Design and analysis issues for economic analysis alongside clinical trials.

INTRODUCTION: Clinical trials can offer a valuable and efficient opportunity to collect the health resource use and outcomes data for economic evaluation. However, economic and clinical studies differ fundamentally in the question they seek to answer. OBJECTIVE: The design and analysis of trial-based cost-effectiveness studies require special consideration, which are reviewed in this article. SUMMARY: Traditional randomized controlled trials, using an experimental design with a controlled protocol, are designed to measure safety and efficacy for product registration. Cost-effectiveness analysis seeks to measure effectiveness in the context of routine clinical practice, and requires collection of health care resources to allow estimation of cost over an equal timeframe for each treatment alternative. In assessing suitability of a trial for economic data collection, the comparator treatment and other protocol factors need to reflect current clinical practice and the trial follow-up must be sufficiently long to capture important costs and effects. The broadest available population and a measure of effectiveness reflecting important benefits for patients are preferred for economic analyses. Special analytical issues include dealing with missing and censored cost data, assessing uncertainty of the incremental cost-effectiveness ratio, and accounting for the underlying heterogeneity in patient subgroups. Careful consideration also needs to be given to data from multinational studies since practice patterns can differ across countries. CONCLUSION: Although clinical trials can be an efficient opportunity to collect data for economic evaluation, careful consideration of the suitability of the study design, and appropriate analytical methods must be applied to obtain rigorous results.

Resource utilization and cost of influenza requiring hospitalization in Canadian adults: A study from the serious outcomes surveillance network of the Canadian Immunization Research Network.

BACKGROUND: Consideration of cost determinants is crucial to inform delivery of public vaccination programs. OBJECTIVES: To estimate the average total cost of laboratory-confirmed influenza requiring hospitalization in Canadians prior to, during, and 30 days following discharge. To analyze effects of patient/disease characteristics, treatment, and regional differences in costs. METHODS: Study utilized previously recorded clinical characteristics, resource use, and outcomes of laboratory-confirmed influenza patients admitted to hospitals in the Serious Outcomes Surveillance (SOS), Canadian Immunization Research Network (CIRN), from 2010/11 to 2012/13. Unit costs including hospital overheads were linked to inpatient/outpatient resource utilization before and after admissions. RESULTS: Dataset included 2943 adult admissions to 17 SOS Network hospitals and 24 Toronto Invasive Bacterial Disease Network hospitals. Mean age was 69.5 years. Average hospital stay was 10.8 days (95% CI: 10.3, 11.3), general ward stays were 9.4 days (95% CI: 9.0, 9.8), and ICU stays were 9.8 days (95% CI: 8.6, 11.1) for the 14% of patients admitted to the ICU. Average cost per case was $14 612 CAD (95% CI: $13 852, $15 372) including $133 (95% CI: $116, $150) for medical care prior to admission, $14 031 (95% CI: $13 295, $14 768) during initial hospital stay, $447 (95% CI: $271, $624) post-discharge, including readmission within 30 days. CONCLUSION: The cost of laboratory-confirmed influenza was higher than previous estimates, driven mostly by length of stay and analyzing only laboratory-confirmed influenza cases. The true per-patient cost of influenza-related hospitalization has been underestimated, and prevention programs should be evaluated in this context.

Cost-effectiveness of a fixed combination of hydroquinone/tretinoin/fluocinolone cream compared with hydroquinone alone in the treatment of melasma.

BACKGROUND: A once-daily fixed combination of hydroquinone, tretinoin, and fluocinolone acetonide (Tri-luma) is a newly available treatment for melasma. OBJECTIVE: To assess cost-effectiveness of triple combination therapy (TCT) applied once daily and hydroquinone alone applied twice daily in the U.S., Argentina, Brazil, Chile, and Colombia from a payer's perspective. METHODS: Clinical data and utilization of key health resources (medication only) were assessed within an 8-week clinical trial conducted in Brazil. Total cost per primary success (complete clearing) was used to compare each treatment with not treating and incremental cost effectiveness ratios were used to compare between treatments. RESULTS AND CONCLUSION: TCT had a 30% better rate of complete clearing than hydroquinone with a lower cost in the U.S. and an incremental cost in other countries. In every country, cost per primary success was lower for TCT than for hydroquinone. Results were robust to varying assumptions of success rates and quantity used.

A Cost-effectiveness Analysis of Brentuximab Vedotin in Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Objective: To evaluate the cost-effectiveness of brentuximab vedotin in patients with R/R sALCL from a UK NHS perspective. Methods: A partitioned survival model used clinical outcomes for brentuximab vedotin from the pivotal phase-2 single-arm trial of brentuximab vedotin in 58 patients with R/R sALCL (SG035-0004; NCT00866047), over a lifetime (30-year) time horizon. Comparison with conventional chemotherapy was based on data from the Canadian British Columbia Cancer Agency registry from 40 patients starting salvage chemotherapy after front-line treatment between 1980 and 2012. Survival was extrapolated using parametric distributions, with brentuximab vedotin risk after the trial period assumed equal to conventional chemotherapy. Other modelling assumptions were based on a systematic literature review and clinical expert opinion. Results: Based on statistical extrapolation, brentuximab vedotin was associated with 3.1 years longer duration in the progression-free survival health state and an overall survival improvement of 5.4 years, prior to discounting. In addition, brentuximab vedotin was associated with 2.5 quality-adjusted life years (QALYs) gained at a total incremental cost of £88 556, resulting in an incremental cost-effectiveness ratio (ICER) of approximately £35 400. Sensitivity analyses of alternative model assumptions provided ICERs ranging from approximately £28 100 to £61 900. Comparing only first-line salvage patients reduced the ICER to £26 800 per QALY gained. Conversely, considering only patients with Eastern Corporative Oncology Group performance status of 0 or 1 increased the ICER to approximately £38 200. At a willingness-to-pay threshold of £50 000, the estimated probability that brentuximab vedotin is cost-effective compared with conventional chemotherapy was 86.5%. Conclusion: Compared to conventional chemotherapy, and considering the full survival period, brentuximab vedotin may provide a valuable treatment choice for patients with R/R sALCL, a population with limited therapeutic options.

An economic evaluation of sequential i.v./po moxifloxacin therapy compared to i.v./po co-amoxiclav with or without clarithromycin in the treatment of community-acquired pneumonia.

STUDY OBJECTIVE: To evaluate costs, clinical consequences, and cost-effectiveness from a German and French health-care system perspective of sequential i.v./po moxifloxacin monotherapy compared to co-amoxiclav with or without clarithromycin (AMC +/- CLA) in patients with community-acquired pneumonia (CAP) who required parenteral treatment. METHODS: Costs and consequences over 21 days were evaluated based on clinical cure rates 5 to 7 days after treatment and health resource use reported for the TARGET multinational, prospective, randomized, open-label trial. This trial compared sequential i.v./po monotherapy with moxifloxacin (400 mg qd) to i.v./po co-amoxiclav (1.2 g i.v./625 mg po tid) with or without clarithromycin (500 mg bid) for 7 to 14 days in hospitalized patients with CAP. Since no country-by-treatment interaction was found in spite of some country differences for length of hospital stays, resource data (antimicrobial treatment, hospitalization, and out-of-hospital care) from all centers were pooled and valued using German and French unit prices to estimate CAP-related cost to the German Sickness Funds and French public health-care sector, respectively. RESULTS: Compared to AMC +/- CLA, treatment with moxifloxacin resulted in 5.3% more patients achieving clinical cure 5 to 7 days after therapy (95% confidence interval [CI], 1.2 to 11.8%), increased speed of response (1 day sooner for median time to first return to apyrexia, p = 0.008), and a reduction in hospital stay by 0.81 days (95% CI, - 0.01 to 1.63) within the 21-day time frame. Treatment with moxifloxacin resulted in savings of 266 euro and 381 euro for Germany and France respectively, primarily due to the shorter length of hospital stay. Cost-effectiveness acceptability curves show moxifloxacin has a > or = 95% chance of being cost saving from French and German health-care perspectives, and higher probability of being cost-effective at acceptability thresholds up to 2,000 euro per additional patient cured. CONCLUSION: i.v./po monotherapy with moxifloxacin shows clinical benefits including increased speed of response and is cost-effective compared to i.v./po AMC +/- CLA in the treatment of CAP.

An economic evaluation of doxazosin, finasteride and combination therapy in the treatment of benign prostatic hyperplasia.

OBJECTIVE: The Proscar Long-Term Efficacy and Safety Study (PLESS) and the Medical Therapy of Prostatic Symptoms (MTOPS) study provide new evidence regarding the benefits of finasteride in the treatment of benign prostatic hyperplasia (BPH). The objective of this study was to utilize data from the PLESS and MTOPS studies to assess the cost-utility of finasteride and finasteride in combination with doxazosin, compared to doxazosin alone in men with moderate to severe BPH symptoms. METHODS: A semi-Markov decision analytic model was constructed to estimate the clinical consequences, costs and cost-utility of doxazosin, finasteride, and combination therapy. Analyses were conducted for a 15-year time frame from the perspective of the Ontario Ministry of Health and Long Term Care (MOHLTC). Results are reported stratified by baseline serum prostate-specific antigen (PSA) level according to all baseline serum PSA levels, patients with baseline serum PSA > 1.3 ng/ml, and patients with baseline serum PSA > 3.2 ng/ml. RESULTS: Compared to doxazosin alone, combination therapy was more expensive but more effective. Cost-utility ratios ranged from 27,823 dollars/QALY for patients with PSA > 3.2 ng/ml to 34,085 dollars/QALY for all patients. Finasteride, although dominated by doxazosin, may be cost-effective compared to watchful waiting in patients who fail doxazosin and do not choose to proceed to surgery. Compared to watchful waiting, cost-utility ratios for finasteride ranged from 35016 dollars/QALY for patients with PSA > 3.2 ng/ml to 44,336 dollars/QALY for all patients. Results were robust across a wide range of sensitivity analyses. CONCLUSIONS: Combination therapy is cost-effective compared to doxazosin with cost-utility ratios under 40,000 dollars/QALY across a wide range of scenarios. The cost-effectiveness of combination therapy increases as serum PSA level increases.

Cost-effectiveness of becaplermin for nonhealing neuropathic diabetic foot ulcers.

Foot ulcers secondary to peripheral neuropathy and vascular disease are a commonly occurring complication for people with diabetes. Becaplermin, a genetically-engineered growth factor in a hydrogel vehicle, has been shown to be more effective than vehicle-only control in healing chronic foot ulcers of patients with adequate vasculature receiving best clinical care. To evaluate the cost-effectiveness of adding up to 20 weeks of becaplermin to a regimen of best clinical care, a 1-year decision-analytic model was developed and tested using data from a previously published controlled clinical study involving 251 people with diabetes (124 becaplermin/127 control) and adequate vasculature presenting with an infection-free ulcer that had failed to heal despite appropriate therapy. A 20-week healing rate was estimated based on the clinical trial data assuming becaplermin treatment was terminated at 10 weeks in non-responding ulcers, and follow-up data were extended to 1 year. Resource utilization was estimated by an expert panel using a modified Delphi approach. Using the model, it was found that incorporating becaplermin with best clinical care resulted in 26 fewer ulcer-days per patient per year compared to best clinical care alone with an incremental cost-effectiveness ratio of $6 per ulcer-day averted. Results were sensitive to becaplermin cost, efficacy, and effect on infection and recurrence rates. The clinical benefits of becaplermin deserve further investigation to enhance cost-effectiveness information for informed treatment decisions.

Cost-effectiveness of memantine compared with standard care in moderate-to-severe Alzheimer disease in Canada.

OBJECTIVE: To conduct a cost-effectiveness analysis comparing the addition of memantine to standard care (that is, without acetylcholinesterase inhibitors) with standard care alone in moderate-to-severe Alzheimer disease (AD) in Canada. METHODS: A 2-year Markov model estimated clinical effects in terms of quality-adjusted life years (QALYs) and time in complete dependence as well as societal costs in four 6-month cycles. Health states were defined by AD severity assessed with the Mini-Mental State Examination (moderate = 10 to 19; severe < 10), by level of dependence in activities of daily living, and by death. Transition probabilities were estimated by combining data of patients with moderate-to-severe AD from all relevant clinical trials. QALYs were estimated from a UK epidemiologic study. The initial distribution and use of medical and support services for each health state was obtained from the Canadian Study on Health and Aging with current estimates of frequency of use and unit prices applied. RESULTS: Compared with standard care, the memantine strategy saved more than 1 month of complete dependence and produced 0.03 additional QALYs, with no additional cost. Probabilistic sensitivity analyses give an 83.3% chance that memantine treatment is cost-neutral, an 89.5% chance of its being cost-effective if the decision maker is willing to pay $20 000 for a QALY, and a 96.2% chance with a willingness to pay $100 000 per QALY. Robustness of results was confirmed through 1-way and scenario-based sensitivity analyses. CONCLUSIONS: Our evaluation found that memantine monotherapy produced relevant health benefit, compared with standard care alone, with no additional costs. Results are consistent with other economic evaluations of memantine conducted in Europe and the United States.

Health care resource use and stroke outcome. Multinational comparisons within the GAIN International trial.

BACKGROUND AND PURPOSE: Outcome in patients hospitalized for acute stroke varies considerably between populations. Within the framework of the GAIN International trial, a large multicenter trial of a neuroprotective agent (gavestinel, glycine antagonist), stroke outcome in relation to health care resource use has been compared in a large number of countries, allowing for differences in case mix. METHODS: This substudy includes 1,422 patients in 19 countries grouped into 10 regions. Data on prognostic variables on admission to hospital, resource use, and outcome were analyzed by regression models. RESULTS: All results were adjusted for differences in prognostic factors on admission (NIH Stroke Scale, age, comorbidity). There were threefold variations in the average number of days in hospital/institutional care (from 20 to 60 days). The proportion of patients who met with professional rehabilitation staff also varied greatly. Three-month case fatality ranged from 11% to 28%, and mean Barthel ADL score at three months varied between 64 and 73. There was no relationship between health care resource use and outcome in terms of survival and ADL function at three months. The proportion of patients living at home at three months did not show any relationship to ADL function across countries. CONCLUSIONS: There are wide variations in health care resource use between countries, unexplained by differences in case mix. Across countries, there is no obvious relationship between resource use and clinical outcome after stroke. Differences in health care traditions (treatment pathways) and social context seem to be major determinants of resource use. In making comparisons between countries, great care should be exercised in using outcome variables as indicators of quality of stroke care.

The burden of illness of severe nausea and vomiting of pregnancy in the United States.

OBJECTIVE: Our purpose was to determine the extent to which nausea and vomiting of pregnancy affects a woman's quality of life (QOL), ability to function, and health care resource use. STUDY DESIGN: We conducted an observational, multicenter, prospective cohort study by gathering data on the symptoms, QOL, and health care resource use from women who have nausea and vomiting of pregnancy. RESULTS: All 8 domains of health measured by the Short Form-36 QOL survey were limited by patient symptoms. This limitation manifested itself as patient-time loss from work and other normal activities, unpaid caregiver-time loss from work, and use of health care resources (eg, hospitalization). All types of time loss were correlated to severity of symptoms. CONCLUSIONS: Nausea and vomiting of pregnancy can severely reduce a woman's QOL and ability to function. The degree of limitation is associated with the severity of symptoms.