Clinical pharmacology studies in patients with renal impairment: Past experience and regulatory perspectives

The objective of this report is to provide a regulatory perspective on the quality of pharmacokinetic studies in renal impairment (RI) studies submitt ed in support of new drug applications (NDAs) or supplements to NDAs (sNDAs ) submitted to the Food and Drug Administration (FDA). Fifty-one NDA and 20 sNDA submissions reviewed between 1996 and 1997 by the Office of Clinical Pharmacology and Biopharmaceutics were evaluated for the following: (1) whe ther an RI study was conducted; (2) contribution of the renal clearance to the overall clearance in subjects without renal impairment; (3) degree of p lasma protein binding (%PB) in subjects without renal impairment; (4) dose proportionality of single and multiple doses; (5) study design, including d osing regimen; (6) definition of renal impairment; (7) stratification of re nal functions; (8) number of subjects/group; (9) data analysis and interpre tation; and (10) impact on labeling. Results of the analysis indicated that 67% of the NDAs and 30% of supplemental NDAs contained RI studies (34/51 f or NDAs and 6/20 for sNDAs). No obvious differences in the pharmacokinetic characteristics (e.g., percentage excreted unchanged in urine and %PB) were observed between drugs for which RI studies were conducted versus those no t conducted. Most studies conducted were designed as single dose (70%). Sev enty-five percent of the studies used doses within the therapeutic dosage r ange of the drug. The measured 24-hour creatinine clearance was most often used to assess the renal function. Stratification of renal function ranged from one to five groups, with 6 to 8 subjects enrolled per group. In most s tudies conducted (38/40), data were analyzed by point estimate using ANOVA. Results of RI studies were adequately reflected in the labeling. The surve y reveals that RI study design can be improved for regulatory review purpos es. In part based on this analysis, the FDA has prepared a guidance that pr ovides recommendations on the design, analysis, and impact on dosing and la beling for RI studies to include recommendations on when RI studies do not need to be performed. The guidance proposes an equivalence approach with co nfidence intervals, as opposed to a point estimate approach, to assess the impact of RI on systemic exposure measures. (C) 2000 the American College o f Clinical Pharmacology.