1. Skin Care Products: Claim Substantiation & Clinical Testing
Barbara Dvoracek
Senior Research Scientist
Kimberly-Clark Corporation
Benedictine University
Cosmetic Chemistry
November 13, 2007

2. Personal Background
M.S. in Microbiology: University of Wisconsin – Oshkosh
Employed at Kimberly-Clark Corporation since 2000
Skin Science Research
Research Scientist
Present
Clinical Study Coordinator
Team Product Safety & Regulatory Affairs liaison

3. Regulation of Skin Care Claims in US
Food & Drug Administration (FDA)
Product is “misbranded” if labeling is false or misleading
Federal Trade Commission (FTC)
Prohibits unfair and deceptive acts or practices
National Advertising Division (NAD)
Council of Better Business Bureaus
Self-regulatory mechanism
State Laws

4. ASTM Standards ASTM International
Formerly American Society for Testing and Materials
ASTM E Guide for Sensory Claim Substantiation
Standard covers reasonable practices for designing and implementing sensory tests that validate claims pertaining only to the sensory or perceptual attributes, or both, of a product. 

5. FDA – Definitions of Cosmetics vs. Drugs
"articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body...for cleansing, beautifying, promoting attractiveness, or altering the appearance" [FD&C Act, sec. 201(i)]
Drugs:
"(A) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease…and (B) articles (other than food) intended to affect the structure or any function of the body of man or other animals" [FD&C Act, sec. 201(g)(1)]
Cosmeceuticals:
“A product can be a drug, a cosmetic, or a combination of both, but the term "cosmeceutical" has no meaning under the law.”

6. How is intended use established?
Claims stated on the product labeling, in advertising, on the Internet, or in other promotional materials.
Consumer perception, which may be established through the product's reputation.
Ingredients that may cause a product to be considered a drug because they have a well known (to the public and industry) therapeutic use.

7. FDA Warning Letter Excerpts
“The review of this labeling found the products being offered are promoted for conditions that cause them to be drugs under sections 201(g)(1)(B) and 201(g)(1)(C) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 321(g)(1)(B) and 321(g)(1)(C)]. Claims in your labeling, including your web sites, establish that these products are drugs because they are intended for use in the cure, mitigation, treatment, or prevention of disease and are intended to affect the structure or function of the body.”…

8. FDA Warning Letter Excerpts - Continued
Examples of some of the claims observed for these products include:
Claims on the boxes for each of your … products:
"Reduces Redness"
"Smoothes Scaly Skin"
Claims on the … Dramatic Relief for Oily and Acne Prone Skin box:
"[I]ntended for individuals with chronic skin redness and flaking associated with dermatologic conditions like seborrheic dermatitis or rosacea ." …
"Inflamed oily skin associated with troublesome dermatologic conditions. . .Dramatic Relief. . .for Oily and Acne Prone Skin. . .clinically proven to reduce redness, eliminate scaling, and help soft, smooth skin reappear."
Claims on the … Dramatic Relief for Normal To Dry Skin box:
"[I]ntended for individuals with chronic skin redness accompanied by severely dry skin, often associated with dermatologic inflammatory conditions like eczema or rosacea." …
"Inflamed, dry and scaly skin often associated with troublesome dermatologic conditions. . . Dramatic Relief. . .for Normal to Dry Skin ... clinically proven to reduce redness, eliminate scaling and itching, and help smooth, soft skin reappear.“

9. NAD – Advertising Industry Self-Regulation
Review national advertising for truthfulness and accuracy
Routine monitoring of advertisements
Mediate challenges between companies
Review of challenges done within 60 business days
Data are confidential, while advertiser and challenger positions, and NAD decisions are available to the public
Will refer to other government agencies (FTC) as appropriate if advertisers do not cooperate

10. NAD Review - Example Claims at issue:
“Now it’s skincare that actually lifts wrinkles from the inside out.”
NAD recommended that the company discontinue or modify the claim … to reflect a reduction in the appearance of lines and wrinkles, rather than the elimination of lines and wrinkles.
“XXX with unique dermatological-nutrients refuels cells within skin’s deepest surface layers: OMEGA 3 locks in moisture; VITAMIN A visibly reduces wrinkles; RICE PROTEIN fortifies skin.”
NAD determined that there is a reasonable basis to support the “unique dermatological-nutrients” claim as it relates to OMEGA 3 and rice protein, but recommended the reference to Vitamin A be modified to reflect that it helps reduce, rather than visibly reduces, fine lines and wrinkles.
“A clinical study proves: in 3 weeks wrinkles are visibly lifted and skin is noticeably firmer.”
NAD recommended that the claim … be modified to reflect the wording of the company’s clinical study.

11. So, why do claims need substantiation?
Comply with regulations
Need to provide a reasonable basis for claims
Consumer acceptance of the product!
If product doesn’t meet expectations, there will be limited success in the market place

12. Claim Substantiation Process
Claims development process should begin early in the product development process
Product development driven by desired claims
Review of claims by cross-functional team:
Marketing
R&D/Technical
Regulatory Affairs
Legal
Product Safety

13. Claims Related Questions
Is the product a cosmetic, drug, or medical device?
Can changing the claim, change product classification?
Will claims be on package, on the internet, in print, or on television?
Do claims require testing to substantiate?
What type of testing is required?
Is there a standard or industry accepted method to substantiate?

14. Categories of Claims Composition/Ingredient Claims Safety
Efficacy/Performance
Cosmetic
Drug

15. Claims can be further classified as…
Monadic
Comparative
Superiority
Parity

16. Composition Claims
“X contains Vitamin C, a potent anti-oxidant to help fight visible signs of aging”
How much vitamin C is present in formulation?
Is it shown to be effective at that concentration?
What form is it in?
Is it effective in the formulation?

17. A note about claims relating to safety…
FDA states:
If the safety of a cosmetic is not adequately substantiated, the product may be considered misbranded and may be subject to regulatory action unless the label bears the following statement: "Warning - The safety of this product has not been determined." See 21 CFR

18. Determining Cosmetic Product Safety
Determination of product safety is the responsibility of the manufacturer/marketing company
Cosmetic Ingredient Review (CIR) panel
Established in 1976 by the Cosmetic, Toiletry & Fragrance Association (CTFA) with support FDA and the Consumer Federation of America
Thoroughly reviews and assesses the safety of ingredients used in cosmetics in an open, unbiased, and expert manner, and publishes the results in the open, peer-reviewed scientific literature

19. Product Safety Testing
Testing needs are determined by the company marketing the product
May include:
In vitro testing
Cumulative Irritation testing
Repeat Insult Patch Tests (RIPT)
Sensitization
Ocular Irritation
Facial Sting
Phototoxicity
Photoallergy
Comedogenicity
Acnegenicity

20. Hypoallergenic No Federal standards or definitions of "hypoallergenic"
Term is defined by the company making the claim
Type of testing used to substantiate hypoallergenic varies from company to company

21. Product Performance Claims
It is the responsibility of the company marketing a cosmetic product to substantiate performance claims.
Types of testing and the degree of testing can vary widely within the industry.

22. Creative cosmetic claims…
“Olay Regenerist regenerates skin's appearance without such drastic measures as chemical peels, cosmetic surgery or lasers. Clinical tests prove that amino-peptides help regenerate damaged skin. Now Olay Regenerist uses this technology to beautifully regenerate skin's appearance by renewing its outer layer, revealing newer skin.
Regenerist Daily Regenerating Serum uses a concentrated form of an exclusive amino-peptide complex and combines it with Olay moisture to offer the maximum regeneration and hydration within the Regenerist line. This formula leaves your skin feeling velvety smooth and is designed for everyday use.”

23. Cosmetic Claims
L’OREAL RevitaLift Double Lifting: The first double-action treatment that instantly re-tightens skin and effectively fights wrinkles. The double-pump system combines two exclusive formulas, an intense re-tightening gel and an anti-wrinkle treatment, in just one application.
Benefit 1: The Intense Re-Tightening Gel, containing Pro-Tensium, works to immediately form a resistant and flexible network that instantly re-tightens skin. 75% of women reported skin lifted and tightened immediately.*
*Effectiveness in a test of 52 women immediately after application.
Benefit 2: The Anti-Wrinkle Comfort Cream with Nanosomes of Pro-Retinol A penetrate the skin’s surface, effectively fighting wrinkles and reducing the appearance of fine neck creases. 20% of women tested had fewer surface wrinkles in one week.*
*Effectiveness in reduction of overall surface wrinkles in a test of 40 women.

24. OTC Drug Claims Limited by monographs Sunscreen claims
Antimicrobial formulations
Skin protectants
Diaper rash cream
Acne
Skin bleaching
Testing requirements addressed in monograph

25. OTC Example – Sunscreen
Drug label claims:
Helps prevent sunburn
Broad spectrum sunscreen must provide at least low protection against UVB and UVA
Water Resistant/Very Water Resistant
Retains SPF after [40 or 80] minutes of activity in the water [and/or sweating or perspiring]
SPF 50+
Provides highest protection against sunburn and tanning
For skin extremely sensitive to sunburn
Testing is required to establish UVB SPF, UVA and water resistant claims
Test methodology found in monograph

26. OTC Example: Skin Protectant – Lip Protectant
Drug label claims:
Temporarily protects [and helps relieve] chapped or cracked lips
Helps protect lips from the drying effects of wind and cold weather
No testing requirements established by the monograph
Additional cosmetic claims such as “moisturizing” allowed outside of the Drug Facts box

27. Is testing needed to substantiate the claim?
Puffery – typically cannot be tested or measured
Technical Opinion – substantiation based on sound technical judgment of expert in the field
Substantiation testing – required, for example, when claim speaks to effectiveness of a product or a benefit or improvement in a skin attribute as a result of using the product; in vivo or in vitro

28. Group Activity
Identify the following types of claims in the magazine ads provided:
Composition claims
Cosmetic claims
Drug claims
Which claims do you think need testing to substantiate?

29. Types of substantiation testing
Laboratory Test (in vitro)
Clinical Test (in vivo)
Consumer Use Tests

30. Vendor Information, key questions to ask:
What is the mechanism of action?
How was it tested?
Laboratory?
Clinical?
Use test?
What concentrations of the ingredient were used?
How many data points were captured?
Were proper controls used?
Are the methods clearly described?
Is all of the data being presented?
Is statistical significance demonstrated?
Does the data support the vendor’s conclusions?
How will this ingredient work in the final formulation?

31. What is a Clinical Study?
Controlled investigation involving consenting human volunteers
Subjects recruited based on specific inclusion/exclusion criteria – not necessarily “consumers”
Follow Good Clinical Practices
Designed to gain fundamental knowledge of a biological condition or to evaluate test article safety, efficacy, or specific product attributes
Not typically preference, sensory, or consumer use tests

32. Categories of Skin Clinical Studies
Fundamental skin research
Evaluation of product performance or product characteristics
Claim substantiation

33. Study categories vs. Product Development timeline
Concept Development Product Development Product Launch Post-Launch
Fundamental Skin Studies
Consumer Feedback
Product Performance/Characteristics
Product Improvements
Claim substantiation

34. Fundamental Skin Attributes
Small number of subjects
Often geared toward understanding differences between populations or conditions
Age: Infant, adult, elderly
Race/Ethnicity: Caucasian, African-American, Latino, Asian
Gender
Condition: healthy intact skin vs. compromised skin
Skin type: normal, oily, dry skin

35. Product Performance or Characteristics
Small number of subjects
Used to determine whether a product has a desired benefit
Does the lotion moisturize for 24 hours?
Is the antimicrobial lotion effective at killing bacteria?
Compare multiple product prototypes
Potential issues with a product

36. Claims Substantiation
Larger numbers of subjects
Designed to substantiate product claims
Final product tested
Target population
May utilize normal usage instructions

37. Factors to Consider when Developing a Protocol
Population
Number of subjects
Methodology
Study length
Product availability
Product Classification
Cosmetic, drug, or medical device
Institutional Review Board (IRB) approval
ASTM Guidelines (if using as an Ad Claim)

38. Where should the study be placed?
Several specialized test facilities throughout US
Capabilities – strengths/weakness
Geographic location
Climate
Population base
Flexibility of timing
Cost

39. Methodology Instrumental Evaluation Expert Grade
Subject Self-Assessment

40. Instrumental Measurements
Advantages
Objective measurements
May provide increased sensitivity
Disadvantages
Effect may be more complex than one instrument can measure
Differences detected by instrumentation may not be meaningful to consumers

41. Examples of Instrumental Measurements
Moisturization → Conductance/Impedance
Skin barrier function → TEWL
Skin texture → Topography
Skin elasticity → Elastometer
Skin thickness → Ultrasound
Skin surface characteristics → Microscopy
Temperature → Infrared Thermography
pH → Skin pH probe
Color → Chromameter
Blood flow→ Laser Doppler
Sebum (oiliness) → Sebumeter

42. Moisturization
Measurement based on the premise that electrical properties of the skin change with hydration
Instruments that measure skin conductance, impedance, and capacitance used to measure skin hydration
Skicon (IBS Co. Ltd., Japan) – conductance
Dermalab (Cortex, Denmark) - conductance
Corneometer (Courage + Khazaka Electronic GmbH, Germany) – capacitance
Nova™ Dermal Phase Meter (DPM) (Nova Technologies, US) – impedance

43. Skin Barrier
Transepidermal Water Loss (TEWL) is used to measure vapor loss from the skin
Tewameter (Courage + Khazaka Electronic GmbH, Germany)
Dermalab (Cortex, Denmark)
Servo Med Evaporimeter (Servo Med, Sweeden)

44. Skin Texture
Topography can be measured through profilometry measurements
Silicone Replicas
Skin-Visiometer® SV 600 (Courage + Khazaka Electronic GmbH, Germany)
Laser Profilometry

45. Fine Lines/Wrinkles
Can be done in similar fashion to skin texture measurements
Silicone Replicas
Digital image assessments
PRIMOS (GFMesstechnik GmbH , Germany) – 3D imaging

46. Photography Systems Canfield VISIA Facial photography
Front and side images
Standard lighting
Standard flash
Parallel Polarized
Accentuate surface characteristics
Cross Polarized
Accentuates sub-surface characteristics UV
Sun damage
Acne

47. Skin Elasticity
A number of techniques can be used to measure the mechanical properties of the skin
Dermal Torque Meter (Diastron, UK)
Torsion
Dermlab Elasticity Module (Cortex, Denmark)
Suction
Ballistometer (Diastron, UK)
Indentation

48. 20 MHz Sharp Focus Transducer
Skin Thickness
Can be measured using ultrasound techniques
Dorsal Forearm
25 year old year old
20 MHz Sharp Focus Transducer

49. Temperature Infrared Thermography Thermocouples
Used to measure skin surface temperature
Thermocouples
Can measure heat between surfaces

50. Blood Flow
Laser Doppler imaging can be used to assess blood flow which can be associated with irritation or heat
Lower back before and after heating pad use

51. Color
Various imaging techniques can be used for assessing redness, tanning, and overall skin color
Chroma Meter (Konica Minolta, Japan)
Uses L*a*b* color space system
DSM Color Meter (Cortex, Denmark)
Measuring erythema and melanin

52. Expert Grade Advantages Can assess multiple parameters at once
Assess features for which there is no instrumental measurement available
Provide more consistency than subject self-assessment
Disadvantages
Subjective measurements
Differences may not be perceived by consumers
Should be trained and able to demonstrate repeatable, consistent responses
More expensive
Advantageous to have more than one, but not always practical

53. Examples of Traits Assessed by Expert Grader
Skin Dryness/Moisturization
Irritation
Fine lines
Dark circles (under eye)
Puffiness (under eye)
Texture/Smoothness
Color
Radiance
Clarity
Youthfulness

54. Subject Self-Assessment
Advantages
Assessments most similar to consumer perception
Most meaningful to consumer
Disadvantages
Subjective measurements
Larger sample sizes to differentiate (noisier data)
Subjects will sometimes perceive differences that are not detected by other means

55. Subject Self-Assessment
Can evaluate same attributes as expert grade
Mirror evaluations
Less expensive
Perception changes over time
Photography
Allows subjects to compare baseline photos to post-treatment photos
Both types of assessments require controlled and consistent lighting

56. Study Design Objective Inclusion/Exclusion Criteria Methods
Pretreatment Phase
Treatment Phase
Data Analysis

57. Forearm Moisturization Study - Example
30 subjects
Six test sites (including one control site)
Acclimation to controlled temperature & humidity environment
Baseline conductance measurements taken
Apply controlled amount of formulation to each test site
Take additional conductance measurements: 30 minutes to 24 hours after application
Compare pre- and post-application measurements
Compare test and untreated control sites

58. Fine Line/Wrinkle Study – Example
30 subjects
Periorbital and/or perioral wrinkles present
Baseline instrumental, expert grade, and subject self-assessment (photography)
Subjects use product twice daily for up to 12 weeks
Fine line assessments repeated periodically
Compare to baseline measurements

59. Questions?

60. References Food & Drug Administration (FDA)
Over the Counter (OTC) Drug
National Advertising Division (NAD)
Federal Trade Commission
Cosmetic, Toiletry, and Fragrance Association (CTFA)
Cosmetic Ingredient Review
American Society for Testing and Materials (ASTM)
Bioengineering of the Skin: Methods and Instrumentation Eds. E. Berardesca, P. Elsner, K. P. Wilhelm, H. I. Maibach
Skin Moisturization Eds. J. J. Leyden, A. V. Rawlings