Korean Post-marketing Surveillance for Xeljanz(Registered) in Rheumatoid Arthritis and Psoriatic Arthritis Patients
Conditions: Rheumatoid Arthritis, Psoriatic Arthritis
Sponsor: Pfizer

Xeljanz® (tofacitinib citrate)
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Korean Post-marketing Surveillance for 
Xeljanz® in Rheumatoid arthritis and 
Psoriatic arthritis patients
Protocol number
A3921249
Protocol version identifier
Amendment 
Date of last version of protocol
26 Apr 2022
Active substance
Tofacitinib citrate
Selective immunosuppressant (L04AA29)
Medicinal product
Xeljanz®
(5 mg: contains tofacitinib citrate 8.078 mg 
in 1 tablet)
Research question and objectives
To identify any problems and questions with 
respect to the safety and efficacy of Xeljanz
during the post-marketing period as required 
by the regulation of Ministry of Food and 
Drug Safety (MFDS).
Author
Pfizer Pharmaceuticals Korea Ltd.
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD
PPD

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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................4
2. RESPONSIBLE PARTIES....................................................................................................6
3. AMENDMENTS AND UPDATES.....................................................................................10
5. RATIONALE AND BACKGROUND................................................................................10
6. RESEARCH QUESTION AND OBJECTIVES .................................................................11
7. RESEARCH METHODS ....................................................................................................12
7.1. Study design ..........................................................................................................121
7.2. Setting....................................................................................................................121
7.2.1. Inclusion criteria .........................................................................................12
7.2.2. Exclusion criteria........................................................................................13
7.2.3. Duration of the study ..................................................................................13
7.2.5. Study procedures ........................................................................................15
7.2.5.1. Information of Institution..........................................................15
7.2.5.2. Demography and baseline characteristics .................................16
7.2.5.3. Administrative status for medicinal product .............................17
7.2.5.4. Concomitant treatments.............................................................17
7.2.5.5. Safety and efficacy data ............................................................18
7.3. Variables..................................................................................................................18
7.3.1. Safety variables...........................................................................................18
7.3.1.1. Adverse events ..........................................................................18
7.3.1.2. Laboratory test...........................................................................21
7.3.2. Efficacy variables .......................................................................................20
7.3.2.1. Efficacy evaluation....................................................................20
7.4. Data sources ............................................................................................................22
7.4.1. Case report forms........................................................................................22
7.4.2. Record retention..........................................................................................22
7.6. Data management....................................................................................................23
7.7. Data analysis ...........................................................................................................23
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7.7.1. Safety analysis ............................................................................................25
7.7.2. Efficacy analysis.........................................................................................26
7.8. Quality control.........................................................................................................27
7.9. Limitations of the research methods .......................................................................27
7.10. Other aspects .........................................................................................................27
8. PROTECTION OF HUMAN SUBJECTS ..........................................................................27
8.1. Patient information..................................................................................................27
8.2. Patient concent ........................................................................................................27
8.3. Patient withdrawal...................................................................................................28
8.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............29
8.5. Ethical conduct of the study....................................................................................29
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................29
9.1. Requirements...........................................................................................................29
9.2. Reporting period......................................................................................................30
9.3. Causality assessment...............................................................................................31
9.4. Definition of safety events ......................................................................................31
9.4.1. Adverse events............................................................................................31
9.4.2. Serious adverse events................................................................................30
9.4.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours ...........31
9.5. Single reference safety document............................................................................37
11. REFERENCES ..................................................................................................................37
12. LIST OF TABLES.............................................................................................................38
13. LIST OF FIGURES ...........................................................................................................38
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................38
ANNEX 2. ADDITIONAL INFORMATION.........................................................................38
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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
ACR20
American College of Rheumatology 20% 
improvement criteria
ADR
Adverse drug reaction
AE
adverse event
AEM
adverse event monitoring 
ANC
absolute neutrophil count
CRF
case report form
CRP
C-reactive protein
CYP
cytochrome P450
DAS
Disease Activity Score 
DAS28
Disease Activity Score using 28 joint counts
DMARD
disease-modifying anti-rheumatic drug
EDP
exposure during pregnancy 
EULAR
European League Against Rheumatism
ESR
erythrocyte sedimentation rate
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
HDL
high density lipoprotein
IEA
International Epidemiological Association
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology

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LDL
low density lipoprotein
MFDS
Ministry of Food and Drug Safety
NIS
non-interventional study 
PhRMA
Pharmaceutical Research and Manufacturers 
Association
PMS
post-marketing surveillance
PsA
psoriatic arthritis
RA
rheumatoid arthritis 
RMP
Risk Management Plan
SAE
serious adverse event
SAP
statistical analysis plan
SRSD
single reference safety document
SJC28
28 swollen joint count
TC
total cholesterol
TJC28
28 tender joint count
VAS
visual analogue scale
WHO-ART
World Health Organization - Adverse Reaction 
Terminology
Xeljanz
tofacitinib citrate

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Title
Affiliation
Address
, MD
Non-Interventional 
Study Lead
Pfizer Pharmaceuticals 
Korea Ltd.
 
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3. AMENDMENTS AND UPDATES
Protocol Amendments 1 to 11 are summarized in the table below.
Amendment 
number
Date
Substantial or 
administrative 
amendment
Protocol section(s) 
changed 
Summary of amendment(s)
Reason
Amendment 1
14 April 2015
Substantial 
Section 5 Rationale 
and background
Section 7 Research 
methods
Section 8 Protection of 
human subjects
Section 9 Management 
and reporting of 
adverse events/adverse 
reactions
Section 11 References

Change study design 
from retrospective to 
prospective.

Add more detailed data 
collection procedures.

Add the description of 
data privacy statement 
requirement and patient
withdrawal.

Change safety language 
to prospective study.

Correct indication as per 
local product document.

Add MFDS guidelines 
as references.
The design of the 
original protocol 
dated 
28 October 2014 
was not accepted 
by the MFDS. 
The protocol is 
amended to 
satisfy MFDS’
requirements
Amendment 2
29 October 2015
Substantial
Section 1 List of 
abbreviations
Section 4 Milestones
Section 7.1 Study 
design
Section 7.2.5.2 
Demography and 
baseline characteristics
Section 7.3.1.2 
Laboratory test
Section 7.3.2 Efficacy 
variables
Section 7.7.1 Safety 
analysis
Section 7.7.2 Efficacy 
analysis
Section 9.4.2 Serious 
adverse events
Section 11 References
Section 12 List of 
tables

Add some 
abbreviations.

Change planned date for 
end of data collection 
from 01 March 2020 to 
01 April 2020.

Add recording medical 
histories of latent 
tuberculosis, renal 
disorder and hepatic 
disorder.

Add recommended 
laboratory tests. 

Add efficacy variable 
ACR20, its definition, 
and assessment. 

Add statement that 
SAEs such as serious 
infection, tuberculosis, 
cancer, or lymphocyte 
proliferative disorders 
will be considered as 
SAEs of special interest 
and summarized 
separately.

Add a reference about 
ACR20.

Add a list of tables. 
The protocol is 
amended to 
reflect MFDS’
comments on 
Amendment 1. 

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Amendment 03
25 January 2016
Substantial
Section 7.2.2  
Exclusion criterial
Section 7.3.2 Efficacy 
Variables 
Section 7.6 Data 
management
•
Change for exclusion 
criteria to clarify the 
standard according to 
dosage and 
administration
•
Add the investigators 
overall assessment 
about efficacy based on 
DAS 28 or ACR 20
•
Change the coding 
dictionary for Disease to 
WHO-ART.
Clarification of 
exclusion criteria 
and efficacy 
assessment
Amendment 04
01 August 2016
Substantial
Section 7.2.2 
Exclusion criterial
Section 7.3.1.2 
Laboratory Test
Section 7.7.2. 7.7.2. 
Efficacy analysis
•
Change the contents 
from exclusion criterial 
to Laboratory Test 
about drug 
discontinuation criterial
in accordance with 
laboratory test result by
MFDS requirementsU
•
Include the contents of 
effectiveness ratio and 
less effectiveness ratio 
about overall efficacy 
assessment by MFDS 
requirement
Amended to 
reflect MFDS’ 
comments on 
Amendment 3
Amendment 05
11December 
2018
Substantial
Section 5 Rationale 
and background
Section 7.1 Study 
design
Section 7.5 Study size
•
Considering the disease 
prevalence and status of 
administration, the 
number of target 
subjects is amended 
Amended to 
adjust the 
number of target 
subjects

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Administrative 
Section 7.6 Data 
management
•
Specified coding 
dictionary of 
concomitant medication 
as an ATC code.
Specified con-
med coding 
dictionary
Amendment 06
21 February 
2019
Substantial
Section 7.2.1 
Inclusion criteria
Section 7.2.2 
Exclusion criteria
Section 7.2.4 Dosage 
and administration
Section 7.2.5.2 
Demography and 
baseline characteristics
Section 7.3.2.1 
Efficacy evaluation
7.4.1 Case report 
forms
Section 8.1 Patient 
information 
Section Patient 
concent
Section 8.4 
institutional Review 
Board(IRB)/Independe
nt Ethics Committee 
(IEC)
•
Add new indications
according to the updated 
label
Add new 
indications (for 
psoriatic 
rheumatoid 
arthritis (PsA)P
Amendment 07
17 June 2019
Substantial
Section 7.2.5.2
Demography and 
baseline characteristics
•
Add the severity criteria 
of disease activity for 
PsA indication
The protocol is 
amended to 
reflect MFDS’
comments on 
Amendment 6.
Amendment 08
07 August 2019
Substantial
Study title
Section 5 Rationale 
and background
Section 7.1 Study 
design
Section 7.2.3 Duration 
of the study
Section 7.2.5 Study 
procedures
Section 7.5 Study size
•
Specify the indication in 
the title
•
Add 
abbreviationsSample 
size adjust, add RMP 
scope
•
Add retrospective data 
collection method
Target sample 
size adjustment, 
add RMP scope 
according to the 
MFDS 
comments.

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Amendment 09
14 January 2020
Substantial
Section 4 Milestones
Section 7.7.1 Safety 
analysis

Add RMP report 
submission timeline

Add analysis and 
evaluation methods for 
safety specification 
according to RMP
Amended 
according to the 
MFDS comments
Amendment 10
19 March 2020
Administrative
Substantial
Section 2  Responsible 
parties
Section 7.2.1 
Inclusion criterial
Section 7.2.2 
Exclusion criterial
Section 7.2.5.1 
Information of 
Institution
Section 7.2.5.2 
Demography and 
baseline characteristics

Change the non-
interventional study lead

Add the abbreviation

Change the collected 
data 

Guidance for obtaining 
the data privacy 
statement in the subjects 
to be collected data 
retrospectively

Change the collected 
data
Coordination of 
internal task 
Change of 
research methods
Amendment 11
26 Apr 2022
Minor
Section 2 Responsible 
parties
Section 4 Milestones
Section 5 Rationale 
and Background
Section 7.1 Study 
design
Section 7.2.3 Duration 
of the study
Section 7.5 Study size

Change of NISL

Change of study period
Coordination of 
internal task
Amended 
according to 
MFDS’ 
comments
Abbreviations: ACR20=American College of Rheumatology 20% improvement criteria, MFDS=Ministry of Food and Drug 
Safety, SAE=serious adverse event.

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4. MILESTONES
Milestone
Planned date
Start of data collection 
01 May 2015
End of data collection
01 April 2020
First year (1-1) periodic report (MFDS)
01 December 2014
First year (1-2) periodic report (MFDS)
01 June 2015
Second year (2-1) periodic report (MFDS)
01 December 2015
Second year (2-2) periodic report (MFDS)
01 June 2016
Third year annual report (MFDS)
01 June 2017
Fourth year annual report (MFDS)
01 June 2018
Fifth year annual report (MFDS)
01 June 2019
Final study report (MFDS)
01 July 2020
RMP periodic report will be submitted every year after RMP approval
Abbreviations: MFDS=Ministry of Food and Drug Safety.
5. RATIONALE AND BACKGROUND
Xeljanz® (tofacitinib) is a potent, oral janus kinase inhibitor. Xeljanz was approved by the 
Ministry of Food and Drug Safety (MFDS) on 02 April 2014 for the treatment of adult patients 
with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate 
response or intolerance to methotrexate.  It may be used as monotherapy or in combination 
with methotrexate or other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs).
In addition, MFDS approved new indications for the treatment of adult patients with active 
psoriatic arthritis (PsA) who have had an inadequate response or intolerance to previous 
antirheumatic drugs (DMARDs) on 20 Sep 2018. It may be used in combination with 
methotrexate or other nonbiologic disease‑modifying anti‑rheumatic drugs (DMARDs). The 
efficacy of Xeljanz as a monotherapy has not been studied in psoriatic arthritis.
 
 
  
 
 
 
 
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Background information on Xeljanz can be obtained from the current version of the local 
product document (ie, local labelling), which is the single reference safety document (SRSD) 
for information relating to Xeljanz in this study.
6. RESEARCH QUESTION AND OBJECTIVES
The objective of this study is to identify any problems and questions with respect to the safety 
and efficacy of Xeljanz during the post-marketing period as required by the regulation of
MFDS.
7. RESEARCH METHODS 
7.1. Study design
This is an open-label, non-comparative, non-interventional, prospective, and multi-center 
study conducted in Korean health care centers by accredited physicians (ie, investigators).  The 
study population will be adult patients with moderately to severely active RA who have had 
an inadequate response or intolerance to methotrexate. Xeljanz will be administered according 
to the “Dosage and Administration” of the approved labeling.  There is no visit or activity 
mandated by this study.  The investigator will collect patient data and record the information 
on each patient’s case report form (CRF).
 
 
 
 
 
Also, investigators collect data on the Xeljanz retrospectively from the subjects who have been 
administered the Xeljanz according to the local product documents but not participated in this 
study until 26 June 2022.
Safety is the primary interest of this study, which will be assessed based on adverse events
(AEs) that occur during the 6 months from the first dose of Xeljanz. The efficacy endpoints 
will be the modified Disease Activity Score using 28 joint counts (DAS28) change from 
baseline, European League Against Rheumatism (EULAR) response, and American College 
of Rheumatology 20% improvement criteria (ACR20) response after treatment (see 
Section 7.3).
7.2. Setting
7.2.1. Inclusion criteria
To be included in the study all patients will have received at least 1 dose of Xeljanz for the 
treatment of the following indication as per local labelling:
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Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
•
Moderately to severely active RA in adult patients who have had an inadequate response 
or intolerance to methotrexate.  
•
Active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or 
intolerance to previous antirheumatic drugs (DMARDs)
•
Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects 
of the study. (In case of subjects to be collected data retrospectively, whether or not to 
obtain the informed consent document depends on the decision by the institutional review 
board (IRB)/independent ethics committee (IEC)).
7.2.2. Exclusion criteria
Patients meeting any of the following criteria as per the local labeling will not be included in 
the study:
1. Patients with a history of hypersensitivity to any ingredients of this product.
2. Patients with serious infection (sepsis, etc.) or active infection including localized 
infection.
3. Patients with active tuberculosis.
4. Patients with severe hepatic function disorder.
5. Patients with an absolute neutrophil count (ANC) <1,000 cells/mm3.
6. Patients with an absolute lymphocyte count(ALC) <500 cells/mm3.
7. Patients with a hemoglobin level <9 g/dL.
8. Pregnant or possibly pregnant women.
9. Because of lactose contained in this drug, it should not be administered to patients with 
hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose 
malabsorption.
7.2.3. Duration of the study
 
  The re-
examination period is from 02 April 2014 to 01 April 2020, and the final re-examination report 
should therefore be submitted by 01 July 2020. Additional safety and effectiveness result 
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report from prospective and retrospective studies until 26 June 2022 would be submitted as 
part of RMP.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.2.5. Study procedures
The investigator should enroll all patients to whom Xeljanz is prescribed for the first time
according to the local product document and who agree to participate in this study by signing 
the data privacy statement (used in place of the informed consent form) by continuous 
registration method.  In case of the patients who already have been administered Xeljanz but 
not participated in this study, study related information from the first administration until the 
last day of the observation period should be collected retrospectively. Xeljanz tablets will be 
medicated by the investigator’s prescription under usual clinical practice. Pfizer Korea will 
not provide the medicinal product for this study.
There will be no mandatory visit during the study.  The investigators will collect relevant data 
from the time of initiating administration of Xeljanz until 6 months of treatment.  If the patient 
does not complete 6 months of treatment, relevant data should be collected based on the last
assessment performed at the time of treatment discontinuation. The investigator should record 
the following information on the patient’s CRF:
7.2.5.1. Information of institution
The following will be recorded on the CRF for each patient:
•
Name of institution: Enter the code number assigned to each institution.
•
Patient number: The investigator will sequentially assign each patient a patient 
identification number, which will be a 4-digit number.  The total number of cases that need 
to be collected will be allocated to each study site by Pfizer at the time of execution of a 
contract with each site. 
•
Completion of the study: If the patient completed 6 months treatment, check “yes”.  
Otherwise, check “no” and choose reason for the discontinuation: AE; lack of efficacy; 
others.
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•
Date of CRF completion: Record the date of CRF completion. 
•
Signature of investigator: Contracted investigator must sign after identifying the CRF. 
•
Confirmation of data privacy statement: If the patient has signed the data privacy statement 
to indicate agreement for using his/her personal and medical information, check the box of 
“yes” on the CRF in case of subjects to be collected data prospectively. If not, check “no”
and exclude the case from the study. If the patient has signed the data privacy statement, 
check the box of “yes” on the CRF in case of subjects to be collected data retrospectively, 
and if not, check “no” on the CRF and check if it is available for the exempt of the data 
privacy statement according to the IRB/IEC’s decision
7.2.5.2. Demography and baseline characteristics
The following will be recorded on the CRF for each patient:
•
Age: Record actual age of the patient at the time of enrollment in case of subjects to be 
collected data prospectively. Record age of the patient at the first dosing of Xeljanz in case 
of subjects to be collected data retrospectively. The age should be calculated by the year of 
birth.  
•
Sex: Check the box next to “male” or “female” on the CRF.
•
Height: Record by unit of þcm’ in case of subjects to be collected data prospectively. 
Check the box indicated to the range of height(unit of ‘cm’) in case of subjects to be 
collected data retrospectively
•
Weight: Record by unit of þkg’ in case of subjects to be collected data prospectively. 
Check the box indicated to the range of weight(unit of ‘kg’) in case of subjects to be 
collected data retrospectively
•
Herpes zoster vaccination: Record if the patient had received vaccine of herpes zoster: yes;
no; unknown.
•
Smoking: Record smoking status of the patient: ex-smoking; current smoking;
non-smoking; unknown.
•
Duration of the disease: Record the duration of disease since the date that the patient was 
initially diagnosed with RA and PsA. 
•
Severity of disease activity:
RA: Disease activity should be assessed by initial DAS28.  DAS28 >5.1 is considered to 
be indicative of high disease activity; DAS28 >3.2 and İ5.1 indicates moderate disease 
activity; DAS28 İ3.2 indicates low disease activity.  A patient scoring less than 2.6 is 
defined as being in remission. 

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PsA: Disease activity should be assessed by initial DAS28.  DAS28 >5.1 is considered to 
be indicative of high disease activity; DAS28 >3.2 and İ5.1 indicates moderate disease 
activity; DAS28 İ3.2 indicates low disease activity.  A patient scoring less than 2.6 is 
defined as being in remission.  
•
Radiologic progression: Radiologic progression based on clinically relevant evaluation 
methods, such as X-ray, ultrasonography, or magnetic resonance imaging, should be
recorded, if evaluated.
•
Previous treatments: Only record RA and PsA treatments received 6 months prior to the 
initiation of Xeljanz.  Record name of the medication/therapy, route and duration of the 
administration, and overall response, if possible.
•
Latent tuberculosis: Record if the patient has latent tuberculosis: yes; no; unknown.
•
Renal disorder: Record if the patient has renal disorder: yes (severe/moderate/mild); no. 
•
Hepatic disorder: Record if the patient has hepatic disorder: yes (severe/moderate/mild); 
no.
•
Other past/present diseases: Record “yes” or “no” for medical history. If “yes”, record 
adequate full name of the past or present disease according to the Medical Terminology 
Dictionary written by the Korean Medical Society.
Past or present disease will be 
determined based on the date of the first dose of Xeljanz.
•
Allergic history: Check either “yes” or “no” on the CRF. If “yes”, record the trigger factors
and the corresponding symptoms.
7.2.5.3. Administrative status for medicinal product
The following will be recorded on the CRF for each patient:
•
Treatment duration: Record start date and stop date (year/month/day) of the treatment of 
Xeljanz. If the medication is being continued at the completion of the study, record the 
start date only. 
•
Daily dose: Record total daily dose of Xeljanz in mg. 
•
Daily dosing frequency: Record dosing frequency per day.
•
Reason for dose adjustment: If there are any dose adjustments during the study, record the 
reason(s). 
7.2.5.4. Concomitant treatments
Any concomitant treatments should be recorded on the CRF for each patient. The information 
should include:

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
Name of the drug: Record generic name of the concomitant medication.

Daily dose: Record total daily dose of the concomitant medication.

Duration of the treatment: Record the start date and stop date (year/month/day) of the 
concomitant medication. If the medication is being continued at the completion of the 
study, record the start date only and check “ongoing”.

Purpose of the treatment: Record purpose of the concomitant treatment in detail.
7.2.5.5. Safety and efficacy data
Please refer to Section 7.3 for safety and efficacy assessment and data collection. 
7.3. Variables
7.3.1. Safety variables
Safety will be assessed by the investigator based on AEs that occur during 6 months from the 
first treatment for all patients who have received at least 1 dose of Xeljanz according to the 
local product document.
7.3.1.1. Adverse events 
Please refer to Section 9 for the definition of non-serious and serious adverse events (SAEs).  
Any AEs observed and reported within the reporting period will be recorded on the CRF by 
the investigator, regardless of the causal relationship with Xeljanz (see Section 9.2).  The AEs 
can be reported by the patients.  The investigator will also collect AE data by asking the patient 
questions such as “Have you had any health problem since the last visit?”
Check either “yes” or “no” in the AE section of CRF.  If “yes”, record the following 
information:
Event name: Record the name of the AE according to the Korean Version of World Health 
Organization - Adverse Reaction Terminology (WHO-ART) distributed by Korean Ministry 
of Health and Welfare. If there is no not an appropriate term in the WHO-ART, record the 
name of the AE according to the Medical Terminology Dictionary written by the Korean 
Medical Society.  If possible, specify diagnosis, not individual symptoms.
Date of onset: Record the onset date of the AE.  Record approximate date if an actual date is 
unknown.
Date of recovery: Record the stop date of the AE if the outcome of the AE is recovered or 
recovered with sequelae (see below).  Record approximate date if an actual date is unknown.
Seriousness: Check either “yes” or “no” to indicate if the event is a SAE.  If “yes’ record 
appropriate category of the seriousness (see Section 9 for the definition and reporting of SAEs). 

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Severity: Evaluation of AE severity must be done according to the following categories:

Mild: Not causing any significant problem to the patient.  Administration of medicinal 
product continues without dose adjustment. 

Moderate: Causes a problem that does not interfere significantly with usual activities 
or the clinical status.  Dose of the medicinal product is adjusted or other therapy is 
added due to the AE.

Severe: Causes a problem that interferes significantly with usual activities or the 
clinical status. The medicinal product is stopped due to the AE.
If the severity of an AE changes, the AE must be entered separately. Record the stop date of 
the previous severity and onset date of the new severity – along with completion of all other 
related items.
Causality assessment: The causal relationship of AEs to the medicinal product must be 
allocated by the investigator according to the following criteria in alignment with the 
requirements of MFDS:

Certain

It follows a reasonable time sequence from administration of the drug (before and 
after the study medication);

It could not be explained by other drugs, chemical substances or accompanying 
diseases;

It has clinically reasonable reaction on cessation of the drug;

It has pharmacological or phenomenological reaction to re-administration of the 
drug, where necessary.

Probable/likely

It follows a reasonable time sequence from administration of the drug (before and 
after the study medication);

It could not be explained by other drugs, chemical substances or accompanying 
diseases;

It has clinically reasonable reaction on cessation of the drug (no information on 
re-administration).

Possible

It follows a reasonable time sequence from administration of the drug;

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
It could also be explained by other drugs, chemical substances or accompanying 
diseases;

It lacks information or has unclear information on discontinuation of the drug.

Unlikely

It is not likely to have a reasonable causal relationship from administration of the 
drug. Rather, it seems to be temporary;

It could also be reasonably explained by other drugs, chemical substances or latent
diseases.

Conditional/unclassified

It needs more data to make an appropriate assessment or its additional data are 
being reviewed.

Unassessible/unclassifiable

Lack of sufficient information or conflicting information hampers accurate 
causality assessment or supplementation or confirmation.
All AEs, except for those with a causality of “unlikely”, are considered as AEs whose causal 
relationship to the study drug can not be excluded (ie, adverse drug reaction [ADR]). 
Action taken: With regard to the medicinal product, actions will include: 

Permanently discontinued;

Temporarily discontinued or delayed;

Dose reduced;

Dose increased;

No change;

Not applicable. 
Outcome: Evaluation of outcome will include: 

Recovered;

Recovered with sequelae;

Recovering;

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
Not recovered;

Unknown.
Please refer to Section 9 for the requirements for reporting safety events to Pfizer Safety during 
the study.
7.3.1.2. Laboratory test 
Recommended laboratory tests and time points are included in Table 1. Test results of chest 
X-ray, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), other blood chemistry, 
hematology, and tuberculin test should be recorded, if conducted.  
Table 1
Recommended Laboratory Test
Lymphocyte
Neutrophils
Hemoglobin
Lipids (TC, HDL, LDL)
Baseline
√
√
√
√
4 to 8 weeks after treatment
√
√
√
Every 3 months
√
√
√
Abbreviations: TC=total cholesterol, HDL= high density lipoprotein, LDL=low density lipoprotein.
In case there are any clinically significant laboratory abnormalities (as per the investigator’s 
judgment) that occur after the treatment of Xeljanz compared to baseline, the tests should be 
recorded in detail on the CRF, including the laboratory normal ranges of the center, test results 
before and after Xeljanz treatment, a causal relationship to Xeljanz, and any comments from 
the investigator.
According to Contraindication on label, the investigator should discontinue the patient’s 
treatment if the laboratory test results are as below
- Patients with an absolute neutrophil count (ANC) <500 cells/mm3*
- Patients with a hemoglobin level <8 g/dL
Please refer to Section 9.4.1 for the criteria for determining whether an abnormal objective test 
finding should be reported as an AE. 
7.3.2. Efficacy variables
Efficacy variables include DAS28, EULAR response, and ACR20 response. The investigator 
can make an assessment of the overall efficacy – improved, no change, aggravated - based on 
each test results and clinical judgment.
7.3.2.1. Efficacy evaluation
Efficacy assessment will be performed by the accredited investigator in the Korean health care 
center.  In the case of RA, The investigator will perform the efficacy assessment at baseline 
and after 6 months of treatment by any of the commonly used efficacy assessment criteria such 

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as DAS28 and American College of Rheumatology 20% improvement criteria (ACR20), and 
record the assessment results in each patient’s CRF.  If the patient dose not complete 6 months 
of treatment, relevant data should be collected based on the last assessment performed at the 
time of treatment discontinuation. 
DAS28, a modified version of the original Disease Activity Score (DAS), is a quantitative 
measure of disease activity used to monitor the treatment of RA. DAS28 is calculated using 
the following formula that includes the number of tender joints and swollen joints (28 joints 
maximum)3.
DAS28 (ESR) = 0.56×√(TJC 28) + 0.28×√(SJC 28) + 0.014×VAS+ 0.70×ln(ESR)
or,
DAS28 (CRP) = 0.56×√(TJC 28) + 0.28×√(SJC 28) + 0.014×VAS + 0.36×ln(CRP+1)+0.96
Of which, CRP=C-reactive protein, ESR=erythrocyte sedimentation rate, SJC28=28 swollen 
joint count, TJC28=28 tender joint count, VAS=visual analogue scale
The DAS-based EULAR response criteria (see Figure 1) classify individual patients as none, 
moderate, or good responders, depending on the extent of change and the level of disease 
activity reached.
Figure 1
DAS28-based EULAR response criteria
DAS28 at endpoint
Improvement in DAS28 from baseline
>1.2
>0.6 and ≤1.2
≤0.6
≤3.2
Good
>3.2 and ≤5.1
Moderate
>5.1
None
An ACR20 response is defined as at least 20% improvement in both the tender joint count and 
the swollen joint count and at least 20% improvement in 3 of the 5 other disease activity 
measures (items 3 to 7) listed in Table 2.  If ACR20 is assessed in the usual clinical practice, 
the results should be recorded as “done-achieved” or “done-not achieved”.  If ACR20 is not 
assessed, the investigator records “not done” in the CRF. 
In the case of PsA, the number of active joints, including number of tender and swollen joints 
at 3 months of treatment is measured. DAS28 can be calculated based on the number of 
active joints, and DAS28 calculation is the same as calculation of RA above.

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Table 2
American College of Rheumatology Preliminary Definition of Improvement 
in Rheumatoid Arthritis4
Disease activity measures:
1. Tender joint count
2. Swollen joint count
3. Patient’s assessment of pain
4. Patient’s global assessment of disease activity
5. Physician’s global assessment of disease activity
6. Patient’s assessment of physical function
7. Acute-phase reactant value: ESR or CRP level
Abbreviations: CRP=C-reactive protein, ESR=erythrocyte sedimentation rate.
7.4. Data sources
7.4.1. Case report forms
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient. The completed original 
CRFs are the sole property of Pfizer and should not be made available in any form to the third 
parties, except for authorized representatives of Pfizer or appropriate regulatory authorities, 
without written permission from Pfizer. The investigator shall ensure that the CRFs are 
securely stored at the study site in encrypted electronic form and will be password protected  
to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs, any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made on the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital’s or the physician’s patient chart.  In these 
cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document. 
7.4.2. Record retention
To enable evaluations and/or inspections audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 

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informed consent documents copies of all CRFs, safety reporting forms source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports). The records should be 
retained by the investigator according to local regulations, or as specified in the Clinical Study
Agreement, whichever is longer. The investigator must ensure that the records continue to be 
stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The study 
records must be transferred to a designee acceptable to Pfizer, such as another investigator, 
another institution, or to an independent third party arranged by Pfizer. Investigator records 
must be kept for a minimum of 15 years after completion or discontinuation of the study or for 
longer if required by applicable local regulations. 
The investigator must obtain Pfizer’s written permission before disposing of any records, even
if retention requirements have been met.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.6. Data management 
CRF data collected by the investigator will be entered into the clinical database.  Verifications 
will be performed after comparison of the double data entry.  All missing data or data to be 
checked will be reported on a query sheet for further verification at the study site. Any data 
modification will be recorded. 
AEs and Medical history will be coded using MedDRA(Medical Dictionary for Regulatory 
Activities). Concomitant medication will be coded via ATC code.
Statistical analysis will be carried out with SAS software version 9.2 or a more recent version.
7.7. Data analysis 
Analysis will be performed for the pooled data collected by each investigator during the 
re-examination period.  Total number of centers participating, total number of cases enrolled 
and retrieved, and total number of cases included in the analysis will be presented in summary
tables.  Evaluation of data will primarily consist of summary displays (eg, descriptive statistics, 
tables, and graphs).  
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be dated, filed and maintained 
by Pfizer. The SAP may modify the plans outlined in the protocol; any major modifications 
of primary endpoint definitions or their analyses will be reflected in a protocol amendment.
7.7.1. Safety analysis
The primary interest of this study is the incidence of AEs investigated during the 
re-examination period. Incidence of each AE will be presented with 95% confidence interval. 
Serious, related, and/or unexpected AEs will be summarized separately. 
To identify the factors that affect safety, subgroup analysis for various factors will be 
performed, including the classification of AEs by body system, and comparison of incidence 
of AEs by sex, age, presence of concurrent diseases, presence of concomitant medications, 
baseline disease activity, etc.
In case the drug was administered to special populations such as children, elderly people, or 
patients with renal or hepatic disorders during the study, subgroup analysis will also be 
performed for each of those populations.
Unexpected AEs/ADRs will be classified by medical review with reference to the local product 
document.  Events already included in the “Precautions for use” section of the local product 
document will be classified as “expected”.  All other events that are not included in the 
“Precautions for use” section of the local product document will be classified as “unexpected”.  
An unexpected AE includes any events that may be symptomatically and patho-physiologically 
related to an event listed in the labeling, but differs from the labeled event because of greater 
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In the case of an adverse event with important potential risks and important identified risks in 
relation to the safety specification under the risk management plan, or if missing information 
patient group is recruited, actions according to the label will be taken, and the safety 
information is presented separately.
 
 
 
7.7.2. Efficacy analysis
Efficacy analysis will be performed on an intent-to-treat basis. It will be analyzed for all 
patients entering this study, who received at least 1 dose of Xeljanz according to the local 
product document, and are available for an efficacy assessment performed after 6 months of 
treatment, or based on the last assessment performed at the time of treatment discontinuation
if the patient dose not complete 6 months of treatment. 
Analysis with effectiveness of treatment based on change from baseline in DAS28, after a 
treatment EULAR response and after a treatment ACR20 response. Evaluation of overall 
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assessment including ‘Improve’, ‘Changeless’, ‘Aggravated’ - based on each test results and 
clinical judgment analysis. As a result of evaluation, ‘Without any assessment’ remains with 
not available effectiveness result. ‘Improve’, ‘Changeless’, ‘Aggravated’ remain with 
available effectiveness. Overall assessment evaluation conclude with ‘Improve’ that Xeljanz 
is effective. Overall assessment evaluation conclude with ‘Changeless’ or ‘Aggravated’ that 
Xeljanz is less effective.
 
 
If the patient discontinues prematurely without completing the 6 months treatment, the reason 
of discontinuation will be analyzed.
7.8. Quality control
Quality assurance audits will be performed at study centers by Pfizer’s own independent 
quality assurance group or by the clinical research organization.  These audits will be
conducted 
according 
to 
Pfizer’s 
procedures 
and 
the
guidelines
for 
Good 
Pharmacoepidemiology Practices (GPP) (see Section 8.5).
7.9. Limitations of the research methods
This is a non-interventional PMS study conducted in the Republic of Korea to satisfy the 
requirements of MFDS:  The protocol is determined by regulation of MFDS and not the 
specific disease and drug characteristics.  The observational, non-controlled, and 
non-randomized design of this study has intrinsic limitations.
7.10. Other aspects
Not applicable.
8. PROTECTION OF HUMAN SUBJECTS
8.1. Patient information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any reports, 
publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic form and will be
password protected to ensure that only authorized study staffs have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of personal 
data, when study data are compiled for transfer to Pfizer and other authorized parties, patient 
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names will be removed and will be replaced by a single, specific, numerical code, based on a 
numbering system defined by Pfizer.  All other identifiable data transferred to Pfizer or other 
authorized parties will be identified by this single, patient-specific code. The investigator site 
will maintain a confidential list of patients who participated in the study, linking each patient’s 
numerical code to his or her actual identity.  In case of data transfer, Pfizer will maintain high 
standards of confidentiality and protection of patients’ personal data consistent with the clinical 
study agreement and applicable privacy laws.
8.2. Patient concent 
The informed consent documents and any patient recruitment materials must be in compliance 
with local regulatory requirements and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the institutional 
review board (IRB)/independent ethics committee (IEC) before use, and available for 
inspection.
The investigator must ensure that each study patient, or his/her legally acceptable 
representative is fully informed about the nature and objectives of the study the sharing of data 
relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the patient’s personal data. The investigator, or a person 
designated by the investigator, will obtain the written data privacy statement from each patient
or the patient’s legally acceptable representative before any study-specific activity is 
performed.  The investigator will retain the original of each patient’s signed data privacy 
statement. The investigator further must ensure that each study patient or his or her legally 
acceptable representative, or parent(s) is fully informed about his or her right to access and 
correct his or her personal data and to withdraw consent for the processing of his or her 
personal data.
Whenever consent is obtained from a patient’s legally acceptable representative/parent(s), the 
patient’s assent (affirmative agreement) must subsequently be obtained when the patient has 
the capacity to provide assent, as determined by the IRB/IEC.  If the investigator determines 
that a patient’s decisional capacity is so limited that he or she cannot reasonably be consulted, 
then, as permitted by the IRB/IEC and consistent with local regulatory and legal requirements, 
the patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (e.g., minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (e.g., parent, 
spouse), and that the patient’s assent was obtained or waived.  If assent is obtained verbally, it 
must be documented in the source documents.
8.3. Patient withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or Pfizer for safety, behavioral, or 

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administrative reasons.  In any circumstance, every effort should be made to document the
patient outcome, if possible.  The investigator should inquire about the reason for withdrawal 
and follow-up with the patient regarding any unresolved AEs.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
8.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
The study protocol will be submitted to MFDS prior to the study. The ethical consideration 
on this study will be evaluated by the IRB/ IEC in each clinical site prior to the study, if the 
site has an approval process for this PMS study according to the local standard operation 
procedure of the site. 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents
(e.g., recruitment advertisements), if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained by the investigator.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
8.5. Ethical conduct of the study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for GPP issued by the International Society for Pharmacoepidemiology 
(ISPE), Good Epidemiological Practice (GEP) guidelines issued by the International 
Epidemiological Association (IEA), Pharmaceutical Research and Manufacturers Association 
(PhRMA) guidelines, and Korea PMS regulations and/or guidelines.
9. MANAGEMENT 
AND 
REPORTING 
OF 
ADVERSE 
EVENTS/ADVERSE 
REACTIONS
9.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the non-interventional study (NIS) adverse event monitoring (AEM) 
Report Form to Pfizer Safety.  These requirements are delineated for three types of events: (1) 
SAEs; (2) non-serious AEs (as applicable); and (3) scenarios involving drug exposure, 
including exposure during pregnancy, exposure during breast feeding, medication error, 
overdose, misuse, extravasation, and occupational exposure.  These events are defined in 
Section 9.4.  
Safety event
Recorded on the CRF
Reported on the NIS AEM 
Report Form to Pfizer Safety 
within 24 hours of awareness
SAE
All
All
Non-serious AE
All
None

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Safety event
Recorded on the CRF
Reported on the NIS AEM 
Report Form to Pfizer Safety 
within 24 hours of awareness
Scenarios involving exposure to a 
drug under study, including exposure 
during pregnancy, exposure during 
breast feeding, medication error, 
overdose, misuse, extravasation; lack 
of efficacy; and occupational 
exposure
All (regardless of whether 
associated with an AE), except 
occupational exposure
All (regardless of whether 
associated with an AE)
For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
(see section "Serious Adverse Events” below) 
Safety events listed in the table above must be reported to Pfizer within 24 hours of awareness 
of the event by the investigator regardless of whether the event is determined by the 
investigator to be related to a drug under study. In particular, if the SAE is fatal or life-
threatening, notification to Pfizer must be made immediately, irrespective of the extent of 
available event information. This timeframe also applies to additional new (follow-up) 
information on previously forwarded safety event reports. In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the events.
For safety events that are considered serious or that are identified in the far right column of the 
table above that are reportable to Pfizer within 24 hours of awareness, the investigator is 
obligated to pursue and to provide any additional information to Pfizer in accordance with this 
24-hour timeframe. In addition, an investigator may be requested by Pfizer to obtain specific 
follow-up information in an expedited fashion.  This information is more detailed than that 
recorded on the CRF. In general, this will include a description of the AE in sufficient detail 
to allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses must be provided.  In the case of a patient death, a summary of available autopsy 
findings must be submitted as soon as possible to Pfizer or its designated representative. 
9.2. Reporting period 
For each patient, the safety event reporting period begins at the time of the patient’s first dose 
of Xeljanz or the time of the patient’s data privacy statement if s/he is already exposed to 
Xeljanz, and lasts through the end of the observation period of the study which must include 
at least 28 calendar days following the last administration of Xeljanz; a report must be 
submitted to Pfizer Safety (or its designated representative) for any of the types of safety events 
listed in the table above occurring during this period. If a patient was administered a drug 
under study on the last day of the observation period, then the reporting period should be 
extended for 28 calendar days following the end of observation. 

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Most often, the date of data privacy statement is the same as the date of enrollment. In some 
situations, there may be a lag between the dates of data privacy statement and enrollment.  In 
these instances, if a patient provides data privacy statement but is never enrolled in the study 
(eg, patient changes his/her mind about participation), the reporting period ends on the date of 
the decision to not enroll the patient.  
If the investigator becomes aware of a SAE occurring at any time after completion of the study 
and s/he considers the SAE to be related to Xeljanz, the SAE must also be reported to Pfizer 
Safety. 
9.3. Causality assessment
The investigator is required to assess and record the causal relationship.  For all AEs, sufficient 
information should be obtained by the investigator to determine the causality of each AE.  For 
AEs with a causal relationship to Xeljanz, follow-up by the investigator is required until the 
event and/or its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer
concurs with that assessment.
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that Xeljanz caused or contributed to an AE. 
If the investigator’s final 
determination of causality is “unknown” and s/he cannot determine whether Xeljanz caused 
the event, the safety event must be reported within 24 hours.
If the investigator cannot determine the etiology of the event but s/he determines that Xeljanz
did not cause the event, this should be clearly documented on the CRF and the NIS AEM 
Report Form.
9.4. Definition of safety events
9.4.1. Adverse events
An AE is any untoward medical occurrence in a patient administered a medicinal product.  The 
event need not necessarily have a causal relationship with the product treatment or usage.  
Examples of AEs include but are not limited to:  

Abnormal test findings (see below for circumstances in which an abnormal test finding 
constitutes an AE);

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease; 

Lack of efficacy; 

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
Drug abuse; 

Drug dependency.
Additionally, for medicinal products, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Off-label use; 

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure during breast feeding;

Medication error;

Occupational exposure.
Abnormal test findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.

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9.4.2. Serious adverse events
A SAE is any untoward medical occurrence in a patient administered a medicinal or nutritional 
product (including pediatric formulas) at any dose that:

Results in death;

Is life-threatening;

Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute AEs);

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse.
In this study, the onset of disease includes but is not limited to the following, which should be 
considered as medically important SAEs of special interest: serious infection, tuberculosis, 
cancer, or lymphocyte proliferative disorders.  These events will be monitored, analyzed, and 
reported.  
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a Pfizer 
product.  The terms “suspected transmission” and “transmission” are considered synonymous.  
These cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel.  Such cases are also considered for reporting as product defects, 
if appropriate.
Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 

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however, an event leading to an emergency room visit should be assessed for medical 
importance. 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. For 
example, the following reports of hospitalization without a medical AE are not to be reported.

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly exam);

Optional admission not associated with a precipitating medical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Admission for treatment of a pre-existing condition not associated with the development 
of a new AE or with a worsening of the pre-existing condition (eg, for work-up of persistent 
pre-treatment lab abnormality);

Protocol-specified admission during clinical study (eg, for a procedure required by the 
study protocol).
9.4.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below.
Exposure during pregnancy
An exposure during pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been  
exposed to (eg, environmental) Xeljanz or the female becomes, or is found to be, 
pregnant after discontinuing and/or being exposed to Xeljanz (maternal exposure).
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed, either due to treatment or environmental exposure to Xeljanz
prior to or around the time of conception and/or is exposed during the partner 
pregnancy (paternal exposure).
As a general rule, prospective and retrospective exposure during pregnancy reports from any 
source are reportable, irrespective of the presence of an associated AE and the procedures for 
SAE reporting should be followed.

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If a study participant or study participant’s partner becomes, or is found to be, pregnant during 
the study participant’s treatment with Xeljanz, this information must be submitted to Pfizer, 
irrespective of whether an AE has occurred using the NIS AEM Report Form and the EDP 
Supplemental Form. 
In addition, the information regarding environmental exposure to Xeljanz in a pregnant woman 
(eg, a patient reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) must be submitted using the NIS AEM Report Form and the EDP 
supplemental form. This must be done irrespective of whether an AE has occurred.  
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-up 
is conducted to obtain information on EDP outcome for all EDP reports with pregnancy 
outcome unknown.  A pregnancy is followed until completion or until pregnancy termination 
(eg, induced abortion) and Pfizer is notified of the outcome.  This information is provided as a 
follow up to the initial EDP report.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (eg, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the procedures 
for reporting SAEs should be followed.
Additional information about pregnancy outcomes that are reported as SAEs includes: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product
Additional information regarding the exposure during pregnancy may be requested.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm 
infants to identify developmental delays).  
In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner.  It must be documented that the 
study participant was given this letter to provide to his partner.
Exposure during breastfeeding

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Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE. An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (eg, vitamins) is administered in accord 
with authorized use.  However, if the infant experiences an AE associated with such a drug’s 
administration, the AE is reported together with the exposure during breastfeeding.
Medication error
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer.  Such events may be 
related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use.  
Medication errors include:

Near misses, involving or not involving a patient directly (eg, inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or 
prescription on the part of the healthcare provider or the patient/consumer);

Confusion with regard to invented name (eg, trade name, brand name).
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE:

Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE.

Medication errors that do not involve a patient directly (eg, potential medication errors 
or near misses).  When a medication error does not involve patient exposure to the 
product the following minimum criteria constitute a medication error report:

An identifiable reporter;

A suspect product;

The event medication error.
Overdose, Misuse, Extravasation
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE.
Lack of Efficacy

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Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product.
Occupational Exposure
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE.
9.5. Single reference safety document
The local product document will serve as the SRSD during the course of the study, which will 
be used by Pfizer safety to assess any safety events reported to Pfizer Safety by the investigator 
during the course of this study. 
The SRSD should be used by the investigator for prescribing purposes and guidance.
 
  
 
 
COMMUNICATION OF ISSUES
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of any 
serious breaches of this NIS protocol that the investigator becomes aware of.
11. REFERENCES
 
 
 
3. DAS-score.nl. 
Home 
of 
the 
DAS: 
Disease 
activity 
score 
and 
DAS28, 
http://www.das-score.nl/das28/en/(accessed 16 October 2014).
4. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology: preliminary
definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727-35.
CCI
CCI

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5. Eypasch E, et al. Probability of adverse events that have not yet occurred: a statistical 
reminder. BMJ. 1995 Sep 2;311(7005):619-20.
12. LIST OF TABLES
Table 1
Recommended Laboratory Test
Table 2
American College of Rheumatology Preliminary Definition of Improvement in 
Rheumatoid Arthritis
13. LIST OF FIGURES
Figure 1
DAS28-based EULAR response criteria
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 2. ADDITIONAL INFORMATION
Not applicable.