Surrogate endpoint

In clinical trials, a surrogate endpoint (or marker) is a measure of effect of a certain treatment that may correlate with a "real" endpoint but doesn't necessarily have a guaranteed relationship. The National Institutes of Health (USA) define surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint". [Controlled Clinical Trials 22:485–502 (2001))] [cite journal | author = Cohn JN | title = Introduction to Surrogate Markers | journal = Circulation | volume = 109 | pages = IV20–1 | publisher = American Heart Association | date = 2004 | doi = 10.1161/01.CIR.0000133441.05780.1d | accessdate = | pmid=15226247 ]

Surrogate markers are used when the primary endpoint is undesired (e.g., death), or when the number of events is very small, thus making it impractical to conduct a clinical trial to gather a statistically significant number of endpoints. The FDA will often accept evidence from clinical trials that show a benefit to surrogate markers instead of to endpoints.fact|date=January 2008

A commonly used example is cholesterol. While elevated cholesterol levels increase the likelihood for heart disease, the relationship is not linear - many people with normal cholesterol develop heart disease, and many with high cholesterol do not. "Death from heart disease" is the endpoint of interest, but "cholesterol" is the surrogate marker. A clinical trial may show that a particular drug (for example, simvastatin (Zocor)) is effective in reducing cholesterol, without showing directly that simvastatin prevents death. Proof of Zocor's efficacy in reducing cardiovascular disease was only presented five years after its original introduction, and then only for secondary prevention. [cite journal|author=Pedersen TR, Olsson AG, Faergeman O, "et al."|title=Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)|journal=Circulation|year=1998|volume=97|pages=1453–1460] In another case, AstraZeneca has been accused of marketing rosuvastatin (Crestor) without providing hard endpoint data, relying instead on surrogate endpoints. The company counters that it had been tested on larger groups of patients than any other drug in the class, and that its effects should be comparable to the other statins.

Examples of other surrogate markers include:
* fragmented blood cells are a surrogate marker for organ failure or stroke in TTP;
* S phase duration may be used as a surrogate marker for breast cancer occurrence;
* CD4 count is a surrogate marker for death from HIV infection.

Criticism

There have been a number of instances when studies using surrogate markers have been used to show benefit from a particular treatment, but later, a repeat study looking at endpoints has not shown a benefit, or even a harm. [cite journal|author=Psaty BM, Weiss NS, Furberg CD, "et al." | title=Surrogate end points, health outcomes, and the drug approval process for the treatment of risk factors for cardiovascular disease | journal=JAMA | year=1999 | volume=282 | pages=786–790|doi=10.1001/jama.282.8.786 | pmid=10463718]

References