Anthony J. Hatswell

Patient-reported utilities in advanced or metastatic melanoma, including analysis of utilities by time to death

BackgroundHealth-related quality of life is often collected in clinical studies, and forms a cornerstone of economic evaluation. This study had two objectives, firstly to report and compare pre- and post-progression health state utilities in advanced melanoma when valued by different methods and secondly to explore the validity of progression-based health state utility modelling compared to modelling based upon time to death.MethodsUtilities were generated from the ipilimumab MDX010-20 trial (Clinicaltrials.gov Identifier: NCT00094653) using the condition-specific EORTC QLQ-C30 (via the EORTC-8D) and generic SF-36v2 (via the SF-6D) preference-based measures. Analyses by progression status and time to death were conducted on the patient-level data from the MDX010-20 trial using generalised estimating equations fitted in Stata®, and the predictive abilities of the two approaches compared.ResultsMean utility showed a decrease on disease progression in both the EORTC-8D (0.813 to 0.776) and the SF-6D (0.648 to 0.626). Whilst higher utilities were obtained using the EORTC-8D, the relative decrease in utility on progression was similar between measures. When analysed by time to death, both EORTC-8D and SF-6D showed a large decrease in utility in the 180 days prior to death (from 0.831 to 0.653 and from 0.667 to 0.544, respectively). Compared to progression status alone, the use of time to death gave similar or better estimates of the original data when used to predict patient utility in the MDX010-20 study. Including both progression status and time to death further improved model fit. Utilities seen in MDX010-20 were also broadly comparable with those seen in the literature.ConclusionsPatient-level utility data should be analysed prior to constructing economic models, as analysis solely by progression status may not capture all predictive factors of patient utility and time to death may, as death approaches, be as or more important. Additionally this study adds to the body of evidence showing that different scales lead to different health state values. Further research is needed on how different utility instruments (the SF-6D, EORTC-8D and EQ-5D) relate to each other in different disease areas.

Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999–2014

Introduction The efficacy of pharmaceuticals is most often demonstrated by randomised controlled trials (RCTs); however, in some cases, regulatory applications lack RCT evidence. Objective To investigate the number and type of these approvals over the past 15 years by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Methods Drug approval data were downloaded from the EMA website and the ‘Drugs@FDA’ database for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014. The details of eligible applications were extracted, including the therapeutic area, type of approval and review period. Results Over the period of the study, 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), demonstrating that a substantial number of treatments reach the market without undergoing an RCT. The majority was for haematological malignancies (34), with the next most common areas being oncology (15) and metabolic conditions (15). Of the applications made to both agencies with a comparable data package, the FDA granted more approvals (43/44 vs 35/44) and took less time to review products (8.7 vs 15.5 months). Products reached the market first in the USA in 30 of 34 cases (mean 13.1 months) due to companies making FDA submission before EMA submissions and faster FDA review time. Discussion Despite the frequency with which approvals are granted without RCT results, there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate. We recommend a more open debate on the role of marketing authorisations granted without RCT results, and the development of guidelines on what constitutes an acceptable data package for regulators.

Carbetocin versus oxytocin for prevention of post-partum haemorrhage at caesarean section in the United Kingdom: An economic impact analysis.

OBJECTIVE To determine the economic impact of the introduction of carbetocin for the prevention of postpartum haemorrhage (PPH) at caesarean section, compared to oxytocin. STUDY DESIGN The model is a decision tree conducted from a UK National Health Service perspective. 1500 caesarean sections (both elective and emergency) were modelled over a 12 month period. Efficacy data was taken from a published Cochrane meta-analysis, and costs from NHS Reference costs, the British National Formulary and the NHS electronic Medicines Information Tool. A combination of hospital audit data and expert input from an advisory board of clinicians was used to inform resource use estimates. The main outcome measures were the incidence of PPH and total cost over a one year time horizon, as a result of using carbetocin compared to oxytocin for prevention of PPH at caesarean section. RESULTS The use of carbetocin compared to oxytocin for prevention of PPH at caesarean section was associated with a reduction of 30 (88 vs 58) PPH events (>500ml blood loss), and a cost saving of £27,518. In probabilistic sensitivity analysis, carbetocin had a 91.5% probability of producing better outcomes, and a 69.4% chance of being dominant (both cheaper and more effective) compared to oxytocin. CONCLUSION At list price, the introduction of carbetocin appears to provide improved clinical outcomes along with cost savings, though this is subject to uncertainty regarding the underlying data in efficacy, resource use, and cost.

Mapping EORTC-QLQ-C30 to EQ-5D-3L in patients with colorectal cancer

Abstract Aims: The primary aim of this study was to perform a mapping of the EORTC-QLQ-C30 scores to EQ-5D-3L for the SIRFLOX study; a large dataset of patients with previously untreated liver-only or liver-dominant metastatic colorectal cancer (mCRC). A secondary aim was to compare the predictive validity of existing mappings from EORTC-QLQ-C30 to EQ-5D-3L conducted in other cancers. Methods and materials: Questionnaires (completed within 529 patients) were used in a linear mixed regression to model EQ-5D-3L utility values (scored using the UK tariff) as a function of the five function scores, nine symptom scores, and the global score from the EORTC-QLQ-C30 questionnaire. A Tobit regression was also performed. The mean EQ-5D-3L values for the SIRFLOX trial were calculated and compared with predicted EQ-5D-3L values derived using published mapping algorithms. Results: The linear mixed regression model provided a satisfactory mapping between the EORTC-QLQ-C30 and the EQ-5D-3L, whilst the Tobit model did not perform as well. When utilities from the SIRFLOX data were calculated with previously published mapping studies, three out of five studies performed well (< 10% mean difference). Limitations: The main limitation of the study was the lack of meaningful observations post-progression (67 paired observations). For this reason, this study was unable to test whether the mapping holds by disease stage. Additionally, although the study adds to the literature of mappings to the EQ-5D-3L, it is not known how results would differ using the EQ-5D-5L. Conclusion: This study is the first of its kind in liver-only or liver-dominant mCRC, and mCRC in general. The mapping constructed showed a good fit to the data and provides practitioners with an additional mapping between EORTC-QLQ-C30 to EQ-5D-3L using a large dataset (529 patients, 707 paired observations). The study also confirmed the generalizability of mappings published by Proskorovsky, Kontodimopoulos, and Longworth to liver-only or liver-dominant mCRC.

The Predicted Impact of Ipilimumab Usage on Survival in Previously Treated Advanced or Metastatic Melanoma in the UK

Background Evaluating long-term prognosis is important for physicians, patients and payers. This study reports the results of a model developed to predict long-term survival for UK patients receiving second-line ipilimumab. Methods MDX010-20 trial data were used to predict survival for ipilimumab versus UK best supportive care. Two aspects of this analysis required novel approaches: 1) The overall survival Kaplan–Meier data shape is unusual: an initial steep decline is observed before a ‘plateau’. 2) The need to extrapolate beyond the trial end (4.6 years). Based upon UK clinician advice, a three-part curve fit was used: from 0–1.5 years, Kaplan–Meier data from the trial; from 1.5–5 years, standard parametric curve fits; after 5 years, long-term data from the American Joint Committee on Cancer registry. Results This approach provided good internal validity: low mean absolute error and good match to median and mean trial data. Lifetime predicted means were 2.77 years for ipilimumab and 1.07 for best supportive care, driven by increased long-term survival with ipilimumab. Conclusion To understand the full benefit of treatment and to meet reimbursement requirements, accurate estimation of treatment benefit is key. Models, such as the one presented, can be used to extrapolate beyond trials.

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. Micro‐Abstract: A cost‐effectiveness model predicting the outcomes of treatment with trifluridine/tipiracil based on the results of the randomised controlled trials conducted for regulatory agencies. The results demonstrate improved outcomes compared to standard care and improved outcomes and lower cost (dominance) compared to regorafenib.

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

BACKGROUND The 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. OBJECTIVES To 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. METHODS Patient-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. RESULTS Compared 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. CONCLUSIONS Estimation 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.

Sharing is Caring: The Case for Company-Level Collaboration in Pharmacoeconomic Modelling.

In the recent NICE appraisals for rheumatoid arthritis the six companies involved each independently conducted systematic reviews, economic modelling and network meta-analyses [1]. Each will have incurred substantial agency fees and internal time to manage the projects. Given the models were also based on a very similar structure, each needed to solve very similar problems (independently) from the perspective of disease progression. This is a typical situation, with examples ranging from psoriasis, chronic obstructive pulmonary disease, and multiple myeloma with multiple companies creating almost identical models. In contrast, only a few examples exist of standardised models available to use by all (under varying frameworks [2,3]) diabetes is the only example that readily springs to mind [4].

Economic Evaluations of Pharmaceuticals Granted a Marketing Authorisation Without the Results of Randomised Trials: A Systematic Review and Taxonomy

BackgroundPharmaceuticals are usually granted a marketing authorisation on the basis of randomised controlled trials (RCTs). Occasionally the efficacy of a treatment is assessed without a randomised comparator group (either active or placebo).ObjectiveTo identify and develop a taxonomic account of economic modelling approaches for pharmaceuticals licensed without RCT data.MethodsWe searched PubMed, the websites of UK health technology assessment bodies and the International Society for Pharmacoeconomics and Outcomes Research Scientific Presentations Database for assessments of treatments granted a marketing authorisation by the US Food and Drug Administration or European Medicines Agency from January 1999 to May 2014 without RCT data (74 indications). The outcome of interest was the approach to modelling efficacy data.ResultsFifty-one unique models were identified in 29 peer-reviewed articles, 30 health technology appraisals, and 15 International Society for Pharmacoeconomics and Outcomes Research abstracts concerning 30 indications (44 indications had not been modelled). We noted the high rate of non-submission to health technology assessment agencies (28/98). The majority of models (43/51) were based on ‘historical controls’—comparisons to previous meta-analysis or pooling of trials (5), individual trials (16), registries/case series (15), or expert opinion (7). Other approaches used the patient as their own control, performed threshold analysis, assumed time on treatment was added to overall survival, or performed cost-minimisation analysis.ConclusionsThere is considerable variation in the quality and approach of models constructed for drugs granted a marketing authorisation without a RCT. The most common approach is of a naive comparison to historical data (using other trials/registry data as a control group), which has considerable scope for bias.

Cost-Effectiveness Analysis of Ipilimumab in Previously Untreated Patients With Unresectable Malignant Melanoma in Scotland

• The survival outcomes for first-line ipilimumab were modelled, in the SMC base case model, using data from the Phase III RCT CA184-024, due to local requirements of the SMC. However, as the CA184-024 trial contained an unlicensed 10mg/kg dose of ipilimumab and the combination with DTIC (licensed dose is 3mg/kg), multiple sources were used to produce a range of reliable estimates of the incremental cost-effectiveness ratio (ICER) for ipilimumab: