Skin Care Products: Claim Substantiation & Clinical Testing

Barbara Dvoracek
Senior Research Scientist Kimberly-Clark Corporation
Benedictine University Cosmetic Chemistry November 13, 2007

Personal Background
M.S. in Microbiology: University of Wisconsin Oshkosh

Employed at Kimberly-Clark Corporation since 2000

Skin Science Research
2000 - 2004
Research Scientist

2004 - Present
Clinical Study Coordinator Team Product Safety & Regulatory Affairs liaison

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

ASTM Standards
ASTM International
Formerly American Society for Testing and Materials

ASTM E-1958-06 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.

FDA Definitions of Cosmetics vs. Drugs

Cosmetics:

"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 diseaseand (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.

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.

http://www.cfsan.fda.gov/~dms/cos-218.html

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.

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.

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

NAD Review - Example

Claims at issue: Now its 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 skins 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 companys clinical study.

So, why do claims need substantiation?

Comply with regulations
Need to provide a reasonable basis for claims

Consumer acceptance of the product!

If product doesnt meet expectations, there will be limited success in the market place

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

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?

Categories of Claims
Composition/Ingredient Claims

Safety
Efficacy/Performance
Cosmetic

Drug

Claims can be further classified as

Monadic

Comparative
Superiority Parity

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?

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 740.10.

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, peerreviewed scientific literature

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

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

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.

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.
http://www.olay.com/boutique/regenerist/products/re1012

Cosmetic Claims
LOREAL 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 ProRetinol A penetrate the skins 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.
http://www.lorealparisusa.com/frames.asp?0.5192384361169118#skincare/brand/revitalift.asp

OTC Drug Claims

Limited by monographs

Sunscreen claims
Antimicrobial formulations Skin protectants
Diaper rash cream

Acne Skin bleaching

Testing requirements addressed in monograph

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

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

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

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?

Types of substantiation testing

Laboratory Test (in vitro)

Clinical Test (in vivo)

Consumer Use Tests

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 vendors conclusions? How will this ingredient work in the final formulation?

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

Categories of Skin Clinical Studies

Fundamental skin research

Evaluation of product performance or product characteristics

Claim substantiation

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

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

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

Claims Substantiation
Larger numbers of subjects

Designed to substantiate product claims

Final product tested Target population May utilize normal usage instructions

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)

Where should the study be placed?

Several specialized test facilities throughout US

Capabilities strengths/weakness
Geographic location
Climate

Population base
Flexibility of timing Cost

Methodology
Instrumental Evaluation

Expert Grade
Subject Self-Assessment

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

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

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

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)

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

Laser Profilometry

Fine Lines/Wrinkles
Can be done in similar fashion to skin texture measurements
Silicone Replicas

Digital image assessments

PRIMOS (GFMesstechnik GmbH , Germany) 3D imaging

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

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

Skin Thickness
Can be measured using ultrasound techniques

Dorsal Forearm
25 year old 51 year old
20 MHz Sharp Focus Transducer

Temperature
Infrared Thermography
Used to measure skin surface temperature

Thermocouples
Can measure heat between surfaces

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

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

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

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

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

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 posttreatment photos

Both types of assessments require controlled and consistent lighting

Study Design
Objective

Inclusion/Exclusion Criteria
Methods
Pretreatment Phase

Treatment Phase

Data Analysis

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

Fine Line/Wrinkle Study Example

30 subjects

Periorbital and/or perioral wrinkles present

Baseline instrumental, expert grade, and subject selfassessment (photography)

Subjects use product twice daily for up to 12 weeks

Fine line assessments repeated periodically Compare to baseline measurements

Questions?

References
Food & Drug Administration (FDA)
http://www.fda.gov/ Over the Counter (OTC) Drug http://www.fda.gov/cder/offices/otc/default.htm

National Advertising Division (NAD)

http://www.nadreview.org/

Federal Trade Commission

http://www.ftc.gov/

Cosmetic, Toiletry, and Fragrance Association (CTFA)

http://www.ctfa.org/

Cosmetic Ingredient Review

http://www.cir-safety.org/

American Society for Testing and Materials (ASTM)

http://www.astm.org/

Bioengineering of the Skin: Methods and Instrumentation. 1995. Eds. E. Berardesca, P. Elsner, K. P. Wilhelm, H. I. Maibach Skin Moisturization. 2002. Eds. J. J. Leyden, A. V. Rawlings