Authors' objectives: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of ceftazidime-avibactam in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. This evaluation is one of two performed as part of a pilot conducted by the National Institute for Health and Care Excellence (NICE), NHS England (NHSE) and NHS Improvement to assess the feasibility of innovative models that pay for antimicrobials (AMs) based on an evaluation of their value to the NHS as opposed to the volumes used. These projects informed commercial discussions regarding contract value for a period of up to 10 years. This report details the evaluation phase for ceftazidime with avibactam (CAZ-AVI, brand name Avycaz), a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a beta-lactamase inhibitor manufactured by Pfizer which received a marketing authorisation in June 2016 for treatment in adults and paediatric patients (> 3 months) for complicated intra-abdominal infections (cIAI), complicated UTI (cUTI), hospital-acquired pneumonia, including ventilator-associated pneumonia (HAP/VAP), bacteraemia (adults only) associated with the aforementioned infections and treatment of infections caused by aerobic Gram-negative organisms with limited treatment options.

Authors' results and conclusions: The clinical effectiveness of ceftazidime-avibactam relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. In the base case, ceftazidime-avibactam was associated with a statistically significantly higher susceptibility relative to colistin (odds ratio 7.24, 95% credible interval 2.58 to 20.94). The remainder of the treatments were associated with lower susceptibility than colistin (odds ratio < 1). The results were sensitive to the definition of resistance and the studies included in the analysis. In the base case, patient-level benefit of ceftazidime-avibactam was between 0.08 and 0.16 quality-adjusted life-years, depending on the site of infection and the usage scenario. There was a high degree of uncertainty surrounding the benefits of ceftazidime-avibactam across all subgroups, and the results were sensitive to assumptions in the meta-analysis used to estimate susceptibility. There was substantial uncertainty in the number of infections that are suitable for treatment with ceftazidime-avibactam, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time, and rates of emergence of resistance. The population-level benefit varied substantially across the scenarios, from 531 to 2342 quality-adjusted life-years over 20 years. This work has provided quantitative estimates of the value of ceftazidime-avibactam within its areas of expected usage within the NHS. The mapping reviews of RCT and observational studies identified insufficient evidence to inform an assessment of clinical effectiveness since the RCTs included very small numbers of OXA-48 Enterobacterales infections and did not report these data as a subgroup analysis and the observational data were not reported separately for the sites of interest (cUTI and HAP/VAP), the studies were small and highly heterogeneous with respect to prognostic factors, and individual patient data (IPD) were not available within the timeframe of this evaluation. In the review of susceptibility studies, 28 data sources met the initial inclusion criteria. One, from PHE, which included isolates submitted voluntarily to the antimicrobial resistance and healthcare-associated infections (AMRHAI) reference laboratory, had high relevance, but several limitations. EEPRU therefore included a broader set of evidence synthesised using network meta-analysis (NMA). Sixteen studies and data sources met the inclusion criteria. In the synthesis, CAZ-AVI was associated with a statistically significantly higher susceptibility relative to colistin [odds ratio (OR) 7.24, 95% credible interval (CrI) 2.58 to 20.94]. The remainder of the treatments were associated with lower susceptibility than colistin (OR < 1). Heterogeneity was extremely high [standard deviation (SD) 1.56, 95% CrI 1.28 to 1.93] and sensitivity analyses were conducted to investigate the sources of heterogeneity. The evidence network using EUCAST methods and breakpoints to assess susceptibility was selected as the base-case analysis to inform the economic evaluation since heterogeneity was lower and there was a clinical rationale to support restricting to studies that had used EUCAST laboratory methods and breakpoints as these are more commonly used in England. A scenario analysis was planned to include the result from the full analysis set. A further scenario was planned restricted to studies with no-MBLs and that had used EUCAST laboratory methods and breakpoints, which left one study (Vazquez-Ucha et al.). A further scenario analysis was planned using the PHE data alone, due to its high relevance to the evaluation. Review 4 identified two studies that reported mortality or hospital length of stay conditional on susceptibility to empiric treatment and were selected for use in the ES model. No useful evidence relating to the MDS was identified. Review 5 did not identify any relevant literature, but an unpublished study (CARBAR) was submitted by Shionogi during the parallel appraisal of cefiderocol. Review 6 indicated that CAZ-AVI does not appear to increase the risk of acute kidney injury (AKI), C. difficile, or any other serious adverse events (SAE), compared to non-toxic comparators (i.e. comparators that were not colistin or an aminoglycoside). No study reported a comparison of CAZ-AVI exclusively with colistin or aminoglycosides. Event rates were generally very low or zero. Discussion of clinical evidence: there were some limitations to the approach selected and analyses done. Key limitations include: susceptibility could be considered, at best, a surrogate outcome; linking data were limited and not specific to the pathogen–mechanism combination, and expert elicitation had to be relied upon to evidence the link in the MDS; uncertainties relating to the determination and application of breakpoints and the NMA results were associated with high levels of heterogeneity. Patient-level INHEs in the HVCS The benefits of CAZ-AVI are driven by similar susceptibility but improved safety compared to colistin/aminoglycoside-based treatments, and, in the ES, by higher susceptibility than non-colistin/aminoglycoside-based treatment. The two most significant sources of uncertainty relate to the ES and are (1) the susceptibility evidence and (2) the proportion of patients in the ES who are suspected of having OXA-48 Enterobacterales who are later confirmed to have this resistant pathogen. CAZ-AVI generated INHEs of 0.16 QALYs per patient in the ES (range across scenarios 0.00–0.26) and 0.08 (0.05–0.12) in the microbiology-directed settings. Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions were unable to select a base case for the population-level results. Population-level results are, therefore, presented for two different approaches to estimating current infection numbers (based on different methods to classify infections from clinical specimen sites), two alternative approaches to forecasting infections over time (based on whether observed trends are assumed to persist indefinitely or not) and three different trajectories with respect to CAZ-AVI resistance emergence (1%, 5% and 10% at 20 years). Across these scenarios, population INHEs varied from 531 to 2342 QALYs. The population size estimates are subject to additional uncertainties relating to the challenges of inferring patient population size from microbiology data and in forecasting population size in the future. Estimates were generated using a number of strong assumptions about the generalisability of patient-level INHEs between settings, for example, that patient-level INHEs for bloodstream infections can be generalised to HAP/VAP infections. These assumptions were based on discussions with clinical experts. Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions considers that it is possible that CAZ-AVI use will facilitate additional or at least more prompt receipt of required treatments/procedures for certain groups and therefore provide additional enablement value not captured within the model estimates of INHEs. The magnitude of these enablement benefits remains highly uncertain. Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions’s quantitative assessment of value of CAZ-AVI was associated with a base-case population INHE across its areas of expected usage of 531–2342 QALYs over 20 years. These values were informed by interlinked decision-analytic models informed by systematic reviews of the literature and evidence synthesis, additional national data provided by PHE, structured expert elicitation and, where necessary, assumptions informed by clinical opinion. The quantitative estimates of the value for CAZ-AVI within the areas of expected usage within the NHS indicate that the maximum amount the NHS could pay for CAZ-AVI was £11 million to £47 million if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using CAZ-AVI. The high level of uncertainty could be addressed via further research; however, the appropriateness of amending payments to reflect revised estimates of value requires further consideration. A broader and important question is ‘what would represent the “optimal” scope of usage for CAZ-AVI?’ Further methodological and quantitative work is required to address this question.

Authors' methods: The health benefit of ceftazidime-avibactam was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients’ mortality risks and health-related quality of life. Patient-level costs and health-related quality of life of ceftazidime-avibactam under various usage scenarios compared with alternative management strategies in the high-value clinical scenarios were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population in quality-adjusted life-years using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for ceftazidime-avibactam. Given existing evidence, the estimates of the value of ceftazidime-avibactam are highly uncertain. A mapping review was undertaken to establish available evidence and ascertain which approach to estimating comparative effectiveness could inform an economic model. Reviews 1 and 2 considered RCTs and observational studies in patients with HAP/VAP or cUTI infections caused by OXA-48 Enterobacterales or suspected to be caused by carbapenem-resistant Enterobacterales. In Review 3 in vitro susceptibility studies of OXA-48 Enterobacterales isolates which reported the proportion of isolates from any infection site that were susceptible to the HVCS treatment and at least one relevant comparator (colistin, meropenem, tigecycline, aztreonam, fosfomycin, gentamicin, amikacin, tobramycin) were sought. Systematic searches across relevant databases (MEDLINE, EMBASE and Centre for Review and Dissemination (CRD) database) were conducted in March 2021. EEPRU also considered evidence submitted by Pfizer and Public Health England (PHE). After mapping, only Review 3 was pursued, since there was insufficient evidence from Reviews 1 and 2 (see details in Results below). Risk-of-bias assessment was performed using a bespoke tool developed for this evaluation. A random-effects NMA of susceptibility studies was conducted. Subgroup and sensitivity analyses were planned to investigate the impact of clinical sources of heterogeneity including: inclusion criteria (use of resistance to a comparator to select study sample); co-carriage of MBLs; the proportion who were carbapenem-sensitive; whether the sample was recruited consecutively; and what laboratory methods and breakpoints were used to assess susceptibility. Review 4 aimed to provide evidence on the link between susceptibility and clinical outcomes and Review 5 between susceptibility and long-term outcomes in the sites of interest. Review 6 aimed to assess the safety of CAZ-AVI. No published existing economic evaluations that assessed the use of CAZ-AVI in the HVCSs or areas of expected usage were identified. The manufacturer’s cost-effectiveness model estimated that introduction of CAZ-AVI was associated with an expected INHE benefit of approximately 20,000 quality-adjusted life-years (QALYs) over a 10-year time horizon, based on a cost-effectiveness threshold of £30,000 per QALY. EEPRU considered the model to contain several strong assumptions and it assumed a much broader population of patients would receive CAZ-AVI than considered appropriate by clinical advisors to EEPRU. Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions developed a de novo decision-analytic model to predict the cost and health consequences (summarised as population-level INHEs) of introducing CAZ-AVI within the HVCSs. These estimates assumed CAZ-AVI was supplied free of charge to the NHS, and use an estimate of health opportunity cost of £20,000/QALY. This quantitative analysis comprises three components assessing INHEs of the HVCSs at the patient level, INHEs of the HVCSs at the population level, and how INHEs within the HVCSs might appropriately be rescaled to reflect expected usage across the English NHS. The patient-level component characterises the cost, mortality and morbidity consequences of introducing CAZ-AVI over a patient’s lifetime. Separate but related models were developed for the ES and MDS. In the ES, treatment with CAZ-AVI was compared to non-colistin/aminoglycoside-based treatment and colistin/aminoglycoside-based treatment (considered more toxic). In the MDS, outcomes in the overall microbiology-directed cohort using CAZ-AVI were compared to outcomes using existing AMs only. In the ES, outcomes were modelled both for patients in whom OXA-48 Enterobacterales suspicion was confirmed and for those in whom this suspicion turned out to be incorrect. The probability of having the suspected pathogen/resistance mechanism was informed by national surveillance data supplied by PHE. The key driver of effectiveness was in vitro susceptibility (see evidence syntheses above). A combination of evidence from the literature and structured expert elicitation informed the model. Higher rates of AKI for colistin and aminoglycoside-based therapy (compared to other agents, including CAZ-AVI) were informed by published systematic reviews. Lifetime costs, quality of life and mortality were predicted accounting for the highly comorbid nature of the patient population and the increased risk of chronic kidney disease resulting from AKI. The population-level component used a forecast-based approach to aggregate the patient-level predictions to the population-level accounting for the size of, and growth over time in, the eligible patient population within each HVCS. This component also reflects how resistance is likely to develop to CAZ-AVI and existing AMs over time. Predictions were presented for patients initiated on treatment over the next 20 years. National surveillance data were used to estimate current numbers of patients within the HVCS and to forecast growth in patient numbers over time. A series of scenarios reflect the potential emergence of resistance to CAZ-AVI. Changes in resistance to existing AMs over time were not modelled due to the sparsity of evidence available to inform these forecasts. Predicted overall population INHEs corresponding to the expected use of CAZ-AVI in the English NHS were generated by rescaling the population INHEs from the HVCSs to reflect additional areas of expected usage (known or suspected OXA-48 Enterobacterales bloodstream and intra-abdominal infections). Rescaling was based on surveillance data on population size and expert assessments of the similarity in per-patient INHEs between the HVCSs and these additional sites of interest. The literature on the economic evaluation of AMs has described a range of elements of value associated with these products that are not relevant to evaluations of other healthcare interventions. We summarised the extent to which these elements of value were captured within the quantitative estimates and, where this has not been possible, whether they were likely to substantively modify the quantitative estimates of value presented.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/NIHR135592

Year Published: 2024

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/YAPL9347

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/YAPL9347

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk