Reporting guidelines for population pharmacokinetic analyses

Abstract

The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including PKPD and simulation reports.

Fig. 1

Components of a population PK report and their perceived importance. Each symbol represents the response for a single report section, subsection or content element

Fig. 2

Preferred location and importance of content elements within “Methods section”: Data Sources (circles): 1. overall data sources 2. study design 3. population. Data Handling (triangles): 1. overall data handling 2. handling of missing data 3. handling of covariates 4. handling of outliers 5. data exclusions. Modeling and Statistical Methods (squares): 1. general approach 2. structural model development 3. random effects 4. covariate model development 5. model qualification 6. simulation methods. Note: X-axis jitter added to data to distinguish overlapping values

Fig. 3

Preferred location and importance of Results content elements: Data Description (light blue square): 1. demographics 2. covariate distributions 3. sampling time distribution 4. display of raw data versus time 5. other. Structural Model Description (orange circle): 1. overall random effects (light yellow triangle): 1. overall 2. residual variability 3. inter-individual variability 4. inter-occasion variability. Covariate Analysis (green diamond): 1. overall 2. covariates tested 3. covariates selected. Final Model (black square): 1. overall. Model Qualification (gray circle): 1. overall. Application/Interpretation of Model Results (red triangle): 1. overall 2. simulation results 3. size of identified differences among covariates. Note: X-axis jitter added to data to distinguish overlapping values