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.

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.

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.

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.

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.

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.

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.

Adalimumab for Treating Moderate-to-Severe Hidradenitis Suppurativa: 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 adalimumab (AbbVie) to submit evidence on the clinical effectiveness and cost effectiveness of adalimumab for the treatment of moderate-to-severe hidradenitis suppurativa (HS). The appraisal assessed adalimumab as monotherapy in adult patients with an inadequate response to conventional systemic HS therapy. The School of Health and Related Research Technology Appraisal Group was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology based on the company's submission to NICE. The evidence was mainly derived from three randomised controlled trials comparing adalimumab with placebo in adults with moderate-to-severe HS. The clinical-effectiveness review found that significantly more patients achieved a clinical response in the adalimumab groups than in the control groups but that the treatment effect varied between trials and there was uncertainty regarding its impact on a range of other relevant outcomes as well as long-term efficacy. The company's submitted Markov model assessed the incremental cost effectiveness of adalimumab versus standard care for the treatment of HS from the perspective of the UK NHS and Personal Social Services (PSS) over a lifetime horizon. The original submitted model, including a patient access scheme (PAS), suggested that the incremental cost-effectiveness ratio (ICER) for adalimumab versus standard care was expected to be £16,162 per quality-adjusted life-year (QALY) gained. Following a critique of the model, the ERG's preferred base case, which corrected programming errors and structural problems surrounding discontinuation rules and incorporated a lower unit cost for HS surgery, resulted in a probabilistic ICER of £29,725 per QALY gained. Based on additional analyses undertaken by the company and the ERG following the publication of the appraisal consultation document (ACD), the Appraisal Committee concluded that the maximum possible ICER for adalimumab compared with supportive care was between £28,500 and £33,200 per QALY gained but was likely to be lower. The Appraisal Committee recommended adalimumab (with the PAS) for the treatment of active moderate-to-severe HS in adults whose disease has not responded to conventional systemic therapy.

Issues Related to the Frequency of Exploratory Analyses by Evidence Review Groups in the NICE Single Technology Appraisal Process.

BACKGROUND: Evidence Review Groups (ERGs) critically appraise company submissions as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process. As part of their critique of the evidence submitted by companies, the ERGs undertake exploratory analyses to explore uncertainties in the company's model. The aim of this study was to explore pre-defined factors that might influence or predict the extent of ERG exploratory analyses. OBJECTIVE: The aim of this study was to explore predefined factors that might influence or predict the extent of ERG exploratory analyses. METHODS: We undertook content analysis of over 400 documents, including ERG reports and related documentation for the 100 most recent STAs (2009-2014) for which guidance has been published. Relevant data were extracted from the documents and narrative synthesis was used to summarise the extracted data. All data were extracted and checked by two researchers. RESULTS: Forty different companies submitted documents as part of the NICE STA process. The most common disease area covered by the STAs was cancer (44%), and most ERG reports (n = 93) contained at least one exploratory analysis. The incidence and frequency of ERG exploratory analyses does not appear to be related to any developments in the appraisal process, the disease area covered by the STA, or the company's base-case incremental cost-effectiveness ratio (ICER). However, there does appear to be a pattern in the mean number of analyses conducted by particular ERGs, but the reasons for this are unclear and potentially complex. CONCLUSIONS: No clear patterns were identified regarding the presence or frequency of exploratory analyses, apart from the mean number conducted by individual ERGs. More research is needed to understand this relationship.

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.

The use of exploratory analyses within the National Institute for Health and Care Excellence single technology appraisal process: an evaluation and qualitative analysis.

BACKGROUND: As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal (STA) process, independent Evidence Review Groups (ERGs) critically appraise the company submission. During the critical appraisal process the ERG may undertake analyses to explore uncertainties around the company's model and their implications for decision-making. The ERG reports are a central component of the evidence considered by the NICE Technology Appraisal Committees (ACs) in their deliberations. OBJECTIVE: The aim of this research was to develop an understanding of the number and type of exploratory analyses undertaken by the ERGs within the STA process and to understand how these analyses are used by the NICE ACs in their decision-making. METHODS: The 100 most recently completed STAs with published guidance were selected for inclusion in the analysis. The documents considered were ERG reports, clarification letters, the first appraisal consultation document and the final appraisal determination. Over 400 documents were assessed in this study. The categories of types of exploratory analyses included fixing errors, fixing violations, addressing matters of judgement and the ERG-preferred base case. A content analysis of documents (documentary analysis) was undertaken to identify and extract relevant data, and narrative synthesis was then used to rationalise and present these data. RESULTS: The level and type of detail in ERG reports and clarification letters varied considerably. The vast majority (93%) of ERG reports reported one or more exploratory analyses. The most frequently reported type of analysis in these 93 ERG reports related to the category 'matters of judgement', which was reported in 83 (89%) reports. The category 'ERG base-case/preferred analysis' was reported in 45 (48%) reports, the category 'fixing errors' was reported in 33 (35%) reports and the category 'fixing violations' was reported in 17 (18%) reports. The exploratory analyses performed were the result of issues raised by an ERG in its critique of the submitted economic evidence. These analyses had more influence on recommendations earlier in the STA process than later on in the process. LIMITATIONS: The descriptions of analyses undertaken were often highly specific to a particular STA and could be inconsistent across ERG reports and thus difficult to interpret. CONCLUSIONS: Evidence Review Groups frequently conduct exploratory analyses to test or improve the economic evaluations submitted by companies as part of the STA process. ERG exploratory analyses often have an influence on the recommendations produced by the ACs. FUTURE WORK: More in-depth analysis is needed to understand how ERGs make decisions regarding which exploratory analyses should be undertaken. More research is also needed to fully understand which types of exploratory analyses are most useful to ACs in their decision-making. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A systematic review and economic evaluation of exercise referral schemes in primary care: a short report.

BACKGROUND: It is estimated that only 39% of men and 29% of women in England achieve the levels of physical activity that are recommended to protect health and prevent disease. One approach to addressing this problem has been the development of exercise referral schemes (ERSs), in which health professionals refer patients to external exercise providers. These schemes have been widely rolled out across the UK despite concerns that they may not produce sustained changes in levels of physical activity and, therefore, may not be cost-effective interventions. The evidence to determine clinical effectiveness and cost-effectiveness was evaluated in 2009. This review seeks to update this earlier work by incorporating new evidence and re-examining the cost-effectiveness. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of ERSs compared with usual care. DESIGN: Exhaustive searches of relevant electronic databases and journals were undertaken to identify new studies evaluating ERSs using a randomised controlled trial (RCT) design. RCTs that incorporated a qualitative evaluation of the intervention were identified in order to explore the barriers and facilitators to the uptake of and adherence to ERSs. Data were extracted using a previously designed tool and study quality assessed for potential bias. Where data could be pooled, meta-analyses were carried out. Qualitative analysis was also undertaken using a thematic approach. The cost-effectiveness was evaluated using a Markov structure which estimated the likelihood of becoming physically active and the subsequent risk reduction on coronary heart disease (CHD), stroke and type 2 diabetes mellitus. The model adopts a lifetime horizon, and a NHS and Personal Social Services perspective was taken with discounting at 1.5% for both costs and benefits. RESULTS: The search identified one new RCT and one new qualitative study. The new data were pooled with existing data from the 2011 review by Pavey et al. [Pavey TG, Anokye N, Taylor AH, Trueman P, Moxham T, Fox KR, et al. The clinical effectiveness and cost-effectiveness of exercise referral schemes: a systematic review and economic evaluation. Health Technol Assess 2011;15(44)] to give a total of eight studies with 5190 participants. The proportion of individuals achieving 90-150 minutes of at least moderate-intensity activity per week at 6-12 months' follow-up was greater for ERSs than usual care (relative risk 1.12; 95% confidence interval 1.04 to 1.20). Older patients and those referred for CHD risk factors appeared to be more likely than others to increase their levels of physical activity. Qualitative evidence suggests that interventions enabling the development of social support networks are beneficial in promoting uptake and adherence. Exercise referral gained 0.003 quality-adjusted life-years (QALYs) at an additional cost of £225 per person. The estimated mean incremental cost-effectiveness ratio (ICER) in the probabilistic sensitivity analysis was £76,276. In the univariate sensitivity analysis the results were very sensitive (ICERs ranged from < £30,000 to > £100,000) to changes in the effect of ERSs on physical activity uptake and the duration of the protective effects and the direct health-related quality-of-life gains attributable to physical activity. CONCLUSIONS: Exercise referral schemes result in a small improvement in the number of people who increase their levels of physical activity. The cost-effectiveness analysis indicates that the ICER for ERSs compared with usual care is around £76,000 per QALY, although the cost-effectiveness of ERSs is subject to considerable uncertainty. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005200. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Psychological and psychosocial interventions for cannabis cessation in adults: a systematic review short report.

BACKGROUND: Cannabis is the most commonly used illicit drug worldwide. Cannabis dependence is a recognised psychiatric diagnosis, often diagnosed via the Diagnostic and Statistical Manual of Mental Disorders criteria and the International Classification of Diseases, 10th Revision. Cannabis use is associated with an increased risk of medical and psychological problems. This systematic review evaluates the use of a wide variety of psychological and psychosocial interventions, such as motivational interviewing (MI), cognitive-behavioural therapy (CBT) and contingency management. OBJECTIVE: To systematically review the clinical effectiveness of psychological and psychosocial interventions for cannabis cessation in adults who use cannabis regularly. DATA SOURCES: Studies were identified via searches of 11 databases [MEDLINE, EMBASE, Cochrane Controlled Trials Register, Health Technology Assessment (HTA) database, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, NHS Economic Evaluation Database, PsycINFO, Web of Science Conference Proceedings Citation Index, ClinicalTrials.gov and metaRegister of Current Controlled Trials] from inception to February 2014, searching of existing reviews and reference tracking. METHODS: Randomised controlled trials (RCTs) assessing psychological or psychosocial interventions in a community setting were eligible. Risk of bias was assessed using adapted Cochrane criteria and narrative synthesis was undertaken. Outcomes included change in cannabis use, severity of cannabis dependence, motivation to change and intervention adherence. RESULTS: The review included 33 RCTs conducted in various countries (mostly the USA and Australia). General population studies: 26 studies assessed the general population of cannabis users. Across six studies, CBT (4-14 sessions) significantly improved outcomes (cannabis use, severity of dependence, cannabis problems) compared with wait list post treatment, maintained at 9 months in the one study with later follow-up. Studies of briefer MI or motivational enhancement therapy (MET) (one or two sessions) gave mixed results, with some improvements over wait list, while some comparisons were not significant. Four studies comparing CBT (6-14 sessions) with MI/MET (1-4 sessions) also gave mixed results: longer courses of CBT provided some improvements over MI. In one small study, supportive-expressive dynamic psychotherapy (16 sessions) gave significant improvements over one-session MI. Courses of other types of therapy (social support group, case management) gave similar improvements to CBT based on limited data. Limited data indicated that telephone- or internet-based interventions might be effective. Contingency management (vouchers for abstinence) gave promising results in the short term; however, at later follow-ups, vouchers in combination with CBT gave better results than vouchers or CBT alone. Psychiatric population studies: seven studies assessed psychiatric populations (schizophrenia, psychosis, bipolar disorder or major depression). CBT appeared to have little effect over treatment as usual (TAU) based on four small studies with design limitations (both groups received TAU and patients were referred). Other studies reported no significant difference between types of 10-session therapy. LIMITATIONS: Included studies were heterogeneous, covering a wide range of interventions, comparators, populations and outcomes. The majority were considered at high risk of bias. Effect sizes were reported in different formats across studies and outcomes. CONCLUSIONS: Based on the available evidence, courses of CBT and (to a lesser extent) one or two sessions of MI improved outcomes in a self-selected population of cannabis users. There was some evidence that contingency management enhanced long-term outcomes in combination with CBT. Results of CBT for cannabis cessation in psychiatric populations were less promising, but may have been affected by provision of TAU in both groups and the referred populations. Future research should focus on the number of CBT/MI sessions required and potential clinical effectiveness and cost-effectiveness of shorter interventions. CBT plus contingency management and mutual aid therapies warrant further study. Studies should consider potential effects of recruitment methods and include inactive control groups and long-term follow-up. TAU arms in psychiatric population studies should aim not to confound the study intervention. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014008952. FUNDING: The National Institute for Health Research HTA programme.

Improving search efficiency for systematic reviews of diagnostic test accuracy: an exploratory study to assess the viability of limiting to MEDLINE, EMBASE and reference checking.

BACKGROUND: Increasing numbers of systematic reviews evaluating the diagnostic test accuracy of technologies are being published. Currently, review teams tend to apply conventional systematic review standards to identify relevant studies for inclusion, for example sensitive searches of multiple bibliographic databases. There has been little evaluation of the efficiency of searching only one or two such databases for this type of review. The aim of this study was to assess the viability of an approach that restricted searches to MEDLINE, EMBASE and the reference lists of included studies. METHODS: A convenience sample of nine Health Technology Assessment (HTA) systematic reviews of diagnostic test accuracy, with 302 included citations, was analysed to determine the number and proportion of included citations that were indexed in and retrieved from MEDLINE and EMBASE. An assessment was also made of the number and proportion of citations not retrieved from these databases but that could have been identified from the reference lists of included citations. RESULTS: 287/302 (95 %) of the included citations in the nine reviews were indexed across MEDLINE and EMBASE. The reviews' searches of MEDLINE and EMBASE accounted for 85 % of the included citations (256/302). Of the forty-six (15 %) included citations not retrieved by the published searches, 24 (8 %) could be found in the reference lists of included citations. Only 22/302 (7 %) of the included citations were not found by the proposed, more efficient approach. CONCLUSIONS: The proposed approach would have accounted for 280/302 (93 %) of included citations in this sample of nine systematic reviews. This exploratory study suggests that there might be a case for restricting searches for systematic reviews of diagnostic test accuracy studies to MEDLINE, EMBASE and the reference lists of included citations. The conduct of such reviews might be rendered more efficient by using this approach.

Systematic review and economic modelling of the clinical effectiveness and cost-effectiveness of art therapy among people with non-psychotic mental health disorders.

BACKGROUND: Mental health problems account for almost half of all ill health in people under 65 years. The majority are non-psychotic (e.g. depression, anxiety and phobias). For some people, art therapy may provide more profound and long-lasting healing than more standard forms of treatment, perhaps because it can provide an alternative means of expression and release from trauma. As yet, no formal evaluation of art therapy for non-psychotic mental health disorders has been conducted. AIM: This review aimed to evaluate evidence for the clinical effectiveness and cost-effectiveness of art therapy for non-psychotic mental health disorders. METHODS: Comprehensive literature searches for studies examining art therapy in populations with non-psychotic mental health disorders were performed in major health-related and social science bibliographic databases including MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Allied and Complementary Medicine Database (AMED) and Applied Social Sciences Index and Abstracts (ASSIA) from inception up to May 2013. A quantitative systematic review of clinical effectiveness, a qualitative review to explore the acceptability, relative benefits and potential harms, and a cost-utility analysis of studies evaluating cost-effectiveness of art therapy were conducted. RESULTS: In the quantitative review, 15 randomised controlled trials (RCTs) were included (n = 777). Meta-analysis was not possible because of clinical heterogeneity and insufficient comparable data on outcome measures across studies. A narrative synthesis reports that art therapy was associated with significant positive changes relative to the control group in mental health symptoms in 10 out of the 15 studies. The control groups varied between studies but included wait-list/no treatment, attention placebo controls and psychological therapy comparators. Four studies reported improvement from baseline but no significant difference between groups. One study reported that outcomes were more favourable in the control group. The quality of included RCTs was generally low. In the qualitative review, 12 cohort studies were included (n = 188 service users; n = 16 service providers). Themes relating to benefits of art therapy for service users included the relationship with the therapist, personal achievement and distraction. Areas of potential harms were related to the activation of emotions that were then unresolved, lack of skill of the art therapist and sudden termination of art therapy. The quality of included qualitative studies was generally low to moderate. In the cost-effectiveness review, a de novo model was constructed and populated with data identified from the clinical review. Scenario analyses were conducted allowing comparisons of group art therapy with wait-list control, group art therapy with group verbal therapy, and individual art therapy versus control. Art therapy appeared cost-effective compared with wait-list control with high certainty, although generalisability to the target population was unclear. Verbal therapy appeared more cost-effective than art therapy but there was considerable uncertainty and a sizeable probability that art therapy was more clinically effective. The cost-effectiveness of individual art therapy was uncertain and dependent on assumptions regarding clinical benefit and duration of benefit. CONCLUSIONS: From the limited available evidence, art therapy was associated with positive effects when compared with a control in a number of studies in patients with different clinical profiles, and it was reported to be an acceptable treatment and was associated with a number of benefits. Art therapy appeared to be cost-effective compared with wait-list but further studies are needed to confirm this finding as well as evidence to inform future cost-effective analyses of art therapy versus other treatments. STUDY REGISTRATION: The study is registered as PROSPERO CRD42013003957. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Interventions to treat premature ejaculation: a systematic review short report.

BACKGROUND: Premature ejaculation (PE) is commonly defined as ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it. PE can be either lifelong and present since first sexual experiences (primary), or acquired (secondary), beginning later (Godpodinoff ML. Premature ejaculation: clinical subgroups and etiology. J Sex Marital Ther 1989;15:130-4). Treatments include behavioural and pharmacological interventions. OBJECTIVE: To systematically review evidence for clinical effectiveness of behavioural, topical and systemic treatments for PE. DATA SOURCES: The following databases were searched from inception to 6 August 2013 for published and unpublished research evidence: MEDLINE; EMBASE; Cumulative Index to Nursing and Allied Health Literature; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects and the Health Technology Assessment database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science. The US Food and Drug Administration website and the European Medicines Agency (EMA) website were also searched. METHODS: Randomised controlled trials (RCTs) in adult men with PE were eligible (or non-RCTs in the absence of RCTs). RCT data were extrapolated from review articles when available. The primary outcome was intravaginal ejaculatory latency time (IELT). Data were meta-analysed when possible. Other outcomes included sexual satisfaction, control over ejaculation, relationship satisfaction, self-esteem, quality of life, treatment acceptability and adverse events (AEs). RESULTS: A total of 103 studies (102 RCTs, 65 from reviews) were included. RCTs were available for all interventions except yoga. The following interventions demonstrated significant improvements (p < 0.05) in arithmetic mean difference in IELT compared with placebo: topical anaesthetics - eutectic mixture of local anaesthetics (EMLA(®), AstraZeneca), topical eutectic mixture for PE (Plethora Solutions Ltd) spray; selective serotonin reuptake inhibitors (SSRIs) - citalopram (Cipramil(®), Lundbeck), escitalopram (Cipralex(®), Lundbeck), fluoxetine, paroxetine, sertraline, dapoxetine (Priligy(®), Menarini), 30 mg or 60 mg; serotonin-noradrenaline reuptake inhibitors - duloxetine (Cymbalta(®), Eli Lilly & Co Ltd); tricyclic antidepressants - inhaled clomipramine 4 mg; phosphodiesterase-5 (PDE5) inhibitors - vardenafil (Levitra(®), Bayer), tadalafil (Cialis(®), Eli Lilly & Co Ltd); opioid analgesics - tramadol (Zydol SR(®), Grünenthal). Improvements in sexual satisfaction and other outcomes compared with placebo were evident for SSRIs, PDE5 inhibitors and tramadol. Outcomes for interventions not compared with placebo were as follows: behavioural therapies - improvements over wait list control in IELT and other outcomes, behavioural therapy plus pharmacotherapy better than either therapy alone; alpha blockers - terazosin (Hytrin(®), AMCO) not significantly different to antidepressants in ejaculation control; acupuncture - improvements over sham acupuncture in IELT, conflicting results for comparisons with SSRIs; Chinese medicine - improvements over treatment as usual; delay device - improvements in IELT when added to stop-start technique; yoga - improved IELT over baseline, fluoxetine better than yoga. Treatment-related AEs were evident with most pharmacological interventions. LIMITATIONS: Although data extraction from reviews was optimised when more than one review reported data for the same RCT, the reliability of the data extraction within these reviews cannot be guaranteed by this assessment report. CONCLUSIONS: Several interventions significantly improved IELT. Many interventions also improved sexual satisfaction and other outcomes. However, assessment of longer-term safety and effectiveness is required to evaluate whether or not initial treatment effects are maintained long term, whether or not dose escalation is required, how soon treatment effects end following treatment cessation and whether or not treatments can be stopped and resumed at a later time. In addition, assessment of the AEs associated with long-term treatment and whether or not different doses have differing AE profiles is required. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005289. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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.

The effectiveness of sexual health interventions for people with severe mental illness: a systematic review.

BACKGROUND: Severe mental illnesses (SMIs), such as schizophrenia and bipolar disorder, persist over time and can cause extensive disability leading to impairments in social and occupational functioning. People with SMI have higher morbidity and mortality due to physical illness than the general population and may be more likely to engage in high-risk sexual behaviour (e.g. unprotected intercourse, having multiple partners, involvement in the sex trade and illicit drug use), putting them at risk of poorer sexual health outcomes including sexually transmitted infections. Sexual health promotion interventions, developed and implemented for people with SMI, may improve participants' knowledge, attitudes, beliefs or behavioural practices and could lead to a reduction in risky sexual behaviour. OBJECTIVES: To evaluate the effectiveness of sexual health interventions for people with SMI compared with usual care and their applicability to the UK NHS setting. DATA SOURCES: Thirteen electronic databases were searched from inception to December 2012. All controlled trials (randomised or non-randomised) that met the following criteria were included: any sexual health promotion intervention or combination of interventions intended to change the knowledge, attitudes, beliefs, behaviours or practices of individuals with SMI (defined as adults aged ≥ 18 years who have received a diagnosis of schizophrenia or bipolar disorder) living in the community. REVIEW METHODS: A systematic review of the clinical evidence was undertaken following recommended guidelines. Data were tabulated and discussed in a narrative review. RESULTS: Thirteen randomised controlled studies met the inclusion criteria. The methodological quality of the included studies varied considerably, with only a minority of studies (n = 2) being considered as having very few methodological limitations. Despite wide variations in the study populations, interventions, comparators and outcomes, four studies showed significant improvements in all measured sexual risk behaviour outcomes (e.g. human immunodeficiency virus knowledge and behaviour change) in the intervention groups compared with the control groups. In contrast, four studies found significant improvements in the intervention groups for some outcomes only and three studies found significant improvements in certain subgroups only, based on either gender or ethnicity. Finally, two studies reported no significant differences in any sexual risk behaviour outcomes between the intervention and control groups. Moreover, positive findings were not consistently sustained at follow-up in many studies. LIMITATIONS: Little detail was provided in the studies regarding the content of interventions, how they were delivered and by whom, making replication or generalisability difficult. CONCLUSIONS: Owing to the large between-study variability (especially in the populations, interventions, comparators and reported outcomes) and mixed results, there is insufficient evidence to fully support or reject the identified sexual health interventions for people with SMI. In addition, there are considerable uncertainties around the generalisability of these findings to the UK setting. Further research recommendations include well-designed, UK-based trials of sexual health interventions for people with SMI as well as training and support for staff implementing sexual health interventions. STUDY REGISTRATION: PROSPERO number CRD42013003674. FUNDING: The National Institute for Health Research Health Technology Assessment Programme.

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.

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.