TABLE 1.
Comparison of the key guidelines for renal impairment study as per FDA and EMA guidance
| FDA Guidance 8 | EMA Guidance 9 | |
|---|---|---|
| Timing of study | No specific details mentioned | If dosing adjustment is required in patients with impaired renal function, a recommendation is provided to conduct the study in phase III |
| Large molecules/biologics | RI study not necessary for large molecules such as cytokines or cytokine modulators with MW > 69 kDa | Large proteins with MW > 60 kDa, such as monoclonal antibodies are not expected to undergo glomerular filtration, and therefore do not require a full RI study |
| GFR assessment methods | Recommends the use of eGFR assessment from the MDRD or CKD‐EPI methods for renally eliminated drugs. | Recommends the use of absolute GFR and the GFR normalized to a body surface area of 1.73 m2 for renally eliminated drugs |
| ESRD definition | ESRD definition has been modified in the current draft version and now refers to kidney failure (i.e., patients with renal function < 15 ml/min or dialysis patients on non‐dialysis days) | ESRD is defined as subjects with absolute GFR < 15 ml/min and requiring dialysis |
| Topically administered and hepatically eliminated drugs | A dedicated study may not be important for locally acting drugs (i.e., topical products) with limited systemic absorption | Waiver for conducting the RI study for both topically administered as well as hepatically cleared drugs without relevant systemic absorption |
| Data analysis | Model‐based analyses to establish a relationship between renal function (i.e. creatinine clearance CLcr or eGFR) and relevant PK parameters (AUC, C max , CL/F, t 1/2, and renal clearance CLR) | Both graphical and model‐based analysis to establish a relationship between the parameters defining renal elimination capacity and the PK parameters |
Abbreviations: AUC, area under the plasma‐concentration‐time curve; BSA, body surface area; CKD‐EPI, Chronic Kidney Disease Epidemiology Collaboration; CLcr, creatinine clearance; CL/F, apparent clearance; CLR, renal clearance; Cmax, maximum plasma concentration; eGFR, estimated glomerular filtration rate; EMA, European Medicines Agency; ESRD, end‐stage renal disease; FDA, US Food and Drug Administration; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; MW, molecular weight; PK, pharmacokinetic; RI, renal impairment; t1/2, terminal half‐life.