081: Exclusion of Pediatric Patients With Renal Impairment in Clinical Trials for Antiviral Products

Statement of Purpose, Innovation or Hypothesis: For renally eliminated drugs, dosing recommendations in adult patients with renal impairment (RI) are supported by the pharmacokinetic (PK) and/or clinical safety and efficacy data and often based on estimated Glomerular Filtration Rate (eGFR) or estimated Creatinine Clearance (CLCr). However, dosing adjustment recommendations in pediatric patients with RI are not often available in product labeling, or not as clear as those for adults. Determining appropriate dosing regimens in pediatric patients with RI is challenging due to multiple reasons such as lack of observed PK data and difficulty in identifying pediatric renal function cutoffs corresponding to those in adults. It is possible that lack of data is, at least in part, due to unnecessary exclusion of pediatric patients from trials. As an initial step to address this issue, a survey was conducted to summarize inclusion/exclusion criteria related to renal function in pediatric trials for antiviral products.

Description of Methods & Materials:

Pediatric studies among currently approved antiviral drugs were identified and included in this analysis if drugs are substantially eliminated by the renal route (fe≥ 0.3); or are approved with specific minimum renal function requirements or dose adjustments based on renal function regardless of fe or renal elimination information. Additionally, pediatric studies conducted exclusively in adolescents (i.e., ≥ 12 years of age) or pediatric studies completed prior to 2009 (when the revised Schwartz formula became available) were excluded.

Data & Results: A total of 34 studies were identified for 18 approved antiviral products. 1) In 19 studies involving children < 1 year old, 13 (68.4%) utilized eGFR values determined by modified or bedside Schwartz equations; in 8 out of the 10 studies that used modified Schwartz equation, the proportionality constant k was specified as 0.45; k was set as 0.33 for neonates with low birth weight ( < 2500 g) in one study. 63% protocols (12/19) utilized the renal function related exclusion criteria as those applied to pediatric patients above 1 year old despite the fact that renal function is not fully matured in this age group. For the remaining protocols (7/19, 37%), different equations and/or different cutoff, were used for children < 1 year vs. children >1 year. 2) In studies involving children ≥ 2 years of age, 22 out of 25 (88%) utilized Schwartz equations for renal related inclusion/exclusion. 3) In all surveyed pediatric studies, over half of them had more stringent renal exclusion criteria compared to those used in adult registrational trials or approved renal dosing cutoff for adults. Only one protocol specified dose adjustments in pediatric patients with RI. In addition, inconsistencies in the use of terminology and equations were also noted, such as differences in defining the modified Schwartz equation.

Interpretation, Conclusion or Significance: A survey was conducted to assess renal impairment criteria used in pediatric clinical trials for antiviral products. Further landscape analysis is warranted to establish a consistent approach for enabling the participation of pediatric patients with renal impairment in clinical trials, especially those involving infants.

Disclosures:

The views expressed are those of the authors and do not reflect official policy of the US Food & Drug Administration.

Citations/References:

Additional Information/Authors: Not applicable.