Background:

CKD leads to declining kidney function, end-stage renal disease (ESRD), cardiovascular (CV) events or death. Its global prevalence is 9.1%, representing a large burden to health care systems. To optimize development of new therapeutics by shortening trial duration, extensive academic research has been done evaluating surrogate end-points. The change in eGFR slope as a surrogate end-point directly linked to clinical outcomes (ESRD and death) was selected based on multiple studies including a meta-analysis of 47 randomized control trials, 12 interventions, 60,620 subjects. Economic evaluations, traditionally based on long-term clinical outcomes, require adaptation to build on surrogacy. Our objective is to highlight the related challenges and suggest recommendations.

Methods:

Published statistical analyses of surrogacy and economic evaluations in CKD were reviewed. A patient level simulation model comparing standard-of-care (SoC) and a hypothetical therapy was designed including the following components: CKD sub-model tracking continuous eGFR trajectories based on SoC slopes and assumed treatment effect (and translated into CKD stages to capture costs/utilities, including dialysis and/or transplant); CV sub-model predicting CV outcomes including CV death; non-CV death. Treatment effect was formalized as time-dependent impact on eGFR slope/trajectory. Assumptions were made on shape of eGFR trajectory and on dependence of CV risks and mortality on CKD stage. Inputs were based on publicly available risk equations and slope estimates. Clinical outcomes are presented along with sensitivity and scenario analyses.

Implications and Conclusions:

Shorter-term CKD trials with surrogate endpoint of eGFR slope change will require additional assumptions on long-term eGFR trajectories and treatment effects, to capture all relevant clinical outcomes. We propose an eGFR slope-based model structure capturing individual heterogeneities. We highlight model limitations and gaps in understanding complex clinical relationships. Economic models of CKD will be required to evolve with clinical research and regulatory/payer acceptance of surrogate end-points to advance optimal therapeutic development.