Assessment of the quality and quantity of drug-drug interaction studies inrecent NDA submissions: Study design and data analysis issues

This report investigates the quality and quantity of drug-drug interaction studies in recent new drug applications (NDAs). Eighty-nine studies contain ed in 14 NDAs submitted between December 1995 and November 1996 to the U.S. Food and Drug Administration (FDA) were reviewed. The results indicated th at the median number of clinical drug-drug interaction studies per NDA was 6, almost double that of a 1994-1995 survey: In vitro metabolism data were present in 70% of the submissions. More than 50% of the submissions contain ed interaction studies using a battery of drugs (cimetidine, digoxin, or wa rfarin) without optimal use of the in vitro metabolism or in vivo mass bala nce data. Various study designs using a median number of 12 subjects were e mployed in the evaluation of drug-drug interactions. Some of the important study design factors such as dose size, dosing regimen, dosing duration, an d timing of coadministration were considered, although not consistently by the sponsors in their study design. Seventy-five percent of the studies use d normal, healthy male subjects, and 25% used patients for whom the new mol ecular entities were intended in 33% of the studies, female subjects were a lso recruited Although the majority (80%) of the submissions still used p-v alues to determine the significance of drug interactions, 30% used a more r elevant equivalence approach with 90% confidence intervals for key pharmaco kinetic and/or pharmacodynamic parameter ratios to assess the extent of dru g interactions. Overall, 82% of the studies concluded no interaction. Altho ugh population pharmacokinetic analysis can be a useful tool in studying dr ug-drug interactions, only 21% of the submissions used this approach. In su mmary, this assessment reveals that the quantity and qualify of drug-drug i nteraction studies in NDAs have improved over the pears. These improvements , as wen as others that can be implemented should result in more informativ e labeling and better patient care. FDA guidance for industry dealing with the design, analysis, and labeling language of in vivo metabolic drug-drug interactions has been developed to assist sponsors and FDA reviewers with t hese issues. Journal of Clinical Pharmacology 1999;39:1006-1014 (C)1999 the American College of Clinical Pharmacology.