FDA Revises Guidelines for Evaluating Dermal Irritation and Sensitization of Generic Transdermal and Topical Products
The U.S. Food and Drug Administration (FDA) has revised its draft guidance in April 2023 regarding the evaluation of dermal irritation and sensitization (I/S) for generic drug products administered via transdermal and topical delivery systems (TDS). This guidance applies to generic products seeking approval through the abbreviated new drug application (ANDA) pathway and replaces the October 2018 draft. It provides more detailed criteria for the design and conduct of in vivo studies. As a non-binding recommendation and not the final implementation guideline, companies should consult with the FDA during the development phase to discuss the possibility of test exemptions and study design.
Skin reactions can impact bioequivalence. Patches and topical systems can cause irritant or allergic contact dermatitis due to the active ingredient, adhesive, excipients, and skin occlusion/hydration. If skin reactions cause premature product detachment or patient removal, the drug delivery may change, potentially affecting the determination of bioequivalence (BE) compared to the reference product. The FDA aims to standardize patient selection, application site, evaluation methods, and statistical analysis in comparative studies, going beyond simply recording adverse events.
The revised guidance will impact existing products. Products such as Exelon Patch (rivastigmine, an acetylcholinesterase inhibitor), Duragesic (fentanyl, a mu-opioid receptor agonist), and Nicoderm CQ (nicotine, a nicotinic acetylcholine receptor agonist), along with their generics, are included. The standard treatment comparison group includes oral rivastigmine and donepezil, oral or injectable opioids, and non-transdermal nicotine products like gum and lozenges, depending on the indication. Exelon Patch is used for Alzheimer's disease and Parkinson's disease-related dementia, and the patch formulation was approved in the U.S. in 2007. The product label includes application site reactions suggestive of allergic contact dermatitis, highlighting the clinical need for this guidance.
The revised guidance presents both challenges and opportunities. The revision outlines a pathway for demonstrating that sensitization testing is unnecessary or ethically inappropriate, helping to avoid unnecessary additional clinical burdens. Conversely, ANDAs with weak arguments for exemption may need to strengthen their comparative clinical studies and statistical plans, potentially increasing development costs and timelines. With generic drugs accounting for over 90% of prescriptions in the U.S., and the FDA reporting that 773 generic drugs approved in 2023 resulted in a net savings of USD 18.6 billion within 12 months of approval, this is not just about individual drug approvals or FDA Advisory Committee (AdComm) votes. It is a regulatory infrastructure change that affects the predictability of complex generic drug reviews and patient access.
The revised draft guidance redefines the standards for comparative dermal irritation and sensitization studies for ANDA developers replicating existing transdermal products, rather than Phase 1, 2, or 3 new drug trials. In the short term, this may increase the cost of study design and statistical documentation, but developers who utilize FDA pre-consultation can reduce the likelihood of deficiencies and delays. In the competition between Exelon Patch, Duragesic, Nicoderm CQ, and oral dementia medications, non-transdermal opioids, and nicotine gum, adhesion and skin tolerability will be strengthened as product differentiators. Given that generic drugs account for over 90% of prescriptions in the U.S. and new approvals in 2023 resulted in USD 18.6 billion in net savings within 12 months, standardization will promote complex generic entry and price competition in the medium to long term, while also acting as a barrier to entry for companies with lower quality standards.