Surrogate endpoint
Encyclopedia
In clinical trial
s, a surrogate endpoint (or marker) is a measure of effect of a certain treatment that may correlate with a real clinical endpoint
but doesn't necessarily have a guaranteed relationship. The National Institutes of Health
(USA) defines surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint".
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
and other regulatory agencies will often accept evidence from clinical trial
s that show a direct clinical benefit to surrogate markers.
A correlate does not make a surrogate. It is a common misconception that if an outcome is a correlate (that is, correlated with the true clinical outcome) it can be used as a valid surrogate end point (that is, a replacement for the true clinical outcome). However, proper justification for such replacement requires that the effect of the intervention on the surrogate end point predicts the effect on the clinical outcome—a much stronger condition than correlation.
The term "surrogate" should not be used in describing end points. Instead, descriptions of results and interpretations should be formulated in terms that designate the specific nature and category of variable assessed.
A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.
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. 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.
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, a surrogate endpoint (or marker) is a measure of effect of a certain treatment that may correlate with a real clinical endpoint
Clinical endpoint
In a clinical research trial, a clinical endpoint generally refers to occurrence of a disease, symptom, sign or laboratory abnormality that constitutes one of the target outcomes of the trial, but may also refer to any such disease or sign that strongly motivates the withdrawal of that individual...
but doesn't necessarily have a guaranteed relationship. The National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(USA) defines surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint".
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
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
number of endpoints. The FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
and other regulatory agencies will often accept evidence from clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s that show a direct clinical benefit to surrogate markers.
A correlate does not make a surrogate. It is a common misconception that if an outcome is a correlate (that is, correlated with the true clinical outcome) it can be used as a valid surrogate end point (that is, a replacement for the true clinical outcome). However, proper justification for such replacement requires that the effect of the intervention on the surrogate end point predicts the effect on the clinical outcome—a much stronger condition than correlation.
The term "surrogate" should not be used in describing end points. Instead, descriptions of results and interpretations should be formulated in terms that designate the specific nature and category of variable assessed.
A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.
A commonly used example is cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. While elevated cholesterol levels increase the likelihood for heart disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, 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
Simvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
(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. In another case, AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
has been accused of marketing rosuvastatin
Rosuvastatin
Rosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. It was developed by Shionogi.-Medical uses:The primary uses of rosuvastatin is for the treatment of dyslipidemia...
(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.