title: The value, qualification, and regulatory use of surrogate end points in drug development.
abstract: The acceptance and use of either surrogate end points (SEPs) or efficient clinical end points are associated with greater and more rapid availability of new medicines as compared with disease situations for which clinical end points are inefficient or no surrogates exist. This review of the history of the development, qualification, and acceptance of key SEPs shows that both successes and failures had three key characteristics: (i) apparent biologic plausibility, (ii) prognostic value for the outcome of the disease, and (iii) an association between changes in the SEP and changes in outcome with therapeutic intervention--the three factors recommended for SEPs in the International Conference on Harmonisation's "Statistical Principles for Clinical Trials." We recommend that only prognostic value be an absolute prerequisite for surrogacy, because therapeutic interventions may not exist a priori, and biological plausibility can be subjective. Ideally, all three of these factors would be traded off against one another in a consistent and transparent risk-management process.
authors.affiliation: Clinical Pharmacology, Bayer Pharmaceuticals, Montville, New Jersey, USA. chetan.lathia@bayer.com
authors.forename: C D
authors.initials: CD
authors.lastname: Lathia
authors.forename: D
authors.initials: D
authors.lastname: Amakye
authors.forename: W
authors.initials: W
authors.lastname: Dai
authors.forename: C
authors.initials: C
authors.lastname: Girman
authors.forename: S
authors.initials: S
authors.lastname: Madani
authors.forename: J
authors.initials: J
authors.lastname: Mayne
authors.forename: P
authors.initials: P
authors.lastname: MacCarthy
authors.forename: P
authors.initials: P
authors.lastname: Pertel
authors.forename: L
authors.initials: L
authors.lastname: Seman
authors.forename: A
authors.initials: A
authors.lastname: Stoch
authors.forename: P
authors.initials: P
authors.lastname: Tarantino
authors.forename: C
authors.initials: C
authors.lastname: Webster
authors.forename: S
authors.initials: S
authors.lastname: Williams
authors.forename: J A
authors.initials: JA
authors.lastname: Wagner
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D055808:Drug Discovery / Q000331:legislation & jurisprudence* / Q000592:standards*; D006801:Humans; D014481:United States; D014486:United States Food and Drug Administration / Q000331:legislation & jurisprudence / Q000592:standards
chemical_list: D015415:Biomarkers