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Developing Clinical Studies for
Successful Regulatory Filing
Poohglin Tresukosol, M.D.
Institute of Dermatology
December 2009
Scopes
 Allergenicity/Sensitizing
 Anti-aging
 Comedogenicity
 Irritation/Anti-irritation
The Skin
… in numbers:
• 16% of body weight
(= largest organ of the human body)
• Area = 1.8 m²
• 3 million cells per cm²
• Epidermis regenerates every 4 weeks
• Water 70% within the human body vs. 10%
water in the top layer of the stratum corneum
The Skin
Functions:
• Barrier between the body and the environment
• Controlling of moisture movement into and out
of the body
• Mediation of sensory experiences
• Assistance in temperature control
• Protection from ultraviolet radiation
• Synthesis of Vitamin D
How can we study?
 In
vitro
 In vivo
Animal model
 Human model

COLIPA
European Cosmetic Trade Association
 The testing of cosmetic products is conducted
using volunteers from the same population in
which they are intended to be marketed in
( e.g. in terms of sex, age, ethnic origin and skin
type ).
The effect of population diversity on skin irritation. CD 2006:55:357-363
Scopes
 Allergenicity/Sensitizing
 Anti-aging
 Comedogenicity
 Irritation/Anti-irritation
การทดสอบความสามารถในการก่ อภูมแิ พ้
 The
Maximization test: standard method
 Skin sensitization
 Animal model
 Human test
การทดสอบความสามารถในการก่ อภูมแิ พ้
 Avialable
human test
Schwartz-Peck test
 HRIPT

Draize test
 Shelanski-Shelanski test
 Voss-Griffith test
 Modified Draize test


Human maximization test
Allergenicity of substance
Challenging test
Sensitizing period
Resting period
2 weeks
Allergens of the year

2003
Bacitracin

2004
Cocamidopropyl betaine

2005
Steroid

2006
PPD

2007
Fragrance

2008
Thiourea
Dr.David AAD 2006
Dermatitis 2007;18(1):3-7
Sensitizers in Cosmetics
 Fragrances
 Preservatives

Parahydroxybenzoic acid
(PHBA); minimal sensitizer
J Eur Acad Dermatol Venereol 2007 Sep;21 Suppl 2:9-13
The Provocative Use Test
or Open Test





valuable in confirming positive reactions
suspected material is rubbed directly on to
normal skin ( anticubital fossa ) twice daily
for 1 wk; 3 cm2 area
no reaction = negative
false negative reaction are common
for contact urticaria : 15-30 min. reading;
retroauricular area or outer aspect of arm
immediately above the elbow
Fisher’s CD; 6th ed.
Scopes
 Allergenicity
 Anti-aging
 Comedogenicity
 Irritation/Anti-irritation
 Sensitizing
Wrinkle: Mechanical Methods
for Evaluating Skin Surface
Architecture
 Profilometric
methods
 Two-dimensional methods
 Scanning electron microscopic
methods
 Confocal microscopic methods
 Three-dimensional methods
J Derm Sciences 2001;27:S5-S10
Wrinkle: Mechanical Methods
for Evaluating Skin Surface
Architecture
 Profilometric
methods
Mechanical tracing analysis
 Laser tracing analysis

J Derm Sciences 2001;27:S5-S10
Wrinkle: Mechanical Methods
for Evaluating Skin Surface
Architecture
 Two-dimensional
methods
Image analysis
 Gray levelanalysis

J Derm Sciences 2001;27:S5-S10
Wrinkle:
Two-dimensional methods: Image
Analysis
Photographing
Setting the area measured
Binalization
Projecting angle;
30 degree
Lens magnification;
X15
Noise elimination
Area ratio calculation
J Derm Sciences 2001;27:S5-S10
Wrinkle: Mechanical Methods
for Evaluating Skin Surface
Architecture
 Three-dimensional
methods
Light cutting analysis
 Grating projection analysis

J Derm Sciences 2001;27:S5-S10
Wrinkle:
Three-dimensional methods: Principle
of Light Cutting Analysis
J Derm Sciences 2001;27:S5-S10
Wrinkle: Mesurement of 3-D
pattern: Light Cutting Analysis
J Derm Sciences 2001;27:S5-S10
Scopes
 Allergenicity
 Anti-aging
 Comedogenicity
 Irritation/Anti-irritation
 Sensitizing
Comedogenicity Concept
Comedogenic Assays :
 Rabbit
 An
ear model ( ultra-sensitive )
improved rabbit ear model
 Human
model
J Am Acad Dermatol 2006;54:3
Arch Derm 1982,118
BJD 1979;100:699
Cutis 1976;17:344
Human Model
 The
test substances are applied under
occlusion for one month to the upper
part of the backs of young adults, black
men who have large follicles
 The
degree of follicular hyperkeratosis
 Non-invasive
“follicular biopsy”
techniques
Arch Dermatol 1982;118:903.
Human model
 Human
model could be used to evaluate
comedogenicity, however the result were
dissimilar from those observed in the
rabbit ear model.
Draelos ZD. J Am Acad Dermatol 2006;54:No3
Human model
A
percent change from baseline was calculated:
degree of microcomedone formation
A
percent change in micromedone of greater or
less than 10% of neg. control : noncomedogenic
Draelos ZD. J Am Acad Dermatol 2006; 54:No3
Human model
 The
controversial aspect of any model is
definition of the end point
 Human
model has strengths and weaknesses

Test material applied under occlusion

Selection of prominent of follicular orifice

This is but one of many tests used by
manufacturers to determine safety
Draelos ZD. J Am Acad Dermatol 2006; 54:No3
Comedogenicitiy of Sunscreen
 UVB
& UVA radiation would regularly
enhance the formation of comedones when
acnegenic substances were applied to the
external ear canal of the rabbit
 Patients
who experienced summertime
exacerbations of acne were frequently heavy
user of sunscreens
Arch Dermatol 1982;118: June
Comedogenicitiy of Sunscreen
 UV
dose : Solar-Simulating
Radiation

two MEDs at wk1
Monday,
Wednesday,
 Three MEDs at wk2
Friday
 Grading
scale for the degree of
comedone formation from 0 to 4





0
1
2
3
4
None
Slight
Moderate
Strong
Severe
Arch Dermatol 1982;118:June
Strategies for skin irritation
 The
assessment of the skin corrosion and
skin irritation potential of chemicals and
finished product is an essential part of the
toxicological evaluation prior to
manufacture, transport or marketing
Robinson MK. Annal New York Academy of Sciences
Predictive irritancy testing (1)
 Predictive
irritancy testing involves
specific tests for the irritant potential of
individual chemicals as well as test for
individual susceptibility to irritation
Irritant dermatitis: Derm Clin
Predictive irritancy testing (2)
 Bioassay
 In
vitro skin irritation
Irritant dermatitis: Derm Clin
Bioassays of irritation skin
Measuring subtle degree of noninflammatory
skin damage
 Transepidermal water loss ( TEWL)
 Electrical impedance
 Rates of CO2 emission
 Chloride ion flux
Irritant dermatitis: Derm Clin
Skin irritation/corrosion potential
 Animal
model

Rabbit Draize Test

Chamber scarification test
 Human
model

Human 4-hour patch test

21-day cumulative irritation test

Soap chamber test

Modified soap chamber test

Cup shake test
CD 1996:34:204-212
The irritant contact dermatitis syndrome : Toxicology
Anti-irritants
 The
irritant potential of known eye
and skin irritant components of
formulating skin care products
varied greatly depending on
components of the formulation
CD 2006;55:148-154
Anti-irritants
 Goldemberg:
Anti-irritants (AIs)
“ Agents that used in conjunction
with skin or eye irritants, reduces
their irritant potential sufficiently
CD 2006;55:148-154
Anti-irritants
 Possible
mechanisms of AIs
Elimination of irritancy
 Reduce spread of the irritants:
Prevention of complete contact with
skin
 Blocking of skin-reactive sites by oily
substances to the skin prior to
application of aqueous irritants

CD 2006;55:148-154
Anti-irritants
 AIs
as treatment modalities:
mechanism
Anti-inflammatiory
 Stabilization of the stratum corneum
lipid barrier

CD 2006;55:148-154
AIs as Treatment Modalities
for Acute Irritation
 24-hours
Patch Test
 Cumulative Irritation Model: more
relevant for efficacy
CD 2006;55:155-159
SPF / UVB
MED of the sun screen – protected
skin
MED of the unprotected skin
Minimal Erythematous Dose
PPD / +++ / UVA
Overview
Eur J Pharmaceitics Biopharmaceutics 2009;72:295-303
Thank you