1. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 Considerations for Extrapolation of Efficacy from Adults to Children Examples and Experience from the Division of Pulmonary and Allergy Products Peter R. Starke, MD Associate Director for Safety Charles E. Lee, M.D. Medical Team Leader Division of Pulmonary and Allergy Products Peter R. Starke, MD Associate Director for Safety Charles E. Lee, M.D. Medical Team Leader Division of Pulmonary and Allergy Products

2. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 2 OverviewOverview 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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/ 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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/ 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 15 Natural cold study Treatment group means, 2-way ANOVA, ITT population DayTavist-1PlaceboDiffp-value Sneeze 1 (baseline)1.171.320.150.077 20.741.160.42<0.001 30.540.900.360.001 40.310.700.39<0.001 Rhinorrhea 1 (baseline)1.731.65-0.080.419 21.461.580.120.179 31.021.390.37<0.001 40.761.100.34<0.001

16. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 16 SummarySummary 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 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. Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting October 18-19, 2007 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