Transcript Considerations for Extrapolation of Efficacy from Adults to Children

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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
2
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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
3
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* Draft Guidance for Industry: How to Comply with the Pediatric Research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/
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
5
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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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/
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
14
Natural cold study
Treatment group means, 2-way ANOVA, ITT population
Day
Tavist-1
Placebo
Diff
p-value
1 (baseline)
1.17
1.32
0.15
0.077
2
0.74
1.16
0.42
<0.001
3
0.54
0.90
0.36
0.001
4
0.31
0.70
0.39
<0.001
1 (baseline)
1.73
1.65
-0.08
0.419
2
1.46
1.58
0.12
0.179
3
1.02
1.39
0.37
<0.001
4
0.76
1.10
0.34
<0.001
Sneeze
Rhinorrhea
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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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
Joint Non-Prescription Drugs and Pediatric Advisory Committee Meeting
October 18-19, 2007
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