systems offer localized or systemic therapeutic effects through skin application. While convenient and non-invasive, these formulations pose unique challenges during early-phase testing. Phase 1 clinical trials for such products must evaluate dermal absorption, site-specific reactions, systemic exposure, and formulation tolerability. This article outlines the strategic considerations, design adaptations, and regulatory nuances involved in conducting Phase 1 trials for topical and transdermal drugs.

Types of Topical and Transdermal Products

• Topical (local action): Creams, gels, ointments, foams (e.g., corticosteroids, antibiotics)
• Transdermal (systemic action): Patches, gels (e.g., nicotine, fentanyl, estradiol)
• Hybrid systems: Microneedles, iontophoresis, thermal ablation devices

Key Objectives in Phase 1 Trials

• Evaluate local safety and tolerability (e.g., erythema, edema, pruritus)
• Assess systemic absorption and PK profile (for transdermal products)
• Determine formulation acceptability and adhesion performance

Study Design Considerations

1. Population Selection

• Healthy volunteers are typically used
• For irritant or cytotoxic agents, patients with target conditions may be required

2. Dose Selection

• Test multiple concentrations or application areas
• Surface area exposure should reflect therapeutic use (e.g., 10%, 20% BSA)

3. Application Methodology

• Standardize dose amount (mg/cm²) and duration of application
• Define occlusive vs. non-occlusive application

4. Site Control and Rotation

• Use multiple sites (e.g., forearm, back, thigh) to assess site variability
• Rotate sites to minimize cumulative irritation

Dermal Safety Assessments

• Draize scoring system for erythema and edema
• Photographic documentation of skin sites
• Transepidermal water loss (TEWL) and colorimetry for objective evaluation
• Patch testing and delayed hypersensitivity assessment (if needed)

Systemic PK Considerations (Transdermal)

• Collect plasma samples over 24–72 hours to capture absorption phase
• Calculate lag time, steady-state concentration (C_ss), and bioavailability
• Assess flip-flop kinetics where absorption is rate-limiting

Device and Adhesion Evaluation

• Assess patch integrity, displacement, and adhesion score over time
• Measure residual drug content in patch after removal
• Subject questionnaires for usability, comfort, and skin feel

Regulatory Expectations

FDA

• Guidance on skin irritation and sensitization testing
• For transdermal products, BE studies and adhesive performance required

EMA

• Encourages use of in vitro-in vivo correlation (IVIVC) for dermal absorption
• Expects separate data on systemic vs. local safety signals

CDSCO

• Requires AV consent and clear labeling of application area and schedule
• Dermal tolerability and systemic exposure must be assessed even in FIH

Common Pitfalls

• Underestimating inter-subject variability in skin permeability
• Improper patch application or detachment skewing PK data
• Lack of objective metrics for skin irritation grading

Best Practices

• Conduct pilot studies for site feasibility and adhesion performance
• Use crossover design for multiple formulations or dose levels
• Standardize patch handling and documentation of application/removal time
• Correlate local reactions with systemic exposure where relevant