Costo efectividad en salud y medicina

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Recommendations of the Panelon Cost-Effectivenessin Health and MedicineMilton C. Weinstein, PhD; Joanna E. Siegel, ScD; Marthe R. Gold, MD, MPH; Mark S. Kamlet, PhD;

Louise B. Russell, PhD; for the Panel on Cost-Effectiveness in Health and Medicine

Objective.\p=m-\Todevelop consensus-based recommendations for the conduct of

cost-effectiveness analysis (CEA). This article, the second in a 3-part series, de-

scribes the basis for recommendations constituting the reference case analysis, theset of practices developed to guide CEAs that inform societal resource allocation

decisions, and the content of these recommendations.

Participants.\p=m-\ThePanel on Cost-Effectiveness in Health and Medicine, a

nonfederal panel with expertise in CEA, clinical medicine, ethics, and health out-$

comes measurement, was convened by the US Public Health Service (PHS).Evidence.\p=m-\Thepanel reviewed the theoretical foundations of CEA, current

practices, and alternative methods used in analyses. Recommendations were de-

veloped on the basis of theory where possible, but tempered by ethical and prag-matic considerations, as well as the needs of users.

Consensus Process.\p=m-\Thepanel developed recommendations through 21/2

years of discussions. Comments on preliminary drafts prepared by panel working

groups were solicited from federal government methodologists, health agency of-ficials, and academic methodologists.Conclusions.\p=m-\Thepanel's methodological recommendations address

(1) components belonging in the numerator and denominator of a cost\x=req-\

effectiveness (C/E) ratio; (2) measuring resource use in the numerator of a C/E

ratio; (3) valuing health consequences in the denominator of a C/E ratio; (4) esti-

mating effectiveness of interventions; (5) incorporating time preference and dis-

counting; and (6) handling uncertainty. Recommendations are subject to the "rule

of reason," balancing the burden engendered by a practice with its importance to

a study. If researchers follow a standard set of methods in CEA, the quality and

comparability of studies, and their ultimate utility, can be much improved.JAMA. 1996:276:1253-1258

COST-EFFECTIVENESS analysis(CEA) has emerged as a basic tool inthe evaluation of health care practices.

Despite widespread application, there r e¬

main disparities in the methods that

investigators employ.1 Some of these dis¬

parities can be traced to a misunder¬

standing of the principles of CEA, whileothers reflect divergent views on keymethodological choices. For example, an

investigator who fails to account for im¬

portant negative side effects of a therapyin estimating effectiveness is making a

clear error, while investigators who in¬clude or exclude the financial costs oflost productivity that accompany ill¬

ness are reflecting different views of howproductivity should be accounted for in

a CEA.The divergence of methods used to con-

duct CEA interferes with the ability ofdecision makers charged with resource

allocation to make appropriate compari¬sons of cost-effectiveness (C/E) ratiosacross programs. As described in the firstarticle of this series,2 this concern aboutlack of standardization has led the Panelon Cost-Effectivenessin Health and Medi¬cine to develop a set of recommendationsfor the practice of CEA that can serve as

a point of reference for investigators whoseek comparability with other analyses inthe literature. The panel refers to this setof methodological practices as the refer¬ence case.

The reference case will not address all

types of questions regarding the cost-effectiveness of interventions. In some

cases, depending on the goals of the analy¬sis, the author may prefer to highlight an

analysis based on a slightly different setof principles, or one based on quite dif¬ferent assumptions. In the interest of com¬

parability, however, we urge that the ref¬erence case set of assumptions and

practices be included in every CEA thatis designed to permit broad comparisonsacross interventions or that might be usedfor this purpose.

The recommendations outlined here,together with others that provide more

detailed methodological guidance, are ex¬

panded in the full report of the panel.3While this article focuses on the refer¬ence case recommendations, we also de¬scribe a few recommendations that are

intended to improve the conduct ofanaly¬ses but that are not explicitly incorpo¬rated within the reference case.

RATIONALES FORRECOMMENDATIONS

Reference case analyses are intended

to inform resource allocation decisionsand, as described in the first article of this

series, are conducted from the societal

perspective for this reason.2 Specific ree-

From the Departments of Health Policy and Man-agement (Dr Weinstein) and Maternal and Child Health

(Dr Siegel), Harvard School of Public Health, Boston,Mass; Office of Disease Prevention and Health Promo-tion, US Public Health Service, Washington, DC (DrGold); Heinz School, Carnegie Mellon University, Pitts-$

burgh, Pa (Dr Kamlet); and the Institute for Health,Health Care Policy, and Aging Research, Rutgers Uni-

versity, New Brunswick, NJ (Dr Russell).A complete list of the Panel on Cost-Effectiveness in

Health and Medicine membership and staff appears at

the e nd of this article.Corresponding author: Marthe Gold, MD, MPH, Of-

fice of Disease Prevention and Health Promotion, 200

Independence Ave SW, Room 738G, Washington, DC20201.

wnloaded From: http://jama.jamanetwork.com/ by a New York University User on 06/04/2015



mmendations for conducting CEAs frome societal perspective were based on a

umber of considerations, including eco¬

omic and decision theory; consistency ine accounting of costs and consequences;hical concerns; pragmatic concerns; and

eeds of users of analyses. In some in¬ances, where neither theory nor theseher considerations led to a clear choice,e panel recommended a conventional

actice for the sake ofconsistency across

udies.Where possible, recommendations were

ased on theoretical considerations in or¬

er to provide a defensible, logical, andonsistent framework for methodologicalhoices. At one level, CEA can be based

olely on the mathematical theory ofptimization."4 In that formulation, the

ecision maker is free to select any ob¬

ctive to maximize (eg, life-years or qual¬y-adjusted life-years [QALYs]) and to

pecify the particular resource constraintnder which

allocations must be made

g, national health care costs). However,is framework alone provides no guid¬ce on key issues that arise from a so¬

etal perspective, such as which costs toclude in the analysis, how to measure

osts, and whose values to incorporateto the definition of health consequences.herefore, drawing from recent litera¬re suggesting a link between CEA andelfare economic theory,5 the panel re¬

ed on economic theory for many of thecommendations for the reference case.

addition to economic theory, principlesdecision theory were invoked to definee basis for individual preferences.Some recommendations were dictated

y the need to maintain a logical account¬

g of costs and health effects. For ex¬

mple, theoretical considerations, alongith a basic presumption about the defi¬tion of the C/E ratio,2 led to a clear

ecision concerning the placement of allealth effects in the denominator of the/E ratio. Then, the "accounting" prin¬ple that no cost or effect should be

ounted twice disallowed the inclusion ofealth effects—even in

monetaryform—

the numerator of the C/E ratio.The implications of welfare economics

ere often modified in the interest ofoducing recommendations that were

oth pragmatic and ethically acceptable.he practicalneed to obtain data on healthtcomes, utilization of services and unit

sts, and weights for health-related qual-y-of-life (HRQL) states led to such com¬

omises. For example, while medicalces are not an exact reflection of the

ue value of resources, pragmatism sug¬ests that prices be used to approximate

sts except where distortions are likelybe significant and important to thealysis.Ethical considerations sometimes tem-

pered recommendations based on eco¬

nomic theory or were decisive in choices

among alternatives. Most fundamentally,the decision to use QALYs as the effec¬tiveness measure reflects the ethicalstance that QALYs accruing to differentpeople or at different stages in life shouldbe valued equally, even though welfareeconomics implies that health benefitsshould be weighted by willingness to pay.

Where theory did not offer a clearchoice, the panel based some recommen¬

dations simply on the need for a clearconvention to which analysts would ad¬here in the reference case. In some cases,the recommendation was somewhat ar¬

bitrary. For example, the choice of a stan¬dard time discount rate, while guided bytheory and data, is fixed by the need fora standard practice.

Finally, needs of the potential users ofCEAs influenced several recommenda¬

tions, playing a particularly great role inthe

panel's recommendations for the re¬

porting of CEAs as described in the thirdarticle of this series.6 They also enteredinto the recommendations regarding theevidence of effectiveness used in analysesand the treatment of uncertainty. For ex¬

ample, sensitivity analyses,which explorethe implications of alternative assump¬tions and data, are often recommended so

that decision makers can gain confidencein the conclusions of a n analysis or iden¬

tify areas for further investigation.While some of the reference case rec¬

ommendations address common errors in

the practice of CEA, many more repre¬sent the panel's view of the best amongseveral defensible choices. The task of de¬

veloping CEA standards is analogous tothe formulation of the consumer price in¬dex (CPI), which is used to adjust forinflation based on the prices of a typicalmarket basket of goods and services. Thechoice of what items go into that marketbasket, and how they are weighted, re¬

flects judgments made by the Bureau ofLabor Statistics and its advisors. Legiti¬mate opposing views exist.7 However,there is an

implied consensus that the

CPI will be used so that industry, gov¬ernment, and consumers can have a shared

understanding of the inflation rate. In¬

deed, flows of resources, such as the levelof Social Security payments, depend in

part on the CPI. While this country doesnot base policy directly on C/E ratios as

it does with the CPI, it is important formany decision makers to be able to relyon a dependable yardstick for measuringcost-effectiveness of health services.

RECOMMENDATIONS

The panel's recommendations falllargely into 8 categories: (1) the natureand limits of CEA and of the reference

case; (2) components belonging in the

numerator and the denominator of a C/Eratio; (3) measuring terms in the numera¬

tor of a C/E ratio (costs); (4) valuing thehealth consequences in the denominatorof a C/E ratio; (5) estimating effective¬ness of interventions; (6) time preferenceand discounting; (7) handling uncertaintyin CEA; and (8) reporting guidelines. Thefirst group of recommendations, regard¬ing the nature and limits of CEA, has

been described in the first article of thisseries.2 The last group, regarding report¬ing guidelines, is the subject of the thirdarticle.6 Additional recommendations re¬

garding research to develop improveddata for CEA and improved methods are

described in the full report of the panel.8This article summarizes the remaining 6

categories of recommendations.

Components Belonging in theNumerator and the Denominatorof a C/E Ratio

Cost-effectiveness analysisrestson

theproposition that a decision maker wishesto select programs so as to maximize some

desired objective subject to a resource

constraint. In practice, CEA in healthcare has been based on the premise thathealth benefits are the objective that so¬

cietal decision makers wish to maximize,subject to a constraint on health care re¬

sources. This formulation leads directlyto the construction of a C/E ratio in whichthe net expenditure of health care re¬

sources (a monetary measure) goes in thenumerator and the net improvement in

health (a nonmonetary measure) goes inthe denominator.

Unfortunately, however, this definitionis incomplete. It leaves open to questionwhether certain costs and consequencesshould be thought of as health care costsor savings (numerator), or health decre¬ments or improvements (denominator),and it completely ignores nonhealth costsand effects, such as those associated witheconomic productivity, the environment,or education. Therefore, ifanalyses are tohandle such issues consistently, the choicebetween numerator

(resource impact)and

denominator (HRQL impact) must fol¬low an established convention. In any case,the societal perspective dictates that all

important impacts on human health andon resources must be included some¬

where, either in the numerator or thedenominator. With this principle in mind,the panel reached the following recom¬

mendations regarding the distinction be¬tween costs and health consequences.

By convention, the denominator of a

C/E ratio is reserved for the improve¬ment in health associated with an inter¬

vention. Thus, effects of an interventionon length of life and o n morbidity, includ¬

ing the full value of HRQL to patients,should be incorporated in the denomina-




tor. In order to avoid double counting,monetary values for lost life-years shouldnot be imputed in CEA and should not beincluded in the numerator of the C/E ra¬

tio. For a reference case analysis, HRQLshould be captured by a measure that, ata minimum, implicitly incorporates theeffects of morbidity on productive timeand leisure. When instruments used tomeasure health states ar e silent concern¬

ing the consideration of lost income, weassume that financial effects have beenconsidered by the respondent and that itis therefore not necessary to account forthese effects in the numerator. Prefer¬ences for health states ideally should beelicited using health status measures that

explicitly invite respondents to considerthe full range of impacts of the healthstatus change, including loss of incomeand leisure activities.

Currently, some instruments used tomeasure health states explicitly excludeconsideration of lost income.

Moreover,methods that measure changes in HRQLin monetary terms, such as contingentvaluation (willingness to pay), have alsobeen used. While these approaches are

technically valid, a CEA in which these

practices were used would not constitutea reference case analysis.

The numerator of a C/E ratio captureschanges in resource use associated withan intervention. The major categories ofresource use that should be included are

costs of health care services; costs of pa¬tient time expended for the intervention;costs associated with caregiving (paid or

unpaid); other costs associated with ill¬

ness, such as child care and travel ex¬

penses; economic costs borne by employ¬ers, other employees, and the rest of

society, including so-called friction costsassociated with absenteeism and employeeturnover8; and costs associated with non-

health impacts of the intervention, suchas on the educational system, the criminal

justice system, or the environment.The handling of patient time in CEA

presents challenges and is the focus ofseveral reference case recommendations.Time spent by individuals seeking healthcare or undergoing an intervention is a

component of the intervention, and thusit should be valued in monetary termsand incorporated into the numerator ofthe C/E ratio. Time spent sick (morbiditytime) is part of the health outcome mea¬

sured in the denominator of the CEA, as

described above. In some instances (eg,when recuperating from surgery), timecould be categorized either as morbiditytime (valued in the denominator) or as a n

input to the intervention itself (costed

out in the numerator); as a general rule,this time should be considered as mor¬

bidity time. These recommendations a re

not based on any fundamental theoretical

consideration, but are made for consis¬

tency across reference case analyses.

Measuring Terms in the Numeratorof a C/E Ratio (Costs)

A change in the use of a resource caused

by a health intervention should be valuedat its opportunity cost, which is the valuethe resource could have produced if it were

spent in its best available alternative use.

In economics, this principle is the basisfor valuing resource flows in society.

Several implications arise from the op¬portunity cost principle. First, it is thedifference in resource use between an

intervention and the intervention withwhich it is being compared that should beincluded in the numerator of the C/E ra¬

tio. That is, costs should reflect the mar¬

ginal or incremental resources consumedor saved, rather than total resources.

Fixed costs—costs unaffected by the levelof implementation of an intervention—should

generally be excluded from

consideration. However, resource costsshould be measured from a long-term per¬spective, which implies that many coststhat may be fixed in the short run (suchas most of what is usually considered over¬

head in the financial accounts of hospi¬tals and other health care providers) are

in fact variable in the long run and shouldbe included in CEAs.

Direct measurement of opportunitycosts is difficult and often impossible. Tothe extent that market prices of health¬care inputs reflect opportunity costs, they

provide an appropriate means for valuingchanges in resources. According to eco¬

nomic theory, prices in competitive mar¬

kets reflect opportunity costs of resources.

However, when prices do not adequatelyreflect opportunity costs because of mar¬

ket distortions, they should be adjustedappropriately. Examples of adjustmentscommonly used in CEAs include the use

of ratios of cost to charge (RCCs) to ad¬

just hospital prices, the use of manage¬ment accounting systems to estimate

costs, and the use ofthird-party paymentsto

providers in lieu of fees to reflect

pro¬vider opportunity costs. When substan¬tial bias is present in prices and adjust¬ment is not feasible, the panel recommendsthat more suitable proxies for opportu¬nity costs be considered, includingthe pos¬sibility of conducting "microcosting" stud¬ies within provider organizations. (Suchstudies collect information on the range of

inputs to a service, such as the nursingcare, supplies, and ancillary services con¬

stituting a day of hospital care.)Costs should be measured in constant

dollars, that is, in the dollars of a fixed

year. When the original data are for dif¬ferent years, the effect of price inflationmust be removed, either by inflating thedata from an earlier year to the chosen

year or by deflating the data from a later

year. Dependingon whether the resources

being valued are more representative of

goods and services in the economy at largeor in the medical care sector, either theCPI or its medical care component(s) issuitable for inflation adjustment in CEAs.

Transfer payments (such as cash trans¬fers from taxpayers to welfare recipients)associated with a health intervention re¬

distribute resources from one individualto another. While administrative costs as¬

sociated with such transfers could be in¬cluded in the numerator of a C/E ratio,the transfers themselves should not be

since, by definition, their impact on thetransferor and the recipient cancel outfrom the societal perspective.

Time costs for individuals in the laborforce should generally be valued by the

wage rate as an acceptable measure of

opportunity cost of time. The referencecase recommendation is to us e wages cor¬

responding to the

age and

gender com¬

position of the target population. How¬

ever, group-specific wages may influencethe conclusions of an analysis in ethicallyproblematic ways. For example, a policy¬maker might object to having the wagedifferential between men and women re¬

flected in the results of a CEA. In these

instances, sensitivity analyses should beconducted to explore the specific natureof this influence. Because of such ethical

concerns, and because of practical prob¬lems in obtaining data on wages by char¬acteristics other than age and gender, the

panel does not recommend using wagesspecific to target groups defined by race,ethnicity, or other characteristics.

Wage rates generally do not adequatelyreflect the value of time for persons en¬

gaged primarily in leisure—such as re¬

tired persons—or in activities for which

they are notcompensated—such as house¬hold activities. Average age- and gender-specific wages among persons in the la¬bor force may be applied to approximatethe opportunity cost of time for personsof similar age and gender not in the laborforce.

Should health care costs that resultsolely from the fact that a successfullytreated patient lives longer be attributed

to the health intervention? Which futurecosts should be included in a CEA? For

example, a cost-effective analysis of an-

tihypertensive therapy found that exclud¬

ing noncardiovascular disease costs in fu¬ture years would reduce the C/E ratio by5% to 20%, with the greatest impacts on

the ratios for younger population groups.9To clarify the issues, we define 5 catego¬ries of induced costs that may or may not

be germane in a CEA. These are (1) costsfor intervention-related diseases incurredin years oflife that would have been lived

anyway; (2) costs for unrelated diseases




hat are incurred in years of life that wouldave been lived anyway; (3) health care

osts for related diseases that ensue in

ears of life added (or subtracted) as a

esult of the intervention, (4) health care

osts for unrelated diseases that occur in

ears oflife added (or subtracted) by the

ntervention, and (5) nonhealth care costs

ypified by commodities such as food andhelter that occur in years of life added

or subtracted) by the intervention.The handling of some of these catego¬

es of costs is uncontroversial. Costs ofelated diseases in the original life spanlearly must be included in the analysis.

For example, costs and savings associ¬ted with treatment of strokes and myo-ardial infarctions must be included in

nalyses ofhypertension programs. Costsf treating adverse effects of treatment

must be included as well. On the other

and, because unrelated health and non-

ealth care costs occurring throughouthe

expected years lived without the in¬

ervention would cancel from the incre¬mental cost calculation in the numerator

f the C/E ratio, these may be omittedom the analysis. It may actually bepref¬rable to omit these unrelated costs be¬ause their measurement may add to er¬

or in the estimation of costs with andwithout the intervention.

Costs for intervention-related diseaseshat occur in added years of life are typi¬ally included in CEAs. For example, if a

atal myocardial infarction is delayed 5

ears by a coronary bypass operation or

cholesterol-lowering regimen, the costsf treating coronary events ensuing

hroughout the 5 years should be, and

sually are, included. Similarly, costs ofn ongoing therapy throughout added

ears of life, such as lifelong antihyper-ensive treatment and its medication side

ffects, are always included.Costs of diseases unrelated to the in¬

ervention and ensuing as a result of added

ears of life have been the source of more

ebate.4,5,10"12 Difficulties with the choiceo include o r exclude them ar e illustrated

y the

example of a

cholesterol-loweringntervention. The analyst might decide toxclude all unrelated costs occurring in

ears of life gained because of the pro¬ram. In this case, costs of illnesses suchs arthritis and Alzheimer disease woulde excluded. However, age-specific "back¬

round" costs of coronary heart disease—hat is, the level of disease that would

ccur among people who are not candi¬ates for the intervention—are also "un¬elated" to the intervention and shouldlsobe excluded. To neglect to do so would

rovide an uneven playing field for com¬

arisons of interventions affecting differ¬nt diseases: life-prolonging heart disease

nterventions would be encumbered withll future costs of heart disease even

though they only target an excess risk,while suicide prevention programs wouldnot. To avoid the practical and conceptualproblems in disengagingthe "related" and"unrelated" elements of costs for "related"

diseases, it would be preferable to in¬clude all these costs. However, this choicewould impose a burden on the analystfrequently not warranted by the impor¬tance of future costs.

Because there are unresolved theoreti¬cal and empirical questions and becausehealth care costs in added years of life are

typically small compared with the othercosts in an analysis, the panel concludedthat the reference case may either in¬clude or exclude these costs. Wheneverthe investigator has reason to believe thatinclusion or exclusion offuture health care

costs may make a significant differenceto the analysis, a sensitivity analysisshould be performed to assess the effecton the C/E ratio.

We now consider nonhealth care costsin added life-years. Although there is no

precedent in CEA for including these

costs, one could reasonably argue that ifhealth care costs in added years can be

included, future expenditures on food,clothing, and shelter should also be in¬cluded. The theoretical answer is that thenet economic burden of survivors on therest of society (consumption minus pro¬ductivity) should indeed be included a s a

cost. However, if these nonhealth care

costs are truly "unrelated," then theirconsistent inclusion or exclusion would

only add or subtract a constant from theC/E ratio.5 Whether nonhealth care costsare in fact "unrelated," or at least ap¬proximately so, is an unresolved empiri¬cal question. Nonetheless, on the assump¬tion that these costs can reasonably beconsidered to be unrelated and to avoid

placing an unnecessaryburden on the ana¬

lyst, the panel does not recommend in¬

cluding future nonhealth care costs in ref¬erence case analyses.

Valuing the Health Consequencesin the Denominator of a C/E Ratio

As discussed in the first article of thisseries,2 a reference case analysis shouldmeasure health effectiveness in terms of

QALYs. These QALYs incorporatechanges in survival and changes in HRQLby weighting years of Ufe to reflect thevalue of the HRQL during each year.13,14In order to be consistent with the QALY

construct, the quality weights must bemeasured by or transformed into the in¬terval scale on which optimal health hasa value of 1 and death has a value of 0.

The weights used in QALYs should be

based on a health-state classification sys¬tem that reflects health-related domains(attributes) that are important for the par¬ticular analysis. In order to qualify as a

reference case analysis, the CEA shoulduse a generic health-state classification,that is, a classification that appliesbroadlyacross diseases and conditions. Disease-

specific health-state classifications are ap¬propriate for a reference case analysis pro¬vided that they are designed to bemappedonto or embedded within a generic sys¬tem. Some examples of commonly usedhealth-state classification systems that

may be suitable for CEA include theHealth Utilities Index,14,15 the EuroQol,16the Quality of Well-Being Scale,17 and theYears of Healthy Life measure.18 TheHealth Utilities Index, for example, con¬

sists of 8 domains (vision, hearing, speech,dexterity, mobility, cognition, emotion, and

pain), each of which is classified into ei¬ther 5 or 6 levels. Each combination oflevels is assigned a weight, using a for¬mula based on multiattribute utility theoryand a community preference survey.13,14

The weights used in QALYs should bebased on

preferencesfor health states. In

a reference case analysis, these weightsshould be based on community prefer¬ences, rather than those of patients, pro¬viders, or investigators. The rationale for

community preferences has been de¬scribed in the first article of this series.2Health status scales that are not prefer¬ence weighted, such as the Medical Out¬comes Study Short-Form Health Survey(SF-36),19 are not suitable for CEA intheir present form. Use of patient pref¬erences to value health states is accept¬able in a reference case analysis only when

adequate information is unavailable re¬

garding community preferences.The weights assigned to health states

should be interval scaled; that is, themethod of measurement should be o ne inwhich the ratio of differences betweenvalues is meaningful. (By analogy, the

Fahrenheit, Celsius, and Kelvin scales are

equivalent and appropriate measures of

temperature, because the intervals be¬tween degrees reflect meaningful differ¬ences in temperature.) According to de¬cision theory, preferenceweights obtainedfrom standard

gamble questions and, un¬

der certain conditions, time trade-offques¬tions satisfy the interval property. At thesame time, psychometric research sug¬

gests that rating scales can produce in¬terval data. These claims are mutuallyinconsistent, since there is apparently nota linear relationship between rating scalesand standard gambles or time trade¬offs.20,21

It remains an open question whetherstandard gambles, time trade-offs, rat¬

ing scales, or other measures such as

person trade-offs22 produce the closest

approximation to the type of interval-scaled weights needed for QALYs. For

example, some research suggests that

respondents may introduce distortions




into responses to utility questions suchas the standard gamble, compromisingtheir theoretical desirability. Therefore,the panel does not recommend one

source of weights over the others; forpurposes of the reference case, prefer¬ence weights can come from measure¬

ment systems that rely on any of these

techniques. The discrepancies associatedwith different measurement strategiespose a problem for standardization thatwill be important to address in futureresearch.

To date, most CEAs using QALYshave assumed that a year of life gainedby an intervention is valued at 1.0 QALY.In fact, people are rarely in the state ofoptimal health that a full QALY implies;the u se of a value of 1.0 for years that lifeis prolonged will therefore overstate an

intervention's effectiveness and under¬estimate the true C/E ratio. The panelrecommends that, when calculating

QALYs gained from a

life-extending in¬tervention, estimates of age- and sex-

specific HRQL should be applied to the

years of extended life—even if the inter¬vention itself has no effect on HRQL. Simi¬larly, when estimating QALYs gained byameliorating disease symptoms, a re¬

turn to average rather than optimal HRQLshould be credited. It should be noted thatthis use of average quality of life in ref¬erence case analyses means that studies

using ratios of cost per year (unad¬ justed) of life saved will not be compa¬rable to reference case results.

Sociodemographic characteristics, suchas age, sex, or race, are associated with

HRQL. When the QALYs produced byan intervention vary as a result of these

sociodemographic differences, referencecase results a re affected in ways that maybe ethically problematic. For example, an

intervention that extends the lives of 80-

year-olds may appear less cost-effectivethan an equally effective intervention ap¬plied to 20-year-olds, not only becausefewer years are gained, but also becausethe average quality of those years is less.

In these instances, sensitivity analysesshould be conducted to indicate explic¬itly how results are affected.

Estimating Effectivenessof Interventions

The quality and validity of a CEA de¬

pend crucially on the quality of the un¬

derlying data that describe the effective¬ness of interventions and the course ofillness without intervention. Data maybe obtained from primary data collectionefforts specifically intended to inform theCEA or from secondary data sources. The

appropriatenessof various sources of datawill depend on the purpose of a CEA. The

consequences of misestimation of cost-effectiveness may be regarded as more

serious by some decision makers than byothers. For example, the Food and DrugAdministration might desire a greaterlevel of certainty in distinguishing thecost-effectiveness of very similar drugsfor the purpose of reviewing marketingclaims than a formulary manager mightdemand in adopting a new drug.

For the purpose of a reference case

analysis, acceptable data for estimation

of effectiveness may come from a varietyof sources: randomized controlled trials,observational studies, uncontrolled ex¬

periments, or descriptive series. The ana¬

lyst should select outcome probabilitiesfrom the best-designed (and least-biased)sources that are relevant to the questionand population under study. There are

often trade-offs between the internal va¬

lidity of data (optimized in randomizedtrials) and their external validity in ac¬

tual practice. Meta-analysis and other syn¬thesis methods can be used when no single

study has sufficient power to detect ef¬fects or when studies produce conflictingresults. Expert judgment should be used

only as placeholders where no adequateempirical data exist, or when the param¬eter ofinterest plays only a minor role inthe analysis.

Modeling is a valid and necessary sci¬entific procedure for estimating effec¬tiveness for CEA. Typically, data fromrandomized trials a re combined with ob¬servational data and public health sta¬tistics in models that are used to esti¬mate changes in life expectancy and

quality-adjusted life expectancy. Mod¬els may incorporate features such a s lo¬

gistic regression to estimate incidenceof disease or death contingent on risk

factors; Bayesian analysis to estimate

posttest probabilities of disease fromdata on sensitivity, specificity, and

prevalence; and life-table analysis to es¬

timate life expectancy from survivalcurves. Models include population andcohort models, deterministic and proba¬bilistic models, decision analysis andstate-transition models. Because of lim¬

ited time horizons and selected studypopulations in clinical studies, failure touse models to extrapolate from primarydata can lead to greater error than themodels themselves would introduce.Models should be used as complementsto, not substitutes for, direct primary or

secondary empirical evaluation of effec¬tiveness. Readers are referred to thefull report of the panel for more discus¬sion of the roles of particular types ofdata and models in CEA.3

Time Preference and Discounting

Interest rates reflect people's prefer¬ence forhaving money and material goodssooner rather than later. Similarly, people

value health outcomes that occur in dif¬ferent time periods differently. In CEA,time preference for resources is reflected

by discounting future costs to presentvalue. Discounting the value of future ex¬

penditures requires that health effects ex¬

perienced in the future also be discountedat the same rate. This conclusion is basedon the observation that people have op¬portunities to exchange money for health,and vice versa, throughout their Uves. Fail¬ure to discount health effects will lead toinconsistent choices over time; for ex¬

ample, it will appear that delaying invest¬ments will always result in a program'sbecoming more cost-effective. For this rea¬

son and based on other evidence and con¬

siderations outlined in its full report,3 the

panel recommends that costs and healthoutcomes occurring during different time

periods should be discounted to their pres¬ent value and that they should be dis¬counted at the same rate.

Although a wide variety of discountrates are used in the literature and ca n be

defended, a convention is needed toachieve consistencyacross analyses. Theo¬retical considerations suggest that thereal (inflation-adjusted) discount rateshould be based on time preference, thedifference in value people assign to events

occurring in the present vs the future.

Further, economic theory suggests thattime preference is reflected in the rate ofreturn on riskless, long-term securities.

Empirical evidence is consistent with thisrate's being in the vicinity of 3% per an¬

num (net of inflation). Direct evidence o n

time preferences for health outcomes isalso consistent with a discount rate of 3%.

The panel therefore recommends theuse of a real, 3% discount rate in thereference case. Before discounting, allcosts should be adjusted for inflation. Be¬cause many published CEAs have used a

discount rate of5%, future analyses shouldinclude sensitivity analysis using 5% as

well as other rates in the range of 0% to7%. The discount rate should be reviewedand possibly revised periodically, to re¬

flect important changes in economic con¬ditions. To ensure that analyses will re¬

main comparable, however, both 3% and5% should continue to be used for at leastthe next 10 years.

Handling Uncertainty in CEA

Cost-effectiveness analyses are subjectto uncertainty with regard to estimatesof effectiveness, the course of illness,HRQL consequences and preferences,and health care utilization and costs. Us¬ers of analysis need information on the

degree to which CEA conclusions mightchange with changes in assumptions or

values.

Sensitivity analysis is an appropriatetool with which to respond to this need.




The simplest method, which should besed in all CEAs, is a univariate (1-way)ensitivity analysis, in which estimates or

ssumptions are changed one at a time.hese establish where uncertainty or lackf agreement about some key parameter'salue could have substantial impact on

he conclusion of a CEA. They suggestreas where efforts to obtain additionalata might be warranted in terms of im¬

act on decisions and, conversely, areas

where additional precision would be un¬

kely to change results. For example, thestimated cost-effectiveness of thrombo-

ytic therapy in older patients with sus¬

pected myocardial infarction was showno be stable when the efficacy of therapy,he prevalence of myocardial infarction,

or the incidence of stroke was varied, thus

uggesting that further research to evalu¬ate the risks and benefits of streptokinasen this age group was not warranted.23

One-way sensitivity analyses under¬

tate the overall uncertainty in

the C/E

atio; therefore, analysts should also con¬

uct multivariate (multiway) sensitivityanalyses, in which several estimates or

assumptions are changed at the same

me, for important parameters. If pos¬sible, a reasonable confidence interval or

credible interval for the C/E ratio shouldbe estimated based either on statisticalmethods or on simulation. The value ofmultivariate sensitivity analysis is great¬est when there is reason to believe thatestimation errors for key parameters are

correlated, for example, if studies that

overestimated the effectiveness of throm-bolysis also tended to underestimate the

associated risk of stroke. Several meth¬ods for performing such statistical analy¬ses and simulations are described in the

panel's full report.3CONCLUSION

The panel recognizes that many of therecommended methodological approachesare not broadly practiced at present, andthere may be gaps in the availability of

data to satisfy the criteria for the refer¬ence case. For example, there is no broadconsensus on which health-state classifi¬cation systems are suitable for CEA, andvalues of community-based weights forsome systems are not publicly available.The ability to weight years of life by popu¬lation averages of community preferenceweights is limited by the lack of appro¬priate (age- and sex-specific) populationdata for some systems. In the area ofcosts, there are no well-accepted meth¬ods for determining time costs for indi¬

viduals outside the labor

force, and few

good-quality data on resource use, reflect¬

ing costs rather than charges and clearlyapplicable to the populations under study,are readily available to analysts.

The intention of these recommendationsis to move the field of CEA closer to stan¬dardization in the near term where pos¬sible and to identify desirable practicewhere optimal methods are not currentlyfeasible. All of these recommendations forthe reference case, and for CEAs in gen¬eral, are subject to a "rule of reason."When a parameter estimate or an ele¬

ment of the analysis is unlikely to have an

appreciable effect on the result, then it

may be acceptable to us e shortcuts to ob¬tain them; expert opinion may be used toassess them; or they may be excludedfrom the analysis altogether. Examplesmay include the weightsassigned to short-term and mild impairments of HRQL,costs of unrelated health care in added

years of life, or the incidence or costs ofminor side effects of treatments. The ruleof reason applies if the cost of obtainingmore precise estimates of the parameterin question would exceed the value of

achieving more precision in the final cost-effectiveness result. However, the bur¬den is on the analyst to justify suboptimalmethods of parameter estimation or ex¬

clusion of effects from an analysis.Ifresearchers endeavor to follow a stan¬

dard set of methods in CEA and to obtainthe required inputs fortheir studies, muchwill have been accomplished toward im¬

proving the utility of this form of analy¬sis. It is hoped that the recommendationscontained here will stimulate

rapidprogress toward availability of the nec¬

essary data and tools, so that the practiceof CEA can soon become as establishedas many other forms of scientific inquiry.

The Panel on Cost-Effectiveness in Health andMedicine membership and staff: Norman Daniels,PhD; Dennis G. Fryback, PhD; Alan M. Garber,MD, PhD; Marthe R. Gold, MD, MPH; David C.

Hadorn, MD; Mark S. Kamlet, PhD; JosephLipscomb, PhD; Bryan R. Luce, PhD; Jeanne S.

Mandelblatt, MD, MPH; Willard G. Manning, Jr,PhD; Donald L. Patrick, PhD; Louise B. Russell,PhD; Joanna E. Siegel, ScD; George W. Torrance,PhD; Milton C. Weinstein, PhD.

We thank Kristine I. McCoy, MPH, for coordina¬

tion, research, and editorial assistance in associationwith this project.

References

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ectly? Ann Intern Med. 1992;116:238-244.. Russell LB, Gold MR, Siegel JE, Daniels N,

Weinstein MC, for the Panel on Cost-Effectivenessn Health and Medicine. The role o f cost-effective-

ess analysis in health and medicine. JAMA. 1996;76:1172-1177.. Gold MR, Siegel JE, Russell LB, Weinstein MC,ds. Cost-Effectiveness in Health and Medicine.

New York, NY: Oxford University Press; 1996.

. Weinstein MC, Stason WB. Foundations of cost\x=req-\ffectiveness analysis for health and medical prac-ces. N Engl J Med. 1977;296:716-721.. Garber AM, Phelps CE. Economic foundationsf cost-effectiveness analysis. J Health Econ. In

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Medicine. Recommendations for reporting cost-ef-ectiveness analyses. JAMA. In press.. Newhouse JP. Medical care costs: how much

welfare loss? J Econ Perspect. 1992;6:3-21.. Koopmanschap MA, Rutten FFH, van Ineveld

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measuring indirect costs of disease. J Health Econ.

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Washington, DC: Brookings Institution; 1986.12. Meltzer DO. Accounting for future costs in medi-

cal cost-effectivenessanalysis.J Health Econ. In press.13. Torrance GW, Feeny D. Utilities and quality-$adjusted life years. Int J Technol Assess HealthCare. 1989;5:559-575.14. Patrick DL, Erickson P. Health Status andHealth Policy: Allocating Resources to Health Care.New York, N Y: Oxford University Press; 1993.15. Torrance GW, Boyle MH, Horwood SP. Appli-cation of multiattribute utility theory to measure

social preferences for health states. Operations Res.

1982;30:1043-1069.16. EuroQol Group. EuroQol: a new facility for themeasurement of health-related quality of life. HealthPolicy. 1990;16:199.

17. Kaplan RM, Anderson JP. A general healthpolicy model: update and applications. Health ServRes. 1988;23:203-235.18. Erickson P, Wilson R, Shannon I. Years ofHealthy Life. Hyattsville, Md: Centers for DiseaseControl and Prevention, National Center for HealthStatistics; 1995. Dept of Health and Human Ser-vices publication (PHS) 95-1237.19. Ware JE Jr, Sherbourne CD. The MOS 36-ItemShort-Form Health Survey, I: conceptual frameworkand item selection. Med Care. 1992;30:473-483.20. Torrance GW. Social preference for health

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