Surrogate endpoint

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In clinical trials, a surrogate endpoint (or marker) is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship. The National Institutes of Health (USA) defines surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint".[1][2]

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 trials that show a direct clinical benefit to surrogate markers. [3]

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. [4]

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. [5]

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. [6]

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.[7] 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.

Criticism[edit]

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.[8]

References[edit]

  1. ^ Controlled Clinical Trials 22:485–502 (2001)[full citation needed]
  2. ^ Cohn JN (2004). "Introduction to Surrogate Markers". Circulation (American Heart Association) 109 (25 Suppl 1): IV20–1. doi:10.1161/01.CIR.0000133441.05780.1d. PMID 15226247. 
  3. ^ Alexandra Goho, "An Imperfect Substitute" CR Magazine, Spring 2009
  4. ^ Fleming T, David D. Surrogate End Points in Clinical Trials: Are We Being Misled? Ann Intern Med. 1996 Oct 1;125(7):605-13
  5. ^ Sobel B, Furberg C, Surrogates, Semantics, and Sensible Public Policy. Circulation. 1997;95:1661-1663
  6. ^ Temple RJ. A regulatory authority's opinion about surrogate endpoints. Clinical Measurement in Drug Evaluation. Edited by Nimmo WS, Tucker GT. New York: Wiley; 1995.
  7. ^ Pedersen TR, Olsson AG, Faergeman O, et al. (1998). "Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)". Circulation 97 (15): 1453–1460. PMID 9576425. 
  8. ^ Psaty BM, Weiss NS, Furberg CD, et al. (1999). "Surrogate end points, health outcomes, and the drug approval process for the treatment of risk factors for cardiovascular disease". JAMA 282 (8): 786–790. doi:10.1001/jama.282.8.786. PMID 10463718.