TY - JOUR
T1 - GFR decline as an end point for clinical trials in CKD
T2 - A scientific workshop sponsored by the national kidney foundation and the US food and drug administration
AU - Levey, Andrew S.
AU - Inker, Lesley A.
AU - Matsushita, Kunihiro
AU - Greene, Tom
AU - Willis, Kerry
AU - Lewis, Edmund
AU - De Zeeuw, Dick
AU - Cheung, Alfred K.
AU - Coresh, Josef
N1 - Funding Information:
Financial Disclosure: Dr Cheung reports receiving consulting fees from Baxter and Amgen, speaking fees from Merck, and royalties from contributions to Up-to-Date. Dr Coresh reports receiving a research grant from Amgen during the past 3 years. Dr de Zeeuw reports receiving funds to his institution from consultant agreements with Astra Zeneca, Amgen, Abbott, MSD, BMS, Novartis, VITAE, Takeda, Hemocuem, J&J, REATA, Abbott, Astellas, Abbvie, and Chemocentryx. Dr Greene reports receiving research grants from Pharmalink AB, Jansen Pharmaceuticals, Keryx Biopharmaceuticals, and Genkyotex SA. Dr Inker reports receiving research grants from Pharmalink AB and Gilead Sciences and a consulting agreement with Otsuka. Dr Levey reports funding to Tufts Medical Center for research and contracts with the National Institutes of Health, NKF, Amgen, Pharmalink AB, and Gilead Sciences. Dr Matsushita reports receiving an honorarium from Mitsubishi Tanabe Pharm. Drs Lewis and Willis report that they have no relevant financial interests.
Funding Information:
Support: The workshop was supported and facilitated by the NKF. NKF gratefully acknowledges Abbott, Amgen, ChemoCentryx, Lilly, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Reata, Sanofi, and Takeda, which provided grants to the NKF to support the workshop and the related publications.
Publisher Copyright:
© 2014 National Kidney Foundation, Inc.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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 erroneousConclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.
AB - 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 erroneousConclusions regarding benefits or harms of interventions. We encourage careful consideration of these alternative end points in the design of future clinical trials.
KW - Kidney end point
KW - biomarker chronic kidney disease (CKD)
KW - eGFR trajectory
KW - end-stage renal disease (ESRD)
KW - estimated glomerular filtration rate (eGFR) decline
KW - kidney disease outcome
KW - kidney disease progression
KW - renal end point
KW - renal function
KW - serum creatinine
KW - surrogate end point
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U2 - 10.1053/j.ajkd.2014.07.030
DO - 10.1053/j.ajkd.2014.07.030
M3 - Article
C2 - 25441437
AN - SCOPUS:84911459484
VL - 64
SP - 821
EP - 835
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
SN - 0272-6386
IS - 6
ER -