1. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS Chris Hendy Ph.D. Novum Pharmaceutical Research Services Pittsburgh, PA

2. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS 21 CFR 320.24 states “The following in-vivo and in-vitro approaches in descending order of accuracy, sensitivity and reproducibility, are acceptable for the determining the bioavailability or bioequivalence of a drug product”

3. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS The preferred method in the hierarchy is defined as follows. “An in-vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate its active metabolite(s), in whole blood, plasma, serum or other appropriate biological fluid is measured as a function of time”

4. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS Using a pharmacodynamic method (e.g. vasoconstrictor assay for corticosteroids) is third in the hierarchy Using a comparative clinical endpoint is fourth.

5. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS Many topical products are also available in oral formulations with the same indication as the topical formulation. They also cover a wide range of indications. For example Metronidazole (antibiotic) Terbinafine (antifungal) Acyclovir (antiviral) Mesalamine (antiinflammatory) Bexarotene (anticancer)

6. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS The fact that many topical products are also available as oral formulations means that circulating blood levels must be relevant to the safety and efficacy of the product. Bioequivalence of the oral formulation would be evaluated by measuring blood concentration.

7. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS The current draft Guidance for Industry “Topical Dermatological Drug product NDA’s and ANDA’s - In Vivo Bioavailability, Bioequivalence, In-Vitro Release, and Associated Studies” confirms the hierarchical requirements of 21 CFR 320.24 with the following rider. “For topical dermatological drug products, PK measurements in blood, plasma, and/or urine are usually not feasible to document BE because topical dermatological products, generally do not produce measurable concentrations in extra cutaneous biological fluids.”

8. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS Since the development of the draft guidance and with the development of new and more sensitive analytical assays for many products, this statement no longer holds true. The following data are examples of a variety of different topical products where the time course of the absorption and eliminationof the active moiety can be accurately characterized. In all examples the amount and method of drug application is consistent with the product labeling.

9. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS

13. Many topical products are absorbed to such an extent that the measurement of the active moeities in biological fluids is feasible Many topical products have a site of action such that circulating blood levels are relevant to efficacy as they are also available in oral or other formulations Some topical products are absorbed to such an extent that circulating blood levels could pose potential safety issues

14. SYSTEMIC ABSORPTION AS THE MOST ACCURATE AND SENSITIVE METHOD OF DETERMINING BIOEQUIVALENCE OF GENERIC TOPICAL PRODUCTS Most topical products have very poor clinical efficacy dose relationships. Clinical efficacy studies are the least sensitive method of determining bioinequivalent formulations. Evaluating systemic absorption raises the bar for the generic formulation and is more sensitive in determining a “bioinequivalent” product than any other current methodologies. Using a pharmacokinetic approach is consistent with the requirements of 21 CFR 340.21 and should always be considered the gold standard methodology.