. This project responds to the Funding Opportunity, RFA-FD-13-016, "In vitro release tests for topical dermatological products (U01)". The development of appropriate methods to determine bioequivalence (BE) of topical dermatological products is a significant objective of the Food &Drug Administration (FDA). While the agency has identified limited situations - for example when formulations contain the same inactive ingredients in the same amounts - in which alternatives to clinical endpoint bioequivalence studies may be possible, the FDA has a long-standing challenge to determine surrogate test methods (including in vitro techniques) to predict whether formulations, which differ in composition, result in equivalent drug delivery to and across the skin. The long-term goal of this project, therefore, is to demonstrate that in vitro measurements related to the performance of topical drug products are correlated with in vivo outcomes, such that simpler experimental approaches can be reliably and reproducibly used for the establishment of (in)equivalence between formulations containing the same active pharmaceutical ingredient (API) for application to the skin. The proposed research strategy broadly aims to test three hypotheses: 1. That topical BE assessment can be accomplished through the use of appropriately selected in vitro and/or in vivo surrogate tests. 2. That all surrogate tests have limitations but that they do not all have the same limitations;it follows that the results of one test complement those of another. 3. That the test(s) chosen depend on the complexity of the formulation and whether or not the inactive ingredients in the product are quantitatively and/or compositionally equivalent. The project has been designed in two phases, with individual specific aims: [A] An initial, intensive, 12-month program of work focused on econazole, betamethasone valerate (BMV) and diclofenac. For the anti-fungal and BMV, to generate in vitro skin penetration and release test data for comparison and correlation with published in vivo data, specifically, dermatopharmacokinetic (DPK) information for both, and vasoconstriction measurements for the corticosteroid. For diclofenac, to complement in vivo DPK experiments with blood level determinations using highly sensitive liquid chromatography/mass spectrometry methods and to correlate these results with in vitro skin penetration and release test studies. [B] A further 4-year investigation to validate the predictability of in vitro tests when appropriate, and to identify the potential of simpler in vivo approaches as alternative surrogates for the default assessment of topical (in)equivalence using a clinical trial. A systematic examination of several key classes of topical drug products will be undertaken including, but not limited to lidocaine, triamcinolone acetonide, tretinoin, acyclovir and metronidazole.
Statement The long-term goal of this project is to demonstrate that in vitro measurements related to the performance of topical drug products are correlated with in vivo outcomes, such that simpler experimental approaches can be reliably and reproducibly used for the establishment of (in)equivalence between formulations containing the same active pharmaceutical ingredient (API) for application to the skin. These simplified experimental approaches, as compared to full-scale clinical trials, could decrease the cost and improve the efficiency of the generic topical drug approval process.