Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am excited to be talking with Dr. Hao Zhu, who is the acting Director of the Division of Pharmacometrics in CDER’s Office of Clinical Pharmacology. Dr. Zhu will be sharing some thoughts with us on the newly published final guidance titled, “Population Pharmacokinetics.” Welcome, Dr. Zhu! Thank you for speaking with us today.
For those in the audience less familiar with this topic, can you provide a simple definition for population pharmacokinetics and give some of the reasons that FDA issued this guidance?
Sure, for listeners less familiar, let’s begin with the definition of pharmacokinetics (also called PK), which is the science of measuring a drug’s concentration change in the patient’s body over time. PK studies help determine the appropriate dose for a medication that will produce a drug concentration in the patient’s body high enough to be therapeutically effective and low enough to be safe. However, there can be PK variability within a population. Population PK is the science of describing the PK variability within a population and identifying the cause of this variability. This information is important for designing aspects of the clinical trials and for optimizing dosing and dose adjustment for patients.
FDA published the first version of this guidance in 1999 to provide the agency’s thinking on the data and model requirements needed for population PK studies to support regulatory decisions. We then published a revised draft version of the guidance in 2019 to provide recommendations containing the most up-to-date science and advice on reporting population PK results in the labeling. FDA is now publishing the final version of the guidance, and it contains technical and editorial changes that address public comments received on the revised draft guidance and improves the clarity of the document.
What are general considerations for planning population PK analyses during drug development?
An important consideration for planning population PK - analyses is for sponsors to ensure the study design includes adequate samples and sampling points in order to get sufficient data to inform the PK analysis. Population PK study design factors vary from drug to drug based on the formulation, PK characteristics, and the intended patient population. We generally recommend that sponsors perform simulations of these variables to optimally design their population PK analyses and ensure sufficient data is obtained.
During drug development, population PK study design is typically informed by PK studies performed during phase 1 clinical trials and samples for population PK analyses are generally collected during phase 2 and phase 3 clinical trials in the intended patient population.
What does population PK data inform during the regulatory review process, and when is it evaluated?
Population PK results typically inform trial design and dose selection during the regulatory review process, and these two areas ultimately contribute to the product approval decision. Trial design decisions generally occur during the Investigational New Drug (or IND) review stage but may happen during the New Drug Application (NDA) or Biologics License Application (BLA) review stage, for example when designing pediatric studies. Dose selection decisions for subpopulations identified by population PK studies generally occur during the NDA or BLA review stage.
Where are population PK results in labeling, and how can clinicians and patients find the dosing recommendations made from the population PK results?
Population PK analyses can be found in a few places in the labeling. The most common location for population PK data in the labeling is the PK subsection 12.3 in the Clinical Pharmacology section (or Section 12) of the labeling. Dosing recommendations for specific patient populations identified in population PK analyses are generally listed under Section 8, Use in Specific Populations, but can sometimes this information can also be found in Section 2, Dosage and Administration, or Section 7, Drug Interactions.
As we wrap up this episode, what are a couple of key items that you especially want listeners to remember?
That is a great question. I want listeners to remember that that there can be subgroups within a patient population that require a dose adjustment for a medication due to a variety of factors. Population PK is the science of describing the PK variability within a population and identifying the cause of this variability to inform accurate dose adjustment for these subgroups of patients. Scientific approaches are fast evolving, and this guidance provides the agency’s most up-to-date recommendations for optimizing population PK study design to obtain adequate information that informs accurate dose selection. This guidance also provides content and formatting recommendations for submitting population PK report to the agency and provides best practices for reporting population PK results in the labeling to communicate this information to both clinicians and patients.
Dr. Zhu, thank you for speaking with us today about the final guidance on Population Pharmacokinetics. We have learned so much from your insights on this document. We would also like to thank the guidance working group for writing and publishing this final guidance.
To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.