TABLE 1.

Workshop Discussion of Factors that Influence Assessment of Prospect of Direct Benefit and Tools to Support and Maximize Benefit and Minimize Burden

Factors That Influence Assessment of Prospect of Direct Benefit	Tools to Support and Maximize Benefit and Minimize Burden
Evidence to support the proof of concept
• Biological plausibility  ο Scientific justification for the proposed mechanism of action and the expected effect in the condition of interest	In vitro data can provide valuable information about the product’s activity, particularly for studies conducted using cells or tissues derived from patients with the condition of interest
• Nonclinical data  ο In vitro mechanistic studies  ο In vivo studies in animal disease models	In vivo data obtained by using an animal disease model can provide insight into the product’s impact on disease pathophysiology and can help guide dosing decisions for a clinical trial
• Clinical data  ο Studies in adults with the condition  ο Previous studies in adults or pediatric patients with relevant conditions	Pediatric extrapolation of adult efficacy data to children can reduce the amount of data needed in children and allow for less burdensome pediatric trials
Structure of the study intervention
	Modeling and simulation of adult and/or pediatric pharmacokinetic/pharmacokinetic data to identify a pediatric dose based on predicted exposure-response relationship
• Dosing justification  ο Evidence to support that the proposed dosages for study are likely to have the intended treatment effect	PBPK modeling incorporating underlying physiologic parameters and product-specific information to predict the dose-exposure relationship Adaptive trial design to allow for dose exploration and optimization within the context of a trial designed to offer prospect of direct benefit
• Trial duration  ο Proposed trial duration is long enough for participants to experience a potential treatment effect	Consider treatment duration decisions made in clinical practice Measure clinically meaningful or validated surrogate end points when possible

PBPK, physiologically based pharmacokinetic.