KardiaMobile 6L for measuring QT interval in people having antipsychotic medication to inform early value assessment: a systematic review.

Background: The indication for this assessment is the use of the KardiaMobile six-lead electrocardiogram device for the assessment of QT interval-based cardiac risk in service users prior to the initiation of, or for the monitoring of, antipsychotic medications, which are associated with an established risk of QT interval prolongation. Objectives: To provide an early value assessment of whether KardiaMobile six-lead has the potential to provide an effective and safe alternative to 12-lead electrocardiogram for initial assessment and monitoring of QT interval-based cardiac risk in people taking antipsychotic medications. Review methods: Twenty-seven databases were searched to April/May 2022. Review methods followed published guidelines. Where appropriate, study quality was assessed using appropriate risk of bias tools. Results were summarised by research question; accuracy/technical performance; clinical effects (on cardiac and psychiatric outcomes); service user acceptability/satisfaction; costs of KardiaMobile six-lead. Results: We did not identify any studies which provided information about the diagnostic accuracy of KardiaMobile six-lead, for the detection of corrected QT-interval prolongation, in any population. All studies which reported information about agreement between QT interval measurements (corrected and/or uncorrected) with KardiaMobile six-lead versus 12-lead electrocardiogram were conducted in non-psychiatric populations, used cardiologists and/or multiple readers to interpret electrocardiograms. Where reported or calculable, the mean difference in corrected QT interval between devices (12-lead electrocardiogram vs. KardiaMobile six-lead) was generally small (≤ 10 ms) and corrected QT interval measured using KardiaMobile six-lead was consistently lower than that measured using 12-lead electrocardiogram. All information about the use of KardiaMobile six-lead, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication, was taken from retrospective surveys of staff and service users who had chosen to use KardiaMobile six-lead during pilots, described in two unpublished project reports. It is important to note that both these project reports relate to pilot studies which were not intended to be used in wider evaluations of KardiaMobile six-lead for use in the NHS. Both reports included survey results which indicated that the use of KardiaMobile six-lead may be associated with reductions in the time taken to complete an electrocardiogram and costs, relative to 12-lead electrocardiogram, and that KardiaMobile six-lead was preferred over 12-lead electrocardiogram by almost all responding staff and service users. Limitations: There was a lack of published evidence about the efficacy of KardiaMobile six-lead for initial assessment and monitoring of QT interval-based cardiac risk in people taking antipsychotic medications. Conclusions: There is insufficient evidence to support a full diagnostic assessment evaluating the clinical and cost effectiveness of KardiaMobile six-lead, in the context of QT interval-based cardiac risk assessment for service users who require antipsychotic medication. The evidence to inform the aims of this early value assessment (i.e. to assess whether the device has the potential to be clinically effective and cost-effective) was also limited. This report includes a comprehensive list of research recommendations, both to reduce the uncertainty around this early value assessment and to provide the additional data needed to inform a full diagnostic assessment, including cost-effectiveness modelling. Study registration: This study is registered as PROSPERO CRD42022336695. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135520) and is published in full in Health Technology Assessment; Vol. 28, No. 19. See the NIHR Funding and Awards website for further award information.

Some medicines used for people with certain mental health problems can increase the risk of developing serious heart conditions. Although these heart conditions are rare, it is generally recommended that people have an electrocardiogram examination before starting to take these medicines. People who need to continue these medications over a period of time may need additional electrocardiograms every so often, to check for any heart problems that have developed recently. KardiaMobile six-lead (or 6-lead) is a portable electrocardiogram that may offer a less intrusive way to take electrocardiogram measurements. This is because less undressing is needed as the electrodes are only applied to fingers of the left and right hand and the left ankle or knee and the cold gel is not needed. Testing using the KardiaMobile six-lead device can be carried out at the patient's home. These features might mean that the KardiaMobile six-lead device could be more acceptable than the 12-lead electrocardiogram to some patients. This assessment considered whether the KardiaMobile six-lead device has the potential to provide an effective and safe alternative to 12-lead electrocardiogram for initial assessment and monitoring of the risk of heart problems in people taking antipsychotic medications. Based on the available evidence, it remains unclear whether KardiaMobile six-lead has adequately demonstrated sufficient evidence of potential advantage(s) over current practice to justify further research to inform assessment of its clinical effectiveness and cost effectiveness. Our report provides detailed recommendations about the research needed, to provide further information about potential benefits so that a decision can be made about whether it should be used in the NHS in England, after further research has been completed.

Digital interventions to moderate physical inactivity and/or nutrition in young people: a Cancer Prevention Europe overview of systematic reviews.

Background: Strategies to increase physical activity (PA) and improve nutrition would contribute to substantial health benefits in the population, including reducing the risk of several types of cancers. The increasing accessibility of digital technologies mean that these tools could potentially facilitate the improvement of health behaviours among young people. Objective: We conducted a review of systematic reviews to assess the available evidence on digital interventions aimed at increasing physical activity and good nutrition in sub-populations of young people (school-aged children, college/university students, young adults only (over 18 years) and both adolescent and young adults (<25 years)). Methods: Searches for systematic reviews were conducted across relevant databases including KSR Evidence (www.ksrevidence.com), Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE; CRD). Records were independently screened by title and abstract by two reviewers and those deemed eligible were obtained for full text screening. Risk of bias (RoB) was assessed with the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool. We employed a narrative analysis and developed evidence gap maps. Results: Twenty-four reviews were included with at least one for each sub-population and employing a range of digital interventions. The quality of evidence was limited with only one of the 24 of reviews overall judged as low RoB. Definitions of "digital intervention" greatly varied across systematic reviews with some reported interventions fitting into more than one category (i.e., an internet intervention could also be a mobile phone or computer intervention), however definitions as reported in the relevant reviews were used. No reviews reported cancer incidence or related outcomes. Available evidence was limited both by sub-population and type of intervention, but evidence was most pronounced in school-aged children. In school-aged children eHealth interventions, defined as school-based programmes delivered by the internet, computers, tablets, mobile technology, or tele-health methods, improved outcomes. Accelerometer-measured (Standardised Mean Difference [SMD] 0.33, 95% Confidence Interval [CI]: 0.05 to 0.61) and self-reported (SMD: 0.14, 95% CI: 0.05 to 0.23) PA increased, as did fruit and vegetable intake (SMD: 0.11, 95% CI: 0.03 to 0.19) (review rated as low RoB, minimal to considerable heterogeneity across results). No difference was reported for consumption of fat post-intervention (SMD: -0.06, 95% CI: -0.15 to 0.03) or sugar sweetened beverages(SSB) and snack consumption combined post-intervention (SMD: -0.02, 95% CI:-0.10 to 0.06),or at the follow up (studies reported 2 weeks to 36 months follow-up) after the intervention (SMD:-0.06, 95% CI: -0.15 to 0.03) (review rated low ROB, minimal to substantial heterogeneity across results). Smartphone based interventions utilising Short Messaging Service (SMS), app or combined approaches also improved PA measured using objective and subjective methods (SMD: 0.44, 95% CI: 0.11 to 0.77) when compared to controls, with increases in total PA [weighted mean difference (WMD) 32.35 min per day, 95% CI: 10.36 to 54.33] and in daily steps (WMD: 1,185, 95% CI: 303 to 2,068) (review rated as high RoB, moderate to substantial heterogeneity across results). For all results, interpretation has limitations in terms of RoB and presence of unexplained heterogeneity. Conclusions: This review of reviews has identified limited evidence that suggests some potential for digital interventions to increase PA and, to lesser extent, improve nutrition in school-aged children. However, effects can be small and based on less robust evidence. The body of evidence is characterised by a considerable level of heterogeneity, unclear/overlapping populations and intervention definitions, and a low methodological quality of systematic reviews. The heterogeneity across studies is further complicated when the age (older vs. more recent), interactivity (feedback/survey vs. no/less feedback/surveys), and accessibility (type of device) of the digital intervention is considered. This underscores the difficulty in synthesising evidence in a field with rapidly evolving technology and the resulting challenges in recommending the use of digital technology in public health. There is an urgent need for further research using contemporary technology and appropriate methods.

A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel.

OBJECTIVE: To understand the benefit-risk profile for historical and current treatments for MLD. METHODS: A systematic review was conducted on the effectiveness, safety, and costs of MLD treatments: allogeneic haematopoietic stem cell transplantation (HSCT) and atidarsagene autotemcel (arsa-cel) according to best practice. RESULTS: A total of 6940 titles and abstracts were retrieved from the literature searches and 26 from other sources. From these, 35 manuscripts reporting on a total of 12 studies were selected for inclusion in the review. There were no controlled multi-armed trials. However, we provide observations comparing two interventional therapies (alloHSCT and arsa-cel) and each of these to standard/supportive care (natural history). There were no benefits for survival, gross motor function and cognitive function for LI patients receiving alloHSCT, as patients experienced disease progression similar to LI natural history. For juvenile patients receiving alloHSCT, no differences in survival were observed versus natural history, however stabilisation of cognitive and motor function were reported for some patients (particularly for pre- or minimally-symptomatic LJ patients), while others experienced disease progression. Furthermore, alloHSCT was associated with severe complications such as treatment-related mortality, graft versus host disease, and re-transplantation in both LI and EJ treated patients. Most LI and EJ patients treated with arsa-cel appeared to have normal development, preservation, or slower progression of gross motor function and cognitive function, in contrast to the rapid decline observed in natural history patients. A survival benefit for arsa-cel versus natural history and versus alloHSCT was observed in LI patients.LI and EJ patients treated with arsa-cel had better gross motor function and cognitive function compared to alloHSCT, which had limited effect on motor and cognitive decline. No data has been reported for arsa-cel treatment of LJ patients. CONCLUSIONS: Overall, this systematic review indicates that compared to NHx and HSCT, treatment with arsa-cel results in clinically relevant benefits in LI and EJ MLD patients by preserving cognitive function and motor development in most patients, and increased survival for LI patients. Nevertheless, further research is required to confirm these findings, given they are based on results from non-RCT studies.

Digital interventions to moderate alcohol consumption in young people: a Cancer Prevention Europe overview of systematic reviews.

Background: Strategies to reduce alcohol consumption would contribute to substantial health benefits in the population, including reducing cancer risk. The increasing accessibility and applicability of digital technologies make these powerful tools suitable to facilitate changes in behaviour in young people which could then translate into both immediate and long-term improvements to public health. Objective: We conducted a review of systematic reviews to assess the available evidence on digital interventions aimed at reducing alcohol consumption in sub-populations of young people [school-aged children, college/university students, young adults only (over 18 years) and both adolescent and young adults (<25 years)]. Methods: Searches were conducted across relevant databases including KSR Evidence, Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE). Records were independently screened by title and abstract and those that met inclusion criteria were obtained for full text screening by two reviewers. Risk of bias (RoB) was assessed with the ROBIS checklist. We employed a narrative analysis. Results: Twenty-seven systematic reviews were included that addressed relevant interventions in one or more of the sub-populations, but those reviews were mostly assessed as low quality. Definitions of "digital intervention" greatly varied across systematic reviews. Available evidence was limited both by sub-population and type of intervention. No reviews reported cancer incidence or influence on cancer related outcomes. In school-aged children eHealth multiple health behaviour change interventions delivered through a variety of digital methods were not effective in preventing or reducing alcohol consumption with no effect on the prevalence of alcohol use [Odds Ratio (OR) = 1.13, 95% CI: 0.95-1.36, review rated low RoB, minimal heterogeneity]. While in adolescents and/or young adults who were identified as risky drinkers, the use of computer or mobile device-based interventions resulted in reduced alcohol consumption when comparing the digital intervention with no/minimal intervention (-13.4 g/week, 95% CI: -19.3 to -7.6, review rated low RoB, moderate to substantial heterogeneity).In University/College students, a range of E-interventions reduced the number of drinks consumed per week compared to assessment only controls although the overall effect was small [standardised mean difference (SMD): -0.15, 95% CI: -0.21 to -0.09]. Web-based personalised feedback interventions demonstrated a small to medium effect on alcohol consumption (SMD: -0.19, 95% CI: -0.27 to -0.11) (review rated high RoB, minimal heterogeneity). In risky drinkers, stand-alone Computerized interventions reduced short (SMD: -0.17, 95% CI: -0.27 to -0.08) and long term (SMD: -0.17, 95% CI: -0.30 to -0.04) alcohol consumption compared to no intervention, while a small effect (SMD: -0.15, 95% CI: -0.25 to -0.06) in favour of computerised assessment and feedback vs. assessment only was observed. No short-term (SMD: -0.10, 95% CI: -0.30 to 0.11) or long-term effect (SMD: -0.11, 95% CI: -0.53 to 0.32) was demonstrated for computerised brief interventions when compared to counsellor based interventions (review rated low RoB, minimal to considerable heterogeneity). In young adults and adolescents, SMS-based interventions did not significantly reduce the quantity of drinks per occasion from baseline (SMD: 0.28, 95% CI: -0.02 to 0.58) or the average number of standard glasses per week (SMD: -0.05, 95% CI: -0.15 to 0.05) but increased the risk of binge drinking episodes (OR = 2.45, 95% CI: 1.32-4.53, review rated high RoB; minimal to substantial heterogeneity). For all results, interpretation has limitations in terms of risk of bias and heterogeneity. Conclusions: Limited evidence suggests some potential for digital interventions, particularly those with feedback, in reducing alcohol consumption in certain sub-populations of younger people. However, this effect is often small, inconsistent or diminishes when only methodologically robust evidence is considered. There is no systematic review evidence that digital interventions reduce cancer incidence through alcohol moderation in young people. To reduce alcohol consumption, a major cancer risk factor, further methodologically robust research is warranted to explore the full potential of digital interventions and to form the basis of evidence based public health initiatives.

Oral Azacitidine for Maintenance Treatment of Acute Myeloid Leukaemia After Induction Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of oral azacitidine (ONUREG), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of oral azacitidine for maintenance treatment of acute myeloid leukaemia (AML) after induction therapy compared with watch-and-wait plus best supportive care (BSC) and midostaurin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. In the QUAZAR AML-001 trial, oral azacitidine significantly improved overall survival (OS) versus placebo: median OS gain of 9.9 months (24.7 months versus 14.8 months; hazard ratio (HR) 0.69 (95% CI 0.55-0.86), p < 0.001). The median time to relapse was also better for oral azacitidine, and the incidences of TEAEs were similar for the two arms. The company excluded two of the comparators listed in the scope, low-dose cytarabine and subcutaneous azacitidine, informed only by clinical expert opinion, leaving only best supportive care (BSC) and midostaurin for the FLT3-ITD and/or FLT3-TKD (FLT3 mutation)-positive subgroup. An ITC comparing oral azacitidine to midostaurin as maintenance therapy in the appropriate subgroup demonstrated that the OS and relapse-free survival (RFS) HRs were favourable for oral azacitidine when compared with midostaurin. However, in the only available trial of midostaurin as maintenance treatment in AML that was used for this ITC, subjects were not randomised at the maintenance phase, but at induction, which posed a substantial risk of bias. The revised and final probabilistic incremental cost-effectiveness ratio (ICER) presented by the company, including a commercial arrangement, was £32,480 per quality-adjusted life year (QALY) gained for oral azacitidine versus watch-and-wait plus BSC. Oral azacitidine was dominant versus midostaurin in the FLT-3 subgroup. The ERG's concerns included the approach of modelling haematopoietic stem cell transplantation (HSCT), the generalisability of the population and the number of cycles of consolidation therapy pre-treatment in the QUAZAR AML-001 trial to UK clinical practice, and uncertainty in the relapse utility. The revised and final ERG base case resulted in a similar probabilistic ICER of £33,830 per QALY gained versus watch-and-wait plus BSC, but with remaining uncertainty. Oral azacitidine remained dominant versus midostaurin in the FLT-3 subgroup. After the second NICE appraisal committee meeting, the NICE Appraisal Committee recommended oral azacitidine (according to the commercial arrangement), within its marketing authorisation, as an option for maintenance treatment for AML in adults who are in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and cannot have or do not want HSCT.

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

Ixekizumab for Treating Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz®), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of £25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of £39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost-effectiveness ratio was within the range that could be considered a cost-effective use of National Health Service resources.

Lenalidomide for the Treatment of Low- or Intermediate-1-Risk Myelodysplastic Syndromes Associated with Deletion 5q Cytogenetic Abnormality: An Evidence Review of the NICE Submission from Celgene.

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

KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis.

BACKGROUND: Bowel cancer is the third most common cancer in the UK. Most bowel cancers are initially treated with surgery, but around 17% spread to the liver. When this happens, sometimes the liver tumour can be treated surgically, or chemotherapy may be used to shrink the tumour to make surgery possible. Kirsten rat sarcoma viral oncogene (KRAS) mutations make some tumours less responsive to treatment with biological therapies such as cetuximab. There are a variety of tests available to detect these mutations. These vary in the specific mutations that they detect, the amount of mutation they detect, the amount of tumour cells needed, the time to give a result, the error rate and cost. OBJECTIVES: To compare the performance and cost-effectiveness of KRAS mutation tests in differentiating adults with metastatic colorectal cancer whose metastases are confined to the liver and are unresectable and who may benefit from first-line treatment with cetuximab in combination with standard chemotherapy from those who should receive standard chemotherapy alone. DATA SOURCES: Thirteen databases, including MEDLINE and EMBASE, research registers and conference proceedings were searched to January 2013. Additional data were obtained from an online survey of laboratories participating in the UK National External Quality Assurance Scheme pilot for KRAS mutation testing. METHODS: A systematic review of the evidence was carried out using standard methods. Randomised controlled trials were assessed for quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using the QUADAS-2 tool. There were insufficient data for meta-analysis. For accuracy studies we calculated sensitivity and specificity together with 95% confidence intervals (CIs). Survival data were summarised as hazard ratios and tumour response data were summarised as relative risks, with 95% CIs. The health economic analysis considered the long-term costs and quality-adjusted life-years associated with different tests followed by treatment with standard chemotherapy or cetuximab plus standard chemotherapy. The analysis took a 'no comparator' approach, which implies that the cost-effectiveness of each strategy will be presented only compared with the next most cost-effective strategy. The de novo model consisted of a decision tree and Markov model. RESULTS: The online survey indicated no differences between tests in batch size, turnaround time, number of failed samples or cost. The literature searches identified 7903 references, of which seven publications of five studies were included in the review. Two studies provided data on the accuracy of KRAS mutation testing for predicting response to treatment in patients treated with cetuximab plus standard chemotherapy. Four RCTs provided data on the clinical effectiveness of cetuximab plus standard chemotherapy compared with that of standard chemotherapy in patients with KRAS wild-type tumours. There were no clear differences in the treatment effects reported by different studies, regardless of which KRAS mutation test was used to select patients. In the 'linked evidence' analysis the Therascreen KRAS RGQ PCR Kit (QIAGEN) was more expensive but also more effective than pyrosequencing or direct sequencing, with an incremental cost-effectiveness ratio of £17,019 per quality-adjusted life-year gained. In the 'assumption of equal prognostic value' analysis the total costs associated with the various testing strategies were similar. LIMITATIONS: The results assume that the differences in outcomes between the trials were solely the result of the different mutation tests used to distinguish between patients; this assumption ignores other factors that might explain this variation. CONCLUSIONS: There was no strong evidence that any one KRAS mutation test was more effective or cost-effective than any other test. STUDY REGISTRATION: PROSPERO CRD42013003663. FUNDING: The National Institute for Health Research Health Technology Assessment programme.