# Presentation: 534411

## Topical Bioequivalence Update

- Robert Lionberger, Ph.D.
- Office of Generic Drugs

## Current State of Topical Bioequivalence

- Demonstration of bioequivalence requires clinical studies
- Exceptions
- Topical solutions
- Corticosteroids
- (Skin blanching pharmacodynamics)

## Example Bioequivalence Studies

-  Topical anti-fungals
- Test, reference, placebo arms in patients
- 90% confidence interval on test – reference cure rate
- Estimated CV’s ~100%

| N | %CureTest | %CureRef | 90%CI |
| --- | --- | --- | --- |
| 728 | 50% | 48% | [-12,+16] |
| 453 | 46% | 40% | [-8,+20] |
| 447 | 29% | 27% | [-9,+13] |

## Is There a Problem?

- Barriers to product improvement and generic drugs
- Need to demonstrate BE after formulation change or in product development
- Clinical endpoints have high variability
- Inefficient detection of formulation differences
- Unnecessary human testing

## Goals

- Identify when clinical studies are not necessary to demonstrate bioequivalence of topical products
- Provide alternative methods that assure product quality

## Topical Bioequivalence

- Bioequivalence strategy
- Mechanistic understanding of key parameters that affect bioavailability
- Identification of in vivo and in vitro tests
- Classification of formulation similarity
- Proposed decision tree based on site of action (stratum corneum)
- External research projects

## Topical Absorption Process

- G. L. Flynn, *Cutaneous and Transdermal Delivery: Processes and Systems of Delivery*,
-  Modern Pharmaceutics .Dekker, New York, third edition, 1996.

## Bioequivalence

- Is about the formulation
- Clinical effectiveness has already been established
- Defined as no significant difference in rate and extent of absorption
- Rate at which drug can leave the formulation
- Rate at which drug can cross the SC

- G. L. Flynn, *Cutaneous and Transdermal Delivery: Processes and Systems of Delivery*,
-  Modern Pharmaceutics .Dekker, New York, third edition, 1996.

## The stratum corneum permeability is the limiting resistance

Thermodynamic activity of the drug in the formulation is the driving force for absorption 
Formulation additives can alter barrier properties of the skin (permeability)

- Thermodynamic activity of the drug in the formulation is the driving force for absorption
- Formulation additives can alter barrier properties of the skin (permeability)

- Key Aspects of Absorption

## Causes of Inequivalence(for equal drug content)

- Application
- Different spreading on the skin
- In the formulation
- Drug does not leave formulation
- Thermodynamic activity is different (suspension v. dissolved drug)
- Across the stratum corneum
- Formulations have different effects on stratum corneum
- One formulation prefers follicular pathway

## In Vitro Tests

- Diffusion Cell
- Measures diffusion through the formulationand fraction of free drug
- Not predictive of bioavailability (does not measure limiting resistance) but sensitive to formulation differences
- Safety: Drug release in absence of SC
- Rheology
- Determines how vehicle spreads on the skin
- Dosage form classification
- Pharmaceutical equivalence (patient experience)

## In Vitro Tests (Suspensions)

- Dissolution (for suspension formulations)
- Particle size
- Identify particle sizes that could preferentially transport via follicles

## In Vivo Tests

- Skin Stripping
- Can measure D,K in the SC independently1
- Microdialysis
- Measures concentration that has reached the dermis
- Recently used for evaluations of BE2
- Not appropriate for drugs that target stratum corneum
**In vivo tests quantify the effect of formulation on the stratum corneum**

- 2 Eva Benfeldt, Unpublished Data

- 1 A. Bungie. Presentation to FDA advisory committee for pharmaceutical science, October 2003.

## Future Directions

- First focus on products that target SC
- Classify product similarity
- Q1: Same components
- Q2: Same components in same amount
- Q3: Same components in same amount with the same arrangement of matter (microstructure)
- Select appropriate in vivo and in vitro tests

## Q3 Identical Products

- Q3 identical products are bioequivalent
- Example: Topical solutions
- For formulations more complex than solutions direct demonstration of Q3 equivalence is a challenge
- Particle size

## Q1 and Q2 Identical

- Is the rheology the same?
- Adhesion to the skin
- Is the solubility of the drug in the formulation the same?
- Are excipients released at same rate?
- Is particle size the same? (suspensions)
- Dissolution
- Follicular transport

## Q1 and Q2 Identical

- Require equivalence in
- Rheology
- In vitro release (diffusion cell)
- Are in vitro tests sufficient to ensure BE?
- All concerns are potential Q3 differences due to the manufacturing process
- In vitro tests are the best evaluation method for manufacturing quality

## Q1 Identical

- Excipients’ effect on skin barrier properties can be concentration dependent
- Thermodynamic activity could differ
- All tests for Q1 and Q2 similar products plus,
- In vivo test required if composition differences in excipients could potentially alter either skin permeability or the solubility of drug in the formulation

## Q1 Differences

- All tests for Q1 and Q2 similar products
- In vivo test required to demonstrate that new excipients do not alter permeability

## Decision Tree (Targeting SC)

- If Q1 and Q2 equivalent
- in vitro testing
- in vivo testing waived based on in vitro results
- If Q1 equivalent but Q2 difference
- in vitro testing
- in vivo tests if Q2 difference is potentially significant
- if Q1 and Q2 differ
- in vitro testing
- in vivo tests required to demonstrate no formulation effect on absorption

## Research Projects

- In vivo skin stripping (Colorado School of Mines)
- Reduce variability
- Measure thickness removed via TEWL
- Measure D (effect of formulation on SC) andK (effect of formulation on partition)
- In vitro characterization (Kentucky)
- Prepare Q1 and Q2 formulations with known manufacturing differences
- Measure rheology and in vitro release