1 Surrogat - endepunkter: Teori og empiri Fagdag i helseøkonomi 3. mars 2009 Ivar Sønbø Kristiansen Institutt for helseledelse og helseøkonomi, UiO Institut for Sundhedstjenesteforskning, Syddansk Universitet, Odense

2 Conflict of interest Institutt for helseledelse og helseøkonomi har mottatt et doktorgradsstipend av Legemiddelindustriforeningen for blant annet å studere validiteten av surrogat- endepunkter

3 Surrogate endpoint ”Any end point that substitutes for and predicts a final patient-related outcome” May lead to shorter and smaller studies and faster times to licensing and dissemination of new technologies (Taylor-RS and Elston-J. Health Technology Assessment 2009; 13: No. 8)

4 Surrogate endpoints (Taylor-RS and Elston-J. Health Technology Assessment 2009; 13: No. 8) DiseaseSurrogate endpoint Clinical endpoint HIV infectionCD4 countAIDS or death Colorectal cancerTumour progression Life years Cardiovascular disease Blood pressure Cholesterol level Life years GaucomaIntrocular pressureVision loss OsteoporosisBone mineral density Bone fracture

5 Surrogate endpoint ”successes” Coronary Heart Disease Policy Model (Goldman et al., 1991) corroborated by 4S trial of statins in secondary prevention Others

6 Surrogate endpoint failures AZT treatment for HIV/AIDS Premature ventricular beats: CAST I/II trials (encainide, flecainide, moricizine) WHO clofibrate study

7 RCT clofibrate versus placebo (n=3,898) 5-year mortality: 20.9% vs 20.9% (p=0.55) Clofibrate 80%+ dose: 15.0% mortality Clofibrate 0-79% dose: 24.6% mortality Placebo 80%+ dose: 15.1% mortality Placebo 0-79% dose: 24.6% mortality Placebo-difference adjusted for 40 explanatory variables: 16.4% vs 25.8% (p< ) Cholesterol as surrogate endpoint NEJM 1980; 303: )

8 Perfect surrogate endpoints Surrogate endpoint Clinical outcome One single causal link

9 Perfect surrogate endpoints Surrogate endpoint Clinical outcome One single causal link

10 Perfect surrogate endpoints Surrogate endpoint Clinical outcome Rabies One single causal link

11 Reasons for surrogate endpoint failure (Taylor-RS and Elston-J. Health Technology Assessment 2009; 13: No. 8)

12 Prentice-kriteriene “For a valid surrogate endpoint, a test of the null hypothesis of no relationship to the treatment groups for the surrogate endpoint is also a valid test of the corresponding null hypothesis for the true clinical outcome.” Prentice anførte fire kriterier for at dette kravet skal være oppfylt. Disse benyttes lite i dag da de er ansett å være for strenge, men teoretisk sett optimale (Prentice. Surrogate endpoints in clinical trials: definition and operational criteria. Statistics in medicine 1989;8(4):431)

13 Prentice-kriteriene f(S|T) ≠f(S) (treatment affects distr. surrogate) f(C|T)≠f(C) (treatment affects clinical outcome) f(C|S)≠f(C) (surrogate affects clinical outcome) f(C|S,T)=f(C|S) (all treatment effects go through surrogate) S = Surrogat C = Clinical outcome T = Treatment (Prentice. Surrogate endpoints in clinical trials: definition and operational criteria. Statistics in medicine 1989;8(4):431)

14 Validering i praksis Det vanlige i praksis er å lage en regresjonsmodell: C = f(a+bS) Beregner a og b ved en eller annen regresjonsteknikk. a=0 betyr at bare S påvirker C (Prentice kriterium 4) b ≠ 0 betyr at S påvirker C (Prentice kriterium 1-3) Individ-data versus aggregerte data Mange meta-regresjoner på kreft, få på hjertekarsykdom Medline: 50,000 hits for RCT and (hypercholesterolaemia or hypertension) Håvard Andre Larsen et al: Blood pressure as surrogate endpoint in antihypertensive treatment: A Bayesian meta regression (unpublished)

15 Validering i praksis datagrunnlag Kunnskapssenterets rapport om medikamentell primærprevensjon med antihypertensiva og kolesterolsenkende medikamenter 29 studier på hypertensjon Ekskluderte studier med diabetes og/eller behandlingsskifte i studien, eller manglende info om varians i surrogat og/klinisk endepunkt (n=20) Surrogat-endepunkt: blodtrykk Klinisk endepunkt: slag og død (antall slag og dødsfall) Håvard Andre Larsen et al: Blood pressure as surrogate endpoint in antihypertensive treatment: A Bayesian meta regression (unpublished)

16 Validering i praksis: studiene StudyTreatmentLn RR(Stroke) b + SD(b) Ln RR(Death) B SD(b) BP difference Mean (SD) STOPHydrochlorothazide and triameterene vs placebo (0.20) (0.23) (0.89) STOP2ACE-inhibitor vs beta-blocker and diuretics (0.067) (0.09) 2.14 (0.28) VALUEValsartan vs amlodipine (0.046) (0.08) 2.0 (0.065) NORDIL Dilitiazem vs Diuretic (0.091) (0.11) 3.20 (0.105) SHEP Chlorthalidone vs Placebo (0.089) (0.12) (0.23) SYST EUR Nitrendipine vs Placebo (0.121) (0.18) -9.0 (0.24) ASCOT BPLA Amlodipine vs Atenolol (0.049) (0.07) -3.8 (0.064) SCOPE Candersatan vs Placebo (0.14) (0.28) -5.0 (0.62) ALLHAT Amlodipine vs chlorthalidone (0.033) (0.06) 1.6 (0.041)

17 Validering i praksis Bayesian meta regression with DIC criterion performed in Winbugs Poorest fit: model without surrogate Best fit: model with intercept, covariance between endpoints included, but between-trial variance=0. Surrogate impacts clinical outcomes, but larger SDs for stroke – more uncertain predictions for stroke than mortality

18 Validering i praksis Håvard Andre Larsen et al: Blood pressure as surrogate endpoint in antihypertensive treatment: A Bayesian meta regression (unpublished)

19 Prediksjon av effekt av blodtrykksreduksjon på dødelighet (n=2.000) Blood pressure difference (mmHg) SERR Håvard Andre Larsen et al: Blood pressure as surrogate endpoint in antihypertensive treatment: A Bayesian meta regression (unpublished)

20 RCTs and clinical endpoints 324 consecutive CVD trials JAMA, Lancet, NEJM Surrogate as primary endpoint: 77/115 (67%) ”positive” Clinical as primary endpoint: 113/209 (54%, p=0,02) ”positive” (Ridker et al. Jama 2006; 295: )

21 UK HTA study UK HTA program monographs (n=100) 4 based on cost-effectiveness models Recommendation: –Primarily clinical relevant endpoints incl HRQOL –Review of the evidence of the surrogate Level 1: association in RCTs Level 2: association in observational studies Level 3: plausibility based on biological models (Taylor&Elston: HTA 2009; 13: No. 8

22 Tentative konklusjoner Surrogatendepunkter kan gi valid prediksjon av kliniske endepunkter Surrogatendepunkter behøver ikke gi valid prediksjon av kliniske endepunkter Hvorfor skulle man unnlate å gjøre studier med kliniske endepunkter når det likevel genereres lastbil-lass med dokumentasjon?