June 16, 2023
My name is Sophia Phillips and I am a Health Policy Associate speaking on behalf of the National Center for Health Research. Our nonprofit think tank scrutinizes research on the safety and effectiveness of medical products, and we do not accept funding from companies that make those products. Therefore, we have no conflicts of interest.
We strongly support the safety and tolerability specifications identified in the January 2023 draft guidance included in the FDA briefing document. It is essential that duration of exposure, dosage interruptions, and adverse events be compared across varying dosages. We agree that safety monitoring rules should be pre-specified for trial designs. We also agree that adverse reactions, even those considered less severe, should be carefully assessed and considered when selecting the dosage for follow-up clinical trials.
We also strongly support the statement that “Population pharmacokinetics, or PK, data should be evaluated to identify specific populations ( For example, defined based on weight, age, sex, race and ethnicity, or organ impairment) in which the PK demonstrates clinically meaningful differences in exposure.” However, the September 2022 guidance on General Pharmacology Considerations provided a more detailed list of important variables to consider, such as calculated BMI, gestational age, postnatal age for neonates, and laboratory tests reflecting the function of organs responsible for drug elimination. We urge that these be added to the new guidance on dosing.
It is also essential that these variables not only be evaluated separately; instead relevant covariates should be incorporated into analyses to identify potential differences in safety or effectiveness for relevant subpopulations. For example, within an age group there may need to be different dosages due to weight, sex, and race or ethnicity. While this does require a substantial number of patients representing these different groups to be enrolled in a study, it is better to do that prior to a drug approval at particular doses than to find out that dosages are too high or too low for some groups years after the product is approved.
The proper use of covariates and phenotype data was clearly expressed in the September 2022 FDA guidance on General Clinical Pharmacology Considerations. Unfortunately, it was not included in the January 2023 guidance specific to dosage optimization and it should be added to that guidance as well.
Thank you.