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 Doug Bierer, PhD Vice President, Regulatory and Scientific Affairs Consumer Healthcare Products Association (CHPA)

Boni E. Elewski, M.D. P rofessor of Dermatology University of Alabama, Birmingham Practicing dermatologist: almost 25 years Practicing dermatologist: almost 25 years Clinical researcher for over 15 years Clinical researcher for over 15 years Author of 3 text books on cutaneous fungal infections Author of 3 text books on cutaneous fungal infections Over 150 publications and 40 book chapters (mostly 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 Chaired Guidelines of Care Committee: Treatment of Tinea Pedis (and Other Fungal Infections) -- American Academy of Dermatology Consultant: CHPA and industry Consultant: CHPA and industry

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

Presentation of Interdigital Tinea Pedis

Interdigital Tinea Pedis Easily recognized by the consumer Easily recognized by the consumer Consistent symptoms Consistent symptoms –Itching and burning Consistent signs Consistent signs –Erythema –Scaling/hyperkeratosis –Fissures/cracking

Topical OTC Treatments for Tinea Pedis Large selection of effective OTC topical antifungal products Large selection of effective OTC topical antifungal products –Monographed –NDA switches at full Rx strength As effective as Rx topical antifungal products As effective as Rx topical antifungal products As safe 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) 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) Duration of treatment: 1 or 4 weeks (as recommended on OTC label) Signs and symptoms generally improve during or shortly after the treatment Signs and symptoms generally improve during or shortly after the treatment

Objective of Treatment Eliminate fungus (dermatophyte) 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 Itching and burning alleviated early in therapy Some clinical signs take longer to improve or may not fully resolve 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 Inflammation is a response to dermatophyte presence in stratum corneum As dermatophyte is eliminated, erythema improves As dermatophyte is eliminated, erythema improves

Healing Dynamics: Scaling/Hyperkeratosis Scaling/hyperkeratosis caused by presence of dermatophyte in stratum corneum Scaling/hyperkeratosis caused by presence of dermatophyte in stratum corneum Some scaling/hyperkeratosis may not completely resolve after dermatophyte eliminated 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 Residual scaling/hyperkeratosis is not uncommon after elimination of dermatophyte

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

Study Methodology Microbiological parameters Microbiological parameters Clinical efficacy parameters Clinical efficacy parameters

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

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

Defining “Cure”: What Is Clinically Meaningful? Dermatophyte is eliminated (mycological cure) Dermatophyte is eliminated (mycological cure) No more than “mild” signs and symptoms remain 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 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: Effective Treatment: Mycological cure + Mycological cure + Clinical improvement Clinical improvement

Clinical Insights Current OTC antifungal drugs deliver safe and effective treatment Current OTC antifungal drugs deliver safe and effective treatment Clinically meaningful endpoint is effective treatment Clinically meaningful endpoint is effective treatment Dose response studies are not needed because topical antifungals easily reach dermatophytes in excess of MICs 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 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 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 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 Presence of dermatophyte may cause fissures that serve as portals of entry for secondary bacterial infections Prompt and effective treatment is essential 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 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 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 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 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 ( ) 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 ( ) 1468 reports of lack of efficacy 1468 reports of lack of efficacy >180 million total unit packages sold >180 million total unit packages sold Less than 9 lack of efficacy reports per million units 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 Lack of efficacy may be due to some consumers stopping treatment prematurely Overwhelming consumers with complicated data should be avoided 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 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 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 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 improve after 1 week of treatment as the skin naturally treatment as the skin naturally replaces itself” 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 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) “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) “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) “new symptoms develop or condition worsens” (Warning section)

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

Conclusions Risk of secondary bacterial infections is very low 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 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 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 Current OTC products are safe and provide effective treatment when used as directed