Transcript Document 7397197

Perspectives on Enhancing
Consumer Outcomes
with Topical Antifungals
Helmut H. Albrecht, MD, MS, FFPM
Vice President
Clinical & Medical Development
Novartis Consumer Health
Overview
 Enhanced labeling to improve compliance and
achieve optimal treatment benefit
 Terbinafine offers unique efficacy and safety
profile
 Appropriate endpoints should guide product
development, consumer expectation and
labeling
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Presentation of Interdigital Tinea Pedis
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The Consumer Experience:
Time Course of Mycology, Signs & Symptoms
Mycology
Symptoms
Signs
4 Weeks
1 Week:
Consumer Symptom
Recognition/Treatment
Initiation
8-12 Weeks
Symptom Resolution
Consumer Decides to
Discontinue Treatment
Schematic based upon market research: Athlete’s Foot Category Assessment Study. Protocol Research. December 2002
(n=300)
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Topical Terbinafine – Product Overview
 Synthetic allylamine with fungicidal activity
 Efficacy with only 1 week treatment; no need for
additional therapy
 Rx in US in 1992 and OTC in 1999
 Demonstrated safety profile (>200 million
exposures)
 Only active ingredient in Lamisil AT line
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Efficacy
Terbinafine Activity
in vitro:
• MICs:
- 0.003 – 0.006 μg/mL
- 100 – 1000x more potent than other antifungals
in vivo:
• 7 days of treatment: 1000x MIC
• 7 days post-treatment: 100x MIC
Hill, S, Thomas, R, Smith, SG and Finlay, AY. Br. J. Derm 127: 396-400, 1992
Petranyi, G, Meingassner, JG, Mieth, H. Antimicrobial Agents Chemother 31: 1365 – 1368, 1987.
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Pivotal Study for OTC Switch
1 Week BID Treatment Study
100%
(pivotal study # 2506-01 (n=67) in Lamisil AT Cream NDA)
- Terbinafine
88%
- Vehicle
64%
7%
21%
20%
0%
Mycological Cure
p<0.001
Effective
Treatment
p<0.001
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0%
Complete Cure
p<0.001
1 Week Treatment vs. Clotrimazole
100%
- Terbinafine
92%
- Clotrimazole
55%
61%
38%
19%
0%
Mycological Cure
p<0.001
Effective
Treatment
p=0.065
Novartis Lamisil AT 1% Cream Study # 2508-01 (n=97)
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13%
Complete Cure
p=0.532
4 Week Treatment vs. Clotrimazole
100%
- Terbinafine
83%
84%
- Clotrimazole
71%
47%
24%
0%
13%
Mycological Cure
p>0.999
Effective
Treatment
p=0.029
Novartis Lamisil AT 1% Cream Study # 2508-01 (n=97)
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Complete Cure
p=0.271
Relapse/Reinfection Rates at 12 Weeks
100%
- Terbinafine
- Clotrimazole
47%
30%
9%
0%
1 Week Treatment
Novartis Lamisil AT 1% Cream Study # 2508-01 (n=193)
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11%
4 Week Treatment
Time Course for Negative Mycology
Mycological Response
% Negative Mycology
100 %
Terbinafine 1 Week
Terbinafine
Weeks
T erbinafine
- 1 W eek4BID
T erbinafine - 4 W eek BID
Clotrimazole
Clotrimazole
- 1 W eek1BWeek
ID
Cotrimazole - 4 W eek BID
Clotrimazole 4 Weeks
0%
0
1
2
3
4
5
6
7
8
9
10
Study Week
1 Week BID – Terbinafine vs. Clotrimazole: p=0.003 (6 weeks); p<0.001 (12 weeks)
Bergstresser PR et al. J Am Acad Dermatol. 28:648-51, 1993.
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Time Course for Signs & Symptoms
Clinical Response
% Reduction in Signs and
Sypmtoms
100%
Terbinafine 1 Week
Terbinafine
4 Weeks
Terbinafine
- 1 Week
Terbinafine - 4 Week
Clotrimazole
1 Week
Clotrimazole
- 1 Week
Clotrimazole - 4 Week
Clotrimazole 4 Weeks
0%
0
1
2
3
4
5
6
7
8
9
10
Study Week
1 Week BID – Terbinafine vs. Clotrimazole: p=0.055 (6 weeks); p=0.006 (12 weeks)
Bergstresser PR et al. J Am Acad Dermatol. 28:648-51, 1993.
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New Product Development Requirements
Efficacy to be established based solely on
separation from placebo
 New Chemical Entities (NCEs):
 Dose ranging studies needed
 Line Extensions:
 Dermal PK/MIC data to establish dose
 Frequency and duration studies may be necessary
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Safety
Evaluating Lack of Effectiveness Reports
LOE Cases as % of Purchases
0.006%
0.005%
0.003%
0.003%
0.002%
0.002%
0.000%
Year
1999
2000
2001
2002
2003
LOE Cases
221
178
169
135
139
Units Sold
4,106,655
5,529,761
5,515,180
5,561,519
6,085,244
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Terbinafine Effectiveness Over Time
1991 - 1992
100%
1995 - 1999
Study # 2-1 (n=77) and # 2-2 (n=91)
Study # 98-001 (n=135) and # 351 (n=86)
100%
-Terbinafine
88%
85%
- Vehicle
65%
67%
11%
23%
30%
8%
1%
0%
14%
26%
3%
0%
Mycological
Cure
Effective
Treatment
Complete
Cure
Mycological
Cure
Effective
Treatment
Complete
Cure
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
(each represents avg. of 2 double-blind, placebo controlled studies, 1 week BID)
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Cellulitis
 Rare Occurrence
− 13 cases since 1965
− 5 cases with Lamisil since 1993
 Relationship to drug unclear
 Associated with underlying condition
− Risk reduced by treatment
− Labeling recommendation to include warnings for at
risk populations (e.g. diabetics)
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Labeling
Relationship Between Clinical Outcomes
and Patient Assessment
100%
- Effective Treatment
- Complete Cure
61.6%
54.8%
30.8%
22.6%
16.1%
7.7%
6.5%
0%
Poor
Good
Fair
Novartis Data on File (sub-analysis from a controlled clinical trial)
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Very Good
Excellent
Goals of Recommended Label
•
•
•
•
Set appropriate expectations
Enhance compliance
Optimize treatment outcomes
Provide stronger safety guidance
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Proposed
Product
Labeling
Current
Product
Labeling
 Remove “Cures Most Athlete’s
Foot”
 Replace with “Athlete’s
Foot Treatment”
 To enhance compliance
 Add “Must be used
twice daily for full 7
days to eliminate fungal
infection”
 Move “Relieves itching
and burning” to Drug
Facts
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Proposed Product Labeling: Drug Facts
Optimize treatment outcomes
 Set appropriate expectations
 “Many get relief from their symptoms (itching and
burning) after 1 week of treatment. Signs such as
redness will last longer until the outer layer of skin
naturally replaces itself.”
• Provide stronger safety guidance
 “Stop use and ask a doctor if condition worsens or
new symptoms develop; this is especially important if
you have diabetes.”
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Conclusions
 Terbinafine is a safe and effective 1-week treatment for
tinea pedis
 No evidence of increases in LOE or resistance development
 Effective Treatment appropriate endpoint for efficacy data
in labeling
 New product developments require different standards for
NCEs and NDA line extensions
 Approval standard based on separation from placebo
 Proposed label would set appropriate expectations,
enhance compliance, optimize treatment outcomes and
provide stronger safety guidance
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