at least two researchers. Findings were presented as tabular and narrative summaries based on accepted guidance. RESULTS: Psychometric evaluation of 6 generic and 7 condition-specific PROMs reported in 14 studies contributed data to the review. The frequently reported measure was the SF-36 (n = 11 studies); others included the Walking Impairment Questionnaire (n = 8 studies), EQ-5D (n = 5 studies) and the Vascular Quality of Life Questionnaire (n = 3 studies). Studies included a diverse PAD population and varied in methodology, including approach to validation of PROMs. CONCLUSIONS: Various PROMs have been validated in patients with PAD but no study provided evidence of a full psychometric evaluation in the patient population. Careful selection is required to identify reliable and valid PROMs to use in clinical and research settings.

Tramadol for premature ejaculation: a systematic review and meta-analysis.

BACKGROUND: Tramadol is a centrally acting analgesic prescribed off-label for the treatment of premature ejaculation (PE). However, tramadol may cause addiction and difficulty in breathing and the beneficial effect of tramadol in PE is yet not supported by a high level of evidence. The purpose of this study was to systematically review the evidence from randomised controlled trials (RCT) for tramadol in the management of PE. METHODS: We searched bibliographic databases including MEDLINE to August 2014 for RCTs. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. Between-group differences in IELT and other outcomes were pooled across RCTs in a meta-analysis. Statistical and clinical between-trial heterogeneity was assessed. RESULTS: A total of eight RCTs that evaluated tramadol against a comparator were included. The majority of RCTs were of unclear methodological quality due to limited reporting. Pooled evidence (four RCTs, 721 participants), suggests that tramadol is significantly more effective than placebo at increasing IELT over eight to 12 weeks (p = 0.0007). However, a high level of statistical heterogeneity is evident (I-squared = 74%). Single RCT evidence indicates that tramadol is significantly more effective than paroxetine taken on-demand, sildenafil, lidocaine gel, or behavioural therapy on IELT in men with PE. Tramadol is associated with significantly more adverse events including: erectile dysfunction, constipation, nausea, headache, somnolence, dry mouth, dizziness, pruritus, and vomiting, than placebo or behavioural therapy over eight to 12 weeks of treatment. However, addiction problems or breathing difficulties reported by patients for PE is not assessed in the current evidence base. CONCLUSIONS: Tramadol appears effective in the treatment of PE. However, these findings should be interpreted with caution given the observed levels of between-trial heterogeneity and the reporting quality of the available evidence. The variability across placebo-controlled trials in terms of the tramadol dose evaluated and the treatment duration does not permit any assessment of a safe and effective minimum daily dose. The long-term effects and side effects, including addiction potential, for men with PE have not been evaluated in the current evidence base. TRIAL REGISTRATION: The review is registered on PROSPERO 2013: CRD42013005289 .

Sexual health risk reduction interventions for people with severe mental illness: a systematic review.

BACKGROUND: Despite variability in sexual activity among people with severe mental illness, high-risk sexual behavior (e.g. unprotected intercourse, multiple partners, sex trade and illicit drug use) is common. Sexual health risk reduction interventions (such as educational and behavioral interventions, motivational exercises, counselling and service delivery), developed and implemented for people with severe mental illness, may improve participants' knowledge, attitudes, beliefs behaviors or practices (including assertiveness skills) and could lead to a reduction in risky sexual behavior. This systematic review evaluates the effectiveness of sexual health risk reduction interventions for people with severe mental illness. METHODS: Thirteen electronic databases (including MEDLINE, EMBASE and PsycINFO) were searched to August 2014, and supplemented by hand-searching relevant articles and contacting experts. All controlled trials (randomized or non-randomized) comparing the effectiveness of sexual health risk reduction interventions with usual care for individuals living in the community with severe mental illness were included. Outcomes included a range of biological, behavioral and proxy endpoints. Narrative synthesis was used to combine the evidence. RESULTS: Thirteen controlled trials (all from the USA) were included. Although there was no clear and consistent evidence that interventions reduce the total number of sex partners or improved behavioral intentions in sexual risk behavior, positive effects were generally observed in condom use, condom protected intercourse and on measures of HIV knowledge, attitudes to condom use and sexual behaviors and practices. However, the robustness of these findings is low due to the large between study variability, small sample sizes and low-to-moderate quality of included studies. CONCLUSIONS: There is insufficient evidence at present to fully support or reject the identified sexual health risk reduction interventions for people with severe mental illness. Given the serious consequences of high-risk sexual behaviors, there is an urgent need for well-designed UK based trials, as well as training and support for staff implementing sexual health risk reduction interventions. TRIAL REGISTRATION: PROSPERO CRD42013003674 .

Identification and review of cost-effectiveness model parameters: a qualitative study.

OBJECTIVES: Health economic models are developed as part of the health technology assessment process to determine whether health interventions represent good value for money. These models are often used to directly inform healthcare decision making and policy. The information needs for the model require the use of other types of information beyond clinical effectiveness evidence to populate the model's parameters. The purpose of this research study was to explore issues concerned with the identification and use of information for the development of such models. METHODS: Three focus groups were held in February 2011 at the University of Sheffield with thirteen UK HTA experts. Attendees included health economic modelers, information specialists and systematic reviewers. Qualitative framework analysis was used to analyze the focus group data. RESULTS: Six key themes, with related sub-themes, were identified dealing with decisions and judgments; searching methods; selection and rapid review of evidence; team communication; modeler experience and clinical input and reporting methods. There was considerable overlap between themes. CONCLUSIONS: Key issues raised by the respondents included the need for effective communication and teamwork throughout the model development process, the importance of using clinical experts as well as the need for transparent reporting of methods and decisions.

Reviewing the evidence to inform the population of cost-effectiveness models within health technology assessments.

OBJECTIVES: Health technology assessments (HTAs) typically require the development of a cost-effectiveness model, which necessitates the identification, selection, and use of other types of information beyond clinical effectiveness evidence to populate the model parameters. The reviewing activity associated with model development should be transparent and reproducible but can result in a tension between being both timely and systematic. Little procedural guidance exists in this area. The purpose of this article was to provide guidance, informed by focus groups, on what might constitute a systematic and transparent approach to reviewing information to populate model parameters. METHODS: A focus group series was held with HTA experts in the United Kingdom including systematic reviewers, information specialists, and health economic modelers to explore these issues. Framework analysis was used to analyze the qualitative data elicited during focus groups. RESULTS: Suggestions included the use of rapid reviewing methods and the need to consider the trade-off between relevance and quality. The need for transparency in the reporting of review methods was emphasized. It was suggested that additional attention should be given to the reporting of parameters deemed to be more important to the model or where the preferred decision regarding the choice of evidence is equivocal. DISCUSSION: These recommendations form part of a Technical Support Document produced for the National Institute for Health and Clinical Excellence Decision Support Unit in the United Kingdom. It is intended that these recommendations will help to ensure a more systematic, transparent, and reproducible process for the review of model parameters within HTA.

Is group cognitive behaviour therapy for postnatal depression evidence-based practice? A systematic review.

BACKGROUND: There is evidence that psychological therapies including cognitive behaviour therapy (CBT) may be effective in reducing postnatal depression (PND) when offered to individuals. In clinical practice, this is also implemented in a group therapy format, which, although not recommended in guidelines, is seen as a cost-effective alternative. To consider the extent to which group methods can be seen as evidence-based, we systematically review and synthesise the evidence for the efficacy of group CBT compared to currently used packages of care for women with PND, and we discuss further factors which may contribute to clinician confidence in implementing an intervention. METHODS: Seventeen electronic databases were searched. All full papers were read by two reviewers and a third reviewer was consulted in the event of a disagreement on inclusion. Selected studies were quality assessed, using the Cochrane Risk of Bias Tool, were data extracted by two reviewers using a standardised data extraction form and statistically synthesised where appropriate using the fixed-effect inverse-variance method. RESULTS: Seven studies met the inclusion criteria. Meta-analyses showed group CBT to be effective in reducing depression compared to routine primary care, usual care or waiting list groups. A pooled effect size of d = 0.57 (95% CI 0.34 to 0.80, p < 0.001) was observed at 10-13 weeks post-randomisation, reducing to d = 0.28 (95% CI 0.03 to 0.53, p = 0.025) at 6 months. The non-randomised comparisons against waiting list controls at 10-13 weeks was associated with a larger effect size of d = 0.94 (95% CI 0.42 to 1.47, p < 0.001). However due to the limitations of the available data, such as ill-specified definitions of the CBT component of the group programmes, these results should be interpreted with caution. CONCLUSIONS: Although the evidence available is limited, group CBT was shown to be effective. We argue, therefore, that there is sufficient evidence to implement group CBT, conditional upon routinely collected outcomes being benchmarked against those obtained in trials of individual CBT, and with other important factors such as patient preference, clinical experience, and information from the local context taken into account when making the treatment decision.

The National Institute for Health and Clinical Excellence Single Technology Appraisal process: lessons from the first 4 years.

OBJECTIVES: The National Institute for Health and Clinical Excellence (NICE) Single Technology Appraisal (STA) process in the United Kingdom was established in 2005 in order to provide guidance on new technologies as close to their launch as possible. The NICE recommended timeframe for completion of an STA is 34 weeks. The purpose of this study was to map the first 95 STAs to collect information on a range of issues including timelines and appraisal decisions. METHODS: A mapping tool was devised to collect information from the NICE Web site. Data were analyzed by calculating frequencies. Simple descriptive statistics were applied where appropriate. RESULTS: Ninety-five STAs were included in the analysis. Almost one-third (30/95) initially identified topics did not go on to be appraised often due to licensing issues. Timelines were measured for 29 completed STAs. Eight (28%) of these were completed by 37 weeks and 20 (69%) by 42 weeks. When STAs with appeals were excluded, 31% (8/26) were completed by 37 weeks and 85% (22/26) by 42 weeks. The incremental cost-effectiveness ratios reported by manufacturers were consistently lower than those estimated by the evidence review groups. In all, 76% (38/50) of the completed STAs resulted in an approval. CONCLUSIONS: The NICE Web site enabled access to almost all necessary information, although electronic documents were sometimes difficult to locate. One-third of the referred topics were suspended or terminated. The NICE STA process is slower than initially anticipated and this is primarily due to events outside of NICE's direct control.

Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. 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 detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company's health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG's probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed.

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.

Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model.

BACKGROUND: Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq®; Ipsen, Paris, France) and vandetanib (Caprelsa®; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC. OBJECTIVES: (1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England. DATA SOURCES: Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions. REVIEW METHODS: A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model. RESULTS: The systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo (p < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower. LIMITATIONS: The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population. CONCLUSIONS: The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained. FUTURE RESEARCH PRIORITIES: (1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016050403. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Medullary thyroid carcinoma (MTC) is a rare form of cancer that presents as a mass of tumours in the thyroid gland of the neck. MTC affects both patients' health-related quality of life and survival. Targeted therapies (cabozantinib and vandetanib) are currently used to treat unresectable progressive and symptomatic MTC. The evidence for the use of cabozantinib and vandetanib in patients with unresectable locally advanced or metastatic MTC was reviewed, and two clinical trials were identified. The trials suggest that both drugs improve progression-free survival. Neither trial demonstrated significant survival benefits for cabozantinib or vandetanib. Both drugs produced frequent adverse events, often leading to dose interruption or reduction. Whether or not these therapies represent good value for money for the NHS was also assessed. Analyses indicate that the incremental cost-effectiveness ratios (ICERs) (a measure of cost-effectiveness) for cabozantinib and vandetanib versus best supportive care (BSC) in patients with symptomatic and progressive MTC are > £138,000 per quality-adjusted life-year (QALY) gained. Within a subgroup of patients with symptomatic and progressive MTC and carcinoembryonic antigen and/or calcitonin doubling times of ≤ 24 months, the ICER for vandetanib versus BSC remains > £66,000 per QALY gained.

Delphi consensus reached to produce a decision tool for SelecTing Approaches for Rapid Reviews (STARR).

OBJECTIVES: There are many rapid review methods; however, there is little pragmatic guidance on which methods to select. This study aimed to reach consensus among international rapid review experts outlining areas to consider when selecting approaches for rapid reviews. STUDY DESIGN AND SETTING: A two-round modified online Delphi survey was conducted between May and July 2018. Participants were asked to rank the importance of a predefined list of 19 items. A consensus definition of at least 70% agreement for each item was decided a priori. RESULTS: Thirty experts from ten countries participated in round 1 and 24 in round 2. During round 1, consensus was reached on all items. One additional item on quality assessment was suggested by respondents and comments suggested wording changes to improve clarity and understanding of the tool. Respondents in the second round indicated a high level of importance and all 20 items achieved consensus. These items addressed interaction with commissioners, scoping and searching the evidence-base, data extraction and synthesis methods, and reporting of rapid review methods. CONCLUSION: International consensus was reached to produce the SelecTing Approaches for Rapid Reviews (STARR) decision tool for planning rapid reviews and will lead to improved shared understanding between review teams and review commissioners.

Comparing methods for full versus single technology appraisal: a case study of docetaxel and paclitaxel for early breast cancer.

OBJECTIVE: The aim of this study is to compare and contrast the reports of the rapid National Institute for Health and Clinical Excellence (NICE) single technology (STA) process with the full Health Technology Assessment Report (TAR) for the same technologies (docetaxel and paclitaxel for the adjuvant treatment of early breast cancer). METHODS: Documentary analysis was used to compare three reports. A data extraction form was developed to record information on the decision problem addressed in each report, literature searching methods, the clinical effectiveness review, cost-effectiveness analysis, conclusions and issues of concern. RESULTS: The decision problems and search strategies for the STAs differed from those reported in the TAR. Not all trials of clinical effectiveness included in the TAR were reported by manufacturers. The methods and assumptions used to assess the cost-effectiveness of the technologies were generally similar between reports, although only one common health economic comparison was presented across the three reports. The TAR supports the STA results for docetaxel but suggested that the manufacturer's cost-effectiveness estimates for paclitaxel were highly optimistic. CONCLUSIONS: Although the STA process provides the opportunity for rapid appraisal of new technologies, there remains uncertainty concerning the extent to which STAs adequately address the specific decision problem under consideration.

Barriers and Facilitators to the Implementation of Interventions to Prevent Youth Violence in Latin America: A Systematic Review and Qualitative Evidence Synthesis.

Youth violence in Latin America is an important public health problem. However, the evidence from preventive programs within the region to address this problem is limited. Identifying context-specific factors that facilitate or hinder the success of interventions is necessary to guarantee the successful implementation of new preventive strategies. We present a systematic review and synthesis of qualitative studies to identify factors affecting the implementation of programs to prevent youth violence in Latin America. We searched 10 electronic databases and websites of international institutions. The quality of the studies was assessed using the critical appraisal skills program checklist, while the certainty of the findings of the synthesis was assessed using the certainty of the qualitative evidence approach. We included eight papers describing five programs in Argentina, Venezuela, Peru, El Salvador, and Mexico. Most of the factors affecting the implementation of programs were aspects related to features of the programs and social/political constraints. The synthesis suggests that future programs can benefit from having a multidisciplinary and/or multisectoral approach involving different key players. At the same time, potential strategies for avoiding problems related to such active engagement should be planned via promoting effective channels for communication and supervision. The review also suggests the importance of increasing awareness and motivation toward the problem of youth violence among relevant agencies and stakeholders. While the limited volume and quality of the literature impact on the ability to draw conclusions, the results could be useful for new programs being designed and the ones seeking to be adapted from other contexts.

Pertuzumab for the Neoadjuvant Treatment of Early-Stage HER2-Positive Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer of pertuzumab (Perjeta®; Roche Products Limited) to submit evidence of its clinical and cost- effectiveness for the neoadjuvant treatment of women with high-risk, early-stage, HER2-positive breast cancer when used in combination with trastuzumab and chemotherapy. High-risk women included those with locally advanced (including inflammatory) breast cancer and women with high-risk early-stage breast cancer (classified as T2/3 or N1). 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. This article presents the critical review of the company's submission by the Evidence Review Group and the outcome of the National Institute for Health and Care Excellence guidance. The clinical data were mainly taken from a phase II, randomised, open-label, active controlled study (NeoSphere), which reported a significant advantage in terms of pathological complete response rates of pertuzumab in combination with trastuzumab and chemotherapy, compared with trastuzumab alone with chemotherapy (45.8 vs. 29.0%, p = 0.0141). The company did not make any indirect comparisons. A meta-analysis of 12 neoadjuvant studies investigating the relationship between pathological complete response and event-free survival was used to extrapolate the outcomes reported in the NeoSphere study. A cardiac safety study (TRYPHAENA) demonstrated the safety of pertuzumab. The company undertook a model-based economic evaluation of neoadjuvant pertuzumab plus trastuzumab and docetaxel compared with neoadjuvant trastuzumab and docetaxel over a lifetime horizon from the National Health Service and Personal Social Services perspective. The probabilistic incremental cost-effectiveness ratio was estimated to be £20,104 per quality-adjusted life-year gained for pertuzumab alongside trastuzumab and docetaxel compared with trastuzumab and docetaxel, which was revised to £21,869 per quality-adjusted life-year gained following the clarification process. The Evidence Review Group corrected an error in the digitisation of the survivor functions and modified the clinically inappropriate assumption that recurrence is zero after 7 years. The Evidence Review Group's probabilistic base case was £23,962 per quality-adjusted life-year gained. During the appraisal, to mitigate the uncertainties associated with the evidence, the company offered a patient access scheme, which led to the National Institute for Health and Care Excellence Appraisal Committee recommending pertuzumab in this patient group, subject to the company providing the agreed discount in the patient access scheme.