Development Plans: Study Design and Dose Selection

1. 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

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

3. 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)

4. 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

5. Objectives • Should be stated, not always done • 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?

6. 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

7. 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?

8. 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

9. 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

10. Dose Selection • Mechanism of Action • 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?)

11. Dose Selection • Adequate dose exploration • 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

12. 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