Skin Care Products:Claim Substantiation & Clinical Testing

Barbara DvoracekSenior 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 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.”

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 - ContinuedExamples 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 - ExampleClaims 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.

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

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, peer-reviewed 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 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.

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 vendor’s 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

Fundamental Skin Studies

Product Performance/Characteristics

Claim substantiation

Consumer Feedback

Product Improvements

Concept Development Product Development Product Launch Post-Launch

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 post-treatment 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 self-assessment (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 Commissionhttp://www.ftc.gov/

• Cosmetic, Toiletry, and Fragrance Association (CTFA)http://www.ctfa.org/

• Cosmetic Ingredient Reviewhttp://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