Transcript Slide 1
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