Abstract
The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR > 30 mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0 mL/min/1.73 m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 84-104 |
| Number of pages | 21 |
| Journal | American Journal of Kidney Diseases |
| Volume | 75 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2020 |
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Keywords
- albuminuria
- albuminuria change
- biomarker
- chronic kidney disease (CKD)
- clinical trials
- drug approval
- eGFR slope
- eGFR trajectory
- estimated GFR (eGFR)
- evidence synthesis
- glomerular filtration rate (GFR)
- kidney disease progression
- renal outcome
- Surrogate endpoints
- trial design
ASJC Scopus subject areas
- Nephrology
Cite this
Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD : A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency. / Levey, Andrew S.; Gansevoort, Ron T.; Coresh, Josef; Inker, Lesley A.; Heerspink, Hiddo L.; Grams, Morgan E.; Greene, Tom; Tighiouart, Hocine; Matsushita, Kunihiro; Ballew, Shoshana H.; Sang, Yingying; Vonesh, Edward; Ying, Jian; Manley, Tom; de Zeeuw, Dick; Eckardt, Kai Uwe; Levin, Adeera; Perkovic, Vlado; Zhang, Luxia; Willis, Kerry.
In: American Journal of Kidney Diseases, Vol. 75, No. 1, 01.2020, p. 84-104.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD
T2 - A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency
AU - Levey, Andrew S.
AU - Gansevoort, Ron T.
AU - Coresh, Josef
AU - Inker, Lesley A.
AU - Heerspink, Hiddo L.
AU - Grams, Morgan E.
AU - Greene, Tom
AU - Tighiouart, Hocine
AU - Matsushita, Kunihiro
AU - Ballew, Shoshana H.
AU - Sang, Yingying
AU - Vonesh, Edward
AU - Ying, Jian
AU - Manley, Tom
AU - de Zeeuw, Dick
AU - Eckardt, Kai Uwe
AU - Levin, Adeera
AU - Perkovic, Vlado
AU - Zhang, Luxia
AU - Willis, Kerry
PY - 2020/1
Y1 - 2020/1
N2 - The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR > 30 mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0 mL/min/1.73 m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.
AB - The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR > 30 mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0 mL/min/1.73 m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.
KW - albuminuria
KW - albuminuria change
KW - biomarker
KW - chronic kidney disease (CKD)
KW - clinical trials
KW - drug approval
KW - eGFR slope
KW - eGFR trajectory
KW - estimated GFR (eGFR)
KW - evidence synthesis
KW - glomerular filtration rate (GFR)
KW - kidney disease progression
KW - renal outcome
KW - Surrogate endpoints
KW - trial design
UR - http://www.scopus.com/inward/record.url?scp=85073817116&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073817116&partnerID=8YFLogxK
U2 - 10.1053/j.ajkd.2019.06.009
DO - 10.1053/j.ajkd.2019.06.009
M3 - Article
C2 - 31473020
AN - SCOPUS:85073817116
VL - 75
SP - 84
EP - 104
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
SN - 0272-6386
IS - 1
ER -