Can Pediatric Dosing be Extrapolated from Adult Dosing? FDA Suggests Ways
(Thursday, August 18, 2022)
Conducting clinical trials in children is extremely challenging so very few drugs are tested and approved based on pediatric clinical trials. Pediatricians frequently guesstimate dosing for their patients based on subjective assessment of the dosing data approved for adults. However, there might be an FDA-acceptable statistical methodology for formal extrapolation of adult doses to children according to FDA statisticians. In the real world, extrapolation of efficacy from adults to children, although mostly subjective, has been found to be useful particularly when disease progression and treatment response are similar in adult and pediatric populations. Extrapolation of adult doses to children is based on analysis of the drug exposure-response similarity between adults and children. The most common method is to plot the maximum exposure (Cmax) against an efficacy endpoint of interest. Such curve uses data from the various age groups who participated in clinical trials or for whom exposure-response data is available from other sources. The main medical principle governing such extrapolation is that of non-inferiority which is the assumption that drug would be at least non-inferior to (i.e., no worse than) the other options available whether it is another drug or the standard of care. The expectation is that the drug exposure will elicit similar pharmacological effects regardless of age. The major limitation of this method is lack of sufficient data in all age groups for an accurate extrapolation. FDA statisticians seem to agree. According to FDA statisticians, sponsors can use the non-inferiority paradigm to justify dosing regimen for children based on results from adult populations in the pivotal clinical trials. FDA proposes two statistical approaches: bootstrap and Bayesian methods. In the FDA analysis, both methods were effective in determining non-inferiority between the adult and pediatric response for the eight drugs evaluated. FDA contend that certain conditions where there is similarity of the disease and expected response to treatment between the adult and pediatric patients, “less additional data may be needed to provide evidence to support pediatric drug approval.” Although not new, this is an innovative statistical suggestion that should be useful for any developer working on a drug to treat diseases that affect adults and children alike. Its not a formal policy but since it comes directly from FDA, it is something worth investing statistical resources into.
Dr. Mukesh Kumar
Founder & CEO, FDAMap
Linkedin: Mukesh Kumar, PhD, RAC