Rescuing Clinical Trial Data For Economic Evaluation Paul Kind, Ph.D. Jan van Busschbach, Ph.D. Frank de Charro, Ph.D.

Overview of the workshop Frank de Charro: Introduction Jan van Busschbach: How to shoot straight at the goal Paul Kind: How to score with more subtle combinations

The problem Many clinical studies do not generate outcomes data that are suitable for economic evaluation They may include condition-specific measures but these were generally not designed for the type of analysis required Such studies may include measures of health-related quality of life as secondary endpoints

Economic evaluation Cost Effectiveness Analysis Measure of effectiveness can be anything as long as scaling properties are ok Cost Utility Analysis Measure of effectivenss: QALYs

EQ-5D: Descriptive System Classification of health states using 5 dimensions mobility self care usual activity pain / discomfort anxiety / depression 3 problem levels for each (none / some / extreme) defines a total of 35 = 243 health states Pain Self-care Mood Health state Health multi dimensional EuroQol Group chose fice dimension Three levels 243 helath states The instrument can be used to generate a single index for a health state Mobility Usual activities 22

EQ-5D questionnaire

Scoring EQ-5D health states State A : 1 1 2 2 3 State B : 1 1 3 2 2 Population TTO weights State B : 1 1 3 2 2

The challenge To devise methodologies that can be used to convert outcomes data collected in clinical studies into a form that have the necessary attributes to support economic evaluation (CUA)

Rescuing economic analysis Clinical study Clinical analysis/report Economic analysis / report Cost-effectiveness Cost-utility Secondary data Primary

A word of caution Quality adjustment is one of the most important outcome characteristics Indirect approaches involve uncertainty and diminish the potential to differentiate between a treatment and its alternativess Cost effectiveness will be judged taking into account uncertainty and using probabilistic models So crosswalks are second best but better than no coverage of utility at all

The valuation of disease-specific health states Jan J. v. Busschbach, Ph.D. Erasmus MC Institute for Medical Psychology and Psychotherapy www.busschbach.nl Sildenafil (Viagra)

The effects of Sildenafil in terms QALY’s is complicated QALYs are measured with standardised and validated quality of life questionnaires EQ-5D or HUI III were not included Not sensitive for erectile dysfunction?

Clinical outcomes Gradations erectile dysfunction were chosen as clinical outcomes Measured with the IIEF International Index of Erectile Function Primary end points: Question 3 and 4 Ability to attain an erection Example: During intercourse I am sometimes able to penetrate Ability to maintain an erection I can almost never maintain the erection during intercourse after penetration

Clinical, disease specific outcomes Goldstein et al., N Engl J Med, 1998

How to convert clinical outcomes into QALYs ? 2 questions 5 answer levels = 25 health states Why not value the 25 these health states with Time Trade-Off ? 169 subjects of the general public Valued the 25 health states with TTO Individual administration within groups sessions Validation of procedure in students (group versus individual)

25 Erectile Dysfunction States During intercourse I am sometimes able to penetrate I can almost never maintain the erection during intercourse after penetration

TTO values have logic structure

Transferred clinical outcomes into QALYs On the basis of Goldstein et al., N Engl J Med, 1998

QALY league table

Disease specific utilities are not equal to generic utilities Healthy Death No complains All complains Only the disutility of the specific disease is valued Generic and specific utilities are not on the same scale Generic top anchor: absence of any impairment Specific top anchor: absence of specific impairment Co morbidity might still be present

How to interpret disease specific utilities Value of life years “traded off” in TTO differ Healthy subject: 1 life year is 1.0 QALY Sick subject: 1 life year is 0.5 QALY Life years of healthy persons are more worth than those of sick Overall health states influence disutility 20% trade off at 1.00: disutility = 0.20 20% trade off at 0.80: disutility = 0.16 20% trade off at 0.60: disutility = 0.12 Raw disease specific trade-off overestimated gains

Specific utilities should be corrected for average morbidity Solution: multiplicative model Multiply disease specific value with average value Values have to be multiplied by average value for age group. For instance in IPSS male age 55-64: overall QoL utility: 0.81 Most severe BPH: 0.87 Male age 55-64 with most severe BPH: 0.81 x 0.87 = .7047 Maximum gain reduces from Raw score 1.00 - 0.87 = 0.13 Adjust score 0.81 - 0.70 = 0.11 15 % reduction

Rue of thumb Overestimated CE-ration by 15% using specific utilities Proposed by Fryback & Lawrence, MDM 1997 For not completely the same problem… …for own health states, not imaginable health states

Conclusion (1) We validated the IIEF and the IPSS for the use in economic appraisal Now, IPSS and IIEF has QALY-weights Many other applications possible (health states of…) diabetic foot ulcers Advantage High sensitive disease specific measures for QALY-analysis No need for generic instrument Disadvantages Not directly compatible with generic utilities…. ± 15 % correction needed

Overestimation? Does the focus on the disease makes the disutility to high?

Crosswalks: recalibrating Paul Kind Visiting Professor University of Uppsala, Sweden Principal Investigator Outcomes Research Group Centre for Health Economics University of York England pk1@york.ac.uk

Recalibration – the task Source assumed to be a clinical / condition-specific (sensitive) measure Format Summary score / Index Subscale scores / dimension scores Items (all or selected) Target assumed to be a generic index weighted using social preferences Task – to recalibrate source in terms of target

Recalibration strategies - direct Derive direct estimates of social preferences for source index May require simplification of complex descriptive system Will have implications for time and resourcing May conflict with instrument developer agenda

Recalibration strategies - indirect Multiple solutions linking all or part of source instrument with the target index (directly or indirectly) Strategy A Estimate target index from A1 source index A2 sources subscales A3 source items Strategy B Estimate target dimension/levels from B1 source subscales B2 source items

Strategy A1 25 item condition sensitive instrument with widespread usage in its therapeutic field Yes/no answers coded to 1/0 All items assumed equal weight Summary index General population survey of circa 1,000 yielded parallel observations with EQ-5D

A mean estimated observed EQ-5D’ = 0.9696 – 0.0204* A 0.000 0.943 0.970 1.000 0.931 0.949 2.000 0.893 0.929 3.000 0.873 0.908 4.000 0.900 0.888 5.000 0.817 0.868 6.000 0.872 0.847 7.000 0.820 0.827 8.000 0.806 9.000 0.852 0.786 10.000 0.743 0.766 11.000 0.795 0.745 12.000 0.780 0.725 13.000 0.747 0.704 14.000 0.793 0.684 15.000 0.712 0.664 16.000 0.564 0.643 17.000 0.626 0.623 18.000 0.761 0.602 19.000 0.275 0.582 20.000 0.562 21.000 0.541 22.000 0.521 23.000 0.500 24.000 0.480 25.000 0.460 EQ-5D’ = 0.9696 – 0.0204* A

Issues Number of observations across “severity” range Subgroup impact Age / gender Significant factors but small effect Regression on mean observations Why not micro level ? Less good fit Tricky / messy business May not significantly improve estimation EQ5D’ = 0.9419 – 0.0163

Strategy A3 EORTC QLQC-30 EORTC QLQC-30 is a generic measure of health-related quality of life (HrQoL) in cancer. Version #3 consists of 28 items with a 4-category response and 2 further items (general health and quality of life) are coded on a 7-point response category scale (see selected items below). Responses are converted into corresponding numeric scores that may be summed to produce a total score. However, QLQC-30 cannot be used in cost-effectiveness analysis because it is not standardized on a value scale where full health = 1 and dead = 0.

EORTC QLQC-30 selected items

Data Baseline observations from a previously reported study of 177 patients with pancreatic cancer were available for analysis. HrQoL in these patients had been assessed by self-report using both the QLQ-C30 and EQ-5D measures. Additional baseline data on patients included their Karnofsky Performance Scale rating

Methods The first 28 QLQC-30 items were dichotomised (not at all = 0 ; quite a bit to very much = 1) and these items, together with the uncoded response to item 29 (general health) were entered in a stepwise linear regression in which EQ-5Dindex was the dependent variable.

Results The results of this regression analysis are given in Table 1, showing that only 6 of the QLQC-30 items proved to be significant. The r2 of 0.490 equates with levels seen in other such calibration studies. Correlation between observed EQ-5Dindex and estimated values was generally high. However, correlation between observed EQ-5Dindex and estimated value amongst female patients is higher than for male patients in the sample (r = 0.725 vs 0.662). Mean differences across all patients was -0.001 Figure 1 shows the scatterplot of observed EQ-5D and the value derived for each patient using the 6-item QLQC-30 model

Table 1 : Coefficients from stepwise OLS regression model Unstandardized Coefficients Std. Error Significance (Constant) 0.633 .071 .000 Q29 Overall health 0.047 .013 .001 QX3 trouble with short walk -0.124 .031 QX26 physical family life impact -0.082 .009 QX5 help with dressing washing -0.167 .047 QX20 difficulty concentrating -0.102 .033 .002 QX11 trouble sleeping -0.086 .032 .007

Figure 1 : Observed and estimated values for EQ-5Dindex

Figure 2 : Mean observed and estimated EQ-5Dindex values for categories of Karnofsky Performance Scale

Try to keep going straight if possible Have a nice walk But also Try to keep going straight if possible www.euroqol.org rabin@frg.eur.nl userinformationservice@euroqol.org