The Cost of Costing Treatments Incorrectly: Errors in the Application of Drug Prices in Economic Evaluation Due to Failing to Account for the Distribution of Patient Weight

AbstractBackgroundThe cost of pharmaceuticals dosed by weight or body surface area (BSA) can be estimated in several ways for economic evaluations. A review of 20 recent National Institute for Health and Care Excellence appraisals showed that 17 of them took the mean weight or BSA of patients, 2 costed the individual patient data from trials, and 2 fitted a distribution to patient-level data.ObjectivesTo investigate the estimated drug costs using different methodologies to account for patient characteristics for pharmaceuticals with a weight- or BSA-based posology. The secondary objective was to explore the suitability of general population data as a proxy for patient-level data.MethodsPatient-level data were pooled from three clinical trials and used to calculate a hypothetical cost per administration of eight licensed pharmaceuticals, applying the three methods used in recent National Institute for Health and Care Excellence appraisals. The same analysis was performed using data from the Health Survey for England (in place of patient-level data) to investigate the validity of using general population data as a substitute for patient-level data.ResultsCompared with using patient-level data from clinical trials, the mean patient characteristics (weight or BSA) led to an underestimation of drug cost by 6.1% (range +1.5% to −25.5%). Fitting a distribution to patient-level data led to a mean difference of +0.04%. All estimates were consistent using general population data.ConclusionsEstimation of drug costs in health economic evaluation should account for the distribution in weight or BSA to produce accurate results. When patient data are not available, general population data may be used as an alternative

What is the impact of the analysis method used for health state utility values on QALYs in oncology? A simulation study comparing progression-based and time-to-death approaches

Background Health state utility values (‘utilities’) are an integral part of health technology assessment. Though traditionally categorised by disease status in oncology (i.e. progression), several recent assessments have adopted values calculated according to the time that measures were recorded before death. We conducted a simulation study to understand the limitations of each approach, with a focus on mismatches between the way utilities are generated, and analysed. Methods Survival times were simulated based on published literature, with permutations of three utility generation mechanisms (UGMs) and utility analysis methods (UAMs): (1) progression based, (2) time-to-death based, and (3) a ‘combination approach’. For each analysis quality-adjusted life-years (QALYs) were estimated. Goodness of fit was assessed via percentage mean error (%ME) and mean absolute error (%MAE). Scenario analyses were performed varying individual parameters, with complex scenarios mimicking published studies. The statistical code is provided for transparency and to aid future work in the area. Results %ME and %MAE were lowest when the correct analysis form was specified (i.e. UGM and UAM aligned). Underestimates were produced when a time-to-death element was present in the UGM but not included in the UAM, while the ‘combined’ UAM produced overestimates irrespective of the UGM. Scenario analysis demonstrated the importance of the volume of available data beyond the initial time period, for example follow-up. Conclusions We show that the use of an incorrectly or over-specified UAM can result in substantial bias in the estimation of utilities. We present a flowchart to highlight the issues that may be faced. Key Points for Decision Makers A mismatch between the data structure and analysis method results in biased and inaccurate estimates of utility values. Unexpectedly, analysing utilities as a combination of progression- and TTD-based values performed poorly, even if utilities were generated within a corresponding framework. Over-specification of analyses should therefore be avoided. The volume of data available has a marked impact on the accuracy of estimates; this especially means the duration of follow-up and number of long-term survivors

Cost-effectiveness of trifluridine/tipiracil for previously treated metastatic colorectal cancer in England and Wales

Background Treatment options at third-line and beyond for patients with late-line metastatic colorectal cancer (mCRC) are limited, and outcomes are poor with best supportive care (BSC). This study investigated the cost-effectiveness of trifluridine/tipiracil and regorafenib relative to BSC alone in patients with mCRC who have been previously treated with, or are not considered candidates for, standard chemotherapies. Materials and Methods A partitioned survival model was constructed to assess the lifetime costs and benefits accrued by patients. Clinical data were derived from the pivotal phase III (Randomized, Double-Blind, Phase 3 Study of TAS-102 plus Best Supportive Care [BSC] versus Placebo plus BSC in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapies [RECOURSE]) and supporting phase II (J003-10040030) randomized controlled trial of trifluridine/tipiracil + BSC versus placebo + BSC, as well as the phase III Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy (CORRECT) randomized controlled trial of regorafenib, and were extrapolated to estimate lifetime outcomes. Costs were taken from published sources, and health effects sourced from previous mCRC studies. Results Trifluridine/tipiracil was associated with a 0.27 incremental life year versus BSC alone, which corresponds to a 0.17 quality-adjusted life year gain. The incremental cost of treatment with trifluridine/tipiracil was £8,479, resulting in an incremental cost-effectiveness ratio of £51,194 per quality-adjusted life year gained. Trifluridine/tipiracil was shown to dominate regorafenib (improve outcomes with reduced costs). Sensitivity analyses showed principal areas of uncertainty were survival estimates and patient utility. Conclusions The results show that trifluridine/tipiracil is more clinically and cost-effective than regorafenib, with clinical outcomes greatly exceeding those for patients treated with BSC alone. Based on the results of the analysis, trifluridine/tipiracil offers an important new treatment option for patients with mCRC maintaining good performance status at the end of life

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

Cost-effectiveness analysis of recombinant factor VIII Fc-fusion protein (rFVIIIFc) for the treatment of severe hemophilia A in Italy incorporating real-world dosing and joint health data

Background Patients with severe hemophilia A (SHA) in Italy are routinely treated with standard half-life recombinant factor VIII (rFVIII) products. rFVIII Fc-fusion protein (rFVIIIFc) is an extended half-life rFVIII product that enables less frequent administration than rFVIII, which may support improved adherence. Available data indicate low breakthrough bleed rates and potentially improved long-term joint health for patients treated with rFVIIIFc prophylaxis. Objective This study assessed the cost effectiveness of rFVIIIFc versus rFVIII from an Italian healthcare perspective. Methods A Semi-Markov model was constructed to assess the lifetime costs and benefits of rFVIII and rFVIIIFc prophylaxis. rFVIII product acquisition costs from a published Italian database were included for both prophylaxis and the resolution of breakthrough bleeding. Clinical outcomes within the model were determined based on published annualized bleeding rates and literature regarding the development of target joints (TJs) as the incidence of bleeds and TJs is associated with impaired health-related quality of life. Cost effectiveness was assessed using cost per quality-adjusted life-year (QALY) gained. Results Compared with rFVIII, rFVIIIFc was associated with a per-patient cost saving of approximately €1.3 million and QALY gains of 0.39 over a lifetime horizon. Sensitivity analyses considering alternative efficacy, dosing, and structural assumptions each showed that rFVIIIFc dominated rFVIII (i.e., provided more QALYs at a reduced cost). Conclusions This cost-effectiveness analysis demonstrated that rFVIIIFc may offer a cost-effective treatment option for patients with SHA in Italy

NICE, in confidence : an assessment of redaction to obscure confidential information in single technology appraisals by the National Institute for Health and Care Excellence

Introduction Health technology assessment (HTA) aims to provide a transparent framework within which normative judgements can be applied for decision making. Such transparency enables the public to understand the rationale for decision making, but conflicts with companies being able to offer commercially sensitive discounts. We investigated how to balance these conflicting ideals. Methods National Institute for Health and Care Excellence (NICE) submissions were reviewed for products with an approved, simple Patient Access Scheme (PAS) discount. The approach to censoring was noted (e.g. total cost and clinical outcomes redacted). Submissions were then assessed for transparency (i.e. whether the decision appeared justifiable given the available information) and confidentiality (i.e. whether the PAS discount could be ‘back calculated’). Results One hundred and eighteen products have an approved commercial arrangement, of which 110 have simple PAS discounts considered within the NICE Single Technology Appraisal programme. A definitive incremental cost-effectiveness ratio was presented within final NICE guidance in only 20 appraisals. Documentation for seven appraisals allowed for the straightforward ‘back calculation’ of PAS discounts. Furthermore, a large amount of information was censored as academic-in-confidence and remains so many years later. Conclusion Appropriate redaction ensures discounts remain confidential, yet maintains the transparency of the HTA decisions made. Complete redaction does not allow for transparent, justifiable decision making. However, redacting ‘enough’ information to preclude direct estimation of discounts provides a means of maintaining both transparency and confidentiality. This study demonstrates a lack of consensus regarding presentation of results, and the importance of appropriate redaction