Discontinuation of anti-tumour necrosis factor alpha treatment owing to blood test abnormalities, and cost-effectiveness of alternate blood monitoring strategies.

BACKGROUND: There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment. OBJECTIVES: To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests. METHODS: A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment. RESULTS: The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring. CONCLUSIONS: Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs.

Cost-effectiveness of spinal muscular atrophy newborn screening based on real-world data in Belgium.

The objective of the study was to assess the cost-effectiveness of real-world spinal muscular atrophy newborn screening followed by treatment. We modeled the lifetime cost-effectiveness of the spinal muscular atrophy newborn screening followed by treatment (screening) compared to treatment without screening (no screening) from the Belgian healthcare perspective. Real-world data, including quality of life, costs, and motor development data, were collected on 12 patients identified by screening and 43 patients identified by their symptoms. "Screening" was associated with slightly higher healthcare costs (€ 6,858,061 vs. € 6,738,120) but more quality-adjusted life years (QALY) (40.95 vs. 20.34) compared to "no screening", leading to an incremental cost-effectiveness ratio of € 5,820 per QALY gained. "Screening" was dominant from a societal perspective (negative incremental costs: € -14,457; incremental QALY = 20.61), when incorporating the burden on caregivers (negative incremental costs = € -74,353; incremental QALY = 27.51), and when the treatment was chosen by the parents (negative incremental costs = € -2,596,748; incremental QALY = 20.61). Spinal muscular atrophy newborn screening coupled with early treatment is thus cost-effective compared with late treatment following clinical diagnosis and is dominant when societal perspective, caregiver burden, and treatment based on parental preference were considered.

Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation.

Background: Patients established on thiopurines (e.g., azathioprine) are recommended to undergo three-monthly blood tests for the early detection of blood, liver, or kidney toxicity. These side-effects are uncommon during long-term treatment. We developed a prognostic model that could be used to inform risk-stratified decisions on frequency of monitoring blood-tests during long-term thiopurine treatment, and, performed health-economic evaluation of alternate monitoring intervals. Methods: This was a retrospective cohort study set in the UK primary-care. Data from the Clinical Practice Research Datalink Aurum and Gold formed development and validation cohorts, respectively. People age ≥18 years, diagnosed with an immune mediated inflammatory disease, prescribed thiopurine by their general practitioner for at-least six-months between January 1, 2007 and December 31, 2019 were eligible. The outcome was thiopurine discontinuation with abnormal blood-test results. Patients were followed up from six-months after first primary-care thiopurine prescription to up to five-years. Penalised Cox regression developed the risk equation. Multiple imputation handled missing predictor data. Calibration and discrimination assessed model performance. A mathematical model evaluated costs and quality-adjusted life years associated with lengthening the interval between blood-tests. Findings: Data from 5982 (405 events over 16,117 person-years) and 3573 (269 events over 9075 person-years) participants were included in the development and validation cohorts, respectively. Fourteen candidate predictors (21 parameters) were included. The optimism adjusted R2 and Royston D statistic in development data were 0.11 and 0.76, respectively. The calibration slope and Royston D statistic (95% Confidence Interval) in the validation data were 1.10 (0.84-1.36) and 0.72 (0.52-0.92), respectively. A 2-year period between monitoring blood-test was most cost-effective in all deciles of predicted risk but the gain between monitoring annually or biennially reduced in higher risk deciles. Interpretation: This prognostic model requires information that is readily available during routine clinical care and may be used to risk-stratify blood-test monitoring for thiopurine toxicity. These findings should be considered by specialist societies when recommending blood monitoring during thiopurine prescription to bring about sustainable and equitable change in clinical practice. Funding: National Institute for Health and Care Research.

A Systematic Review of Methods to Incorporate External Evidence into Trial-Based Survival Extrapolations for Health Technology Assessment.

BACKGROUND: External evidence is commonly used to inform survival modeling for health technology assessment (HTA). While there are a range of methodological approaches that have been proposed, it is unclear which methods could be used and how they compare. PURPOSE: This review aims to identify, describe, and categorize established methods to incorporate external evidence into survival extrapolation for HTA. DATA SOURCES: Embase, MEDLINE, EconLit, and Web of Science databases were searched to identify published methodological studies, supplemented by hand searching and citation tracking. STUDY SELECTION: Eligible studies were required to present a novel extrapolation approach incorporating external evidence (i.e., data or information) within survival model estimation. DATA EXTRACTION: Studies were classified according to how the external evidence was integrated as a part of model fitting. Information was extracted concerning the model-fitting process, key requirements, assumptions, software, application contexts, and presentation of comparisons with, or validation against, other methods. DATA SYNTHESIS: Across 18 methods identified from 22 studies, themes included use of informative prior(s) (n = 5), piecewise (n = 7), and general population adjustment (n = 9), plus a variety of "other" (n = 8) approaches. Most methods were applied in cancer populations (n = 13). No studies compared or validated their method against another method that also incorporated external evidence. LIMITATIONS: As only studies with a specific methodological objective were included, methods proposed as part of another study type (e.g., an economic evaluation) were excluded from this review. CONCLUSIONS: Several methods were identified in this review, with common themes based on typical data sources and analytical approaches. Of note, no evidence was found comparing the identified methods to one another, and so an assessment of different methods would be a useful area for further research.HighlightsThis review aims to identify methods that have been used to incorporate external evidence into survival extrapolations, focusing on those that may be used to inform health technology assessment.We found a range of different approaches, including piecewise methods, Bayesian methods using informative priors, and general population adjustment methods, as well as a variety of "other" approaches.No studies attempted to compare the performance of alternative methods for incorporating external evidence with respect to the accuracy of survival predictions. Further research investigating this would be valuable.

The Cost-Effectiveness of Belimumab and Voclosporin for Patients with Lupus Nephritis in the United States.

BACKGROUND AND OBJECTIVES: Despite existing therapies, people with lupus nephritis progress to kidney failure and have reduced life expectancy. Belimumab and voclosporin are two new disease-modifying therapies recently approved for the treatment of lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A de novo economic model was developed to estimate the cost-effectiveness of these therapies, including the following health states: "complete response," "partial response," and "active disease" defined by eGFR and proteinuria changes, kidney failure, and death. Short-term data and mean cohort characteristics were sourced from pivotal clinical trials of belimumab (the Belimumab International Study in Lupus Nephritis) and voclosporin (the Aurinia Urinary Protection Reduction Active-Lupus with Voclosporin trial and Aurinia Renal Response in Active Lupus With Voclosporin). Risk of mortality and kidney failure were on the basis of survival modeling using published Kaplan-Meier data. Each drug was compared with the standard of care as represented by the comparator arm in its respective pivotal trial(s) using US health care sector perspective, with a societal perspective also explored. RESULTS: In the health care perspective probabilistic analysis, the incremental cost-effectiveness ratio for belimumab compared with its control arm was estimated to be approximately $95,000 per quality-adjusted life year. The corresponding incremental ratio for voclosporin compared with its control arm was approximately $150,000 per quality-adjusted life year. Compared with their respective standard care arms, the probabilities of belimumab and voclosporin being cost effective at a threshold of $150,000 per quality-adjusted life year were 69% and 49%, respectively. Cost-effectiveness was dependent on assumptions made regarding survival in response states, costs and utilities in active disease, and the utilities in response states. In the analysis from a societal perspective, the incremental ratio for belimumab was estimated to be approximately $66,000 per quality-adjusted life year, and the incremental ratio for voclosporin was estimated to be approximately $133,000 per quality-adjusted life year. CONCLUSIONS: Compared with their respective standard care arms, belimumab but not voclosporin met willingness-to-pay thresholds of $100,000 per quality-adjusted life year. Despite potential clinical superiority in the informing trials, there remains high uncertainty around the cost-effectiveness of voclosporin.

Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis.

OBJECTIVES: The aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses. METHODS: Systematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical. RESULTS: Forty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs. CONCLUSIONS: In MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD.

Conceptual model for the health technology assessment of current and novel interventions in rheumatoid arthritis.

The objective of this study was to evaluate current approaches to economic modeling in rheumatoid arthritis (RA) and propose a new conceptual model for evaluation of the cost-effectiveness of RA interventions. We followed recommendations from the International Society of Pharmacoeconomics and Outcomes Research-Society of Medical Decision Making (ISPOR-SMDM) Modeling Good Research Practices Task Force-2. The process involved scoping the decision problem by a working group and drafting a preliminary cost-effectiveness model framework. A systematic literature review (SLR) of existing decision-analytic models was performed and analysis of an RA registry was conducted to inform the structure of the draft conceptual model. Finally, an expert panel was convened to seek input on the draft conceptual model. The proposed conceptual model consists of three separate modules: 1) patient characteristic module, 2) treatment module, and 3) outcome module. Consistent with the scope, the conceptual model proposed six changes to current economic models in RA. These changes proposed are to: 1) use composite measures of disease activity to evaluate treatment response as well as disease progression (at least two measures should be considered, one as the base case and one as a sensitivity analysis); 2) conduct utility mapping based on disease activity measures; 3) incorporate subgroups based on guideline-recommended prognostic factors; 4) integrate realistic treatment patterns based on clinical practice/registry datasets; 5) assimilate outcomes that are not joint related (extra-articular outcomes); and 6) assess mortality based on disease activity. We proposed a conceptual model that incorporates the current understanding of clinical and real-world evidence in RA, as well as of existing modeling assumptions. The proposed model framework was reviewed with experts and could serve as a foundation for developing future cost-effectiveness models in RA.

Probabilistic Sensitivity Analysis in Cost-Effectiveness Models: Determining Model Convergence in Cohort Models.

Probabilistic sensitivity analysis (PSA) demonstrates the parameter uncertainty in a decision problem. The technique involves sampling parameters from their respective distributions (rather than simply using mean/median parameter values). Guidance in the literature, and from health technology assessment bodies, on the number of simulations that should be performed suggests a 'sufficient number', or until 'convergence', which is seldom defined. The objective of this tutorial is to describe possible outcomes from PSA, discuss appropriate levels of accuracy, and present guidance by which an analyst can determine if a sufficient number of simulations have been conducted, such that results are considered to have converged. The proposed approach considers the variance of the outcomes of interest in cost-effectiveness analysis as a function of the number of simulations. A worked example of the technique is presented using results from a published model, with recommendations made on best practice. While the technique presented remains essentially arbitrary, it does give a mechanism for assessing the level of simulation error, and thus represents an advance over current practice of a round number of simulations with no assessment of model convergence.

Enhancements to angioplasty for peripheral arterial occlusive disease: systematic review, cost-effectiveness assessment and expected value of information analysis.

BACKGROUND: There have been rapid technological developments aimed at improving short- and long-term results of percutaneous transluminal balloon angioplasty (PTA) in peripheral arterial occlusive disease (PAD). OBJECTIVES: To assess current clinical effectiveness and cost-effectiveness evidence of additional techniques to standard PTA for PAD, develop a health economic model to assess cost-effectiveness and to identify where further research is needed. DATA SOURCES: Relevant electronic databases, including MEDLINE, EMBASE and The Cochrane Library were searched from inception to 2011, between May and October 2011. METHODS: Systematic reviews were conducted of clinical effectiveness and cost-effectiveness. The population was participants with symptomatic PAD undergoing endovascular treatment for disease distal to the inguinal ligament. Interventions were modifications of and adjuncts to PTA in the peripheral circulation, compared with conventional PTA. Outcomes included measures of clinical effectiveness and costs. Data were extracted from randomised controlled trials (RCTs), which were quality assessed using standard criteria. Where appropriate, meta-analyses using fixed- and random-effects methods produced relative risks (RRs). A discrete-event simulation model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The patient populations of intermittent claudication (IC) and critical limb ischaemia (CLI) were modelled separately. Univariate and probabilistic sensitivity analyses were undertaken. RESULTS: In total, 40 RCTs were included, many of which had small sample sizes. Significantly reduced restenosis rates were shown in meta-analyses of self-expanding stents (SES) {RR 0.67 [95% confidence interval (CI) 0.52 to 0.87]}, endovascular brachytherapy (EVBT) [RR 0.63 (95% CI 0.48 to 0.83)] at 12 months and drug-coated balloons (DCBs) at 6 months [RR 0.40 (95% CI 0.23 to 0.69)], and single studies of stent-graft or drug-eluting stent (DES), compared with PTA; a single study showed improvements with DES versus bare-metal stents (BMSs). Compared with PTA, walking capacity was not significantly affected by cutting balloon, balloon-expandable stents or EVBT; in SES, there was evidence of improvement in walking capacity after up to 12 months. The use of DCBs dominated both the assumed standard practice of PTA with bailout BMS and all other interventions because it lowered lifetime costs and improved quality of life (QoL). These results were seen for both patient populations (IC and CLI). Sensitivity analyses showed that the results were robust to different assumptions about the clinical benefits attributable to the interventions, suggesting that the use of DCBs is cost-saving. LIMITATIONS: Differing definitions of restenosis made direct comparison across trials difficult. There were few data available for walking capacity and QoL. CONCLUSIONS: The evidence showed a significant benefit to reducing restenosis rates for self-expanding and DESs, stent-graft, EVBT and DCBs. If it is assumed that patency translates into beneficial long-term clinical outcomes, then DCB and bail-out DES are most likely to be the cost-effective enhancements to PTA. A RCT comparing current recommended practice (PTA with bail-out BMS) with DCB and bail-out DES could assess long-term follow-up and cost-effectiveness. Data relating patency status to the need for reintervention and to the probability of symptoms returning should be collected, as should health-related QoL measures [European Quality of Life-5 Dimensions (EQ-5D) and maximum walking distance]. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002014. FUNDING: The National Institute for Health Research Health Technology Assessment programme.