Conditions: Bioavailability
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 12
Healthy volunteers: yes

Brief summary:
The study will utilize already FDA-approved marketed diclofenac products in healthy adults to generate data for establishing rate of drug delivery comparisons between diclofenac epolamine patches and diclofenac sodium solution in healthy adults and to determine skin concentrations.

Detailed description:
The study will utilize already FDA-approved marketed diclofenac products in healthy adults to generate data for establishing rate of drug delivery comparisons between diclofenac epolamine patches and diclofenac sodium solution in healthy adults and to determine skin concentrations. This study supports FDA's continuing effort to identify the most accurate, sensitive, reproducible and efficient methods to evaluate topical dermatological drug products.

Arms:
arm 1: Study Session 1: diclofenac epolamine patches (PK) \[51 h study duration\] arm 2: Study Session 2: diclofenac sodium solution (PK) \[47 h study duration\] arm 3: Study Session 3: diclofenac epolamine patch pieces and diclofenac sodium solution (no PK, for skin tape stripping) \[51 h study duration\]

Interventions: intervention 1: Diclofenac Epolamine Patch intervention 2: diclofenac sodium solution
Intervention descriptions: intervention 1: patch intervention 2: solution

Protocol document:
Prot_SAP_000.pdf: 
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EVALUATION OF THE BIOAVAILABILITY OF DICLOFENAC DERMAL PRODUCTS 
 
Short title: PK and TS of diclofenac dermal products 
UMB IRB #:  HP-00067047 
 
Principal Investigator:  
Audra L. Stinchcomb (contact), PhD, RPh 
 
Medically Accountable Investigator(s): 
Jeffrey Fink, MD, MS 
Lee-Ann Wagner, MD 
 
Sponsor: 
Food and Drug Administration 
Office of Generic Drugs 
 
Grant Number: 1U01FD004947  
NCT03145259 
Version 11.0 
07 June 2019 
 


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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP) and the applicable Food and Drug 
Administration and other Department of Health and Human Services regulatory requirements. 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 


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PROTOCOL SUMMARY 
Title:  
Evaluation of the bioavailability of diclofenac dermal products 
Population: 
Healthy adults age 18 - 45 years 
Number of Sites: 
Single site: University of Maryland School of Medicine 
Study Duration: 
Approximately up to 1 year 
 
Subject Participation 
Duration: 
Approximately 10 weeks including the screening period 
 
Description of Study 
Product: 
Diclofenac epolamine (Flector®) patch 1.3%, Teikoku Seiyaku 
Co., Ltd; Diclofenac sodium (Pennsaid®) topical solution 2%, 
Horizon Pharma USA Inc. 
 
Objective: 
 
 
The present study aims to generate human tape stripping (TS) 
and pharmacokinetic (PK) data in healthy subjects for the 
purpose of establishing a reference for in vitro-in vivo correlation 
(IVIVC) with an in vitro model following the application of 
diclofenac products: Flector® (diclofenac epolamine 1.3% patch) 
or Pennsaid® (diclofenac sodium 2% topical solution).   
 
Description of Study 
Design: 
The study will be an open-label, non-placebo controlled, 
crossover study (n=12 healthy subjects) over 10 weeks includes 
three study sessions and up to a 45 day screening period with 
one week washout period between study sessions. 
The study contains nine procedure days: 
Study Session 1 
• 
Procedure Day 1:  Flector® patches (4 patches) containing 
1.3% diclofenac epolamine to be worn for 10 h.  Blood 
samples obtained on Procedure Days 1, 2 and 3. 
 
Study Session 2 
• 
Procedure Day 4:  Pennsaid® topical solution (2 g of 
solution applied to 200 cm2 area on each upper arm for a 
total of 4 g) containing diclofenac sodium to be worn for 6 h.  
Blood samples obtained on Procedure Days 4, 5 and 6. 
 
Study Session 3 
• 
Procedure Day 7:  Six applications of Flector® 1.3% patch 
pieces and six applications of Pennsaid® topical solution 2%; 


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removal of patches at 10 h and solution at 6 h, followed by 
tape stripping at 10 h and 6 h, respectively (Uptake or 
Absorption) 
• 
Procedure Day 8:  Tape stripping at 27 or 23 h [17 h after 
removal] (Clearance) 
• 
Procedure Day 9:  Tape stripping at 51 or 47 h [41 h after 
removal] (Clearance)  
A)  Pharmacokinetics 
Each subject will be his/her own control (pre-dose blood 
sample) and each subject will sign an institutional review board–
approved consent form explaining the purpose, nature, risks, 
benefits, and duration of the study. The study will be conducted 
in accordance with good clinical practice guidelines and with the 
ethical principles originating in the Declaration of Helsinki.  
The subject’s skin in the area of application will be relatively free 
of hair before patch and topical solution application. For each 
treatment, the patch/solution will be applied to a previously 
unused application site. Blood samples (approximately 5 mL (1 
tsp) each) will be drawn in BD vacutainer  tubes.  On Procedure 
Days 1, 2, 3, 4, 5 and 6, blood samples will be obtained as 
follows: 
• 
Within 60 min pre-patch/solution application and then up to 
51 h for patches and 47 h for solution, during wear and post 
patch/solution removal.  No blood samples will be obtained 
during Procedure Days 7, 8 and 9. 
 
B)  Residual Drug Analysis of Diclofenac Patches 
In conjunction with the above described study residual drug 
analysis will also be conducted for the previously worn Flector® 
patches and patch pieces from Study Session 1-3.    
• 
Prior to administration to the subject as described in Part A, 
the patches will be weighed and the weight recorded.  
• 
The pouch, release liner and all items coming into contact 
with the patches (gloves, forceps, etc.) to be applied in Part 
A will be retained for analysis.    
• 
The used patches will be retained for drug content analysis.  


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• 
Upon removal of the patches after appropriate wear time, the 
skin (at site of application) will be swabbed and the swab 
retained for drug content analysis. 
• 
All items coming into contact with the patches during 
removal from the subject will be stored in a separate labeled 
sealable pouch for analytical retention and drug content 
analysis.   
C) Tape Stripping (TS) of diclofenac patch and topical solution 
(Study Session 3) 
• 
Diclofenac products (6 sites/product, 3 sites/arm/product) will 
be applied to each arm.  All of the patches will be removed 
at 10 h and solution at 6 h.  One-third of the patch sites at 10 
h and one-third of the solution sites at 6 h will be tape 
stripped (uptake or absorption), one-third of the patch sites 
at 27 h and one-third of the solution sites at 23 h will be tape 
stripped (clearance) and remaining patch sites at 51 h and 
solution at 47 h will be tape stripped (clearance).    
• 
Tape strips applied and removed after patch/solution 
removal are extracted to determine drug concentration in 
stratum corneum, which is the outer layer of the epidermis.  
 
 
 
 


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1 KEY ROLES 
U01 Principal Investigator: 
 
 
Audra L. Stinchcomb (contact), PhD, RPh 
Professor 
Department of Pharmaceutical Sciences 
University of Maryland School of Pharmacy 
20 N Pine St, Room PHN521 
Baltimore, MD 21201 
Phone: 410-706-2646 
Fax: 410-706-0886 
Email: astinchc@rx.umaryland.edu  
 
 
 
 
Medically Accountable 
Investigator(s) 
 
 
Jeffrey C Fink MD, MS 
Professor 
Department of Medicine and Epidemiology (secondary) 
University of Maryland School of Medicine 
UMMC, Room NN3E03 
Baltimore, MD 21201 
Phone: 410-328-4822 
Fax: 410-328-5685 
 
E-mail: jfink@medicine.umaryland.edu 
 
 
Lee-Ann Wagner, MD 
University of Maryland School of Medicine 
 
Department of Medicine 
 
Pediatrics 
 
North Hospital 
Baltimore, MD 21201 USA 
Phone:   410-328-7605 or 410-328-3158  
Email:  lwagner@som.umaryland.edu 
 
 
 


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2 BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
The purpose of this project is to investigate the development of appropriate methods to 
determine the in vitro/in vivo correlation (IVIVC) of drug absorption from dermal 
products, which has represented a longstanding challenge. The model drug for this 
study is diclofenac, which is available in two different formulations, patch and topical 
solution, approved by the United States FDA.  This healthy human subject study will 
provide the carefully designed protocols and data for direct comparison (IVIVC) with an 
in vitro human skin diffusion study model.  Generic drugs are approved based upon 
bioequivalence (BE) testing, and with respect to oral drug delivery, the accepted BE 
approach is relatively straightforward and is principally based on matching blood level 
profiles. In some cases, in vitro dissolution tests can be done to help determine the 
bioequivalence of an oral dosage form.  For topical drug products in the United States, 
with the exception of corticosteroids and a few other products, a comparative clinical 
endpoint study is often necessary for approval of a generic product or for replacement of 
an approved dermatological drug product with one that has major changes. Comparative 
clinical trials are relatively insensitive, time-consuming and costly.  It is especially difficult 
to gain the adequate statistical power needed to evaluate bioequivalence in some 
dermatological conditions, and can require a large number (i.e., hundreds1,2) of subjects. 
This study supports FDA’s continuing effort to identify the most accurate, sensitive, 
reproducible and efficient methods to evaluate topical dermatological drug products.  
In 1998, the FDA issued draft guidance for the dermatopharmacokinetics (DPK) method 
to assess the bioequivalence of topical products for application to the skin3. The 
approach required quantification of the total amount of drug in the stratum corneum  
(SC) as a function of time, akin to the typical concentration-time profiles of traditional PK 
studies using blood sampling. Tape-stripping, a technique that involves multiple 
applications and removal of individual pieces of tape to a formulation-treated area of the 
skin of a healthy human subject, is the biosampling method used in TS to remove layers 
of the SC in serial.  The draft guidance was withdrawn in 2002 following the inconsistent 
results of two studies4. The lack of agreement in the results prompted concern about 
both the reproducibility and the adequacy of this method to assess drugs whose target 
site is beyond the SC.  
Considerable subsequent effort was directed at identification of problems/limitations of 
the original TS protocol and development of an improved procedure to generate 
reproducible data of much higher quality5,6.   
The end product of this research was a relatively straightforward method that examines 
only one uptake and one elimination time per formulation. This allows replicate sites to 


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be studied, and higher statistical power to be achieved with fewer volunteers. No tapes 
are discarded, but tapes are combined and extracted in groups to achieve high 
concentrations for analysis. The total amount of drug in the SC is measured for each 
site, and the ratios of these quantities for a reference listed drug (RLD) and test 
formulations can then be compared in the usual “80:125” area under the curve 
bioequivalence fashion.  The method has been successively applied retrospectively to 
the comparison of retinoid gels and prospectively to the analysis of DPK data obtained 
for 3 econazole creams. 
It follows that TS data obtained with the optimized protocol, which emerged from a 
previously FDA-funded project, represent suitable in vivo information for comparison and 
correlation with in vitro skin penetration. This study will evaluate two commercially 
available products; Flector® (diclofenac 1.3% patch) and Pennsaid® 2% diclofenac 
topical solution when administered in healthy adults.  One uptake/absorption TS time 
point sample will be obtained, and two clearance time points will be obtained.  Important 
systemic pharmacokinetic data in the form of blood drug levels will also be gathered 
during an identical protocol of absorption and clearance phase, in order to be able to 
cross compare all three methods, in vivo systemic PK, in vivo TS, and in vitro 
permeation techniques for thorough IVIVC.  The diclofenac patch and topical solution 
have been chosen for this study because they are one of the few drug product types that 
will provide detectable blood levels of drug. Upon completion of this in vivo study, skin 
and blood diclofenac levels obtained after application of each product will be coupled 
with in vitro data generated in our laboratory at UMSOP to develop IVIVC models. These 
models would help in predicting in vivo skin and blood diclofenac levels from in vitro 
studies.   The measurement of blood drug levels is the gold standard test for evaluation 
of pharmacokinetic parameters for systemically acting products.  The systemic blood 
levels measured in this study will allow us to evaluate the TS and in vitro studies, as 
these latter two methods are currently not accepted as regulatory standard of practice.  
Some topical products may not provide measurable systemic blood levels, so in that 
case, future surrogate methods for clinical endpoint studies may be using TS or in vitro 
studies.  The diclofenac product has systemic absorption to allow us to validate the two 
non-standard techniques. 
 
2.2 
Rationale 
The goal of this study is to help establish more efficient pathways for approval of topical 
drug products by developing better tools to assess bioavailability. This study with Flector® 
(diclofenac epolamine 1.3%) topical patch and Pennsaid® (diclofenac sodium 2%) topical 
solution will provide sufficient systemic concentrations of diclofenac to characterize the 
systemic bioavailability. The systemic concentration will be compared with the local 
bioavailability of diclofenac in the skin using the products, measured by TS the skin to 
quantify the concentrations of diclofenac in the SC. The same products will also be 
studied (under a parallel but separate in vitro study protocol) using an in vitro permeation 
test (IVPT) model with excised human skin which has demonstrated IVIVC in previous 


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studies. This research will help establish whether the IVPT model correlates with and is 
predictive of in vivo bioavailability, and whether IVPT and/or in vivo TS can be utilized as 
part of a collective weight-of-evidence approach to support an approval pathway for 
topical drug products. 
 
The multi-dimensional design of the current study minimizes the human subject research 
that would otherwise be expanded by the performance of multiple independent studies to 
assess local and systemic bioavailability, all of which can be now be directly compared in 
this study to support multiple, inter-related in vivo analyses relating to the bioavailability 
and bioequivalence.  These coordinated evaluations also collectively provide the in vivo 
reference datasets that are needed to establish IVIVC for the IVPT model which may then 
be utilized to support a new pathway for approval of numerous topical drug products for 
patients. 
Flector® patch and Pennsaid® topical solution 
  
Flector® 1.3% patch 
Pennsaid® 2% topical 
solution 
Inactive 
ingredients 
1,3-butylene glycol, 
dihydroxyaluminum 
aminoacetate, disodium 
edetate, D-sorbitol, 
fragrance (Dalin PH), 
gelatin, kaolin, 
methylparaben, 
polysorbate 80, povidone, 
propylene glycol, 
propylparaben, sodium 
carboxymethylcellulose, 
sodium polyacrylate, 
tartaric acid, titanium 
dioxide and purified water 
dimethyl sulfoxide USP 
(DMSO, 45.5% w/w), 
ethanol, purified water, 
propylene glycol and 
hydroxypropyl cellulose 
  
 
Formulation 
patch 
topical solution 
  
  
 
Manufacturer 
Teikoku Seiyaku Co., Ltd 
Horizon Pharma USA Inc. 


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3 OBJECTIVES 
3.1 
Study Objectives 
1)  Generate human PK data for the purpose of establishing an IVIVC model by 
collecting data following the application of two diclofenac formulations:  Flector® 1.3% 
diclofenac epolamine patches and Pennsaid® 2% diclofenac sodium topical solution. 
 
2)  Generate TS data for the purpose of establishing a fundamental IVIVC model by 
collecting skin concentration data following the application of two diclofenac 
formulations:  Flector® 1.3% diclofenac epolamine patches and Pennsaid® 2% 
diclofenac sodium topical solution. 
   
3.2 
Study Outcome Measures 
For the TS study the main outcome measure is the ratio of clearance and uptake of 
diclofenac drug concentrations for each diclofenac formulation. For the PK study the 
main outcome measure is the maximum serum concentration (Cmax); time of maximum 
serum concentration (Tmax) of diclofenac and area under the curve (AUC) attained from 
Flector® 1.3% diclofenac epolamine patches and Pennsaid® 2% diclofenac sodium 
topical solution.  In addition, the residual drug content from worn Flector® patches will be 
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4   STUDY DESIGN 
This is designed as an open-label, non-placebo controlled, crossover study. The 
products tested are already FDA approved; however, the products are used outside of 
the approved indications by using healthy subjects.  The products being tested are for 
research purposes only; this is not a treatment study.  The study is not blinded because 
PK and TS assessment is not subject to participant and/or observer bias.  The study will 
consist of three study sessions.  Each of the 12 selected subjects will be enrolled to 
complete three study sessions, nine procedure days.   There will be no overnight stays 
during the study.  There will be at least a one week washout period between each study 
session.  
 
The studies are as follows: 
 
STUDY SESSION 1 (PK study) 
Procedure Day 1:  Four Flector® patches [140 cm2 each; two patches/arm] will be 
applied for 10 h and removed.  Blood samples will be collected at specified times.   
Procedure Day 2:  Blood samples will be collected at specified times.   
Procedure Day 3:  Blood samples will be collected at specified times.  There will be at 
least a one week washout period before proceeding to the next study session. 
 
STUDY SESSION 2 (PK study)  
Procedure Day 4:  Pennsaid® topical solution [4 g of solution over 400 cm2 area; 2 
g/200 cm2 on each upper arm] will be applied to the skin for 6 h and removed.  Blood 
samples will be collected at specified times.   
Procedure Day 5:  Blood samples will be collected at specified times.   
Procedure Day 6:  Blood samples will be collected at specified times.  There will be at 
least a one week washout period before proceeding to the next study session. 
 
STUDY SESSION 3 (TS study)  
Procedure Day 7:  Six sites (3 sites/arm/product) will be designated on the volar 
forearms for each diclofenac product and 1 site for a negative control (volar skin area 
where no drug is applied). Flector® 1.3% patches [8.25 cm2 each] and Pennsaid® 2% 
topical solution [82.5 mg/8.25 cm2 each] will be applied.   At 10 h post application for 
patches and 6 h post application for solution, all products will be removed from their 
respective sites.  Two sites for each product will be tape stripped at the designated 
uptake (absorption) time (10 h and 6 h post application).     
Procedure Day 8:  An additional two sites for each product will be tape stripped at the 
designated clearance period (27 and 23 h post application; 17 h after product removal). 
Procedure Day 9:  The remaining two sites for each product will be tape stripped at the 
designated clearance period (51 and 47 h post application; 41 h after product removal). 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Only healthy adult volunteers who meet the inclusion/exclusion criteria will be eligible for 
enrollment into this study.  Twelve subjects will be recruited as well as at least another 
five alternates who could replace subjects who drop out from the study for any 
unforeseen reason.  The study population selected for this study includes healthy adult 
men and women without other comorbidities ages 18-45, inclusive.  The selection 
criteria are designed to exclude people who might have medical conditions that could 
pose a safety risk and people whose medical conditions might interfere with the 
objectives and results of the study.   
Subjects will be recruited by local advertisements to the study center, online recruitment, 
newspaper ads or The Elm Weekly.  Potential subjects who are interested in the study 
will be informed of the study and if they wish to participate, will receive additional study 
information, including an onsite screening appointment and informed consent form.  
Each of the 12 selected subjects enrolled will be expected to complete all three study 
sessions.   
We aim to target at least 40% participants of each gender. There are no specific 
ethnicity/race category recruitment targets, although such information will be recorded by 
the researchers.  
5.1 
Subject Inclusion Criteria 
Subjects are eligible for this study if they fulfill the inclusion criteria specified below: 
1. Men or non-pregnant, women who are of any ethnic background between the 
age of 18 and 45 years old. 
2. Subjects must be non-smokers (must have refrained from the use of nicotine-
containing substances, including tobacco products (e.g., cigarettes, cigars, 
chewing tobacco, snuff, gum, patches or electronic cigarettes) over the previous 
2 months and are not currently using tobacco products. 
3. Provide written informed consent before initiation of any of the study procedures. 
4. Agree not to participate in another clinical trial/study during the study period or to 
participate in an investigational drug study for at least 1 month after the last study 
session.   
5. Able to adhere to the study protocol schedule and study restrictions.   
6. Able to participate in all study sessions. 


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7. Has a volar forearm of either at least 24 cm (9.45 inches) in length or of sufficient 
size that can accommodate the products to be tested in a study area that begins 
at least 5 cm (1.97 inches) above the wrist and ends a minimum of 0.5 cm (0.197 
inches) below the antecubital fossa (i.e., the bend in the arm at the elbow). 
8. Subjects have upper arms large enough to allow for the placement of two 140 
cm2 [21.7 in2] patches (distance from acromion process of the scapula to 
olecranon process should be a minimum of 35 cm [13.8 inches]; circumference of 
upper arms should be a minimum of 28 cm [11.02 inches] and 200 cm2 [31 in2] 
area for application of solution. 
9. Subjects deemed to be healthy as judged by the Medically Accountable 
Investigator (MAI) and determined by medical history, physical examination and 
medication history. 
10. Negative urine drug screening test (cannabinoids, amphetamines, barbiturates, 
benzodiazepine, cocaine, methadone, opiates, PCP). 
11. Have normal screening laboratories for white blood cells (WBC), hemoglobin 
(Hgb), platelets, sodium, potassium, chloride, bicarbonate, blood urea nitrogent 
(BUN), creatinine, alanine transaminase (ALT) and aspartate aminotransferase 
(AST). 
12. Have normal screening laboratories for urine protein and urine glucose.  
13. Female subjects must be of non-childbearing potential (as defined as surgically 
sterile [i.e. history of hysterectomy or tubal ligation] or postmenopausal for more 
than 1 year), or if of childbearing potential must be non-pregnant at the time of 
enrollment and on the morning of each study day, and must agree to use 
hormonal or barrier birth control such as implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence, or a 
vasectomized partner.  
14. Agrees not to donate blood to a blood bank throughout participation in the study 
and at least 3 months after the last study session. 
15. Have a normal ECG; must not have the following to be acceptable: pathologic Q 
wave abnormalities, significant ST–T wave changes, left ventricular hypertrophy, 
right bundle branch block, left bundle branch block. (sinus rhythm is between 55–
100 beats per minute). 
16. Have normal vital signs (see Appendix C) 
• 
Temperature 35-37.9°C (95-100.3°F) 
• 
Systolic blood pressure 90-165 mmHg 
• 
Diastolic blood pressure 60-100 mmHg 
• 
Heart rate 55-100 beats per minute 
• 
Respiration rate 12-20 breaths per minute 


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5.2 
Subject Exclusion Criteria 
Subjects will be excluded for any of the following conditions/reasons: 
1. Women who are pregnant, lactating, breast feeding or have a positive serum 
pregnancy test at enrollment or positive urine pregnancy test on the morning of 
the first day of each study session. 
2. Smokers (current use or use over the previous 2 months of nicotine-containing 
substances, including tobacco products (e.g., cigarettes, cigars, chewing 
tobacco, snuff, gum, patch or electronic cigarettes). 
3. Participation in any ongoing investigational drug trial/study or clinical drug 
trial/study. 
4. History as either reported by the subject or evident to the Medically Accountable 
Investigator (MAI) of infectious disease or skin infection or of chronic skin 
disease (e.g., psoriasis, atopic dermatitis). 
5. History of diabetes. 
6. History of significant skin cancers (e.g., melanoma, squamous cell carcinoma), 
except basal cell carcinomas that were superficial and did not involve the 
investigative sites. 
7. Body Mass Index (BMI) ≥30 kg/m2. 
8. History of chronic obstructive pulmonary disease or cor pulmonale, or 
substantially decreased respiratory reserve, hypoxia, hypercapnia or pre-existing 
respiratory depression. 
9. Active positive Hepatitis B, C and/or HIV serologies (see Appendix B). 
10. Positive urine drug screening test. 
11. Use of any prescription medication during the period 0 to 30 days or over-the-
counter medication e.g. antihistamines, topical corticosteroids during the period 
0-5 days before entry to the study (vitamins, herbal supplements and birth control 
medications not included). 
12. Currently taking daily oral nonsteroidal anti-inflammatory drug [NSAIDs] (aspirin, 
ibuprofen, naproxen, etc…). 
13. Currently taking daily anticoagulants or within the past month prior to entry into 
the study (warfarin, heparin, rivaroxaban, dabigatran, etc…) ACE-inhibitors, 
cyclosporine, diuretics, lithium or methotrexate. 
14. Donation or loss of greater than one pint of blood within 60 days of entry to the 
study. 


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15. Any prior adverse reaction or hypersensitivity to diclofenac, aspirin, ibuprofen, 
naproxen or other nonsteroidal anti-inflammatory drug (NSAID), other inactive 
ingredients in the patch or topical solution or to adhesives or tapes used to cover 
or tape strip the treatment sites.  
16. Received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within 1 month before enrollment in this study or expects to 
receive an experimental agent during the study. 
17. Eat or drink anything containing alcohol within 24 hours prior to dose 
administration. 
18. Any condition that would, in the opinion of the Medically Accountable Investigator 
(MAI), place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol. 
19. Subject has an obvious difference in skin color between arms or the presence of 
a skin condition, excessive hair at the application site (upper arms/volar 
forearms), sunburn, raised moles and scars, open sores at application site (upper 
arms/volar forearms), scar tissue, tattoo, or coloration that would interfere with 
placement of diclofenac products, skin assessment, or reactions to diclofenac. 
20. History of asthma or urticaria, hypertension, myocardial infarction, thrombotic 
events, stroke, congestive heart failure, impaired renal function or liver disease. 
21. History of gastrointestinal bleeding or peptic ulcer disease. 


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6 STUDY PRODUCT 
6.1 
Study Product Description 
6.1.1 Flector® (diclofenac epolamine 1.3%) patch [140 cm2] 
Flector® is a prescription diclofenac-containing patch that releases diclofenac through 
the skin into the body.  The patch releases diclofenac over a 12 h period, the 
recommended duration of patch application. The patch is for the topical treatment of 
acute pain due to minor strains, sprains and contusions. 
6.1.2 Pennsaid® (diclofenac sodium 2%) topical solution 
Pennsaid® 2% topical solution is a prescription diclofenac-containing solution that 
releases diclofenac through the skin into the body.  The solution releases diclofenac 
over a 12 h period. The solution is a nonsteroidal anti-inflammatory drug (NSAID) 
indicated for the treatment of the pain from osteoarthritis of the knee(s).   
6.2 
Formulation, Packaging, and Labeling 
6.2.1 Flector® (1.3% diclofenac epolamine) patch 
Active ingredient (in each patch): diclofenac epolamine, 180 mg (13 mg per gram adhesive) 
in an aqueous base.  In addition to the active ingredient (diclofenac epolamine), the 
following inactive ingredients are present in the patch: dihydroxyaluminum aminoacetate, 
disodium edetate, D-sorbitol, fragrance (Dalin PH), gelatin, kaolin, methylparaben, 
polysorbate 80, povidone, propylene glycol, propylparaben, sodium carboxymethylcellulose, 
sodium polyacrylate, tartaric acid, titanium dioxide and purified water. This patch is 
manufactured by Teikoku Seiyaku Co., Ltd.  This product should be stored at room 
temperature. 


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6.2.2 Pennsaid® 2% diclofenac sodium topical solution 
In each pump of solution there is 1 g of solution (20 mg diclofenac sodium per gram 
solution).  In addition to the active ingredient (diclofenac sodium), the following inactive 
ingredients are present in the solution:  dimethyl sulfoxide USP (DMSO, 45.5% w/w), 
ethanol, purified water, propylene glycol and hydroxypropyl cellulose.  This solution is 
manufactured by Horizon Pharma USA Inc.  This product should be stored at room 
temperature. 
 


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7 
PHARMACOKINETICS AND STATISTICAL 
CONSIDERATIONS 
7.1 
Study Hypothesis 
 
TS and PK 
The tested diclofenac products are non-bioequivalent hence, we will test the null 
hypothesis (H0) that the mean clearance/uptake diclofenac amount ratio, and the PK 
parameters (Cmax and AUC) between these products are different (i.e., outside the 80–
125% range). 
7.2 
Analyses 
Diclofenac concentrations will be measured in serum samples collected from each 
subject. Blood samples (approximately 5 mL (1 tsp)) will be collected during Study 
Session 1 prior to dosing and then at 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 24 h, 
27 h, 30 h, 32 h and 51 h post-patch application. Blood samples (approximately 5 mL (1 
tsp)) will be collected during Study Session 2 prior to dosing and then at 1 h, 2 h, 3 h, 4 
h, 5 h, 6 h, 7 h, 23 h, 26 h, 29 h, 31 h and 47 h post-solution application.  After the PK 
study, TS study will be conducted at 10 h [patches] and 6 h [solution] (skin drug 
uptake/absorption), 27 h [patches] and 23 h [solution] (skin drug clearance), and 51 h 
[patches] and 47 h [solution] (skin drug clearance) post product application.  Non 
compartmental analyses (NCA) will be conducted to estimate the  PK parameters such 
as: maximum serum concentration (Cmax); apparent elimination rate constant (k); 
apparent half-life (t1/2), calculated as 0.693/k; AUC0-last of the serum concentration–time 
determined by the linear trapezoidal method; and AUC value extrapolated to infinity 
(AUCinf), calculated as the sum of AUC0-last and the area extrapolated to infinity: AUCinf = 
AUC0-last + Clast/k where Clast would be the last quantifiable concentration. All NCA 
analyses will be conducted using Phoenix® WinNonlin® 6.4 (Pharsight, a Certara 
Company, CA). 
7.3 
Final Analysis Plan 
An objective of this study is to determine PK parameters (Cmax, AUC and ratio of SC 
drug concentration during uptake and clearance) of diclofenac in healthy adults and TS 
data after using Flector® (diclofenac epolamine 1.3% patch) and Pennsaid® (2% 
diclofenac sodium topical solution) for the purpose of IVIVC by collecting data over two 
separate application periods.  


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Analysis of variance (ANOVA) followed by post-hoc Bonferroni test will be used for 
comparing the differences in the means of the PK parameters and significant differences 
will be declared at p<0.05. The statistical comparisons will be conducted as follow: 
 
If diclofenac PK concentrations are found to be non-normally distributed, then we will 
examine Box-Cox transformations (e.g., log, square-root, etc.) that can achieve 
normality. If no transformation can achieve normality, then will use permutation tests to 
compute empirical p-values, and will use the bootstrap to compute standard errors and 
confidence intervals that account for within-person correlation. 
  
IVIVC will be conducted comparing PK parameters and profiles to predicted PK 
parameters and profiles using IVPT and in vitro TS results.  Multiple methods will be 
implemented to develop an IVIVC.  The first method is to compare the steady state 
concentrations.  The predicted steady state concentration using IVPT data will employ 
the following formula: 
𝐶𝑠𝑠= 𝐽𝑠𝑠 ∗𝐴
𝐶𝐿
 
 
The second method will compare the PK profiles of the clinical and IVPT study by 
predicting diclofenac concentrations at each time point in the IVPT study and comparing 
it to the clinical PK profile.  The third method will be to determine and compare residual 
patch analysis between in vitro and in vivo.    
 
In terms of developing an IVIVC for the TS study a comparison will be made between in 
vitro and in vivo uptake (absorption) and clearance diclofenac amounts.  The second 
method is to compare the clearance to uptake diclofenac amount ratio between in vitro 
and in vivo.