Rashmi R Shah
Medicines Control Agency, London, UK
The theoretical principles behind population approaches during the clinical development of a new drug may be expected to result in provision of valuable information and optimise drug development process. Three areas where population approach might be useful were the design of dose schedules, an estimation of the effects of covariates (eg demography, co-medications, disease states, environmental factors, laboratory values) and the extrapolation of concentration-effect relationship to efficacy and toxic effects. PK/PD analyses have been used successfully to design dosing schedules.
However, from the regulatory point of view, the interest in population approach focuses on its other applications. The areas of particular interest are (i) PK/PD relationship to characterise optimal plasma concentrations for efficacy and adverse effects, (ii) interactions with disease states and (iii) interactions with drug combinations.
In practice, a number of deficiencies are encountered in the dataset and these restrict the regulatory utility of population approach as provided by the applicants in their dossiers. Unless these deficiencies are recognised, there is a risk of drawing inappropriate conclusions. The deficiencies relate not only to the quality of data but also to the nature of information that may be obtained, or conclusions that may be drawn, even when the data collected were of high quality. From the regulatory point of view, the essential questions are:
* What has been measured and when?
* What has not been measured?
* What is known about the relevance of these measured and unmeasured entities?
* In whom are the entities measured?
* In whom have these entities not been measured?
* Given the above, are the conclusions appropriate?
This lecture will focus on the following aspects that limit the regulatory utility of population approaches:
* Quality of data
* Enrolment criteria
* Variability in pharmacokinetics (particularly drug metabolism)
* Variability in pharmacodynamics
* Role of active metabolites
* Role of enantiomers of chiral drugs
* Reciprocity of metabolic inhibition
* Role of specific drugs versus therapeutic classes of drugs
Reference: PAGE 7 (1998) Abstr 672 [www.page-meeting.org/?abstract=672]
Poster: oral presentation