# Presentation: 387529

## 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

## 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

## 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]

## 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?

## 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

## 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)*

## Key Questions

- Can comparable DPK profiles be used to assesses bioequivalence between two (*pharmaceutical equivalent)* products?
- Equivalent SC exposure  (SCT/SCR) = equivalent follicular exposure (FT/FR)?
- 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

## 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?

## Role of follicular transport on BE assessment? 

- Equivalent SC exposure  (SCT/SCR)= equivalent follicular exposure (FT/FR)?
- 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.”

## Role of follicular transport

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

## 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

## 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

## 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

## Desired Distribution Profile ofCertain Vaginal Formulations

**INTROITUS**

**VAGINA**

**CERVIX**

**MUCUS**

**PROPHYLACTIC COATING**
**CONTRACEPTIVE COATING**

- Desired Distribution Profile ofCertain Vaginal Formulations

## Interactions in the Vagina

**Microbicide**
**Formulation**

**Anatomy,**
**Geometry**

**Surface**
**Properties**

**Fluid**
**Contents**

**Mechanical**
**Properties**

**Notes:**
DEPLOYMENT is the result of the interaction between the product and the vagina. Various features of the vagina play central roles in this interaction, including the anatomy of the organ, surface properties of the epithelium, mechanical properties of the tissues, and the presence of different fluids.

## Pre-Coital Forces Acting on a Bolus of Gel in Vagina

**“****SLIDING”**
**  ****gravity**

*David Katz. Duke University*

**Notes:**
Deployment is complex.  Upon application, a bolus may be SQUEEZED by apposing epithelial surfaces, it may seep into the rugae, it may slide along the cavity due to gravity, it may be sheared during coitus by the penis, all the while being contacted by various fluids that -either by passive miscibility or active mixing - dilute the material. 
While complex, deployment is nonetheless a deterministic process which governed by the laws of mechanics. Mechanics relates the forces subjected upon a material to its subsequent flow and deformation.
In order to study deployment, we have employed a divide-and-conquer approach, dividing the complex flow process into simpler, sub-processes.  The mechanics of each sub-process is studied individually, eventually to be recombined for a better understanding the process as a whole.
In this talk, we will demonstrate our approach by focusing upon the important large-scale flows: SQUEEZING and SLIDING.

## Mechanistic Analysis of Sub-processes (Squeezing)

**Notes:**
This dual approach of using THEORY and EXPERIMENT to understand the deployment behavior of formulations is THE GENERAL BIOPHYSICAL CONSTRUCT from which we study EACH subprocess.  

## SLIDING THEORY

**velocity depends upon...**
**	****vagina properties**
**	****	*****tilt angle****** *******
**	****	*****tissue separation***** ****H****tot**
**	****gel properties**
**	****	*****density***
***	******	******rheology***

**velocity**
**profile**

**V****avg**

****

**H****tot**

*David Katz. Duke University*

**Notes:**
The mathematical simulation of sliding in the vagina takes the form (again) of two parallel surfaces at an angle alpha and separation Htot.  The density and rheological prop of the gel serve as inputs to the model - we apply the laws of fluid mech and extract the EFFECTIVE SLIDING V_x0008_ELOCITYof the bolus within the vagina.

## Viscosity vs. Shear Rate

**Gynol II**
**KY Plus**
**Conceptrol**
**Advantage-S**

*David Katz. Duke University*

## Vaginal Gel Thickness Distribution (Advantage)

**4000**
**3000**
**2000**
**1000**

**0**

**45**

**90**

**135**

**180**

**225**

**270**

**315**

**125**

**100**

**75**

**50**

**25**

**Azimuthal Angle (deg.)**

**Axial Dist. (mm)**

**Depth of Coating (********m)**

**introitus**

*David Katz. Duke University*

## Vaginal Gel Thickness Distribution (Conceptrol)

*David Katz. Duke University*

## Axial and Angular Dependenceof Coating Thickness Distribution

**Advantage**

**Conceptrol**

- 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*