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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

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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
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
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
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
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
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
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
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
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
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

Mechanistic evidence plus distribution and imaging approaches?
body of evidence
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
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
Desired Distribution Profile ofCertain Vaginal Formulations

CERVIX

VAGINA

MUCUS

INTROITUS

PROPHYLACTIC COATING

CONTRACEPTIVE COATING

slide15

Interactionsin the Vagina

Fluid

Contents

Anatomy,

Geometry

Microbicide

Formulation

Mechanical

Properties

Surface

Properties

pre coital forces acting on a bolus of gel in vagina

“SQUEEZING”

visceral contractions

pressure

tissue elasticity

rugae

mucus,

transudate

GEL

“SEEPING”

surface energies

interfacial tensions

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

“SLIDING”

gravity

David Katz. Duke University

mechanistic analysis of sub processes squeezing

THEORY

  • SIMULATION

vehicle

epithelial surfaces

F

R

FORMULATION

2h

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

Area(t)=

David Katz. Duke University

Mechanistic Analysis of Sub-processes (Squeezing)
sliding theory
SLIDING THEORY

Vavg

velocity depends upon…

vagina properties

tilt anglea

tissue separationHtot

gel properties

density

rheology

Htot

velocity

profile

a

David Katz. Duke University

viscosity vs shear rate
Viscosity vs. Shear Rate

Gynol II

KY Plus

Conceptrol

Advantage-S

David Katz. Duke University

vaginal gel thickness distribution advantage
Vaginal Gel Thickness Distribution (Advantage)

4000

3000

2000

1000

Depth of Coating (mm)

125

introitus

100

75

0

45

50

90

Axial Dist. (mm)

135

180

25

Azimuthal Angle (deg.)

225

270

315

David Katz. Duke University

vaginal gel thickness distribution conceptrol

4000

3000

2000

1000

Depth of Coating (mm)

125

100

introitus

75

0

45

50

90

Axial Dist. (mm)

135

180

25

Azimuthal Angle (deg.)

225

270

315

Vaginal Gel Thickness Distribution (Conceptrol)

David Katz. Duke University

axial and angular dependence of coating thickness distribution

David Katz. Duke University

Axial and Angular Dependenceof Coating Thickness Distribution

Conceptrol

Advantage

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%