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

INTROITUS

VAGINA CERVIXMUCUS

PROPHYLACTIC COATINGCONTRACEPTIVE COATING

Desired Distribution Profile ofCertain Vaginal Formulations

InteractionsInteractions in the Vaginain the Vagina

MicrobicideMicrobicideFormulationFormulation

Anatomy,Anatomy,GeometryGeometry

SurfaceSurfacePropertiesProperties

FluidFluidContentsContents

MechanicalMechanicalPropertiesProperties

““SLIDING”SLIDING” gravity““SLIDING”SLIDING” gravity

““SQUEEZING”SQUEEZING” visceral contractions pressure tissue elasticity

““SQUEEZING”SQUEEZING” visceral contractions pressure tissue elasticity

““SEEPING”SEEPING” surface energies interfacial tensions

““SEEPING”SEEPING” surface energies interfacial tensions

rugae

mucus,

transudate

GELGEL

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

David Katz. Duke University

Mechanistic Analysis of Sub-processes (Squeezing)

RF

2h

epithelial surfaces

vehicle

FORMULATION

• THEORYTHEORY • SIMULATIONSIMULATION

V

2

2E n 3 1 2 m

1

n 3n 6

2n 1

2V

n 2

2nt ho

3n 6

2n

2n

3n 6Solution for elastic surfaces (E, ); lubrication approximation; power law fluid (n, m); conserved bolus volume V = 2hoπ R2

Area(t)=

David Katz. Duke University

SLIDING THEORYvelocity depends upon…

vagina propertiestilt angle tissue separation HHtottot

gel propertiesdensityrheology

velocityprofile

VVavgavg

HHtottot

David Katz. Duke University

Viscosity vs. Shear Rate

0.01

0.1

1

10

100

1000

0.01 0.1 1 10 100 1000 10000shear rate (s-1)

visc

osity

(P)

Gynol II

KY Plus

Conceptrol

Advantage-S

David Katz. Duke University

Vaginal Gel Thickness Distribution (Advantage)

4000

3000

2000

1000

045 90

135180

225 270

315

125

100

75

50

25Azimuthal Angle (deg.)

Axial Dist. (mm)

Depth of Coating (m)

introitus

David Katz. Duke University

Vaginal Gel Thickness Distribution (Conceptrol)

4000

3000

2000

1000

045 90

135180

225 270

315

125

100

75

50

25Azimuthal Angle (deg.)

Axial Dist. (mm)

Depth of Coating (m)

introitus

David Katz. Duke University

Axial and Angular DependenceAxial and Angular Dependenceof Coating Thickness Distributionof Coating Thickness Distribution

Axial Dependence

0

500

1000

0 0.5 1

Axial Length

Th

ick

ne

ss

(

m)

AdvantageConceptrol

Angular DependenceThickness in microns

0

500

10000

45

90

135

180

225

270

315

Axial Dependence

0

500

1000

0 0.5 1

Axial Length

Th

ick

ne

ss

(

m)

Scaled to length of 71.11 mm

Angular DependenceThickness in microns

0

500

10000

45

90

135

180

225

270

315

Scaled to length of 51.67 mm

% Volume Distal to Fornix

39% 85%% of Area Coated

36% 100%

David Katz. Duke University