Human Repeated Insult Patch Test
Phase: NA
Conditions: Dermatitis, Allergy, Contact Allergy
Sponsor: NeXtGen Biologics, Inc.

Consumer Product Testing Company, Inc. 
Protocol: 
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Revision Date: 2/13/18 
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Protocol Title: 
Protocol Number: 
Clinical Trial Number: 
Test Materials: 
Testing Facility: 
Sponsor: 
Principal Investigator: 
Sub-Investigators: 
CLINICAL PROTOCOL 
Human Repeated Insult Patch Test 
NNAU0l-001 
C18-0595 
NeoMatriX™ 
Saline Negative control 
0.4% SLS Positive Control 
Consumer Product Testing Company, Inc. 
70 New Dutch Lane 
Fairfield, NJ 07004 
(973) 808-7111 
NeXtGen Biologics, Inc. 
101 SE 2nd Place, #E201H 
Gainesville, FL 32601 
Michael Caswell, Ph.D., CCRC, CCRA 
Vice President, Clinical Evaluations 
Joy Frank, R.N. 
Executive Vice President, Clinical Evaluations 
Richard R. Eisenberg, M.D. 
Board Certified Dermatologist, Medical Director 
PROTOCOL ACCEPTANCE: 
For ~~uc± Testing Co., Inc.: 
A 
c_,,.fu,eRJ 
VP. Clinical Evaluations 
Michael Caswell, Ph.D., CCRC, CCRA 
, , /,/';~ pift , pt---£ 
Executive VP. Clinical Evaluations 
For Sponsor: 
Name 
Title 
Date 
CONFIDENTIAL 
This document is a confidential communication of Consumer Product Testing Company, Inc. Acceptance of 
this document constitutes the agreement by the recipient that no unpublished information contained herein 
will be published or disclosed without prior written approval. 
NNAU01-00L20180213_RIPT 
VP Clinical Operations
13Feb2018
NCT03474874

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Protocol: 
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TABLE OF CONTENTS 
TABLE OF CONTENTS 
2 
ABBREVIATIONS 
3 
DEFINITIONS 
4 
SYNOPSIS 
6 
FLOW CHART OF TRIAL DESIGN 
7 
1 
Background 
8 
2 
Trial Objective 
8 
3 
Proposed Schedule 
: 
,., 
8 
4 
Test Materials 
;.n 
9 
4.1 
Identification 
9 
4.2 
Storage 
9 
4.3 
Controls 
9 
4.4 
Disposition 
9 
5 
Selection and Withdrawal of Subjects 
"" 
9 
5.1 
Number of Subjects 
9 
5.2 
Inclusion Criteria 
;. 10 
5.3 
Exclusion Criteria 
10 
5.4 
Prohibitions and Restrictions 
11 
5.4 
Withdrawal of Subjects 
11 
5.5 
Disposition of Withdrawn Subjects 
11 
6 
Methodology 
11 
6 . .1 
Design 
12 
6.2 
Patch 
12 
6.3 
Test Procedure 
12 
6.4 
Evaluation 
14 
7 
Statistical Methods 
14 
8 
Sc;1fety 
: 
11 
8.1 
Relationship to Test Materials 
15 
8 .. 2 
Severity of Adverse Event .. .. . .. .. . .. . .. .. .. .. .. .. .. . .. .. .. .. . .. .. .. . .. . .. .. .. .. .. .. .. .. . .. .. .. .. .. .. .. .. . .. .. .. .. .. . .. . .. 16 
8.3· 
Serious Adverse Events 
: i.;·; .. 16 
8.4 
Management of Adverse Events 
: 
17 
8.5 
Test Material Deficiency 
17 
9 
Source Data and Documents 
: 
: 
18 
10 
Quality Control and Quality Assurance 
18, 
10.1 Trial Monitoring by the Sponsor 
; 
18 
10.2 Trial Reviewing by CPT Quality Assurance Department 
:: 
18 
10.3 Data Maintenance 
;.;,.. 18 
11 
Obligations of the Sponsor, the Monitor and the Pl.. 
19 
11.1 
Ethics 
1? 
11.2 Institutional Review Board 
19 
11.3 Informed Consent 
1~ 
11.4 Research Subject Confidentiality 
: 
l~ 
11. 5 Deviation from the Protocol 
20 
11.6 Clinical Trial Records 
20 
11.7 Final Report 
20 
11.8 Communication and Publication of Results 
20 
12 
References 
21 
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ABBREVIATIONS 
AE - Adverse Event 
CFR - Code of Federal Regulations 
CPT - Consumer Product Testing Company, Inc. 
CRF - Case Report Forms 
GCP - Good Clinical Practice 
HIPAA - Health Insurance Portability and Accountability Act 
ICF - Informed Consent Form 
IRB- Institutional Review Board 
Pl - Principal Investigator or designee 
SAE - Serious Adverse Event 
SOP- Standard Operating Procedure 
I 
I 
~ I 
'?': 
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DEFINITIONS 
Adverse Event (AE): Any negative experience that a participant has during the course of a clinical trial, 
including new or worsening symptoms or laboratory abnormalities. 
Belmont Report: A document entitled "Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research" that was produced by the National Commission for the Protection of Human Subjects 
of Biomedical and Behavioral Research in 1978. The Belmont Report identifies three fundamental ethical 
principles for all human subjects' research: respect for persons, beneficence, and justice. 
· 
Blinding: When research participants are unaware of the assigned "treatment." In a single-blinded trial, the 
subjects do not know what treatment they are receiving. In a double-blinded trial, the subjects AND the 
investigators are unaware of the treatment assigned, as are the monitors and statisticians in some cases. 
Case Report Form (CRF): A record of information collected on each subject during the clinical trial. 
Clinical Investigation: A systematic trial designed to evaluate a test material in humans. 
Clinical Research: A trial in human subjects. 
Clinical Trial: Any prospective investigation in which the applicant or investigator determines the method 
of assigning the test material or other interventions to one or more human subjects. 
Declaration of Helsinki: A series of guidelines adopted by the 18th World Medical Assembly in Helsinki, 
Finland in 1964. Recommendations include the procedures required to ensure subject safety in clinical trials, 
including informed consent and Ethics Committee reviews. 
Ethics Committee: An independent group of medical and nonmedical people who verify the integrity of a 
trial and ensure the safety, integrity, and human rights of the subjects. 
l 
Exclusion Criteria: Characteristics that would prevent a subject from being eligible to participate in ~ 
research trial, as specified in the protocol. 
· 
Good Clinical Practices (GCPs): International ethical and scientific quality standards for the design, 
conduct, monitoring, recording, auditing, analysis, and reporting of trials. 
Health Insurance Portability and Accountability Act (HIPAA): Legislation passed in 1996 th~t 
includes a privacy rule creating national standards to protect personal health information. 
Inclusion Criteria: A list of requirements that a subject must meet to be eligible to participate in a 
research trial, as specified in the protocol. 
Informed Consent: The verification of a person's willingness to volunteer in a research trial. The 
verification is requested only after the person has received complete, objective information about the 
research, including its objectives, potential benefits, risks and inconveniences, alternative therapies that may 
be available (if applicable), and the subject's rights and responsibilities in accordance with the current 
revision of the Declaration of Helsinki (as amended). Consent is given by executing the Informed Consent 
Form (ICF). 
. 
Institutional Review Board (IRB): An independent group of professionals designated to review and 
approve the clinical protocol, Informed Consent Forms, trial advertisements, and : patient brochures to 
ensure that the trial is safe and effective for human participation. The IRB also ensures that the trial 
adheres to FDA regulations. 
: 
. { 
Investigator: A medical professional, usually a physician but also sometimes a nurse, pharmacist, or other 
professional, under whose direction a test material is given or dispensed. A principal investigator CPI) js 
responsible for the overall conduct of the clinical trial. 
· 
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MedWatch Program: A national educational/promotional initiative to educate health professionals about 
the, importance of reporting serious adverse events and important product problems, to facilitate reporting 
to the FDA if they choose to do so, and to provide feedback to the health professional community as new 
safety information becomes available. 
Monit()r: The Sponsor or CRO representative who reviews trial records to determine that it is beinq 
conducted according to the protocol. 
Monitc;>ring: Reviewing a clinical trial, ensuring that conduct, proper records, and reports are in accordance 
with the approved protocol, standard operating procedures, GCPs, and regulatory requirements. 
· 
Protocol: A detailed plan that sets forth the objectives, design, and methods for a clinical trial. 
Protocol Amendment: Changes or clarifications made in writing to the original protocol. 
Quality Assurance: Systems and procedures designed to ensure that a trial is being performed i~ 
compliance with the approved protocol, standard operating procedures, GCPs, and that the data being 
generated are accurate. 
· 
.· 
~ (t: ; 
' 
Randomization: A method of assigning trial test material such that each subject has an equal chance of 
being assigned to each treatment or control group. Randomization guards against selection bias. 
Serious Adverse Event (SAE): Any adverse event (AE) that is fatal, life-threatening, or permanently 
disabling, or that results in new or prolonged hospitalization, in a congenital anomaly/birth defect, or.ts an 
important medical event. 
Source Data: All information contained in original records and certified copies of results or observations. 
source Documents: Where medical information 
is originally recorded, including physician notes, 
laboratory reports, discharge summaries, autopsy reports, etc. 
Sponsor: The entity who takes responsibility for initiation, management, and financing of research. 
Standard Operating Procedures (SOPs): Official, detailed, written instructions for the management of 
clinical trials. SOPs ensure that all the functions and activities of a clinical trial are carried out consistently 
and efficiently. 
Subject: A patient or healthy person participating in a research trial. 
Test Materials: Any material or product that is the subject of testing or a clinical trial. This may a~o be 
referred to as a "test article" or "investigational material." 
· 
, "1 
I 
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SYNOPSIS 
Name of Company: 
Name of Investigational Test Materials: 
NeXtGen Biologics, Inc. 
NeoMatriX™ Lot: AD17H150932/AD17H150933 
Title of Clinical Trial: A Human Reoeated Insult Patch Test 
-Investloator: Michael Caswell PhD, CCRA. CCRC 
','. 
sub-tnvesnoetors: Joy Frank. RN· Richard Eisenberq, MD 
Clinical Trial Center: Consumer Product Testlno Comoanv, Inc .. 70 New Dutch Lane, Fairfield NJ 07004 
Publication (reference): None 
Clinical Trial Period: Approximately 6 weeks; start 
J Phase of Development: I 
date to be determined 
Clinical Trial Design: This is a single-center repeated insult patch test in healthy male and female subjects 
aced 18 to 79 years. inclusive. 
Objectives: The first primary objective of this trial is to determine by repetitive epidermal contact, the primary 
or cumulative irritation potential of a test material. The second primary objective of this trial is to determine •· 
by reoetitive eoidermal contact, the allergic contact sensitization ootential of a test material. 
Methodology: Subjects will be patched with a test material, a positive control and a negative control 10 times 
over 40 days, 9 during Induction Phase and 1 during Challenge Phase. 
Each patch will be worn for 
approximately two days. Before each patch application, the test site will be evaluated using the Erythemal 
Scoring Scale (ESS) and Additional Reaction Scoring. Following a Rest Phase of approximately 10 to 14 days, 
the subjects will again be patched on a virgin test site with the test material (but not the negative control, nor • 
the positive control). 
After two days of skin contact, the test sites will be evaluated using the ESS and 
Additional Reaction Scoring on removal day and Days 1 and 2 post-removal. The ESS and Additional Reaction , 
Scoring results will be evaluated to determine the allergic potential of the test material. The three test sites · 
will be as follows: test material; saline neoatlve control: and oositive control (0.4% SLS). 
Number of Subjects Planned and Analyzed: Approximately 57 subjects will be enrolled in the trial so that at! 
least ?0 subjects will complete the trial. 
Data from all subjects who complete the Induction Phase will bej 
analyzed for irritant contact dermatitis potential. Data from all subjects who complete the Challenge Phase wi!J 1) 
. be analyzed for allerqic contact sensitization ootential. 
Diagnosis and Main Criteria for Inclusion: Healthy adult male and non-pregnant females aged 18-79 years, 
inclusive. 
Test Material, Dose and Mode of Administration, Batch Number: The test material, approximate 8 mm disc of 
NeoMatriX™, will be applied to the cotton pad of each patch. 
Patches consisting of the test material and 
controls will be aoolied to soecific test sites on the back of each subiect. 
Duration of Treatment: Fresh patches of test material and controls during the Induction Phase (approximately: 
3 weeks); no patches during the Rest Phase (approximately 2 weeks); and one patch of test material d1,1ring 
Challenge Phase (approximately 1 week). No negative control nor positive control will be applied d1,1rir:ig the. 
Challenqe Phase. 
. 
' ., 
Criteria for Evaluation: Irritant contact dermatitis potential and allergic contact sensltlzatlon potential will be 
assessed throuqh the evaluation of the test sites of aoolication uslno the ESS and Additional Reaction Scorlnq. 
Statistical Methods: The ESS scores and Additional Reaction Scoring scores will be tabulated. The tnddence of 
AEs, new-onset AEs, will be summarized. 
Maximum intensity and duration of AEs will be summarized by, 
treatment orouo, 
, 
I 
I, 
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FLOW CHART OF TRIAL DESIGN 
r, 
r. 
Recruit Potential Subiects 
I 
Execute Informed Consent Process 
I 
Medical History, Con Meds 
I 
Initial Evaluation of Test Sites 
I 
Week 1 
Patch Test Material 
I 
Test Site Evaluation 
I 
Week2 
Patch Test Material 
I 
Test Site Evaluation 
I 
Week3 
Patch Test Material 
I 
Test Site Evaluation 
I 
Week4- 
Rest 
5 
I 
Patch Test Material 
I 
Remove Patch and 
Week6 
Evaluate Test Sites at removal, Day 1, 
and Dav 2 
I 
Close Trial 
',, 
. \, 
' 
',,(' 
3x 
' 
'l-,, 
3x 
' 
'! 
\ 
3x 
. ',~ 
', 
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1 
Background 
A repeated insult patch test is a test devised to ascertain if an agent has the potential to cause contact 
irritation or contact allergy in the skin (Reference 12.1 and 12.2). 
Allergy is only elicited in 
immunologically competent individuals who have become sensitized through exposure to the agent 
following repeated cutaneous patch applications. 
2 Trial Objective 
The first primary objective of this trial is to determine by repetitive epidermal contact, the primary or 
cumulative irritation potential of a test material. 
The second primary objective of this trial is to determine by repetitive epidermal contact, the ailf-!rgic 
contact sensitization potential of a test material. 
" 
3 
Pr~posed Schedule 
Proposed trial initiation and termination dates will be established prior to the start of testing. 
The 
summary schedule of Induction Phase visits is shown in the table below. 
Induction Phase Visits 
•• c:• r,·rd ' 
rt 
1 
2 
3 
4 
5 
6 
7 
Pro~ ure1.01 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The summary schedule of Rest Phase and Challenge Phase visits is shown in the table below. 
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Rest Phase and Challenge Phase Visits 
' 
 
 
 
 
 
 
 
 
 
 
 
4 Test Materials 
4.1 Identification 
The Sponsor's coded test material will be uniquely identified by a CPT trial number. CPT will 
record the test material name, physical description, lot number (if applicable), Sponsof and 
date received into the log-in database. 
·' 
4.2 Storage 
 
 
4.3 Controls 
 
 
 
4.4 Disposition 
At the conclusion of the trial, all remaining test material will be retained by CPT for 30 days 
and then discarded in accordance with local, state and federal laws and regulations unless 
the Sponsor has arranged for a different disposition in writing. 
5 
Selection and Withdrawal of Subjects 
5.1 Number of Subjects 
At least 50 subjects will complete the trial. 
Subjects who meet all of the inclusion criteria 
(Section 5.2) and none of the exclusion criteria (Section 5.3) will qualify for the trial. 
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5.2 Inclusion Criteria 
1. Subjects must be 18-79 years of age (inclusive); 
2. 
Subjects must understand and execute an Informed Consent Form that includes a HIPM 
statement; 
' )f. ,, 
3. 
Subjects must be considered dependable and able to follow directions; and 
4. 
Subjects must receive a copy of their executed Informed Consent Form. 
5.3 
Exclusion Criteria 
1. Subjects who are in ill health, i.e., a febrile illness lasting more than 24 hours in the six 
days prior to first patch application; 
2. Subjects who are taking medications other than birth control, which could influence the 
purpose, integrity or outcome of the trial; 
3. 
Female subjects who are pregnant, planning to become pregnant or lactating during the 
course of the trial; 
4. 
 
 
 
 
 
 
 
 
 
9. Subjects with a significant past medical history of hepatic, renal, cardiac, pulmonary, 
digestive, hematological, neurological, locomotor or psychiatric disease; 
10. Subject with a history of asthma only if requiring regular medication or hay fever 
that required prescription treatment in two or more of the previous three years.;:· 
11. Subjects with a history of multiple drug hypersensitivity; 
12. Subjects with immunization less than 10 days prior to the test patch appllcatlon; 
13. Subjects with a medical history indicating atopy; 
14. Subjects with a sensitization or questionable sensitization in a RIPT. 
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5.4 Prohibitions and Restrictions 
1. 
No use of aspirin, excluding a daily dose of 81 mg, or non-steroidal · anti- 
inflammatory drugs for the duration of the trial; 
2. 
No use of tanning beds or sun lamps or deliberate exposure of the test -sltes to 
natural sunlight for the duration of the trial; 
3. 
No immunization during the trial. 
5.4 Withdrawal of Subjects 
The subject is free to withdraw their consent to participate in the trial at any time arf& for 
any reason, in accordance with the principles of the World Medical Association Declaration of 
Helsinki (as amended) and of the Belmont Report. The PI also has the right to withdraw a 
subject from the trial for safety, lack of efficacy or administrative reasons. 
Possible reasons why a subject may be withdrawn from the trial include the following: 
1. 
Experiences a serious or intolerable AE; 
2. 
Develops, during the course of the trial, symptoms or conditions listed in the 
exclusion criteria, including pregnancy; 
3. Takes medications that are contraindicated, as described in the exclusion criteria; 
4. Incurs a protocol violation such as failure to comply with the specified treatment 
regimen or failure to comply with the visit schedule; or 
5. 
Requests an early discontinuation due to: 
• A clinical reaction for which the PI did not consider removal from the trial to be 
necessary; 
• Other (non-specific) subject-initiated reason 
5.5 
Disposition of Withdrawn Subjects 
The date the subject is withdrawn from the trial and the reason for discontinuation will be 
recorded on the CRF. All evaluations scheduled for the final trial visit will be completed as 
soon as possible after the subject is withdrawn from the trial. 
• ~I 
1 
When a subject fails to return for scheduled trial visits, the PI or designee will make a 
reasonable effort to contact the subject and determine why the subject failed to return. Thfs 
information will be recorded on the CRFs. The PI will encourage all subjects who decide to 
withdraw from the trial to complete all evaluations, which may be necessary to assure that 
the subject is free of untoward effects, and to seek appropriate follow-up for any continuing 
problem. 
6 
Methodology 
 
 
 
 
 
 
 
 
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.. !'< 
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6.1 
Design 
This is a single-center RIPT in healthy male and female subjects aged 18 to 79 years; 
inclusive. 
Subjects will be screened for eligibility within 7 days prior to the first .dose 
administration. Subjects will be asked to appear at the Testing Facility on Day 0 for the first 
application of patches. During the Induction Phase subjects will be patched 9 times in 21 
days. Evaluations of the test sites will occur prior to patch application. The scores of these 
evaluations will be analyzed for irritant contact dermatitis potential. 
After an approximately 2 week Rest Phase, subjects will return to the Testing Facility fqr the 
Challenge Phase. Virgin sites on the subjects' back will receive patches. The patches wilJ 
remain on the test sites for two days of continuous skin contact. Evaluations of the sites wi!I 
occur the day of patch removal and 1 day and 2 days after patch removal. The scores of 
these evaluations will be analyzed for allergic contact sensitization potential. 
i 
, 
6.2 Patch 
Prior to the initiation of the trial, the test material will be supplied as an 8mm disc packaqed 
 
 
 
 
 
 
 
 
 
 
 
6.3 Test Procedure 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
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greater require discontinuation of further applications at that test site. Application 
 
 
 
 
 
i,• 
: 
 
 
 
 
 
 
6.3.2 Challenge Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.3 Re-Challenge Phase 
In the event of a significant reaction occurring during the Challenge phase, the PI 
may decide to schedule a Re-Challenge Patch test for confirmatory purposes. This 
follow-up investigation will be conducted approximately 2 weeks after the 
completion of the Challenge Phase. 
The application of the patch to a vi~gin test 
site on the back will be identical to the Challenge Phase. Additionally, the !:?Ubject 
may conduct repetitive applications to the anti-cubital fossa for 4 com:1~cutive 
•. I 
• 
days. 
Observations of both test sites will be recorded Days 1, 2 and 1!3. post 
application. 
· .•:· 
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· 
,, · 
6.4 Evaluation 
6.4.1 ESS 
r 
Erythema at the test site is evaluated according to the ESS shown below. Any 
score of 2 through 4 will be captured as an AE. 
Score 
0 
 
 
 
 
 
 
 
 
 
6.4.2 Additional Reaction Scoring 
j, 
If present, each additional reaction sequela is evaluated according to the following 
letter scale and a corresponding numerical scale to indicate severity shown below. 
Any Severity Score of 2 through 4 will be captured as an AE. 
' 
Description 
B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Description 
Mild 
Moderate 
Marked 
Severe 
7 
Statistical Methods 
None anticipated. 
8 
Safety 
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease that may or may 
not be considered related to the test material. This includes unfavorable or unintended change iri body 
structure (signs), body function (symptoms), abnormal or severely altered laboratory result, or 
worsening of any pre-existing condition that occurs during the course of the trial. 
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' 
Also, each subject will be carefully monitored for the development of any AEs. This information may, be 
obtained from signs and symptoms detected during each examination, observations by the trial 
personnel or spontaneous reports from the subjects. 
This includes AEs resulting from concurrent 
illnesses, reactions to concomitant medications or progressive disease states. 
All AEs, whether volunteered, elicited or noted during examination, shall be recorded on the subject's 
CRF using the Common Terminology Criteria for Adverse Events (CTCAE) v.4. 
The PI will evaluate all AEs for their relationship to, or association with the test material ( or .other 
causes) and their intensity. 
Additionally, the actions taken (e.g., reduction of test material 
concentration, discontinuation of test material application, administration of treatment,. etc.) and the 
resulting outcome of the AE will be indicated on a CRF (e.g., Sponsor, CPT, MedWatch or other 
appropriate Form). 
' 
Any subject who is withdrawn from the trial due to an AE will be followed until the outcome of the event 
is determined, and the PI will prepare a written summary of the event and document the available 
follow-up information on a CRF. 
;. '~ 
. ' 
: \:,\,, 
8.1 Relationship to Test Materials 
The relationship or association of the AE to a test material will be characterized as unlikely, 
possible or probable (Reference 12.3). Assessments shall be recorded on the CRF .. 
' ,f!: 
I \ ~ 
Causality 
' 
Term 
Assessment Criteria 
'· 
Probable 
Event or laboratory test abnormality, with plausible time relationship to test 
material intake 
Unlikely to be attributed to condition (or disease) or other products in use by 
subiect 
Response to withdrawal clinically reasonable 
Rechallenoe satisfactory or not required 
', 
Possible 
Event or laboratory test abnormality, with reasonable time relationship to test 
material intake 
Could also be explained by condition (or disease) or other products in use by 
subiect 
Response to withdrawal unclear or lacking 
' 
. i1 
Unlikely 
Event or laboratory test abnormality, with a time to test material intake thgit 
,. 
' 
makes a relationship improbable (but not impossible) 
: 1: 
' 
Condition (or disease) or other products provide plausible explanations 
: t I 
4 
For safety analyses, AEs that are classified as a possible o r probable association, to a test 
material shall be considered test material-related AEs. 
·• 
· 
. r' 
'; 1 
Follow-up of the AE, after the date of discontinuation of exposure to test material is required 
if the AE or its sequelae persist. Follow-up is required until the event or its sequelae resolve 
or stabilize at a level acceptable to the PI and to the Medical Monitor. 
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8.2 Severity of Adverse Event 
The severity of each AE will be graded using the following criteria: 
. i 
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Grade 
1 
2 
3 
4 
5 
Description 
, 
, 
Mild 
- 
Minor AEs 
requmnq 
no 
specific 
medical 
intervention 
indudinq 
asymptomatic laboratory findings only, or findings of marginal clinical relevance. ,: 
Moderate - AEs requiring minimal, local, and/or noninvasive intervention. 
. ti 
; 
Severe - Severe and undesirable AEs involving significant symptoms req~iring 
hospitalization or invasive intervention; transfusion; elective 
interveh~rona,i 
radiological procedure; or therapeutic endoscopy or operation. 
' 
Life-threatening or debilitating - AEs complicated by acute, life-threatening 
metabolic 
or 
cardiovascular 
complications 
such 
as 
circulatory 
failure, 
hemorrhage, or sepsis. Also, life-threatening physiologic consequences; need for 
intensive care or emergent invasive procedure; 
emergent interventlonel 
radiological procedure, therapeutic endoscopy or operation. 
' 
' 
Death 
If the Grade changes within a day, the maximum Grade shall be recorded. If the Grade 
changes over a longer period of time, the changes shall be recorded as separate _events 
(having separate onset and stop dates for each grade). 
8.3 Serious Adverse Events 
The PI will evaluate all serious AEs as to their intensity, relation to test material, outcome, 
and action taken. An SAE is defined as any AE that suggests a signi_ficant clinical hazard, 
contraindication, side effect, or precaution. This includes any event which: 
' 
• Results in death; 
• Is life-threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Results in a congenital anomaly/birth defect; 
• Is an important medical event based on medical judgment, which jeopardizes the 
subject and requires medical or surgical intervention to prevent one of the outcome's 
listed above. 
1 
-.~ 
• ·; 
,,-, 
,I'\! 
ANY SAE, INCLUDING DEATH DUE TO ANY CAUSE, WHICH OCCURS DURING THE TRIAL, 
WHETHER OR NOT RELATED TO THE TEST MATERIAL, MUST BE REPORTED TO THE 
SPONSOR OR MEDICAL MONITOR WITHIN 24 HOURS OF WHEN THE PI BECAME AWARE OF 
THE SAE. 
Dayna Healy 
dhealy@nextgenbiologics.com 
The PI must complete an AE form and send the form to the Medical Monitor or Sponsor 
within 24 hours of when the PI became aware of the SAE. 
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CPT may supply MedWatch Forms for SAE reporting, but the responsibi,lity for reportinq SAEs 
to FDA rests with the Sponsor or Medical Monitor. 
If additional information regarding :a 
previously submitted SAE is obtained, a follow-up SAE report will be completed and sent to 
the Sponsor or Medical Monitor as indicated above. A copy of safety reports that c1r¢ filed 
with the FDA will be sent to each PI participating in any ongoing trials the Spo~~or is 
conducting with the same test material. 
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The PI will promptly notify the IRB for only the following AEs. 
• A single occurrence of a serious event that is uncommon and strongly associated with 
drug exposure. 
• A single occurrence, or more often a small number of occurrences of a serious, event 
that is not commonly associated with drug exposure, but uncommon in the clinic;a:I trlal 
populations. 
• Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be 
an unanticipated problem. 
There should be a determination that the series pf AEs 
represents a signal that the AEs were not just isolated occurrences and involve risk to 
human subjects. 
• An SAE that is described in the investigator's brochure, protocol, or informed consent 
documents, but occurs at a specificity that is inconsistent with prior observations., AA. 
1 
• An SAE that is described or addressed in the investigator's brochure, protocol' or 
informed consent documents, but for which the rate of occurrence in the trial 
represents a clinically significant increase in the expected rate of occurrence. 
• Any other AE or safety finding that would cause the sponsor to modify the investigator's 
brochure, clinical trial protocol, or informed consent documents, or would prompt other 
action by the IRB to ensure the protection of human subjects. 
8.4 Management of Adverse Events 
All AEs will be reported from the time a signed and dated informed consent form is obtained 
until completion of the last trial-related procedure. Those AEs meeting the definition of SAEs 
must be reported using the Adverse Event Form, including SAEs spontaneously reported to 
the PI within 30 days after the subject has completed the trial (including post-trial follow 
up). The Sponsor assumes responsibility for appropriate reporting of adverse events to the 
appropriate regulatory authorities. 
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All pregnancies occurring during clinical trials must be reported to the Sponsor, or its 
designee, by the PI within 24 hours of observation or notification o~ the occurrence. 
AU 
efforts should be made to obtain follow-up information regarding the outcome of pregnancy 
and any postnatal sequelae in the infant. Although the occurrence of pregnancy is not ah 
SAE, complications or serious outcomes of the pregnancy must be reported as appropriate. 
Events that meet the criteria for an SAE must be reported. 
Pregnancy is consid~(id ah 
exclusion criterion in this trial. 
Any trial subject who becomes pregnant durin~ ; trial 
participation must promptly discontinue further administration of the test material. 
Symptomatic treatment of suspected AEs shall be initiated as medically indicated. '. Any such 
treatment must be recorded on the CRF. Interruption or discontinuation of test rnateri~I 
application may also be required in some circumstances. Causes of AEs other than the trial 
test material (such as intercurrent illness, other medications, or treatments) shall be 
excluded before adjustment, interruption, or discontinuation of the trial test material. 
If 
there is doubt concerning the cause of a serious or potentially serious AE, exposure to the 
trial test material shall be discontinued. 
8.5 Test Material Deficiency 
I 
Any inadequacy of the test material with respect to its identity, quality, durability, .reli9bilit{,, 
or performance will be considered a deficiency. Test material deficiencies can include but 
are not limited to malfunctions, use errors, and inadequate labeling. 
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Any deficiency identified with the test material through the trial will be recorded on th~ 
appropriate CRF along with the date of occurrence and a full description of the deficiency. 
Any AE occurring as a result of the deficiency will be recorded on the AE CRF- page a~ 
described (Section 7). 
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Source Data and Documents 
All data reflecting subject experiences with the trial regimen will be reported by the PI to the Sponsor. 
One document serves as both the source and CRF document. Whenever possible, all data and 
observations shall be recorded on. CRFs. The CRFs are peer reviewed by the clinic staff, as well as 
reviewed by CPT's Quality Assurance Unit. 
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CRFs include all original records of observations, results and activities necessary to reconstruct anJ 
evaluate the trial. CRFs include, for example, ICFs, subject notes, and any other records of procedures 
performed during the trial. All CRFs are to be executed by the PI in a timely manner. Data is reviewed 
by looking at the CRFs. Correction of CRFs will be according to the SOPs at CPT. 
· · 
10 Quality Control and Quality Assurance 
10.1 Trial Monitoring by the Sponsor 
In accordance with current FDA regulations and GCP guidelines, the Sponsor's Mo11itor or 
designee may periodically inspect CRFs, research facilities and clinical laboratory f~cilitie~ 
associated with this trial at mutually convenient times during or after completion of the trial 
(Reference 12.4). 
The monitoring visits provide the Sponsor with the opportunity "to 
evaluate the progress of the trial, verify the accuracy and completeness of CRFs, assure that 
all protocol requirements, applicable FDA laws and regulations and PI's obligations are being 
fulfilled and resolve any inconsistencies in the CRFs. 
10.2 Trial Reviewing by CPT Quality Assurance Department 
The CPT Quality Assurance Department shall periodically audit the trial for compliance with 
the approved protocol (or written instructions provided by the Sponsor), CPT SO~s, '.~nd a11 
applicable laws and regulations. Quality Assurance shall review trial records, documents, 
and reports for accuracy, completeness, consistency and compliance with the approved 
protocol ( or written instructions received from the Sponsor), CPT SOPs, and all applicable 
laws and regulations. 
10.3 Data Maintenance 
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Trial data shall be maintained in accordance with the intent and purpose of GCP guideline$, 
CPT SOPs and all applicable laws and regulations. Where trial data is entered into electronic 
databases, audits shall be conducted to verify accuracy of data entries against CRFs. Quality 
Assurance reviewing will be conducted in accordance with the SOPs of CPT to 9ssure th~ 
quality and integrity of the clinical data. 
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11 Obligations of the Sponsor, the Monitor and the PI 
11.1 Ethics 
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The Sponsor, the Monitor, and the PI will assure that all aspects of this trial are conducted in 
accordance with all regulations and laws guiding the protection of human subjects (including 
the regulations requiring informed consent (Reference 12.5). The trial will be condLI<;:t,d in 
accordance with the Principles of the Declaration of Helsinki (as amended) and the Be(p,ont
Report, with GCP, and with the SOPs of CPT. 
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11.2 Institutional Review Board 
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Prior to enrollment of subjects into the trial, as required by federal regulations (Reference 
12.6), the protocol and ICF will be reviewed and approved by an appropriate IRB. Tne PI 
will assure that all aspects of the institutional review will be conducted in accordance with 
current federal regulations. A letter documenting the IRB approval with the names and titles 
of the IRB members may be received by the Sponsor upon request. Amendments to the 
protocol or the ICF will be subject to the same requirements as the originals. 
The PI shall submit a progress report at least annually to the IRB of those test material­
specific trials approved by the IRB. This report shall include: the total number of test 
materials evaluated using this protocol; a description of any changes in trial procdues or 
amendments to the protocol; deviations from the protocol; the number and type of subjects 
evaluated; the number of subjects who discontinued (and the reasons for discontinuation); 
the number of subjects who completed the trial; and a description of any AEs .. 
The PI shall promptly notify the IRB of SAEs or any other information that may hae ab 
impact on the safety of the trial. 
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11.3 Informed Consent 
Written informed consent must be obtained from each potential subject prior to entering the 
trial (Reference 12.5). Potential subjects will be informed of the nature of the trial'. and shajl 
receive complete answers to any questions raised during the consenting process. · A !g.n 
ICF shall be provided to each subject. The PI must assure that executed ICFs vyiff be
obtained from each subject prior to trial entry, and that the informed consent process will be 
conducted in accordance with current local, state, and federal laws and regulations. 
Executed ICFs will be retained by the PI with the CRFs. 
11.4 Research Subject Confidentiality 
The names and identities of all research subjects shall be maintained in strict confidece b,y
CPT and will not appear on CRFs or other records provided to the Monitor or the, Sponsor, 
While the names and identities of the subjects need not be divulged, the records rt,st b,e 
available for inspection. This can be accomplished by redacting the subject's name$ and 
replacing the name with the subject's trial ID number. The ICF must include appropriate 
statements explaining these requirements. If this policy conflicts 'with local regulatory 
e_s!riions or institutional requirements, the Sponsor or Monitor shall notify CPT prior to trirl
m1t1at1on. 
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11.5 Deviation from the Protocol 
The PI will not deviate intentionally from this protocol for any reason without prior approval 
of the Sponsor, except when the change is necessary to eliminate an apparent immediate 
hazard to the subjects. In that event, the PI must notify the Sponsor in writing within 5 
working days after the change is implemented. 
1 i 
Any other changes to this protocol must be made in the form of a formal amendment: to the 
protocol and must be approved in writing by the PI and the Sponsor prior to implementation. 
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11.6 Clinical Trial Records 
During the trial, the PI will maintain adequate records for the trial. This may include m~dical 
records, records detailing the progress of the trial for each subject, laboratory reports, ~RFs, 
executed ICFs, test material disposition records, AE reports and information regarding 
subject discontinuation or completion of the trial. 
Trial documentation may include all CRFs, monitoring logs, correspondence between the 
Sponsor and the PI, protocols, amendments, and deviations, test material supplies receipt, 
dispensing and final disposition records, and executed ICFs. 
· 
All . records pertaining to the conduct of the clinical trial including signed CRFs, ICFs, drug 
accountability records, and other trial documentation shall be retained in the CPT archives 
for a minimum of 10 years. At any time prior to the completion of the tenth archival year, 
the Sponsor may submit a written request to obtain custody of these records and documents 
once the CPT archive period has been completed. This transfer shall be performed· at the 
expense of the Sponsor. In the absence of such written requests, trial-related records and 
documents shall be destroyed at the end of the CPT archive period, with no further notice, ih 
a manner that renders them useless. 
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11.7 Final Report 
A Draft Report, describing all procedures used and a summary of the results, will be 
prepared and sent to the Sponsor following completion of the trial and after review by the 
sponsor and necessary edits, a Final Report will be prepared and sent to the Sponsor: ~:n!ess 
otherwise agreed upon by the Sponsor and CPT. 
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11.8 Communication and Publication of Results 
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The Sponsor shall retain ownership of all CRFs, data analysis and reports, which res~lt frorh 
thls trial. All information obtained as a result of the trial will be regarded as confidential. ' ! ·· 
The Final Report or Report summary is submitted for the exclusive use of the person, 
partnership, or corporation to whom it is addressed, and neither the Report nor the name of 
CPT nor any member of its staff, may be used in connection with the advertising or sale of 
any product or process without prior written authorization by a legally binding officer of cP-r;:. 
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12 References 
12.1 
Shanahan RW, Weiss M, Weiss C, Murphy E. "Consumer Testing and Evaluation of Personal 
Care Products," in The Chemistry and Manufacture of Cosmetics/ Volume I- Basie 5_cience, 
3rd Edition, M. Schlossman,Ed., Allured Publishing Corp, Carol Stream, IL, 2001, PP< 433;. 
452. 
12.2 
McNamee PM, Api AM, Basketter DA, Gerberick GF, Gilpin DA, Hall BM, Jowsey I, & Robinson 
MK. A review of critical factors in the conduct and interpretation of the human repeat insult 
patch test. Regulatory Toxicology and Pharmacology, 2008; 52:24-34. 
12.3 
Guidance for Industry: Good pharmacovigilance practices and pharmacoepldemloloqlc 
assessment, DHHS, FDA, March 2005 
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12.4 
Guidance for Industry: 
Oversight of clinical investigations - A risk-based approach to 
monitoring, DHHA, FDA, August 2013 
12.5 
Informed Consent of Human Subjects 21 CRF Part 50 Subpart B 
12.6 
Institutional Review Boards, 21 CFR, Part 56 
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