Post-Marketing Surveillance of Humira in Korean Pediatric CD Patients Under the "New-Drug Re-examination"
Conditions: Pediatric Crohn's Disease
Sponsor: AbbVie

Adalimumab (Humira®)
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Protocol Amendment 2
Title Page
Title 
Post-Marketing Surveillance of Humira® in Korean Pediatric CD
Patients under the “New-Drug Re-examination”
Protocol Version Identifier
P15-619 
Date of Last Version of 
Protocol
April 29, 2017 
Marketing 
Authorization
Holder(s)
AbbVie Korea Ltd.
Research 
Question 
and 
Objectives 
To evaluate the safety profile of Humira® for Pediatric CD patients in 
normal medical practice
Country(-ies) of Study
South Korea
Author
This study will be conducted in compliance with this protocol.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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Adalimumab (Humira®)
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Protocol Amendment 2
Marketing Authorization Holder(s)
Marketing 
Authorization 
Holder(s)
AbbVie Korea Ltd.
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Adalimumab (Humira®)
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Protocol Amendment 2
1.0
Table of Contents
1.0
Table of Contents ..................................................................3
2.0
Abbreviations ........................................................................5
3.0
Responsible Parties ...............................................................6
4.0
Abstract .................................................................................7
5.0
Amendments and Updates ....................................................8
6.0
Milestones ..............................................................................8
7.0
Rationale and Background ...................................................8
8.0
Research Question and Objectives.....................................10
9.0
Research Methods ...............................................................11
9.1
Study Design........................................................................................ 11
9.2
Setting.................................................................................................. 11
9.3
Variables.............................................................................................. 13
9.4
Data Sources ........................................................................................ 15
9.5
Study Size ............................................................................................ 15
9.6
Data Management ................................................................................ 18
9.7
Data Analysis ....................................................................................... 18
9.8
Quality Control..................................................................................... 22
9.9
Limitations of the Research Methods.................................................... 22
9.10
Other Aspects....................................................................................... 22
10.0
Protection of Human Subjects............................................22
11.0
Management and Reporting of Complaints.......................23
11.1
Medical Complaints ............................................................................. 23
11.1.1
Adverse Event Definition and Serious Adverse Event Categories ......... 23
11.1.2
Severity................................................................................................ 25
11.1.3
Relationship to Pharmaceutical Product................................................ 25
11.1.4
Serious Adverse Event Collection Period.............................................. 26
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11.1.5
Serious Adverse Event Reporting ......................................................... 26
11.1.6
Pregnancy Reporting ............................................................................ 27
11.1.7
Malignancy Reporting .......................................................................... 27
11.2
Product Complaint................................................................................ 27
11.2.1
Definition............................................................................................. 27
11.2.2
Reporting ............................................................................................. 28
12.0
Plans for Disseminating and Communicating Study 
Results..................................................................................28
13.0
References............................................................................30
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2.0
Abbreviations
AE
Adverse Event
5-ASA
5-Aminosalicylic Acid
CDAI
Crohn’s Disease Activity Index
CRA
Clinical Research Associate
CRF
Case Report Form
CD
Crohn’s Disease 
SAE
Serious Adverse Event
MFDS
Ministry of Food and Drug Safety
PCDAI
Pediatric Crohn’s Disease Activity Index
PMS
Post-Marketing Surveillance
PPD test
Purified Protein Derivative test
TB
Tuberculosis
TNF
Tumor Necrosis Factor
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3.0
Responsible Parties
SDP :  
 
 
            
CRO(s):
              
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4.0
Abstract
Title: Post-Marketing Surveillance of Humira® in Korean Pediatric CD Patients under the “New-Drug 
Re-examination”
Rationale and Background: This non-interventional, observational study will be conducted in 
compliance with the New Drug Re-examination Guideline in Korea
Research Question and Objectives:
To evaluate the safety profile of Humira® for Pediatric CD patients in normal medical practice:
(1)   Serious adverse event•adverse drug reaction
(2) Unexpected adverse event•adverse drug reaction 
(3) Already known adverse drug reaction
(4) Non-serious adverse drug reaction
(5) Adverse events resulting from drug misuse, drug abuse or drug interaction
(6) Other information related to the product’s safety and effectiveness (including the influence to the 
laboratory value)
Study Design: Post-Marketing Surveillance
Population: Pediatric CD patients who have been prescribed Humira® by the treating physician
Variables: Demographics, Medical History, PPD Skin Test, Chest X-ray, Interferon Gamma Release 
Assay, Concomitant Medication, Safety, PCDAI score (CDAI score if it is evaluated)
Data Sources: paper Case Report Form
Study Size: 141 patients
Study Duration : 12 Sep 2013 ~ 11 Sep 2017 
Data Analysis:
(1)    The safety analysis data set : all subjects who have received at least one dose of Humira® during 
the study and have been followed up for the safety information
(2)   The effectiveness analysis data set:
x
Effectiveness of Humira® induction therapy: all subjects who have been administered Humira®
and received Humira ® for 4 weeks including induction period (±1 week) and for whom 
effectiveness evaluation parameters have been recorded.
x
Maintenance effectiveness of Humira®: all subjects who have been administered Humira® and 
received Humira® for 6 months (±4 weeks) and for whom effectiveness evaluation parameters 
have been recorded.
Milestones:
(1)  Start of Data  collection : 1Q 2015
(2)  End of Data collection : 3Q 2017 
(3)  Final Report of Study Results : 4Q 2017 
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5.0
Amendments and Updates
The purpose of the amendments and updates is below:
11.1.6 
Pregnancy 
Reporting
To clarify a scope of expedited reporting 
requirements for pregnancy
Amendment 1
11.1.7 
Malignancy 
Reporting
To add Humira specific expedited reporting 
requirements for Malignancies in Pediatric and 
Young Adult Patients according to global SOP
Amendment 1
11.2 
Product 
Complaint
To add a definition of product complaints and 
reporting requirements
Amendment 1
9.5 Study Size/9.7 
Data Analysis
To change the number of subjects to be collected 
for surveillance to meet the local regulatory 
requirements
Amendment 2
In addition, administrative changes were incorporated to clarify the person in charge and 
the references.
6.0
Milestones
Major study milestones and their planned dates are as follows:
Start of Data Collection:
1Q 2015
End of Data Collection:
3Q 2017 
Final Report of Study Results:
4Q 2017 (Date of submission to MFDS: 11 December 2017)
7.0
Rationale and Background
Rationale
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This surveillance will be conducted in compliance with the New Drug Re-examination 
Guideline in Korea and this protocol is written in accordance with the guideline. Safety 
data of this study will be compared to product label claim for evaluation of the 
consistency of the safety profile in the real word setting.
Background
Approximately 25% of IBD patients are diagnosed as children, and the IBD 
characteristics of pediatric patients differ from those of adults as outlined below.1-3 A
recent single center study showed that the incidence of pediatric IBD has been rapidly 
increasing in Korea in recent years.4 In this study, relevant family history was less 
prevalent and phenotypic expression differed from what was seen in Western countries.
Children with Crohn's disease can experience abdominal pain, intestinal obstruction and 
strictures, fistulas, abscesses, perianal disease, adverse events of treatment such as 
corticosteroids and surgery, and nutritional complications. A major difference between 
adult and pediatric CD is an impact of malnutrition. It can lead to delayed puberty and 
growth impairment which result in significant psychosocial complications.5-8 At first, the 
goal of treatment of CD for children is to induce and maintain clinical remission. 
Restoration and/or preservation of normal growth and pubertal development are additional 
therapeutic goals in children with CD.9
The first line conventional therapy for mild patients includes 5-aminosalicylates and 
exclusive enteral nutrition (EEN). Corticosteroids are prescribed for moderate patients for 
induction. Immunomodulators such as azathioprine, 6-MP or MTX are used for 
maintenance for those.10
Therapeutic options for Crohn's disease are evolving, and recently, a new treatment 
approach has been suggested using biological agents to heal mucosa and alter natural 
history of disease.11-12
Until now, TNF blockade including adalimumab and infliximab has been prescribed for 
adult CD patients. In randomized controlled trials, adalimumab rapidly induced and 
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maintained clinical remission in adults.13-17 The efficacy and safety of adalimumab for 
induction and maintenance of clinical remission in Western children with moderate to 
severe CD who had failed corticosteroids or immunosuppressants, including prior 
infliximab in > 40% of subjects, was demonstrated in the Imagine 1 trial.
This study will evaluate the safety and effectiveness of adalimumab for Korean pediatric 
patients with moderate to severe Crohn’s disease (CD).
8.0
Research Question and Objectives
The objective of this surveillance is to evaluate the following items regarding the safety 
profile of Humira® for Pediatric CD patients in normal medical practice:
(1)
Serious adverse event & adverse drug reaction
(2)
Unexpected adverse event & adverse drug reaction
(3)
Already known adverse drug reaction 
(4)
Non-serious adverse drug reaction
(5)
Adverse events profile resulting from drug misuse, drug abuse or drug interaction
(6)
Other information related to the product’s safety and effectiveness (including the 
influence to the laboratory value)
The hypothesis of this study is that Humira® will present a safety profile consistent with 
that seen in the phase 3 clinical studies and will be efficacious in Korean Pediatric CD 
patients.
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9.0
Research Methods
9.1
Study Design
This study is a non-interventional, observational study of Humira® in the treatment of 
pediatric CD as per the New Drug Re-examination Guideline in Korea.
This study will be conducted in institutions which provide a written agreement to AbbVie 
Korea, and where the use of Humira® for pediatric CD is following their normal medical 
practice setting. Pediatric patients who are prescribed Humira® as per physician’s medical 
judgment in accordance with the approved SmPC will be enrolled in the study.
As this is a post marketing surveillance, AbbVie is NOT involved in the product supply 
since the drug is being used according to the approved marketing label and is to be 
prescribed by the physician under usual and customary practice of physician prescription.
9.2
Setting
Selection of Study Population
Pediatric CD patients who has been prescribed Humira® by the treating physician as per 
Korean label will be enrolled.
The patients who are receiving Humira® for pediatric CD during study period and meet 
the inclusion /exclusion criteria will be enrolled in the sites which signed a contract with 
AbbVie.
Once the study agreement is in place, the surveillance will be initiated at the site, and all 
patients who are prescribed Humira® for pediatric CD treatment during the surveillance 
period and who meet the inclusion /exclusion criteria will be enrolled in the study until 
the assigned number of subjects are registered at the site.
Inclusion Criteria
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1. Pediatric patients with Crohn’s Disease who are prescribed Humira in accordance with 
the Korean label for Humira authorization (labeling)
2. Patients who have given written authorization or patients whose legal representatives
have given it to use their personal health data for the purposes of this study.
Physician will refer to the product market authorization (label) for inclusion criteria.
Exclusion Criteria
Patient with any of the following should not be registered in this surveillance:
1. Any contraindications to Humira as listed on the approved product market 
authorization (labeling)
2. Patients who is participating on other clinical trials.
Patients will be observed for 6 months following first dose of Humira®.
It is planned to include all patients who are treated with Humira® until the planned number 
of cases are collected to obtain meaningful safety data including TB incidence in the early 
stage of the study conduct. Once this study has been initiated in an institution, physicians 
are recommended to include/recruit all eligible patients who are prescribed Humira®.
An evaluable patient is a patient who has been administered Humira® at least once and 
has safety information at subsequent visits. (or telephone contact, correspondence)
Drop-out patients also will be considered for safety evaluation, if the safety information is 
obtained by follow-up contact. If there is loss of follow-up, the reason will be recorded.
Investigator Selection Criteria
The surveillance will be conducted in medical institutions in Korea. The institutions 
include clinics and hospitals. The physician must meet the following criteria:
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1. A physician who is working in a hospital or clinic and has a patient pool eligible for
this surveillance.
2. A physician who can conduct the study in accordance with the protocol.
3. A physician who agrees to devote adequate time to conduct of the study including 
enrollment activities, following up the patients and filling out the case report forms.
4. A physician who will report to the sponsor any safety and effectiveness data in 
accordance with the protocol.
9.3
Variables
Demographics
Basic demographics including patient initials, age (year and month of birth), sex, weight, 
height, name of institution, department and physician will be taken and recorded.
Diagnosis and Medical History
Diagnosis and medical history including previous TB history or vaccination, will be taken 
and recorded and will include the following items to get patient’s medical status:
x
CD related history ; date of pediatric CD diagnosis, involved intestinal area, 
presence of draining fistula, previous CD related therapy including antibiotics, 
steroids, 5-ASA, Immunosuppressants, biologics and nutritional therapy
x
Previous TB history ;  presence of TB, TB treatment regimen received, 
completeness and appropriateness of the therapy regimen, vaccination
x
Other medical history ; history of previous disease(s), concurrent disease(s), 
history of allergy, pregnancy etc.
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PPD Skin Test 
PPD skin test will be performed and recorded. It will include: Date of PPD test, induration
at PPD test site (in mm). (Refer to MFDS Guideline for Latent TB Management in TNF-
Antagonist Use and TB screening Aide provided by AbbVie.)
Chest X-ray 
Chest X-ray interpretation result will be taken and recorded and will include: Date of 
Chest-X-Ray, presence of latent or active TB lesion. (Refer to MFDS Guideline for Latent 
TB Management in TNF-Antagonist Use and TB screening Aide provided by AbbVie.)
Interferon gamma release assay
Interferon gamma release assay will be performed, recorded and will include: date of 
interferon gamma release assay and result. (Refer to MFDS Guideline for Latent TB 
Management in TNF-Antagonist Use and TB screening Aide provided by AbbVie.)
Treatment with Humira®
Patients will be administered Humira® as per the package label. Unit dose, frequency, 
length of treatment (start date, end date) will be recorded on the appropriate case report 
form.
Concomitant Medication
Concomitant 
medications,
including 
TB 
prophylaxis 
regimen,
corticosteroids, 
immunosuppressants, will be recorded and will include: generic name (brand name in 
case of combination drug), total daily dose, length of administration (start date and end 
date), indication(s).
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Safety (Adverse Event)
Regardless of results of causality assessment, presence of adverse event(s), type of 
adverse event(s), onset, end date, severity, causality assessment by physician on the 
adverse event(s), action taken, outcome will be captured, during the study, from the first 
administration to the surveillance period (from informed consent to up to 70 days 
following the last administration of Humira®) (Section 11.0 Management and Reporting 
of Complaints).
Effectiveness
From the patients treated with Humira®, the effectiveness data (i.e. PCDAI score) at 
previous times before Humira® treatment, at 4 weeks (visit window: ±1 week) and at 6
months (visit window: ±4 weeks) post-treatment will be collected. (CDAI score will be 
collected as well, if possible.)
9.4
Data Sources
Case Report Forms will be supplied by AbbVie Korea. These forms will be used to 
transmit information collected during this study to AbbVie Korea. Case report form must 
maintain pertinent patient background information, e.g., gender, age, medical history, and 
the information to be evaluated. The case report form must maintain patient 
confidentiality, e.g. patient names must not be collected (patient initials are acceptable) 
and date of birth must not be collected (age or month and year of birth are acceptable).The 
physician or staff under his/her supervision must complete the case report forms and 
neither AbbVie nor any agents acting on behalf of AbbVie may complete the case report 
forms.
9.5
Study Size
Number of Patients to be enrolled
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At least 600 subjects were to be collected for surveillance to meet the local regulatory 
requirements, but the number of subjects was adjusted to 141 subjects based on the 
followings:
1) Significantly low incidence and prevalence of Pediatric CD
Based on the data obtained from 1996 to 2002 in North America, 93.6 per 100,000 people 
suffered from Crohn's disease and the incidence rate of Crohn's disease in children aged 
less than 18 years was 3.0 per 100,000 people.18 Additionally, it is reported that when 
considering the ethnic differences, Crohn's disease is more prevalent in developed 
countries and relatively less common in Asia;19 for example, a retrospective study 
conducted in China revealed than the prevalence of Crohn's disease was estimated to be 
1.4 per 100,000 people,20 which was much less than that reported in North America.
According to the data reported to Korea Health Insurance Review & Assessment Service 
in 2015, the number of patients aged 19 years or younger who are with ‘K50: Crohn's 
disease [regional enteritis]’ was only 3,051. Considering that ages eligible for enrollment 
in this Post-Marketing Surveillance are between 6 years and 17 years according to the its 
approved label in Korea, it is expected that the number of patients eligible for this Post-
Marketing Surveillance would be much less than the number aforementioned, but there is 
no specific domestic data to prove it in Korea.
2) Humira is not a primary therapeutic agent for Pediatric CD
Humira® is indicated only to patients with severely active Crohn's disease with inadequate 
response, intolerance, or contraindication to primary trophotherapy, corticosteroids and/or 
immunomodulators according to the approved label, which is reflected in the very limited 
number of patients with Crohn's disease of all ages who received treatment with biologics, 
based on the data reported to Korea Health Insurance Review & Assessment Service
[Table 1].

[Table 1] The estimated number of patients diagnosed with Crohn's disease and 
proportion of those patients with anti-TNF agents prescription
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The number of patients 
diagnosed*
Patients prescribed with anti-TNF agents
The mean number of 
patients†
LG‡
All ages
17,651
1,684
9.5%
* The number of patients diagnosed: The number of patients diagnosed in 2015 according to the disease code (K50: Crohn's disease 
[regional enteritis]); source: Health Insurance Review & Assessment Service; unit: people
† The mean number of patients: The number of patients prescribed with anti-TNF agents for relevant disease codes (K500, K501, 
K508 or K509); source: Health Insurance Review & Assessment Service; unit: people
‡ Percent: calculated by dividing the mean number of patients by the number of patients diagnosed

3) Difficulties in getting patients’ consents
Pediatric CD is indicated for pediatric patients, it is difficult to get pediatric patients’
consents from their parents.
However, we will make every effort to enroll maximum number of subjects. We expect 
maximum 141 patients will be recruited [Table 2].
[Table 2] The number of subjects expected to be enrolled in this study
Classification
No. of subjects
Enrolled subjects as of October, 2016
100
-
subject who start Humira treatment after enroll in the study
71
-
subject who starts Humira treatment before enroll in the study
29
Estimated No. of subjects to be enrolled
Approx. 41

subject who will start Humira treatment after enroll in the study
31*

subject who starts Humira treatment before enroll in the study
10
Total
Approx. 141
*
Calculated as follows: 5.07 (mean number of newly diagnosed patients per month) x 6 months (remaining enrollment 
period) = 30.42 

About 15 investigators across the country will be participating in this surveillance and the 
number of subjects to be collected by each investigator will vary.

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Study Duration
The study duration designated by MFDS is from 12 September 2013 to 11 September 
2017. The study will start after the launch of the product as a new drug for pediatric CD 
and the final report will be submitted to MFDS by 11 Dec 2017. Interim study reports will 
be submitted to MFDS every 6 months for the first 2 years, then annually thereafter 
during PMS period.
9.6
Data Management
Physician should complete the CRFs, sign and date the CRFs accurately. All CRFs must 
be legible and completed in indelible ballpoint ink. Corrections to the CRFs should be 
made with a single line, be initialed and dated, with the reason for changes given. Data are 
not to be obliterated by blacking out, correction fluid, or by erasing the original entry.
At the conclusion of the study, the completed signed and dated case report forms for the 
enrolled patients should be provided to the AbbVie Korea by the physician for every 
patient enrolled in the study. As distinct case report form should be created for each 
unique instance when data is to be collected ONLY data specified in the protocol should 
be collected and submitted to AbbVie Korea.
CRAs or their designees will be responsible to review the collected CRFs for 
completeness and conclusiveness.  
The data entered by the physician will be reviewed by CRAs or their designees and when 
necessary, query will be generated to correct the data by the physician. After completion 
of the data review, data will be locked to prevent further editing.
9.7
Data Analysis
Justification for the planned sample size
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Information on at least 600 subjects will be collected in this surveillance study in 
accordance with the Korean regulations on New Drug Re-examination (i.e. New Drug Re-
examination Standards: Ministry of Food and Safety (MFDS). 
The sample size of 600 has been selected in order to give at least 95% probability of 
detecting at least one uncommon SAE that occurs in the Korean patient population at a 
rate of at least 0.5%. This estimate is based on the assumption that the occurrence of AEs 
has a Poisson distribution and that if the population rate of occurrence of an AE is 0.5% 
then the expected number of AEs in the proposed sample size of 600 would be 3. The 
probability of observing 1 or more events with a Poisson parameter of 3 is 0.95 or 95%.
If we have an AE with a population probability of 0.5% then the expected number 
of events in a sample size of 600 will be 3. Using the Poisson Distribution with a 
parameter of 3 the probability of getting zero AEs in our sample size of 600 is given 
by the formula: 
^
`
0498
.0
0498
.0
1
!0
3
0
Pr
3
0
 
u
 
u
 
 

e
X
The probability, therefore, of having 1 or more AEs in that sample size is 1 - 0.0498 
= 0.9502.
At least 600 subjects were to be collected for surveillance to meet the local regulatory 
requirements, but number of subjects to be enrolled was adjusted to 141 subjects. (Refer 
to section 9.5)
Analysis Population
Number of collected and analyzed patient will be presented as following items: 
Contracted cases, collected number of CRFs, safety-evaluable cases, effectiveness-
evaluable cases, number of drop-out cases, Reasons for drop-out
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The safety analysis data set will include all subjects who have received at least one 
administration of Humira® following the initiation of surveillance and have completed 
follow up for the safety information.
For induction effectiveness of Humira®, the effectiveness analysis data set will include all 
subjects who have been administered Humira® and prescribed Humira® for 4 weeks
including induction period (±1 week) and for whom effectiveness evaluation parameters 
have been recorded. And for maintenance effectiveness of Humira®, effectiveness 
analysis data set will include all subjects who have been administered Humira® and 
prescribed Humira® for 6 months (±4 weeks) and for whom effectiveness evaluation 
parameters have been recorded. The subjects whose effectiveness evaluation was not 
properly conducted because their data from evaluation parameters were missing or they 
discontinued administration prior to the effectiveness evaluation will be excluded from 
the evaluation.
Safety Analysis
The adverse events will be coded by MedDRA dictionary. The number and percentage of 
subjects reporting any serious adverse events/adverse drug reactions will be tabulated 
overall and by MedDRA 17.0 or more recent version, in preferred term. The number and 
percentage of subjects reporting unexpected (unlabeled) adverse drug reactions will be 
tabulated in a similar fashion.
To investigate the factors affecting the safety, the number and percentage of subjects 
reporting adverse events will also be classified by various background factors (e.g., 
demographic factors, treatment factors such as medical history, dosing and administration, 
concomitant medications, beginning of administration before/after the registration date,
etc.) and tabulated. If the incidence of adverse events in the subjects who began the 
administration before/after the registration date has statistical significance, it will be 
presented as a separate item. In addition, if there are patients who have already been 
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administered Humira® when participating in the surveillance, their adverse events from 
the first administration of Humira® to the inclusion will be presented in a separate table. If 
data from special patient groups are collected, they will be extracted and tabulated 
separately for adverse events/adverse drug reactions.
Effectiveness Analysis
The effectiveness assessment of Humira® induction therapy and maintenance therapy will 
be presented by the number and percentage of the subjects with clinical response. Clinical 
response is defined as decrease in PCDAI score from baseline by 15 points and if CDAI 
score is collected, Clinical response is defined as decrease in CDAI score from baseline 
by 70 points.
To investigate the factors affecting the effectiveness, the number and percentage of 
subjects with clinical response will also be classified by background factors (e.g., 
demographic factors, treatment factors such as medical history, dosing and administration, 
concomitant medications, beginning of administration before/after the registration date, 
etc.) and tabulated. If the effectiveness evaluation of above factors has statistical 
significance, it will be presented as a separate item.
Statistical Methods
The descriptive statistics for safety and effectiveness parameter in each year will be 
presented in annual reports.
In final report (Re-examination report), safety and effectiveness outcome by background 
factor will be summarized and analyzed. The analysis for categorical variables will be 
performed using chi-square test or fisher’s exact test and continuous variables will be 
performed using Wilcoxon rank sum test or t-test. Also, incidence rate of adverse event 
collected in overall PMS period will be analyzed and 95% CI will be presented.
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9.8
Quality Control
Prior to the initiation of the study, an investigator’s meeting or initiation visit will be held 
with AbbVie personnel or his/her designee, the investigators and their study coordinators. 
This meeting will include a review of the protocol and CRF completion.
Investigator must assure that the study is conducted in accordance with the protocol and 
all relevant regulations and CRF is completed accurately.
CRF will be reviewed by CRAs at AbbVie or their designees for completeness and 
conclusiveness and when necessary, query will be generated and will be resolved by the 
site staffs. 
All data hand-entered in the database will be verified by a double-key entry procedure. 
Any discrepancies will be reviewed against the hard copy CRF and corrected. After 
completion of the entry process, computer logic checks will be run. Any necessary 
corrections will be made to the database and documented.
9.9
Limitations of the Research Methods
Open-label data from non-randomized patients; reporting bias with historical safety data.
9.10
Other Aspects
NA
10.0
Protection of Human Subjects
Patient written authorization form to use and/or disclose personal and/or health data from 
legal patient or representative must be obtained prior to enrolling the patient and the 
physician is required to document this authorization.
However, informed consent will not be required because as local pharmaceutical law does 
not require informed consent for regulatory-required post-marketing surveillance.
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Patient confidentiality must be maintained at all times; therefore demographics that could 
identify the patients will not be collected. 
Monitoring for any sites is not required. However internal consistency check for 
completeness and consistency of data will be done to ensure integrity of the information 
reported.
11.0
Management and Reporting of Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The investigational product in this trial contains both: 
x
Biologic compound(s) and
x
Device component(s) (pre-filled syringe, pen).
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 11.2.2). For adverse events, please refer to Sections
11.1.1 through 11.1.6.  For product complaints, please refer to Section 11.2.
11.1
Medical Complaints
11.1.1
Adverse Event Definition and Serious Adverse Event 
Categories
An adverse event (AE) is defined as any untoward medical occurrence in a patient, which 
does not necessarily have a causal relationship with their treatment.  An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product.
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Such an event can result from use of the drug as stipulated in the labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal.  Any worsening of a 
pre-existing condition or illness is considered an adverse event.
If an adverse event meets any of the following criteria, it is considered a serious adverse 
event (SAE):
Death of Patient:
An event that results in the death of a patient.
Life-Threatening:
An  event  that,  in  the  opinion  of  the  investigator, 
would  have  resulted  
in  immediate  fatality  if  medical 
intervention  had  not  been  taken.    This  does  not 
include  an  event  
that  would  have  been  fatal  
if  
it  had 
occurred in a more severe form.
Hospitalization:
An  event  
that  results  
in  an  admission  
to  
the  hospital 
for any length of time.  This does not include an 
emergency room visit or admission to an outpatient 
facility.
Prolongation 
of 
Hospitalization:
An event that occurs while the study patient is 
hospitalized and prolongs the patient's hospital stay.
Congenital Anomaly:
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss.
Persistent  or  Significant 
Disability/Incapacity:
An  event  
that  
results  
in  a  condition  
that  substantially 
interferes with the activities of daily  
living of a study 
patient.    Disability  is  not  intended  to  include 
experiences  of  relatively  minor  medical  significance 
such  as  headache,  nausea,  vomiting,  diarrhea, 
influenza,  and  accidental  trauma  (e.g.,  sprained 
ankle).
Important  Medical  Event 
Requiring  
Medical  or 
Surgical  Intervention  to 
Prevent Serious Outcome:
An  important  medical  event  that  may  not  be 
immediately  life-threatening  or  result  in  death  or 
hospitalization,  but  based  on  medical  judgment  may 
jeopardize  the  patient  and  may  require  medical  or 
surgical  intervention  
to  prevent  any  of  
the  outcomes 
listed  above  (i.e.,  death  of  patient,  life  threatening, 
hospitalization,  prolongation  of  hospitalization, 
congenital  anomaly,  or  persistent  or  significant 
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disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse.
11.1.2
Severity
The following definitions will be used to rate the severity for any adverse event being 
collected as an endpoint/data point in the study and for all serious adverse events.
Mild:
The adverse event is transient and easily tolerated by the patient.
Moderate:
The adverse event causes the patient discomfort and interrupts the 
patient's usual activities.
Severe:
The adverse event causes considerable interference with the 
patient's usual activities and may be incapacitating or life 
threatening.
11.1.3
Relationship to Pharmaceutical Product
The following definitions will be used to assess the relationship of the adverse event to 
the use of product:
Probable
An adverse event has a strong temporal relationship to 
study drug or recurs on re-challenge and another etiology 
is unlikely or significantly less likely.
Possible
An adverse event has a strong temporal relationship to 
the study drug, and an alternative etiology is equally or 
less likely compared to the potential relationship to study 
drug. 
Probably Not
An adverse event has little or no temporal relationship to 
the study drug and/or a more likely alternative etiology 
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exists.
Not Related
An adverse event is due to underlying or concurrent 
illness or effect of another drug and is not related to the 
study drug (e.g., has no temporal relationship to study 
drug or has a much more likely alternative etiology).
If an investigator’s opinion of possibly, probably not, or not related to pharmaceutical 
product is given, an alternate etiology must be provided by the investigator for the serious 
adverse event. 
11.1.4
Serious Adverse Event Collection Period
Serious adverse events will be reported to AbbVie from the time the physician obtains the 
patient's authorization to use and disclose information (or the patient's informed consent) 
until 70 days or 5 half-lives following the intake of the last dose of physician-prescribed 
treatment.
11.1.5
Serious Adverse Event Reporting
In the event of a serious adverse event, the physician will:
x
For events from patients using AbbVie product - notify the AbbVie contact 
person identified below within 24 hours of the physician becoming aware of 
the event.
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11.1.6
Pregnancy Reporting
In the event of a pregnancy occurrence in the patient, the physician will notify AbbVie 
contact person identified in Section 11.1.5 within 24 hours of the physician becoming 
aware of the pregnancy. Pregnancies will be collected from the date of the first dose 
through 150 days following the last dose of study drug. The physician will be requested 
additional information on the progress and results of the pregnancy including fetus/infant 
informat
11.1.7
Malignancy Reporting
For any events of malignancy/premalignancy in subjects 30 years of age and younger 
using adalimumab, whether related to the product or not – the physician will notify 
AbbVie contact person identified in Section 11.1.5 within 24 hours of the physician
becoming aware of the event.
11.2
Product Complaint
11.2.1
Definition
A Product Complaint is any Complaint (see Section 11.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues.
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors.
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Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured.
11.2.2
Reporting
Product Complaints concerning the investigational product and/or device must be reported 
to the Sponsor within 24 hours of the study site's knowledge of the event via local Product 
Complaint reporting practices.  Product Complaints occurring during the study will be 
followed-up to a satisfactory conclusion.  All follow-up information is to be reported to 
the Sponsor (or an authorized representative) and documented in source as required by the 
Sponsor.  Product Complaints associated with adverse events will be reported in the study 
summary.  All other complaints will be monitored on an ongoing basis.
Product complaints involving a non-Sponsor investigational product and/or device should 
be reported to the identified contact or manufacturer, as necessary per local regulations.
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, etc.).  In instances where a return is requested, every effort should 
be made by the investigator to return the product within 30 days.  If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
12.0
Plans for Disseminating and Communicating Study 
Results
Within 3 months of the completion of the study, a final study report will be generated by
AbbVie and submitted to MFDS by December 11, 2017. This report will contain a 
description of the objectives of this Surveillance, the methodology of the study and its 
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results and conclusions. The CRFs and the study reports must be treated as the 
confidential property of AbbVie. It may not be released to unauthorized people in any 
form (publications or presentations) without express written approval from AbbVie. The 
results of this study may be published by AbbVie or by any one of the participating 
investigators upon the provisions of the executed study agreement with AbbVie.
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13.0
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