Special Section: GFR Decline as an End Point for Clinical Trials in CKD
Editorial GFR Decline as an End Point in Trials of CKD: A Viewpoint From the FDA
D
ecline in glomerular filtration rate (GFR) is an intermediate step on the pathway to end-stage renal disease (ESRD) but, whereas the latter is a clinical outcome, the former is considered a biomarker or potential surrogate end point, as it is not typically perceived by a patient. The US Food and Drug Administration (FDA) has accepted doubling of serum creatinine (corresponding to an approximately 57% decline in estimated GFR using the CKD-EPI equation) as a surrogate end point for assessing a drug’s efficacy, and treatment effects on a doubling of serum creatinine were the principal basis for approval of captopril, irbesartan, and losartan (all for diabetic nephropathy); however, in each case FDA also had evidence of drug effects on ESRD or death. Over the past several years, there has been interest in using lesser changes in kidney function as an end point (with correspondingly less opportunity to observe end-stage events) in order to decrease the cost, size, and duration of clinical trials and, sometimes, to extend the conduct of trials to patients at early phases of the disease. Hence, the National Kidney Foundation (NKF) along with academic researchers and with input from FDA, collaborated on research to understand better the ability of lesser changes in eGFR to predict clinical outcomes and thus serve as a valid surrogate end point. The results of this work, reflecting a series of detailed analyses of eGFR as an end point, were presented in December 2012 at a scientific workshop that was sponsored by the NKF and FDA. This issue of AJKD contains a series of articles describing the workshop conclusions and the analyses that were performed to support the use of lesser changes in kidney function as end points in clinical trials of chronic kidney disease (CKD).1-4 As described in the workshop summary,1 data from observational studies and clinical trials were analyzed in advance of the meeting and were used to: (1) evaluate the relationship between specific magnitudes of decline in eGFR and the subsequent risk of progression over Originally published online October 31, 2014. Address correspondence to Aliza Thompson, MD, Center for Drug Evaluation and Research, Food and Drug Administration, White Oak Campus, Bldg 22, Room 4109, 10903 New Hampshire Ave, Silver Spring, MD 20993. E-mail: Aliza.Thompson@ fda.hhs.gov Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386/$0.00 http://dx.doi.org/10.1053/j.ajkd.2014.09.006 836
defined periods of observation; and (2) determine whether the size of the treatment effect was similar when the established end point (ESRD as defined by treatment with dialysis or transplantation, eGFR , 15 ml/min/ 1.73 m2, or creatinine doubling) or newly proposed end points were used. Simulations were also conducted to evaluate the risk of reaching a false conclusion of benefit or harm when using the newly proposed end points. As a whole, the results of these analyses greatly advance our understanding of eGFR decline as an end point. In particular, they have enabled a more precise understanding of the relationship between various magnitudes of decline in eGFR and the subsequent risk of progression to kidney failure. They also illustrate how changes in the pattern of eGFR decline in response to interventions, specifically whether a therapy has acute and reversible effects on eGFR, have important implications for the design of clinical trials and the use of eGFR decline as an end point. Based on the results of these analyses, the planning committee, the analytic group, and the workshop participants concluded that a confirmed decline in eGFR of 40% could be used as an end point in clinical trials of CKD. The group also concluded that a confirmed decline of 30% might be acceptable under some circumstances, depending on the pattern of treatment effects on eGFR. As reported in a separate paper describing the results of the cohort analysis,5 a decline in eGFR of $30% over a 2-year baseline period was associated with an adjusted hazard ratio for ESRD of approximately 5 in participants with a baseline eGFR , 60 mL/min/1.73 m2, whereas a decline of $40% over 2 years was associated with an adjusted hazard ratio of ESRD of approximately 10. In comparison, the adjusted hazard ratio of ESRD was approximately 32 following a decline of $57% over 2 years. For participants with a baseline eGFR of 50 mL/ min/1.73 m2 and a decline in eGFR of 30%, 40%, or 57% over a 2-year period, the estimated average risks of progressing to ESRD over the next 10 years (after adjusting for covariates and competing mortality risk) were 21%, 33%, and 66%, respectively. As would be expected, the absolute risk of progression over 10 years was greater in participants with a lower baseline eGFR than in those with a higher baseline eGFR. One strength of the cohort analysis was its large sample size; the analyses included data from over 1.5 million participants with over 12,000 ESRD events. Another strength was the relatively long duration of follow-up in some of the contributing studies. Nevertheless, it is important to consider how well the newly Am J Kidney Dis. 2014;64(6):836-837
Editorial
proposed end points perform in clinical trials, and specifically, whether treatment effects on these end points are consistent with treatment effects on kidney outcomes. The analytic group approached this issue by evaluating whether the newly proposed end points and the “established end point,” which they defined as a doubling of serum creatinine, ESRD (treatment with dialysis or transplantation), or an eGFR , 15 mL/min/ 1.73 m2, gave a similar estimate of the treatment effect. As might be expected, the point estimate obtained using a confirmed 40% decline in eGFR over 2 years aligned more closely with the point estimate obtained using the established end point than did a confirmed 30% decline in eGFR over 2 years. Across the interventions that were tested, the ratio of the hazard ratios (the hazard ratio for the established end point divided by the hazard ratio for the alternative end point over 2 years) tended to be closer to 1.0 for a 40% decline in eGFR than for a 30% decline. For example, in their analysis of renin angiotensin system blockade versus control, the ratio of the hazard ratios was 0.98 (95% credible interval, 0.89-1.07) for a 40% decline in eGFR over 2 years and 1.08 (95% credible interval, 0.95-1.20) for a 30% decline over 2 years. In simulations, use of a 30% or 40% decline, as opposed to a 57% decline, improved trial power for therapies without acute effects on eGFR; but a 40% decline in eGFR produced valid results across a wider range of acute effects than did a 30% decline. There are advantages to the newly proposed end points with respect to efficiency. Obviously, compared to a doubling of serum creatinine, eGFR declines of 30% and 40% occur sooner and are more common. Moreover, in kidney diseases that are rare or slowly progressive, it may be difficult to conduct trials using a doubling of serum creatinine or ESRD as an end point. However, in type 2 diabetic nephropathy, a leading cause of ESRD, it is possible to use a doubling of serum creatinine as an end point, as evidenced by the fact that trials have been conducted and are being conducted that use this end point, typically as one component of a composite end point. Hence, it is important to consider the implications of using a confirmed decline in eGFR of 40% in trials of diabetic nephropathy, the end point more widely embraced by the workshop. Because using a confirmed 40% decline in eGFR as an end point is expected to shorten the duration and size of trials of diabetic nephropathy, there will be fewer participants who progress to ESRD than in trials that use a doubling of serum creatinine. These trials will therefore provide less direct evidence of how therapy affects progression to ESRD, an
Am J Kidney Dis. 2014;64(6):836-837
inevitable consequence of using any surrogate. It is possible that post-trial follow-up will provide direct evidence of an effect on ESRD, but the effect will be smaller if placebo patients are crossed over to active drug. In the absence of direct evidence of an effect on ESRD, there may also be greater regulatory focus on safety, particularly effects on mortality. This issue takes on added importance given the high prevalence of diabetic nephropathy, as well as the high competing risk of death prior to development of ESRD in individuals with diabetic nephropathy.6 In conclusion, the analyses conducted for this workshop have greatly advanced our understanding of eGFR as an end point in trials of CKD. We thank those involved in planning the workshop and those who participated in the workshop for their efforts. Aliza Thompson, MD John Lawrence, PhD Norman Stockbridge, MD, PhD Center for Drug Evaluation and Research, Food and Drug Administration Silver Spring, Maryland
ACKNOWLEDGEMENTS The authors thank Ellis Unger and Robert Temple from the FDA’s Center for Drug Evaluation and Research for their valuable comments on this editorial. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Levey AS, Inker LA, Matsushita K, et al. 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. Am J Kidney Dis. 2014;64(6):821-835. 2. Inker LA, Lambers Heerspink HJ, Mondal H, et al. GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials. Am J Kidney Dis. 2014;64(6):848-859. 3. Lambers Heerspink HJ, Tighiouart H, Sang Y, et al. GFR decline and subsequent risk of established kidney outcomes: a meta-analysis of 37 randomized controlled trials. Am J Kidney Dis. 2014;64(6):860-866. 4. Greene T, Teng C-C, Inker LA, et al. Utility and validity of estimated GFR–based surrogate time-to-event end points in CKD: a simulation study. Am J Kidney Dis. 2014;64(6): 867-879. 5. Coresh J, Turin TC, Matsushita K, et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA. 2014;311(24):2518-2531. 6. Haynes R, Staplin N, Emberson J, et al. Evaluating the contribution of the cause of kidney disease to prognosis in CKD: results from the study of heart and renal protection (SHARP). Am J Kidney Dis. 2014;64(1):40-48.
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Editorial GFR Decline as an End Point in Trials of CKD: A Viewpoint From the FDA
D
ecline in glomerular filtration rate (GFR) is an intermediate step on the pathway to end-stage renal disease (ESRD) but, whereas the latter is a clinical outcome, the former is considered a biomarker or potential surrogate end point, as it is not typically perceived by a patient. The US Food and Drug Administration (FDA) has accepted doubling of serum creatinine (corresponding to an approximately 57% decline in estimated GFR using the CKD-EPI equation) as a surrogate end point for assessing a drug’s efficacy, and treatment effects on a doubling of serum creatinine were the principal basis for approval of captopril, irbesartan, and losartan (all for diabetic nephropathy); however, in each case FDA also had evidence of drug effects on ESRD or death. Over the past several years, there has been interest in using lesser changes in kidney function as an end point (with correspondingly less opportunity to observe end-stage events) in order to decrease the cost, size, and duration of clinical trials and, sometimes, to extend the conduct of trials to patients at early phases of the disease. Hence, the National Kidney Foundation (NKF) along with academic researchers and with input from FDA, collaborated on research to understand better the ability of lesser changes in eGFR to predict clinical outcomes and thus serve as a valid surrogate end point. The results of this work, reflecting a series of detailed analyses of eGFR as an end point, were presented in December 2012 at a scientific workshop that was sponsored by the NKF and FDA. This issue of AJKD contains a series of articles describing the workshop conclusions and the analyses that were performed to support the use of lesser changes in kidney function as end points in clinical trials of chronic kidney disease (CKD).1-4 As described in the workshop summary,1 data from observational studies and clinical trials were analyzed in advance of the meeting and were used to: (1) evaluate the relationship between specific magnitudes of decline in eGFR and the subsequent risk of progression over Originally published online October 31, 2014. Address correspondence to Aliza Thompson, MD, Center for Drug Evaluation and Research, Food and Drug Administration, White Oak Campus, Bldg 22, Room 4109, 10903 New Hampshire Ave, Silver Spring, MD 20993. E-mail: Aliza.Thompson@ fda.hhs.gov Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. 0272-6386/$0.00 http://dx.doi.org/10.1053/j.ajkd.2014.09.006 836
defined periods of observation; and (2) determine whether the size of the treatment effect was similar when the established end point (ESRD as defined by treatment with dialysis or transplantation, eGFR , 15 ml/min/ 1.73 m2, or creatinine doubling) or newly proposed end points were used. Simulations were also conducted to evaluate the risk of reaching a false conclusion of benefit or harm when using the newly proposed end points. As a whole, the results of these analyses greatly advance our understanding of eGFR decline as an end point. In particular, they have enabled a more precise understanding of the relationship between various magnitudes of decline in eGFR and the subsequent risk of progression to kidney failure. They also illustrate how changes in the pattern of eGFR decline in response to interventions, specifically whether a therapy has acute and reversible effects on eGFR, have important implications for the design of clinical trials and the use of eGFR decline as an end point. Based on the results of these analyses, the planning committee, the analytic group, and the workshop participants concluded that a confirmed decline in eGFR of 40% could be used as an end point in clinical trials of CKD. The group also concluded that a confirmed decline of 30% might be acceptable under some circumstances, depending on the pattern of treatment effects on eGFR. As reported in a separate paper describing the results of the cohort analysis,5 a decline in eGFR of $30% over a 2-year baseline period was associated with an adjusted hazard ratio for ESRD of approximately 5 in participants with a baseline eGFR , 60 mL/min/1.73 m2, whereas a decline of $40% over 2 years was associated with an adjusted hazard ratio of ESRD of approximately 10. In comparison, the adjusted hazard ratio of ESRD was approximately 32 following a decline of $57% over 2 years. For participants with a baseline eGFR of 50 mL/ min/1.73 m2 and a decline in eGFR of 30%, 40%, or 57% over a 2-year period, the estimated average risks of progressing to ESRD over the next 10 years (after adjusting for covariates and competing mortality risk) were 21%, 33%, and 66%, respectively. As would be expected, the absolute risk of progression over 10 years was greater in participants with a lower baseline eGFR than in those with a higher baseline eGFR. One strength of the cohort analysis was its large sample size; the analyses included data from over 1.5 million participants with over 12,000 ESRD events. Another strength was the relatively long duration of follow-up in some of the contributing studies. Nevertheless, it is important to consider how well the newly Am J Kidney Dis. 2014;64(6):836-837
Editorial
proposed end points perform in clinical trials, and specifically, whether treatment effects on these end points are consistent with treatment effects on kidney outcomes. The analytic group approached this issue by evaluating whether the newly proposed end points and the “established end point,” which they defined as a doubling of serum creatinine, ESRD (treatment with dialysis or transplantation), or an eGFR , 15 mL/min/ 1.73 m2, gave a similar estimate of the treatment effect. As might be expected, the point estimate obtained using a confirmed 40% decline in eGFR over 2 years aligned more closely with the point estimate obtained using the established end point than did a confirmed 30% decline in eGFR over 2 years. Across the interventions that were tested, the ratio of the hazard ratios (the hazard ratio for the established end point divided by the hazard ratio for the alternative end point over 2 years) tended to be closer to 1.0 for a 40% decline in eGFR than for a 30% decline. For example, in their analysis of renin angiotensin system blockade versus control, the ratio of the hazard ratios was 0.98 (95% credible interval, 0.89-1.07) for a 40% decline in eGFR over 2 years and 1.08 (95% credible interval, 0.95-1.20) for a 30% decline over 2 years. In simulations, use of a 30% or 40% decline, as opposed to a 57% decline, improved trial power for therapies without acute effects on eGFR; but a 40% decline in eGFR produced valid results across a wider range of acute effects than did a 30% decline. There are advantages to the newly proposed end points with respect to efficiency. Obviously, compared to a doubling of serum creatinine, eGFR declines of 30% and 40% occur sooner and are more common. Moreover, in kidney diseases that are rare or slowly progressive, it may be difficult to conduct trials using a doubling of serum creatinine or ESRD as an end point. However, in type 2 diabetic nephropathy, a leading cause of ESRD, it is possible to use a doubling of serum creatinine as an end point, as evidenced by the fact that trials have been conducted and are being conducted that use this end point, typically as one component of a composite end point. Hence, it is important to consider the implications of using a confirmed decline in eGFR of 40% in trials of diabetic nephropathy, the end point more widely embraced by the workshop. Because using a confirmed 40% decline in eGFR as an end point is expected to shorten the duration and size of trials of diabetic nephropathy, there will be fewer participants who progress to ESRD than in trials that use a doubling of serum creatinine. These trials will therefore provide less direct evidence of how therapy affects progression to ESRD, an
Am J Kidney Dis. 2014;64(6):836-837
inevitable consequence of using any surrogate. It is possible that post-trial follow-up will provide direct evidence of an effect on ESRD, but the effect will be smaller if placebo patients are crossed over to active drug. In the absence of direct evidence of an effect on ESRD, there may also be greater regulatory focus on safety, particularly effects on mortality. This issue takes on added importance given the high prevalence of diabetic nephropathy, as well as the high competing risk of death prior to development of ESRD in individuals with diabetic nephropathy.6 In conclusion, the analyses conducted for this workshop have greatly advanced our understanding of eGFR as an end point in trials of CKD. We thank those involved in planning the workshop and those who participated in the workshop for their efforts. Aliza Thompson, MD John Lawrence, PhD Norman Stockbridge, MD, PhD Center for Drug Evaluation and Research, Food and Drug Administration Silver Spring, Maryland
ACKNOWLEDGEMENTS The authors thank Ellis Unger and Robert Temple from the FDA’s Center for Drug Evaluation and Research for their valuable comments on this editorial. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Levey AS, Inker LA, Matsushita K, et al. 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. Am J Kidney Dis. 2014;64(6):821-835. 2. Inker LA, Lambers Heerspink HJ, Mondal H, et al. GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials. Am J Kidney Dis. 2014;64(6):848-859. 3. Lambers Heerspink HJ, Tighiouart H, Sang Y, et al. GFR decline and subsequent risk of established kidney outcomes: a meta-analysis of 37 randomized controlled trials. Am J Kidney Dis. 2014;64(6):860-866. 4. Greene T, Teng C-C, Inker LA, et al. Utility and validity of estimated GFR–based surrogate time-to-event end points in CKD: a simulation study. Am J Kidney Dis. 2014;64(6): 867-879. 5. Coresh J, Turin TC, Matsushita K, et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA. 2014;311(24):2518-2531. 6. Haynes R, Staplin N, Emberson J, et al. Evaluating the contribution of the cause of kidney disease to prognosis in CKD: results from the study of heart and renal protection (SHARP). Am J Kidney Dis. 2014;64(1):40-48.
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