Systematic Review of Newborn Screening Programmes for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder causing the degeneration of motor neurons in the spinal cord. Recent studies suggest greater effectiveness of treatment in the presymptomatic stage. This systematic review synthesises findings from 37 studies (and 3 overviews) of newborn screening for SMA published up to November 2023 across 17 countries to understand the methodologies used; test accuracy performance; and timing, logistics and feasibility of screening. All studies screened for the homozygous deletion of SMN1 exon 7. Most (28 studies) used RT-PCR as the initial test on dried blood spots (DBSs), while nine studies also reported second-tier tests on DBSs for screen-positive cases. Babies testing positive on DBSs were referred for confirmatory testing via a range of methods. Observed SMA birth prevalence ranged from 1 in 4000 to 1 in 20,000. Most studies reported no false-negative or false-positive cases (therefore had a sensitivity and specificity of 100%). Five studies reported either one or two false-negative cases each (total of six cases; three compound heterozygotes and three due to system errors), although some false-negatives may have been missed due to lack of follow-up of negative results. Eleven studies reported false-positive cases, some being heterozygous carriers or potentially related to heparin use. Time to testing and treatment varied between studies. In conclusion, several countries have implemented newborn screening for SMA in the last 5 years using a variety of methods. Implementation considerations include processes for timely initial and confirmatory testing, partnerships between screening and neuromuscular centres, and timely treatment initiation.

Cefiderocol for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

Background: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods: The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol. Results: Among Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years. Conclusion: This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS. Limitations: Given existing evidence, the estimates of the value of cefiderocol are highly uncertain. Future work: Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value. Study registration: No registration of this study was undertaken. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information.

This project tested new methods for estimating the value to the NHS of an antimicrobial, cefiderocol, so its manufacturer could be paid fairly even if very little drug is used in order to reduce the risk of bacteria becoming resistant to the product. Clinicians said that the greatest benefit of cefiderocol is when used for complicated urinary tract infections and pneumonia acquired within hospitals caused by two types of bacteria (called Enterobacterales and Pseudomonas aeruginosa), with a resistance mechanism called metallo-beta-lactamase. Because there were no relevant clinical trial data, we estimated how effective cefiderocol and alternative treatments were by doing a systematic literature review of studies that grew bacteria from infections in the laboratory and tested the drugs on them. We linked this to data estimating the long-term health and survival of patients. Some evidence was obtained by asking clinicians detailed questions about what they thought the effects would be based on their experience and the available evidence. We included the side effects of the alternative treatments, some of which can cause kidney damage. We estimated how many infections there would be in the UK, whether they would increase over time and how resistance to treatments may change over time. Clinicians told us that they would also use cefiderocol to treat intra-abdominal and bloodstream infections, and some infections caused by another bacteria called Stenotrophomonas. We estimated how many of these infections there would be, and assumed the same health benefits as for other types of infections. The total value to the NHS was calculated using these estimates. We also considered whether we had missed any additional elements of value. We estimated that the value to the NHS was £18­71 million over 20 years. This reflects the maximum the NHS could pay for use of cefiderocol if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using this antimicrobial. However, these estimates are uncertain due to limitations with the evidence used to produce them and assumptions that had to be made.

Association between stress, depression or anxiety and cancer: Rapid review of reviews.

Background: Several studies have suggested links between psychological stress, depression or anxiety, and cancer incidence or outcomes. Existing systematic reviews have addressed this question, with differing results. Aims: This rapid systematic umbrella review summarises existing reviews assessing the association between psychological stress, depression or anxiety and cancer incidence or cancer outcomes. Methods: Systematic reviews assessing stress, depression or anxiety and cancer were identified via searches of MEDLINE, PsycInfo and Cochrane Database of Systematic Reviews from 2010 to November 2020. Results: Twelve systematic reviews were included, summarising cohort and case-control studies, most of which adjusted for confounders. Regarding cancer incidence, one large meta-analysis reported a significant association between depression/anxiety and cancer incidence, while another showed a non-significant trend. Two further meta-analyses reported significant associations between stressful life events and cancer incidence. Conversely, two meta-analyses of work stress showed no significant association with cancer incidence. Regarding outcomes among cancer patients, three meta-analyses reported significant associations between depression/anxiety and cancer mortality, while another reported a non-significant trend for depression and cancer recurrence. One meta-analysis reported a significant association between partner bereavement and cancer mortality, while another showed no significant association between work stress and cancer mortality. Conclusions: There is consistent evidence for an association between psychological stress, depression or anxiety and cancer incidence in general populations, and some evidence for an association with mortality in cancer populations. Future research may focus on confirmation of these findings, as well as the role of social support and stress-reducing interventions in buffering against these effects.

Systematic review of time lag between antibiotic use and rise of resistant pathogens among hospitalized adults in Europe.

Background: Antimicrobial resistance (AMR) causes substantial health and economic burden to individuals, healthcare systems and societies globally. Understanding the temporal relationship between antibiotic consumption and antibiotic resistance in hospitalized patients can better inform antibiotic stewardship activities and the time frame for their evaluation. Objectives: This systematic review examined the temporal relationship between antibiotic use and development of antibiotic resistance for 42 pre-defined antibiotic and pathogen combinations in hospitalized adults in Europe. Methods: Searches in MEDLINE, Embase, Cochrane Library and NIHR Centre for Reviews and Dissemination were undertaken from 2000 to August 2021. Pathogens of interest were Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecium, CoNS, Pseudomonas aeruginosa and Acinetobacter baumannii complex. Results: Twenty-eight ecological studies and one individual-level study were included. Ecological studies were predominantly retrospective in design (19 studies) and of reasonable (20 studies) to high (8 studies) methodological quality. Of the eight pathogens of interest, no relevant data were identified for S. pneumoniae and CoNS. Across all pathogens, the time-lag data from the 28 ecological studies showed a similar pattern, with the majority of studies reporting lags ranging from 0 to 6 months. Conclusions: Development of antibiotic resistance for the investigated antibiotic/pathogen combinations tends to occur over 0 to 6 months following exposure within European hospitals. This information could inform planning of antibiotic stewardship activities in hospital settings.

A Cost-Effectiveness Analysis of Remdesivir for the Treatment of Hospitalized Patients With COVID-19 in England and Wales.

OBJECTIVES: COVID-19 is associated with significant morbidity and mortality. This study aims to synthesize evidence to assess the cost-effectiveness of remdesivir (RDV) for the treatment of hospitalized patients with COVID-19 in England and Wales. METHODS: A probabilistic cost-effectiveness analysis was conducted informed by 2 large trials and uses a partitioned survival approach to assess short- and long-term clinical consequences and costs associated with COVID-19 in a hypothetical cohort of hospitalized patients requiring supplemental oxygen at the start of treatment. Given that it is uncertain whether RDV reduces death, 2 analyses are presented, assuming RDV either reduces death or does not. Published sources were used for long-term clinical, quality of life, and cost parameters. RESULTS: Under the assumption that RDV reduces death, the incremental cost-effectiveness ratio for RDV is estimated at £11 881 per quality-adjusted life-year gained compared with standard of care (SoC) (probabilistic incremental cost-effectiveness ratio £12 400). The probability for RDV to be cost-effective is 74% at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year gained. RDV was no longer cost-effective when the hazard ratio for overall survival compared with SoC was >0·915. CONCLUSIONS: Results from this study suggest that using RDV for the treatment of hospitalized patients with COVID-19 is likely to represent a cost-effective use of National Health Service resources at current willingness-to-pay threshold in England and Wales, only if it prevents death. Results needs to be interpreted caution as vaccination was introduced and the SoC and evidence available have also evolved considerably since the analysis is conducted.

The relationship between chronic kidney disease-associated pruritus and health-related quality of life: a systematic review.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP) is a common and burdensome condition for end-stage kidney disease (ESKD) patients, especially those receiving haemodialysis. High-quality evidence of the relationship between CKD-aP and health-related quality of life (HRQoL) can therefore inform clinicians and policymakers about treatment choice and reimbursement decisions. METHODS: A systematic literature review and narrative synthesis stratified by study design and HRQoL instrument was conducted to evaluate in adult ESKD patients receiving in-centre haemodialysis the relationship between CKD-aP and HRQoL assessed using multi dimensional generic or condition-specific preference- or non-preference-based measures. MEDLINE, Embase, Web of Science, BIOSIS Citation Index, Cochrane Library and PsycINFO from inception to March 2020 were searched, with two reviewers extracting data independently. RESULTS: Searches identified 2684 unique records, of which 20 papers relating to 18 unique studies [5 randomised controlled trials (RCTs) and 13 observational studies] were included. HRQoL was assessed using four generic and eight disease-specific measures. The impact of CKD-aP was assessed by comparison of means, linear regression and correlation. Observational studies employing comprehensively adjusted multivariable linear regression largely found associations between CKD-aP severities and HRQoL. Analyses suggest this relationship is partially mediated by the sleep disturbance caused by CKD-aP. RCTs showing improvements in CKD-aP severity were associated with clinically meaningful improvements in HRQoL. Compared with generic measures, disease-specific HRQoL instruments reported greater changes with reduced CKD-aP. Heterogeneity in study design and reporting precluded meta-analysis. CONCLUSIONS: CKD-aP severity was found to be associated with a worsening of HRQoL in the majority of observational and RCT studies. Parallel improvements in CKD-aP and HRQoL with interventions may support their use (PROSPERO registration 175035).

Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer: a systematic review and economic analysis.

BACKGROUND: Breast cancer and its treatment can have an impact on health-related quality of life and survival. Tumour profiling tests aim to identify whether or not women need chemotherapy owing to their risk of relapse. OBJECTIVES: To conduct a systematic review of the effectiveness and cost-effectiveness of the tumour profiling tests oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA), MammaPrint® (Agendia, Inc., Amsterdam, the Netherlands), Prosigna® (NanoString Technologies, Inc., Seattle, WA, USA), EndoPredict® (Myriad Genetics Ltd, London, UK) and immunohistochemistry 4 (IHC4). To develop a health economic model to assess the cost-effectiveness of these tests compared with clinical tools to guide the use of adjuvant chemotherapy in early-stage breast cancer from the perspective of the NHS and Personal Social Services. DESIGN: A systematic review and health economic analysis were conducted. REVIEW METHODS: The systematic review was partially an update of a 2013 review. Nine databases were searched in February 2017. The review included studies assessing clinical effectiveness in people with oestrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I or II cancer with zero to three positive lymph nodes. The economic analysis included a review of existing analyses and the development of a de novo model. RESULTS: A total of 153 studies were identified. Only one completed randomised controlled trial (RCT) using a tumour profiling test in clinical practice was identified: Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) for MammaPrint. Other studies suggest that all the tests can provide information on the risk of relapse; however, results were more varied in lymph node-positive (LN+) patients than in lymph node-negative (LN0) patients. There is limited and varying evidence that oncotype DX and MammaPrint can predict benefit from chemotherapy. The net change in the percentage of patients with a chemotherapy recommendation or decision pre/post test ranged from an increase of 1% to a decrease of 23% among UK studies and a decrease of 0% to 64% across European studies. The health economic analysis suggests that the incremental cost-effectiveness ratios for the tests versus current practice are broadly favourable for the following scenarios: (1) oncotype DX, for the LN0 subgroup with a Nottingham Prognostic Index (NPI) of > 3.4 and the one to three positive lymph nodes (LN1-3) subgroup (if a predictive benefit is assumed); (2) IHC4 plus clinical factors (IHC4+C), for all patient subgroups; (3) Prosigna, for the LN0 subgroup with a NPI of > 3.4 and the LN1-3 subgroup; (4) EndoPredict Clinical, for the LN1-3 subgroup only; and (5) MammaPrint, for no subgroups. LIMITATIONS: There was only one completed RCT using a tumour profiling test in clinical practice. Except for oncotype DX in the LN0 group with a NPI score of > 3.4 (clinical intermediate risk), evidence surrounding pre- and post-test chemotherapy probabilities is subject to considerable uncertainty. There is uncertainty regarding whether or not oncotype DX and MammaPrint are predictive of chemotherapy benefit. The MammaPrint analysis uses a different data source to the other four tests. The Translational substudy of the Arimidex, Tamoxifen, Alone or in Combination (TransATAC) study (used in the economic modelling) has a number of limitations. CONCLUSIONS: The review suggests that all the tests can provide prognostic information on the risk of relapse; results were more varied in LN+ patients than in LN0 patients. There is limited and varying evidence that oncotype DX and MammaPrint are predictive of chemotherapy benefit. Health economic analyses indicate that some tests may have a favourable cost-effectiveness profile for certain patient subgroups; all estimates are subject to uncertainty. More evidence is needed on the prediction of chemotherapy benefit, long-term impacts and changes in UK pre-/post-chemotherapy decisions. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017059561. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Breast cancer is the most commonly diagnosed cancer in women in England and Wales. Breast cancer, and its treatment, can have an impact on a person's health-related quality of life and survival. Tumour profiling tests are used before chemotherapy. They test small samples of a patient's tumour (removed during surgery) to find out whether the genes in it mean that a person has a high or low risk of the disease returning (relapse). If the risk is low, the patient may be able to avoid having chemotherapy and, therefore, avoid its side effects. Some tests might also be able to identify which patients will respond to chemotherapy. This study looked at the evidence for five tumour profiling tests. A total of 153 studies were identified. This study considered the results and the quality of the studies to find out if the tests are helpful. Most studies had design flaws (e.g. some patients had already had chemotherapy) that meant that the studies were of low quality overall. The results suggest that all of the tests can give information on the risk of relapse; however, some tests may be less useful in patients whose disease has spread to the lymph nodes (lymph node-positive disease). There was limited and varying evidence about whether or not two of these tests can also predict which patients will respond to chemotherapy. This study also looked at whether or not these tests represent good value for money for the NHS through cost-effectiveness analyses. The analyses showed that some of the tests may represent a good use of NHS resources for some patient groups; however, there was still a lot of uncertainty about this.

An Updated Systematic Review of Studies Mapping (or Cross-Walking) Measures of Health-Related Quality of Life to Generic Preference-Based Measures to Generate Utility Values.

BACKGROUND: Mapping is an increasingly common method used to predict instrument-specific preference-based health-state utility values (HSUVs) from data obtained from another health-related quality of life (HRQoL) measure. There have been several methodological developments in this area since a previous review up to 2007. OBJECTIVE: To provide an updated review of all mapping studies that map from HRQoL measures to target generic preference-based measures (EQ-5D measures, SF-6D, HUI measures, QWB, AQoL measures, 15D/16D/17D, CHU-9D) published from January 2007 to October 2018. DATA SOURCES: A systematic review of English language articles using a variety of approaches: searching electronic and utilities databases, citation searching, targeted journal and website searches. STUDY SELECTION: Full papers of studies that mapped from one health measure to a target preference-based measure using formal statistical regression techniques. DATA EXTRACTION: Undertaken by four authors using predefined data fields including measures, data used, econometric models and assessment of predictive ability. RESULTS: There were 180 papers with 233 mapping functions in total. Mapping functions were generated to obtain EQ-5D-3L/EQ-5D-5L-EQ-5D-Y (n = 147), SF-6D (n = 45), AQoL-4D/AQoL-8D (n = 12), HUI2/HUI3 (n = 13), 15D (n = 8) CHU-9D (n = 4) and QWB-SA (n = 4) HSUVs. A large number of different regression methods were used with ordinary least squares (OLS) still being the most common approach (used ≥ 75% times within each preference-based measure). The majority of studies assessed the predictive ability of the mapping functions using mean absolute or root mean squared errors (n = 192, 82%), but this was lower when considering errors across different categories of severity (n = 92, 39%) and plots of predictions (n = 120, 52%). CONCLUSIONS: The last 10 years has seen a substantial increase in the number of mapping studies and some evidence of advancement in methods with consideration of models beyond OLS and greater reporting of predictive ability of mapping functions.

Obinutuzumab with Bendamustine for Treating Follicular Lymphoma Refractory to Rituximab: 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 obinutuzumab (Roche) to submit evidence on its clinical and cost effectiveness when used in combination with bendamustine in patients with follicular lymphoma (FL) refractory to rituximab. The Evidence Review Group (ERG), the School of Health and Related Research Technology Appraisal Group at the University of Sheffield, produced a document summarising the key points from the company submission alongside a critical review. Efficacy for progression-free survival (PFS) and safety was positively demonstrated in the pivotal GADOLIN trial, which compared obinutuzumab in combination with bendamustine followed by obinutuzumab maintenance (O-Benda+O) against bendamustine monotherapy. Data on overall survival were immature. The company submitted a model-based economic analysis, including a patient access scheme. The ERG identified a number of limitations, in particular the absence of subgroup analysis and the approach used by the company to estimate overall survival (OS), which was more favourable to the intervention arm. The key uncertainty was the duration of the treatment effect on OS. This uncertainty is expected to be reduced when the final analysis of the GADOLIN trial is reported. Consequently, the NICE appraisal committee recommended O-Benda+O in the population covered by the marketing authorisation within the Cancer Drug Fund until NICE is able to review the guidance following publication of the final analysis of GADOLIN.

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

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

Mepolizumab for Treating Severe Eosinophilic Asthma: 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 company (GlaxoSmithKline) that manufactures mepolizumab (Nucala®) to submit evidence on the clinical and cost effectiveness of mepolizumab for the treatment of severe eosinophilic asthma. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). The ERG produced a review of the evidence for the clinical and cost effectiveness of mepolizumab as add-on to standard of care (SoC) compared with SoC and omalizumab, based upon the company's submission to NICE. The clinical-effectiveness evidence in the company's submission was based predominantly on three randomised controlled trials (DREAM, MENSA and SIRIUS) comparing add-on mepolizumab with placebo plus SoC. The relevant population was defined in terms of degree of asthma severity (four or more exacerbations in the previous year and/or dependency on maintenance oral corticosteroids [mOCS]) and degree of eosinophilia (a blood eosinophil count of ≥ 300 cells/µl in the previous year) based on post hoc subgroup analyses of the pivotal trials. Other subpopulations were considered throughout the appraisal, defined by different eosinophil measurements, number of exacerbations and dependency (or lack thereof) on mOCS. Statistically significant reductions in clinically significant exacerbations were observed in patients receiving mepolizumab compared with SoC meta-analysed across MENSA and DREAM in the modified intention-to-treat (ITT) population (rate ratio [RR] 0.51; 95% confidence interval [CI] 0.42-0.62) as well as in the relevant population (RR 0.47; 95% CI 0.36-0.62). In terms of quality of life, differences on the St. George's Respiratory Questionnaire in MENSA for add-on subcutaneous mepolizumab 100 mg vs. placebo were 7 and 7.5 units in the modified ITT and relevant populations, respectively. A number of issues in the clinical evidence base warrant caution in its interpretation. The ERG noted that the definition of SoC used in the trials differed from that in clinical practice, where patients with severe uncontrolled asthma start treatment with a mOCS. The company's economic post-consultation analysis incorporating a confidential patient access scheme (PAS) estimated that the incremental cost-effectiveness ratio (ICER) for add-on mepolizumab compared with SoC was £27,418 per quality-adjusted life-year (QALY) gained in the relevant population if patients stopped mepolizumab after 1 year unless (1) the number of exacerbations decreased at least 50% or (2) a reduction in corticosteroids dose was achieved whilst maintaining asthma control. The ERG applied an age adjustment to all utilities and corrected the post-continuation assessment utilities, which resulted in an ICER for add-on mepolizumab compared with SoC of £29,163 per QALY gained. The ERG noted that this ICER was not robust for patients who continued treatment due to a corticosteroid dose reduction where exacerbations had decreased by less than 50%, because corticosteroid dose reduction was not allowed in the main trial in which the evidence was gathered (MENSA). The NICE appraisal committee (AC) concluded that add-on mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults for the relevant population when the stopping rule suggested by the company was applied. The AC also concluded that the comparison between mepolizumab and omalizumab was not clinically relevant or methodologically robust.

Olaparib for Maintenance Treatment of BRCA 1 or 2 Mutated, Relapsed, Platinum-Sensitive Ovarian, Fallopian Tube and Peritoneal Cancer in People Whose Relapsed Disease has Responded to Platinum-Based Chemotherapy: 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 (NICE) invited the manufacturer of olaparib (AstraZeneca) to submit evidence on the clinical and cost effectiveness of olaparib for the maintenance treatment of BRCA1/2 mutated (BRCAm), platinum-sensitive relapsed (PSR) ovarian, fallopian tube and peritoneal cancer in people whose relapsed disease has responded to platinum-based chemotherapy. The Evidence Review Group (ERG) produced a critical review of the evidence contained within the company's submission (CS) to NICE. The clinical evidence related to one phase II, double-blind randomised controlled trial that recruited 265 patients with PSR serous ovarian cancer (OC) regardless of BRCAm status. Patients received olaparib 400 mg twice daily (b.i.d.) or matched placebo. In the whole population, the primary endpoint of progression-free survival (PFS) was met (hazard ratio [HR] 0.35; 95 % confidence interval [CI] 0.25-0.49, p < 0.01) for olaparib versus placebo. The BRCAm subgroup analysis (added after the study commenced but 1 month before the primary analysis was undertaken) reported an HR for PFS of 0.18 (95 % CI 0.10-0.31, p < 0.0001) for olaparib versus placebo, though interaction tests appeared inconclusive. Overall survival was not statistically significant in the whole group (HR 0.88; 95 % CI 0.64-1.21; p = 0.44) or the BRCAm subgroup (0.73; 95 % CI 0.45-1.17; p = 0.19), though treatment switching may have confounded results. The exclusion of data from sites allowing crossover resulted in an HR for overall survival (OS) of 0.52 (95 % CI 0.28-0.97, p = 0.039) in the BRCAm group. Health-related quality-of-life measures were not significantly different between groups. All post hoc exploratory outcomes (time to treatment discontinuation/death, time to first subsequent therapy/death, and time to second subsequent therapy/death) were statistically significantly better in the olaparib arm in the whole population and the BRCAm subgroup analyses. Adverse events were more frequent for olaparib but were largely minor or manageable. The company's semi-Markov model assessed the cost effectiveness of olaparib versus routine surveillance in patients with BRCAm PSR OC from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a lifetime horizon. The model suggests that the incremental cost-effectiveness ratio (ICER) for olaparib versus routine surveillance is expected to be approximately £49,146 per quality-adjusted life-year (QALY) gained. The ERG did not consider the company's cost-effectiveness estimates to be credible. Additional ERG analyses suggested that the ICER is likely to be more than £92,214 per QALY gained. Additional analyses provided by the company in patients who received three or more lines of chemotherapy suggested a more favourable cost-effectiveness profile for olaparib. The NICE Appraisal Committee recommended olaparib for this subgroup provided the cost of olaparib for people who continue to receive treatment after 15 months will be met by the company.

Vedolizumab for Treating Moderately to Severely Active Crohn's Disease After Prior Therapy: 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 (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn's disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6-52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn's disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company's model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues.

Association between Transfusion Status and Overall Survival in Patients with Myelodysplastic Syndromes: A Systematic Literature Review and Meta-Analysis.

INTRODUCTION: Multiple studies show that transfusion independence (TI) in myelodysplastic syndrome (MDS) has a positive impact on overall survival (OS). To assess this, a systematic review and meta-analysis of the association between TI and OS in patients with MDS was conducted (PROSPERO ID: CRD42014007264). METHODS: Comprehensive searches of 5 key bibliographic databases were conducted and supplemented with additional search techniques. Included were studies that had recruited adults aged >18 years with MDS and had examined the impact of transfusion status on OS. RESULTS: Fifty-five studies (89 citations) were included. The vast majority reported a statistically significant hazard ratio (HR) for OS in favor of TI patients or in patients who acquired TI after treatment. A random-effects meta-analysis was conducted. Patients classed as TI at baseline showed a 59% decrease in the risk of death compared with transfusion-dependent (TD) patients [HR 0.41; 95% credible interval (CrI) 0.29-0.56], and this effect did not appear to interact significantly with illness severity (interaction coefficient HR 1.38; 95% CrI 0.62-3.41). A meta-analysis of studies where patients acquired TI was not possible, but those studies consistently reported a survival benefit for those who acquired TI. CONCLUSION: The findings revealed a 59% pooled reduction in mortality among TI patients when compared with TD patients.

Fractional exhaled nitric oxide for the management of asthma in adults: a systematic review.

The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults.13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed.Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63-1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43-1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of -0.24 (95% CI -0.56-0.07). No statistically significant differences for health-related quality of life or asthma control were found.FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or inhaled corticosteroid use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most.

A systematic review of fractional exhaled nitric oxide in the routine management of childhood asthma.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker of eosinophilic inflammation which may be used to guide the management of asthma in childhood. OBJECTIVES: To synthesise the available evidence on the efficacy of FeNO-guided management of childhood asthma. METHODS: Databases including MEDLINE and the Cochrane Library were searched, and randomised controlled trials (RCTs) comparing FeNO-guided management with any other monitoring strategy were included. Study quality was assessed using the Cochrane risk of bias tool for RCTs, and a number of outcomes were examined, including: exacerbations, medication use, quality of life, adverse events, and other markers of asthma control. Meta-analyses were planned if multiple studies with suitable heterogeneity were available. However, due to wide variations in study characteristics, meta-analysis was not possible. RESULTS: Seven RCTs were identified. There was some evidence that FeNO-guided monitoring results in improved asthma control during the first year of management, although few results attained statistical significance. The impact on severe exacerbations was unclear. Similarly, the impact on use of anti-asthmatic drugs was unclear, and appears to depend on the step up/down protocols, and the clinical characteristics of patients. CONCLUSIONS: The potential benefit of FeNO monitoring is equivocal. Trends toward reduced exacerbation and increased medication use were seen, but typically failed to reach statistical significance. There are a number of issues that complicate data interpretation, including differences in the likely severity of included cohorts and variations in treatment algorithms. Further work is needed to systematically explore the impact of these parameters.

Measurement of exhaled nitric oxide concentration in asthma: a systematic review and economic evaluation of NIOX MINO, NIOX VERO and NObreath.

BACKGROUND: High fractions of exhaled nitric oxide (FeNO) in the breath of patients with symptoms of asthma are correlated with high levels of eosinophils and indicate that a patient is likely to respond to inhaled corticosteroids. This may have a role in the diagnosis and management of asthma. OBJECTIVE: To assess the diagnostic accuracy, clinical effectiveness and cost-effectiveness of the hand-held electrochemical devices NIOX MINO(®) (Aerocrine, Solna, Sweden), NIOX VERO(®) (Aerocrine) and NObreath(®) (Bedfont Scientific, Maidstone, UK) for the diagnosis and management of asthma. DATA SOURCES: Systematic searches were carried out between March 2013 and April 2013 from database inception. Databases searched included MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, Science Citation Index Expanded and Conference Proceedings Citation Index - Science. Trial registers such as ClinicalTrials.gov and the metaRegister of Controlled Trials were also searched in March 2013. All searches were updated in September 2013. REVIEW METHODS: A rapid review was conducted to assess the equivalence of hand-held and chemiluminescent FeNO monitors. Systematic reviews of diagnostic accuracy and management efficacy were conducted. A systematic review of economic analyses was also conducted and two de novo health economic models were developed. All three reviews were undertaken according to robust high-quality methodology. RESULTS: The rapid review (27 studies) found varying levels of agreement between monitors (Bland-Altman 95% limits of agreement up to ±10 parts per billion), with better agreement at lower FeNO values. Correlation was good (generally r > 0.9). The diagnostic accuracy review identified 22 studies in adults (all ages) and four in children. No studies used NObreath or NIOX VERO and seven used NIOX MINO. Estimates of diagnostic accuracy varied widely. FeNO used in combination with another test altered diagnostic accuracy only slightly. High levels of heterogeneity precluded meta-analysis. Limited observations included that FeNO may be more reliable and useful as a rule-in than as a rule-out test; lower cut-off values in children and in smokers may be appropriate; and FeNO may be less reliable in the elderly. The management review identified five randomised controlled trials in adults, one in pregnant asthmatics and seven in children. Despite clinical heterogeneity, exacerbation rates were lower in all studies but not generally statistically significantly so. Effects on inhaled corticosteroid (ICS) use were inconsistent, possibly because of differences in management protocols, differential effectiveness in adults and children and differences in population severity. One UK diagnostic model and one management model were identified. Aerocrine also submitted diagnostic and management models. All had significant limitations including short time horizons and the selective use of efficacy evidence. The de novo diagnostic model suggested that the expected difference in quality-adjusted life-year (QALY) gains between diagnostic options is likely to be very small. Airway hyper-responsiveness by methacholine challenge test is expected to produce the greatest QALY gain but with an expected incremental cost-effectiveness ratio (ICER) compared with FeNO (NObreath) in combination with bronchodilator reversibility of £1.125M per QALY gained. All remaining options are expected to be dominated. The de novo management model indicates that the ICER of guidelines plus FeNO monitoring using NObreath compared with guidelines alone in children is expected to be approximately £45,200 per QALY gained. Within the adult subgroup, FeNO monitoring using NObreath compared with guidelines alone is expected to have an ICER of approximately £2100 per QALY gained. The results are particularly sensitive to assumptions regarding changes in ICS use over time, the number of nurse visits for FeNO monitoring and duration of effect. CONCLUSIONS: Limitations of the evidence base impose considerable uncertainty on all analyses. Equivalence of devices was assumed but not assured. Evidence for diagnosis is difficult to interpret in the context of inserting FeNO monitoring into a diagnostic pathway. Evidence for management is also inconclusive, but largely consistent with FeNO monitoring resulting in fewer exacerbations, with a small or zero reduction in ICS use in adults and a possible increased ICS use in children or patients with more severe asthma. It is unclear which specific management protocol is likely to be most effective. The economic analysis indicates that FeNO monitoring could have value in diagnostic and management settings. The diagnostic model indicates that FeNO monitoring plus bronchodilator reversibility dominates many other diagnostic tests. FeNO-guided management has the potential to be cost-effective, although this is largely dependent on the duration of effect. The conclusions drawn from both models require strong technical value judgements with respect to several aspects of the decision problem in which little or no empirical evidence exists. There are many potential directions for further work, including investigations into which management protocol is best and long-term follow-up in both diagnosis and management studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004149. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The cost effectiveness of dry powder antibiotics for the treatment of Pseudomonas aeruginosa in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) affects over 9,000 people in the UK and limits life expectancy. CF patients are susceptible to lung infections, most commonly Pseudomonas aeruginosa. Once infection is established, patients require lifetime treatment using nebulised antibiotics. Newer dry powder formulations of antibiotics may reduce treatment burden and improve compliance. OBJECTIVE: Our objective was to evaluate the cost effectiveness of (i) colistimethate sodium dry powder for inhalation (DPI) and (ii) tobramycin DPI versus nebulised tobramycin for the treatment of chronic P. aeruginosa lung infection in patients with CF from the perspective of the National Health Service (NHS) and Personal Social Services (PSS). METHODS: We developed a state transition model based on transitions between three strata of lung function measured in terms of forced expiratory volume in 1 second (FEV1) % predicted. Additional health states representing post-lung transplantation and dead are also modelled. The model structure was informed by systematic reviews of evidence concerning the plausibility of potential relationships between intermediate endpoints and final outcomes. The model assumes that treatment impacts on FEV1 trajectory, which manifest as changes in health-related quality of life. No survival benefit is assumed due to the absence of robust quantifiable evidence. Model parameters were informed by patient-level and aggregate data from two randomised controlled trials together with the best available evidence from the literature. Resource use and costs associated with drug acquisition, the management of exacerbations and reduced nebuliser maintenance were drawn from reference sources and expert opinion. Costs were valued at 2011/2012 prices. Costs and health outcomes were discounted at a rate of 3.5 %. Simple and probabilistic sensitivity analyses were undertaken, including additional analyses of Patient Access Scheme (PAS) price discounts offered by the manufacturers of both DPI products. RESULTS: Colistimethate sodium DPI is expected to produce fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Based on its list price, colistimethate sodium DPI is expected to be dominated by nebulised tobramycin. When the PAS is incorporated, the incremental cost-effectiveness ratio (ICER) for colistimethate sodium DPI versus nebulised tobramycin is expected to be approximately £288,600 saved per QALY lost. Based on its current list price, the ICER for tobramycin DPI versus nebulised tobramycin is expected to be approximately £124,000 per QALY gained. When the proposed PAS is included, tobramycin DPI is expected to dominate nebulised tobramycin. CONCLUSIONS: Under their list prices, neither DPI product is likely to represent good value for money for the NHS given current cost-effectiveness thresholds. The PAS discounts have a significant impact upon the economic attractiveness of both DPI products compared against nebulised tobramycin. The clinical effectiveness and cost effectiveness of the DPIs against other nebulised antibiotics, such as aztreonam and inhaled colistimethate sodium, remains unclear.

Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease.

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

Systematic review of the dry powder inhalers colistimethate sodium and tobramycin in cystic fibrosis.

This systematic review evaluated evidence for two dry powder formulations, colistimethate sodium and tobramycin, for the treatment of chronic Pseudomonas aeruginosa in cystic fibrosis, as part of the UK national recommendation process for new technologies. Electronic bibliographic databases were searched in May 2012 (MEDLINE, MEDLINE in-Process, EMBASE, Cochrane Library databases, CINAHL, Web of Science, Conference Proceedings Citation Index and BIOSIS Previews). Relevant outcomes included rate and extent of microbial response (e.g. sputum density of P. aeruginosa), lung function (e.g. forced expiratory volume in 1 s (FEV1)), frequency, severity of acute exacerbations and adverse events. Three trials were included, and both dry powder formulations were reported to be non-inferior in the short term to nebulised tobramycin for FEV1. However, long-term follow-up data were missing and the effect on exacerbation rates was not always reported. Whilst short-term results showed that both dry powder drugs were non-inferior to nebulised tobramycin, there was no long-term follow-up and no phase 3 trials compared nebulised and dry powder colistimethate sodium. The use of FEV1 as the primary end-point may not accurately represent changes in lung health. This review illustrates the difficulty in assessing new technologies where the evidence base is poor.