Surrogate endpoint
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
In clinical trials, a surrogate endpoint 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 endpoints as: "A biomarker intended to substitute for a clinical endpoint".[1]
The advantages of a surrogate endpoint
The assessment of "hard" primary clinical endpoints (such as death and heart attack) often requires large long-term clinical trials which can be quite expensive. The use of surrogate endpoints can allow trials to evaluate the efficacy of a new drug or device more rapidly, more efficiently and more inexpensively.
The disadvantage of surrogate endpoints
There are several potential disadvantages of a surrogate endpoint.
1. The surrogate endpoint may intuitively be hypothesized to be related to a "hard endpoint" such as death or heart attack, but may not be.
2. While a surrogate endpoint may be related to a "hard endpoint" such as death or heart attack, it is not clear that a reduction in the surrogate endpoint will lead to an improvement in the "hard endpoint" in death or heart attack. Anti-diabetic agents have been shown to reduce long term glucose (Hemoglobin A1c or HbA1C). It was hypothesized that more intense glucose control (a reduction in HbA1C) would be associated with a lower rate of death and heart attack. However, despite lowering of HbA1C, rosiglitazone or Avandia was not associated with a reduction in death and MI, but with an increase.
3. While a surrogate endpoint may be related to a "hard endpoint, it may be an acausal association (the surrogate may not lie in the causal pathway to the "hard endpoint" and changing the surrogate endpoint may not change the "hard endpoint".)
4. The agent may reduce the surrogate endpoint, but due to off target toxicity, may increase the risk of "hard endpoints" such as death or MI. Lower HDL is associated with a higher risk of adverse cardiac outcomes, Torcetrapib raises HDL and should therefore improve clinical outcomes, however, Torcetrapib administration was found to be associated with a higher rate of adverse clinical outcomes. It was felt that the potential benefit of Torcetrapib was reversed due to off target toxicity of a slight increase in blood pressure associated with Torcetrapib administration.
5. The relationship between the surrogate endpoint and the "hard endpoint" may be non-linear or may be a threshold effect. For example, in antiplatelet agent studies, it is unclear if ever greater levels of inhibition of platelet aggregation are associated with ever greater reductions in adverse outcomes, or if one must achieve just a certain "threshold" level of inhibition to improve outcomes.
Examples of Surrogate Endpoints
For example, most cholesterol-lowering drugs (e.g. the statins) are used to control cardiovascular disease, yet they were introduced with only information on their capacity to decrease cholesterol levels. 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. In the case of simvastatin (Zocor®), proof of its efficacy in reducing cardiovascular disease was only presented five years after its original introduction, and then only for secondary prevention. 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.
References
- ↑ Controlled Clinical Trials 22:485–502 (2001))