1. Methods for Assessing Bioequivalence of Topical Products: How should FDA Redirect its Research Program? Ajaz Hussain, Ph.D. Director (Act.), Office of Testing and Research OPS, CDER, FDA 17 November 2000

2. Bioavailability of Topical Drugs Factors that effect bioavailability –Drug attributes (solubility and dissolution rate in the vehicle, size, charge, membrane permeability and metabolism) –Vehicle attributes (drug solubility and dissolution rate, spreading-ability, adhesion, ability to alter membrane permeability) –Membrane attributes (status of barrier function, exudates, blood flow, metabolic capacity,..) –Method of application

3. Bioequivalence of Topical Products Equivalent rate and extent of exposure at the intended “site(s) of action” –Equivalent rates of membrane penetration and permeation function of vehicle effects on these processes function of rate of drug release from the vehicle Equivalent application site - formulation contact time and area [Equivalent systemic exposure]

4. How should FDA Redirect its Research Program? Current research projects –DPK projects –[Topical (Vaginal) Microbicide Products] Proposed research projects –Body of evidence need for regulatory acceptance of DPK approach? –Other tests to complement DPK? –New methods for bioequivalence assessment?

5. Current DPK Research Activities DPK Study at University of Utah - Tretinoin “reference” product plus two test products (based on clinical evidence 1 equivalent to RP and 1 inequivalent to RP) –FDA Investigators- Surendra Shrivastava and Don Hare Intramural DPK Study - Reproducibility of Utah Study plus other “method” issues –PI’s Robbe Lyon, Tapash Ghosh, Mamta Gokhle, Martin Okun –Near-IR study - PI: Everette Jefferson If both studies are “positive,” would this evidence be sufficient to introduce DPK in regulatory practice? –Yes –No

6. DPK Approach for Bioequivalence: Concerns Stratum corneum  skin Can not be derived from first principles –Generalization of collected empirical evidence? Clinical relevance? DPK will not provide accurate estimates of drug bioavailability under certain disease conditions and for other routes of administration (e.g., vaginal products)

7. Key Questions Can comparable DPK profiles be used to assesses bioequivalence between two (pharmaceutical equivalent) products? –Equivalent SC exposure (SC T /SC R ) = equivalent follicular exposure (F T /F R )? –Equivalent SC (healthy) exposure = equivalent exposure in disease states? –Does [Q1 + Q2] criteria ensure equivalent physical attributes for multi-phasic systems? Increases the divide between innovator and generic firms Management issues

8. Rephrasing the Concerns with DPK Two topical products applied to skin surface provide equivalent rate and extent of drug exposure in all layers of the skin when these products exhibit equivalent –thermodynamic activity of drug in vehicle –interfacial transport kinetics SC Vs. follicles? –effect of excipients on skin permeability healthy Vs. disease? –skin contact time and area healthy Vs. disease?

9. Role of follicular transport on BE assessment? Equivalent SC exposure (SC T /SC R )= equivalent follicular exposure (F T /F R )? –Likely when drug is in solution (single phase system)? Equivalent SC exposure  Equivalent (thermodynamic activity + excipient effects on SC) –Higher potential for differences when drug is encapsulated or suspended (particle size differences) and/or multi-phase system? Retin-A Micro - acrylate copolymer porous microspheres –“contribution to decreased irritancy by Microsponge system has not been established.”

10. Role of follicular transport Possible to modulate follicular transport (iontophoresis or low intensity ultrasound) - a approach to challenge DPK?

11. Mechanistic evidence plus distribution and imaging approaches? Supporting evidence can be generated via in vitro experiments using excised human skin –different anatomical sites –possible to maintain viability (~ 24 hr) –emulate compromised SC barrier functions? Indirect supporting evidence via transport and skin distribution studies Direct supporting evidence via visualization of follicular and nonfollicular transport –laser scanning confocal microscopy

12. Body of Evidence? Empirical evidence –DPK Vs. Clinical Studies –Proof of concept for the products evaluated Generalization of empirical evidence? –Mechanistic basis (“Reductioinst” approach) ----------------------------------------------------- New methods –Complementary or stand-alone

13. Vaginal Products The following slides provide a brief summary of current research on topical microbicide vaginal products –this research has a broader scope than bioequivalence –is an example of the “reductionist” approach linking physics with physiology to identify critical product attributes and explain how these attributes effect product performance

14. INTROITUS VAGINA CERVIX MUCUS PROPHYLACTIC COATING CONTRACEPTIVE COATING Desired Distribution Profile of Certain Vaginal Formulations

15. Interactions in the Vagina MicrobicideFormulation Anatomy,Geometry SurfaceProperties FluidContents MechanicalProperties

16. “SLIDING” gravity“SLIDING” “SQUEEZING” visceral contractions pressure tissue elasticity“SQUEEZING” visceral contractions pressure tissue elasticity“SEEPING” surface energies interfacial tensions“SEEPING” surface energies interfacial tensions rugae mucus, transudate GEL Pre-Coital Forces Acting on a Bolus of Gel in Vagina David Katz. Duke University

17. Mechanistic Analysis of Sub- processes (Squeezing)

18. SLIDING THEORY velocity depends upon… vagina properties  tilt angle  H tot tissue separation H tot gel properties density rheology velocity profile V avg  H tot David Katz. Duke University

19. Viscosity vs. Shear Rate Gynol II KY Plus Conceptrol Advantage-S David Katz. Duke University

20. Vaginal Gel Thickness Distribution (Advantage) 4000 3000 2000 1000 0 4545 90 135 180 22 5 270 315 12 5 100 75 5050 25 Azimuthal Angle (deg.) Axial Dist. (mm) Depth of Coating (  m) introitus David Katz. Duke University

21. Vaginal Gel Thickness Distribution (Conceptrol) 4000 3000 2000 1000 0 4545 90 135 180 22 5 270 315 12 5 100 75 5050 25 Azimuthal Angle (deg.) Axial Dist. (mm) Depth of Coating (  m) introitus David Katz. Duke University

22. Axial and Angular Dependence of Coating Thickness Distribution AdvantageConceptrol Scaled to length of 71.11 mm Scaled to length of 51.67 mm % Volume Distal to Fornix 39%85% % of Area Coated 36%100% David Katz. Duke University