a multinational study to measure the value that patients with cancer place on improved emesis...

A Multinational Study to Measure theValue that Patients with Cancer Placeon Improved Emesis Control FollowingCisplatin ChemotherapyGeorge Dranitsaris,1,2 Pauline Leung,1 Renoto Ciotti,3 Ana Ortega,4 Maria Spinthouri,5Lycurgus Liaropoulos,5 Roberto Labianca6 and Antonello Quadri6

1 Department of Pharmaceutical Services, University Health Network/Princess Margaret Hospital,Toronto, Ontario, Canada

2 Molecular Biology, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada3 Department of Medical Oncology, Azienda Ospedaliera, Treviglio, Italy4 Servicio de Farmacia, Clinica Universitaria de Navarra, Pamplona, Spain5 Center for Health Services Management and Evaluation, University of Athens, Athens, Greece6 Azienda Ospedaliera, Ospedali Riuntiti di Bergamo, Bergamo, Italy

Abstract Background: The neurokinin-1 (NK1) receptor antagonists are a new class ofagents designed to reduce the risk of emesis following chemotherapy, particularlywith cisplatin. Early data from double-blind randomised trials suggest that anorally administered NK1 antagonist can reduce the absolute risk of acute anddelayed emesis following cisplatin by 20 and 30%, respectively.Objective: To measure the value that patients with cancer place on improvedemesis control and quality of life.Design:Willingness-to-pay analysis.Setting: Five study sites in Canada, Italy, Spain and Greece.Patients and participants: 245 patients with cancer either receiving chemother-apy with cisplatin or who had received cisplatin-based chemotherapy within theprevious 6 months.Methods:After background information had been presented, patients were askedto define the maximum that they would pay per day for a drug that reduced theirrisk of acute and delayed (days 2 to 5) emesis by 20 and 30%, respectively. Costswere converted to US dollars ($US) using year 2000 exchange rates.Results: For a 20% improvement in acute emesis, Canadian, Italian and Spanishpatients with cancer were willing to pay $US46, $US34 and $US63 per day,respectively, compared with $US8 for patients from Greece (p < 0.001). For a30% improvement in delayed emesis, Canadian, Italian and Spanish patients withcancer were also willing to pay more than their Greek counterparts ($US41,$US31, $US50 and $US9 daily for 4 days, respectively; p < 0.001). These sig-nificant differences in patient value between countries remained, even after ad-justing for socioeconomic variables and previous history of emesis.Conclusions: There are substantial cultural differences in how patients with can-

ORIGINAL RESEARCH ARTICLE Pharmacoeconomics 2001; 19 (9): 955-9671170-7690/01/0000-0955/$22.00/0

© Adis International Limited. All rights reserved.

cer value benefit and improved quality of life. Since the majority of the world’spopulation resides outside North America and Western Europe, there may be aneed to re-evaluate perceived levels of patient benefit and measures of qualityof life.

The development of emesis (vomiting or retch-ing) and nausea are considered by patients to bethe most severe adverse effects of cancer chemo-therapy.[1,2] The onset of nausea and vomiting hasbeen separated into an acute and delayed phase.Acute vomiting typically occurs within the first24 hours after the completion of chemotherapy,whereas delayed vomiting develops between days2 to 5 following the administration of anticancertreatment.[3] This temporal division was estab-lished becausemolecular studies demonstrated thatthe mechanisms of acute and delayed emesis aredifferent. The former phase is believed to be pri-marily mediated through serotonin (5-hydroxy-tryptamine; 5-HT) receptor stimulation, whereasthe latter is caused by multiple neurotransmitterinvolvement with the opioid and neurokinin (NK)receptors playing a dominant role.[4]Among the many anticancer drugs, cisplatin is

considered to be the most emetogenic with rates ofacute vomiting that approach 100% in patients re-ceiving no antiemetic therapy. Doses of cisplatinabove 50 mg/m2 are more emetogenic than lowerdoses, and the drug has an increased emetogeniceffect when given in combination with other anti-cancer agents. This is of major concern to clini-cians, because cisplatin is one of the most activeagents in oncology and is part of standard treatmentprotocols for lung, testicular, ovarian, endometrial,head and neck and bladder cancer.Investigations in the late 1980s suggested that

the serotonin 5-HT3 receptors were prominent inthe onset of emesis following cancer chemother-apy.[5] Ondansetron was the first selective seroto-nin receptor antagonist that was approved world-wide for the control of emesis. Randomisedcomparative trials demonstrated that ondansetronwas superior to metoclopramide-containing re-gimens in the prevention of acute emesis followingcisplatin chemotherapy.[6,7] Other 5-HT3 receptor

antagonists that are clinically equivalent to ondan-setron using approved doses include granisetron,dolasetron and tropisetron.[8,9] The current stand-ard for the prevention of acute emesis is a 5-HT3receptor antagonist in combination with dexameth-asone.[3,10,11]Despite these advances, 20 to 30% of patients

with cancer receiving cisplatin fail to achieve com-plete control of acute emesis.[10,11] Furthermore,delayed emesis remains a problem in approxi-mately 40 to 50% of patients, and the addition ofa 5-HT3 receptor antagonist provides marginalbenefit compared with dexamethasone alone.[12,13]New antiemetic drugs are needed to improve thecontrol of both acute and delayed emesis.Substance P is a neurotransmitter that has an

important role in emesis.[14] In animal models, itbinds to the NK1 receptor and blocking this inter-action has been found to inhibit the emetic poten-tial of a wide range of stimuli.[14,15] NK1 receptorantagonists are a novel class of antiemetics andare currently under investigation for the control ofacute and delayed emesis following cisplatin che-motherapy.[16] Early data from phase II randomisedstudies demonstrate that an NK1 receptor antago-nist can reduce the absolute risk of acute and de-layed emesis following cisplatin by 20 and 30%respectively.[17] If these results are confirmed byphase III trials, NK1 antagonists will represent amajor advance in cancer supportive care.Since delayed emesis can last for up to 5 days,

the addition of an NK1 receptor antagonist tocurrent antiemetic protocols will have a large eco-nomic impact on hospital and national drug bud-gets. This is particularly important because the 5-HT3 antagonists are already expensive drugs. Priorto the introduction of the NK1 receptor antagonists,it would be important to determine the value thatpatients with cancer place on improved emesis con-trol. If patients with cancer place a high value on

956 Dranitsaris et al.

© Adis International Limited. All rights reserved. Pharmacoeconomics 2001; 19 (9)

these benefits, then local and national drug formu-lary committees will have important evidence tojustify budgetary increases for this new class ofdrugs. To measure the value that patients withcancer place on improved emesis control and theassociated quality-of-life improvement, we con-ducted a willingness-to-pay (WTP) analysis in 245patients with cancer from Canada, Italy, Spain andGreece.

Methods

Patient Population

This multinational study was designed to mea-sure the maximum that patients with cancer wouldbe willing to pay for reducing their risk of acuteand delayed emesis following cisplatin chemother-apy. Patients were recruited from 5 study sites lo-cated in Canada, Italy, Spain and Greece. To beeligible, patients had to be receiving treatment withcisplatin or had received cisplatin-based chemo-therapy within the previous 6 months. The tumoursites selected in the current study were those thatare primarily treated with cisplatin-based chemo-therapy such as lung, gynaecological, genitouri-nary and head and neck cancers.

Measuring Patient Value

Patient value was measured by using a contin-gent valuation approach that measures WTP fora given health benefit.[18,19] WTP has been suc-cessfully used in the past to estimate the valuethat patients with cancer place on oncology prod-ucts.[20,21] Briefly, this method presents to patientsthe relative advantages and risks of a new therapy(i.e. NK1 receptor antagonists), and asks themwhatmonetary sum (if any) they would be willing to payfor the potential benefits of the new treatment.In the case of the NK1 receptor antagonists, a

series of WTP scenarios for the prevention of acuteand delayed emesis were presented to each patient.The literature suggests that the combination of a5-HT3 antagonist with dexamethasone lowers therisk of acute emesis to between 20 and 35%.[12,22]Therefore, an emesis rate of 30% was used as the

current level for the acute phase following chemo-therapy. Randomised phase II trials suggest thatthe addition of an NK1 antagonist may reducethe absolute risk of acute emesis to approximately20%.[17] To encompass all of the possible out-comes, the maximum WTP was assessed for thefollowing reductions in the absolute risk of acuteemesis: 30 vs 25%, 30 vs 20%, 30 vs 10% and 30vs 0%.In the case of delayed emesis following cispla-

tin chemotherapy, the current treatment standardreduces the risk of emesis from day 2 to 5 after che-motherapy to approximately 40% of patients.[13,23]Therefore, WTPwas assessed for the following re-ductions in the absolute risk of delayed emesis: 40vs 30%, 40 vs 20%, 40 vs 10% and 40 vs 0%.The WTP responses were elicited via patient in-

terviews. Patients were informed prior to the ses-sion that the scenarios presented to them were en-tirely imaginary and did not relate to their ownpersonal situation. Once informed consent was re-ceived, the first part of the session attempted tostandardise their knowledge base by presenting tothem information on cisplatin chemotherapy, a de-scription of nausea and vomiting, the risk of emesisfollowing cisplatin and the current treatments usedto prevent emesis.Each clinical scenario, along with visual aids

and all the relevant information about nausea andvomiting, were presented to each patient. Duringthe interview, patients were told that the NK1 re-ceptor antagonists are new drugs that are not yetavailable for use. Once all of the information waspresented, patients were asked to indicate, on a 10-point ordinal scale, how important they consideredeach of the emesis risk reductions (0 = not at allimportant, 10 = very important). Respondents werethen asked about the maximum amount that theywould be willing to pay for 1 day of therapy in thecase of acute emesis and for 4 days (days 2 to 5) toprevent delayed emesis. Figure 1 shows an exam-ple of the questionnaire used. Additional informa-tion collected from patients consisted of age, mar-ital status, education, family income, religious

Emesis Control in Cancer 957


affiliation, diagnosis and history of previous che-motherapy, as well as present clinical status.To minimise the effect of starting point bias, the

payment-card method was used as described byMitchell and Carson.[24] Briefly, the payment cardmethod is a visual aid that contains a large array ofpotential WTP amounts ranging from zero to verylarge amounts. By using this method, the offeringof a single starting point is avoided and respon-dents are able to chose from a large array of num-bers. Pre-study testing of the questionnaire deter-mined the expected WTP range for this evaluationto be between zero and 100 US dollars ($US). Asa result, the outer value was increased to >$US100to provide extremes that would seem unreasonableto most participants. The respondent’s initial value

was recorded as their WTP estimate and a ‘bid up’was not attempted by the surveyor.For the non-English speaking countries, the

WTP questionnaire was translated by the localinvestigator into a form that was suitable for thepatient to understand, and evaluated for face andcontent validity. Prior to implementation, the ques-tionnaire was pilot tested in all countries to ensurepatient understanding. All WTP responses wereconverted and presented in $US, using year 2000exchange rates.

Sample Size and Statistical Considerations

This study was designed to compare maximumWTP differences between patients from 4 coun-tries, with the hypothesis that patients from the

Not at all important Somewhat important Very important0 1 2 3 4 5 6 7 8 9 10

Out of 100 patients who receive cancer chemotherapy, 30 will vomit at least once within the first 24 hours following chemotherapy (Situation A)

Suppose there is a new drug available to patients with cancer. If it is taken by mouth before chemotherapy, it can protect patients from vomiting. With the new drug, the chance of vomiting during the first 24 hours following chemotherapy is reduced to 20 of 100 patients (Situation B).

Pause for a moment and ask yourself whether it would be important for you to receive this drug.

Indicate on the scale below how important it would be for you to reduce your chance of vomiting during the first 24 hours after chemotherapy from 30 in 100 to 20 in 100.

Now imagine that you are receiving chemotherapy, and that the cost of this new drug is not paid by the national healthcare system nor by your private insurance company. Thinking realistically about how much you can afford to pay, what is the maximum amount you would be willing to pay to receive the drug for one day?

Situation A(Risk = 30%)

Situation B: with new drug(Risk = 20%)

Fig. 1. Example of importance score and willingness-to-pay questionnaire incorporating a visual aid illustrating the absolute riskreduction of vomiting following treatment with a hypothetical new antiemetic drug in patients receiving cisplatin-based chemotherapy.



province of Ontario, Canada, would be willing topay more for the new drug compared with the otherpatient groups. This was based on the knowledgethat the healthcare systems in the three Europeancountries would provide prescription drugs free ofcharge (or with a small copayment) to patients withcancer. In contrast, only patients aged ≥65 years inOntario would be eligible for provincial drug cov-erage. The rest of the Ontario population wouldhave to rely on third party insurance or have to payfor drugs out of pocket. Therefore, the hypothesiswas that European patients with cancer would beless willing to pay for the benefits of a new drugbecause they would expect it to be provided free ofcharge by their respective healthcare systems. Byaccepting an α of 5% (two tailed), power of 80%and a minimum difference in maximum WTP be-tween Canada and any of the other countries at$US10, the case sample size for the unpaired t-testwith equal variance was 60 patients per country.Therefore, a total of 240 patients had to be enrolledto complete the study.Demographic and clinical data and WTP esti-

mates are presented as descriptive statistics aseither means, medians or proportions. Parametricor nonparametric multiple comparison inferentialstatistics were used to evaluate the mean WTP be-

tween countries. To measure the association be-tween maximum WTP and patient characteristics(such as age, family income, country, previouschemotherapy or history of vomiting), a multivar-iate analysis was performed. Before the regressionanalysis was initiated, the relevant covariates formodel inclusion were identified by a bivariatescreening process with a preset α = 0.15. This isa recommended approach for removing unimport-ant covariates so that a more manageable set ofvariables can be submitted to multivariate tech-niques.[25] The cut-off for significance for all ofthe statistical procedures was at the p = 0.05 level.All of the statistical analyses were performed withStata release 6.0 (Stata Corp., College Station,Texas, USA).

Results

A total of 245 patients with cancer were enteredinto the study. Since this was not a randomisedtrial, differences were noted between countrieswith respect to socioeconomic factors such as em-ployment status, household income, religion andhistory of alcohol consumption (table I). Similarly,differences between groups were also observed inpatient clinical and treatment characteristics (table

Table I. Patient socioeconomic characteristics

Characteristic Canada (n = 60) Italy (n = 60) Greece (n = 65) Spain (n = 60)Mean age (years) [SD] 60.7 (10.8) 55.5 (12.3) 57.6 (12.6) 55.3 (10.6)Males (%) 48.3 55.0 72.3 63.3Married (%) 71.7 86.7 80.0 85.0Employed full-time(%) 40.0 36.7 47.7 29.3

Household income (%)US19 000 48.3 33.3 96.9 28.3$US20 000 to $US49 000 38.3 53.3 3.1 53.3≥$US50 000 13.3 13.3 0.0 5.0unknown 0.0 0.0 0.0 13.3

Median number in household 2 3 3 2Christian (%) 68.3 100 98.5 100Smokers (%) 16.7 26.7 30.8 0.0

Alcohol history (%)nondrinkers 46.7 36.7 52.3 81.01-4/wk (equivalent to 1 ounce of spirits) 30.0 0.0 26.2 3.45-9/wk 6.7 11.7 20.0 5.210/wk 16.7 51.7 1.5 10.0

SD = standard deviation.



II). Over 50% of patients were currently receivingcisplatin chemotherapy and at least 25% of all pa-tients had experienced emesis. There were also dif-ferences in the disease site, the use of concomitantanticancer agents, the use of 5HT3 antiemetics andthe location of where the chemotherapy was beingadministered (table II). All of these differences im-ply that the sample in the current study was heter-ogeneous between countries, which requiredmulti-variable adjustment techniques.When the data from all patients were combined

regardless of country, responses from the rating

scores suggested an almost linear increase withevery 5 to 10% absolute reduction in the risk ofacute emesis (table III). As expected, patients gavethe highest importance rating score when the riskof acute emesis was reduced from a baseline riskof 30% to 0% (table III). When the mean WTPresponses were assessed, patients were willing topay from $US26 for a 5% risk reduction to $US46if the risk of emesis was reduced to 0% (table III).Similar results were also observed in the case ofdelayed emesis, where the maximum rating scorewas recorded if delayed emesis was eliminated (ta-

Table II. Patient clinical characteristics

Characteristic Canada (n = 60) Italy (n = 60) Greece (n = 65) Spain (n = 60)Previous chemotherapy (%) 91.7 35.0 87.7 100.0Previous cisplatin (%) 91.7 31.7 49.2 91.7Previous emesis (%) 43.3 26.7 64.6 63.3

Number of emetic episodes (%)no emesis 48.3 8.3 23.1 41.71-2 16.7 16.7 30.8 15.03-5 5.0 6.7 16.9 1.7>5 21.7 1.7 16.9 31.7not applicablea 8.3 65.0 12.3 8.3unknown 0.0 1.7 0.0 1.7

Disease site (%)ovarian 6.7 13.3 9.2 10.0body of uterus 11.7 3.3 0.0 6.7testes/bladder 11.7 10.0 13.8 3.3lung 60.0 31.7 61.5 30.0head and neck 10.0 13.3 4.6 3.3othersb 0.0 28.3 10.9 38.3unknown 0.0 0.0 8.3

Current cisplatin (%) 53.3 93.3 75.4 100.0

Concomitant chemotherapy (%)alkylating agents 6.7 5.0 7.7 1.7anthracyclines 5.0 26.7 10.8 11.7antimetabolites 3.3 23.3 1.5 3.3plant alkaloids 25.0 36.7 50.8 56.7others 13.3 1.7 4.6 26.7cisplatin alone 46.7 6.7 24.6 0.0

Previous treatment with 5-HT3 (%) 93.3 36.7 64.6 100.0Scheduled treatment with 5-HT3 (%) 61.7 96.7 58.5 100.0

Treatment location (%)inpatient 0.0 5.0 27.7 100.0outpatient 100.0 95.0 72.3 0.0

a Patients were cisplatin naïve prior to the current treatment.b Breast, lymphoma, endometrial, etc.5-HT3 = serotonin (5-hydroxytryptamine; 5-HT) type 3 receptor antagonist.



ble III). When asked howmuch they would pay fora 4-day period, patients were willing to pay $US24daily if the risk of delayed emesis was reducedfrom 40 to 30% and an additional $US4 for every10 percentage point reduction to 10%. Howeverwhen the risk was reduced from 40% to the com-plete elimination of emesis (0%), patients werewilling to pay $US40 per day (table III).The analysis was continued with a comparison

between countries. In the case of acute emesis, pa-tients from all countries consistently ranked thereduction from 30% to 0% as being the most im-portant to them (table IV). Nonetheless, there ap-peared to be differences between Spanish patientsand the other countries. Unlike the other ethnicgroups, where incremental importance was placedon each unit of reduction in risk, Spanish patientsplaced their maximum score only when the risk of

acute emesis was reduced to at least 10% (tableIV). The mean WTP for reducing the risk of acuteemesis was then compared between countries (ta-ble IV). It appeared that patients from Greece werewilling to pay substantially less than each of the 3other countries, across all the incremental risk re-ductions. In contrast, patients from Spain wereconsistently willing to pay the largest amount ofmoney to reduce their risk of emesis (table IV).The mean WTP was then assessed for delayed

emesis. As in the acute phase, patients fromGreecewere willing to pay less for the entire series of ben-efits than patients from the other countries (tableV). As in the previous comparison in acute emesis,there was also a trend that suggested that patientsfrom Spain were willing to pay more than the othercountries. However, before quantitative statementsabout statistical significance could be made, the

Table III. Rating scores and WTP for emesis risk reductionsOutcome Reduced to 30% Reduced to 25% Reduced to 20% Reduced to 10% Reduced to 0%

Acute emesisa

Median rating score (range)b 6 (0-10) 7 (0-10) 8 (0-10) 10 (0-10)Mean WTP ($US) [95% CI] 26 (21-30) 31 (26-36) 37 (32-42) 46 (40-52)

Delayed emesisc

Median rating score (range)b 6 (0-10) 7 (0-10) 8 (0-10) 10 (0-10)Mean WTP ($US) [95% CI] 24 (19-28) 28 (23-32) 32 (28-37) 40 (34-45)a Baseline risk for acute emesis = 30%.b Scale of 0 to 10 (perceived importance of emesis risk reduction; 0 = not at all important, 10 = very important).c Baseline risk for delayed emesis = 40%.CI = confidence interval; WTP = willingness to pay.

Table IV. Rating scores and WTP for acute emesis risk reduction by country. The baseline risk of acute emesis was 30%

Risk reduced to Canada Italy Greece Spain

Median rating scale scoresa

25% 5 5 6 720% 7 7 8 710% 8 8 9 80% 10 10 10 8

Mean WTP ($US) [SD]25% 35 (27) 17 (16) 5 (12) 47 (55)20% 40 (29) 24 (18) 6 (13) 54 (58)10% 46 (35) 34 (22) 8 (15) 63 (58)0% ≥55 (45) ≥45 (24) ≥15 (33) ≥72 (65)a Scale of 0 to 10 (perceived importance of emesis risk reduction; 0 = not at all important, 10 = very important).SD = standard deviation; WTP = willingness to pay.



data underwent statistical adjustment because dif-ferences existed between groups with respect tosocioeconomic and clinical characteristics (tablesI and II).Multivariable regression analysis was used to

compare maximum WTP between countries afteradjusting for differences in socioeconomic andclinical variables. The dependent variables in thetwo models were maximum WTP for a risk reduc-tion from 30 to 20% in the case of acute emesis and40 to 30% in delayed emesis. These risk reductionswere chosen because early data suggested that theyrepresent conservative estimates of the benefitoffered by the NK1 antagonists.[16,17]In the case of acute emesis, the only variables

that were significantly associated with maximumWTP were country and family income (table VI).Using Canadian patients as the base comparator,patients from Spain were willing to pay approxi-mately $US16 more for a 10% risk reduction inacute emesis (p = 0.01). In contrast, Italian patientswere willing to pay $US17 less than Canadian pa-tients (p = 0.006). Even though the data fromGreekpatients also suggested differences in WTP, the re-sults should be interpreted with caution since 97%of these patients were from the lowest income cat-egory (table I), which compromised the statisticaladjustment.Family incomewas also significantly associated

with WTP. Patients in the middle ($US20 000 to

$US49 000) and high (>$US50 000) income cate-gories were willing to pay significantly more forthe drug than patients with the lowest family in-comes (<$US19 000). Similar results were also ob-served in the analysis of delayed emesis, where sig-nificant differences between countries wereidentified and income was the only other variablesignificantly associated with WTP (table VI). Sur-prisingly, none of the clinical variables such as pre-vious history of emesis and the number of vomitingepisodes were associated with maximum WTP foreither acute or delayed emesis.

Comparison of Patient SubgroupsBetween Countries

The current study was not a randomised trial. Asa result, there existed considerable heterogeneityin clinical and socioeconomic variables betweencountries (tables I and II). Even though multivari-able analysis was used to adjust for these differ-ences, it would be of interest to compare WTP insimilar patients. Two relevant patient subgroupsassociated with the development of emesis are cur-rent treatment with platinum-based chemotherapyand a diagnosis of lung cancer. The latter group isunique because it typically consists of people in thelower socioeconomic level.In patients who were currently receiving plati-

num-based chemotherapy, the differences in WTPbetween countries remained for both the preven-

Table V. Rating scores and WTP for delayed emesis risk reduction by country. The baseline risk of delayed emesis was 40%

Risk reduced to Canada Italy Greece Spain

Median rating scale scoresa

30% 4 6 5 720% 6 7 7 710% 8 8 9 80% 10 10 10 8

Mean WTP ($US) [SD]30% 32 (29) 17 (14 5 (11) 42 (53)20% 37 (31) 23 (16) 6 (14) 45 (53)10% 41 (34) 31 (19) 9 (18) 50 (53)0% 49 (39) 40 (21) 15 (36) 56 (53)a Scale of 0 to 10 (perceived importance of emesis risk reduction; 0 = not at all important, 10 = very important).SD = standard deviation; WTP = willingness to pay.



tion of acute and delayed emesis. The findings in-dicated that Spanish patients had higher WTP esti-mates for all of the risk reductions relative to theother countries (table VII). The comparison be-tween Italian and Spanish patients is particularlyinteresting. Despite the close geographical prox-imity and similarity in religion, Spanish patientswere willing to pay approximately twice as muchto prevent acute and delayed emesis than a similargroup of Italian patients who were actively receiv-ing cisplatin chemotherapy (table VII).Similar outcomes were also observed when the

analysis was confined to lung cancer. Spanish pa-tients with lung cancer were willing to pay morethan patients from either Italy or Greece. However,the magnitude of the difference between Spanishand Canadian patients with lung cancer was notas wide as in the previous subgroup (table VIII).

Notwithstanding, the results in both subgroupsimply that even in patients with similar diseasecharacteristics receiving the same anticancer drug(i.e. cisplatin), the differences in WTP remained.Hence, these results support the findings of themultivariable analysis in that socioeconomic asopposed to clinical variables have amore dominantrole in a patient’s utility for new drugs.

Discussion

The 5HT3 receptor antagonists are already ex-pensive drugs; in North America alone, they repre-sent almost a billion dollar market. If phase IIIrandomised trials confirm the benefits offeredby the NK1 receptor antagonists, they will have asubstantial impact on hospital or national phar-macy budgets. As a result, important provisionsand planning will have to be made by formulary

Table VI. Multivariable analysis factors associated with WTP to reduce the risk of acute and delayed emesis

Variable Parameter estimate SEM p-Value Effect on WTP ($US)

Acute emesisa

Intercept 30.8 5.0Countryb

Italy –16.7 6.1 0.006 Overall ↓ by $US17Greece –24.8 6.4 <0.001 Overall ↓ by $US25Spain 16.2 6.4 0.01 Overall ↑ by $US16

Income categoryc

$US20 000 to $US49 000 12.6 5.3 0.01 Overall ↑ by $US13>$US50 000 24.5 8.6 0.007 Overall ↑ by $US24

Adjusted r-squaredd 24%

Delayed emesise

Intercept 24.3 4.7Countryb

Italy –15.9 5. 0.005 Overall ↓ by $US16Greece –19.5 6.0 0.001 Overall ↓ by $US19Spain 12.3 5.9 0.04 Overall ↑ by $US12

Income categoryc

$US20 000 to $US49 000 11.3 5.0 0.024 Overall ↑ by $US11>$US50 000 17.8 8.0 0.027 Overall ↑ by $US18

Adjusted r-squaredd 19%a Dependent variable: maximum WTP to reduce the risk of acute emesis from 30% to 20%.b Relative to Canadian patients.c Relative to low (<$US19 000) income patients.d Percentage of variability in the dependent variable that was accounted for by the model.e Dependent variable: maximum WTP to reduce the risk of delayed emesis from 40% to 30%.SEM = standard error of the mean; WTP = willingness to pay; ↑ = increase; ↓ = decrease.



committees in anticipation of the NK1 agents. Toprovide data on how patients would value the po-tential benefits offered by these agents, a multina-tional WTP study was conducted. Based on our re-view of the pharmacoeconomic literature, this isthe first study to use a contingent valuation ap-proach to compare patient value for a new drugbetween different countries. Furthermore, it can beargued that in the current study, WTP is a surrogatemeasure for quality of life improvement.For a series of potential risk reductions in eme-

sis ranging from 5 to 30% in the acute phase wherethe NK1 antagonist would be given for a single day,patients were willing to pay from $US26 to $US46.These results are interesting because they implythat patients would even value a benefit as small as5%,which supports the hypothesis that emesis con-tinues to have major impact on patient quality oflife. The results were even more striking in the caseof delayed emesis. Even for the smallest risk reduc-tion of 10%, patients were willing to pay $US24daily for 4 days (total cost $US96) for a new drugthat would offer such a benefit. Therefore, the find-ings suggest that formulary committees shouldconsider adopting the NK1 receptor antagonists forclinical use, even if the randomised phase III trialsdetermine that the benefits of these agents relativeto the current standard of care are marginal.

Given the multinational design of the currentstudy, it was possible to compare differences in pa-tient value from different cultural perspectives. Af-ter adjustment for socioeconomic and clinical vari-ables, Spanish patients were willing to pay morefor the new drug than Canadian patients. In con-trast, patients from Italy were not willing to pay asmuch as their Canadian counterparts. These varia-tions between countries in how patients with can-cer value benefit and improved quality of life areprobably related to cultural differences and pos-sibly to variations in the respective healthcaresystems. Cultural differences are directly associ-ated with underlying beliefs and attitudes that areunique in different groups of people. Hence, thesedifferences should be taken into considerationwhen generalising the results from quality-of-life(QOL) studies to different countries. Areas wherecontingent valuation and QOL research has to beextended include Africa, Asia and theMiddle East.To our surprise, clinical variables such as his-

tory of emesis or the number of previous vomitingepisodes during uncontrolled emesis were not sig-nificantly associated with the amount that a patientwould pay for a new drug. The only variable thathad an impact on WTP was income level. As hasbeen reported in other WTP studies, patients withhigher family incomes were typically willing to

Table VII. Comparison of maximum WTP in patients who were currently receiving platinum-based chemotherapy

Risk reduced to Mean maximum WTP ($US) [SD]Canada (n = 32) Italy (n = 56) Greece (n = 49) Spain (n = 60)

Acute emesisa

25% 42 (31) 17 (16) 6 (13) 47 (55)20% 43 (31) 23 (18) 7 (14) 54 (58)10% 49 (37) 33 (22) 8 (17) 63 (58)0% 61 (48) 44 (24) 16 (36) 72 (65)

Delayed emesisb

30% 36 (32) 16 (14) 6 (12) 42 (53)20% 41 (34) 23 (16) 8 (15) 45 (53)10% 46 (38) 30 (18) 9 (20) 50 (53)0% 56 (45) 39 (20) 18 (41) 56 (53)a Baseline risk for acute emesis = 30%.b Baseline risk for delayed emesis = 40%.SD = standard deviation; WTP = willingness to pay.



pay more for the incremental benefits of new phar-maceuticals than those in the lower income catego-ries.[21,26] The findings of the multivariable analy-sis imply that family economic circumstancesrather than clinical conditions have the most influ-ence on a patient’s decision to pay (or not to pay)for a new drug.In the sample size calculation, it was thought

that differences in healthcare systems betweencountries would have an impact on patient’s WTPfor a new cancer supportive care drug, the hypoth-esis being that patients managed in healthcaresystems that supply all prescription drugs free ofcharge would be less willing to pay for a new drug.A comparison between the 4 reference countriessuggested some similarities between systems withrespect to pharmaceuticals.In Greece, drugs are covered by public health

insurance through a variety of providers. There isa 25% copayment for all patients with the excep-tion of certain drugs for serious diseases such ascancer, which are reimbursed at 100%. In Italy andSpain, both public and private hospitals are avail-able to patients. All citizens are insured under thepublic health system, but people have the option ofseeking additional private health insurance. A pre-scription written by an Italian physician workingin the public healthcare system is reimbursed withonly a small copayment. In Spain, patients aged

<65 years have to pay 40% of the prescription costif written by physicians authorised to work in thepublic system. For patients from Spain aged ≥65years, the copayment is reduced to 10%. In con-trast, only patients aged ≥65 years in the provinceof Ontario would qualify for provincial drug insur-ance. This would consist of complete drug reim-bursement, with a $US2 copayment for each pre-scription. The rest of the population would have torely on private insurance or out-of-pocket paymentfor drugs.Given these circumstances in the different juris-

dictions, it was expected that the latter groupwould have been willing to pay more for a newdrug. Canadian patients were willing to pay morethan patients from Italy or Greece. However, thiswas not the case with patients from Spain. It wasalso interesting to note that the latter group placedless importance on additional emetic control, butwere willing to pay more than patients from othercountries (table IV and V). This finding did notsupport the underlying assumption in the samplesize calculation. However, a deviation in this as-sumption would not affect the overall power in thestatistical analysis.Given this finding, a closer description of the

Spanish patients is warranted. These patients camefrom the Clinica Universitaria de Navarra (Pam-plona, Spain) which is a privately funded institu-

Table VIII. Comparison of maximum WTP in patients with lung cancer

Risk reduced to Mean maximum WTP ($US) [SD]Canada (n = 36) Italy (n = 19) Greece (n = 40) Spain (n = 18)

Acute emesisa

25% 41 (29) 16 (18) 8 (15) 48 (61)20% 46 (33) 23 (21) 9 (15) 52 (61)10% 51 (41) 31 (23) 10 (18) 63 (52)0% 61 (52) 41 (24) 20 (41) 69 (65)

Delayed emesisb

30% 36 (32) 18 (16) 7 (13) 41 (62)20% 41 (34) 24 (17) 9 (17) 42 (61)10% 45 (38) 31 (19) 11 (22) 50 (61)0% 53 (45) 39 (21) 21 (45) 53 (62)a Baseline risk for acute emesis = 30%.b Baseline risk for delayed emesis = 40%.SD = standard deviation; WTP = willingness to pay.



tion with a strong religious affiliation. It is possiblethat given their background, these patients mayhave had higher overall expectations in terms ofbenefits from new drugs. Some of these expecta-tions would go beyond emesis control to diseasecure, resulting in a lower importance rank score.There are several limitations in the present study

that have to be addressed. The sample size was rel-atively small and the centres from each countrywere not randomly selected, which contributed topatient selection bias. Some biases may also havebeen introduced into the questionnaire followingtranslation. To minimise the effect of the transla-tion bias, all of the clinical scenarios were pre-sented using pictorial diagrams and pilot testedbefore implementation. The benefits of the NK1antagonists have not as yet been established inrandomised phase III trials. Therefore, in the cur-rent study, patients may be willing to pay for a non-existent benefit. The lowest benefit evaluated inthis study was 5%. If phase III trials fail to showthat NK1 antagonists offer patients significant ben-efits, then the findings of the present study shouldnot be applied. The final drawback to the study isrelated to the fact that patients from a truly market-driven healthcare system, such as in the US, werenot included. It would have been interesting tocompare the results from the 4 countries to thosefrom patients who received treatment in the US.

Conclusion

The findings of this multinational WTP studyshowed that reducing the risk of acute and delayedemesis following chemotherapy is a major concernto patients with cancer, and their WTP reflected thevalue that they placed on new and effective anti-emetics. However, there were substantial varia-tions between countries in how patients valuedbenefit and improved quality of life. This study hasshown significant differences across what mighthave been expected to be a relatively homogeneous‘Western’ population, suggesting that other studieswith ‘non-Western’ populations would show evengreater differences. Since the majority of theworld’s population resides outside North America

and Western Europe, there is a need to re-evaluateour perceived level of patient benefit and measuresof quality of life.

Acknowledgements

This study was supported in part through a research grantfrom Glaxo Wellcome, United Kingdom. The authors aremembers of the Pharmacoeconomics Study Group in CancerSupportive Care.

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Correspondence and offprints: George Dranitsaris, Depart-ment of Molecular Biology, The University Health Net-work/Princess Margaret Hospital, 610 University Avenue,Room 9-113, Toronto, Ontario M5G 2M9, Canada.E-mail: [email protected]



a multinational study to measure the value that patients with cancer place on improved emesis...

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