Publications by authors named "Steven Duffy"

56 Publications

Chromosome level reference of Atlantic halibut Hippoglossus hippoglossus provides insight into the evolution of sexual determination systems.

Mol Ecol Resour 2021 Mar 2. Epub 2021 Mar 2.

Biology Department, Dalhousie University, Halifax, NS, Canada.

Changes in the genetic mechanisms that control sexual determination have occurred independently across the tree of life, and with exceptional frequency in teleost fishes. To investigate the genomic changes underlying the evolution of sexual determination, we sequenced a chromosome-level genome, multitissue transcriptomes, and reduced representation population data for the Atlantic halibut (Hippoglossus hippoglossus), which has an XY/XX sex determination mechanism and has recently diverged (0.9-3.8 Ma) from the Pacific halibut (Hippoglossus stenolepis), which has a ZZ/ZW system. We used frequency and coverage-based population approaches to identify a putative sex-determining factor, GSDF. We characterized regions with elevated heterozygosity and linkage disequilibrium indicating suppression of recombination across a nascent sex chromosome. We detected testis-specific expression of GSDF, the sequence of which is highly conserved across flatfishes. Based on evidence from genome-wide association, coverage, linkage disequilibrium, testis and brain transcriptomes, and sequence conservation with other flatfishes, we propose a mechanism for the recent evolution of an XY sex-determination mechanism in Atlantic halibut. Changes to the ancestral sex-determining gene DMRT1 in regulating the downstream gene GSDF probably coincided with GSDF, or a proximal regulatory element of it, becoming the primary sex-determining factor. Our results suggest changes to a small number of elements can have drastic repercussions for the genomic substrate available to sex-specific evolutionary forces, providing insight into how certain elements repeatedly evolve to control sex across taxa. Our chromosome-level assembly, multitissue transcriptomes, and population genomic data provide a valuable resource and understanding of the evolution of sexual systems in fishes.
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http://dx.doi.org/10.1111/1755-0998.13369DOI Listing
March 2021

Systematic review search methods evaluated using the Preferred Reporting of Items for Systematic Reviews and Meta-Analyses and the Risk Of Bias In Systematic reviews tool.

Int J Technol Assess Health Care 2020 Dec 7;37:e18. Epub 2020 Dec 7.

Kleijnen Systematic Reviews Ltd, York, UK.

Objectives: To evaluate the methodological and reporting characteristics of search methods of systematic reviews (SRs) using the Preferred Reporting of Systematic Reviews and Meta-Analyses (PRISMA) checklist and the Risk Of Bias In Systematic reviews (ROBIS) tool.

Methods: A sample of 505 SRs published in 2016 was taken from KSR Evidence, a database of SRs, and analyzed to assess compliance with Information sources and Search of the PRISMA checklist. Domain 2 (D2) (Identification and Selection of Studies) of the ROBIS tool was used to judge the risk of bias in search methods.

Results: Regarding Information sources and Search of PRISMA, twenty percent of SRs which claimed to be PRISMA-compliant in their methods, were compliant; twenty-four percent of SRs published in journals that require PRISMA reporting were compliant; nineteen percent in total were found to be compliant. Twenty-eight percent of SRs were judged to be at a low risk of bias in D2 and so searched widely with an effective strategy and, finally, ten percent were both compliant with the reporting of Information sources and with Search of PRISMA and were judged to be at a low risk of bias in D2.

Conclusions: Ninety percent of SRs are failing to report search methods adequately and to conduct comprehensive searches using a wide range of resources. Editors of journals and peer reviewers need to ensure that they understand the requirements of PRISMA and that compliance is adhered to. Additionally, the comprehensiveness of search methods for SRs needs to be given more critical consideration.
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http://dx.doi.org/10.1017/S0266462320002135DOI Listing
December 2020

Lenalidomide with Rituximab for Previously Treated Follicular Lymphoma and Marginal Zone Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pharmacoeconomics 2021 Feb 4;39(2):171-180. Epub 2020 Nov 4.

Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre+, Maastricht, The Netherlands.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of lenalidomide (Revlimid), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of lenalidomide in combination with rituximab (MabThera), together referred to as R, for the treatment of adults with treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). 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. The CS included one relevant study, for the comparison of R versus rituximab monotherapy (R-mono): the AUGMENT trial. In addition, the company performed an unanchored indirect comparison of R versus rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and rituximab combined with cyclophosphamide, vincristine, and prednisolone (R-CVP), using data for R from the AUGMENT trial and pooled data for R-CHOP/R-CVP from the Haematological Malignancy Research Network (HMRN) database. During the STA process, the company provided an addendum containing evidence on only the FL population, in line with the marketing authorisation obtained at that time, which did not include MZL. The probabilistic incremental cost-effectiveness ratios (ICERs) presented by the company were £27,768 per quality-adjusted life year (QALY) gained for R versus R-CHOP, £41,602 per QALY gained for R versus R-CVP, and £23,412 per QALY gained for R versus R-mono. The ERG's concerns included the validity of the unanchored comparison, the unavailability of a state transition model to verify the outcomes of the partitioned survival model, substantial uncertainty in survival curves, and potential over-estimation of utility values. The revised ERG base case resulted in ICERs ranging from £16,874 to £44,888 per QALY gained for R versus R-CHOP, from £23,135 to £59,810 per QALY gained for R versus R-CVP, and from £18,779 to £27,156 per QALY gained for R versus R-mono. Substantial uncertainty remained around these ranges. NICE recommended R within its marketing authorisation, as an option for previously treated FL (grade 1-3A) in adults, contingent on the company providing lenalidomide according to the commercial arrangement.
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http://dx.doi.org/10.1007/s40273-020-00971-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867510PMC
February 2021

Avatrombopag and lusutrombopag for thrombocytopenia in people with chronic liver disease needing an elective procedure: a systematic review and cost-effectiveness analysis.

Health Technol Assess 2020 10;24(51):1-220

Kleijnen Systematic Reviews, York, UK.

Background: There have been no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Established management largely involves platelet transfusion prior to the procedure or as rescue therapy for bleeding due to the procedure.

Objectives: To assess the clinical effectiveness and cost-effectiveness of two thrombopoietin receptor agonists, avatrombopag (Doptelet; Dova Pharmaceuticals, Durham, NC, USA) and lusutrombopag (Mulpleta; Shionogi Inc., London, UK), in addition to established clinical management compared with established clinical management (no thrombopoietin receptor agonist) in the licensed populations.

Design: Systematic review and cost-effectiveness analysis.

Setting: Secondary care.

Participants: Severe thrombocytopenia (platelet count of < 50,000/µl) in people with chronic liver disease requiring surgery.

Interventions: Lusutrombopag 3 mg and avatrombopag (60 mg if the baseline platelet count is < 40,000/µl and 40 mg if it is 40,000-< 50,000/µl).

Main Outcome Measures: Risk of platelet transfusion and rescue therapy or risk of rescue therapy only.

Review Methods: Systematic review including meta-analysis. English-language and non-English-language articles were obtained from several databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, all searched from inception to 29 May 2019.

Economic Evaluation: Model-based cost-effectiveness analysis.

Results: From a comprehensive search retrieving 11,305 records, six studies were included. Analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy or rescue therapy only, and mostly with a statistically significant difference (i.e. 95% confidence intervals not overlapping the point of no difference). However, only avatrombopag seemed to be superior to no thrombopoietin receptor agonist in reducing the risk of rescue therapy, although far fewer patients in the lusutrombopag trials than in the avatrombopag trials received rescue therapy. When assessing the cost-effectiveness of lusutrombopag and avatrombopag, it was found that, despite the success of these in avoiding platelet transfusions prior to surgery, the additional long-term gain in quality-adjusted life-years was very small. No thrombopoietin receptor agonist was clearly cheaper than both lusutrombopag and avatrombopag, as the cost savings from avoiding platelet transfusions were more than offset by the drug cost. The probabilistic sensitivity analysis showed that, for all thresholds below £100,000, no thrombopoietin receptor agonist had 100% probability of being cost-effective.

Limitations: Some of the rescue therapy data for lusutrombopag were not available. There were inconsistencies in the avatrombopag data. From the cost-effectiveness point of view, there were several additional important gaps in the evidence required, including the lack of a price for avatrombopag.

Conclusions: Avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy, but they were not cost-effective given the lack of benefit and increase in cost.

Future Work: A head-to-head trial is warranted.

Study Registration: This study is registered as PROSPERO CRD42019125311.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 51. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681416PMC
October 2020

A Systematic Review and Mixed Treatment Comparison of Pharmaceutical Interventions for Multiple Sclerosis.

Neurol Ther 2020 Dec 28;9(2):359-374. Epub 2020 Sep 28.

School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, The Netherlands.

Background: Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued evolution in the field of MTCs. Additionally, limitations in methodological approach and reporting transparency, even in the most recent publications, makes interpretation and comparison of existing studies difficult.

Objectives: The objectives of this study are twofold: (1) to estimate the efficacy and safety of DMTs at European Commission-approved doses compared with placebo in adults with relapsing-remitting multiple sclerosis (RRMS) using MTC, and (2) to identify and address methodological challenges when performing MTC in RRMS, thereby creating a baseline for comparisons with future treatments.

Methods: Searches were completed in 14 databases, including MEDLINE, Embase, CENTRAL, CDSR and DARE, from inception to June 2018 to identify published or unpublished prospective, randomised controlled trials of all European Union-approved DMTs or DMTs expected to be approved in the near future in RRMS or rapidly-evolving severe RRMS. No language or date restrictions were applied. Studies were included in the MTC if they were judged to have sufficiently similar characteristics, based on the following: patient age; proportion of male participants; Expanded Disability Status Scale (EDSS) score; duration of disease; number of relapses prior to enrolment and proportion of previously treated patients. Background information from the included studies, as well as effect size and confidence intervals (where relevant) of defined outcomes were extracted. Reporting of the MTC was consistent with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) network meta-analysis guidelines.

Results: In total, 33 studies were included in the MTC. Annualised relapse rate (ARR 28 trials) was significantly reduced in all treatments compared with placebo. Alemtuzumab had the highest probability (63%) of being the most effective treatment in terms of ARR compared with placebo (rate ratio [RR] 0.28, 95% credible interval [CrI] 0.21-0.38), followed by natalizumab (30% probability; RR 0.32, 95% CrI 0.23-0.43). The risk of 3- and 6-month confirmed disability progression (CDP3M, 13 trials; CDP6M, 14 trials) were similar; CDP6M was significantly reduced for alemtuzumab (hazard ratio [HR] 0.365; 95% CrI 0.165-0.725), ocrelizumab (HR 0.405, 95% CrI 0.188-0.853) and natalizumab (HR 0.459, 95% CrI 0.252-0.840) relative to placebo. There were no significant differences in the odds of serious adverse events (SAEs, 6 trials) between any treatment and placebo. The results of the MTC were limited by the lack of studies reporting direct comparisons between the included treatments and by heterogeneous reporting of key outcome data.

Conclusions: Meta-analyses confirmed the benefit of all DMTs in terms of relapse rate compared with placebo with a comparable rate of SAEs for the DMTs that could be included in the network. The rigor and transparency of reporting in this study provide a benchmark for comparisons with future new agents.
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http://dx.doi.org/10.1007/s40120-020-00212-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606402PMC
December 2020

Overview of Differences and Similarities of Published Mixed Treatment Comparisons on Pharmaceutical Interventions for Multiple Sclerosis.

Neurol Ther 2020 Dec 25;9(2):335-358. Epub 2020 Sep 25.

School for Public Health and Primary Care, Maastricht University, Maastricht, The Netherlands.

Introduction: Mixed treatment comparisons (MTCs) are increasingly important in the assessment of the benefit-risk profile of pharmaceutical treatments for relapsing-remitting multiple sclerosis (RRMS). Interpretation of MTCs requires a clear understanding of the methods of analysis and population studied. The objectives of this work were to compare MTCs of pharmaceutical treatments for RRMS, including a detailed description of differences in populations, treatments assessed, methods used and findings; and to discuss key considerations when conducting an MTC.

Methods: Fourteen databases were searched until July 2019 to identify MTCs (published during or after 2010) in adults (at least 18 years of age) with RRMS or rapidly evolving severe RRMS treated with any form of pharmaceutical treatment. No language restriction was imposed.

Results: Twenty-seven MTCs assessing 21 treatments were identified. Comparison highlighted many differences in conduct and reporting between MTCs relating to the patient populations or treatments included, duration of follow-up and outcomes of interest measured. The lack of similarity between the MTCs leads to questions about variability in the robustness of analyses and makes comparisons between studies challenging.

Conclusion: Given the importance of MTCs for healthcare decision-making, it is imperative that reporting of methods, results and assumptions is clear and transparent to allow accurate interpretation of findings. For MTCs to be relevant, the choice of outcome measures should reflect clinical practice. Combination of treatments or of outcomes measured at different points of time should be avoided, as should imputation without justification. Furthermore, all approved treatment options should be included and updates of MTCs should be conducted when data for new treatments are published.
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http://dx.doi.org/10.1007/s40120-020-00213-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606374PMC
December 2020

Resolving fine-scale population structure and fishery exploitation using sequenced microsatellites in a northern fish.

Evol Appl 2020 May 20;13(5):1055-1068. Epub 2020 Feb 20.

Department of Ocean Sciences Memorial University of Newfoundland St. John's NL Canada.

The resiliency of populations and species to environmental change is dependent on the maintenance of genetic diversity, and as such, quantifying diversity is central to combating ongoing widespread reductions in biodiversity. With the advent of next-generation sequencing, several methods now exist for resolving fine-scale population structure, but the comparative performance of these methods for genetic assignment has rarely been tested. Here, we evaluate the performance of sequenced microsatellites and a single nucleotide polymorphism (SNP) array to resolve fine-scale population structure in a critically important salmonid in north eastern Canada, Arctic Charr (). We also assess the utility of sequenced microsatellites for fisheries applications by quantifying the spatial scales of movement and exploitation through genetic assignment of fishery samples to rivers of origin and comparing these results with a 29-year tagging dataset. Self-assignment and simulation-based analyses of 111 genome-wide microsatellite loci and 500 informative SNPs from 28 populations of Arctic Charr in north-eastern Canada identified largely river-specific genetic structure. Despite large differences (~4X) in the number of loci surveyed between panels, mean self-assignment accuracy was similar with the microsatellite loci and the SNP panel (>90%). Subsequent analysis of 996 fishery-collected samples using the microsatellite panel revealed that larger rivers contribute greater numbers of individuals to the fishery and that coastal fisheries largely exploit individuals originating from nearby rivers, corroborating results from traditional tagging experiments. Our results demonstrate the efficacy of sequence-based microsatellite genotyping to advance understanding of fine-scale population structure and harvest composition in northern and understudied species.
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http://dx.doi.org/10.1111/eva.12922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232759PMC
May 2020

Estimating the relative fitness of escaped farmed salmon offspring in the wild and modelling the consequences of invasion for wild populations.

Evol Appl 2019 Apr 28;12(4):705-717. Epub 2019 Jan 28.

Science Branch, Fisheries and Oceans Canada St. John's Newfoundland and Labrador Canada.

Throughout their native range, wild Atlantic salmon populations are threatened by hybridization and introgression with escapees from net-pen salmon aquaculture. Although domestic-wild hybrid offspring have shown reduced fitness in laboratory and field experiments, consequential impacts on population abundance and genetic integrity remain difficult to predict in the field, in part because the strength of selection against domestic offspring is often unknown and context-dependent. Here, we follow a single large escape event of farmed Atlantic salmon in southern Newfoundland and monitor changes in the in-river proportions of hybrids and feral individuals over time using genetically based hybrid identification. Over a three-year period following the escape, the overall proportion of wild parr increased consistently (total wild proportion of 71.6%, 75.1% and 87.5% each year, respectively), with subsequent declines in feral (genetically pure farmed individuals originating from escaped, farmed adults) and hybrid parr. We quantify the strength of selection against parr of aquaculture ancestry and explore the genetic and demographic consequences for populations in the region. Within-cohort changes in the relative proportions of feral and F1 parr suggest reduced relative survival compared to wild individuals over the first (0.15 and 0.81 for feral and F1, respectively) and second years of life (0.26, 0.83). These relative survivorship estimates were used to inform an individual-based salmon eco-genetic model to project changes in adult abundance and overall allele frequency across three invasion scenarios ranging from short-term to long-term invasion and three relative survival scenarios. Modelling results indicate that total population abundance and time to recovery were greatly affected by relative survivorship and predict significant declines in wild population abundance under continued large escape events and calculated survivorship. Overall, this work demonstrates the importance of estimating the strength of selection against domestic offspring in the wild to predict the long-term impact of farmed salmon escape events on wild populations.
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http://dx.doi.org/10.1111/eva.12746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439497PMC
April 2019

Arsenic Trioxide for Treating Acute Promyelocytic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pharmacoeconomics 2019 07;37(7):887-894

Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Center, Maastricht, The Netherlands.

The National Institute for Health and Care Excellence (NICE) invited Teva, the company manufacturing arsenic trioxide (ATO; tradename Trisenox), to submit evidence for the clinical and cost effectiveness of ATO for untreated and relapsed or refractory acute promyelocytic leukaemia (APL). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG's critical review of the clinical and cost effectiveness evidence in the CS, key methodological considerations and the development of the NICE guidance by the Appraisal Committee (AC). The CS presented three randomized controlled trials (RCTs). Two of these were trials in newly diagnosed APL (APL0406 and AML17) and the third trial was in patients with relapsed APL. Results from APL0406 showed that more people having AATO [ATO plus all-trans retinoic acid (ATRA)] were alive at 50 months compared with people having AIDA (ATRA in combination with idarubicin) (99% vs. 93%; p = 0.007). There was also a statistically significant lower cumulative incidence of relapse with AATO compared with AIDA at 50 months (2% vs. 14%; p = 0.001). At 4 years, results from AML17 showed a significant difference in event-free survival (91% vs. 70%; p = 0.002) favouring AATO but not in overall survival (93% vs. 89%; p = 0.250). The only trial presented for relapsed/refractory patients compared AATO with ATO, which was not a relevant comparison according to the NICE scope. The AC concluded that AATO was effective for untreated APL while for relapsed or refractory APL the effectiveness of ATO was considered uncertain and the long-term safety remains unexplored. In the CS base-case, AATO was less expensive (£31,088 saved) and more effective (2.546 quality-adjusted life-years (QALYs) gained) than AIDA and thus the dominating strategy for newly diagnosed low- to intermediate-risk APL. However, the ERG's critical assessment highlighted a number of concerns, including deviations from the NICE reference case and a lack of detailed description and justification of parameters and assumptions related to (the extrapolation of) treatment effectiveness. However, it was reassuring that AATO for untreated APL remained dominant in the ERG base-case, and that the worst-case scenario produced by the ERG resulted in an incremental cost-effectiveness ratio (ICER) of £21,622. The AC concluded that although there was uncertainty in the model, it could recommend ATO for both untreated and relapsed or refractory APL.
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http://dx.doi.org/10.1007/s40273-018-0738-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559128PMC
July 2019

Extensive hybridization following a large escape of domesticated Atlantic salmon in the Northwest Atlantic.

Commun Biol 2018 9;1:108. Epub 2018 Aug 9.

Science Branch, Fisheries and Oceans Canada, 80 East White Hills Road, St. John's, Newfoundland, A1C 5X1, Canada.

Domestication is rife with episodes of interbreeding between cultured and wild populations, potentially challenging adaptive variation in the wild. In Atlantic salmon, , the number of domesticated individuals far exceeds wild individuals, and escape events occur regularly, yet evidence of the magnitude and geographic scale of interbreeding resulting from individual escape events is lacking. We screened juvenile Atlantic salmon using 95 single nucleotide polymorphisms following a single, large aquaculture escape in the Northwest Atlantic and report the landscape-scale detection of hybrid and feral salmon (27.1%, 17/18 rivers). Hybrids were reproductively viable, and observed at higher frequency in smaller wild populations. Repeated annual sampling of this cohort revealed decreases in the presence of hybrid and feral offspring over time. These results link previous observations of escaped salmon in rivers with reports of population genetic change, and demonstrate the potential negative consequences of escapes from net-pen aquaculture on wild populations.
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http://dx.doi.org/10.1038/s42003-018-0112-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123692PMC
August 2018

Ribociclib with an Aromatase Inhibitor for Previously Untreated, HR-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pharmacoeconomics 2019 02;37(2):141-153

Institute for Medical Technology Assessment (iMTA), Erasmus School of Health Policy & Management (ESHPM), Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.

The National Institute for Health and Care Excellence, as part of the institute's single technology appraisal process, invited the manufacturer of ribociclib (Kisqali, Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer's decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3-not reached) vs. 14.7 months (95% confidence interval 13.0-16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.
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http://dx.doi.org/10.1007/s40273-018-0708-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386053PMC
February 2019

Environmental extremes drive population structure at the northern range limit of Atlantic salmon in North America.

Mol Ecol 2018 10 17;27(20):4026-4040. Epub 2018 Sep 17.

Science Branch, Department of Fisheries and Oceans Canada, St. John's, NL, Canada.

Conservation of exploited species requires an understanding of both genetic diversity and the dominant structuring forces, particularly near range limits, where climatic variation can drive rapid expansions or contractions of geographic range. Here, we examine population structure and landscape associations in Atlantic salmon (Salmo salar) across a heterogeneous landscape near the northern range limit in Labrador, Canada. Analysis of two amplicon-based data sets containing 101 microsatellites and 376 single nucleotide polymorphisms (SNPs) from 35 locations revealed clear differentiation between populations spawning in rivers flowing into a large marine embayment (Lake Melville) compared to coastal populations. The mechanisms influencing the differentiation of embayment populations were investigated using both multivariate and machine-learning landscape genetic approaches. We identified temperature as the strongest correlate with genetic structure, particularly warm temperature extremes and wider annual temperature ranges. The genomic basis of this divergence was further explored using a subset of locations (n = 17) and a 220K SNP array. SNPs associated with spatial structuring and temperature mapped to a diverse set of genes and molecular pathways, including regulation of gene expression, immune response, and cell development and differentiation. The results spanning molecular marker types and both novel and established methods clearly show climate-associated, fine-scale population structure across an environmental gradient in Atlantic salmon near its range limit in North America, highlighting valuable approaches for predicting population responses to climate change and managing species sustainability.
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http://dx.doi.org/10.1111/mec.14849DOI Listing
October 2018

Genotyping-by-sequencing of genome-wide microsatellite loci reveals fine-scale harvest composition in a coastal Atlantic salmon fishery.

Evol Appl 2018 Jul 11;11(6):918-930. Epub 2018 Mar 11.

Department of Biology Dalhousie University Halifax NS Canada.

Individual assignment and genetic mixture analysis are commonly utilized in contemporary wildlife and fisheries management. Although microsatellite loci provide unparalleled numbers of alleles per locus, their use in assignment applications is increasingly limited. However, next-generation sequencing, in conjunction with novel bioinformatic tools, allows large numbers of microsatellite loci to be simultaneously genotyped, presenting new opportunities for individual assignment and genetic mixture analysis. Here, we scanned the published Atlantic salmon genome to identify 706 microsatellite loci, from which we developed a final panel of 101 microsatellites distributed across the genome (average 3.4 loci per chromosome). Using samples from 35 Atlantic salmon populations ( = 1,485 individuals) from coastal Labrador, Canada, a region characterized by low levels of differentiation in this species, this panel identified 844 alleles (average of 8.4 alleles per locus). Simulation-based evaluations of assignment and mixture identification accuracy revealed unprecedented resolution, clearly identifying 26 rivers or groups of rivers spanning 500 km of coastline. This baseline was used to examine the stock composition of 696 individuals harvested in the Labrador Atlantic salmon fishery and revealed that coastal fisheries largely targeted regional groups (<300 km). This work suggests that the development and application of large sequenced microsatellite panels presents great potential for stock resolution in Atlantic salmon and more broadly in other exploited anadromous and marine species.
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http://dx.doi.org/10.1111/eva.12606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999200PMC
July 2018

A systematic literature review comparing methods for the measurement of patient persistence and adherence.

Curr Med Res Opin 2018 09 4;34(9):1613-1625. Epub 2018 Jun 4.

d Uppsala Clinical Research Center (UCR), Department of Medical Sciences , University of Uppsala , Uppsala , Sweden.

Objectives: A systematic literature review was conducted comparing different approaches estimating persistence and adherence in chronic diseases with polypharmacy of oral and subcutaneous treatments.

Methods: This work followed published guidance on performing systematic reviews. Twelve electronic databases and grey literature sources were used to identify studies and guidelines for persistence and adherence of oral and subcutaneous therapies in hypercholesterolemia, type 2 diabetes, hypertension, osteoporosis and rheumatoid arthritis. Outcomes of interest of each persistence and adherence data collection and calculation method included pros: accurate, easy to use, inexpensive; and cons: inaccurate, difficult to use, expensive.

Results: A total of 4158 records were retrieved up to March 2017. We included 16 observational studies, 5 systematic reviews and 7 guidelines, in patients with hypercholesterolemia (n = 8), type 2 diabetes (n = 4), hypertension (n = 2), rheumatoid arthritis (n = 1) and mixed patient populations (n = 13). Pharmacy and medical records offer an accurate, easy and inexpensive data collection method. Pill count, medication event monitoring systems (MEMs), self-report questionnaires and observer report are easy to use. MEMS and biochemical monitoring tests can be expensive. Proportion of days covered (PDC) was recommended as a gold standard calculation method for long-term treatments. PDC avoids use of days' supply in calculation, hence is more accurate compared to medication possession ratio (MPR) to assess adherence to treatments in chronic diseases.

Conclusions: Decisions on what method to use should be based on considerations of the route of medication administration, the resources available, setting and aim of the assessment. Combining different methods may provide wider insights into adherence and persistence, including patient behavior.
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http://dx.doi.org/10.1080/03007995.2018.1477747DOI Listing
September 2018

Ticagrelor for Secondary Prevention of Atherothrombotic Events After Myocardial Infarction: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pharmacoeconomics 2018 05;36(5):533-543

Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Centre+, Maastricht, The Netherlands.

The National Institute for Health and Care Excellence (NICE) invited AstraZeneca, the manufacturer of ticagrelor (Brilique), to submit evidence on the clinical and cost effectiveness of ticagrelor 60 mg twice daily (BID) in combination with low-dose aspirin [acetylsalicylic acid (ASA)] compared with ASA only for secondary prevention of atherothrombotic events in patients with a history of myocardial infarction (MI) and who are at increased risk of atherothrombotic events. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Centre+, was commissioned as the evidence review group (ERG). This paper summarises the company submission (CS), the ERG report and the NICE guidance produced by the appraisal committee (AC) for the use of ticagrelor in England and Wales. The ERG critically reviewed the clinical- and cost-effectiveness evidence in the CS. The systematic review conducted as part of the CS identified one randomised controlled trial (RCT), PEGASUS-TIMI 54. This trial reported the time to first occurrence of any event from the composite of cardiovascular death, MI and stroke as the primary outcome (hazard ratio 0.84 ticagrelor 60 mg BID vs. placebo, 95% confidence interval 0.74-0.95). The population addressed in the CS was a subgroup of the PEGASUS-TIMI 54 trial population, i.e. the 'base-case' population, which comprised patients who had experienced an MI between 1 and 2 years ago, whereas the full trial population included patients who had experienced an MI between 1 and 3 years ago. While the ERG believed the findings of this RCT to be robust, doubts concerning the applicability of the trial to UK patients were raised. The company submitted an individual patient simulation model to estimate the cost-effectiveness of ticagrelor 60 mg BID + ASA versus ASA only. Parametric time-to-event models were used to estimate the time to first and subsequent (cardiovascular) events, time to treatment discontinuation and time to adverse events. The company's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £20,098 per quality-adjusted life-year (QALY) gained. The main issues surrounding the cost effectiveness of ticagrelor 60 mg BID + ASA were the use of parametric time-to-event models estimated based on the full trial population instead of being fitted to the 'label' population (the 'label' population comprised the 'base-case' population and patients who started ticagrelor 60 mg BID within 1 year of previous adenosine diphosphate inhibitor treatment), the incorrect implementation of the probabilistic sensitivity analysis (PSA) of the individual patient simulation, and simplifications of the model structure that may have biased the health benefits and costs estimations of the intervention and comparator. The ERG believed the use of the full trial population to inform the parametric time-to-event models was not appropriate because the 'label' population was the main focus of the scope and CS. The ERG could not investigate the magnitude of the bias introduced by this assumption. The PSA of the individual patient simulation provided unreliable probabilistic results and underestimated the uncertainty surrounding the results because it was based on a single patient. The ERG used the cohort simulation presented in the cost-effectiveness model to perform its base-case and additional analyses and to obtain probabilistic results. The ERG amended the company cost-effectiveness model, which resulted in an ERG base-case ICER of £24,711 per QALY gained. In its final guidance, the AC recommended treatment with ticagrelor 60 mg BID + low-dose ASA for secondary prevention of atherothrombotic events in adults who have had an MI and are at increased risk of atherothrombotic events.
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http://dx.doi.org/10.1007/s40273-017-0607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906512PMC
May 2018

Assessing the performance of methodological search filters to improve the efficiency of evidence information retrieval: five literature reviews and a qualitative study.

Health Technol Assess 2017 11;21(69):1-148

Healthcare Improvement Scotland, Glasgow, UK.

Background: Effective study identification is essential for conducting health research, developing clinical guidance and health policy and supporting health-care decision-making. Methodological search filters (combinations of search terms to capture a specific study design) can assist in searching to achieve this.

Objectives: This project investigated the methods used to assess the performance of methodological search filters, the information that searchers require when choosing search filters and how that information could be better provided.

Methods: Five literature reviews were undertaken in 2010/11: search filter development and testing; comparison of search filters; decision-making in choosing search filters; diagnostic test accuracy (DTA) study methods; and decision-making in choosing diagnostic tests. We conducted interviews and a questionnaire with experienced searchers to learn what information assists in the choice of search filters and how filters are used. These investigations informed the development of various approaches to gathering and reporting search filter performance data. We acknowledge that there has been a regrettable delay between carrying out the project, including the searches, and the publication of this report, because of serious illness of the principal investigator.

Results: The development of filters most frequently involved using a reference standard derived from hand-searching journals. Most filters were validated internally only. Reporting of methods was generally poor. Sensitivity, precision and specificity were the most commonly reported performance measures and were presented in tables. Aspects of DTA study methods are applicable to search filters, particularly in the development of the reference standard. There is limited evidence on how clinicians choose between diagnostic tests. No published literature was found on how searchers select filters. Interviewing and questioning searchers via a questionnaire found that filters were not appropriate for all tasks but were predominantly used to reduce large numbers of retrieved records and to introduce focus. The Inter Technology Appraisal Support Collaboration (InterTASC) Information Specialists' Sub-Group (ISSG) Search Filters Resource was most frequently mentioned by both groups as the resource consulted to select a filter. Randomised controlled trial (RCT) and systematic review filters, in particular the Cochrane RCT and the McMaster Hedges filters, were most frequently mentioned. The majority indicated that they used different filters depending on the requirement for sensitivity or precision. Over half of the respondents used the filters available in databases. Interviewees used various approaches when using and adapting search filters. Respondents suggested that the main factors that would make choosing a filter easier were the availability of critical appraisals and more detailed performance information. Provenance and having the filter available in a central storage location were also important.

Limitations: The questionnaire could have been shorter and could have included more multiple choice questions, and the reviews of filter performance focused on only four study designs.

Conclusions: Search filter studies should use a representative reference standard and explicitly report methods and results. Performance measures should be presented systematically and clearly. Searchers find filters useful in certain circumstances but expressed a need for more user-friendly performance information to aid filter choice. We suggest approaches to use, adapt and report search filter performance. Future work could include research around search filters and performance measures for study designs not addressed here, exploration of alternative methods of displaying performance results and numerical synthesis of performance comparison results.

Funding: The National Institute for Health Research (NIHR) Health Technology Assessment programme and Medical Research Council-NIHR Methodology Research Programme (grant number G0901496).
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http://dx.doi.org/10.3310/hta21690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723931PMC
November 2017

Trifluridine-Tipiracil for Previously Treated Metastatic Colorectal Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Pharmacoeconomics 2018 03;36(3):285-288

Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Center, Maastricht, The Netherlands.

The National Institute for Health and Care Excellence (NICE) invited Servier, the company manufacturing trifluridine and tipiracil (T/T; trade name: Lonsurf), to submit evidence for the clinical and cost effectiveness of T/T compared with best supportive care (BSC) for metastatic colorectal cancer (third-line or later). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company's submission (CS), the ERG report and the development of the NICE guidance for the use of this drug in England and Wales by the appraisal committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of T/T based upon the CS. In the CS, pooled evidence of two trials (a phase II trial and RECOURSE) showed that T/T resulted in a significant increase in overall survival [OS; hazard ratio (HR) 0.67, 95% CI 0.58-0.78] and progression-free survival (PFS; HR 0.46, 95% CI 0.40-0.53). The AC considered the survival benefit of T/T clinically meaningful although relatively small. The ERG highlighted that none of the participants in the phase II trial and approximately half of the RECOURSE participants (394 of 800) were from Europe, which might limit the applicability of the study findings to the NHS. Moreover, the ERG's critical assessment of the company's economic evaluation highlighted a number of concerns that resulted in 11 adjustments to the company's base-case analysis. The ERG adjustments that had the largest impact were using the RECOURSE trial data only (instead of the pooled evidence), fixing errors and violations and using the utilities from the CORRECT trial (identified in the literature review) only. The ERG preferred to use the RECOURSE trial data only given the suboptimal methodology used by the company to pool the evidence. However, since there were no fundamental arguments to prevent the two trials from being pooled, the ERG also presented its base-case analysis based on the pooled effectiveness estimates. The company base-case resulted in an incremental cost effectiveness ratio (ICER) of £44,032 per QALY gained while the ERG base-case resulted in ICERs of £52,695 and £49,392 per QALY gained based on the RECOURSE trial only and pooled evidence, respectively. Since the AC concluded that the most plausible ICER was £49,392 per QALY gained, and that T/T meets end-of-life criteria, T/T was recommended as a cost effective use of NHS resources.
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http://dx.doi.org/10.1007/s40273-017-0591-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834593PMC
March 2018

Supplementary searches of PubMed to improve currency of MEDLINE and MEDLINE In-Process searches via Ovid.

J Med Libr Assoc 2016 Oct;104(4):309-312

Objective: The research investigated whether conducting a supplementary search of PubMed in addition to the main MEDLINE (Ovid) search for a systematic review is worthwhile and to ascertain whether this PubMed search can be conducted quickly and if it retrieves unique, recently published, and ahead-of-print studies that are subsequently considered for inclusion in the final systematic review.

Methods: Searches of PubMed were conducted after MEDLINE (Ovid) and MEDLINE In-Process (Ovid) searches had been completed for seven recent reviews. The searches were limited to records not in MEDLINE or MEDLINE In-Process (Ovid).

Results: Additional unique records were identified for all of the investigated reviews. Search strategies were adapted quickly to run in PubMed, and reviewer screening of the results was not time consuming. For each of the investigated reviews, studies were ordered for full screening; in six cases, studies retrieved from the supplementary PubMed searches were included in the final systematic review.

Conclusion: Supplementary searching of PubMed for studies unavailable elsewhere is worthwhile and improves the currency of the systematic reviews.
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http://dx.doi.org/10.3163/1536-5050.104.4.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079494PMC
October 2016

A Systematic Review of Cardiovascular Outcomes-Based Cost-Effectiveness Analyses of Lipid-Lowering Therapies.

Pharmacoeconomics 2017 03;35(3):297-318

IHE-Institutet för Hälso-och Sjukvårdsekonomi, Lund, Sweden.

Background: Previous reviews have evaluated economic analyses of lipid-lowering therapies using lipid levels as surrogate markers for cardiovascular disease. However, drug approval and health technology assessment agencies have stressed that surrogates should only be used in the absence of clinical endpoints.

Objective: The aim of this systematic review was to identify and summarise the methodologies, weaknesses and strengths of economic models based on atherosclerotic cardiovascular disease event rates.

Methods: Cost-effectiveness evaluations of lipid-lowering therapies using cardiovascular event rates in adults with hyperlipidaemia were sought in Medline, Embase, Medline In-Process, PubMed and NHS EED and conference proceedings. Search results were independently screened, extracted and quality checked by two reviewers.

Results: Searches until February 2016 retrieved 3443 records, from which 26 studies (29 publications) were selected. Twenty-two studies evaluated secondary prevention (four also assessed primary prevention), two considered only primary prevention and two included mixed primary and secondary prevention populations. Most studies (18) based treatment-effect estimates on single trials, although more recent evaluations deployed meta-analyses (5/10 over the last 10 years). Markov models (14 studies) were most commonly used and only one study employed discrete event simulation. Models varied particularly in terms of health states and treatment-effect duration. No studies used a systematic review to obtain utilities. Most studies took a healthcare perspective (21/26) and sourced resource use from key trials instead of local data. Overall, reporting quality was suboptimal.

Conclusions: This review reveals methodological changes over time, but reporting weaknesses remain, particularly with respect to transparency of model reporting.
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http://dx.doi.org/10.1007/s40273-016-0464-2DOI Listing
March 2017

Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

Pharmacoeconomics 2017 02;35(2):191-202

Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.

The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting (i.e. best supportive care [BSC]) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG report, subsequent addenda, and the development of the NICE guidance for the use of this drug in England and Wales by the Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of AAP based on the CS. An important question in this appraisal was, according to the ERG, whether AAP followed by docetaxel is more effective than BSC followed by docetaxel. In the COU-AA-302 trial, 239 of 546 (43.8 %) AAP patients and 304 of 542 (56.1 %) BSC patients received docetaxel as subsequent therapy, following AA or placebo. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here. The ERG's critical assessment of the company's economic evaluation highlighted a number of concerns, including (a) not using the intention-to-treat (ITT) population; (b) inconsistencies in estimating prediction equations; (c) not fully incorporating the impact of adverse events; (d) incorrectly incorporating the new patient access scheme (PAS); and (e) the assumption that AA non-compliance leads to recoverable drug costs. Although some of these issues were adjusted in the ERG base case, the ERG could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. With the exception of the ERG's preference for using the ITT population, the AC agreed with the approach taken in the ERG base case. The original company and ERG base-case incremental cost-effectiveness ratios (ICERs) were £46,722 and £57,688 per QALY gained, respectively; these changed to £28,563 and £38,061 per QALY gained, respectively, in the revised base cases applying a new PAS. Regarding the end-of-life criteria, after 24 months approximately 63 % of patients in the control group of the COU-AA-302 trial were still alive, and the median survival was 30.1 months (95 % CI 27.3-34.1). Therefore, it is unlikely that life expectancy would be less than 24 months. The AC stated that the most plausible ICER is likely between £28,600 and £32,800 per QALY gained, and concluded that AAP at this stage in the treatment pathway did not meet the end-of-life criterion for short life expectancy. Moreover, in March 2016, the AC produced the final guidance, stating that AAP is recommended, within its marketing authorisation, as an option for treating mCRPC.
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http://dx.doi.org/10.1007/s40273-016-0445-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253156PMC
February 2017

Integrated sensor-augmented pump therapy systems [the MiniMed® Paradigm™ Veo system and the Vibe™ and G4® PLATINUM CGM (continuous glucose monitoring) system] for managing blood glucose levels in type 1 diabetes: a systematic review and economic evaluation.

Health Technol Assess 2016 Feb;20(17):v-xxxi, 1-251

Kleijnen Systematic Reviews Ltd, York, UK.

Background: In recent years, meters for continuous monitoring of interstitial fluid glucose have been introduced to help people with type 1 diabetes mellitus (T1DM) to achieve better control of their disease.

Objective: The objective of this project was to summarise the evidence on the clinical effectiveness and cost-effectiveness of the MiniMed(®) Paradigm™ Veo system (Medtronic Inc., Northridge, CA, USA) and the Vibe™ (Animas(®) Corporation, West Chester, PA, USA) and G4(®) PLATINUM CGM (continuous glucose monitoring) system (Dexcom Inc., San Diego, CA, USA) in comparison with multiple daily insulin injections (MDIs) or continuous subcutaneous insulin infusion (CSII), both with either self-monitoring of blood glucose (SMBG) or CGM, for the management of T1DM in adults and children.

Data Sources: A systematic review was conducted in accordance with the principles of the Centre for Reviews and Dissemination guidance and the National Institute for Health and Care Excellence Diagnostic Assessment Programme manual. We searched 14 databases, three trial registries and two conference proceedings from study inception up to September 2014. In addition, reference lists of relevant systematic reviews were checked. In the absence of randomised controlled trials directly comparing Veo or an integrated CSII + CGM system, such as Vibe, with comparator interventions, indirect treatment comparisons were performed if possible.

Methods: A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), was used for this assessment. This model is an internet-based, interactive simulation model that predicts the long-term health outcomes and costs associated with the management of T1DM and type 2 diabetes. The model consists of 15 submodels designed to simulate diabetes-related complications, non-specific mortality and costs over time. As the model simulates individual patients over time, it updates risk factors and complications to account for disease progression.

Results: Fifty-four publications resulting from 19 studies were included in the review. Overall, the evidence suggests that the Veo system reduces hypoglycaemic events more than other treatments, without any differences in other outcomes, including glycated haemoglobin (HbA1c) levels. We also found significant results in favour of the integrated CSII + CGM system over MDIs with SMBG with regard to HbA1c levels and quality of life. However, the evidence base was poor. The quality of the included studies was generally low, often with only one study comparing treatments in a specific population at a specific follow-up time. In particular, there was only one study comparing Veo with an integrated CSII + CGM system and only one study comparing Veo with a CSII + SMBG system in a mixed population. Cost-effectiveness analyses indicated that MDI + SMBG is the option most likely to be cost-effective, given the current threshold of £30,000 per quality-adjusted life-year gained, whereas integrated CSII + CGM systems and Veo are dominated and extendedly dominated, respectively, by stand-alone, non-integrated CSII with CGM. Scenario analyses did not alter these conclusions. No cost-effectiveness modelling was conducted for children or pregnant women.

Conclusions: The Veo system does appear to be better than the other systems considered at reducing hypoglycaemic events. However, in adults, it is unlikely to be cost-effective. Integrated systems are also generally unlikely to be cost-effective given that stand-alone systems are cheaper and, possibly, no less effective. However, evidence in this regard is generally lacking, in particular for children. Future trials in specific child, adolescent and adult populations should include longer term follow-up and ratings on the European Quality of Life-5 Dimensions scale at various time points with a view to informing improved cost-effectiveness modelling.

Study Registration: PROSPERO Registration Number CRD42014013764.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta20170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809467PMC
February 2016

A systematic review of randomised controlled trials of radiotherapy for localised prostate cancer.

Eur J Cancer 2015 Nov 5;51(16):2345-67. Epub 2015 Aug 5.

Kleijnen Systematic Reviews Ltd, York, UK; Care and Public Health Research Institute (CAPHRI), Maastricht University, The Netherlands.

Background: Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males. A systematic review of randomised controlled trials (RCTs) of radiotherapy and other non-pharmacological management options for localised prostate cancer was undertaken.

Methods: A search of thirteen databases was carried out until March 2014. RCTs comparing radiotherapy (brachytherapy (BT) or external beam radiotherapy (EBRT)) to other management options i.e. radical prostatectomy (RP), active surveillance, watchful waiting, high intensity focused ultrasound (HIFU), or cryotherapy; each alone or in combination, e.g. with adjuvant hormone therapy (HT), were included. Methods followed guidance by the Centre for Reviews and Dissemination and the Cochrane Collaboration. Indirect comparisons were calculated using the Bucher method.

Results: Thirty-six randomised controlled trials (RCTs, 134 references) were included. EBRT, BT and RP were found to be effective in the management of localised prostate cancer. While higher doses of EBRT seem to be related to favourable survival-related outcomes they might, depending on technique, involve more adverse events, e.g. gastrointestinal and genitourinary toxicity. Combining EBRT with hormone therapy shows a statistically significant advantage regarding overall survival when compared to EBRT alone (Relative risk 1.21, 95% confidence interval 1.12-1.30). Aside from mixed findings regarding urinary function, BT and radical prostatectomy were comparable in terms of quality of life and biochemical progression-free survival while favouring BT regarding patient satisfaction and sexual function. There might be advantages of EBRT (with/without HT) compared to cryoablation (with/without HT). No studies on HIFU were identified.

Conclusions: Based on this systematic review, there is no strong evidence to support one therapy over another as EBRT, BT and RP can all be considered as effective monotherapies for localised disease with EBRT also effective for post-operative management. All treatments have unique adverse events profiles. Further large, robust RCTs which report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups following established reporting standards are needed. These will strengthen the evidence base for newer technologies, help reinforce current consensus guidelines and establish greater standardisation across practices.
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http://dx.doi.org/10.1016/j.ejca.2015.07.019DOI Listing
November 2015

Systematic review of the economic evidence on home visitation programmes for vulnerable pregnant women.

Br Med Bull 2015 Sep 28;115(1):19-44. Epub 2015 Jul 28.

South East Wales Trials Unit (SEWTU), School of Medicine, Cardiff University, Cardiff, UK.

Introduction: A systematic review of the economic evidence on home visitation programmes for young or vulnerable pregnant women was undertaken to provide a summary of the existing literature of these interventions.

Sources Of Data: Relevant studies were identified from a number of sources including large databases, free text search on Google Scholar as well as hand-searching of the obtained references. The search yielded a large number of papers, of which 12 were considered appropriate to be included in the review. These were either full or partial economic evaluations: four studies were cost-benefit analyses, three were cost-effectiveness analyses and the remaining were costing studies.

Areas Of Agreement: The review highlighted the paucity of good quality economic evaluations in the area of home visiting programmes for young or vulnerable pregnant women. Methods varied substantially between the studies spanning from differing data sources (e.g. single randomized trials or meta-analyses) to different perspectives taken, cost items and outcomes included in the analysis.

Areas Of Controversy: It is difficult to establish a coherent body of economic evidence for these interventions and draw a firm conclusion on their value for money.

Growing Points: Home visiting programmes are complex interventions, with impact on the lives of mothers and their children. The funding of such interventions should be based on rigorous effectiveness and economic evidence.

Areas Timely For Developing Research: There is a need for well-designed economic evaluations which will follow the appropriate methodological guidelines and also take into account the complexity of such interventions. These analyses should preferably consider multiple perspectives and allow for the fact that the majority of the benefits accrue in the long-term future.
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http://dx.doi.org/10.1093/bmb/ldv032DOI Listing
September 2015

Clinical effectiveness and cost-effectiveness of parenting interventions for children with severe attachment problems: a systematic review and meta-analysis.

Health Technol Assess 2015 Jul;19(52):vii-xxviii, 1-347

Hull York Medical School, University of York, York, UK.

Background And Objectives: Services have variable practices for identifying and providing interventions for 'severe attachment problems' (disorganised attachment patterns and attachment disorders). Several government reports have highlighted the need for better parenting interventions in at-risk groups. This report was commissioned to evaluate the clinical effectiveness and cost-effectiveness of parenting interventions for children with severe attachment problems (the main review). One supplementary review explored the evaluation of assessment tools and a second reviewed 10-year outcome data to better inform health economic aspects of the main review.

Data Sources: A total of 29 electronic databases were searched with additional mechanisms for identifying a wide pool of references using the Cochrane methodology. Examples of databases searched include PsycINFO (1806 to January week 1, 2012), MEDLINE and MEDLINE In-Process & Other Non-Indexed Citations (1946 to December week 4, 2011) and EMBASE (1974 to week 1, 2012). Searches were carried out between 6 and 12 January 2012.

Review Methods: Papers identified were screened and data were extracted by two independent reviewers, with disagreements arbitrated by a third independent reviewer. Quality assessment tools were used, including quality assessment of diagnostic accuracy studies - version 2 and the Cochrane risk of bias tool. Meta-analysis of randomised controlled trials (RCTs) of parenting interventions was undertaken. A health economics analysis was conducted.

Results: The initial search returned 10,167 citations. This yielded 29 RCTs in the main review of parenting interventions to improve attachment patterns, and one involving children with reactive attachment disorder. A meta-analysis of eight studies seeking to improve outcome in at-risk populations showed statistically significant improvement in disorganised attachment. The interventions saw less disorganised attachment at outcome than the control (odds ratio 0.47, 95% confidence interval 0.34 to 0.65; p < 0.00001). Much of this focused around interventions improving maternal sensitivity, with or without video feedback. In our first supplementary review, 35 papers evaluated an attachment assessment tool demonstrating validity or psychometric data. Only five reported test-retest data. Twenty-six studies reported inter-rater reliability, with 24 reporting a level of 0.7 or above. Cronbach's alphas were reported in 12 studies for the comparative tests (11 with α > 0.7) and four studies for the reference tests (four with α > 0.7). Three carried out concurrent validity comparing the Strange Situation Procedure (SSP) with another assessment tool. These had good sensitivity but poor specificity. The Disturbances of Attachment Interview had good sensitivity and specificity with the research diagnostic criteria (RDC) for attachment disorders. In our supplementary review of 10-year outcomes in cohorts using a baseline reference standard, two studies were found with disorganised attachment at baseline, with one finding raised psychopathology in adolescence. Budget impact analysis of costs was estimated because a decision model could not be justifiably populated. This, alongside other findings, informed research priorities.

Limitations: There are relatively few UK-based clinical trials. A 10-year follow-up, while necessary for our health economists for long-term sequelae, yielded a limited number of papers.

Conclusions: Maternal sensitivity interventions show good outcomes in at-risk populations, but require further research with complex children. The SSP and RDC for attachment disorders remain the reference standards for identification until more concurrent and predictive validity research is conducted. A birth cohort with sequential attachment measures and outcomes across different domains is recommended with further, methodologically sound randomised controlled intervention trials. The main area identified for future work was a need for good-quality RCTs in at-risk groups such as those entering foster care or adoption.

Study Registration: This study is registered as PROSPERO CRD42011001395.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta19520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780895PMC
July 2015

The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis.

Health Technol Assess 2015 Jun;19(43):1-336

Centre for Reviews and Dissemination, University of York, York, UK.

Background: It is uncertain which simple measures of childhood obesity are best for predicting future obesity-related health problems and the persistence of obesity into adolescence and adulthood.

Objectives: To investigate the ability of simple measures, such as body mass index (BMI), to predict the persistence of obesity from childhood into adulthood and to predict obesity-related adult morbidities. To investigate how accurately simple measures diagnose obesity in children, and how acceptable these measures are to children, carers and health professionals.

Data Sources: Multiple sources including MEDLINE, EMBASE and The Cochrane Library were searched from 2008 to 2013.

Methods: Systematic reviews and a meta-analysis were carried out of large cohort studies on the association between childhood obesity and adult obesity; the association between childhood obesity and obesity-related morbidities in adulthood; and the diagnostic accuracy of simple childhood obesity measures. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and a modified version of the Quality in Prognosis Studies (QUIPS) tool. A systematic review and an elicitation exercise were conducted on the acceptability of the simple measures.

Results: Thirty-seven studies (22 cohorts) were included in the review of prediction of adult morbidities. Twenty-three studies (16 cohorts) were included in the tracking review. All studies included BMI. There were very few studies of other measures. There was a strong positive association between high childhood BMI and adult obesity [odds ratio 5.21, 95% confidence interval (CI) 4.50 to 6.02]. A positive association was found between high childhood BMI and adult coronary heart disease, diabetes and a range of cancers, but not stroke or breast cancer. The predictive accuracy of childhood BMI to predict any adult morbidity was very low, with most morbidities occurring in adults who were of healthy weight in childhood. Predictive accuracy of childhood obesity was moderate for predicting adult obesity, with a sensitivity of 30% and a specificity of 98%. Persistence of obesity from adolescence to adulthood was high. Thirty-four studies were included in the diagnostic accuracy review. Most of the studies used the least reliable reference standard (dual-energy X-ray absorptiometry); only 24% of studies were of high quality. The sensitivity of BMI for diagnosing obesity and overweight varied considerably; specificity was less variable. Pooled sensitivity of BMI was 74% (95% CI 64.2% to 81.8%) and pooled specificity was 95% (95% CI 92.2% to 96.4%). The acceptability to children and their carers of BMI or other common simple measures was generally good.

Limitations: Little evidence was available regarding childhood measures other than BMI. No individual-level analysis could be performed.

Conclusions: Childhood BMI is not a good predictor of adult obesity or adult disease; the majority of obese adults were not obese as children and most obesity-related adult morbidity occurs in adults who had a healthy childhood weight. However, obesity (as measured using BMI) was found to persist from childhood to adulthood, with most obese adolescents also being obese in adulthood. BMI was found to be reasonably good for diagnosing obesity during childhood. There is no convincing evidence suggesting that any simple measure is better than BMI for diagnosing obesity in childhood or predicting adult obesity and morbidity. Further research on obesity measures other than BMI is needed to determine which is the best tool for diagnosing childhood obesity, and new cohort studies are needed to investigate the impact of contemporary childhood obesity on adult obesity and obesity-related morbidities.

Study Registration: This study is registered as PROSPERO CRD42013005711.

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta19430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781104PMC
June 2015

Cannabinoids for Medical Use: A Systematic Review and Meta-analysis.

JAMA 2015 Jun 23-30;313(24):2456-73

Kleijnen Systematic Reviews Ltd, Escrick, York, United Kingdom10School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, the Netherlands.

Importance: Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear.

Objective: To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids.

Data Sources: Twenty-eight databases from inception to April 2015.

Study Selection: Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome.

Data Extraction And Synthesis: Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis.

Main Outcomes And Measures: Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs.

Results: A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

Conclusions And Relevance: There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.
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http://dx.doi.org/10.1001/jama.2015.6358DOI Listing
July 2015

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

N Engl J Med 2015 Jun 30;372(26):2509-20. Epub 2015 May 30.

From the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine, Baltimore; Department of Medicine, Stanford University School of Medicine, Stanford, CA (G.A.F.); Providence Cancer Center at Providence Health and Services, Portland, OR (T.S.C.); Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh (J.J.L.); Bon Secours Cancer Institute, Richmond, VA (S.M.D.); Division of Medical Oncology, Ohio State University Comprehensive Cancer Center-James Cancer Center and Solove Research Institute, and Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, Columbus (R.M.G., A.C.); and Merck, Kenilworth, NJ, and North Wales, PA (M.K.).

Background: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

Methods: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.

Results: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).

Conclusions: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).
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http://dx.doi.org/10.1056/NEJMoa1500596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481136PMC
June 2015

The Clinical and Cost Effectiveness of Aflibercept in Combination with Irinotecan and Fluorouracil-Based Therapy (FOLFIRI) for the Treatment of Metastatic Colorectal Cancer Which has Progressed Following Prior Oxaliplatin-Based Chemotherapy: a Critique of the Evidence.

Pharmacoeconomics 2015 May;33(5):457-66

Centre for Reviews and Dissemination (CRD), University of York, York, YO10 5DD, UK,

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of aflibercept (Sanofi) to submit clinical and cost-effectiveness evidence for aflibercept in combination with irinotecan and fluorouracil-based therapy [irinotecan/5-fluorouracil/folinic acid (FOLFIRI)] for the treatment of metastatic colorectal cancer which has progressed following prior oxaliplatin-based chemotherapy, as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA307 issued in March 2014. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The clinical effectiveness data were derived from one good-quality double-blind randomised controlled trial (RCT), the VELOUR trial, which compared aflibercept plus FOLFIRI with placebo plus FOLFIRI. This RCT found a small but statistically significant increase in overall survival (OS); the difference in median OS was 1.44 months (13.5 months in the aflibercept group and 12.06 months in the placebo group). There was also a statistically significant increase in progression-free survival (PFS) with aflibercept; the difference in median PFS was 2.23 months (6.9 months in the aflibercept group and 4.67 months in the placebo group). However, grade 3-4 adverse events were more frequent in the aflibercept group than the placebo group: 83.5% compared with 62.5%. Treatment-emergent adverse events led to permanent discontinuation of treatment in 26.8% of patients in the aflibercept group and 12.1% of patients in the placebo group. The manufacturer's submission included an estimation of mean OS benefit based on extrapolation of the data, which was considerably longer than the median OS benefit reported (4.7 vs. 1.44 months). The ERG considered this to be an over estimate. The base-case incremental cost-effectiveness ratio (ICER) for the overall population was reported by the manufacturer to be £36,294 per quality-adjusted life-year (QALY). After correcting the model programming and updating the model to include the ERG's preferred parameter estimates, the ICER from the ERG's alternative base case was £54,368 per QALY. The extrapolation of the OS curves was the key cost-effectiveness driver and a major source of uncertainty in the model. Additional scenarios related to the extrapolation of OS undertaken by the ERG resulted in ICERs between £62,894 and £92,089 per QALY. After consideration of the manufacturer's submission and the ERG's critique, and submissions from other stakeholders, the NICE Appraisal Committee concluded that aflibercept in combination with irinotecan and fluorouracil-based therapy could not be considered a cost effective use of National Health Service resources for treating metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen. Aflibercept in combination with irinotecan and fluorouracil-based therapy is not recommended for the treatment of metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing regimen in NICE guidance TA307.
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http://dx.doi.org/10.1007/s40273-015-0257-zDOI Listing
May 2015