# Presentation: 849251

##  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**

## Presentation of Interdigital Tinea Pedis

**Presentation of Interdigital Tinea Pedis**

## The Consumer Experience:Time Course of Mycology, Signs & Symptoms 

**Symptom Resolution**
**Consumer Decides to Discontinue Treatment**

**The Consumer Experience:****Time Course of Mycology, Signs & Symptoms **

|  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Mycology |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Symptoms |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| Signs |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| 

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|  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |
|  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |

**4 Weeks**

**8-12 Weeks**

**Consumer Symptom Recognition/Treatment Initiation**

**Schematic based upon market research: Athlete’s Foot Category Assessment Study. Protocol Research. December 2002 (n=300)**

## 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**

## Efficacy

## Terbinafine Activity

_***in vitro***_***:***
**MICs: **
**0.003 – 0.006 *****μ*****g/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.**

## Pivotal Study for OTC Switch

**Pivotal Study for OTC Switch**

- - **Terbinafine**

**- Vehicle**

**1 Week BID Treatment Study**

**(pivotal study # 2506-01 (n=67) in Lamisil AT Cream NDA)**

**Mycological Cure**

**Effective **
**Treatment**

**Complete Cure**

**88%**

**20%**

**64%**

**7%**

**21%**

**0%**

**p<0.001**

**p<0.001**

**p<0.001**

## 1 Week Treatment vs. Clotrimazole

**1 Week Treatment vs. Clotrimazole**

- - **Terbinafine**

**- Clotrimazole**

**Mycological Cure**

**Complete Cure**

**92%**

**55%**

**61%**

**38%**

**19%**

**13%**

**Novartis Lamisil AT 1% Cream Study # 2508-01 (n=97)**

**p<0.001**

**p=0.065**

**p=0.532**

**Effective **
**Treatment**

## 4 Week Treatment vs. Clotrimazole

**4 Week Treatment vs. Clotrimazole**

- - **Terbinafine**

**- Clotrimazole**

**Mycological Cure**

**Complete Cure**

**Novartis Lamisil AT 1% Cream Study # 2508-01 (n=97)**

**83%**

**84%**

**71%**

**47%**

**13%**

**24%**

**p>0.999**

**p=0.029**

**p=0.271**

**Effective **
**Treatment**

## Relapse/Reinfection Rates at 12 Weeks

**1 Week Treatment**

**4 Week Treatment**

**-** **Terbinafine**

**- Clotrimazole**

**Novartis Lamisil AT 1% Cream Study # 2508-01 (n=193)**

## Time Course for Negative Mycology

**Time Course for Negative Mycology**

**Mycological Response**

**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.**

**Study Week**

**% Negative Mycology**

**	****Terbinafine 1 Week**
**	****Terbinafine 4 Weeks**
**	****Clotrimazole 1 Week**
**	****Clotrimazole 4 Weeks**

## Time Course for Signs & Symptoms

**Time Course for Signs & Symptoms**

**Clinical Response**

**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.**

**Study Week**

**% Reduction in Signs and Sypmtoms**

**	****Terbinafine 1 Week**
**	****Terbinafine 4 Weeks**
**	****Clotrimazole 1 Week**
**	****Clotrimazole 4 Weeks**

## 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**

## Safety

## Evaluating Lack of Effectiveness Reports

**LOE Cases as % of Purchases**

| 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 |

## Terbinafine Effectiveness Over Time

**Study # 98-001 (n=135) and # 351 (n=86)**

**Terbinafine Effectiveness Over Time**

-  -**Terbinafine**

- - **Vehicle**

**1991 - 1992**

**1995 - 1999**

**Effective Treatment**

**Mycological Cure**

**(each represents avg. of 2 double-blind, placebo controlled studies, 1 week BID)**

**Effective Treatment**

**Mycological Cure**

- 85%

- 14%

- 67%

- 8%

- 26%

- 3%

**Complete Cure**

**Complete Cure**

- 88%

- 23%

- 65%

- 11%

- 30%

- 1%

**Study # 2-1 (n=77) and # 2-2 (n=91)**

**p<0.001**

**p<0.001**

**p<0.001**

**p<0.001**

**p<0.001**

**p<0.001**

## 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)**

## Labeling

## Relationship Between Clinical Outcomes and Patient Assessment

**Relationship Between Clinical Outcomes and Patient Assessment**

**-** **Effective Treatment**

**- Complete Cure**

**6.5%**

**16.1%**

**7.7%**

**22.6%**

**30.8%**

**54.8%**

**61.6%**

**Novartis Data on File (sub-analysis from a controlled clinical trial)**

**Poor**

**Fair**

**Good**

**Very Good**

**Excellent**

## Goals of Recommended Label

**Set appropriate expectations**
**Enhance compliance**
**Optimize treatment outcomes**
**Provide stronger safety guidance**

## 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**

**Proposed Product Labeling**

## 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.”***

## 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**