FDA drafts guidance on pediatric clinical pharmacology studies

Regulatory NewsRegulatory News | 08 September 2022 | By

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The US Food and Drug Administration (FDA) has laid out its thinking on the ethical and physiological issues sponsors should consider when planning to run clinical pharmacology studies for pediatric products. The agency acknowledges that such studies may not always be warranted but in cases where benefits significantly outweigh the risks, they may help better understand a drug or biologic’s risk-benefit profile.
On 7 September, the FDA published the draft guidance titled, General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products. In the guidance, the agency distills its thinking on how pediatric pharmacology studies for drugs and biologics may be conducted. The document specifically looks at clinical pharmacology, ethical and pediatric trial design considerations.
“The measurement or prediction of a drug’s pharmacokinetics (exposure) and pharmacodynamics (response) is essential to the clinical pharmacology assessment,” FDA said. “It is important to describe the exposure-response relationship of a drug in the pediatric population when possible to enhance the understanding of effective dose ranges or support the ability to extrapolate information from older pediatric participants.”
Regulators go on to say that pediatric drug development programs should also consider the time course of the drug-metabolizing enzymes, drug excretory systems, transporters and drug target/receptors relevant to the drug being studied. To achieve this, sponsors can characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the drug across the age ranges it’s being developed for using PK/PD studies.
FDA elaborates on the definitions of pharmacokinetic and pharmacodynamic in the proposed guidance, and how to conduct PK/PD studies. In terms of pharmacokinetic studies, the agency wants sponsors to factor in issues such as how a drug is absorbed, distributed in the body, metabolized, binds to proteins and is cleared from the body.
Whenever possible, regulators want sponsors to collect pharmacodynamic data as well as pharmacokinetic data to understand how the two are linked in pediatric studies.
“PD data can include the effect of the drug on biomarkers or clinical endpoints for both effectiveness and safety,” FDA said. “These measurements can allow a better understanding of whether the PK-PD relationships of the drug in pediatrics are similar to those observed in adults and can help derive rational dosing strategies in pediatrics.”
The agency goes on to say that if the clinical endpoint cannot be measured directly because the effect is delayed or infrequent, then sponsors must pick an appropriate biomarker to substitute for the clinical effectiveness or toxicity endpoint.
While not always possible, FDA also wants sponsors to try to present pharmacogenomics data that may explain how genetic differences may explain drug exposure and response. The agency acknowledges that the relationship between genomic profiles and regulated gene expressions have not been extensively studied in children.
“Genotype-phenotype relationships observed in adults are not always representative of those observed in pediatric populations, particularly neonates and infants,” regulators said. “Nevertheless, if drug exposure and/or response is dependent on a well-known pharmacogenomic biomarker (e.g., cytochrome P4502D6), collecting and analyzing pharmacogenetic samples in a pediatric clinical pharmacology study could provide additional information for the interpretation of the PK and PD results.”
When taking into consideration ethical issues in pediatric trials, FDA largely relies on regulations already developed for Institutional Review Boards (IRB). The agency points out that if the drug or procedure does not potentially have a direct benefit to the child being studied, that typically means study researchers are limited to a minimum risk standard unless FDA allows it under the oversight of an IRB. With that in mind, the regulators note that clinical pharmacology studies typically don’t provide a direct benefit to individual pediatric participants, so IRBs generally allow at most a minor increase over minimal risk standard in such studies.
“However, if a clinical pharmacology study offers the prospect of direct benefit to the participant, such as by ensuring that serum levels of a drug remain within the therapeutic range, then the study potentially could be approvable by an IRB,” they added.
FDA reminds sponsors that under its regulations, clinical trial pediatric participants must have a disorder or condition that is the focus of the study and must be directly applicable to improving their situation.
“For IRB approval of a clinical investigation [according to regulation], the pediatric participants must have a prospect of direct clinical benefit from administration of the investigational product, the risk to the pediatric participants must be justified by the anticipated benefit, and the relation of the anticipated benefit to the risk must be at least as favorable to the pediatric participants as that presented by available alternative approaches,” the agency added.
Besides considerations for PK/PD studies and ethical issues, the draft guidance also more broadly discusses pediatric study plan designs and other considerations.
FDA notes when developing a pediatric drug or biologic, sponsors are required to present them with an initial pediatric study plan (iPSP) unless the product is for an already assigned orphan designation. The agency says submission of such study plans is meant to encourage sponsors to think about pediatric studies early on in their product development and should take into consideration factors including type of study design that’s appropriate, the objective of the study, the age group and population researchers plan on studying, and endpoints and their justification.
“When designing pediatric clinical studies, sponsors should be mindful that modeling and simulation and pharmacologic considerations are often critical for the successful completion of a study,” FDA said. “Modeling and simulation (e.g., PK, PD, and trial simulations) should use all of the information available and be an integral part of all pediatric development programs followed by verification using results from pediatric clinical studies.”
With that in mind, the draft guidance delves into a discussion of the appropriateness of different pediatric studies depending on factors such as disease and population types, alternative approaches to pharmacokinetic studies, pediatric dose selection and formulation, issues surrounding sampling and drug-drug interaction considerations.


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