Developing Drugs for Pediatric Populations with Heart Failure, Dysrhythmias &

Structural Heart Disease: An FDA View of Objectives & Pitfalls

Lisa L. Mathis, M.D., FAAP CAPT, USPHS OND Associate Director Pediatric and Maternal Health Staff

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Objectives of Studies

To determine – Dosing– Efficacy – Safety

To label the product

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Labeling of Product

Data in Labeling– Represents a standardized, rigorous

approach to study– Has been independently reviewed– Statistical, Clinical Pharmacology, and

Medical Reviews available on FDA websitehttp://www.fda.gov/Drugs/DevelopmentAppr

ovalProcess/DevelopmentResources/ucm049872.htm

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FDA homepage www.fda.gov

Pediatric TherapeuticsPediatrics

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Pitfalls of Studies in Pediatrics

Dosing Enrollment Assessments

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Dosing

The dose must be right for the drug to work. Pediatric patients may have– decreased response to medications (e.g. platelet

agonists such as collagen, thrombin) – Increased sensitivity to medication (e.g. cardiac

action potential duration prolongation of Class II and III effect)

– Neonates may be altogether different Need pk, pd, modeling, dose ranging Fractionating adult dose is not appropriate

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Enrollment

Differences from programs in adults– Primarily academic centers– Large multi-center trials with low enrollment/site

Inefficient and slow to enroll Expensive per patient High number of sites/trial

– Adult vs. Pediatric fosinopril trial 220 adult pts in 9 sites in US: 5 months to complete

efficacy study (24 pts /site) 253 pediatric pts (6-16 yo) in 70 sites in 3 countries

taking 1 yr for study (3.5 pts/site)

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Enrollment

Often difficult Critical to know where patients are (do

studies need to be done at a specialty center?) Centers seem to overestimate how many

pediatric patients they will be able to enroll Inadequate number of patients results in

inability to interpret results

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Assessments

Must be clinically relevant (lab test without clinical correlate is not meaningful for the patients)– Surrogates can be considered (peripheral

vascular resistance could be considered a surrogate for exercise tolerance in some clinical settings)

Must be standardized across centers (timing of assessments is critical)

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Summary

Pediatric studies complex and difficult Adequate planning is critical to the success of

the study Obtaining appropriate dose(s) is critical to

outcome of study Power is critical to outcome of study and

endpoint must be meaningful All studies must be conducted using good

scientific principles