Step by step guide to economicevaluation in cancer trialsWhat is CREST?The Centre for HealthEconomics Research andEvaluation (CHERE) at UTShas been contracted byCancer Australia toestablish a dedicatedCancer ResearchEconomics Support Team(CREST) to provide highquality, expert advice andsupport to Multi-siteCollaborative CancerClinical Trials Groups.FactsheetsCREST will produce aseries of factsheets asresources for cancercollaborative groupresearchers wishing toinclude economicevaluation in their clinicaltrials.Authors: Alison Pearceand Rosalie VineyPrepared: August 2011SUMMARYThis factsheet provides a guide to the steps in aneconomic evaluation in cancer trials. These include:1. Define the alternatives to be assessed in the trial2. Consider the perspective and timeframe. Thisincludes the timeframes for:a. Trialb. Follow upc. Beyond the trial3. Identify, measure and value the resource useassociated with each alternative4. Identify, measure and value the consequences ofeach alternative5. Combine the costs and consequences to producean Incremental Cost-Effectiveness Ratio (ICER)6. Assess the robustness of the results through asensitivity analysis7. Interpret the resultsAn example of a cost utility analysis of radiotherapy innon-small cell lung cancer will be used to illustrateeach of these steps.For more information about CREST, or for other factsheets in thisseries, please see our website:www.chere.uts.edu.au/crest
Step by step guide to economicevaluation in cancer trialsWhat are the steps in an economic evaluationin the context of cancer research?Economic evaluation is “thethe comparativeanalysis of alternative courses of action interms of both their costs and consequences”consequences(Drummond 2005, p9). Figure 1 below showsshothe typical representation of an economicevaluation.This example article describes a ‘societal costcostutility analysis of a Dutch multicenterrandomised trial. that compared the efficacyof radiotherapy schedules.in 297 patientswith inoperable non-smallsmall-cell lung cancer’.Step 1: Define alternativesFigure 1: Economic evaluation frameworkThere are seven main steps which are typicalto economic evaluations, including thoseconducted within or alongside cancer clinicaltrials. Each of these will be described in thisfactsheet.An example from the literature has beenselected to demonstrate each of these stepsin practice. The reference for this paper is:van den Hout WB, Kramer GWPM,Noordijk EM, and Leer JWH. 2006. Costutility analysis of short- versus long-courselongpalliative radiotherapy in patients withnon-small-cell lung cancer. Journal of theNational Cancer Institute, 98(24):1786-94.98(24):1786This article is available for download from theCREST website est)or is freely available online.Economic evaluation is always concerned withcomparing alternatives. It may be that one ofthe alternatives is a ‘do nothing’ or ‘standardpractice’ arm, however the costs andoutcomes of such alternatives must still bedefined, measured and valued.In defining the alternatives,alternatives you must considerwhat kind of economic evaluation will bemost appropriate. This decision should bebased on the nature of the research question,and the anticipatedicipated differences between thecosts and consequences of your alternatives.The three types of economic evaluation toconsider are cost effectiveness analysis, costutility analysis and cost benefit analysis.In a cost effectiveness analysis (CEA), thebenefits of the interventions are measured in“natural” units. For example, such measuresinclude cases detected, or life yearsyear saved. Ina CEA, the research question is directed atassessing how to maximise the achievementof a particular health outcome using availablehealth resources. Thus, the results of a CEAare reported as (for example) cost per casedetected or cost per life year gained.
Step by step guide to economicevaluation in cancer trialsIn a cost utility analysis (CUA), effectiveness ismeasured in preference based units. Thismeans that the natural units (eg lives saved orlife years gained) are combined with ameasure of the value that individuals place onthat outcome. The most common example ofa preference-based measure is the QualityAdjusted Life Year (QALY). In a CUA theresearch question is directed at assessing howto maximise health gain from availableresources. The results of a CUA are reportedas cost per QALY gained.Finally, in a cost benefit analysis (CBA), theeffectiveness of an intervention is measuredterms of its monetary value (ie in dollars).This allows the net benefit (ie the cost ofintervention minus the value of the benefit)to be calculated. In a CBA, the researchquestion is directed at assessing how tomaximise social welfare. Whilst this has somelogical appeal, the valuation of health careoutcomes in dollar terms is difficult, and CBAis not often used in health research.ExampleThe alternatives to be considered in theexample paper are long course versus shortcourse radiotherapy. The background sectionto the paper describes the differences that theauthors anticipate observing between longand short course treatment in terms ofsurvival gains (evidence was inconclusive priorto their study which found long course moreeffective) and costs (higher medical, patientand ongoing costs with long coursetreatment). The type of study selected was acost-utility analysis, as they used QALYs as an‘overall measure of the patients’ quantity andquality of life’, and compared this to the totalcosts to society.Step 2: Define perspective, timeframe andpopulationThe time period for an economic evaluationshould be considered in the context of thecosts and consequences of the interventionsunder investigation. A clinical trial is usuallydesigned to follow patients up until a specificoutcome of interest or endpoint has beenreached. While in some cases this may besufficient time for the relevant costsassociated with the intervention and its longterm outcomes to be observed, in some casesadditional follow up beyond the end of thetrial may be required.An alternative to extended follow up, whichcan be time consuming and expensive, is theuse of modelling. This approach involves theuse of trial data plus additional informationabout the longer term effects (usually sourcedfrom the literature) and local informationabout the ongoing and/or long term costs tobe used to model the costs and effectsbeyond the study follow up period.The perspective of a study is primarily relatedto the intended audience for the results. Inselecting a perspective, you are in effectselecting the range of costs and consequencesto be included in the economic evaluation. Asocietal perspective will include all costs andconsequences which are borne by societyrelated to that intervention. This is the goldstandard for economic evaluations, but can becomplex to implement. In Australia, thePharmaceutical Benefits Advisory Committee
Step by step guide to economicevaluation in cancer trials(PBAC) define a societal perspective to includea broad definition of health care resources,including those paid for by patients,governments, health insurance agencies andany other part of society are included.However indirect costs such as productivitylosses for patients and carers are usually notincluded. While this is not a true societalperspective, it is one which is more practicalthan considering all potential costs. Morecommonly, a hospital or health serviceperspective is taken, as this is often the mostrelevant to the decision makers who will beutilising the results of the economicevaluation.Similarly, defining a target population is alsoimportant for perspective, because factorssuch as age, comorbidities, risk factors,location and socioeconomics can influenceboth the resource use and consequences ofinterventions.ExampleThe example paper followed patients for oneyear after randomisation. Given the relativelyshort survival time of patients receivingpalliative care for non-small-cell lung cancer,this would appear to be an appropriatetimeframe for both costs and consequences.The perspective taken in the example paper isan example of the societal perspective asdefined by PBAC, including “medical costs ofradiotherapy as well as other health care costsand costs incurred by the patients during theirremaining lifetime”.Step 3: Identify, measure and value resourceuseFirst, the resources required for each arm ofthe trial need to be identified. Things toconsider include who is required to do whatto patients, when each activity occurs andhow often, and how these activities may bedifferent to standard clinical practice.The next consideration is what reliablesources of information can be accessed tomeasure the resource use. Options includecollecting data directly from patients orproviders during the trial (patient diaries forexample), identifying similar work donepreviously which can be adapted to yourstudy (through a literature review), or usingadministrative data applied to your sample(for example, local admission rates forchemotherapy).Finally, the value of each resource used needsto be determined. In this step, dollar valuesare obtained for all resources. Again, somecosts may be able to be collected directlyduring the trial (eg patient out-of-pocketcosts), but it is also common to useadministrative data or tariffs to determineappropriate dollar values. Examples of thisinclude using MBS item numbers andassociated values to determine the cost ofdiagnostic, medical or procedural costs, or thePBS to determine prescription drug costs.ExampleThe resources identified for inclusion in theexample paper were medical costs ofradiotherapy, non-medical costs ofradiotherapy, such as time and travel costs for
Step by step guide to economicevaluation in cancer trialspatients, other medical costs, health relatednon-medical costs, and additional health costsrelated to longer survival.The usage rates and values for these resourceswere obtained from a variety of sourcesincluding previously published information,patient questionnaires, local ‘standard pricing’lists for medical services and pharmaceuticalproducts, and national administrative data.Step 4: Identify, measure and valueconsequencesThe same process then needs to be followedto identify, measure and value theconsequences of treatment. These outcomesof treatment are often related to health gainssuch as a reduction in mortality, reduction inmorbidity or improvements in quality of life.However additional outputs may includeinformation, convenience, reassurance,patient satisfaction or impacts onproductivity.instrument, where the scoring capturespreferences for different health states. Insome cases it may be necessary tosupplement information collected in a trialwith additional data. For example, aneconomic evaluation may be concerned withoutcomes beyond the endpoint of the trial,and so may use the results of previous studieswith longer follow up, or administrative datato extrapolate beyond the end of the trial.ExampleThe example paper collected survival andquality of life as the treatment outcomes,allowing a cost utility analysis to beconducted. Survival is specified as beingcollected through ‘systematic assessment’.Quality of life was measured using the EQ-5Dinstrument, as well as a visual analogue scale.These data were collected at baseline, weeklyfor the first 12 weeks, and then every secondweek for the rest of the year.Step 5: Combine costs and consequencesIt is increasingly common for economicevaluations to use cost utility analyses, inwhich both duration and quality of life arecollected.Where an economic evaluation is beingconducted alongside a clinical trial, thetreatment consequences are usually collecteddirectly from patients during the trial period.Measures such as survival, time toprogression or adverse events are collectedthrough clinical assessments, while quality oflife and patient preferences are capturedthrough patient questionnaires. To calculateQALYs, ideally the quality of life instrumentsshould include a multi-attribute utilityCost effectiveness analysis is a comparison oftwo or more options, in terms of the costsand outcomes associated with each. Thefundamental question is whether thedifference in outcomes between theapproaches justify the difference in costs.The tool used for the comparison is theIncremental Cost-Effectiveness Ratio (ICER).This is defined as the extra cost of theadditional service, divided by the extraoutcome of effectiveness. We are interestedin how much we, as a society, are paying foreach unit of outcome (year of life gained,adverse event avoided etc), and whether we
Step by step guide to economicevaluation in cancer trialscould gain more of these units by using ourlimited resources elsewhere.ExampleOverall, the example paper found long-courselongradiotherapy increased survival, increasedcosts and improved quality of life. There wasa survival advantage of long course over shortcourse radiotherapy (38.1 vs 27.4 weeks,difference 10.7 weeks, 95% CI 0.9 to 20.6weeks, p 0.03). However, long courseradiotherapy hadd a total societal cost of 16,490,490, compared to short course societalcosts of 11,164. The average utility(measured using the EQ-5D) of long coursewas also higher (0.41) than for short course(0.37).These results can then be combined to obtainquality adjusted life expectancy,, in this case inweeks (QALWs). The long coursee radiotherapyresulted in 20 QALWs, compared to shortshortcourse, with 13.2 QALWs. This is a differenceof 6.8 QALWs (85% CI 0.1 to 13.5 weeks,p 0.05).The Incremental cost-utilityutility ratio for 10x2Gyvs 2x8Gy was 40,900 per QALY gained(95%CI 19,400- 1,100,000100,000 per QALYgained).Step 6: Assess robustnessSensitivity analysis helps to test therobustness of the results of the economicevaluation, and thus indicates the degree ofuncertainty associatedsociated with the ICER.ICERSensitivity analysis also provides anunderstanding of the key drivers of the resultsand ensures transparency. If the conclusionsdo not change significantly as a result of thesensitivity analysis then the results are said tobe ‘robust’.Good quality trial data can overcome many ofthe problems which sensitivity analysisattempts to address;; however, one aspect ofuncertainty which cannot be overcome in thisway is sampling, which can beb addressed withbootstrapping. For more information aboutthe different methods of sensitivity analysis,please contactntact the CREST team.teamExampleThe areas of uncertainty identified in theexample article were the unknown date ofdeath, the utilities used, and the costestimates. Changing the date of death toassumee longer survival led to increasedincrease lifeexpectancy and quality adjusted lifeexpectancy, however costs also increasedinandso overall the ICER decreased ( 40,800/QALYgained).assessed health utilities ratherBy using self-assessedthan the values collected through the EQ-5D,EQthe number of QALYs gained increased forboth groups, and differences in terms ofQALYs gained betweentween the groups werereduced. In this case the ICER decreased to 43,300/QALY gained.
Step by step guide to economicevaluation in cancer trialsFinally, the cost estimates had a significantimpact on the ICER. Excluding the survivalrelated costs reduced the ICER to 20,900/QALY gained. Including consumptioncosts led to a ICER of 64,500/QALY gained,while excluding non-radiotherapy costsdecreased the ICER to 12,800/QALY gained.Step 7: Interpret results.The ICER represents the additional amount ofresources required to gain an additional unitof health outcome. However, in order tointerpret this result we need to know eitherhow much society is willing to spend to gain aunit of health outcome (ie to have a thresholdabove which an ICER is not considered costeffective), or to be faced with a budgetconstraint (ie to have a fixed amount ofmoney we are able to spend). If there is anon-fixed (endogenous) budget the thresholdmay be interpreted as the societal willingnessto spend on health care. In cases where thereis a fixed (exogenous) budget the thresholdmay be interpreted as the opportunity cost ofthe health intervention displaced by theexpenditure on the new intervention.ExampleIn Australia in the context of MSAC and PBACdecision making, the budget is not fixed.Previous research has indicated that animplicit threshold of 50,000 per QALY existsin Australia. In other words interventions areusually funded if they have an ICER that is lessthan 50,000 per QALY, however thesecommittees do not have a fixed or explicitthreshold. At a threshold of 50,000 per QALYthe long-course radiotherapy may have anacceptable ICER and consequently may beaccepted for funding. However,considerations such as the extent ofuncertainty associated with the ICER, whetherthe increased costs can be afforded by thefunding body, the radiotherapy servicescapacity, and the ability of these results to begeneralized to other contexts would all needto be considered.For more informationFor more information on any part of thisfactsheet, please contact eitherRosalie Viney(email@example.com)orAlison ond, MF, Sculpher, MJ, Torrance GW.2005. Methods for the economic evaluationof health care programmes. Oxford: OxfordUniversity Press.van den Hout WB, Kramer GWPM, NoordijkEM, and Leer JWH. 2006. Cost-utility analysisof short- versus long-course palliativeradiotherapy in patients with non-small-celllung cancer. Journal of the National CancerInstitute, 98(24):1786-94
Economic evaluation is " the comparative analysis of alternative courses of action in terms of both their costs and consequences (Drummond 2005, p9). Figure 1 below sho the typical representation of an economic evaluation. Figure 1: Economic evaluation framework There are seven main steps which are typical to economic evaluations, including those
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