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 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?

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?

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 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?)

11. 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

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