title: Biomarkers and surrogate markers: an FDA perspective.
abstract: 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.
authors.affiliation: Division of Neuropharmacological Drug Products, United States Food and Drug Administration, Rockville, Maryland 20852, USA. katzr@cder.fda.gov
authors.forename: Russell
authors.initials: R
authors.lastname: Katz
mesh_terms: D015415:Biomarkers; D002986:Clinical Trials as Topic / Q000592:standards*; D006801:Humans; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards*
chemical_list: D015415:Biomarkers
references.citation: Arch Neurol. 2000 Mar;57(3):339-44
references.pmid: 10714659
references.citation: Control Clin Trials. 2002 Dec;23(6):703-7
references.pmid: 12505247
references.citation: AJNR Am J Neuroradiol. 2003 Jan;24(1):75-81
references.pmid: 12533330
references.citation: J Clin Oncol. 2003 Apr 1;21(7):1404-11
references.pmid: 12663734
references.citation: N Engl J Med. 1990 Mar 22;322(12):802-9
references.pmid: 2407957
references.citation: N Engl J Med. 1991 Mar 21;324(12):781-8
references.pmid: 1900101
references.citation: JAMA. 1999 Aug 25;282(8):790-5
references.pmid: 10463719
references.citation: Brain. 1996 Apr;119 ( Pt 2):585-91
references.pmid: 8800950
references.citation: Ann Intern Med. 1996 Oct 1;125(7):605-13
references.pmid: 8815760
references.citation: Alzheimer Dis Assoc Disord. 1997;11 Suppl 5:S10-21; discussion S37-9
references.pmid: 9348423
references.citation: Neurobiol Aging. 1998 Mar-Apr;19(2):109-16
references.pmid: 9558143
references.citation: Eur J Pharmacol. 1999 Jun 30;375(1-3):75-86
references.pmid: 10443566
references.citation: Fed Regist. 1992 Dec 11;57(239):58942-60
references.pmid: 10123232