Development Plans: Study Design and Dose Selection John Alexander, MD, MPH Deputy Director, Division of Pediatric and Maternal Health, CDER Pediatric Clinical Investigator Workshop Feb 28, 2019

Disclaimer slide This presentation reflects the views of the presenter, and should not be construed to represent FDA’s views or policies.

Purpose Describe study design considerations (in 15 minutes) Focus on pediatric trial issues Selected clinical protocol sections Objectives Background Selection Criteria Endpoints Study Procedures Dose selection Safety (discussed in another presentation)

My Perspective Overview of pediatric protocols FDA sees a wide range of protocols First use to approved, widely-used agents Context important to understanding determining the right study design Comments on selected protocol section For consideration in planning pediatric studies For investigators reviewing a protocol

Objectives Should be stated, not always done Type of study Goals of study Type of study Fit for purpose Superiority, non-inferiority Randomized withdrawal Blinded or open-label Is the type of study appropriate for the objectives?

Study Background Typically includes disease description For pediatrics, epidemiology/age of onset Other questions to answer What is known about the drug/disease (in adults)? Has the drug been used/approved for pediatric patients (in other conditions)? What is the standard of care? What makes this study the right next step? www.fda.gov

Selection Criteria To identify intended population for study Sufficient for consistent population across study sites? Homogeneity versus inclusivity Age range Exclusions for safety, risk/benefit Review for relevance to intended pediatric population Avoid laundry list Investigator discretion Often included, but has drawbacks How does it affect enrolled population? What is missing from other selection criteria?

Endpoint(s) Primary endpoint should be clearly identified Clinically meaningful endpoints: direct measures of how a patient feels, functions, or survives Objective measures Often focus on quantitative Patient-reported outcomes Validation Statistical analysis plan Handling missing information

Study Procedures Should include detailed plan description Often outlined by study visit Requires careful review (inconsistencies) Individually consider invasive procedures Standard of care for pediatric patients Not for research purposes only Blood volume sampling Measures of growth and development

Dose Selection Mechanism of Action Prior adult studies Not always known Can be important to support reliance on in vitro or animal models Receptor ontogeny Prior adult studies Exposure-matching Pediatric-only conditions Dose rationale/prospect of direct benefit Dose for other conditions (relevance?)

Dose Selection Adequate dose exploration Locally-acting drugs Consider pilot study Locally-acting drugs Protocol considerations Dose rationale often lacking, should have clear basis for chosen dose Review administration instructions for pediatric patients

Summary Study design involves a complex interplay of factors that all contribute to the ability to conduct a trial For pediatric studies, need to consider pediatric growth and development in the planning of a clinical trial