1. Dermatopharmacokinetics Perspectives from Bioequivalence Viewpoint Historical Development of Dermatopharmacokinetics and Overview of the Guidance Vinod P. Shah, Ph.D. Chair, Topical Drug Products WG OPS/CDER/FDA

2. Historical Development of Dermatopharmacokinetics and Overview of the Guidance –Methods to Assess BE of Topical Drug Products –History of DPK –Draft Guidance –On Going studies in Utah

3. Methods to Document Bioequivalence ClinicalDifficult Expensive Insensitive PharmacodynamicApplicable only to few classes of compounds, e.g., Glucocorticoids DermatopharmacokineticFeasible Logical Universally applicable In Vitro drug releaseUniversally applicable Signal of possible inequivalence

4. Dermatopharmacokinetics –Pharmacokinetics applied to drug concentration measurements in stratum corneum (SC) is termed DPK –Tape stripping method is a tool to measure drug concentration in SC and to determine drug uptake and elimination (disappearance) from SC

5. Topical Dermatological Drug Products Dermatopharmacokinetics Chronology : Workshops - AAPS/FDA: May 1989, March 1990, December 1991 FDA/Industry conference: March 1992 Advisory Committee (GDAC) - BE/DPK: April 1992 Bio-International: Bad Homburg, Germany, May 1992 Workshop: AAPS/FDA on SUPAC (+DPK): May 1993 EUFEPS/Nuremburg Conference: December 1995 Bio-International: Tokyo, Japan, April 1996 Workshop - AAPS/FDA on BE of topicals (DPK) September 1996 Trade Association Meetings: April 1997, December 1997

6. Topical Dermatological Drug Products Dermatopharmacokinetics cont’d) Chronology (cont’d) : Advisory Committee (ACPS) - BE/DPK: December 1997 Advisory Committee meeting (DODAC) - BE/DPK: March 1998 Draft Guidance for comments (GGP-Level 1): June 18, 1998 Joint Advisory Committee (ACPS and DODAC): October 23, 1998 Expert Member + SGE meeting: July 30, 1999 Expert Members + Representatives from ACPS+DODAC: October 23, 1999 Symposium: AAPS - Annual Meeting - November 1, 2000 Joint Advisory Committee (ACPS and DODAC): November 17, 2000

7. Guidance for Industry Topical Dermatological Drug Product NDAs and ANDAs - In Vivo Bioavailability, Bioequivalence, In Vitro Release, and Associated Studies Draft Guidance:63 FR 33375, June 18, 1998 Docket No. 98D-0388 Level 1 document, consistent with FDA’s good guidance practices (62 FR 8961, February 17, 1997) Comments by August 17, 1998 On Internet:http://www.fda.gov/cder/guidance

8. Defining and Understanding the problem & issues Scientific Input Research Workshops Advisory Committee Experts DPK Draft Guidance  Comments Review Research Advisory Committee Experts Revision to Draft Guidance Final Guidance  Guidance Process

9. Dermatopharmacokinetics What is needed to have a confidence in DPK? Relevance to clinical efficacy (data) Ability of DPK to differentiate between formulations –Can DPK predict the properties of a vehicle? Reliability and reproducibility of the method.

10. Dermatopharmacokinetics Relevance to clinical efficacy (data) Can DPK differentiate products with same concentration of active but with different clinical efficacy?

12. Tretinoin Research Products: A. Retin-A gel, 0.025%, Ortho B. Tretinoin gel, 0.025%, Spear C. Avita tretinoin gel, 0.025%, Bertek Clinical Findings: Retin-A gel = Tretinoin gel (A=B) Retin-A gel  Avita gel (A  C), but Avita gel is effective DPK Research: To confirm and validate Clinical Findings A=B A  C

13. Dermatopharmacokinetics Can DPK differentiate between formulations? Same vehicle, but different concentration of active Concentration/dose response relationship Same concentration of the active, but different vehicles Significantly different formulations Can DPK predict the properties of a vehicle?

17. Dermatopharmacokinetics What is needed to have a confidence in DPK? Relevance to clinical efficacy (data) - Can DPK differentiate products with same concentration of active but with different clinical efficacy? Ability of DPK to differentiate between formulations –Same vehicle, but different concentration of active Concentration/dose response relationship –Same concentration of the active, but different vehicles Significantly different formulations? Can DPK predict the properties of a vehicle? Reliability and reproducibility of the method.

18. Dermatopharmacokinetics What are the applications of DPK ? –Bioequivalence Assessment Comparison of two products - T & R –Bioavailability Assessment BA of the product, application in line extension

19. Topical Dermatological Drug Products Bioequivalence Determination Dermatopharmacokinetics Same % of active drug Same route of administration - application Same dosage form category, i.e., - cream vs. cream - ointment vs. ointment - gel vs. gel Generally qualitatively (Q1) same ingredients and quantitatively (Q2) similar composition (  5%) Ref: 21 CFR 314.94(a)(9)(v)

20. Dermatopharmacokinetics Bioequivalence Assessment Comparison of T and R Products - BE Documentation –Dermatopharmacokinetics –Q1 and Q2 –In vitro release

21. In Vitro Release In vitro release can differentiate between: - Different formulations - Two products manufactured differently - Products containing different particle size of the actives In vitro release test is used to assure product sameness under SUPAC-SS related changes

22. Dermatopharmacokinetics What is needed to accept DPK? –Validated tape stripping (skin stripping) procedure –Validated analytical methodology –Mass balance information/study data –Pilot study –Pivotal BE study –DPK data meeting 90% CI, and BE limits of 80-125% for AUC and Cmax

23. Dermatopharmacokinetics Advantages: –Noninvasive procedure –Good dose response effect –Can differentiate significantly different formulations –Measures drug concentration in the vicinity of the site of action in the skin –It is sensitive, reliable, reproducible and cost effective –Is applicable to all topical dermatological drug products

24. Dermatopharmacokinetics Disadvantages: –Requires validation of the stripping procedure –Requires good sensitive analytical methodology and validation

25. Dermatopharmacokinetics Drug Uptake in SC and Drug Elimination from SC: SC Stripping Procedure Apply the Test and Reference drug products concurrently at multiple sites After X hours, clean the area 3 times lightly with tissue Apply the adhesive tape (e.g., Transpore or Cuderm) with uniform pressure, remove and discard the first stripping Apply, remove and collect nine successive tapestrippings (at the same spot) - extract the drug and determine the concentration using appropriate validated analytical method Express results as amount per surface area (ng/sq. cm)

26. Dermatopharmacokinetics Drug Uptake and Elimination: Each application site yields a single drug concentration in SC Drug uptake in SC (e.g., after 0.25, 05, 1 and 3 hours) Drug elimination from SC (e.g., 3, 4, 6, 8 and 24 hours)

30. Applicable to all topical drug products (including vaginal drug products, retinoids) Applicable to generic drug products with Q1 and Q2 (  10%) Changes Made Applicable to retinoid and other products Not applicable to vaginal drug products Q1 and Q2 (  5%) In vitro release test Draft Guidance

31. Therapeutic ClassComments High RiskVaginalDifferent physiological environment, mucous membrane Antiacne (Retinoid) Follicular penetration AntiviralSite of action not well defined Antibiotics Glucocorticoid Low RiskAntifungalClose to site of action Dermatopharmacokinetics

32. Topical Dermatological Drug Products Bioequivalence Determination Primary means to document BE - Dermatopharmacokinetic Data Supportive Information - In vitro release - Particle size distribution of active drug substance

33. Conclusions For Bioequivalence Determination: -DPK is a reliable, reproducible and relevant method to document BE between T and R drug products -DPK is applicable to all topical dermatological drug products, and is cost effective