Topical Corticosteroid Bioequivalence – An Evaluation of the FDA Guidance
Nick Holford (1), Nick Fleischer (2)
(1) Dept of Pharmacology & Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand. (2) Weinberg Group Inc, Washington DC, USA.
Objective: The US FDA has issued a guidance describing a methodology for the conduct and analysis of clinical studies aiming to establish bioequivalence of topical corticosteroids (1). The guidance and a subsequent report from FDA authors (2) recommend that bioequivalence is based on skin blanching observations obtained with an application duration ("ED50") estimated to produce 50% of the maximum area under the blanching effect curve (AUEC) after removal of the formulation. A population analysis of data provided in the guidance was used to evaluate the robustness of the "ED50" estimate to the estimation method and model assumptions. A simulation study was undertaken to explore the rationale for the choice of the "ED50" as the optimal design point for detecting differences in rate and extent of absorption.
Methods: NONMEM was used to estimate the "ED50" using different models and estimation methods. The uncertainty of the "ED50" estimate was evaluated by bootstrapping the data.
A semi-physiological compartmental model was constructed to simulate the rate and extent of absorption from the epidermis to skin vasculature. Corticosteroid loss from the vasculature was assumed to be determined by blood flow so that vasoconstriction induced by a corticosteroid would affect the time course of skin blanching. An Emax model was used to describe the relationship between corticosteroid concentration at the vasculature and changes in blood flow. Skin blanching was assumed to be proportional to the effect of the corticosteroid on blood flow.
Results: The estimate of "ED50" reported in the FDA guidance is 1.89 h. NONMEM estimates ranged from 0.7 to 3.73 h depending on the model and estimation method. Using a model similar to that proposed in the guidance and the FOCE method the median "ED50" was 2.54 with 90% confidence interval of 0.88 to 8.06 h.
The simulation study showed that AUEC reflected differences in extent of bioavailability (0.8 - 1.25 x reference) and potency (0.5 – 2 x reference) but was insensitive to the choice of the duration of application. With a 60 min reference absorption half-life differences in test absorption half-life (30 – 120 min) were detected with increasing sensitivity to AUEC as duration of application increased. AUEC was insensitive to application duration with rapid absorption half-life (10 min reference).
Conclusion: The method proposed in the FDA guidance for estimation of "ED50" is not robust. Differences in rate and extent of absorption of topical corticosteroids are largely insensitive to the timing of the AUEC design point unless absorption is slow. There is no mechanistic support for choosing the "ED50" as the optimal design point for assessment of bioequivalence.
References:
[1] FDA Guidance for Industry. Topical dermatological corticosteroids:in vivo bioequivalence. http://www.fda.gov/cder/guidance/old098fn.pdf 1995:1-36.
[2] Singh GJ, Adams WP, Lesko LJ, Shah VP, Molzon JA, Williams RL, et al. Development of in vivo bioequivalence methodology for dermatologic corticosteroids based on pharmacodynamic modeling. Clin Pharmacol Ther 1999;66(4):346-57.