FDA Updates Bioequivalence Guidance for Generic Topical Corticosteroids

FDA has finalized updated guidance for industry outlining current recommendations for demonstrating bioequivalence (BE) of generic topical dermatologic corticosteroids, replacing a policy that had been in place since 1995. The guidance, “Topical Dermatologic Corticosteroids: In Vivo Bioequivalence,” provides ANDA sponsors with expanded recommendations on designing and conducting pharmacodynamic vasoconstrictor studies used to establish bioequivalence between generic topical corticosteroids and their reference products.

Topical corticosteroids produce skin blanching by constricting dermal blood vessels, an effect that FDA considers a surrogate measure of the amount of drug reaching its site of action. The updated guidance describes how sponsors should use that pharmacodynamic response to demonstrate bioequivalence for products across all potency classes.

The revised guidance provides substantially more detailed recommendations on conducting pilot dose-duration and pivotal vasoconstrictor bioequivalence studies. The pilot dose-duration vasoconstrictor response study using only the reference standard is recommended to identify the optimal dose duration for measuring the drug's pharmacodynamic effect. That information is then used to design a pivotal vasoconstrictor bioequivalence study comparing the generic product with the reference standard.

The agency also provides more detailed recommendations than were included in the 1995 guidance, including advice on study design, statistical modeling, method qualification, subject selection, sample size determination and data reporting.

FDA recommends using an Emax dose-response model to characterize the relationship between exposure duration and skin blanching, although applicants may propose alternative models if scientifically justified. The agency also encourages sponsors to discuss alternative bioequivalence approaches, including characterization-based methods, during pre-ANDA meetings for complex products.

The guidance introduces detailed expectations for qualifying chromameters — the instruments used to measure skin blanching — and for demonstrating consistency among both instruments and study operators. FDA recommends that variability in measurements remain below 15% for both intra- and inter-device as well as intra- and inter-operator assessments.

For pivotal studies, FDA recommends enrolling enough subjects to ensure an adequate number of "detectors"— participants who demonstrate sufficient responsiveness to the reference product for inclusion in the bioequivalence analysis. Based on prior ANDA experience, the agency notes that studies generally include 40 or more evaluable subjects.

Additionally, the guidance provides expanded recommendations on subject inclusion and exclusion criteria. FDA advises excluding participants with conditions or medications that could alter vascular responses, including hypertension, smoking, excessive caffeine consumption, vasoactive medications, or dermatologic conditions affecting the forearms.