The true treatment benefit is unpredictable in clinical trials using surrogate outcome measured with diagnostic tests.
OBJECTIVE
Clinical trials increasingly use results of diagnostic tests as surrogate outcomes. Our objective was to answer the following questions: (1) is the parameter measured by the reference standard a valid surrogate? (2) How does the tests accuracy influence the estimate of the treatment benefit on surrogate? (3) Is it possible to correct the measured treatment effect given by results of inaccurate tests?


METHODS
We reviewed the literature on asymptomatic deep venous thrombosis (DVT), detected by the reference standard and other imaging techniques, as surrogate for venous thromboembolism. The influence of test inaccuracy on the measurement of treatment benefit was calculated as a function of the patient baseline risk, the treatment effect model, and test performances.


RESULTS
We show that: (1) asymptomatic DVT is correlated with clinical outcomes but is yet to be established as a surrogate; (2) inaccurate diagnostic test underestimates the treatment effect on surrogate; (3) the prevalence of the disease, the treatment effect model, and the accuracy of the test and the reference standard used to evaluate it need to be known to correct this underestimation.


CONCLUSIONS
Even when the surrogate end point is valid, without a reliable study of the diagnostic test we cannot quantify the true treatment effect.
Kassaï
Behrouz
B
Department of Clinical Pharmacology/EA 3736, University Hospital of Lyon, Rue Guillaume Paradin, BP 8071, Lyon cedex 08 69376, France. bk@upcl.univ-lyon1.fr
Shah
Nirav R
NR
Leizorovicza
Alain
A
Cucherat
Michel
M
Gueyffier
Francois
F
Boissel
Jean-Pierre
JP
D015415:Biomarkers / Q000032:analysis; D002986:Clinical Trials as Topic / Q000379:methods*; D003955:Diagnostic Tests, Routine; D006801:Humans; D011183:Postoperative Complications / Q000517:prevention & control; D011859:Radiography; D012015:Reference Standards; D012107:Research Design; D013923:Thromboembolism / Q000000981:diagnostic imaging / Q000517:prevention & control; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000000981:diagnostic imaging* / Q000517:prevention & control*
D015415:Biomarkers