Impact of population pharmacokinetic-pharmacodynamic analyses on the drug development process - Experience at Parke-Davis

Background: Continued scepticism about the benefits of population pharmacok inetics and/or population pharmacodynamics, here referred to collectively a s the population approach, hampers its widespread application in drug devel opment. At the same time the sources of this scepticism have not been clear ly defined. In an attempt to capture and clearly define these concerns and to help communicate the value of the population approach in drug developmen t at Parke-Davis we conducted a survey of customers within the company. The results of this survey are presented here. Methods: All drug development programmes conducted over the past 10 years t hat included a population approach in data analysis and interpretation were identified. A brief description of the population analysis was prepared to gether with a brief description of how the resulting information was used i n each drug development programme. These synopses were forwarded to relevan t members of each drug development team together with a survey designed to solicit opinions as to the relevance and impact of these analyses. Results: The most frequent use of information derived from population-based analysis was in labelling. In all cases of drugs making to New Drug Applic ation (NDA) submission the analyses resulted in information that was includ ed in approved or proposed labelling. In almost half of the cases summarise d here (5 of 12), population-based analysis was perceived to have resulted in information that influenced the direction of individual development prog rammes. In many of these cases the information was serendipitous. It is als o noted that most of these analyses were not the result of clearly defined objectives and prospective analysis plans. Conclusions: Use of the population approach, even when applied retrospectiv ely, may have value in complementing or supporting interpretation of other data collected during the course of a trial. Atypical systemic exposure is quickly and easily assessed for correlation with adverse events or exceptio nal efficacy in retrospective or ad hoc evaluation. Although we know of no direct evidence, it is possible that such use of population pharmacokinetic data has facilitated NDA review and approval by providing insight into the role of atypical systemic drug exposure in otherwise spurious events.