surrogat - endepunkter: teori og empiri
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Surrogat - endepunkter:Teori og empiri
Fagdag i helseøkonomi 3. mars 2009Ivar Sønbø Kristiansen (ivarsk@c2i.net)
Institutt for helseledelse og helseøkonomi, UiO
Institut for Sundhedstjenesteforskning, Syddansk Universitet, Odense
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Conflict of interest
• Institutt for helseledelse og helseøkonomi har mottatt et doktorgradsstipend av Legemiddelindustriforeningen for blant annet å studere validiteten av surrogat-endepunkter
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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)
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Surrogate endpoints
(Taylor-RS and Elston-J. Health Technology Assessment 2009; 13: No. 8)
Disease Surrogate endpoint
Clinical endpoint
HIV infection CD4 count AIDS or death
Colorectal cancer Tumour progression
Life years
Cardiovascular disease
Blood pressure Cholesterol level
Life years
Gaucoma Introcular pressure Vision loss
Osteoporosis Bone mineral density
Bone fracture
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Surrogate endpoint ”successes”
• Coronary Heart Disease Policy Model (Goldman et al., 1991) corroborated by 4S trial of statins in secondary prevention
• Others
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Surrogate endpoint failures
• AZT treatment for HIV/AIDS • Premature ventricular beats: CAST I/II trials
(encainide, flecainide, moricizine)• WHO clofibrate study
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• 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<0.000000007)
Cholesterol as surrogate endpoint
NEJM 1980; 303: 1038-41)
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Perfect surrogate endpoints
Surrogate endpoint
Clinical outcome
One single causal link
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Perfect surrogate endpoints
Surrogate endpoint
Clinical outcome
One single causal link
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Perfect surrogate endpoints
Surrogate endpoint
Clinical outcome
Rabies
One single causal link
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Reasons for surrogate endpoint failure
(Taylor-RS and Elston-J. Health Technology Assessment 2009; 13: No. 8)
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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)
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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 = SurrogatC = Clinical outcomeT = Treatment
(Prentice. Surrogate endpoints in clinical trials: definition and operational criteria.
Statistics in medicine 1989;8(4):431)
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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)
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Validering i praksisdatagrunnlag
• 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)
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Validering i praksis: studieneStudy Treatment Ln RR(Stroke)
b + SD(b)
Ln RR(Death)
B SD(b)
BP difference
Mean (SD)
STOP Hydrochlorothazide and triameterene vs placebo
-0.556 (0.20)
-0.599 (0.23)
-22.0 (0.89)
STOP2 ACE-inhibitor vs beta-blocker and diuretics
0.033 (0.067) -0.094
(0.09)
2.14 (0.28)
VALUE Valsartan vs amlodipine
0.021 (0.046)
0.129(0.08)
2.0(0.065)
NORDIL
Dilitiazem vsDiuretic
0.024(0.091)
-0.198(0.11)
3.20(0.105)
SHEP Chlorthalidone vs Placebo
-0.125(0.089)
-0.428(0.12)
-14.0(0.23)
SYST EUR Nitrendipine vs
Placebo-0.151
(0.121)-0.537(0.18)
-9.0(0.24)
ASCOT BPLA Amlodipine vs
Atenolol-0.108
(0.049)-0.257(0.07)
-3.8(0.064)
SCOPE Candersatan vsPlacebo
-0.080(0.14)
-0.546(0.28)
-5.0(0.62)
ALLHAT Amlodipine vs chlorthalidone
-0.040(0.033)
-0.060(0.06)
1.6(0.041)
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Validering i praksis
2 2 2 2 21 1 1 1 1 1 1 2
2 2 2 2 22 2 2 1 2 2 2 2
~ ,i i i i i
i i i i i
N
• 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
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Validering i praksis
-24 -22 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 2 4 6 8
-0.6
-0.4
-0.2
BP difference
LN(RR)
Håvard Andre Larsen et al: Blood pressure as surrogate endpoint in antihypertensive treatment: A Bayesian meta regression (unpublished)
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Prediksjon av effekt av blodtrykksreduksjon på dødelighet
(n=2.000)Blood pressure
difference (mmHg)SE RR
1 0.4 0.99
3 0.4 0.96
5 0.4 0.93
7 0.4 0.91
Håvard Andre Larsen et al: Blood pressure as surrogate endpoint in antihypertensive treatment: A Bayesian meta regression (unpublished)
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RCTs and clinical endpoints
• 324 consecutive CVD trials• JAMA, Lancet, NEJM 2000-2005• 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: 2270-4)
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UK HTA study
• UK HTA program monographs 2005-6 (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
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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?
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