Peter R. Starke, MD Associate Director for Safety Charles E. Lee, M.D. Medical Team Leader Division of Pulmonary and All

1. Considerations for Extrapolation of Efficacy from Adults to ChildrenExamples and Experience from the Division of Pulmonary and Allergy Products Peter R. Starke, MDAssociate Director for Safety Charles E. Lee, M.D.Medical Team Leader Division of Pulmonary and Allergy Products

2. Overview • Pediatric Use Information requirement – Pediatric Rules and Pediatric Research Equity Act (PREA) • Decision tree regarding extrapolation • Example: Allegra – allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) • Example of an antihistamine studied for a “cold” indication in patients ≥12 years of age

3. Pediatric Use Information under the Pediatric Research Equity Act (PREA) • Pediatric Rules • 1994 Pediatric Rule (pediatric use information and extrapolation of efficacy) • 1998 Pediatric Rule (pediatric study requirement) • PREA (December 3, 2003) • Codifies both Pediatric Rules (21 CFR 314.55) • Requires submission of pediatric assessments and allows for extrapolation of efficacy • Applies to drug and biologic applications submitted on or after April 1, 1999, if the disease occurs in both adult and pediatric populations • Does not apply to monographed drugs

4. Extrapolation under PREA* • Extrapolation of efficacy from adult studies (or studies in other pediatric age groups) may be supported IF: “the course of the disease and the effects of the drug [both beneficial and adverse] are sufficiently similar in pediatric and adult populations” • Supplemented by dosing, PK, and safety data in the appropriate pediatric age groups • Clinical studies are necessary when extrapolation is not appropriate • Safety not extrapolated – confirm safety findings from adults and older age groups * Draft Guidance for Industry: How to Comply with the Pediatric Research Equity Act, September 2005; http://www.fda.gov/cder/guidance/

5. Extrapolation of Efficacy to Children • Depends upon • Course and pathophysiology of disease / lower bounds of disease process • Immune maturation and response • Anatomical differences • Response to drug • Other factors • Experience with the disease and drug / drug class • Systemic vs local activity and exposure • Estimation of the efficacy / safety balance

6. Systemic vs Locally Acting Drugs • Systemic drugs • Drug measurable in blood • Blood is relevant biospace • PK allows estimation of dose from adult data • Examples: Oral drug products • Locally active drugs • Drug may be measurable in blood, but • Blood is not relevant biospace (relevant biospace is lung or nose) • PK not helpful for estimation of dose • Examples: Intranasal and orally inhaled drugs

7. Difficulties with Performing Studies in Children • Consent / assent • Ethics • Limitations of blood draws • General lack of accepted endpoints and validated pediatric assessment tools (depends upon disease being studied) • Subjective endpoints • Objective endpoints • Maturational impact on dosing • Limited populations for certain diseases • Limited marketing potential compared with adults

8. Extrapolation in DPAP • DPAP has accepted applications using extrapolation from older age groups for: • Allergic rhinitis • Seasonal (SAR) – 2 years* • Perennial (PAR) – 6 months* • Chronic idiopathic urticaria (CIU) – 6 months* • For allergic rhinitis and CIU, the biology of the disease and drug’s effect are well established and substantially similar between children and adults • DPAP has not yet made a decision regarding extrapolation for a “common cold” indication * Lower age bounds based on totality of understanding of the disease process

9. Pediatric Development Programs – Allergic Rhinitis and CIU • Efficacy and safety generally established in adults and adolescents first • Evaluate efficacy in patients as young as can cooperate • PK in all ages • Safety in all ages

10. Allergic Rhinitis Efficacy Assessments* • Total Nasal Symptom Scores • Rhinorrhea, nasal congestion, nasal itching, sneezing • Severity rated on 4-point scale, 0-3 • Patient-assessed • Over 2 weeks for SAR • Over 4 weeks for PAR • Reflective and instantaneous scoring recorded in a diary at least as often as the dosing interval * Draft Guidance for Industry: Allergic Rhinitis: Clinical Development Programs for Drug Products, June 2000; http://www.fda.gov/cder/guidance/

11. Allegra (fexofenadine), Pediatric patients • Approved in 1996 for SAR in patients ≥12 years of age at a dose of 60 mg twice daily • SAR, 6-11 years (30 mg BID) • PK – comparable exposure to adults • Efficacy and Safety: 2 randomized, double-blind, placebo-controlled, 2-week SAR studies (N >400) • SAR, 2-5 years (30 mg BID) • Extrapolation of efficacy • 3 PK and 3 Safety studies in children with allergic rhinitis 6 months through 5 years (N=969) • CIU, 6 months - 11 years (15 and 30 mg BID) • Extrapolation of efficacy from three 4-week CIU studies in patients ≥12 years • PK and Safety in all ages

12. Tavist-1 (clemastine fumarate, 1.34 mg) • Clemastine fumarate • Antihistamine of the ethanolamine class (structurally similar to diphenhydramine and carbinoxamine) • Anticholinergic activity • Rx to OTC switch approved in 1992 for allergic rhinitis • Rx supplement approved in 1996 for treatment of colds in patients ≥12 years of age

13. Tavist-1, Colds, ≥12 years • Program included • 1 natural and 1 induced cold study • Additional information from 4 natural cold marketing studies not performed under the IND • Subject of a joint Pulmonary-Allergy and Nonprescription AC meeting, November 1995 • AC Recommended approval for the treatment of rhinorrhea and sneezing in adults and children 12 years of age and older with the common cold

14. Natural cold study • Randomized, double-blind in 403 previously enrolled patients, treated with Tavist-1 or placebo for 5 days within 24 hours of the start of cold symptoms • 1° efficacy endpoint: Change from Day 1 (baseline – instantaneous) to Day 2 and 3 (retrospective 24-hour) scores for sneezing and rhinorrhea, 0-4 scale

15. Natural cold studyTreatment group means, 2-way ANOVA, ITT population

16. Summary • Pediatric Use requirements and extrapolation of efficacy • Decision tree for extrapolation • Course and pathophysiology of disease • Immune maturation and response • Anatomical differences • Response to drug • Systemic vs local activity and exposure • Experience with the disease and drug / drug class • Estimation of efficacy / safety balance • Example to illustrate a relevant pediatric development program for allergic rhinitis and chronic idiopathic urticaria • Example of an antihistamine studied for a “cold” indication in patients ≥12 years of age

17. Division of Pulmonary and Allergy Products White Oak Bldg 22, HFD-570 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 Phone: 301-796-2300 Fax: 301-796-9728