Skin stripping adequate as bioequivalence determinant in topicals -- draft guidance.

SKIN STRIPPING ADEQUATE FOR DERMATOLOGIC BIOEQUIVALENCE STUDIES for most topical drugs, an FDA draft guidance states. "Skin strip-ping," or dermatopharmacokinetics (DPK), "principles should be generally applicable to all topical dermatological drug products including antifungal, antiviral, anti-acne, antibiotic, corticosteroid and vaginally applied drug products," the draft guidance states. The draft, "Topical Dermatological Drug Product NDAs and ANDAs -- In Vivo Bioavailability, Bioequivalence, In Vitro Release and Associated Studies," was published in the Federal Register June 18.

The guidance embodies a proposal made by FDA to the Advisory Committee for Pharmaceutical Science in December and to the Dermatologic & Ophthalmic Drugs Advisory Committee in March. The pharmaceutical sciences committee endorsed the proposal but the dermatologic committee did not ("The Tan Sheet" April 6, p. 4).

FDA plans to bring the draft guidance back to the dermatologic committee, perhaps during the fall, Center for Drug Evaluation & Research Deputy Director for Pharmaceutical Science Roger Williams, MD, told the Pharmaceutical Sciences Advisory Committee June 24.

Committee member Gayle Brazeau, PhD, University of Florida College of Pharmacy, suggested the "reluctance" of the derm committee to look at the issue of skin stripping as an appropriate determinant of bioequivalence for topical drugs "was because it was a very rushed meeting. I think the real reluctance was that they didn't understand what was going on," Brazeau said. "I would encourage, if you are going to bring the two committees back together, that it has got to be very educational," she continued. "It will be critical that that committee have a chance to reflect on the material and really understand the process."

"You said very nicely what perhaps I heard a little more bluntly," FDA's Williams responded. "We will work very hard to get a good package out to the advisory committees next time....We are speaking to a very important constituency, namely the physicians who use these drugs. We have to build a solid case to say why they should be willing to rely" on DPK.

The guidance differs in one particular aspect from the recommendations of the pharmaceutical sciences committee, which concluded DPK tests might not be appropriate for follicle-targeted topical products ("The Tan Sheet" Jan. 5, p. 16).

The draft guidance states that when the target sites are hair follicles and sebaceous glands, "the DPK approach is still expected to be applicable." FDA cited new data supporting the validity of DPK for follicle-targeted products presented by L'Oreal Scientific Director Hans Schaefer, PhD, at the March 20 meeting of the derm committee.

Two different skin-stripping methods are included in the draft as viable techniques. One method would establish "a dose-response relationship between the drug concentration in the applied dosage form and the drug concentration in the stratum corneum." This method is "analogous to a dose proportionality study performed with solid oral dosage forms," the draft guidance states. It can be performed "using three different strengths," and the "amount of the drug in the stratum corneum at the end of a specified time interval, such as three hours, can provide a dose-response relationship."

The other acceptable skin stripping method is one "capable of detecting differences of +/- 25% in the strength of a product." The second method can be performed "by applying different concentrations (e.g., 75%, 100%, 125%)...for a specified exposure time such as three hours, executing the skin stripping method and...comparing the strength applied to the measure drug concentration in the stratum corneum," the draft guidance states.

Drugs for which "a DPK approach is not generally applicable" include topical drugs for which "a single application of the dermatological preparation damages the stratum corneum," as well as otic and ophthalmic preparations.