BackgroundTumour necrosis factor (TNF)-α inhibitors (anti-TNFs) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-AxSpA) have not responded adequately to conventional therapy. Current National Institute for Health and Care Excellence (NICE) guidance recommends treatment with adalimumab, etanercept and golimumab in adults with active (severe) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS. Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE.ObjectiveTo determine the clinical effectiveness, safety and cost-effectiveness within the NHS of adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, within their licensed indications, for the treatment of severe active AS or severe nr-AxSpA (but with objective signs of inflammation).DesignSystematic review and economic model.Data sourcesFifteen databases were searched for relevant studies in July 2014.Review methodsClinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis methods. Results from other studies were summarised narratively. Only full economic evaluations that compared two or more options and considered both costs and consequences were included in the systematic review of cost-effectiveness studies. The differences in the approaches and assumptions used across the studies, and also those in the manufacturer’s submissions, were examined in order to explain any discrepancies in the findings and to identify key areas of uncertainty. A de novo decision model was developed with a generalised framework for evidence synthesis that pooled change in disease activity (BASDAI and BASDAI 50) and simultaneously synthesised information on function (BASFI) to determine the long-term quality-adjusted life-year and cost burden of the disease in the economic model. The decision model was developed in accordance with the NICE reference case. The model has a lifetime horizon (60 years) and considers costs from the perspective of the NHS and personal social services. Health effects were expressed in terms of quality-adjusted life-years.ResultsIn total, 28 eligible RCTs were identified and 26 were placebo controlled (mostly up to 12 weeks); 17 extended into open-label active treatment-only phases. Most RCTs were judged to have a low risk of bias overall. In both AS and nr-AxSpA populations, anti-TNFs produced clinically important benefits to patients in terms of improving function and reducing disease activity; for AS, the relative risks for ASAS 40 ranged from 2.53 to 3.42. The efficacy estimates were consistently slightly smaller for nr-AxSpA than for AS. Statistical (and clinical) heterogeneity was more apparent in the nr-AxSpA analyses than in the AS analyses; both the reliability of the nr-AxSpA meta-analysis results and their true relevance to patients seen in clinical practice are questionable. In AS, anti-TNFs are approximately equally effective. Effectiveness appears to be maintained over time, with around 50% of patients still responding at 2 years. Evidence for an effect of anti-TNFs delaying disease progression was limited; results from ongoing long-term studies should help to clarify this issue. Sequential treatment with anti-TNFs can be worthwhile but the drug survival response rates and benefits are reduced with second and third anti-TNFs. The de novo model, which addressed many of the issues of earlier evaluations, generated incremental cost-effectiveness ratios ranging from £19,240 to £66,529 depending on anti-TNF and modelling assumptions.ConclusionsIn both AS and nr-AxSpA populations anti-TNFs are clinically effective, although more so in AS than in nr-AxSpA. Anti-TNFs may be an effective use of NHS resources depending on which assumptions are considered appropriate.Future work recommendationsRandomised trials are needed to identify the nr-AxSpA population who will benefit the most from anti-TNFs.Study registrationThis study is registered as PROSPERO CRD42014010182.FundingThe National Institute for Health Research Health Technology Assessment programme.

Background Obtaining reliable estimates of the health-related quality of life (HR-QoL) of people with predementia Alzheimer’s disease [AD] (preclinical or prodromal AD), mild cognitive impairment (MCI) and dementia is essential for economic evaluations of related health interventions. Aims To provide an overview of which quality of life instruments are being used to assess HR-QoL in people with predementia AD, MCI or dementia; and, to summarise their reported HR-QoL levels at each stage of the disease and by type of respondent. Methods We systematically searched for and reviewed eligible studies published between January 1990 and the end of April 2017 which reported HR-QoL for people with predementia AD, MCI or dementia. We only included instruments which are preference-based, allowing index scores/utility values to be attached to each health state they describe based on preferences obtained from population surveys. Summary results were presented by respondent type (self or proxy), type of instrument, geographical location and, where possible, stage of disease. Health state utility values derived using the EuroQoL 5-Dimensions (EQ-5D) were meta-analysed by pooling reported results across all studies by disease severity (MCI, mild, mild to moderate, moderate, severe dementia, not specified) and by respondent (person with dementia, carer, general public, not specified), using a fixed-effects approach. Results We identified 61 studies which reported HR-QoL for people with MCI or dementia using preference-based instruments, of which 48 used the EQ-5D. Thirty-six studies reported HR-QoL for mild and/or moderate disease severities, and 12 studies reported utility values for MCI. We found systematic differences between self-rated and proxy-rated HR-QoL, with proxy-rated utility valued being significantly lower in more severe disease states. Conclusions A substantial literature now exists quantifying the impact of dementia on HR-QoL using preference-based measures, giving researchers and modellers a firmer basis on which to select appropriate utility values when estimating the effectiveness and cost-effectiveness of interventions in this area. Further research is required on HR-QoL of people with preclinical and prodromal AD and MCI, possible differences by type of dementia, the effects of comorbidities, study setting and the informal caregiver’s own HR-QoL, including any effect of that on their proxy-ratings.

The successful development of an economic model for the evaluation of future Alzheimer's disease (AD) interventions is critical to accurately inform policy makers and payers. As our understanding of AD expands, this becomes an increasingly complex and challenging goal. Advances in diagnostic techniques for AD and the prospect of disease‐modifying treatments raise an urgent need to define specifications for future economic models and to ensure that the necessary data to populate them are available. This Perspective article provides expert opinions from health economists and governmental agency representatives on how future economic models for AD might be structured, validated, and reported. We aim to stimulate much‐needed discussion about the detailed specification of future health economic models for AD.

Objective: Ado-trastuzumab emtansine (T-DM1) was recently approved for patients with human epidermal growth factor receptor 2 positive (HER2+) early breast cancer (eBC) with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. Cost-effectiveness analysis was conducted to compare T-DM1 versus trastuzumab in the United States. Materials and Methods:A Markov cohort-based model tracked clinical and economic outcomes over a lifetime horizon from a US payer perspective. The model included 6 health states: invasive disease-free, nonmetastatic (locoregional) recurrence, remission, first-line and second-line metastatic BC and death. Model state transitions were based on statistical extrapolation of the head-to-head KATHERINE study and published sources. Dosing and treatment duration reflected prescribing information and trials. Costs (2019 US dollars) associated with pharmaceutical treatment (wholesale acquisition costs), health state specific care, adverse events, and end-of-life care were included. Health state utilities were obtained from KATHERINE and published literature.Results: T-DM1 dominated trastuzumab, yielding lower lifetime costs (−$40,271), and higher life-years (2.980) and quality-adjusted life-years (2.336). Results were driven by patients receiving T-DM1 spending less time in more costly downstream health states, as these patients are less likely to experience a recurrence overall, despite having a higher likelihood of metastatic disease (distant recurrence) in the subset of patients who experience recurrence. Probabilistic sensitivity analysis indicated robust results, with 96.7% of 5000 stochastic simulations producing dominance for T-DM1. The most influential variables were related to treatment costs, off treatment utilities, and health state costs. Additional scenario analyses tested a range of model inputs and assumptions, and produced consistent results. Conclusion:Relative to trastuzumab, T-DM1 treatment for patients with HER2+ eBC who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment is likely to reduce the overall financial burden of cancer, while simultaneously improving patient outcomes.

Purpose The Quality of Life Alzheimer’s Disease Scale (QoL-AD) is commonly used to assess disease specific health-related quality of life (HRQoL) as rated by patients and their carers. For cost-effectiveness analyses, utilities based on the EQ-5D are often required. We report a new mapping algorithm to obtain EQ-5D indices when only QoL-AD data are available. Methods Different statistical models to estimate utility directly, or responses to individual EQ-5D questions (response mapping) from QoL-AD, were trialled for patient-rated and proxy-rated questionnaires. Model performance was assessed by root mean square error and mean absolute error. Results The response model using multinomial regression including age and sex, performed best in both the estimation dataset and an independent dataset. Conclusions The recommended mapping algorithm allows researchers for the first time to estimate EQ-5D values from QoL-AD data, enabling cost-utility analyses using datasets where the QoL-AD but no utility measures were collected.

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Objectives: Ado-trastuzumab emtansine (T-DM1) is a HER2-targeted antibody drug conjugate (ADC) indicated for the adjuvant treatment of patients with HER2+ early breast cancer (eBC) who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment. In a phase 3 clinical trial (KATHERINE, NCT01772472), T-DM1 demonstrated a statistically significant 50% reduction in the risk of invasive BC recurrence or death compared with trastuzumab (H) (HR= 0.5, 95% CI 0.39-0.64; p<0.001). This study explored the cost-effectiveness of T-DM1 use versus H from a US third-party payer perspective. Methods: A Markov-based cost-effectiveness model with a lifetime horizon was developed to compare the clinical and cost outcomes of T-DM1 versus H from the US payer perspective. The model considered the population from the KATHERINE trial and included six health states: invasive disease-free, non-metastatic (locoregional) recurrence, remission, first- and second-line metastatic breast cancer (mBC), and death. Invasive disease-free survival (iDFS) projections over patients' lifetimes were derived from statistical extrapolation of the KATHERINE clinical trial data, while overall survival, estimated as the risk of death in each health state, was derived from several BC clinical trials and US life tables. The model included costs for treatments in all health states, except for remission and death. Dosing and treatment duration was from product prescribing information and/or published literature. Drug costs were estimated using the wholesale acquisition cost (WAC) for drugs from Medispan PriceRx. Additional costs included health state-related medical resource use, adverse events during iDFS, and costs associated with end of life. These costs were derived from Medicare physician and laboratory fee schedules, prescribing information for adverse event rates and the published literature for both adverse event and end of life costs. Health state utilities were derived from the KATHERINE clinical trial and the published literature. All costs were adjusted to 2019 US dollars. Results: In the base case, T-DM1 dominated H (incremental costs: -$41,003, incremental quality-adjusted life years [QALYs]: 1.79, incremental life years [LYs]: 2.22). Results were driven by cost offsets observed in health states beyond iDFS. T-DM1 produced cost savings due to fewer patients with invasive recurrence, and hence, fewer patients undergoing first- and second-line mBC (e.g., $1,540 vs $6,684, $49,512 vs $85,795, and $35,204 vs $62,435 lifetime costs for T-DM1 and H in non-metastatic recurrence, first- and second-line mBC, respectively). The probabilistic sensitivity analysis found consistent cost savings in all iterations (T-DM1 was dominant 96.6% of the simulations). Scenario analyses showed that base case results remain robust across input variations. Conclusions: The cost-effectiveness analysis shows that T-DM1 as an adjuvant therapy for patients with HER2-positive eBC who have residual invasive disease after neoadjuvant therapy is a dominant treatment option (less costly, more effective) compared to H in the US. Citation Format: Hans-Peter Goertz, Oscar Herrera-Restrepo, Elizabeth Wehler, Pinar Bilir, Vincent Antao, Gurleen Singh Jhuti. Cost-effectiveness of ado-trastuzumab emtansine (T-DM1) versus trastuzumab (H) for the adjuvant treatment of patients with residual invasive HER2+ early breast cancer in the US [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-13-01.