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Venetoclax is a first-in-class targeted therapy option that is an inducer of apoptosis in chronic lymphocytic leukemia (CLL) cells. The open-label phase III CLL14 clinical trial showed that venetoclax combined with obinutuzumab (VEN+O) is superior to obinutuzumab combined with chlorambucil in newly diagnosed patients with CLL. The aim of this study was to assess the health economic value of VEN+O for the frontline treatment of CLL in Canada from a publicly funded healthcare system perspective.A partitioned survival analyses model was developed including three health states: progression free, progressed, and death. A cycle length of 28 days and a time horizon of 10 years was assumed. VEN+O treatment for a fixed duration of 12 months was compared to obinutuzumab combined with chlorambucil, fludarabine plus cyclophosphamide plus rituximab, bendamustine plus rituximab, chlorambucil plus rituximab, ibrutinib, and acalabrutinib. The population in the model included both unfit and overall frontline CLL patients, two subgroups were also assessed (patients with del17p/TP53 mutations and patients without del17p/TP53 mutations). Survival data extrapolated from the CLL14 trial were used to populate the model. Uncertainty was assessed via one-way sensitivity analyses, probabilistic analyses, and scenario analyses.Based on the probabilistic analyses, unfit frontline CLL patients receiving VEN+O were estimated to incur costs of Canadian dollars ($) 217,727 [confidence interval (CI) $170,725, $300,761] (del17p/TP53: $209,102 [CI $159,698, $386,190], non-del17p/TP53: $217,732 [CI $171,232, $299,063]) and accrue 4.96 [CI 4.04, 5.82] quality-adjusted life-years (del17p/TP53: 3.11 [CI 2.00, 4.20], non-del17p/TP53: 5.04 [CI 4.05, 5.92]). Obinutuzumab combined with chlorambucil, bendamustine plus rituximab, chlorambucil plus rituximab, and ibrutinib accrued lower quality-adjusted life-years and higher costs and as such, VEN+O was the dominant treatment option. The full incremental analysis showed that acalabrutinib was more expensive and more efficacious compared with VEN+O with an incremental-cost-effectiveness-ratio of $2,139,180/quality-adjusted life-year versus VEN+O and not a cost-effective option in Canada. Probabilistic analyses show that at a willingness to pay of $50,000/quality-adjusted life-year gained, VEN+O has the greatest probability of being cost effective.VEN+O is a cost-effective treatment option for unfit frontline CLL patients and provides value for money to healthcare payers.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a significant health and economic burden in the United States. Treatments include chemoimmunotherapy, such as obinutuzumab (G) plus chlorambucil (Clb) or bendamustine plus rituximab (BR), and chemotherapy-free regimens incorporating oral targeted therapies such as ibrutinib (Ibr), acalabrutinib (Acala), or venetoclax (Ven). Most chemotherapy-free regimens require continuous treatment to progression, while Ven plus G (VenG) is given for a fixed duration of 12 months, based on the CLL14 trial that led to its approval. Fixed-duration VenG has the potential for cost savings compared with treat-to-progression chemotherapy-free regimens. OBJECTIVE: To evaluate the cost-effectiveness of 12 months fixed-duration VenG in first-line treatment of unfit patients with CLL from a US health care payer perspective compared with GClb, BR, Ibr, Ibr + G, Ibr + R, Acala, and Acala + G. METHODS: A partitioned survival model was developed with 3 health states: progression-free survival (PFS), postprogression survival, and dead. The patient population, as based on the CLL14 trial, comprised previously untreated unfit patients with CLL (mean age 71.1 years, 33.1% female). The distribution of patients in each health state over time was estimated using extrapolated PFS and overall survival (OS) curves for VenG and GClb, based on CLL14 data 2 or more years after treatment cessation. PFS and OS for the other comparators were estimated using hazard ratios vs VenG, based on a network metaanalysis. Adverse events, utility values, and costs were obtained from published literature. The model estimated life-years gained, quality-adjusted life-years (QALYs) gained, and costs. The time horizon was 20 years, with a cycle time of 28 days. Outcomes and costs were discounted at 3.0% per year, and costs were estimated from a US health care payer perspective. One-way and probabilistic sensitivity analyses were conducted. RESULTS: In this cross-trial analysis of unfit CLL patients, in the base case, VenG had lower projected total costs than all comparators investigated. VenG also had larger projected health benefits (more QALYs gained) than GClb, BR, Ibr, and Ibr + R. VenG was therefore more effective and less costly than these comparators (dominant). Ibr + G, Acala, and Acala + G showed higher QALYs gained vs VenG (0.022, 0.672, and 0.961, respectively), and substantially higher projected costs vs VenG ($1,488,400, $1,579,737, and $1,656,154, respectively). Thus, Ibr + G, Acala, and Acala + G would cost more than $1,000,000 per QALY gained vs VenG. At the commonly used willingness-to-pay threshold of $150,000 per QALY gained, Ibr + G, Acala, and Acala + G were not cost-effective compared with VenG. CONCLUSIONS: Fixed-duration VenG for 12 months is a cost-effective first-line treatment option for unfit CLL patients compared with other available options and provides value for money to US health care payers at a threshold of $150,000 per QALY gained. Future studies with longer trial follow-up and more mature survival data may help to confirm longer-term cost benefits of VenG. DISCLOSURES: Genentech Inc. and AbbVie provided financial support for this study. Genentech Inc., AbbVie, and Pharmerit - An OPEN Health Company participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. Venetoclax is being developed in a collaboration between Genentech Inc. and AbbVie. Ravelo and Shapouri are employed by Genentech Inc. and have ownership interests. Manzoor and Sail are employed by AbbVie and have ownership interests. Chatterjee, van de Wetering, and Qendri, employees of Pharmerit - An OPEN Health Company, received consultancy fees from AbbVie. Davids has received consultancy fees from AbbVie, AstraZeneca, Eli Lilly, Genentech Inc., Janssen, MEI Pharma, Novartis, Pharmacyclics, and Verastem; research funding from Ascentage Pharma, Genentech Inc., MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, and Verastem; and has served on board of directors or advisory committees for AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Eli Lilly, Genentech Inc., Janssen, Pharmacyclics, TG Therapeutics, and Verastem. This study was presented as a poster at ASH 61st Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL.

Funder: Merck Sharp and Dohme; doi: http://dx.doi.org/10.13039/100009947, Background: Human papillomavirus (HPV) infection is a pre-requisite for cervical cancer, which represents the third most common cancer among women worldwide. A causal relationship also exists between HPV and cancer in other areas of the female reproductive system including the vagina and vulva. Whilst the incidence of vaginal cancer in the UK has remained relatively stable over the past 25 years, vulval cancer rates are increasing. A body of literature exists on the epidemiology and aetiology of vaginal and vulval cancer, but little is known about the economic burden. The objective of this study was to quantify the costs of treating these cancers on the National Health Service (NHS) in England. Methods: Inpatient and outpatient episodes were derived from Hospital Episode Statistics (HES). Health Resource Group (HRG) tariffs and National Reference Costs were used to estimate the cost of treating pre-cancerous and invasive vaginal and vulval lesions in England. Results: The study showed that for the 5 years from 2009/2010 to 2014/2015 the total cost associated with pre-cancerous and invasive vaginal and vulval lesions was over £14 million per year on average (95% of which was attributed to inpatient costs). Vulval cancer accounted for the largest proportion; an estimated 60% of the total cost (£8.82 million). On average 4316 patients per year in England were admitted to hospital and 912 patients attended outpatient settings for pre-cancerous and invasive disease of the vagina and vulva. Conclusion: The results indicate that vaginal and vulval cancer cost the English health care system over £14 million per year. Given the causal role of HPV in a proportion of these cancers, preventative measures such as the national HPV immunisation programme have the potential to reduce the economic burden. To ensure optimal use of NHS resources, it is important that future economic evaluations of such preventative measures consider the full burden of HPV related disease.

OBJECTIVES: To estimate the cost-effectiveness of venetoclax + obinutuzumab (GAZYVA®, G), (VEN+G) in the treatment of first-line (1L) chronic lymphocytic leukemia (CLL) from a Canadian health care system cost perspective. METHODS: A three-state partitioned-survival model was used to extrapolate progression-free survival (PFS) and overall survival (OS) over a 10-year time horizon. Cost-effectiveness was estimated comparing 12-month fixed duration of VEN+G versus (vs) G + Chlorambucil (GClb) based on the CLL14 clinical trial (NCT02242942). Other comparators included Bendamustine + rituximab (BR), Chlorambucil + rituximab (Clb+R), Ibrutinib (Ibr), Acalabrutinib (Acala) and Acalabrutinib + GAZYVA (Acala+G). VEN+G was also compared to the combination of fludarabine, cyclophosphamide and rituximab (FCR) in the overall 1L CLL population which included unfit and fit patients. Relative efficacy of VEN+G vs other comparators was estimated using a network meta-analysis. Health state utilities and adverse event disutilities were derived from a systematic literature review and other published sources. Costs included CLL treatment, routine care and monitoring, adverse events, disease progression costs, subsequent treatment costs, and end of life care. Uncertainty was assessed using an underlying probabilistic model (probabilistic analysis of uncertainty generated from 5,000 iterations), through deterministic sensitivity analyses (i.e., one-way sensitivity analyses (OWSA)), and through a series of alternative scenario analyses. RESULTS: For the overall unfit 1L CLL patient population, the probabilistic total discounted costs incurred over a 10-year time horizon were as follows: $217,727 for VEN+G vs $312,287 for GClb, $399,219 for BR, $380,713 for Clb+R, $736,017 for Ibr, $868,797 for Acala and $916,139 for Acala+G. The probabilistic total discounted quality adjusted life years (QALYs) were 4.964 for VEN+G vs 4.750, 4.550, 4.422, 4.709, 5.269, and 5.359, respectively for the comparators. For the overall 1L CLL patient population, the probabilistic total discounted costs were $219,651 for VEN+G vs $312,570 for GClb, $342,195 for FCR, $397,262 for BR, $380,551 for Clb+R, $757,129 for Ibr, $868,388 for Acala, and $916,798 for Acala+G. The probabilistic total discounted QALYs were 5.888 for VEN+G vs 5.519, 5.067, 5.198, 5.073, 5.597, 6.259 and 6.380, respectively for the comparators. VEN+G was found to be less costly and more efficacious (i.e., dominant) compared to GClb, BR, Clb+R, Ibr and FCR. As a result, incremental cost utility ratios (ICERs) were not calculated for these comparators. Acala and Acala+G resulted in ICERs ranging from $1.4-$2.1 million per QALY gained relative to VEN+G, which is not cost-effective. Based on the probabilistic model and 5,000 simulations, VEN+G was found to be at least 97% cost-effective across all decision maker willingness-to-pay thresholds. The results from the deterministic model were found to be similar to the probabilistic model. Using the deterministic model, and in comparison to the most commonly prescribed treatment for 1L CLL in Canada (i.e., Ibr), the OWSA comparing VEN+G to Ibr found that the most influential variables in the model were the PFS and OS hazard ratios for Ibr and the utility values for PFS and post-progression survival. CONCLUSION: VEN+G is an effective novel fixed duration treatment option which leads to deep and durable responses for the treatment of patients with unfit 1L CLL and provides excellent value-for-money compared with existing chemoimmunotherapy and treat to progression novel combinations. Disclosures Chatterjee: Pharmerit: Current Employment. Van de Wetering:Pharmerit: Current Employment. Goeree:AbbVie Inc.: Consultancy. Desbois:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzi:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzoor:AbbVie: Current equity holder in publicly-traded company. Owen:AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company.

Highlights • Standard gamble approach is used to explore the propensity for wanting antibiotics. • The public seem more reluctant to want antibiotics when effectiveness is reduced. • Mention of negative community impact did appear to alter public decision-making. • Future work should utilise representative samples and hypothesis testing techniques.

Background Accurate estimates of the burden of antimicrobial resistance (AMR) are needed to establish the magnitude of this global threat in terms of both health and cost, and to paramaterise cost-effectiveness evaluations of interventions aiming to tackle the problem. This review aimed to establish the alternative methodologies used in estimating AMR burden in order to appraise the current evidence base. Methods MEDLINE, EMBASE, Scopus, EconLit, PubMed and grey literature were searched. English language studies evaluating the impact of AMR (from any microbe) on patient, payer/provider and economic burden published between January 2013 and December 2015 were included. Independent screening of title/abstracts followed by full texts was performed using pre-specified criteria. A study quality score (from zero to one) was derived using Newcastle-Ottawa and Philips checklists. Extracted study data were used to compare study method and resulting burden estimate, according to perspective. Monetary costs were converted into 2013 USD. Results Out of 5187 unique retrievals, 214 studies were included. One hundred eighty-seven studies estimated patient health, 75 studies estimated payer/provider and 11 studies estimated economic burden. 64% of included studies were single centre. The majority of studies estimating patient or provider/payer burden used regression techniques. 48% of studies estimating mortality burden found a significant impact from resistance, excess healthcare system costs ranged from non-significance to $1 billion per year, whilst economic burden ranged from $21,832 per case to over $3 trillion in GDP loss. Median quality scores (interquartile range) for patient, payer/provider and economic burden studies were 0.67 (0.56-0.67), 0.56 (0.46-0.67) and 0.53 (0.44-0.60) respectively. Conclusions This study highlights what methodological assumptions and biases can occur dependent on chosen outcome and perspective. Currently, there is considerable variability in burden estimates, which can lead in-turn to inaccurate intervention evaluations and poor policy/investment decisions. Future research should utilise the recommendations presented in this review. Trial registration This systematic review is registered with PROSPERO (PROSPERO CRD42016037510). Electronic supplementary material The online version of this article (10.1186/s13756-018-0336-y) contains supplementary material, which is available to authorized users.

Mitigating the risks of antibiotic resistance requires a horizon scan linking the quality with the quantity of data reported on drivers of antibiotic resistance in humans, arising from the human, animal, and environmental reservoirs. We did a systematic review using a One Health approach to survey the key drivers of antibiotic resistance in humans. Two sets of reviewers selected 565 studies from a total of 2819 titles and abstracts identified in Embase, MEDLINE, and Scopus (2005–18), and the European Centre for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and WHO (One Health data). Study quality was assessed in accordance with Cochrane recommendations. Previous antibiotic exposure, underlying disease, and invasive procedures were the risk factors with most supporting evidence identified from the 88 risk factors retrieved. The odds ratios of antibiotic resistance were primarily reported to be between 2 and 4 for these risk factors when compared with their respective controls or baseline risk groups. Food-related transmission from the animal reservoir and water-related transmission from the environmental reservoir were frequently quantified. Uniformly quantifying relationships between risk factors will help researchers to better understand the process by which antibiotic resistance arises in human infections.

INTRODUCTION: Historically chemoimmunotherapy has been the standard of care in the treatment of first-line (1L) chronic lymphocytic leukemia (CLL). More recently several effective oral targeted agents, such as ibrutinib-based regimens, have provided effective chemotherapy-free treatment options in CLL. However, these therapies require continuous treatment until disease progression. Recently FDA approved (May 2019), venetoclax plus obinutuzumab (VenG) is a highly effective chemotherapy-free therapy that is used over a 12-month fixed treatment duration (Fischer et al, N Eng J Med 2019). The objective of this study is to estimate the cost-effectiveness of VenG in the treatment of 1L CLL from a US-payer perspective. METHODS: A three-state partitioned-survival model was used to extrapolate progression-free survival and overall survival over a lifetime horizon (20 years). Cost-effectiveness was estimated by comparing a 12-month fixed duration of VenG versus (vs.) chlorambucil-obinutuzumab (ClbG) based on the CLL14 clinical trial (NCT02242942). Other comparators included treat-to-progression therapies, such as ibrutinib (IBR), IBR + rituximab (IR), and IBR + G (IG), and a 6-month course of bendamustine + rituximab (BR). Using a network meta-analysis, the relative efficacy of VenG and ClbG vs. other selected comparators was estimated. Health state utilities and adverse event (AE) disutilities were derived from a systematic literature review and published health-technology assessment reports. To generate total quality-adjusted life years (QALYs), these health state utilities and AE disutilities were applied to the relative efficacy data. US-specific costs included those for CLL treatment, routine care and monitoring, AEs, disease progression (including subsequent treatment), and end-of-life care. Cost-effectiveness results are presented in terms of incremental cost per QALY. A new treatment that is both lower in total cost and more efficacious (in QALYs) vs. identified comparator treatments is described as being "dominant". Uncertainty in the model was tested through deterministic, probabilistic, and scenario analyses. RESULTS: The benefits in the cost-effectiveness model (CEM) were measured in terms of total discounted QALYs which were 6.47 for VenG, 6.12 for ClbG, 6.11 for IBR, 6.08 for IR, 6.41 for IG, and 5.98 for BR. The total discounted costs incurred by VenG and ClbG were $322,613 and $847,571, respectively. IBR-based treat-to-progression regimens incurred total discounted costs of $1,485,368 for IBR, $1,447,010 for IR, and $1,988,706 for IG. BR incurred total discounted costs of $808,756. Compared to these regimens, VenG is less costly (incremental cost ranges between: -$1,666,093 to -$486,143). The incremental discounted QALYs of VenG was: 0.36 vs. GC, 0.49 vs. BR, 0.37 vs. IBR, 0.06 vs. IG, and 0.39 vs. IR. Thus, VenG with a 12-month fixed duration, has lower total costs and is more efficacious ("dominant") over all comparators in the CEM. The probabilistic sensitivity analysis results were in line with the deterministic results. Sensitivity analysis indicated the post-progression survival utility was the most influential parameter on the model outcomes. As the CLL14 trial data matures, these cost-effectiveness estimates may change and additional scenarios for post-progression survival for VenG will be explored. Updated results will be presented. CONCLUSIONS: VenG is projected to be cost-effective vs. ClbG within accepted US cost-effectiveness thresholds. Compared with BR and IBR-based treat-to-progression regimens (IBR, IR, and IG), a 12-month fixed-duration treatment option with VenG seems cost saving and more efficacious based on the CEM. Taken together, VenG appears to be a cost-effective standard therapy for 1L CLL patients. Disclosures Davids: AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Ravelo:Genentech: Employment, Equity Ownership. Shapouri:Roche: Equity Ownership; Genentech, Inc.: Employment. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Sail:AbbVie: Employment, Other: and may hold stock or stock options. Van de Wetering:AbbVie: Consultancy. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau.