By Kevin Dykstra
Pharmacometrics is a maturing discipline that utilizes mathematical models to provide quantitative insights that lead to better drug development decisions. Pharmacometric analysis integrates data from preclinical experiments, clinical studies, or literature to construct statistically realistic models of drug exposure and response. These models can benefit a number of crucial areas in drug development. Common uses include identifying and justifying optimal dose and regimen both internally and to regulators, simulating clinical trials to decrease the risk of late-stage failure, and verifying that the benefits of a drug candidate are sufficient to warrant further development (or not). Most large pharma and biotech organizations have groups devoted to pharmacometric analysis, and regulatory agencies routinely consider pharmacometric analysis in their licensing and labeling decisions. Surprisingly, smaller pharma and biotech companies have been slow to adopt these tools, often because of the lack of in-house pharmacometrics awareness and know-how.
Pharmacometrics is a highly technical discipline, and effective communication of analysis results beyond technically proficient team members remains a barrier to adoption of the important insights gained in the analysis. As the field matures, so increases the pressure to ensure that these analyses are conducted and reported in a consistent, reliable manner so that the results can be readily understood and endorsed by decision makers.
It was my privilege to collaborate with a group of scientists from various pharmaceutical companies, consultancies, and the Food and Drug Administration to develop updated guidelines for population pharmacokinetic (popPK) reports. This work was carried out under the auspices of the Model-Based Drug Development Consortium, a working group comprised of representatives from the American Society of Clinical Pharmacology and Therapeutics, the American College of Clinical Pharmacology, the American Association of Pharmaceutical Scientists, and the International Society of Pharmacometrics, and the recommendations have been published recently in the Journal of Pharmacokinetics and Pharmacodynamics and in the Journal of Clinical Pharmacology. We focused on popPK because pharmacometric analysis generally starts with a characterization of the kinetics and variability in drug exposure, and these analyses are usually conducted using population methods. The guidelines were partly based on a survey of pharmacometricians’ perceptions and practices, and partly on extended discussions of how best to present analysis results. Our recommendations enable key analysis results to be clearly accessible to all interested readers, including those with minimal exposure to pharmacometric analysis methods, while still fulfilling the crucial function of documenting the analysis for purposes of technical review or replication and extension of the work. We believe this is an important next step in the continuing development and adoption of the discipline.
In pharmacometric reporting, there are typically three groups of readers: technical, drug development, and regulatory, and it is critical to address the needs of each. The technical readers must be able to see that the work was carried out in a proper manner and that the conclusions are supported by the analysis data, methods, and results. The drug development readers must understand the decisions that can be made as a result of the conclusions as well as the limitations of the analysis. The regulatory readers combine both of the aforementioned views to ensure the appropriate benefit-risk for the patient.
It is important to recognize that pharmacometrics encompasses a broad array of methods and analysis types. This diversity should not preclude recognition of common processes and concerns across different analyses, and that a level of consistency in analyses will help make them more usable to all audiences. In this spirit, the guidelines we developed are intended to serve as a basis for all pharmacometric analyses, not just popPK. We hope these guidelines will be widely applied, and that the principles articulated in them will be extended to all pharmacometrics reporting efforts.