Summary
Interest is increasing rapidly in the use of surrogate markers as primary measures of the effectiveness of investigational drugs in definitive drug trials. Many such surrogate markers have been proposed as potential candidates for use in definitive effectiveness trials of agents to treat neurologic or psychiatric disease, but as of this date, there are no such markers that have been adequately “validated,” that is, shown to predict the effect of the treatment on the clinical outcome of interest. While the current law and regulations permit the United States Food and Drug Administration to base the approval of a drug product on a determination the effect of the drug on an unvalidated surrogate marker (that is, one for which it is not known that an effect on the surrogate actually predicts the desired clinical benefit), there are a number of difficulties in interpreting trials that use surrogate markers as primary measures of drug effect. In this article, the relevant regulatory context will be discussed, as well as the epistemological problems related to the interpretation of clinical trials in which unvalidated surrogate markers are used as primary outcomes.
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Rovaris M, Comi G, Ladkani D, Wolinsky JS, Filippi M, and the European/Canadian Glatiramer Acetate Study Group. Short-term correlations between clinical and MR imaging findings in relapsing-remitting multiple sclerosis.AJNR Am J Neuroradiol 24: 75–81, 2003.
Stoof JC, Winogradzka A, van Muiswinkel FL, Wolters EC, Voorn P, Groenewegen HJ et al. Leads for the development of neuroprotective treatment in Parkinson’s disease and brain imaging methods for estimating treatment efficacy.Eur J Pharmacol 375: 75–86, 1999.
The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group. Consensus report of the Working Group on: molecular and biochemical markers of Alzheimer’s disease.Neurobiol Aging 19: 109–116, 1998.
Morrish PK, Sawle GV, Brooks DJ. An18F dopa-PET and clinical study of the rate of progression in Parkinson’s Disease.Brain 119: 585–591, 1996.
Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs?JAMA 282: 790–795, 1999.
New drug, antibiotic, and biological drug product regulations; accelerated approval—FDA. Final rule.Fed Regist 57:58942–58960, 1992.
Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs.J Clin Oncol 21: 1404–1411, 2003.
Fox NC, Cousens S, Scahill R, Harvey RJ, Rossor MN. Using serial registered brain magnetic imaging to measure disease progression in Alzheimer’s disease: power calculations and estimates of sample size to detect treatment effects.Arch Neurol 57: 339–344, 2000.
Leber P. Slowing the progression of Alzheimer disease: methodologic issues.Alzheimer Dis Assoc Disord 11(Suppl 5): S10-S21, 1997.
Fleming TR, DeMets DL. Surrogate endpoints in clinical trials: are we being misled?Ann Intern Med 125: 605–613, 1996.
Riggs BL, Hodgson SF, O’Fallon WM, Chao EYS, Wahner HW, Muhs JM et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis.N Engl J Med 322: 802–809, 1990.
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.N Engl J Med 324: 781–788, 1991.
Hughes MD. Evaluating surrogate endpoints.Control Clin Trials 23: 703–707, 2002.
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Katz, R. Biomarkers and surrogate markers: An FDA perspective. Neurotherapeutics 1, 189–195 (2004). https://doi.org/10.1602/neurorx.1.2.189
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DOI: https://doi.org/10.1602/neurorx.1.2.189