The risky reliance on small surrogate end point studies when planning a large prevention trial

• Published in: Journal of the Royal Statistical Society. Series A, Statistics in society Vol. 176; no. 2; pp. 603 - 608
• Main Authors: Baker, Stuart G., Kramer, Barnett S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2013; Blackwell Publishing; Oxford University Press
• Subjects: Biological markers; Cancer; Cancer prevention; Cardiovascular disease; Cardiovascular diseases; Chronic diseases; Chronic illnesses; Decision making; Diseases; Error rates; Experimentation; Heart disease; Hypotheses; Mathematical extrapolation; Medical treatment; Middle age; Null hypothesis; Prentice criterion; Prevention; Principal stratification; Random allocation; Risk assessment; Sample size; Sample size calculation; Surrogate end point
• ISSN: 0964-1998; 1467-985X
• DOI: 10.1111/j.1467-985X.2012.01052.x

The definitive evaluation of treatment to prevent a chronic disease with low incidence in middle age, such as cancer or cardiovascular disease, requires a trial with a large sample size of perhaps 20000 or more. To help to decide whether to implement a large true end point trial, investigators first typically estimate the effect of treatment on a surrogate end point in a trial with a greatly reduced sample size of perhaps 200 subjects. If investigators reject the null hypothesis of no treatment effect in the surrogate end point trial they implicitly assume that they would probably correctly reject the null hypothesis of no treatment effect for the true end point. Surrogate end point trials are generally designed with adequate power to detect an effect of treatment on the surrogate end point. However, we show that a small surrogate end point trial is more likely than a large surrogate end point trial to give a misleading conclusion about the beneficial effect of treatment on the true end point, which can lead to a faulty (and costly) decision about implementing a large true end point prevention trial. If a small surrogate end point trial rejects the null hypothesis of no treatment effect, an intermediate-sized surrogate end point trial could be a useful next step in the decision-making process for launching a large true end point prevention trial.