Abstracts

Second Joint Meeting of the Society for Clinical Trials and the International Society of Clinical Biostatistics

July 6-lo,1997

Marriott Copley Place, Boston, Massachusetts

01 SURROGATE ENDPOINTS IN CLINICAL TRIALS:

SOME STATISTICAL PERSPECTIVES Lars Frison

Astra H&de AB Molndal, Sweden

Surrogate endpoints (SEs) are frequently employed in clinical trials, for instance, lipid levels as a surrogate for arteriosclerosis and deep vein thrombosis as a surrogate for pulmonary embolism. The benefits are evident smaller sample sires, shorter trial durations, and sometimes avoidance of expensive or uncomfortable (e.g. invasive) measurements. Unfortunately, the other side of the coin is far from empty. In most applications it is known that the SE is correlated with the true endpoint (TE), however, whether a causal relationship exists, or simply association, is often unknown. A titrther complication is the possibility of an interaction causing the treatment effect to differ from SE relative to TE. Many cases have appeared in the literature where convincing positive results on SEs have translated to clearly negative results on the corresponding TEs, one example occurring in cardiac arrhythmia (e.g. the CAST trial). Obviously, the advantages gained by using SEs are often counterbalanced by a loss of relevance of the “new” underlying statistical hypothesis.

In this paper different statistical strategies for assessing the validity and usefulness of SEs will be suggested and contrasted. It will be shown that even strong statistical correlation between a SE and a TE is far from sufftcient for proving validity, evidence of causality is required. For a valid SE displaying convincing results the degree of confidence admissible in extrapolating conclusions to the TE will be suggested. Special interest will focus on the use of composite endpoints as SEs for rare TEs, issues addressed will include: how much treatment effect must persist for less hard endpoints for them to be useful as “add-ins” for a composite endpoint?

02 THE VALIDATION OF SURROGATE BNBPOINTS IN

BANDOMIZBD CLINICAL TRIALS

Gert Molenberghs and Marc Buyse Linsburgs Universitair Centrum

Diepenbeek Belgium

Prentice (Stat in Med 8:431,1989) proposed operational criteria for the validation of intermediate endpoints as surrogates for true endpoints in clinical trials. The criteria essentially require that the effect of treatment on the true endpoint be entirely captured by the surrogate.

Controlled Clinical Trials 18341S19OS (1997) 0 Elsevier Science Inc. 1997 655 Avenue of the Americas, New York, NY 10010

0197-2456/97/$17.00 PII %X97-2456(97)00023-8