title: GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.
abstract: The US Food and Drug Administration currently accepts halving of glomerular filtration rate (GFR), assessed as doubling of serum creatinine level, as a surrogate end point for the development of kidney failure in clinical trials of kidney disease progression. A doubling of serum creatinine level generally is a late event in chronic kidney disease (CKD); thus, there is great interest in considering alternative end points for clinical trials to shorten their duration, reduce sample size, and extend their conduct to patients with earlier stages of CKD. However, the relationship between lesser declines in GFR and the subsequent development of kidney failure has not been well characterized. The National Kidney Foundation and Food and Drug Administration sponsored a scientific workshop to critically examine available data to determine whether alternative GFR-based end points have sufficiently strong relationships with important clinical outcomes of CKD to be used in clinical trials. Based on a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods, the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40% may be more broadly acceptable than a 30% decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. However, there are other circumstances in which these end points could lead to a reduction in statistical power or erroneous conclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA. Electronic address: alevey@tuftsmedicalcenter.org.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Inker
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Division of Epidemiology, University of Utah, Salt Lake City, UT.
authors.forename: Tom
authors.initials: T
authors.lastname: Greene
authors.affiliation: National Kidney Foundation, New York, NY.
authors.forename: Kerry
authors.initials: K
authors.lastname: Willis
authors.affiliation: Rush University Medical Center, Chicago, IL.
authors.forename: Edmund
authors.initials: E
authors.lastname: Lewis
authors.affiliation: Department of Clinical Pharmacy & Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT.
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
mesh_terms: D002986:Clinical Trials as Topic / Q000592:standards / Q000639:trends; D004493:Education / Q000592:standards* / Q000639:trends; D023381:Endpoint Determination / Q000592:standards* / Q000639:trends; D005582:Foundations / Q000592:standards* / Q000639:trends; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis* / Q000453:epidemiology / Q000503:physiopathology; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration / Q000592:standards* / Q000639:trends
keywords: Kidney end point; biomarker; chronic kidney disease (CKD); eGFR trajectory; end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR) decline; kidney disease outcome; kidney disease progression; renal end point; renal function; serum creatinine; surrogate end point