Surrogate endpoint

Overview
A surrogate marker (or surrogate end point) is a term used in medical research for a change to the human body that has been documented to be involved in the causal pathway and necessary for an eventual outcome or end point to occur. In clinical trials, a surrogate endpoint is a measure of the effect (often what is known as a biomarker like cholesterol) of a certain treatment that is substituted in the evaluation of a new drug or device in place of a "hard endpoint" like death or heart attack. The National Institutes of Health (USA) defines surrogate endpoints as: "A biomarker intended to substitute for a clinical endpoint". The use of a surrogate endpoint can lead to more rapid and efficient completion of clinical trials, but the use of a surrogate endpoint has been criticized as reductions of a substitute maker are not always predictive of improvements in clinical outcomes. The classic example of a failed surrogate marker is the use of PVC suppression as a substitute marker of anti-arrhythmia effectiveness. Class III anti-arrhythmias reduced PVCs or extra heart beats, but were associated with a higher risk of death in the Cardiac Arrhythmia Suppression Trial (CAST). Surrogate markers may be used when it is unethical to look for the end point (e.g.,  death) in the experiment, or when the number of end point events is very  small, thus making it impractical to conduct an experiment to look for  the end point. The measurement of surrogate markers provides a way to test the effectiveness of a treatment for a fatal disease without having  to wait for a statistically significant number of deaths to occur. the FDA will often accept evidence from clinical trials that show a benefit to surrogate markers instead of to end points. As stated by Thomas Fleming: "The accelerated-approval regulatory process is intended to address this need by allowing marketing of interventions shown to have strong effects on measures of biological activity, if those measures are potential "surrogates" for true measures of tangible clinical benefit. "

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 in the RECORD trial.

In another example, class III antiarrhythmic agents were associated with suppression of premature ventricular contractions or PVCs, but were associated with a higher rate of death.

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.

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.

Examples of Surrogate Endpoints
Examples of surrogate markers include: TTP;
 * Total cholesterol
 * High density lipoprotein (HDL)
 * Low density lipoprotein (LDL)
 * c reactive protein (cRP)
 * Platelet inhibition by light transmittance aggregometry
 * Coronary blood flow
 * Minimum diameter or an artery and restenosis
 * Fragmented blood cells are a surrogate marker for organ failure or stroke in
 * The 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.
 * Tumor shrinkage
 * CEA levels in colon cancer trials
 * Prostate specific antigen PSA in prostate cancer.

Evaluation of a Surrogate Endpoint
There are multiple criteria that have been proposed to evaluate surrogate endpoints.

Does the surrogate lie in the causal pathway of disease, or is it simply a prognostic marker?
Examples of this criteria include CEA in colon cancer and PSA in prostate cancer. As stated by Thomas Flemming "While CEA and PSA are not the mechanism through which  the disease process induces increased risk of the clinical-efficacy  outcomes, so it is questionable whether treatment-induced changes in  these markers could be relied upon to accurately predict  treatment-induced effects on the clinical endpoints. "

Are there multiple causal pathways present?
If there are multiple causal pathways present, what is the relative strength of the proposed surrogate relative to that of other pathways. This may alternatively lead to an over or under estimate of the impact of the surrogate marker.

Is there "off target" toxicity associated with altering the surrogate endpoint?
It is possible that the intervention being test could be associated with other deleterious mechanisms of action that are independent of its intended therapeutic effects. Very often, because such effects are unintended, they are unanticipated, unrecognized, and unrecorded.The classic example of this is the hypertension caused by torcetrapib, or the pro-arrhytmic effects of class III antiarrhythmia agents as demonstrated in the CAST trial.

Proposed criteria for a surrogate endpoint
One investigator, Ross Prentice, proposed that the following two conditions must be meant :


 * 1) The biological marker must be correlated with the clinical endpoint; and
 * 2) The marker must fully capture the net effect of the intervention on the clinical-efficacy endpoint.

From the persepctive of C. Michael Gibson, author of this chapter, a surrogate may be clinically relevant if the following three criteria are satisfied:


 * 1) The drug or device improves the surrogate
 * 2) Improvement in the surrogate is related to an improvement in a hard clinical endpoint
 * 3) The same drug or device improves the hard clinical endpoint

In order for a surrogate to be validated, there must be at least one large clinical trial that satisfies these criteria. After this, other studies could rely upon the surrogate if it has been validated in a large study.