Clinical trial NCT03582215
Conditions: Systemic Exposure to Sunscreen Ingredients
Keywords: Sunscreen Pharmacokinetics
Sponsor: Food and Drug Administration (FDA)
Start date: 2018-07-18; Completion date: 2019-02-18
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to assess the systemic exposure and pharmacokinetics of sunscreen active ingredients (avobenzone, oxybenzone, ecamsule, octocrylene homosalate, octisalate and octinoxate) when sunscreen product is applied under maximal use conditions.

Part 1 is an open-label, randomized, 4-arm study in 24 healthy adult subjects with the primary objective to explore whether the active components (avobenzone, oxybenzone, ecamsule and octocrylene) of 4 sunscreen products (1 sunscreen product in each arm) are absorbed into the systemic circulation when a sunscreen product is applied under maximal use conditions.

One sunscreen product with the highest avobenzone exposure will be selected for the second part of the study. If there is no quantifiable exposure of avobenzone for any of the sunscreen products, the formulation with the highest oxybenzone exposure will be selected for Part 2. In addition, 3 new sunscreen products are included in Part 2.

Part 2 is an open label, 4-arm study in 48 healthy adult subjects with the primary objective to assess the pharmacokinetics of the active components in the selected product from Part 1 and 3 additional products with a combination of active ingredients (avobenzone, oxybenzone, octocrylene, ecamsule homosalate, octisalate and octinoxate as applicable/contained in the different products).

Detailed description:
Part 1

Part 1 is an open label, randomized, 4-arm pilot study to evaluate the effects of multiple applications of 4 different topical sunscreen formulations in healthy adult subjects. Each arm will include 6 subjects (3 male and 3 female) with 1 formulation. A total of 24 subjects (12 male and 12 female) from all 4 arms will be admitted to the clinical research unit (CRU) on Day 0. On the morning of Days 1 through 4, subjects will receive a topical application of the study drug at approximately 0900 hours. The study product will be weighed in advance and applied by a qualified person from the study team. Subjects will then receive 3 more topical applications on the same day at 2, 4, and 6 hours after the first dose.

Part 2

Part 2 is an open label, 4-arm study to evaluate the pharmacokinetics of avobenzone, oxybenzone, octocrylene, ecamsule homosalate, octisalate and octinoxate (as applicable in the different products) after multiple applications of a topical sunscreen formulation in healthy adult subjects. Part 2 will include 48 subjects (24 male and 24 female) and each arm will include 12 subjects (6 male and 6 female). One of the formulations in Part 2 will be selected based on the plasma exposure data from the pilot study (Part 1). A total of 48 subjects (24 male and 24 female) will be admitted to the CRU on Day 0. On the morning of Days 1 through 4, subjects will receive a topical application of the study product at approximately 0900 hours. The study drug will be weighed in advance and applied by a qualified person from the study team. Subjects will only receive one application on Day 1. On Days 2, 3 and 4 subjects will receive an initial dose and 3 more topical applications on the same day at 2, 4, and 6 hours after the first dose.

Parts 1 and 2

In both parts, approximately 2 mg of active sunscreen ingredient per 1 cm2 of body surface (calculation per method of Dubois) will be evenly applied 4 times per study day (except for a one-time application on the first day in part 2) to areas of the body typically exposed to the sun: face, ears, neck, torso, arms, and legs (approximately 75% of the body surface area). The antecubital areas will be avoided when applying the sunscreen due to potential contamination of the sites used for intravenous pharmacokinetic (PK) blood sample collection. The topical applications of study drug will be administered with subjects in swim wear to simulate real world settings as well as for easy application. In addition to swim wear, subjects may wear scrubs in between applications and at other times throughout the day/night. Subjects are required to shower each morning after the first PK blood sample collection (and before the first dose of the day), but not at other times during the day.

Blood samples (approximately 10 mL per sample) will be collected for determination of plasma concentrations for all active ingredients (avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, octisalate and octinoxate, where applicable).

Safety evaluations will include adverse event (AE) monitoring, vital sign measurements, and physical examinations. All AEs reported by the subject or observed by the investigator or clinical research unit (CRU) staff will be recorded. Any AE reported after the informed consent is signed and before study drug application will be recorded as medical history.

Subjects will remain in the CRU after admission on Day 0 until the morning of Day 7 following completion of scheduled end-of-study activities for Part 1. For Part 2, subjects will undergo the same schedule but will return to the clinic for follow-up visits on Days 10, 14 and 21. Subjects will then be discharged following completion of End-of-Study activities.

Subjects are not allowed to use products containing any of these active ingredients from 7 days before check-in until completion of End-of-Study procedures.

Arms: arm 1: Part 1: Cream

Ingredients: 2% Avobenzone; 10% Octocrylene; 2% Ecamsule arm 2: Part 1: Lotion

Ingredients: 3% Avobenzone; 4% Oxybenzone; 6% Octocrylene arm 3: Part 1: Spray 1

Ingredients: 3% Avobenzone; 6% Oxybenzone; 2.35% Octocrylene; 15% Homosalate; 5% Octisalate arm 4: Part 1: Spray 2

Ingredients: 3% Avobenzone; 5% Oxybenzone; 10% Octocrylene arm 5: Part 2: Lotion

Ingredients: 3% Avobenzone; 4% Oxybenzone; 6% Octocrylene arm 6: Part 2: Aerosol Spray

Ingredients: 3% Avobenzone; 6% Oxybenzone; 10% Octocrylene; 15% Homosalate; 5% Octisalate arm 7: Part 2: Nonaerosol Spray

Ingredients: 3% Avobenzone; 10% Octocrylene; 10% Homosalate; 5% Octisalate; 7.5% Octinoxate arm 8: Part 2: Pump Spray

Ingredients: 3% Avobenzone; 10% Homosalate; 5% Octisalate; 7.5% Octinoxate
Interventions: intervention 1: Part 1: Cream intervention 2: Part 1: Lotion intervention 3: Part 1: Spray 1 intervention 4: Part 1: Spray 2 intervention 5: Part 2: Lotion intervention 6: Part 2: Aerosol Spray intervention 7: Part 2: Nonaerosol Spray intervention 8: Part 2: Pump Spray
Intervention descriptions: intervention 1: Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area intervention 2: Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area intervention 3: Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area intervention 4: Approximately 2 mg per cm2 of body surface will be applied topically 4 times per day for 4 days to approximately 75% of the body surface area intervention 5: Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area intervention 6: Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area intervention 7: Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area intervention 8: Approximately 2 mg per cm2 of body surface will be applied topically 1 time on day 1 and 4 times per day on following 3 days to approximately 75% of the body surface area

Protocol documents:
Prot_000.pdf: 
U.S. Food and Drug Administration
Confidential
Protocol No. SCR-005
13 December 2018
Page 1 of 54
Version 1.4
CLINICAL STUDY PROTOCOL
Assessment of the Human Systemic Absorption of Sunscreen 
Ingredients
PROTOCOL NO. SCR-005
Sponsor:
U.S. Food and Drug Administration
White Oak Building #64, Room 2072
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sponsor Study Lead 
and Medical Monitor:
David Strauss, MD, PhD
Director, Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Telephone: 301-796-6323
Email: david.strauss@fda.hhs.gov
Project Managers:
Murali Matta, PhD
U.S. Food and Drug Administration
Telephone: 240-402-5325
Email: murali.matta@fda.hhs.gov
Robbert Zusterzeel, MD, PhD, MPH
U.S. Food and Drug Administration
Telephone: 301-796-3750
Email: robbert.zusterzeel@fda.hhs.gov
Study Monitor:
Jill Brown
RIHSC Project Manager
U.S. Food and Drug Administration
Version of Protocol:
1.4
Date of Protocol:
13 December 2018
CONFIDENTIAL
The concepts and information contained in this document or generated during the study 
are considered proprietary and may not be disclosed in whole or in part without the 
expressed written consent of U.S. Food and Drug Administration.


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Sponsor Signature Page
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following:
The ethical principles that have their origin in the Declaration of Helsinki;
International Council for Harmonisation (ICH) harmonised tripartite guideline E6 
(R1): Good Clinical Practice; and
All applicable laws and regulations, including without limitation, data privacy laws 
and compliance with appropriate regulations, including human subject research 
requirements.
David Strauss, MD, PhD
Director, Division of Applied Regulatory 
Science
U.S. Food and Drug Administration
Date




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Table of Contents
1.
Protocol Synopsis........................................................................................................ 7
2. 
List of Abbreviations ................................................................................................ 17
3. 
Introduction............................................................................................................... 19
4.
Study Objectives ....................................................................................................... 20
4.1.
Primary Objectives........................................................................................ 20
4.1.1 
Part 1................................................................................................. 20
4.1.2 
Part 2................................................................................................. 20
5. 
Investigational Plan................................................................................................... 20
5.1.
Study Design................................................................................................. 20
5.1.1 
Part 1................................................................................................. 21
5.1.2 
Part 2................................................................................................. 21
5.1.3 
Skin Tape Stripping .......................................................................... 21
5.1.4 
Common Procedures......................................................................... 22
5.1.5 
Risk/Benefit ...................................................................................... 22
5.2. 
Selection of Study Population....................................................................... 24
5.2.1 
Inclusion Criteria .............................................................................. 24
5.2.2 
Exclusion Criteria ............................................................................. 25
5.3. 
Screening Failures......................................................................................... 26
5.4. 
Termination of Study or Investigational Site................................................ 26
5.4.1 
Criteria for Termination of the Study ............................................... 26
5.4.2 
Criteria for Termination of Investigational Site................................ 26
5.5. 
Criteria for Subject Withdrawal.................................................................... 27
5.5.1 
Handling of Withdrawals.................................................................. 28
5.5.2 
Replacement Subjects ....................................................................... 28
5.6. 
Study Visits................................................................................................... 28
5.6.1 
Recruitment....................................................................................... 28
5.6.2 
Screening........................................................................................... 29
5.6.3 
Study Periods .................................................................................... 30
5.6.4 
Discharge (or Early Termination)..................................................... 31
5.6.5 
Follow-up.......................................................................................... 31
5.7. 
Study Procedures .......................................................................................... 32
5.7.1 
Pharmacokinetic Assessments .......................................................... 32
5.7.2 
Safety Assessments........................................................................... 34
5.7.3 
Demographics and Medical History ................................................. 39
5.8. 
Study Treatments .......................................................................................... 39


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5.8.1 
Treatments Administered.................................................................. 39
5.8.2 
Method Assigning Subjects to Treatment......................................... 40
5.8.3
Identity of Study Drug ...................................................................... 41
5.8.4
Management of Clinical Supplies..................................................... 42
5.8.5 
Blinding............................................................................................. 42
5.8.6 
Treatment Compliance...................................................................... 42
5.8.7 
Prior and Concomitant Medications ................................................. 42
5.8.8
Subject Restrictions .......................................................................... 43
5.9.
Statistical Methods........................................................................................ 43
5.9.1 
Sample Size....................................................................................... 43
5.9.2 
Analysis Populations......................................................................... 43
5.9.3 
General Statistical Considerations .................................................... 43
5.9.4 
Subject Disposition........................................................................... 43
5.9.5 
Demographic and Baseline Characteristics ...................................... 44
5.9.6 
Pharmacokinetic Analyses................................................................ 44
5.9.7 
Safety Analyses................................................................................. 44
5.9.8 
Interim Analyses............................................................................... 45
5.9.9 
Missing Data..................................................................................... 45
5.10. Data Quality Assurance ................................................................................ 45
6. 
Ethical Considerations .............................................................................................. 45
6.1. 
Ethical Conduct of the Study........................................................................ 45
7. 
Institutional Review Board (IRB)............................................................................. 46
8. 
Administrative Procedures........................................................................................ 46
8.1. 
Responsibilities of the Investigator............................................................... 46
8.1.1 
Form FDA 1572................................................................................ 46
8.1.2 
Adherence to Protocol....................................................................... 46
8.1.3 
Reporting Requirements ................................................................... 46
8.1.4 
Source Documentation...................................................................... 46
8.1.5 
Retention of Records......................................................................... 47
8.1.6 
Financial Disclosure and Obligations ............................................... 47
8.2. 
Confidentiality and Disclosure of Data......................................................... 47
8.3. 
Certificate of Confidentiality ........................................................................ 48
8.4. 
Subject Consent ............................................................................................ 48
8.5. 
Data Collection ............................................................................................. 49
8.6. 
Publications................................................................................................... 49
9. 
Study Management ................................................................................................... 49
9.1. 
Release of Study Drug to the Study Clinic ................................................... 49


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9.2. 
Monitoring .................................................................................................... 49
9.2.1 
Monitoring of the Study.................................................................... 49
9.3.
Management of Protocol Amendments and Deviations ............................... 50
9.3.1
Modification of the Protocol............................................................. 50
9.3.2 
Protocol Violations and Deviations .................................................. 50
10. Appendices................................................................................................................ 52
10.1. Appendix A: Schedule of Events.................................................................. 52
11. Reference List ........................................................................................................... 54
List of Tables
Table 5-1
Clinical Laboratory and Diagnostic Screening Tests.................................... 38
Table 5-2
Treatment Groups ......................................................................................... 41
Table 10-1
Overall Schedule of Events (Parts 1 and 2) .............................................. 52


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1.
Protocol Synopsis
Protocol Number:
SCR-005
Title:
Assessment of the Human Systemic Absorption of Sunscreen 
Ingredients
Investigators:
Principal Investigator: Carlos Sanabria, MD
Study Phase:
1
Study Period:
This will be a single clinical study conducted in 2 parts. The duration 
of study participation will be approximately 37 days for part 1,
including a 30-day screening period, a 4-day treatment period 
(Days 1-4) and subjects leaving the clinic on the morning of Day 7
following completion of scheduled End-of-Study activities. For part 
2, the duration of participation will be approximately 51 days,
including a 30-day screening period, a 4-day treatment period 
(Days 1-4) and subjects leaving the clinic on the morning of Day 7.
Subjects in part 2 will then return to the clinical for follow-up visits 
on Days 10, 14 and 21 after which End-of-Study activities will be 
completed.
Study Site:
Spaulding Clinical Research LLC, 525 South Silverbrook Drive, 
West Bend, WI 53095
Background and 
Motivation:
Sunscreens prevent skin damage by reflecting or absorbing 
ultraviolet (UV) radiation and they are regulated as drug products in 
the United States (U.S.). Most active ingredients in sunscreens are 
organic chemicals and some have been shown to be absorbed 
through human skin with detectable levels in the blood or urine. As 
part of the safety evaluation for sunscreen products, the Food and 
Drug Administration (FDA) requests an assessment of systemic 
absorption in humans so that human blood levels can be compared 
with exposure levels obtained in nonclinical toxicology studies. If 
testing establishes that the sunscreen is not absorbed through the skin 
into the body, some aspects of toxicology testing may not be needed.
Sunscreen products may be applied multiple times daily as both 
primary sunscreen products and as ingredients in cosmetic products, 
in substantial amounts for a lifetime starting at 6 months of age. The 
amount of sunscreen ingredient in a product can vary, but permitted 
levels can be as high as 15% for some organic active ingredients and 
application to the skin can accumulate to gram quantities in a day 
even with modest use. Because of the significant use of these 
sunscreens, even a low percentage of systemic absorption (e.g., 
0.1%) could represent a significant systemic exposure in a single day 
and over a lifetime.
The Surgeon General’s Call to Action to Prevent Skin Cancer calls 
on partners in prevention from various sectors across the nation to 
address skin cancer as a major public health problem by increasing 
awareness of skin cancer and promoting actions to reduce its risk. 
Given the recognized public health benefits of sunscreen use, the 


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FDA is committed to finding ways to facilitate the marketing of 
sunscreen products that include additional over-the-counter (OTC) 
sunscreen active ingredients. The FDA will continue to work with 
industry and other public health agencies to ensure that the 
sunscreens consumers use are safe and effective for daily, life-long
use.
In November 2016, the U.S. FDA finalized the guidance titled 
“Guidance for Industry: Nonprescription Sunscreen Drug Products 
Safety and Effectiveness Data” (sunscreen guidance). The guidance 
requests an assessment of the human systemic absorption of
sunscreen ingredients with a Maximum Usage Trial (MUsT). The 
FDA sunscreen guidance notes that some nonclinical toxicity studies 
may be waived if results of an adequately conducted human 
pharmacokinetic (PK) MUsT show a steady-state blood level less 
than 0.5 ng/mL.
Periodically, the FDA performs testing of products and formulations 
that the Agency sees as important for public health. This testing is 
not a reflection of rulemaking or other regulatory actions, but instead 
is done independently to measure the agency’s understanding of the 
products’ overall safety and effectiveness.
This study is not intended to meet all requirements of MUsT studies 
as outlined in the FDA guidance referenced above, but will follow 
many of the principles.
Summary and 
Objectives:
Part 1 is an open-label, randomized, 4-arm study in 24 healthy adult 
subjects with the primary objective:
To explore whether the active components (avobenzone, 
oxybenzone, ecamsule and octocrylene) of 4 sunscreen products 
(1 sunscreen product in each arm) are absorbed into the systemic 
circulation when a sunscreen product is applied under 
maximal-use conditions. 
One sunscreen product with the highest avobenzone exposure will be 
selected for the second part of the study. If there is no quantifiable 
exposure of avobenzone for any of the sunscreen products, the 
formulation with the highest oxybenzone exposure will be selected 
for Part 2. In addition, 3 new sunscreen products are being included 
in Part 2.
Part 2 is an open-label, 4-arm study in 48 healthy adult subjects with 
the following primary objective:
To assess the systemic absorption and pharmacokinetics of the 
active components (avobenzone, oxybenzone, octocrylene,
ecamsule, homosalate, octisalate and octinoxate, where applicable
[Part 2 products will not contain ecamsule]) of 4 sunscreen 
products (1 sunscreen product in each arm) under maximal-use 
conditions.


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Study Design:
Part 1
Part 1 is an open-label, randomized, 4-arm pilot study to evaluate the 
effects of multiple applications of 4 different topical sunscreen 
formulations in healthy adult subjects. Each arm will include 
6 subjects (3 male and 3 female) with 1 formulation. A total of 
24 subjects (12 male and 12 female) from all 4 arms will be admitted 
to the clinical research unit (CRU) on Day 0. On the morning of 
Days 1 through 4, subjects will receive a topical application of the 
study drug at approximately 0900 hours. The study product will be 
weighed in advance and applied by a qualified person from the study 
team. Subjects will then receive 3 more topical applications on the 
same day at 2, 4, and 6 hours after the first dose.


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Part 2
Part 2 is an open-label, 4-arm study to evaluate the pharmacokinetics 
of avobenzone, oxybenzone, octocrylene, homosalate, octisalate and 
octinoxate (where applicable [Part 2 products will not contain 
ecamsule]) after multiple applications of a topical sunscreen 
formulation in healthy adult subjects. Part 2 will include 48 subjects 
(24 male and 24 female) and each arm will include 12 subjects (6 
male and 6 female). One of the formulations in Part 2 will be 
selected based on the plasma exposure data from the pilot study (Part 
1) along with 3 additional formulations. A total of 48 subjects (24
male and 24 female) will be admitted to the CRU on Day 0. On the 
morning of Days 1 through 4, subjects will receive a topical 
application of the study product at approximately 0900 hours. 
The study drug will be weighed in advance and applied by a 
qualified person from the study team. Subjects will only receive one 
application on Day 1. On Days 2, 3 and 4, subjects will receive an 
initial dose and 3 more topical applications on the same day at 2, 4, 
and 6 hours after the first dose.
Parts 1 and 2
In both parts, approximately 2 mg of active sunscreen ingredient per 
1 cm2 of body surface (calculation per method of Dubois) will be 
evenly applied 4 times per study day (except for a one-time 
application on the first day in part 2) to areas of the body typically 
exposed to the sun: face, ears, neck, torso, arms, and legs 
(approximately 75% of the body surface area). The antecubital areas 
will be avoided when applying the sunscreen due to potential 
contamination of the sites used for intravenous PK blood sample 
collection. The topical applications of study drug will be 
administered with subjects in swim wear to simulate real-world 
settings as well as for easy application. In addition to swim wear, 
subjects may wear scrubs in between applications and at other times 
throughout the day/night. Subjects are required to shower each 
morning after the first PK blood sample collection (and before the 
first dose of the day), but not at other times during the day.
Blood samples (approximately 10 mL per sample) will be collected 
for determination of plasma concentrations for all active ingredients
(avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, 
octisalate and octinoxate, where applicable).
Safety evaluations will include adverse event (AE) monitoring, vital 
sign measurements, and physical examinations. All AEs reported by 
the subject or observed by the investigator or clinical research unit 
(CRU) staff will be recorded. Any AE reported after the informed 
consent is signed and before study drug application will be recorded 
as medical history.
Subjects will remain in the CRU after admission on Day 0 until the 
morning of Day 7 following completion of scheduled End-of-Study
activities for part 1. For part 2, subjects will undergo the same 


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schedule but will return to the clinic for follow-up visits on Days 10, 
14 and 21. Subjects will then be discharged following completion of 
End-of-Study activities.
Subjects are not allowed to use products containing any of these 
active ingredients from 7 days before check-in until completion of 
End-of-Study procedures.
Inclusion Criteria:
Subjects who meet all of the following inclusion criteria will be 
eligible to participate in the study:
1.
Subject signs an IRB-approved written informed consent and 
privacy language as per national regulations (e.g., Health 
Insurance Portability and Accountability Act authorization) 
before any study-related procedures are performed.
2.
Subject is a healthy man or woman, 18 to 60 years of age, 
inclusive, who has a body mass index of 18.5 to 29.9 kg/m2,
inclusive, at Screening.
3.
Subject has normal medical history findings, clinical laboratory 
results, vital sign measurements, 12-lead electrocardiogram 
(ECG) results, and physical examination findings at Screening 
or, if abnormal, the abnormality is not considered clinically 
significant (as determined and documented by the investigator 
or designee).
4.
Subject must have a negative test result for alcohol and drugs of 
abuse at screening and Check-in (Day 0). 
5.
Subject has no known or suspected allergies or sensitivities to 
any components of the sunscreen formulation.
6.
Female subjects must be of nonchildbearing potential or, if they 
are of childbearing potential, they must: 1) have been strictly 
abstinent for 1 month before Check-in (Day 0) and agree to 
remain strictly abstinent for the duration of the study and for at 
least 1 month after the last application of study drug; OR 
2) be practicing 2 highly effective methods of birth control (as 
determined by the investigator or designee; one of the methods 
must be a barrier technique) from at least 1 month before 
Check-in (Day 0) until at least 1 month after the last application 
of study drug. 
7.
Female subjects must not be pregnant or lactating before 
enrollment in the study.
8.
Male subjects must agree to practice 2 highly effective methods 
of birth control (as determined by the investigator or designee; 
one of the methods must be a barrier technique) from at least 
1 month before Check-in (Day 0) until at least 1 month after the 
last application of study drug.
9.
Subject is highly likely (as determined by the investigator) to 
comply with the protocol-defined procedures and to complete 
the study.


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Note: subjects with any skin type or skin pigment type may be 
eligible for the study.
Exclusion Criteria:
Subjects who meet any of the following exclusion criteria will not be 
eligible to participate in the study:
1.
Subject has broken, irritated, or unhealed skin.
2.
Subject has an active sunburn.
3.
Subject has used a tanning bed in the previous 4 weeks.
4.
Subject has known skin or autoimmune disease(s).
5.
Subject is anemic or has any chronic condition(s) that may 
impact blood sample collection.
6.
Subject has any underlying disease or surgical or medical 
condition (e.g., cancer, human immunodeficiency virus [HIV], 
severe hepatic or renal impairment) that could put the subject at 
risk or would normally prevent participation in a clinical study.
7.
Subject has known or suspected allergies or sensitivities to any 
components of the sunscreen formulation.
8.
Subject has clinical laboratory test results (hematology and 
serum chemistry) at Screening that are outside the reference 
ranges provided by the clinical laboratory and considered 
clinically significant by the investigator.
9.
Subject has a positive test result at Screening for HIV 1 or 2
antibody, hepatitis C virus antibodies, or hepatitis B surface 
antigen.
10. Subject is unable or unwilling to undergo multiple 
venipunctures for blood sample collection because of poor 
tolerability or poor venous access.
11. Subject has received or applied the topical sunscreen 
formulations used in the current study, or any other product 
containing the active ingredients of the topical sunscreen 
formulations used in the current study, within 7 days before 
Check-in (Day 0).
12. Subject has used any personal care product(s) containing any 
active sunscreen ingredient, such sunscreen products, hand or 
body moisturizing lotion, makeup or foundation, lip balm, or 
lipstick, within 7 days before Check-in (Day 0).
13. Subject is unable or unwilling to tolerate the scent of sunscreen 
for the duration of the treatment period.
Study Drug, Dosage, 
and Route of 
Administration:
Part 1
La Roche Posay (Cream), Anthelios SX Daily Moisturizing
Cream with Sunscreen, SPF 15 with Mexoryl SX
Hawaiian Tropic (Lotion); Island Sport Ultra-Light High 
Performance Sunscreen, SPF 50
Neutrogena (Spray), Ultra Sheer Body Mist SPF 45


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Banana Boat (Spray); Sport Performance Coolzone Continuous 
Spray Sunscreen, SPF 50
Approximately 2 mg of sunscreen formulation per 1 cm2 of body 
surface will be applied topically 4 times per day for 4 days to 
approximately 75% of the body surface area.
Part 2
Hawaiian Tropic (Lotion); Island Sport Ultra-Light High 
Performance Sunscreen, SPF 50
Neutrogena (Aerosol Spray), Ultra Sheer Body Mist SPF 100
Supergoop (Non-Aerosol Spray), Sunscreen Mist with Vitamin C 
SPF 50
Supergoop (Pump Spray), Sun Defying Sunscreen Oil with 
Meadowfoam SPF 50
Approximately 2 mg of sunscreen formulation per 1 cm2 of body 
surface will be applied topically once on Day 1 and 4 times per day 
(over eight hours) on Days 2-4 to approximately 75% of the body 
surface area.
Reference Drug, 
Dosage, and Route of 
Administration:
Not applicable.


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Pharmacokinetic 
Assessments:
Pharmacokinetic blood samples (approximately 10 mL per sample) 
will be collected for determination of avobenzone, oxybenzone,
octocrylene, ecamsule, homosalate, octisalate and octinoxate plasma 
concentrations, where applicable to the different sunscreen 
formulations, at the following time points:
Day 1: 0 and 0.5, 1, 1.5, 2, 3 (Part 2 only), 4, 6, 8, 9, 10, 12, and 
14 hours after initial dose
Day 2: 23, 28, 33 h
Day 3: 47, 52, 57 h
Day 4: 71, 73, 74, 76, 78, 81, 82, 84 and 86 h
Day 5: 95 hours 
Day 6: 120 hours 
Day 7: 144 hours
Day 10: 216 hours (Part 2 only)
Day 14: 312 hours (Part 2 only)
Day 21: 480 hours (Part 2 only)
NOTE: when a time point corresponds with sunscreen 
administration, the PK sample will be collected before sunscreen 
administration.
The following PK parameters will be determined for each subject for 
each sunscreen active ingredient:
Across all study days
Maximum concentration (observed peak drug concentration) 
(Cmax)
Day 1
Maximum concentration (observed peak drug concentration) 
(Cmax)
Time at which Cmax occurs (Tmax)
AUC from time 0 to the sampling time corresponding to the last 
quantifiable concentration (Clast) (AUC0-t)
Days 2 and 3
Residual drug concentration (predose level) (Ctrough)
3 h post dose concentration
Day 4
Maximum concentration (observed peak drug concentration) 
(Cmax)
Time at which Cmax occurs (Tmax)
Elimination rate constant (Kel)
Terminal half-life (t1/2)


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AUC from time 0 to the sampling time corresponding to the last 
quantifiable concentration (Clast) (AUC0-t)
AUC from time 0 extrapolated to infinity (AUC0-inf)
Day 5, 6, 7, 10 (Part 2 only), 14 (Part 2 only) and 21 (Part 2 only)
Residual drug concentration (Ctrough)
Tape Stripping to Determine Residual Skin Concentration
In addition, skin tape stripping of the lower back (around 3.8 cm2
area) will be conducted once on Days 7 and 14 in part 2 to determine 
residual sunscreen active ingredients in the superficial layers of the 
skin. 
Safety Assessments:
Safety will be evaluated in terms of AEs, vital sign measurements 
(blood pressure, heart rate, respiratory rate, and oral body 
temperature), and physical examination findings.
Sample Size:
Approximately 72 healthy subjects are planned for enrollment, of 
which 24 subjects will be enrolled and randomized in Part 1 and 
48 subjects will be enrolled and randomized in Part 2. The sample 
size was determined empirically and is typical for exploratory 
investigations of this type.
Statistical Methods:
All data will be presented in data listings. Data from subjects 
excluded from an analysis population will be presented in the data 
listings but not included in the calculation of summary statistics. The 
number of subjects who enroll in the study and the number and 
percentage of subjects who complete each assessment will be 
presented. The frequency and percentage of subjects who withdraw 
or discontinue from the study and the reason for withdrawal or 
discontinuation will be summarized. Demographic and baseline 
characteristics will be summarized overall and by treatment for all 
subjects.
Descriptive statistics will be used to summarize demographic and 
baseline subject characteristics. For continuous variables, the mean, 
median, standard deviation (SD), minimum, and maximum values 
will be reported. For categorical (nominal) variables, the number and 
percentage of subjects (or observations) will be reported.
Pharmacokinetics: The PK population will include all subjects who 
receive study drug and have at least 1 estimable PK parameter after 
dosing. Plasma concentrations and PK parameters of avobenzone, 
oxybenzone, octocrylene, ecamsule, homosalate, octisalate and 
octinoxate, where applicable, will be listed and summarized using 
descriptive statistics (n, arithmetic mean, SD, minimum, median, and 
maximum) by nominal PK sampling time.
Safety: The safety population will include all subjects who receive at 
least 1 dose of any of the study drugs. Any AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). The 
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term, will be summarized with a focus on treatment-emergent AEs. 
Vital sign measurements will be summarized using descriptive 
statistics by time point. All values will be evaluated for clinically 
notable results. Data for additional safety parameters (e.g., physical 
examination findings) will be listed.
Date of Protocol:
13 December 2018


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2.
List of Abbreviations
Abbreviation
Definition
AE
adverse event
AUC
area under the concentration-time curve
AUC0-24
area under the concentration-time curve from time 0 
through 24 hours after dosing
AUC0-inf
area under the concentration-time curve from time 0 
extrapolated to infinity
AUC0-t
area under the concentration-time curve from time 0 to the 
sampling time corresponding to the last quantifiable 
concentration
CFR
Code of Federal Regulations
Clast
time corresponding to the last quantifiable concentration
Cmax
maximum concentration (observed peak drug 
concentration)
CRU
clinical research unit
Ctrough
residual drug concentration (predose level)
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HIV
IAA
human immunodeficiency virus
IRB Authorization Agreement
ICH
International Council for Harmonisation
IRB
institutional review board
IV
intravenous
Kel
elimination rate constant
MedDRA
Medical Dictionary for Regulatory Activities
MUsT
Maximum Usage Trial
OTC
over the counter
PK
pharmacokinetic
SAE
serious adverse event
SD
standard deviation
t1/2
terminal half-life
TEAE
treatment-emergent adverse event
Tmax
time at which Cmax occurs
UV
ultraviolet
U.S.
United States


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3.
Introduction
Sunscreens prevent skin damage by reflecting or absorbing ultraviolet (UV) radiation and 
they are regulated as drug products in the United States (U.S.). Most active ingredients in 
sunscreens are organic chemicals and some have been shown to be absorbed through 
human skin with detectable levels in the blood or urine. As part of the safety evaluation 
for sunscreen products, the Food and Drug Administration (FDA) requests an assessment 
of systemic absorption in humans so that human blood levels can be compared with 
exposure levels obtained in nonclinical toxicology studies. If testing establishes that the 
sunscreen is not absorbed through the skin into the body, some aspects of toxicology 
testing may not be needed.
Sunscreen products may be applied multiple times daily as both primary sunscreen 
products and as ingredients in cosmetic products, in substantial amounts for a lifetime 
starting at 6 months of age. The amount of sunscreen ingredient in a product can vary, but 
permitted levels can be as high as 15% for some organic active ingredients and 
application to the skin can accumulate to gram quantities in a day even with modest use. 
Because of the significant use of these sunscreens, even a low percentage of systemic
absorption (e.g., 0.1%) could represent a significant systemic exposure in a single day 
and over a lifetime.
The Surgeon General’s Call to Action to Prevent Skin Cancer calls on partners in 
prevention from various sectors across the nation to address skin cancer as a major public 
health problem by increasing awareness of skin cancer and promoting actions to reduce 
its risk. Given the recognized public health benefits of sunscreen use, the FDA is 
committed to finding ways to facilitate the marketing of sunscreen products that include 
additional over-the-counter (OTC) sunscreen active ingredients. The FDA will continue 
to work with industry and other public health agencies to ensure that the sunscreens 
consumers use are safe and effective for daily, life-long use.
In November 2016, the U.S. FDA finalized the guidance titled “Guidance for Industry: 
Nonprescription Sunscreen Drug Products Safety and Effectiveness Data” (sunscreen 
guidance) DHHS, 2016) [1]. The guidance requests an assessment of the human systemic 
absorption of sunscreen ingredients with a Maximum Usage Trial (MUsT). The FDA 
sunscreen guidance notes that some nonclinical toxicity studies may be waived if results 
of an adequately conducted human pharmacokinetic (PK) MUsT shows a steady-state 
blood level less than 0.5 ng/mL.
Periodically, the FDA performs testing of products and formulations that the Agency sees 
as important for public health. This testing is not a reflection of rulemaking or other 
regulatory actions, but instead is done independently to measure the agency’s 
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This study is not intended to meet all requirements of MUsT studies as outlined in the 
FDA guidance referenced above, but will follow many of the principles.
4.
Study Objectives
4.1.
Primary Objectives
4.1.1
Part 1
Part 1 is an open-label, randomized, 4-arm study in 24 healthy adult subjects with the 
primary objective:
To explore whether the active components (avobenzone, oxybenzone, ecamsule and 
octocrylene) of 4 sunscreen products (1 sunscreen product in each arm) are absorbed 
into the systemic circulation when sunscreen is applied under maximal-use 
conditions. 
One sunscreen product with the highest avobenzone exposure will be selected for the 
second part of the study. If there is no quantifiable exposure of avobenzone for any of the 
sunscreen products, the formulation with the highest oxybenzone exposure will be 
selected for Part 2.
4.1.2
Part 2
Part 2 is an open-label, 4-arm study in 48 healthy adult subjects with the following 
primary objective:
To assess, where applicable, the pharmacokinetics and systemic absorption of the 
active components (avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, 
octisalate and octinoxate) of 4 sunscreen products (1 sunscreen product in each 
arm) under maximal-use conditions.
5.
Investigational Plan
5.1.
Study Design
This will be a single clinical study conducted in 2 parts. The duration of study 
participation will be approximately 37 days for part 1, including a 30-day screening 
period, a 4-day treatment period (Days 1-4) and subjects leaving the clinic on the 
morning of Day 7 following completion of scheduled End-of-Study activities. For part 2, 
the duration of participation will be approximately 51 days, including a 30-day screening 
period, a 4-day treatment period (Days 1-4) and subjects leaving the clinic on the 
morning of Day 7. Subjects in part 2 will then return to the clinical for follow-up visits on 
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5.1.1
Part 1
Part 1 is an open-label, randomized, 4-arm pilot study to evaluate the effects of multiple 
applications of 4 different topical sunscreen formulations in healthy adult subjects. Each 
arm will include 6 subjects (3 male and 3 female) with 1 formulation. A total of 
24 subjects (12 male and 12 female) from all 4 arms will be admitted to the clinical 
research unit (CRU) on Day 0.
On the morning of Days 1 through 4, subjects will receive a topical application of the 
study product at approximately 0900 hours. The study drug will be weighed in advance 
and applied by a qualified person from the study team. Subjects will then receive 3 more 
topical applications on the same day at 2, 4, and 6 hours after the first dose.
5.1.2
Part 2
Part 2 is an open-label, 4-arm-study to evaluate the pharmacokinetics of avobenzone, 
oxybenzone, octocrylene, homosalate, octisalate and octinoxate (Part 2 products will not 
contain ecamsule) after multiple applications of a topical sunscreen formulation in 
healthy adult subjects. Part 2 will include 48 subjects (24 male and 24 female) and 12 
subjects in each arm (6 male and 6 female). One of the formulations in Part 2 will be 
selected based on the plasma exposure data from the pilot study (Part 1). In addition, 3
new formulations will be added.
On the morning of Days 1 through 4, subjects will receive a topical application of the 
study product at approximately 0900 hours. The study drug will be weighed in advance 
and applied by a qualified person from the study team. Subjects will only receive one 
application on Day 1. On Days 2, 3 and 4, subjects will receive an initial dose and 3 more 
topical applications on the same day at 2, 4, and 6 hours after the first dose.
5.1.3
Tape Stripping
For Part 2 only, skin tape stripping (6 consecutive strippings) of the lower back (area: 
around 3.8 cm2) will be conducted once on Days 7 and 14 to determine residual 
sunscreen active ingredients in the superficial layers of the skin. The intention of the 
stripping is to determine the concentration of sunscreen active ingredients in superficial 
layers to estimate the potential skin deposit and 6-8 strips will be required to remove 
most of the stratum corneum layer [2-3]. The number of strips is restricted to 6 to 
minimize any skin irritation or skin rash [2-3].


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5.1.4
Common Procedures
Details of study visits and study procedures are described in Section 5.6 and Section 5.7,
respectively, and the overall Schedule of Events for both parts of the study is presented in 
Section 10.1.
In both parts of the study, approximately 2 mg of sunscreen per 1 cm2 of body surface 
(calculation per method of Dubois) will be evenly applied 4 times per study day (except 
for a one-time application on the first day in part 2) to areas of the body typically exposed 
to the sun: face, ears, neck, torso, arms, and legs (approximately 75% of the body surface 
area). The antecubital areas will be avoided when applying the sunscreen due to potential 
contamination of the sites used for intravenous (IV) PK blood sample collection. The 
topical applications of the study drug will be administered with subjects in swim wear to 
simulate real world settings as well as for easy application. In addition to swim wear, 
subjects may wear scrubs in between applications and at other times throughout the 
day/night. Subjects are required to shower each morning after the first PK blood sample 
collection (and before the first sunscreen application for that day), but not at other times 
during the day. And, subjects should not use any personal care products which contain 
avobenzone, oxybenzone, ecamsule, octocrylene, homosalate, octisalate or octinoxate
during the study.
Blood samples (approximately 10 mL per sample) will be collected for determination of 
avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, octisalate and octinoxate 
(where applicable) plasma concentrations.
Safety evaluations will include adverse event (AE) monitoring, vital sign measurements, 
and physical examinations. All AEs reported by the subject or observed by the 
investigator or CRU staff will be recorded. Any AE reported after the informed consent is 
signed and before study drug application will be recorded as medical history.
Subjects will remain in the CRU after admission on Day 0 until discharge on the morning 
of Day 7. In Part 2, subjects will return to the clinic on Day 10, 14 and 21 for follow-up
PK sampling (Days 10, 14 and 21) and tape stripping (Days 14).
Subjects are not allowed to use products containing any of the active ingredients from 7
days before check-in until completion of End-of-Study procedures.
5.1.5
Risk/Benefit
Subjects will be informed that participation in a human PK study like the present one 
cannot be of benefit to healthy volunteers. Nevertheless, the information from the 
physical examination, vital sign measurements, and ECG results may be shared with the 
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it is also their choice to inform their personal physician that they are participating in this 
research study.
Subjects will be informed that their contribution to the study is of major importance to 
agencies like the U.S. FDA for helping this agency better evaluate the effects of human 
systemic absorption of sunscreen ingredients. However, since this is a study involving 
healthy volunteers, subjects will be informed that they have the alternative not to 
participate.
Subjects will be informed that they may be exposed to risks associated with the 
pharmacological properties of the study drugs and the study procedures.
The study sunscreen products will not be administered to anyone who is pregnant. All 
women must take a pregnancy test before receiving any study drug in this study. All men 
and all women of childbearing potential enrolled in this study will be informed that they 
must use 2 highly effective birth control methods (as determined by the investigator or 
designee; one of the methods must be a barrier technique) during the study and for at 
least 1 month after the last application of study drug. Subjects will be informed that they 
must notify the investigator if they or their female partners become pregnant during the 
course of the study.
Subjects will be informed that insertion of an IV catheter may be required for blood 
sample collection on Days 1 and 4 and, during insertion of the catheter, soreness, 
bruising, or infection at the insertion site are possible but unlikely. Subjects will also be 
informed that dizziness and lightheadedness may occur during direct venipuncture, 
insertion of the IV catheter, or during blood collection.
Subjects will be informed that tape stripping applied to the skin may cause mild pain or 
irritation and skin rash at the area of tape stripping after the procedure.
Subjects will be informed that they may eat only meals and snacks that are provided 
during periods of their stay in the study clinic, and that they must consume all of each 
meal that is served at a reasonable pace (within 25 minutes).
Subjects will be informed that the confidentiality of their data will be respected at all 
times according to state law, and the study personnel handling their study data are bound 
by confidentiality agreements.
Subjects will be informed that the study drug and all tests, procedures, and visits required 
by the study are provided at no cost to them. If subjects become ill or physically injured 
because of participation in this study, they will be informed that costs of treatment will 
not be covered by the sponsor.


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If a subject becomes pregnant, she will be informed that neither Spaulding Clinical 
Research nor the sponsor will be responsible for the cost of any obstetric or related care, 
or for the child’s care.
Subjects will be informed by the Investigator of significant new findings that may 
develop during the course of this research study that may relate to their willingness to 
continue participation in the study.
5.2.
Selection of Study Population
Subjects will be screened and the data collected will be reviewed by the principal 
investigator. Only those subjects who meet all of the eligibility criteria will be enrolled.
5.2.1
Inclusion Criteria
Subjects who meet all of the following inclusion criteria will be eligible to participate in 
the study:
1. Subject signs an institutional review board (IRB)-approved written informed consent 
and privacy language as per national regulations (e.g., Health Insurance Portability 
and Accountability Act authorization) before any study-related procedures are 
performed.
2. Subject is a healthy man or woman, 18 to 60 years of age, inclusive, who has a body 
mass index of 18.5 to 29.9 kg/m2, inclusive, at Screening.
3. Subject has normal medical history findings, clinical laboratory results, vital sign 
measurements, 12-lead electrocardiogram (ECG) results, and physical examination 
findings at Screening or, if abnormal, the abnormality is not considered clinically 
significant (as determined and documented by the investigator or designee).
4. Subject must have a negative test result for alcohol and drugs of abuse at screening 
and Check-in (Day 0)
5. Subject has no known or suspected allergies or sensitivities to any components of the 
sunscreen formulation.
6. Female subjects must be of nonchildbearing potential or, if they are of childbearing 
potential, they must: 1) have been strictly abstinent for 1 month before Check-in
(Day 0) and agree to remain strictly abstinent for the duration of the study and for at 
least 1 month after the last application of study drug; OR 2) be practicing 2 highly 
effective methods of birth control (as determined by the investigator or designee; one 
of the methods must be a barrier technique) from at least 1 month before Check-in
(Day 0) until at least 1 month after the last application of study drug. 
7. Female subjects must not be pregnant or lactating before enrollment in the study.


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8. Male subjects must agree to practice 2 highly effective methods of birth control (as 
determined by the investigator or designee; one of the methods must be a barrier 
technique) from at least 1 month before Check-in (Day 0) until at least 1 month after 
the last application of study drug.
9. Subject is highly likely (as determined by the investigator) to comply with the 
protocol-defined procedures and to complete the study.
Note: subjects with any skin type or skin pigment type may be eligible for the study.
5.2.2
Exclusion Criteria
Subjects who meet any of the following exclusion criteria will not be eligible to 
participate in the study:
1. Subject has broken, irritated, or unhealed skin.
2. Subject has an active sunburn.
3. Subject has used a tanning bed in the previous 4 weeks.
4. Subject has known skin or autoimmune disease(s).
5. Subject is anemic or has any chronic condition(s) that may impact blood sample 
collection.
6. Subject has any underlying disease or surgical or medical condition (e.g., cancer, 
human immunodeficiency virus [HIV], severe hepatic or renal impairment) that could 
put the subject at risk or would normally prevent participation in a clinical study.
7. Subject has known or suspected allergies or sensitivities to any components of the 
sunscreen formulation.
8. Subject has clinical laboratory test results (hematology and serum chemistry) at 
Screening that are outside the reference ranges provided by the clinical laboratory and 
considered clinically significant by the investigator.
9. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C 
virus antibodies, or hepatitis B surface antigen.
10. Subject is unable or unwilling to undergo multiple venipunctures for blood sample 
collection because of poor tolerability or poor venous access.
11. Subject has received or applied the topical sunscreen formulations used in the current 
study, or any other product containing the active ingredients of the topical sunscreen 
formulations used in the current study, within 7 days before Check-in (Day 0).


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12. Subject has used any personal care product(s) containing any active sunscreen 
ingredient, such sunscreen products, hand or body moisturizing lotion, makeup or 
foundation, lip balm, or lipstick, within 7 days before Check-in (Day 0).
13. Subject is unable or unwilling to tolerate the scent of sunscreen for the duration of the 
treatment period.
5.3.
Screening Failures
Subjects who sign and date the informed consent form but who fail to meet the inclusion 
and exclusion criteria are defined as screening failures. A screening log, which 
documents the subject initials and reason(s) for screening failure, will be maintained by 
the investigator for all screening failures. A copy of the log should be retained in the 
investigator’s study files.
If a subject fails the screening process because of an abnormal laboratory result, they can 
receive a copy of the results upon request. The investigator will determine if follow up 
for the abnormal laboratory result is needed, and will encourage the subject to follow up 
with his or her personal physician as appropriate. All subjects will be informed as to the 
reason(s) they are excluded from study participation, even if follow up is not required. If 
a subject fails the screening process because of a positive test result for human 
immunodeficiency virus or hepatitis, the positive result will be reported to local health 
authorities as required by law.
5.4.
Termination of Study or Investigational Site
5.4.1
Criteria for Termination of the Study
The study will be completed as planned unless one of the following criteria is satisfied 
that requires early termination of the study:
New information regarding the safety or efficacy of the study product(s) that indicates 
a change in the known risk profile for the study drug(s), such that the risk is no longer 
acceptable for subjects participating in the study.
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objective or compromises subject safety.
5.4.2
Criteria for Termination of Investigational Site
The study site may be terminated if the site (including the investigator) is found in 
significant violation of GCP, the protocol, the contractual agreement, or is unable to 
ensure adequate performance of the study.


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In the event that the sponsor elects to terminate the study or the investigational site, a 
study-specific procedure for early termination will be provided by the sponsor; the 
procedure will be followed by the applicable investigational site during the course of 
termination.
5.5.
Criteria for Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn by the investigator without the approval of the subject based on the 
investigator’s clinical judgment. A subject is not required to provide a written request to 
withdraw from the study; however, a written request is required if a subject withdraws 
consent for his or her personal data to be used for study-related purposes.
A subject may be discontinued for any of the following reasons:
AE: The subject has experienced an AE that, in the opinion of the investigator, 
requires early termination. The appropriate electronic case report form (eCRF) must 
be completed for each AE. If a subject is discontinued from the study due to an AE, 
the investigator is required to follow up with the subject until the event resolves or 
becomes stable. If a subject dies during the study, the cause of death must be reported 
as a serious AE (SAE), with an outcome of death noted in the eCRF.
Protocol Violation: The subject failed to meet protocol entry criteria or did not adhere 
to protocol requirements, and continued participation poses an unnecessary risk to the 
subject’s health.
Withdrawal by Subject: The subject (or other responsible individual [e.g., caregiver]) 
wishes to withdraw from the study in the absence of a medical need.
NOTE: Withdrawal due to an AE should not be recorded in the “voluntary 
withdrawal” category.
Study Terminated by Sponsor: The sponsor, IRB, FDA, or other regulatory agency 
terminates the study.
Pregnancy: The subject is found to be pregnant.
NOTE: If the subject is found to be pregnant, the subject must be withdrawn 
immediately. The pregnancy will be followed up to term, and the outcome, including 
any premature termination will be recorded. All live births must be followed for a 
minimum of 30 days or until the first well baby visit.
Other.


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NOTE: This category records withdrawals caused by an accidental or a medical 
emergency, unblinding, and other rare cases. The specific reason should be recorded 
in the comment space of the eCRF.
5.5.1
Handling of Withdrawals
The investigator may terminate a subject’s study participation at any time during the 
study when the subject meets the criteria described in Section 5.5. In addition, a subject 
may discontinue his or her participation without giving a reason at any time during the 
study. Subjects will be informed that their participation in the study is voluntary, that 
refusal to participate will involve no penalty or loss of benefits to which the subject is 
otherwise entitled, and that the subject may discontinue participation at any time without 
penalty or loss of benefits to which the subject is otherwise entitled.
Should a subject’s participation be discontinued, the primary reason for termination must 
be recorded. In addition, efforts should be made to perform all procedures scheduled for 
the early termination visit. Any data and samples collected before subject withdrawal will 
become the property of the sponsor.
5.5.2
Replacement Subjects
Approximately 72 healthy subjects are planned for enrollment, of which 24 subjects will 
be enrolled and randomized in Part 1 and 48 subjects will be enrolled and randomized in 
Part 2. Up to 18 subjects may be qualified as replacements. Thus, a maximum of 
90 subjects may be exposed to study drugs and procedures during the study.
5.6.
Study Visits
5.6.1
Recruitment
Recruitment materials (e.g., internet, radio, and print advertisements, social media posts) 
will be approved by the local IRB before telephone screening. The sponsor is responsible 
for registration of the study on clinicaltrials.gov; however, this may not occur until the 
IRB has approved the final study protocol.
5.6.1.1
Compensation
Subjects will be offered payment for Screening; however, if the results of their alcohol 
and drug screening tests are positive, they will not be compensated. Subjects who 
complete the entire study (Day 0 to Day 7 in Part 1 or Day 0 to Day 21 in Part 2) will 
receive payment according to the schedule provided in the informed consent form. No 
special incentives are offered. Final payment will not be released until all follow-up
procedures have been completed and accepted by the investigator.


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If a subject chooses to withdraw from the study prematurely, he or she will only be 
compensated for completed days. If subjects are withdrawn for medical reasons or if the 
study is halted temporarily or permanently, the subjects will receive compensation 
proportional to the time spent in the study. No compensation will be provided if a subject 
is dismissed from the study for noncompliance (e.g., improper conduct, ingesting alcohol 
and/or drugs [including recreational drugs], tampering with the study drug, consuming 
any prohibited foods or beverages).
If subjects are required to stay in the clinic for a longer period for safety reasons, they 
will be compensated at a rate proportional to the entire compensation for the study. If a 
subject becomes ill or physically injured because of participation in this study, the subject 
will be referred for treatment.
5.6.2
Screening
The following procedures and assessments will be performed at Screening (Day –30 to 
Day –1):
Obtain informed consent/HIPAA authorization (The informed consent process will be 
performed by a clinical research nurse in a private room. The subject will be given 
unlimited time to ask questions regarding study participation, and each subject will be 
questioned to ensure their understanding.)
After informed consent is obtained:
Review inclusion/exclusion criteria to confirm subject eligibility
Record demographic information
Measure height, weight, and calculate body mass index
Perform serology screening (hepatitis B surface antigen, hepatitis C virus antibodies, 
and HIV antibody 1/2 antigen/antibody combination test)
Record medical history, including social history and smoking habits
Perform drug and alcohol screening (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and 
methadone)
Perform a serum pregnancy test (female subjects only)
Record prior medications
Monitor for AEs
Perform clinical laboratory tests (hematology, serum chemistry, and urinalysis)


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Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature)
Perform a safety 12-lead ECG
Perform a complete physical examination
5.6.3
Study Periods
Part 1 and Part 2 of this study are open-label, randomized, 4-arm designs. Part 1 of the 
study has 1 treatment period and 3 follow-up days; subjects stay in the clinic for the full 
treatment and follow-up period. Part 2 of the study has 1 treatment period and 6 follow-
up days; subjects stay in the clinic for the full treatment period and the first 3 follow-up
days (total of 7 days) and will then return to the clinic for one-day visits on the 
subsequent 3 days of follow-up (Day 10, 14 and 21).
5.6.3.1
Check-in
The following procedures and assessments will be performed at Check-in (Day 0) as 
outlined in Appendix A: Schedule of Events:
Review inclusion/exclusion criteria to confirm subject eligibility
Perform drug and alcohol screening (amphetamines, barbiturates, benzodiazepines, 
cannabinoids, cocaine, alcohol, opiates, phencyclidine, propoxyphene, and 
methadone)
Perform a serum pregnancy test (female subjects only)
Perform Fitzpatrick skin type assessment
Admit subject to the study clinic
Randomization (after completion of check-in procedures on Day 0 or just before 
dosing on Day 1) 
Record concomitant medications
Monitor for AEs
5.6.3.2
Treatment
The following procedures and assessments will be performed during the treatment period
(Days 1 through 4) according to the Schedule of Events (Section 10.1):
Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature) before dosing
Collect PK blood sample (10 mL) before and after dosing (see Section 5.7)


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Application of topical sunscreen for Part 1 at approximately 0900 hours and again at 
2, 4, and 6 hours after the first dose. Application of topical sunscreen for Part 2 at 
approximately 0900 hours on Day 1 and again at approximately 0900 hours on Days 
2, 3 and 4 followed by an additional 3 applications at 2, 4, and 6 hours after the first 
dose on Days 2, 3 and 4.
Physical examination of skin at the sites of topical application for signs of irritation
Record concomitant medications
Monitor for AEs
5.6.3.3
Washout
Not applicable.
5.6.4
Discharge (or Early Termination)
The following procedures and assessments will be performed before the subject is 
discharged from the study or upon early termination:
Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature)
Physical examination of skin at the sites of topical application for signs of irritation
Record concomitant medications
Monitor for AEs
Discharge subject from the study clinic after completion of all study procedures
5.6.5
Follow-up
The following procedures and assessments will be performed on Days 10, 14 and 21 for 
Part 2:
Measure vital signs (blood pressure, heart rate, respiratory rate, and oral body 
temperature)
Collect PK blood samples (10 mL) after dosing as follows:
o Day 10: 216 hours after first dose on Day 1 (Part 2 only)
o Day 14: 312 hours after first dose on Day 1 (Part 2 only)
o Day 21: 480 hours after first dose on Day 1 (Part 2 only)
Physical examination of skin at the sites of topical application for signs of irritation
Symptom-directed brief physical examination at the investigator’s discretion


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Record concomitant medications
Monitor for AEs
5.7.
Study Procedures
5.7.1
Pharmacokinetic Assessments
5.7.1.1
Pharmacokinetic Sample Collection
Pharmacokinetic blood samples (approximately 10 mL per sample) will be collected for 
determination of avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, octisalate 
and octinoxate plasma concentrations (where applicable to the different sunscreen 
formulations) at the following time points (the time limit for PK sample draws can be +/-
5 minutes from the nominal time):
Day 1: 0 and 0.5, 1, 1.5, 2, 3 (Part 2 only), 4, 6, 8, 9, 10, 12, and 14 hours after initial 
dose
Day 2: 23, 28, 33 h 
Day 3: 47, 52, 57 h 
Day 4: 71, 73, 74, 76, 78, 81, 82, 84 and 86 h
Day 5: 95 hours 
Day 6: 120 hours 
Day 7: 144 hours
Day 10: 216 hours (Part 2 only)
Day 14: 312 hours (Part 2 only)
Day 21: 480 hours (Part 2 only)
NOTE: when a time point corresponds with sunscreen administration, the PK sample will 
be collected before sunscreen administration.
5.7.1.2
Tape Stripping Sample Collection
For Part 2 only, tape stripping of the lower back to an area of around 3.8 cm2 will be 
conducted once on Days 7 and 14 to determine residual sunscreen active ingredients in 
the superficial layers of the skin. Tape stripping will be applied to different areas of the 
lower back on Day 7 vs. Day 14 to prevent false sampling.
The area on the lower back for each subject will be marked with a skin marker. Before 
executing the tape stripping, hair on the marked area will be removed with the 3M 
trimmer (no razors as this would damage the skin and could lead to false sampling). A 
pre-weighed standard tape (Standard D-Squame ® adhesive tape) will be applied to a 
marked area under constant pressure of 225 g/cm2 for 5 seconds using a D-Squame ® 


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Pressure device. The tape will be removed swiftly and placed in a standard tape rack after 
weighing. Tape stripping will be performed 6 additional consecutive times in the same 
area with sampling intervals of 1 ± 0.5 minutes.
5.7.1.3
Pharmacokinetic Specimen Handling
The PK blood samples (10 mL each) will be collected into tubes containing K2EDTA, 
inverted several times to mix the blood with the anticoagulant, and placed in an ice bath. 
Within 30 minutes of collection, the samples will be centrifuged for 10 minutes, at 
3000 revolutions per minute, at 4°C, by a study team member.
The plasma will be separated using a disposable plastic pipette and approximately half of 
the plasma will be transferred into duplicate cryotube vials labeled as Aliquot A 
(primary) and Aliquot B (backup). The plasma samples will be appropriately labeled and 
stored frozen at –70°C or below until shipment. Temperature monitoring logs should be 
maintained and accessible for review by the study monitor.
The Aliquot A samples (primary) will be shipped first, on dry ice, to the bioanalytical 
laboratory at FDA for processing when requested by the sponsor. The Aliquot B samples 
(backup) will be held for a second shipment at a time after the completion of all Aliquot 
A sample shipment(s) and the timing of the Aliquot B shipment communicated by the 
sponsor. None of the PK blood samples will be stored at clinical facility for future use,
however the sponsor will store them for analytical purposes of this study only.
The tape strips will be transferred to pre-labeled D Squame ® standard storage cards and
stored frozen at –70°C or below until shipment.
Both plasma and skin concentrations of avobenzone, oxybenzone, ecamsule, octocrylene,
homosalate, octisalate and octinoxate (where applicable) will be assayed using a 
validated liquid chromatography with tandem mass spectrometry method.
5.7.1.4
Pharmacokinetic Parameters
The following PK parameters will be determined for each subject for each active 
ingredient:
Across all study days (Primary Endpoint)
Maximum concentration (observed peak drug concentration) (Cmax)
Days 1
Maximum concentration (observed peak drug concentration) (Cmax)
Time at which Cmax occurs (Tmax)


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AUC from time 0 to the sampling time corresponding to the last quantifiable 
concentration (Clast) (AUC0-t), calculated by the mixed linear logarithmic trapezoidal 
method
Days 2 and 3
Residual drug concentration (predose level) (Ctrough)
3 h post dose concentration
Day 4
Elimination rate constant (Kel), obtained by linear regression of the log-linear 
terminal phase of the concentration-time profile using at least 3 data points, excluding 
Cmax, otherwise Kel will not be determined. The acceptability criteria for 
determination of Kel will be a coefficient of regression more than or equal to 0.98. 
When Kel will not be determined, AUC0-inf and t1/2 will not be reported.
Terminal half-life (t1/2), calculated using the equation ln2/k after the last study drug 
application (on Day 4)
Accumulation ratios, calculated using the following formula:
R1 = AUC0-23 Day 4 / AUC0-23 Day 1
AUC from time 0 extrapolated to infinity (AUC0-inf), calculated by the mixed 
linear-logarithmic trapezoidal method as:
AUC0-inf = AUC0-t + Clast / Kel
When the extrapolation represents more than 20%, AUC0-inf and t1/2 will not be 
reported.
Days 5, 6, 7, 10 (Part 2 only), 14 (Part 2 only) and 21 (Part 2 only)
Residual drug concentration (Ctrough)
5.7.2
Safety Assessments
Safety will be evaluated in terms of AEs, vital sign measurements (blood pressure, heart 
rate, respiratory rate, and oral body temperature), and physical examination findings.
5.7.2.1
Adverse Events
5.7.2.1.1 Adverse Event Definitions
An AE is defined as any untoward and/or unintended sign, including an abnormal clinical 
laboratory finding, symptom, or disease temporally associated with the use of a study 
drug, whether or not considered related to the study drug. Events or conditions that 


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increase in frequency or severity during or as a consequence of use of a drug in human 
clinical trials will also be considered AEs.
A treatment-emergent adverse event (TEAE) is defined as an AE that begins after study 
drug administration.
An unexpected AE is any AE having a specificity or severity not consistent with the 
current investigator’s brochure for the study drug(s).
An SAE is defined as any AE occurring at any dose that meets the following criteria:
Results in death,
Is life threatening,
Requires hospitalization or prolongation of existing hospitalization,
Results in persistent or significant disability or incapacity,
Is a congenital anomaly/birth defect, or
Is an important medical event that may not meet the previous criteria but, based upon 
appropriate medical judgment, jeopardizes the subject or requires medical or surgical 
intervention to prevent one of the outcomes listed previously.
5.7.2.1.2 Adverse Event Reporting
The recording of AEs will begin after the subject signs the informed consent form and 
will continue until discharge (or early termination). All AEs, whether serious or 
nonserious and whether or not related to the study drug, must be recorded in the eCRF. 
Study subjects will be instructed to warn study staff if he or she has any unexpected 
symptoms. In addition, all subjects will receive a reminder telephone call approximately 
24 hours before Check-in.
Any SAE (whether expected or unexpected) must be entered into the eCRF system and 
reported by facsimile to the medical monitor or designee using the SAE Reporting Form 
within 24 hours of the investigator or study clinic staff becoming aware of the event. It is 
the responsibility of the investigator to report all SAEs to the medical monitor, to provide 
the most complete report possible, and to assess each SAE for its relationship to the study 
drug. The investigator is responsible for obtaining follow-up information on all SAEs and 
submitting follow-up SAE data. Any unexpected SAEs must be reported promptly to the 
investigator’s IRB as per the IRB’s requirements.
In the event of a fatal or life-threatening SAE, the sponsor will notify the appropriate 
FDA authorities by telephone or facsimile within 7 calendar days of receipt of the report. 
The sponsor will follow all 7-day alert reports with a written report within 10 working 
days of receipt of the case. Serious AE cases that concern nonfatal, nonlife-threatening 


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events that are unexpected and at least possibly related to the study drug will be 
submitted in writing to the FDA within 10 working days of receipt.
Furthermore, any AEs that are not expected, occur at a higher frequency, or would 
require modification of the study protocol and/or informed consent must be reported to 
the FDA within 10 working days.
Adverse events that are assessed by the investigator as possibly or probably related to the 
study drug will be followed until they resolve or stabilize. All SAEs will be followed 
until resolution.
5.7.2.1.3 Assessment of Severity
The investigator will assess the severity of each AE using the following scale:
Mild: The subject is aware of the AE but is still able to perform all activities; minimal 
or no medical intervention or therapy is required.
Moderate: The subject has to discontinue some activities due to the AE; minimal or 
no medical intervention or therapy is required.
Severe: The subject is incapacitated by the AE and is unable to perform normal 
activities; significant medical intervention or therapy is required and hospitalization is 
possible.
5.7.2.1.4 Assessment of Causality
The investigator will assess the causal relationship/relatedness of each AE to the study 
drug using the following scale:
Not Related: Onset of the AE has no reasonable temporal relationship to 
administration of the study drug, a causal relationship to administration of the study 
drug is biologically implausible, or the event is attributed to an alternative etiology.
Unlikely Related: Onset of the AE has a reasonable temporal relationship to study 
drug administration and although a causal relationship is unlikely, it is biologically 
plausible.
Possibly Related: Onset of the AE has a strong temporal relationship to 
administration of the study drug, cannot be explained by the subject’s clinical state or 
other factors, and a causal relationship is biologically plausible.
Probably Related: Onset of the AE shows a distinct temporal relationship to 
administration of the study drug that cannot be explained by the subject’s clinical 
state or other factors, the AE is a known reaction to the product or chemical group, or 
can be predicted by the product’s pharmacology.


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5.7.2.1.5 Pregnancy
A serum pregnancy test will be performed for female subjects at the time points presented 
in the Schedule of Events (Section 10.1). If a subject becomes pregnant while on the 
study, this should be reported immediately to the investigator, the subject will be 
withdrawn from the study and the medical monitor and the subject will be instructed to 
follow-up with his or her personal physician. All pregnancies are to be reported as an AE 
and followed for outcome.
5.7.2.2
Clinical Laboratory Tests
Clinical laboratory and diagnostic screening tests will be performed at the time points 
presented in the Schedule of Events (Section 10.1) and will be collected in accordance 
with acceptable laboratory procedures. Clinical laboratory testing will be performed by 
Spaulding Clinical Laboratory, West Bend, Wisconsin, and Laboratory Corporation of 
America (LabCorp), Dublin, Ohio. The clinical laboratory tests that will be performed are 
presented in Table 5-1. Unused clinical laboratory test samples will not be stored for 
future use.
Clinical laboratory results will be reviewed by the investigator or designee together with 
data in the eCRF. Any values outside the reference range will be evaluated for clinical 
significance. If a value is determined to be clinically significant, the subject will be 
instructed to follow-up with his or her personal physician. The investigator or designee 
may repeat the clinical laboratory tests if deemed appropriate. The investigator will 
maintain a copy of the laboratory accreditation and the reference ranges for the laboratory 
used.


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Table 5-1
Clinical Laboratory and Diagnostic Screening Tests
Hematology
Serum Chemistry
Urinalysis
Complete blood count
Hematocrit
Hemoglobin
Platelet count
Red blood cell count 
White blood cell count 
(with automated differential)
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bicarbonate
Blood urea nitrogen 
Calcium
Chloride
Direct bilirubin
Glucose
Lactic dehydrogenase
Magnesium
Phosphorus
Potassium
Serum creatinine
Sodium
Total bilirubin
Total protein
Uric acid
Appearance
Bilirubin
Color
Glucose
Ketones
Leukocyte esterase
Microscopic examination: red 
blood cells; white blood cells; 
epithelial cells; bacteria, crystals, 
casts, etc. (if present)
Nitrite
Occult blood
pH
Protein
Specific gravity
Urobilinogen
Diagnostic Screening Tests:
Serum
Urine
Hepatitis panel (hepatitis B surface antigen and 
hepatitis C virus antibody) and human 
immunodeficiency virus antibody 1/2 
antigen/antibody combination test
Drug screen including: amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, ethanol, 
opiates, phencyclidine, propoxyphene, and 
methadone
Serum human chorionic gonadotropin pregnancy 
test for all female subjects
5.7.2.3
Vital Sign Measurements
Vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) will be 
measured using an automated device at the time points presented in the Schedule of 
Events (Section 10.1). The subject should be in a supine position, if possible, for a 
minimum of 5 minutes before vital signs are measured.
5.7.2.4
Safety 12-Lead Electrocardiograms
Safety 12-lead ECGs will be performed at the time points presented in the Schedule of 
Events (Section 10.1). The subject should be in a supine position, if possible, for 
approximately 10 minutes before safety 12-lead ECGs are measured. The safety 12-lead 
ECGs will be reviewed by the investigator at the study clinic to detect any immediate 
safety concerns.


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5.7.2.5
Physical Examinations
Physical examinations will be performed at the time points presented in the Schedule of 
Events (Section 10.1).
The complete physical examination at Screening will include, but not be limited to, 
assessments of the head, eyes, ears, nose, throat, skin, thyroid, nervous system, 
respiratory system, cardiovascular system, abdomen (liver and spleen), lymph nodes, and 
extremities. Height, weight (without shoes and wearing the lightest possible clothing), 
and calculation of body mass index (kg/m2) will be performed at Screening only.
During the study, skin at the sites of topical application of the study drug will be 
examined for signs of irritation during the treatment period, upon discharge (or early 
termination), and at the follow-up visits. At the follow-up visits, a symptom-directed 
brief physical examination may be performed at the investigator’s discretion
If an abnormality is observed upon physical examination, the subject will be instructed to 
follow up with his or her personal physician.
5.7.3
Demographics and Medical History
Demographic data (date of birth, gender, race, and ethnicity) will be collected at 
Screening.
Each subject will provide a complete medical history at Screening that will be reviewed 
at Check-in. Specific information relating to any prior or existing medical 
conditions/surgical procedures will be recorded in the subject’s eCRF.
5.8.
Study Treatments
5.8.1
Treatments Administered
Part 1
La Roche Posay (Cream), Anthelios SX Daily Moisturizer Cream, Face Sunscreen 
SPF 15 with Mexoryl SX
Hawaiian Tropic (Lotion); Island Sport Ultra-Light High Performance Sunscreen, 
SPF 50
Neutrogena (Spray), Ultra Sheer Body Mist SPF 45
Banana Boat (Spray); Sport Performance Coolzone Continuous Spray Sunscreen, 
SPF 50
Approximately 2 mg of sunscreen formulation per 1 cm2 of body surface will be applied 
topically 4 times per day for 4 days to approximately 75% of the body surface area.


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Part 2
Hawaiian Tropic (Lotion); Island Sport Ultra-Light High Performance Sunscreen, SPF 
50
Neutrogena (Aerosol Spray), Ultra Sheer Body Mist SPF 100
Supergoop (Non-Aerosol Spray), Sunscreen Mist with Vitamin C SPF 50
Supergoop (Pump Spray), Sun Defying Sunscreen Oil with Meadowfoam SPF 50
Approximately 2 mg of sunscreen formulation per 1 cm2 of body surface will be applied 
topically once on Day 1 and 4 times per day on Days 2-4 to approximately 75% of the 
body surface area.
The antecubital areas will be avoided when applying the sunscreen due to potential 
contamination of the sites used for IV PK blood sample collection.
5.8.2
Method Assigning Subjects to Treatment
5.8.2.1
Randomization Process
Part 1 and Part 2
The FDA project biostatistician will create the specifications that will be used to generate 
the randomization schedule. The specifications will be based on the protocol 
requirements and appropriate statistical programming with consideration for study 
design, number of treatments, number of subjects planned for enrollment, stratification, 
and blocking.
Based on these specifications, the project biostatistician (or designee) will generate a 
dummy randomization schedule. The schedule is generated by a SAS®/ R or other
program, which produces output file(s) and/or SAS or R dataset(s).
The project biostatistician (or designee) distributes the ‘dummy’ randomization schedule 
to specified personnel for review. Any change (e.g., change in block size, change in 
stratification levels) that requires an update to the specifications will reset this process. 
Minor changes (e.g., display formatting) will not require a change to the specifications.
No transfer is necessary if the unblinded randomization biostatistician also created the 
‘dummy’ randomization.
The randomization biostatistician is responsible for generating the final randomization 
schedule. 
Randomization will occur after informed consent is obtained, either after completion of 
check-in procedures on Day 0 or just before dosing on Day 1. Unique subject numbers 
will be used in sequential order based on each subject’s order of qualification. 


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In both Part 1 and Part 2 of the study, subjects will be randomly assigned to 1 of 4
different treatments, thus each subject will receive one of the sunscreen formulations by 
the end of the study. For subjects in Part 1: 1) La Roche Posay (Cream), Anthelios SX 
Daily Moisturizer Cream, Face Sunscreen SPF 15 with Mexoryl SX; 2) Hawaiian Tropic 
(Lotion); Island Sport Ultra-Light High Performance Sunscreen, SPF 50; 3) Neutrogena
(Spray) Ultra Sheer Body Mist SPF 45; or 4) Banana Boat (Spray); Sport Performance 
Coolzone Continuous Spray Sunscreen, SPF 50. For subjects in Part 2: 1) Hawaiian 
Tropic (Lotion); Island Sport Ultra-Light High Performance Sunscreen, SPF 50 ; 2) 
Neutrogena (Aerosol Spray), Ultra Sheer Body Mist SPF 100; 3) Supergoop (Non-
Aerosol Spray), Sunscreen Mist with Vitamin C SPF 50 ; or 4) Supergoop (Pump Spray), 
Sun Defying Sunscreen Oil with Meadowfoam SPF 50.
Replacement subjects (if needed) will be assigned to the treatment group of the subject 
they are replacing.
The treatment groups are presented in Table 5-2.
Table 5-2
Treatment Groups
Study Part
Subjects (n)
Treatment 
Group
Treatment
1
6
A
La Roche Posay (Cream), Anthelios SX Daily 
Moisturizer Cream, Face Sunscreen SPF 15 
with Mexoryl SX
1
6
B
Hawaiian Tropic (Lotion); Island Sport Ultra-
Light High Performance Sunscreen, SPF 50
1
6
C
Neutrogena (Spray) Ultra Sheer Body Mist 
SPF 45 
1
6
D
Banana Boat (Spray); Sport Performance 
Coolzone Continuous Spray Sunscreen, SPF 50
2
12
E
Hawaiian Tropic (Lotion); Island Sport Ultra-
Light High Performance Sunscreen, SPF 50
2
12
F
Neutrogena (Aerosol Spray), Ultra Sheer Body 
Mist SPF 100
2
12
G
Supergoop (Non-Aerosol Spray), Sunscreen 
Mist with Vitamin C SPF 50
2
12
H
Supergoop (Pump Spray), Sun Defying 
Sunscreen Oil with Meadowfoam SPF 50
All randomization information will be secured and housed in a locked storage area, 
accessible only by the randomization personnel and the assigned pharmacist and his or 
her verifier.
5.8.3
Identity of Study Drug


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The topical sunscreen formulations described in Section 5.8.1 are commercially available 
OTC products containing the active components avobenzone, oxybenzone, octocrylene, 
ecamsule, homosalate, octisalate and octinoxate, where applicable.
5.8.4
Management of Clinical Supplies
5.8.4.1
Study Drug Packaging and Storage
The topical sunscreen formulations will be obtained from commercial sources and stored 
according to the manufacturer’s directions.
5.8.4.2
Study Drug Accountability
Good clinical documentation practices will be employed to record the receipt, storage 
conditions, accountability, and use or return of the study drug. The study drug will be 
stored in a secure location with access to the study personnel who will be managing the 
storage, dispensing, and accountability of the study drug.
Upon completion or termination of the study, final accountability review by the study 
monitor, and written authorization from the sponsor, all unused and/or partially used 
study drug should be returned or destroyed at the study clinic. It is the investigator’s 
responsibility to ensure that the sponsor has provided written authorization for study drug 
disposal, the disposal process follows the study clinic’s standard operating procedures, 
and appropriate records of the disposal are documented and maintained. No unused study 
drug may be disposed until fully accounted for by the study monitor (or designee). 
Documentation of unused study drug should include subject number, medication identity 
(medication #, period #), date, and quantity of study drug used.
5.8.5
Blinding
Both parts of this study are open-label; therefore, blinding is not applicable.
5.8.6
Treatment Compliance
At Screening, as part of the eligibility assessment, it will be confirmed that subjects can
comply with the protocol-defined procedure of topical study drug application. All 
applications of the study drug will be administered in the study clinic either under direct 
observation of or administered by clinic personnel, and recorded in the eCRF.
5.8.7
Prior and Concomitant Medications
Subjects are prohibited from having received or applied the topical sunscreen 
formulations used in the current study within 7 days before Check-in (Day 0). Subjects
are also prohibited from having used any personal care product(s) containing any active


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sunscreen ingredient, such sunscreen products, hand or body moisturizing lotion, makeup 
or foundation, lip balm, or lipstick, within 7 days before Check-in (Day 0).
Subjects will be instructed not to take any medications, including OTC products, without 
first consulting with the investigator.
5.8.8
Subject Restrictions
At Screening, as part of the eligibility assessment, it will be confirmed that subjects have 
not used a tanning bed in the previous 4 weeks before the study. As part of the medical 
history assessment at Screening, subjects will be asked about their smoking history. 
Subject responses will be recorded on the eCRF.
Subjects must be willing to comply with study rules throughout the duration of the study.
5.9.
Statistical Methods
5.9.1
Sample Size
Approximately 72 healthy subjects are planned for enrollment, of which 24 subjects will 
be enrolled and randomized in Part 1 and 48 subjects will be enrolled and randomized in 
Part 2. The sample size was determined empirically and is typical for exploratory 
investigations of this type.
5.9.2
Analysis Populations
The PK population will include all subjects who receive study drug and have at least 
1 estimable PK parameter after dosing.
The safety population will include all subjects who receive at least 1 dose of any of the 
study drugs.
5.9.3
General Statistical Considerations
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings but not included in the calculation of 
summary statistics.
5.9.4
Subject Disposition
The number of subjects who enroll in the study and the number and percentage of 
subjects who complete each assessment will be presented. The frequency and percentage 
of subjects who withdraw or discontinue from the study and the reason for withdrawal or 
discontinuation will be summarized.


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5.9.5
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized overall and by treatment 
for all subjects.
5.9.6
Pharmacokinetic Analyses
Plasma concentrations and PK parameters of avobenzone, oxybenzone, octocrylene, 
ecamsule, homosalate, octisalate and octinoxate (where applicable) will be listed and
summarized using descriptive statistics (n, arithmetic mean, SD, minimum, median, and 
maximum) by nominal PK sampling time.
5.9.7
Safety Analyses
5.9.7.1
Adverse Events
Any AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of AEs, organized by system organ class and 
frequency, will be summarized by seriousness, severity, relationship to treatment, and by 
treatment, with a focus on TEAEs. A detailed listing of serious AEs and TEAEs leading 
to withdrawal will also be provided.
5.9.7.2
Clinical Laboratory Tests
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be 
summarized using descriptive statistics (number of subjects, mean, SD, minimum, 
median, and maximum). Clinical laboratory results will be classified as normal or 
abnormal, according to the reference ranges of the individual parameter. The number and 
percentage of subjects with abnormal laboratory results will be provided. No statistical 
testing will be performed on clinical laboratory data.
5.9.7.3
Vital Sign Measurements
Vital sign measurements and changes from Baseline will be summarized using 
descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum) 
by treatment and time point.
5.9.7.4
Safety 12-Lead Electrocardiograms
Safety 12-lead ECG data will be summarized using descriptive statistics (number of 
subjects, mean, SD, minimum, median, and maximum).
5.9.7.5
Physical Examinations


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Physical examination findings will be presented in a data listing, and abnormal physical 
examination findings will be recorded as AEs.
5.9.7.6
Other Safety Data
All concomitant medication usage and medications that changed in daily dose, frequency, 
or both since the subject provided informed consent will be summarized for each subject.
5.9.8
Interim Analyses
No interim analyses are planned.
5.9.9
Missing Data
Missing data will not be imputed. Data that are excluded from the descriptive or 
inferential analyses will be included in the subject data listings. This will include data 
from subjects not in the particular analysis population, measurements from unscheduled 
visits, or extra measurements that may arise from 2 or more analyses of a plasma sample 
at the same time point.
5.10.
Data Quality Assurance
Completed eCRFs are required for each subject randomly assigned to study drug.
Electronic data entry will be accomplished through the ClinSpark® remote electronic data 
capture system, which allows for on-site data entry and data management. This system 
provides immediate, direct data transfer to the database, as well as immediate detection of 
discrepancies, enabling site coordinators to resolve and manage discrepancies in a timely 
manner. Each person involved with the study will have an individual identification code 
and password that allows for record traceability. Thus, the system, and subsequently any 
investigative reviews, can identify coordinators, investigators, and individuals who have 
entered or modified records.
Furthermore, the investigator retains full responsibility for the accuracy and authenticity 
of all data entered into the electronic data capture system. The completed dataset and 
their associated files are the sole property of the sponsor and should not be made 
available in any form to third parties, except for appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
6.
Ethical Considerations
6.1.
Ethical Conduct of the Study
This study will be performed in accordance with the recommendations guiding 
physicians in biomedical research involving human subjects adopted by the 18th World 
Medical Association General Assembly, Helsinki, Finland, 1964 and later revisions, as 


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well as, United States Title 45 Code of Federal Regulations (CFR) Part 46 GCP, and 
International Council for Harmonisation (ICH) guidelines describing technical 
requirements for registration of pharmaceuticals for human use.
7.
Institutional Review Board (IRB)
The investigator will provide the local IRB with all required documents, including the 
study protocol and informed consent form and recruitment materials. The study will not 
be initiated until appropriate IRB approval is obtained. The subjects will be informed that 
they have the right to contact the local IRB or Office for Human Research Protections if 
they have any questions, concerns, complaints, or believe they have been harmed by the 
participation in this research study as a result of investigator negligence. Subjects will be 
given the address and phone number of the local IRB.
8.
Administrative Procedures
8.1.
Responsibilities of the Investigator
The following administrative items are meant to guide the investigator in the conduct of 
the study but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes may be 
reported to the IRB but will not result in protocol amendments.
8.1.1
Form FDA 1572
The investigator will complete and sign the Form FDA 1572.
8.1.2
Adherence to Protocol
The investigator agrees to conduct the study as outlined in this protocol in accordance 
with the ICH E6(R1) and all applicable guidelines and regulations.
8.1.3
Reporting Requirements
By participating in this study, the investigator agrees to submit reports of SAEs according 
to the time line and method outlined in the protocol (Section 5.7.2.1.2). In addition, the 
investigator agrees to submit reports to the IRB as appropriate. The investigator also 
agrees to provide the sponsor with an adequate report shortly after completion of the 
investigator’s participation in the study.
8.1.4
Source Documentation
By participating in this study, the investigator agrees to maintain adequate case histories 
for the subjects treated as part of the research under this protocol. The investigator agrees 
to maintain accurate eCRFs and source documentation as part of the case histories.


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8.1.5
Retention of Records
The investigator agrees to keep the records stipulated in this protocol and those 
documents that include (but are not limited to) the study-specific documents, 
identification log of all participating subjects, medical records, source worksheets, all 
original signed and dated informed consent forms, subject authorization forms regarding 
the use of personal health information (if separate from the informed consent form), 
copies of all eCRFs, query responses, and detailed records of drug disposition, to enable 
evaluations or audits from regulatory authorities, the sponsor, or its designees.
Furthermore, ICH 4.9.5 requires the investigator to retain essential documents specified 
in ICH E6(R1) (Section 8) until at least 2 years after the last approval of a marketing 
application for a specified drug indication being investigated or, if an application is not 
approved, until at least 2 years after the investigation is discontinued and regulatory 
authorities are notified. In addition, ICH 4.9.5 states that the study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the clinical study site agreement between the investigator and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor 
before disposing of any such documents.
8.1.6
Financial Disclosure and Obligations
The investigator is required to provide financial disclosure information to allow the 
sponsor to submit the complete and accurate certification or disclosure statements 
required under 45 CFR 45. In addition, the investigator must provide to the sponsor a 
commitment to update this information promptly if any relevant changes occur during the 
course of the investigation and for 1 year after the completion of the study.
Neither the sponsor nor the study clinic is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process.
8.2.
Confidentiality and Disclosure of Data
All subjects will sign a HIPAA-compliant authorization form containing the mandated 
core elements and requirements before participation in this clinical study. The sponsor 
and designees affirm and uphold the principle of the subject’s right to protection against 
invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s electronic data capture system database or documentation via a unique 
identification number. As permitted by all applicable laws and regulations, limited 
subject attributes such as gender, age or date of birth, and subject initials may be used to 
verify the subject and accuracy of the subject’s unique identification number.


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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires that the investigator allow review of the subject’s original medical 
records (source data or documents) by the study monitor, representatives from any 
regulatory authority (e.g., FDA), the sponsor’s designated auditors, and the appropriate 
IRB. These medical records will include, but will not be limited to, clinical laboratory 
test result reports, ECG reports, admission and discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports. Access 
to a subject’s original medical records requires the specific authorization of the subject as 
part of the informed consent process.
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (i.e., subject name, address, and other 
identifier fields not collected in the subject’s eCRF).
Data will be maintained and backed up in the electronic data capture system. All access 
to the data is protected by username and password, and each staff member and all sponsor 
staff will have separate access that requires a separate username and password. Access is 
only given to site staff and requested sponsor staff who have completed the appropriate 
training.
8.3.
Certificate of Confidentiality
In order to protect the privacy of subjects, Certificates of Confidentiality will be obtained 
prior to the initiation of the study.
8.4.
Subject Consent
Written informed consent in compliance with 45 CFR 46 will be obtained from each 
subject before entering the study or performing any unusual or nonroutine procedure that 
involves risk to the subject. An informed consent template may be provided by the 
sponsor to the study clinic. If any institution-specific modifications to study-related 
procedures are proposed or made by the study clinic, the consent should be reviewed by 
the sponsor or its designee or both before IRB submission. Once reviewed, the consent 
will be submitted by the investigator to the IRB for review and approval before the start 
of the study. If the informed consent form is revised during the course of the study, all 
active participating subjects must sign the revised form.
Before enrollment, each prospective subject will be given a full explanation of the study 
and be allowed to read the approved informed consent form. The informed consent 
process will be performed by a clinical research nurse in a private room. The subject will 
be given unlimited time to ask questions regarding study participation, and each subject 
will be questioned to ensure their understanding. Once the investigator is assured that the 


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subject understands the implications of participating in the study, the subject will be 
asked to give consent to participate in the study by signing the informed consent form.
The investigator will provide a copy of the signed informed consent form to the subject. 
The original form will be maintained in the subject’s medical records at the site.
8.5.
Data Collection
Full details of procedures for data collection and handling will be documented in the data 
management plan, which is initiated with the final protocol receipt. The data management 
plan is a changing document that evolves over the course of the study and is finalized by 
database lock.
8.6.
Publications
No information related to or generated by this study will be released to the public until it 
has been reviewed by the sponsor. The sponsor shall own intellectual rights for the data 
and analysis resulting from this study and results cannot be presented or published 
without written permission from the sponsor. Authorship on publications will be 
determined by standard journal requirements.
9.
Study Management
9.1.
Release of Study Drug to the Study Clinic
Before the study drug can be released to the study clinic, the following documents will be 
collected from the study clinic by the clinical research organization, retained in the trial 
master file, and a study drug shipment approval form will be completed by the clinical 
research organization:
Protocol signature page signed by the investigator
IRB approval of the protocol and informed consent form and IRB membership list
Completed Form FDA 1572, curriculum vitae, and medical licenses from each 
investigator
Financial disclosure and debarment certification from each investigator
Executed contract with investigator and study clinic
9.2.
Monitoring
9.2.1
Monitoring of the Study
The sponsor or its designee will monitor the study to ensure that it is being conducted 
according to the protocol, GCP standards, and applicable region-specific requirements, 


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and to ensure that study initiation, conduct, and closure are adequate. The investigators 
and the study clinic staff will be expected to cooperate fully with the study monitors and 
personnel or agents of the sponsor, and be available during monitoring visits to answer 
questions sufficiently and to provide any missing information. The investigators and their 
institutions will permit direct access to source data/documents for study-related 
monitoring activities, audits, IRB reviews, and regulatory inspections.
During any on-site visits, the study monitor will: 
Check and assess the progress of the study
Review all informed consent forms
Review study data collected
Conduct source document verification
Identify any issues and address their resolution
Verify that the facility remains acceptable
Conduct study drug accountability
These monitoring activities will be done in order to verify that the: 
Data are authentic, accurate, and complete.
The safety and rights of the subjects are being protected.
The study is being conducted in accordance with the currently approved protocol 
(including any amendments), GCP, and all applicable regulatory requirements.
In addition, the sponsor, designated auditors, and government inspectors must be allowed 
access to eCRFs, source documents, and other study files that may be required to evaluate 
the conduct of the study.
9.3.
Management of Protocol Amendments and Deviations
9.3.1
Modification of the Protocol
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the subject, must be submitted to the sponsor or designee and 
reviewed and approved by the IRB before implementation. Amendments to the protocol 
must be submitted in writing to the IRB for approval before subjects are enrolled into an 
amended protocol.
9.3.2
Protocol Violations and Deviations
Any significant protocol deviations that the investigator or study clinic staff believes are 
of major importance (e.g., incorrect randomizations, subject enrolled but not eligible) 


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should be reported to the IRB as soon as possible. Significant protocol deviations may 
include the following:
Deviations from the inclusion/exclusion criteria that may affect subject safety
Deviations (omission or delay) of safety monitoring procedures
Deviations in the administration of the study drug
Deviations in obtaining informed consent
All subjects who are enrolled and receive the study drug, regardless of whether they have 
a major protocol violation, must continue to be followed for safety for all follow-up study 
visits.


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10.
Appendices
10.1.
Appendix A: Schedule of Events
Table 10-1
Overall Schedule of Events (Parts 1 and 2)
Study Procedure
Screen
ing
Chec
k-in
Treatment and Follow-Up Period (In 
House)
In House 
Discharge or 
Early 
Termination
Follow-Up 
Visit (Part 2 
only)
Follow-Up 
Visit (Part 2 
only)
Follow-Up 
Visit (Part 2 
only)
Days –
30 to–
1
Day
0
Da
y 1
Da
y 2
Da
y 3
Day
4
Day 5
Day 6
Day 7
Day 10
Day 14
Day 21
Informed consent/HIPAA 
authorization
X
Eligibility assessment
X
X
Demographics
X
Height, weight, body 
mass index
X
Serology
X
Medical historya
X
Drug and alcohol 
screening
X
X
Serum pregnancy test 
(female subjects)
X
X
Fitzpatrick skin type 
assessment
X
Admission to study clinic
X
Randomizationb
X
Prior and concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory testsc
X
Vital sign measurementsd
X
X
X
X
X
X
X
X
X
X
X
Safety 12-lead ECGe
X


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Physical examinationf
X
X
X
X
X
X
X
X
X
X
X
Study drug 
administrationg
X
X
X
X
PK blood sample collecti
onh
X
X
X
X
X
X
X
X
X
X
Tape stripping (Part 2 
only)i
X
X
Discharge from study 
clinic
X
X
X
X
Abbreviations: ECG, electrocardiogram; HIPAA, Health Insurance Portability and Accountability Act; PK, pharmacokinetic.
a
Medical history assessment will also include social history and smoking habits.
b
Randomization (Part 1 only) will occur either after completion of check-in procedures on Day 0 or just before dosing on Day 1.
c
Clinical laboratory testing will include hematology, serum chemistry, and urinalysis.
d
Vital signs measurements will include blood pressure, heart rate, respiratory rate, and oral body temperature. The subject should be in a supine position, if possible, for a 
minimum of 5 minutes before vital signs are measured. During the treatment period, vital signs will be measured before dosing.
e
The subject should be in a supine position, if possible, for approximately 10 minutes before the safety 12-lead ECG is measured.
f
A complete physical examination will be performed at Screening. The skin at the sites of topical application of the study drug will be examined for signs of irritation during the 
treatment period, upon discharge (or early termination), and at the follow-up visits. At the follow-up visits, a symptom-directed brief physical examination may be performed at 
the investigator’s discretion.
g
Topical sunscreen will be applied (according to the randomization schedule) at approximately 0900 hours and again at 2, 4, and 6 hours after the first dose.
h
Pharmacokinetic blood samples (approximately 10 mL per sample) will be collected at the following time points:
Day 1: 0 and 0.5, 1, 1.5, 2, 3 (Part 2 only), 4, 6, 8, 9, 10, 12, and 14 hours after initial dose
Day 2: 23, 28, 33 h 
Day 3: 47, 52, 57 h 
Day 4: 71, 73, 74, 76, 78, 81, 82, 84 and 86 h
Day 5: 95 hours 
Day 6: 120 hours 
Day 7: 144 hours
Day 10: 216 hours (Part 2 only)
Day 14: 312 hours (Part 2 only)
Day 21: 480 hours (Part 2 only)
NOTE: when a time point corresponds with sunscreen administration, the PK sample will be collected before sunscreen administration.
i
Tape stripping timepoints to determine residual concentration of active ingredients in the superficial layers of the skin


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11.
Reference List
1) Department of Health and Human Services, Food and Drug Administration (US),
Center for Drug Evaluation and Research (CDER). Guidance for Industry:
Nonprescription Sunscreen Drug Products – Safety and Effectiveness Data.
November 2016.
2) Variation in stratum corneum protein content as a function of anatomical site and 
ethnic group, International Journal of Cosmetic Sciences, 38 (2016) 224-31.
3) The tape stripping procedure – evaluation of some critical parameters, European 
Journal of Pharmaceutics and Biopharmaceutics 72 (2009) 317-323.

SAP_001.pdf: 
Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 1 of 12
Statistical Analysis Plan 
SCR-005: Assessment of the Human Systemic Absorption of 
Sunscreen Ingredients
Sponsor:
U.S. Food and Drug Administration
White Oak Building #64, Room 2072
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sponsor Study Lead and 
Medical Monitor:
David Strauss, MD, PhD
Director, Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Telephone: 301-796-6323
Email: david.strauss@fda.hhs.gov
FDA RIHSC Sponsor:
David Strauss, MD, PhD
Project Managers:
Murali Matta, PhD
U.S. Food and Drug Administration
Telephone: 240-402-5325
Email: murali.matta@fda.hhs.gov
Robbert Zusterzeel, MD, PhD, MPH
U.S. Food and Drug Administration
Telephone: 301-796-3750
Email: robbert.zusterzeel@fda.hhs.gov
Study Monitor:
Jill Brown
RIHSC Project Manager
U.S. Food and Drug Administration
Version of SAP:
1.2
Date of SAP:
20 November 2018
CONFIDENTIAL
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed 
written consent of the U.S. Food and Drug Administration.


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 2 of 12
Sponsor Signatures Page
Prepared by
13 December, 2018
Robbert Zusterzeel, MD, PhD, MPH
Staff Fellow Medical Officer
Division of Applied Regulatory Science
U.S. Food and Drug Administration
Date
Reviewed by
13 December, 2018
Murali Matta, PhD
Visiting Associate
Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Date
13 December, 2018
Approved by
David Strauss, MD, PhD
Director
Division of Applied Regulatory Science 
U.S. Food and Drug Administration
Date


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 3 of 12
Contents
Sponsor Signatures Page................................................................................................................. 2
Contents .......................................................................................................................................... 3
1
Study Objectives...................................................................................................................... 4
1.1
Primary Objective (Part 1) ............................................................................................... 4
1.2
Primary Objective (Part 2) ............................................................................................... 4
2
Sample Size ............................................................................................................................. 4
3
Analysis Populations ............................................................................................................... 5
4
General Statistical Considerations, Subject Disposition and Demographics and Baseline 
Characteristics................................................................................................................................. 5
5
Pharmacokinetic (PK) Analyses and Primary/Secondary Outcomes...................................... 6
6
Safety Analyses ....................................................................................................................... 7
7
Missing Data............................................................................................................................ 7
8
Data Quality Assurance........................................................................................................... 8
Attachment A. Pharmacokinetic Sample Collection Schedule....................................................... 9
Attachment B. Randomization Schedule...................................................................................... 10


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 4 of 12
1
Study Objectives
The primary objective of this study is:
1. To explore whether the active components (avobenzone, oxybenzone, ecamsule and 
octocrylene) of sunscreen products are absorbed into the systemic circulation when a 
sunscreen product is applied under maximal-use conditions. 
1.1
Primary Objective (Part 1)
Part 1 is an open-label, randomized, 4-arm study in 24 healthy adult subjects with the primary 
objective:
To explore whether the active components (avobenzone, oxybenzone, ecamsule and 
octocrylene) of 4 sunscreen products (1 sunscreen product in each arm) are absorbed into 
the systemic circulation when a sunscreen product is applied under maximal-use 
conditions. 
One sunscreen product with the highest avobenzone exposure will be selected for the second part 
of the study. If there is no quantifiable exposure of avobenzone for any of the sunscreen 
products, the formulation with the highest oxybenzone exposure will be selected for Part 2.
1.2
Primary Objective (Part 2) 
Part 2 is an open-label, 4-arm study in 48 healthy adult subjects with the following primary 
objective:
To assess, where applicable, the pharmacokinetics and systemic absorption of the active 
components (avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, octisalate and 
octinoxate, of 4 sunscreen products (1 sunscreen product in each arm) under maximal-use 
conditions.
Part 2 will include the sunscreen product with maximal avobenzone exposure from Part 1 and 3 
additional new sunscreen formulations. More detailed information about the study 
(inclusion/exclusion criteria and schedule of events) can be found in the study protocol.
2
Sample Size 
Approximately 72 healthy subjects are planned for enrollment, of which 24 will be assigned to 
Part 1 (randomized to 4 arms of 6 participants each) and 48 will be assigned to Part 2
(randomized to 4 arms of 12 participants each). Subjects are considered enrolled after 
determination by the Principal Investigator on Day 0 that they meet all eligibility criteria and are 
subsequently assigned a randomization/study identification number. The sample size was 
determined empirically and is typical for exploratory investigations of this type.


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 5 of 12
3
Analysis Populations
The analysis population will include all subjects who receive at least 1 dose of any of the study 
drugs and have PK sample data for the treatment period collected before dosing and at 1 or more 
time points after dosing. 
The safety population will include all subjects who receive at least 1 dose of any of the study 
drugs.
4
General Statistical Considerations, Subject Disposition and 
Demographics and Baseline Characteristics 
All data will be presented in data listings. Data from subjects excluded from an analysis 
population will be presented in the data listings but not included in the calculation of summary 
statistics. The number of subjects who enroll in the study and the number and percentage of 
subjects who complete each assessment will be presented. The frequency and percentage of 
subjects who withdraw or discontinue from the study and the reason for withdrawal or 
discontinuation will be summarized. Continuous demographic and baseline characteristic 
variables (age, height, weight, body mass index) will be summarized overall and by treatment 
using descriptive statistics (number of subjects, mean, standard deviation [SD], median,
interquartile range [IQR], and minimum and maximum). The number and percentage of subjects 
in each class of categorical demographic and baseline characteristic variables will also be 
summarized.


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 6 of 12
5
Pharmacokinetic (PK) Analyses and Primary/Secondary Outcomes
The PK sampling schedule for this study is summarized in Appendix A. The following PK 
parameters will be determined for each subject in Part 1 and Part 2:
Across all study days 
Maximum concentration (observed peak drug concentration) (Cmax)
Day 1
Maximum concentration (observed peak drug concentration) (Cmax)
Time at which Cmax occurs (Tmax)
AUC from time 0 to the 23 hour time point (Clast) (AUC0-23)
Days 2 and 3
Residual drug concentration (predose level) (Ctrough)
Concentration 3 hours after the last dose of the day
Day 4
Maximum concentration (observed peak drug concentration) (Cmax)
Time at which Cmax occurs (Tmax)
Elimination rate constant (Kel) and terminal half-life (t1/2); calculated after final dose using all 
the available data up to last study sample (144 hours for Part 1; 432 hours for Part 2) 
AUC from time 71 to the 95 hour time point (AUC73-95)
AUC from time 0 extrapolated to infinity (AUC0-inf) and/or last observed time point
Day 5, 6, 7, 10 (Part 2 only), 14 (Part 2 only) and 21 (Part 2 only)
Residual drug concentration (Ctrough)
The primary and secondary outcomes of this study are as follows:
Primary Outcome:
1. Maximum* Avobenzone concentration (Cmax)
Secondary Outcomes:
1. Maximum* Oxybenzone concentration (Cmax)
2. Maximum* Octocrylene concentration (Cmax)
3. Maximum* Ecamsule concentration (Cmax)
4. Maximum* Homosalate concentration (Cmax)
5. Maximum* Octisalate concentration (Cmax)


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 7 of 12
6. Maximum* Octinoxate concentration (Cmax) (Part 2 Only)
* observed maximum;
Note that Cmax could occur on any of the days of the study. PK parameters Cmax, Clast, Ctrough,
Tmax, AUC0-t, Kel, t1/2 and AUC0-inf, will be summarized using descriptive statistics (number of 
subjects, mean, standard deviation [SD], coefficient of variation [CV], median, minimum, and 
maximum) for the days above for avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, 
octisalate and/or octinoxate (depending on whether the specific sunscreen formulation contains 
each of the active ingredients; see Attachment B) in Part 1 and 2. The PK parameters will be 
analyzed using non-compartmental methods based on actual sampling times. Mean and 
individual concentration-time profiles will be presented in graphs.
6
Safety Analyses
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of treatment-emergent adverse events (TEAEs), organized 
by system organ class and frequency, will be summarized by seriousness, severity, relationship 
to treatment, and by treatment at onset of the TEAE. A detailed listing of serious AEs and 
TEAEs leading to withdrawal will also be provided. 
Clinical laboratory results (hematology, serum chemistry, and urinalysis) will be summarized 
using descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum). 
Clinical laboratory results will be classified as normal or abnormal, according to the reference 
ranges of the individual parameter. The number and percentage of subjects with abnormal 
laboratory results will be provided. No statistical testing will be performed on clinical laboratory 
data.
Vital sign measurements (blood pressure, heart rate, respiratory rate, and oral body temperature), 
safety 12-lead ECG results, and changes from Baseline for these parameters will be summarized 
by treatment and time point using descriptive statistics (number of subjects, mean, SD, 
minimum, median, and maximum). Physical examination findings will be presented in a data 
listing, and abnormal physical examination findings will be recorded as AEs. 
All concomitant medication usage and medications that changed in daily dose, frequency, or 
both since the subject provided informed consent will be summarized for each subject.
7
Missing Data 
Missing data will not be imputed. Data that are excluded from the descriptive or inferential 
analyses will be included in the subject data listings. This will include data from subjects not in 


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 8 of 12
the particular analysis population, measurements from unscheduled visits, or extra measurements 
that may arise from 2 or more analyses of a plasma sample at the same time point.
8
Data Quality Assurance 
Completed eCRFs are required for each subject randomly assigned to study drug. Electronic data 
entry will be accomplished through the ClinSpark remote electronic data capture (EDC) system, 
which allows for on-site data entry and data management. This system provides immediate, 
direct data transfer to the database, as well as immediate detection of discrepancies, enabling site 
coordinators to resolve and manage discrepancies in a timely manner. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and subsequently any investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records.
Furthermore, the investigator retains full responsibility for the accuracy and authenticity of all 
data entered into the electronic data capture system. The completed dataset and their associated 
files are the sole property of the sponsor and should not be made available in any form to third 
parties, except for appropriate governmental health or regulatory authorities, without written 
permission of the sponsor.


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 9 of 12
Attachment A. Pharmacokinetic Sample Collection Schedule
Pharmacokinetic blood samples (approximately 10 mL per sample) will be collected for 
determination of avobenzone, oxybenzone, octocrylene, ecamsule, homosalate, octisalate and 
octinoxate plasma concentrations (where applicable to the different sunscreen formulations), at 
the following time points (the time limit for PK sample draws can be +/- 5 minutes from the 
nominal time):
Day 1: 0 and 0.5, 1, 1.5, 2, 3 (Part 2 only), 4, 6, 8, 9, 10, 12, and 14 hours after initial dose
Day 2: 23, 28, 33 h 
Day 3: 47, 52, 57 h 
Day 4: 71, 73, 74, 76, 78, 81, 82, 84 and 86 h
Day 5: 95 hours 
Day 6: 120 hours 
Day 7: 144 hours
Day 10: 216 hours (Part 2 only)
Day 14: 312 hours (Part 2 only)
Day 21: 480 hours (Part 2 only)
NOTE: when a time point corresponds with sunscreen administration, the PK sample will be 
collected before sunscreen administration.
 


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 10 of 12
Attachment B. Randomization Schedule
Randomization in this study is unblinded.
After screening, subjects will be randomized to one of 4 treatment sequences in either Part 1 (24 
subjects) or Part 2 (48 subjects). Example of treatment codes from the study protocol:
•
Treatment sequences of Part 1:
–
A: La Roche Posay (Cream), Anthelios SX Daily Moisturizing Cream with 
Sunscreen, SPF 15 with Mexoryl SX (6 subjects): Avobenzone (2%), Ecamsule 
(2%) and Octocrylene (10%)
–
B: Hawaiian Tropic (Lotion); Island Sport Ultra-Light High Performance Sunscreen, 
SPF 50 (6 subjects): Avobenzone (3%), Oxybenzone (4%) and Octocrylene (6%)
–
C: Neutrogena (Spray), Ultra Sheer Body Mist SPF 45 (6 subjects): Avobenzone 
(3%), Oxybenzone (6%), Octocrylene (2.35%), Homosalate (15%) and Octisalate 
(5%)
–
D: Banana Boat (Spray); Sport Performance Coolzone Continuous Spray Sunscreen, 
SPF 50 (6 subjects): Avobenzone (3%), Oxybenzone (5%) and Octocrylene (10%)
•
Treatment sequences of Part 2:
–
E: Hawaiian Tropic (Lotion); Island Sport Ultra-Light High Performance Sunscreen, 
SPF 50 (12 subjects): Avobenzone (3%), Oxybenzone (4%) and Octocrylene (6%)
–
F: Neutrogena (Aerosol Spray), Ultra Sheer Body Mist SPF 100 (12 subjects):
Avobenzone (3%), Oxybenzone (6%), Octocrylene (10%), Homosalate (15%) and 
Octisalate (5%)
–
G: Supergoop (Non-Aerosol Spray), Sunscreen Mist with Vitamin C SPF 50 (12 
subjects): Avobenzone (3%), Octocrylene (10%), Homosalate (10%), Octisalate 
(5%) and Octinoxate (7.5%)
–
H: Supergoop (Pump Spray), Sun Defying Sunscreen Oil with Meadowfoam SPF 50
(12 subjects): Avobenzone (3%), Homosalate (10%),Octisalate (5%) and Octinoxate 
(7.5%)
The script performs randomization across treatment groups; all subjects in Part 1 will be studied 
in 1 cohort (cohort 1) and subjects in part 2 will be studied in 2 cohorts (cohorts 2 and 3).
Treatment schedule 
RANDID 
PART 
COHORT 
SEQ 
1001 
1 
1 
D 
1002 
1 
1 
A 
1003 
1 
1 
C 
1004 
1 
1 
B 


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 11 of 12
1005
1
1
D
1006 
1 
1 
B 
1007 
1 
1 
A 
1008 
1 
1 
C 
1009 
1 
1 
C 
1010 
1 
1 
B 
1011 
1 
1 
A 
1012 
1 
1 
D 
1013 
1 
1 
B 
1014 
1 
1 
A 
1015 
1 
1 
D 
1016 
1 
1 
C 
1017 
1 
1 
B 
1018 
1 
1 
A 
1019 
1 
1 
C 
1020 
1 
1 
D 
1021 
1 
1 
A 
1022 
1 
1 
D 
1023 
1 
1 
C 
1024 
1 
1 
B 
2001 
2 
2 
G 
2002 
2 
2 
E 
2003 
2 
2 
F 
2004 
2 
2 
H 
2005 
2 
2 
E 
2006 
2 
2 
G 
2007 
2 
2 
F 
2008 
2 
2 
H 
2009
2
2
G
2010
2
2
E
2011
2012
2013
2014
2
2
2
2
2
2
2
2
H
F
F
G


Statistical Analysis Plan
SCR-005: Assessment of the Human Systemic 
Absorption of Sunscreen Ingredients 
Page 12 of 12
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
E
H
H
E
G
F
E
F
G
H
2025
2
3
F
2026
2
3
H
2027
2
3
G
2028 
2 
3 
E 
2029 
2 
3 
G 
2030 
2 
3 
H 
2031 
2 
3 
E 
2032 
2 
3 
F 
2033 
2 
3 
G 
2034 
2 
3 
E 
2035 
2036 
2037 
2038 
2039 
2040 
2041 
2042 
2043 
2044 
2045 
2046 
2047 
2048 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3
3 
3 
3 
3
3
3
3
H 
F 
H 
E 
F
G
G
E
F
H
G
E
H
F