# Presentation: 642417

## CHPA Comments on Efficacy and Labeling Issues for OTC Drug Products Used in the Treatment of Tinea Pedis

- CHPA Antifungal Task Group
- 6 May 2004

##       Doug Bierer, PhD 

- Vice President, Regulatory and Scientific Affairs
- Consumer Healthcare Products Association (CHPA)

## Boni E. Elewski, M.D.Professor of DermatologyUniversity of Alabama, Birmingham

- Practicing dermatologist: almost 25 years
- Clinical researcher for over 15 years
- Author of 3 text books on cutaneous fungal infections
- Over 150 publications and 40 book chapters (mostly on cutaneous fungal infections)
- Chaired Guidelines of Care Committee:  Treatment of Tinea Pedis (and Other Fungal Infections) -- American Academy of Dermatology
- Consultant:  CHPA and industry

## Tinea Pedis

- Common fungal infection caused by dermatophytes
- Most common cause *T. rubrum*
- Infectious disease that affects interdigital spaces and contiguous skin
- Affects up to 70% of population
- Highly transmissible in communal areas

## Presentation of Interdigital Tinea Pedis

**Presentation of Interdigital Tinea Pedis**

## Interdigital Tinea Pedis

- Easily recognized by the consumer
- Consistent symptoms
- Itching and burning
- Consistent signs
- Erythema
- Scaling/hyperkeratosis
- Fissures/cracking

## Topical OTC Treatmentsfor Tinea Pedis

- Large selection of effective OTC topical antifungal products
- Monographed
- NDA switches at full Rx strength
- As effective as Rx topical antifungal products
- As safe as Rx topical antifungal products

## OTC Treatment of Tinea Pedis

- Apply antifungal products once or twice per day (as recommended on OTC label)
- Duration of treatment:  1 or 4 weeks (as recommended on OTC label)
- Signs and symptoms generally improve during or shortly after the treatment

## Objective of Treatment 

-  Eliminate fungus (dermatophyte)
- Resides in superficial layers of skin
- Topical antifungals easily reach dermatophyte in excess of MICs

## Improvement of Signs and Symptoms

- Itching and burning alleviated early in therapy
- Some clinical signs take longer to improve or may not fully resolve
- Erythema/inflammation
- Scaling/hyperkeratosis
- Fissures

## Healing Dynamics: Erythema

- Inflammation is a response to dermatophyte presence in stratum corneum
- As dermatophyte is eliminated, erythema improves

## Healing Dynamics: Scaling/Hyperkeratosis

- Scaling/hyperkeratosis caused by presence of dermatophyte in stratum corneum
- Some scaling/hyperkeratosis may not completely resolve after dermatophyte eliminated
- Anatomical occlusion
- Pre-existing skin conditions
- Residual scaling/hyperkeratosis is not uncommon after elimination of dermatophyte

## Healing Dynamics: Fissures/Cracking

- Fissures/cracking caused by presence of dermatophyte in stratum corneum
- Resolution of fissures/cracking varies individually
- May be delayed in patients with anatomic occlusion
- Residual fissures/cracking occasionally persists after elimination of dermatophyte

## Study Methodology

- Microbiological parameters
- Clinical efficacy parameters

## Microbiological Parameters

- KOH
- Presence or absence of fungal elements
- Fungal elements may be dead or alive
- Fungal culture
- Identifies organism by genus and species
- Mycological Cure =
- 		Negative KOH + Negative Culture

## Clinical Efficacy Parameters

- Complete Cure = Mycological cure + _no_ signs and _no_ symptoms
- Effective Treatment = Mycological cure + no more than “mild” signs and symptoms
- 	0 = absence of signs/symptoms
-    1 = mild
-    2 = moderate
-    3 = severe

## Defining “Cure”:  What Is Clinically Meaningful?

- Dermatophyte is eliminated (mycological cure)
- No more than “mild” signs and symptoms remain
- 0 = absence of signs/symptoms
- 1 = mild
- 2 = moderate
- 3 = severe

## Defining “Cure”:  What Is Clinically Meaningful?

- Residual erythema, scaling/hyperkeratosis and fissures occasionally persist after elimination of dermatophyte
- Scaling, hyperkeratosis, fissuring, erythema may exist independent of tinea pedis
- Treatment of tinea pedis will not make condition of the skin better than prior to infection

## Defining “Cure”:  What Is Clinically Meaningful?

**   **
**    **Effective Treatment:
**  **Mycological cure +
-    	  Clinical improvement

## Clinical Insights

- Current OTC antifungal drugs deliver safe and effective treatment
- Clinically meaningful endpoint is effective treatment
- Dose response studies are not needed because topical antifungals easily reach dermatophytes in excess of MICs

## No Concern About Dermatophyte Antifungal Drug Resistance

- Likelihood of dermatophytic resistance to current topical OTC antifungal drugs is very low
- When used as directed, topical OTC antifungal drugs are very effective at eliminating the fungus

## Secondary Bacterial Infections

- Rare reports of secondary bacterial infections (e.g. cellulitis) associated with tinea pedis
- Presence of dermatophyte may cause fissures that serve as portals of entry for secondary bacterial infections
- Prompt and effective treatment is essential
- OTC topical antifungals are important because they eliminate the dermatophyte, to allow the skin to naturally replace itself and restore its barrier function

## FDA Reported Lack of Efficacy (LOE)

- FDA reports 35% of all adverse events for topical antifungal agents are lack of efficacy
- Unclear whether reports of LOE were specifically related to tinea pedis or one of other labeled indications (i.e., tinea corporis) or another disorder all together
- To help put these LOE reports into perspective, CHPA looked at LOE reported for OTC topical antifungals relative to units sold

## Lack of Efficacy – An OTC Perspective

- CHPA collected the number of LOE reports from 7 OTC manufacturers who distribute the vast majority of OTC antifungal products used to treat tinea pedis (1999-2003)
- 1468 reports of lack of efficacy
- >180 million total unit packages sold
- Less than 9 lack of efficacy reports per million units sold

## Proposed OTC Labeling

**Drug Facts**

## Directions for Use

- Lack of efficacy may be due to some consumers stopping treatment prematurely
- Overwhelming consumers with complicated data should be avoided
- Graphs and/or tables on package label are confusing to consumers
- Consumers need simple and concise label statements on how to use the product to achieve maximum benefit

## Directions:  All Products

- 		“use daily as directed for the full 	treatment time, even if symptoms 	improve”

## Directions for Use:One-Week Products

- Labeling should convey lag time between completion of treatment and resolution of symptoms
- Helpful to educate consumers on what they can expect under this use condition

## For One-Week Use Products 

- 		“symptoms may continue to
- 		 improve after 1 week of
- 		 treatment as the skin naturally
- 		 replaces itself”

## Warnings

- To address FDA’s concern about secondary bacterial infection (e.g., cellulitis), we propose adding label information about when to see a doctor

## Warnings

- 	“New symptoms develop or condition worsens” should be added after the “Stop use and ask a doctor if” warning      already on the OTC label

## Proposed Label Additions

- “use daily as directed for the full treatment time, even if symptoms improve” (Direction section)
- “symptoms may continue to improve after 1 week of treatment as the skin naturally replaces itself” (Direction section)
- “new symptoms develop or condition worsens” (Warning section)

## Conclusions

- Clinical “cure” should be defined as “effective treatment”
- Dose response studies are not needed because topical antifungals easily reach dermatophytes in excess of MICs
- Dermatophytic resistance is not a concern

## Conclusions

- Risk of secondary bacterial infections is very low
- OTC topical antifungals play an important role by restoring the barrier function of skin and allowing the skin to naturally replace itself

## Conclusions

- Proposed enhanced labeling will reinforce consumer compliance and decrease potential serious adverse events
- Current OTC products are safe and provide effective treatment when used as directed