Comparative Analysis of Outcomes Among Rheumatoid Arthritis Patients Treated With Xeljanz Versus Biologic DMARDs Using a United States Healthcare Claims Database
Conditions: Arthritis, Rheumatoid
Sponsor: Pfizer

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 1
NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Title
Comparative Analysis of Outcomes among 
Rheumatoid Arthritis Patients Treated with 
Xeljanz Versus Biologic DMARDs using a 
United States Healthcare Claims Database
Protocol number
A3921305
Protocol version identifier
1.2
Date 
6 December 2019
Active substance
L04AA29 (tofacitinib)
Medicinal product
Xeljanz (tofacitinib)
Research question and objectives
Primary Objective:
To compare rheumatoid arthritis 
(RA)-related costs among patients treated 
with tofacitinib (Immediate-Release 
formulation (IR); Modified-Release 
formulation (XR) and combined) to patients 
treated with each of the biologic DMARDS
(bDMARDs), individually, as well as to 
TNFi and to non-TNFi each combined as 
groups.
Secondary Objectives:
Explore the differences in demographic and 
clinical characteristics between patients 
treated with tofacitinib vs. each individual 
bDMARD.
Compare treatment patterns including 
dosing, concomitant medication use, 
adherence, persistence, and switching with 
tofacitinib vs. each individual bDMARD.
Compare all-cause and RA-related health 
care utilization of patients treated with 
tofacitinib vs. each individual bDMARD.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 2
Compare all-cause healthcare costs for 
patients treated with tofacitinib vs. each 
individual bDMARD.
Compare medication effectiveness among 
patients treated with tofacitinib vs. each 
individual bDMARD.
Author
, Ph.D.
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

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
1. LIST OF ABBREVIATIONS................................................................................................5
2. RESPONSIBLE PARTIES....................................................................................................6
3. ABSTRACT...........................................................................................................................6
4. AMENDMENTS AND UPDATES.......................................................................................6
5. MILESTONES.......................................................................................................................9
6. RATIONALE AND BACKGROUND................................................................................10
7. RESEARCH QUESTION AND OBJECTIVES .................................................................10
7.1. Primary Objective ...................................................................................................10
7.2. Secondary Objectives..............................................................................................10
8. RESEARCH METHODS ....................................................................................................11
8.1. Study Design ...........................................................................................................11
8.2. Setting......................................................................................................................11
8.2.1. Inclusion Criteria ........................................................................................11
8.2.2. Exclusion Criteria.......................................................................................12
8.3. Cohort Assignment..................................................................................................12
13
8.5. Period of Observation..............................................................................................13
8.6. Variables..................................................................................................................13
8.6.1. Patient Characteristics ................................................................................13
8.6.2. Clinical Characteristics...............................................................................14
8.6.3. Treatment Patterns......................................................................................16
8.6.4. Medication Effectiveness............................................................................17
8.6.5. Health Care Cost and Utilization................................................................21
8.7. Data Sources............................................................................................................23
8.7.1. Truven.........................................................................................................23
8.8. Study Size................................................................................................................25
8.9. Data Management ...................................................................................................25
8.10. Data Analysis ........................................................................................................25
8.10.1. Primary Objective.....................................................................................25
8.10.2. Secondary Objectives ...............................................................................25
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 4
8.10.3. Descriptive Analysis.................................................................................27
.27
28
28
28
28
28
8.12. Quality Control......................................................................................................30
8.13. Limitations of the Research Methods....................................................................30
8.13.1. Claims.......................................................................................................30
8.14. Other Aspects ........................................................................................................30
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................30
9.1. Patient Information..................................................................................................30
9.2. Patient Consent........................................................................................................30
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............31
9.4. Ethical Conduct of the Study ..................................................................................31
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................31
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........31
12. REFERENCES ..................................................................................................................32
13. LIST OF TABLES.............................................................................................................33
14. LIST OF FIGURES ...........................................................................................................33
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................34
ANNEX 2. LIST OF RA TREATMENTS..............................................................................35
ANNEX 3. LIST OF CONVENTIONAL SYNTHETIC DMARDS ......................................36
ANNEX 4. LIST OF OTHER MEDICATIONS .....................................................................37
ANNEX 5. CONSUMER PRICE INDEX VALUES..............................................................38
LIST OF TABLES
Table 1.
Exclusionary Diagnoses............................................................................12
Table 2.
Adherence and Dose Escalation Criteria ..................................................19
CCI
CCI
CCI
CCI
CCI
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 5
1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
bDMARD
Biologic disease-modifying antirheumatic drug
CCAE
Truven MarketScan Commercial Claims and Encounters
CIRAS
Claims-based index for RA severity
COB
Coordination of benefits
COPD
Chronic obstructive pulmonary disease
CPI
Consumer price index
CPT
Current Procedural Terminology
csDMARD
Conventional synthetic disease-modifying antirheumatic drug
ED
Emergency department
ER
Emergency room
FDA
Food and Drug Administration
HCPCS
Healthcare Common Procedure Coding System
HIPAA
Health Insurance Portability and Accountability Act
ICD-9 CM
International Classification of Diseases, 9th Revision, Clinical Modification
ICD-10 CM
International Classification of Diseases, 10th Revision, Clinical Modification
ISPOR
International Society for Pharmacoeconomics and Outcomes Research
IEC
Independent Ethics Committee
IRB
Institutional review board
IR
Immediate-Release formulation of tofacitinib (5 mg)
IV
Intravenous
MPR
Medication Possession Ratio
MTX
Methotrexate
nbDMARD
Non-biologic disease-modifying antirheumatic drug
NDC
National Drug Code
NIS
Non-interventional study
NSAID
Non steroidal anti-inflammatory drug
PDC
Proportion of Days Covered
RA
Rheumatoid Arthritis
RX
Outpatient pharmacy prescription
SC
Subcutaneous
TNFi
Tumor-Necrosis Factor-alpha inhibitor
UHC
Urgent Health Care
US
United States
XR
Modified-Release formulation of tofacitinib (11 mg)
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 6
2. RESPONSIBLE PARTIES
Name, degree(s)
Job Title
Affiliation
Address
, PhD
 
, PharmD, MS
, PharmD, MS
 
, PhD
 
3. ABSTRACT
Not applicable.
4. AMENDMENTS AND UPDATES
Amend-
ment 
number
Date
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Substantial or 
Administrative
Reason
1.2
6
December 
2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
CCI
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 7
Amend-
ment 
number
Date
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Substantial or 
Administrative
Reason
Section 2
Replace “
” 
with “
”
Administrative
Change in team membership.
Section 5
Dates updated to include 
additional data and 
updated data availability
Administrative
Update milestone dates.
Section 8.1, 
and related 
references
Changing the 
identification-period dates
Administrative
Updated dates are more 
relevant for the current usage 
of tofacitinib
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
CCI
CCI
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 8
Amend-
ment 
number
Date
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Substantial or 
Administrative
Reason
 
 
 
 
 
 
 
Annex 3,
Annex 4
Added, “Drug codes will 
be refreshed based on 
latest data.  That is, use the 
dictionaries to obtain the 
most comprehensive lists.  
Examples are displayed 
below.”
Administrative
To ensure that the most up-
to-date codes are used and 
hence most correct 
extraction is performed.
Annex 5 and 
related 
references
Change the display dates 
of the Consumer-Price 
Index.
Administrative
To make consistent with the 
updated identification-period 
dates.
1.1
20 
December 
2018
Global
Tofacitinib IR versus 
Tofacitinib XR distinctions 
made and analyses added.
Substantial
It is felt that a sufficient 
number of Tofacitinib XR 
patients have accrued to 
allow for a set of analyses 
that could yield meaningful 
results.
Global
Changed NBDMARD to
csDMARD.
Administrative
“Conventional synthetic” 
DMARD (csDMARD) is 
more correct.
Global
Changed biologics to 
biologic DMARD 
(bDMARD).
Administrative
“biologic DMARD” 
(bDMARD) is more correct.
5
Milestone Dates updated.
Administrative
Updated to correct schedule 
of work.
7, 8, 
title page, 
Table 2
Added IR and XR to 
objectives, specified 
analyses.
Administrative
XR formulation now 
substantially used to warrant 
investigating it.
8
Changed “Number of prior 
bDMARDs” to 0, 1, 2+.
Administrative
Originally 0, 1, 2, 3+, was 
felt that 3+ is too diluted as a 
category.
8
8.2.1
Changed dates of initiation 
to January 2014 to July 
2018.
Substantial
two years of tofacitinib RA 
prescribing; less likely that 
patients in later-line 
treatment.
Changed definition of
combination therapy.
Administrative
To bring into alignment the 
definition with other 
projects.
 
 
 
 
 
 
 
CCI
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 9
Amend-
ment 
number
Date
Protocol 
section(s) 
changed
Summary of 
amendment(s)
Substantial or 
Administrative
Reason
Added reference to ICD-10
Administrative
ICD-10 will be utilized.
8.4, 8.5
Deleted.
Administrative
Text redundant; details 
found later in protocol.
8.2.1, 8.7 
(now 8.3)
Changed baseline 
censoring from 2011 to 
2012.
Administrative
Change corresponding to 
changed of dates of initiation 
to January 2014 to July 
2018.
8.8.2 (now 
8.6.2)
Clarified the calculation of 
the total daily dose of 
corticosteroids.
Administrative
Clarification needed.
8.8.3
(now 8.6.3)
Proportion of Days 
covered definition 
clarified.
Administrative
Clarification needed.
8.8.5
(now 8.6.5)
Untitled Figure added with 
notes, explaining the 
summation of costs.
Administrative
Clarification needed.
8.12.5 (now 
8.10.5)
Updated methodology for 
analysis of cost data.
Substantial
Previous text was outdated.
 
 
 
 
9, 10, 11
Added up-to-date text, per 
SOP.
Administrative
Updated SOP released 
15-Aug-2018.
References
Added References.
Administrative
Citations added are 
associated with new text; 
adding citations for older 
text for completeness.
Annex 2
Replace table with a 
statement that dictionaries 
will be used instead.
Administrative
Less error prone to use 
existing dictionaries.
Annex 3
Changed to “List of 
conventional synthetic 
DMARDS”.
Administrative
To document the 
csDMARDs used.
Annex 4
Annex 3 from previous 
version moved to Annex 4.
Administrative
More logical flow of the
information presented.
Annex 5
Consumer Price Index 
Values.
Administrative
To document the Consumer 
Price Index for cost-of-living 
adjustments.
5. MILESTONES
Milestone
Planned date
Start of data collection
16 Dec 2019
End of data collection
15 March 2020
Final study report
15 July 2020
CC
I

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 10
6. RATIONALE AND BACKGROUND
Tofacitinib 5 mg immediate release formulation (IR) was approved for a twice daily (BID) 
dosing schedule by the Food and Drug Administration (FDA) in November 2012 for the 
treatment of adult patients with moderately to severely active rheumatoid arthritis who have 
had an inadequate response or intolerance to methotrexate. In February, 2016, an 11 mg 
once a day (QD) modified release tablet (XR) for treatment of rheumatoid arthritis was 
approved in the United States.  It may be used as monotherapy or in combination with
methotrexate (MTX) or other conventional synthetic disease-modifying antirheumatic drugs 
(csDMARDs). Since approval, little is known about the effect of tofacitinib on patient 
outcomes relative to biologic disease-modifying antirheumatic drugs (bDMARDs) among 
rheumatoid arthritis (RA) patients in the real world. Biologic DMARDs currently approved 
for RA include: Tumor-Necrosis Factor-alpha inhibitors (TNFi) [adalimumab (Humira), 
etanercept (Enbrel), certolizumab pegol (Cimzia), golimumab (Simponi), infliximab 
(Remicade)] and non-TNFi’s with alternative mechanisms of action [abatacept (Orencia), 
and rituximab (Rituxan), anakinra (Kineret), tocilizumab (Actemra)]. Biologic DMARDs 
have been used for many years to treat RA with varying levels of success; however, no study 
has compared the effectiveness and treatment patterns of tofacitinib to bDMARDs in a real 
world setting.
A similar comparative analysis focusing on the early experience with tofacitinib was 
previously conducted. This analysis is designed to provide an updated characterization of 
medication effectiveness and health care cost and utilization in RA patients treated with 
tofacitinib vs. bDMARDs in the period following the initial introduction of tofacitinib, as 
well as a comparison of the tofacitinib 11 mg QD and tofacitinib 5 mg BID formulations.
7. RESEARCH QUESTION AND OBJECTIVES
The primary and secondary objectives will be conducted among patients who are identified 
from the Truven Health MarketScan Research Database.
7.1. Primary Objective
To compare RA-related costs among patients treated with tofacitinib (IR, XR and combined 
groups) to patients treated with each of the bDMARDs (individually, as well as to TNFi and 
to non-TNFi each combined as groups).
7.2. Secondary Objectives

Explore the differences in demographic and clinical characteristics between patients 
treated with tofacitinib vs. each individual bDMARD.

Compare treatment patterns including dosing, concomitant medication use,
adherence, persistence, and switching with tofacitinib vs. each individual bDMARD.

Compare all-cause and RA-related health care utilization of patients treated with
tofacitinib vs. each individual bDMARD.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 11

Compare all-cause healthcare costs for patients treated with tofacitinib vs. each
individual bDMARD.

Compare medication effectiveness among patients treated with tofacitinib vs. each 
individual bDMARD.
8. RESEARCH METHODS 
8.1. Study Design
To address the objectives, a retrospective cohort design will be employed to evaluate patient
characteristics, treatment patterns, medication effectiveness, and health care cost and
utilization in RA patients newly initiating tofacitinib or bDMARDs between 
01 February 2016 and 31 July 2019 utilizing the Truven Health MarketScan Research
Database, see Section 8.7 below.
In choosing the January 2014, there will have been potentially two years of tofacitinib 
RA prescribing, and it is less likely that patients in later-line treatment will predominate. 
8.2. Setting
This study will utilize the de-identified claims data in the Truven Health MarketScan
Research Database.
8.2.1. Inclusion Criteria
This study will include individuals who are privately insured (Truven MarketScan 
Commercial Claims and Encounters (CCAE) database) and with Medicare Supplemental 
insurance paid for by their employers and treated with tofacitinib or bDMARDs for RA 
between 01 February 2016 and 31 July 2019. To be included in the final study sample, 
patients must meet the following inclusion criteria:
1. At least one claim for methotrexate during the variable-length pre-index period.
2. At least one claim for tofacitinib or bDMARDs between 01 February 2016 and
31 July 2019 (the identification period).
Medication index date: For patients treated with bDMARDs or tofacitinib, the index 
date will be the date of the first claim for bDMARDs or tofacitinib during the
identification period.
3. Continuously enrolled in a commercial (CCAE) or Medicare Supplemental insurance 
plan for at least one year before the index date through at least 1 year after the index
date.
Note: Patients will have a variable length baseline of at least a year long. The baseline period 
will be censored at January 1, 2012 based on licensed data availability.  The majority of 
baseline measures will use data from the 12 months immediately prior to the index date. 
Select measures will use data during the entire variable length baseline.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 12
4. Presence of The International Classification of Diseases, 9th Revision or 10th
Revision, Clinical Modification (ICD-9 CM or ICD-10 CM) code for RA (in any
position) during the one-year pre-index period or on the index date.
ICD-9 = 714.0x-714.4x & 714.81 or ICD10 = M05.* & M06.0*-M06.3* or 
M06.8*-M06.9*.
5. At least 18 years old as of the index date.
8.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Patients with claims for other conditions for which bDMARDs are used during the 
one-year pre-index period or on the index date: ankylosing spondylitis, Crohn’s
disease, psoriasis, psoriatic arthritis, or ulcerative colitis will be excluded from the
study.
Table 1.
Exclusionary Diagnoses
Disease
ICD-9 diagnosis code
ICD10 diagnosis code
Ankylosing Spondylitis
720.0x
M45.*
Crohn's Disease
555.xx
K50.*
Psoriasis
696.1x
L40.0*-L40.4*, L40.8*- L40.9*
Psoriatic Arthritis
696.0x
L40.5*
Ulcerative Colitis
556.xx
K51.*
Juvenile RA
714.3*
M08.*
2. Patients with evidence of the index medication during the one-year pre-index period
will be removed from the analysis.  Patients will be allowed to have been treated with
(other) bDMARDs during the one-year pre-index period.
3. Patients with more than 1 bDMARD or bDMARD with tofacitinib filled on the index 
date will be removed from the study.
8.3. Cohort Assignment
Patients will be assigned to a study cohort based on the medication received on the index 
date. The tofacitinib cohort will include patients with a pharmacy claim for tofacitinib on the
index date. The bDMARD cohort will include patients with pharmacy or medical claims for 
a bDMARD on the index date. Patients will be further classified by the tofacitinib 

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 13
preparation received (IR or XR) or bDMARD received (TNFI or non-TNFi) on the index 
date.
8.5. Period of Observation
All patients will be required to be continuously enrolled in the health plan for at least 
24 months.  Patients will have a variable length baseline period of at least 12 months. The
12 months prior to the index date will be used to assess the majority of pre-index
characteristics. However, for select measures, eg, use of methotrexate, number of prior
bDMARD therapies, and, years since first RA diagnosis, the entire variable length baseline 
period will be utilized.
Measures utilizing the variable length baseline are noted. All baseline periods will be
censored at January 1, 2012.  The twelve months following the index date will be used to
assess outcomes including treatment patterns, and health care costs, utilization and
medication effectiveness.
8.6. Variables
8.6.1. Patient Characteristics
•
Index month/year: The month and year of the patient’s index date will be identified.
•
Age: Age will be defined as of the index year.
•
Age groups: Patients will be assigned to one of the following age groups: 
18–44, 45–64, and 65+.
•
Sex: sex will be captured from enrollment data; patients with undefined gender will
be removed from the study sample.
•
Geographic region: The United States (U.S.) region in which the study patient is
enrolled in a health plan will be determined and reported and states will be 
categorized into five geographic regions: Northeast, North Central, South, West, 
Unknown.
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 14
8.6.2. Clinical Characteristics

Pre-index bDMARD use: The use of bDMARDs during the pre-index period will be
identified. In addition, indicator variables will identify the specific bDMARD(s) used
during the pre-index period.  A count will be created to identify the number of
different bDMARDs received during the baseline. These measures will be created
during the 12 month baseline and during the entire variable length baseline period.

Pre-index csDMARD use: The use of csDMARDs (methotrexate, sulfasalazine,
hydroxychloroquine, etc., other csDMARDs) will be identified during the pre-index
period. In addition, indicator variables will identify the specific medications used 
during the pre-index period.  A count will be created to identify the number of 
different csDMARDs received during the baseline. These measures will be created 
during the 12 month baseline and during the entire variable length baseline period.

Combination vs. monotherapy: whether the patient is treated with combination
therapy (ie, treated with any csDMARDs) or monotherapy at index will be
determined. Patients with a use of at least one of four specific csDMARDs
(methotrexate, sulfasalazine, hydroxychloroquine, leflunomide) within 90 days on or 
after the index date will be considered as being treated with combination therapy.

Pre-index Quan-Charlson comorbidity score: A comorbidity score will be
calculated based on the presence of diagnosis codes on medical claims in the 
12-months pre-index period.2,3  The Quan-Charlson comorbidity score will also be
categorized into the following groups: zero, one to two, three to four, and five or 
more.

Pre-index medications-The most common medications used during the 12-month
pre- and post-index periods will be identified. The most common 25 medications
received will be identified.

Opioid, non-steroidal anti-inflammatory drug (NSAID) use-The use of weak
and/or strong opioids and/or non-steroidal anti-inflammatory drug (NSAID) during
the 12-month pre- and 12-month post-index periods will be identified. The number of
pharmacy claims for opioids and/or NSAIDs and the number of days from the index
date to the first opioid and/or NSAIDs claim will be identified.

Opioid, NSAID use while persistent. In addition to opioid/NSAID use during the
follow-up, use of opioids/NSAIDs while persistent and after persistence will be
identified in the 12-month follow-up period.

Corticosteroid use.  The use of oral corticosteroids during the 12-month pre- and
12-month post-index periods will be identified. In addition, the total 
prednisone-equivalent dose of oral corticosteroids will be calculated.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 15
Note: The total dose for corticosteroids is calculated as the sum(prednisone 
equivalent dose of administered corticosteroids) divided by the maximum of days 
supplied for medication given on the same date, and then averaged over all dates on 
which patient was given corticosteroids.

Pre-index visit with a rheumatologist.  A 0/1 flag will be created to determine if the
patient had an ambulatory visits (office visit or outpatient visit) in which the physician
was a rheumatologist in the 90 days before or on the index date. A separate variable 
will be created identifying the number of visits with a rheumatologist during the 
entire 12-month baseline.  A flag will also be created identifying the presence of a
rheumatologist visit in the entire variable length baseline and the number of visits in 
the variable length baseline.

Disease duration.  The number of days from the earliest claim with a diagnosis of
RA in the variable length baseline until the index date will be identified. Disease
duration will only be created during the variable length baseline.

Pre-index Out-of-pocket expenses. The patient’s total all-cause and RA-related out
of pocket healthcare cost for healthcare services in the one year before the index date
and during the entire variable length baseline period will be calculated.

Comorbidities of interest. 0/1 flags will be created to identify the presence of the
following comorbidities during the 12-month baseline period.

Cardiovascular diseases;

Chronic obstructive pulmonary disease (COPD);

Asthma;

Kidney disease;

Diabetes;

Depression;

Anxiety;

Liver disease;

Sleep disorders;

Hypertension;

Hyperlipidemia.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 16
8.6.3. Treatment Patterns

Non-persistence. A 0/1 flag will be created to identify if the patient is not persistent
with their index bDMARD before the end of the 12 month follow-up period.  
Non-persistence will be identified based on a gap in treatment with the index
medication or switching to another bDMARD.
Among patients with 1 year of follow-up, persistence through the end of the 1 year follow-up 
will be identified. Persistence will be identified based on the day supply (or presumed day
supply) and fill dates of claims for the index medication (see Table 2 for a listing of 
presumed day supplies).
Persistence with the index medication will be defined as not having a gap in therapy of at 
least 60 days between fills/infusions.  For retail pharmacy (RX) claims the day supply will be 
utilized. For Healthcare Common Procedure Coding System (HCPCS) claims a presumed 
day supply derived from the product label will be utilized. A gap of at least 60 days between 
the run-out date (service date + day supply-1) and the next service date will be considered 
non-persistence. Patients with early refills will be allowed to accumulate a stockpile of the 
index medication of up to 14 days for later use.  Please see Section 8.11, for additional details 
on gap and variables needed.

Post persistence treatment patterns. Patients who are not persistent for the entire
follow-up period will be classified into the following mutually exclusive categories
based on the first occurrence of non-persistence: switch immediately, discontinue
then restart, discontinue then switch, discontinue and never switch or restart.

Switch immediately. Patients will be classified as switching immediately if they
initiate a non-index bDMARD before a 60-day gap in treatment is observed for 
the index medication.

Discontinue then restart.  Patients will be classified as discontinuing and then
restarting if there is a gap in the index therapy of at least 60 days and the first
medication observed after the gap is the index medication.

Discontinue then switch.  Patients will be classified as discontinuing and then
switching if there is a gap in the index therapy of at least 60 days and the first 
medication observed after the gap is a bDMARD (including Tofacitinib) different 
from index medication.

Discontinue without switch or restart. Patients will be classified as discontinuing 
without switch or restart if they have a gap in therapy of at least 60 days and there are 
no claims for either the index med or a different bDMARD for the remainder of the 
follow-up period.

Switch any time. In addition to the 4 mutually exclusive treatment patterns, patients
with a switch medication any time during the 12-month follow-up period will be
identified.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 17

Restart any time. In addition to the 4 mutually exclusive treatment patterns, patients
who have a claim for the index medication any time after they are considered 
non-persistent with the index treatment (ie, including after switching) during the
12-month follow-up, will be identified.

Medication Possession Ratio (MPR): The MPR will be evaluated as the total days
supply between the first and including the last prescription/administration divided by
the time between the first through and including last bDMARD prescription or 
administration days supply. For infusible products (except rituximab), the presumed 
days supply is in Table 2. For MPR calculations, multiple prescriptions having same 
fill date will be treated as one prescription with longest days supply; and for all 
prescriptions days supply will be capped at end of follow-up. Also, the MPR will be 
capped at 1.0.

Proportion of Days Covered (PDC):

For all medications (except rituximab) a proportion of days covered (PDC) will be
calculated based on total days supply over the 1 year follow-up. The PDC will be
calculated by using the date of service and the day supply for each fill of the index 
medication. For patients that receive both infused and subcutaneous (SC)
versions of medications, a presumed days supply will be attributed to each
infusion claim based on the product label Table 2.  Patients with early refills will 
be allowed to stockpile medications up to a maximum of 14 days total for later 
use.

For rituximab, because of the dosing schedule PDC is not easily interpretable and 
may not be relevant. For purposes of inclusion, if there are 3 or more rituximab
administrations, the patient will be considered adherent.

csDMARD adherence/addition. Adherence with or addition of a csDMARD during 
the 12 month follow-up will be identified.

Combination therapy patients.  For patients who initiate combination therapy
with csDMARDs a single measure of adherence will be created using all claims
for csDMARDs during the 12-month follow-up period. Adherence will be
calculated as the total day supply divided by the number of days from the first
claim during the follow-up until the end of the follow-up.

Monotherapy patients. For those who initiated monotherapy, addition of a
csDMARD will be evaluated.
8.6.4. Medication Effectiveness
Among patients with at least one year of follow up, medication effectiveness at one year after
the index date will be determined using the following six criteria.4,5  For each of the 
6 criteria, a 0/1 flag will be created. Patients who are effectively treated for each of the 
6 criteria will be considered effectively treated. Patients who fail any of the 6 criteria are

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 18
therefore not effectively treated. Some of the 6 criteria cannot be measured for all of the
index medications. For example, adherence cannot be calculated for patients treated with
rituximab; therefore, medication effectiveness will not be calculated for patients treated with
rituximab at index.

High adherence to index agent will be determined based on PDC >=0.8 during the 
12 month follow-up period. (Sensitivity analysis will be conducted to determine the 
effect of different adherence threshholds, eg, 0.7, 0.9).

No increase in dose for index medication compared to the starting dose. Dose
escalation will be identified per the criteria listed in Table 2.

No switching from the index medication to a (different) bDMARD or tofacitinib. A 
switch will be defined as use of a different bDMARD or tofacitinib any time during
the follow-up period.

No adding of a new csDMARD to the index therapy. Adding a new bDMARD will 
be considered as having at least 1 claim for any csDMARDs during follow-up and not 
having a claim for the same csDMARD during the baseline. Changing from
1 csDMARD at baseline to a different csDMARD at follow-up will be considered as 
adding a new csDMARD, ie, failing the algorithm.  (That is, any csDMARD present 
during the 1-year post-index and not present during 1-year pre-index results in the 
patient not meeting csDMARD effectiveness criterion).

Oral glucocorticoids. Only National Drug Code (NDC) codes for oral glucocorticoids
will be included:

For patients with no claims for oral glucocorticoid prescriptions in the six months
prior to the index date: cannot receive more than 30 days of oral glucocorticoids
between (index date + 91) to (index date + 365).  30 days of oral glucocorticoids
will be determined by summing up the day supply of all glucocorticoids claims
with a fill date between (index date + 91) to (index date + 365).

For patients with claims for oral glucocorticoids during the six months prior to the 
index date: No increase in oral glucocorticoid dose during months 6-12 after index 
compared to the 6 months before the index date. Increase in oral glucocorticoids 
will be determined from the prednisone equivalent dose for all glucocorticoid 
claims filled during the respective time periods.

At most one parenteral or intra-articular glucocorticoid joint injection on unique 
days after the patient had been on bDMARD treatment for more than three 
months between (index date + 91) to (index date + 365).
NOTE: Patients having more than one glucocorticoid injection code on a single 
day are considered to have failed to meet the glucocorticoid injection criteria. 

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 19
Table 2.
Adherence and Dose Escalation Criteria
Generic Name
Standard dosing schedule
(Presumed) day supply
Criteria for dose escalation 
for medication
effectiveness
subcutaneous/oral only
adalimumab
40 mg every other week.
Some patients may benefit 
from increasing the 
frequency to 40 mg every 
week.
Day supply rounded to the
nearest 28 day period. Day
supplies less than 14 days 
will be rounded to 28 days.
At least 1 claim in the 
follow-up period with an
average weekly dose of at 
least 40mg/week.
certolizumab pegol
400 mg initially and at 
Weeks 2 and 4, followed by 
200 mg every other week;
For maintenance dosing,
400 mg every 4 weeks can 
be considered.
Day supply rounded to the
nearest 28 day period. Day
supplies less than 14 days 
will be rounded to 28 days.
At least 1 claim from index 
date+56 days to the end date 
with an average weekly dose 
greater than or equal to 
200mg/week.
etanercept
50 mg once weekly.
Day supply rounded to the
nearest 28 day period. Day
supplies less than 14 days 
will be rounded to 28 days.
At least 1 claim in the 
follow-up period with an
average weekly dose of at 
least 100mg/week.
tofacitinib
(tofacitinib IR)
5 mg twice daily.
Day supply rounded to the
nearest 30 day period. Day
supplies less than 15 days 
will be rounded to 30 days.
At least 1 claim in the 
follow-up period with an
average daily dose of at least 
15 mg/day.
tofacitinib
(tofacitinib XR)
11 mg once daily.
Day supply rounded to the
nearest 30 day period. Day
supplies less than 15 days 
will be rounded to 30 days.
At least 1 claim in the 
follow-up period with an
average daily dose of at least 
22 mg/day.
IV only
infliximab
3 mg/kg at 0, 2 and 6 weeks,
then every 8 weeks.
Some patients may increase 
to 10 mg/kg or treat every 
4 weeks.
56 days for all claims (for
discontinuation)
Any of the following 
3 criteria:
1. The dose of last Rx claim 
(rounded up to next 100 mg) 
is at least 100 mg greater 
than the first dose (rounded 
up to the next 100).
OR
2. There are ≥11 infusion 
dates during the follow-up
period.
OR
3. There fewer than 7 weeks 

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 20
Generic Name
Standard dosing schedule
(Presumed) day supply
Criteria for dose escalation 
for medication
effectiveness
(49 days), between any
2 consecutive infliximab 
infusions not including the
time between the first and 
second, or second and third 
infusions.
rituximab
N/A
N/A
N/A
IV and subcutaneous
tocilizumab
IV: 4 mg/kg every 4 weeks 
then 8 mg/kg every 4
weeks.
SC <100 kg: 162 mg every
other week. Then increase 
to weekly per response SC 
≥100 kg: 162 mg every
week.
SC: Day supply from claim
rounded to the nearest 
28 day period. Day supplies 
less than 14 days will be 
rounded to
28 days.
IV: 28 days
SC claims: At least 1 SC 
claim with an average
weekly dose greater than 
324mg/week OR
IV claims: identify the dose 
of the first IV Rx claim and 
the dose of the last IV claim. 
If the dose of the last IV 
claim is >2.2 times the dose 
of the first IV claim then the 
patient dose escalated.
golimumab
SC: 50 mg /month.
IV: 2 mg/kg at weeks 0 and 
4, then every 8 weeks.
SC: Day supply from claim
rounded to the nearest 
28 day. Day supplies less 
than 14 days will be 
rounded to 28 days.
IV: 28 days
SC claims: At least 1 SC 
claim with an average
weekly dose greater than 
25 mg/week
OR
IV claims: identify the dose 
of the first IV claim and the 
dose of the last IV claim. If 
the dose of the last IV claim
is at least 50 mg greater than 
the dose of the first IV claim 
then the patient dose 
escalated.
abatacept
SC: 125 mg once weekly 
with or without an 
IV loading dose (see 
IV criteria).
IV: weeks 0, 2, 4, and then
every 4 weeks, dose 
determined by weight.
<60 kg: 500 mg.
60-100 kg: 750 mg.
100 kg+: 1000 mg.
SC: day supply from claim
rounded to the nearest 
28 day. Day supplies less 
than 14 days will be 
rounded to 28 days.
IV: 28 days
SC claims: At least 1 SC 
claim with an average
weekly dose greater than 
250 mg/week
IV claims: identify initial 
dose and last dose. If last
dose is greater than first 
dose +100 mg then the
patient dose escalated.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 21
8.6.5. Health Care Cost and Utilization
All cost and utilization measures will be identified in the 12-month pre-index period and the
12-month post-index period.  Claims occurring on the index date will be considered part of
the post-index period.  Baseline and follow-up costs and the change in 12-month costs from
baseline to follow-up will then be examined.  Cost measures will comprise the total amount
paid by the health plan and patient.

Health care resource utilization-Health care resource utilization will be calculated
for ambulatory visits (office and outpatient), emergency department (ED) visits, and 
inpatient admissions.

RA-related resource health care utilization-Health care resource utilization related
to RA will be calculated for ambulatory visits, emergency room (ER) visits, and
inpatient admissions. Utilization will be defined as RA-related if the claim had a
diagnosis for RA in any position and/or is for the administration of a bDMARD or 
csDMARD.

Health care costs-Health care costs will be computed as the combined health plan
and patient paid amounts. Costs will be calculated as total costs, pharmacy costs, and
medical costs. See figure below.  (Medical costs may be further broken down into
ambulatory costs, emergency services costs, inpatient costs, and other costs).

Costs will be adjusted using the annual medical care component of the Consumer 
Price Index (CPI) to reflect inflation between 2016 (the earliest start of the pre-index
period) and 2018 (the cost of claims occurring in 2019 will not be adjusted).6 See 
Annex 5.

Costs from other payers are of importance for older patients dually eligible for 
commercial and Medicare coverage. Payments from Medicare (and other payers) will
be estimated based on coordination of benefits information obtained by the health 
plan in its usual course of business. This study will incorporate the amounts 
estimated to be paid by other payers for a total paid or allowable amount.7

RA-related health care costs-CPI- and coordination of benefits (COB)-adjusted 
RA-related health care costs will be calculated as total costs related to RA (treatment
and other medical claims with a diagnosis of RA). RA-related treatment costs will
include the cost of tofacitinib, bDMARDs, csDMARDs, and administration of
intravenous (IV) bDMARDs (CPT = 96413 or 96415).

Medical costs will include all utilization with a diagnosis of RA and are also not 
treatment claims. Medical costs will comprise: inpatient costs, ambulatory costs, 
emergency services costs, administration, and other costs.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 22

Monthly costs-Total all-cause and RA-related health care cost will be identified
during each month (30-day period) of the patient’s 12-month baseline and the 
12-month follow-up period.
NOTES:

Outpatient includes:

ER;

Outpatient hospital Office visits;

Home health care;

Urgent care (see note below);

Other medical services.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 23

Urgent Health Care (UHC) visits are stored differently in the Truven Marketscan 
database (not in the variable “SVCSCAT”, another variable in Truven Marketscan) 
and so any visit listed above can have UHC at the same time.  That is UHC cost is not 
mutually exclusive from the other visit types for cost. 
8.7. Data Sources
8.7.1. Truven
The Truven Health MarketScan Research Databases reflects the combined healthcare service
use of individuals covered by Truven Health clients (including employers, health plans, and
hospitals) nationwide. Truven Health builds databases comprise the healthcare experience of
the clients’ covered populations, as well as information about the populations themselves and 
the providers that serve them.  MarketScan Research Databases provide detailed cost, 
utilization, and outcomes data for healthcare services performed in both inpatient and
outpatient settings. In the claims databases, the medical services are linked to outpatient
prescription drug claims and person-level enrollment data using unique enrollee identifiers. 
The MarketScan Commercial Database contains the healthcare experience of privately
insured individuals.  Coverage is provided under a variety of fee-for-service, fully capitated,
and partially capitated health plans, including preferred provider organizations, point of
service plans, indemnity plans, and health maintenance organizations.
The data that make up the Commercial Database are stored in the following tables:

The Inpatient Admissions Table contains records that summarize information about a
hospital admission. Truven Health constructs this table after identifying all of the 
service records associated with an admission (eg, the hospital claims, physician
claims, surgeon claims, and claims from independent labs). Similar information 
(such as payments for professional services) is then summed across the claims. The
admission record includes the principal procedure and diagnosis, Major Diagnostic 
Category, and Diagnosis-Related Group. It also includes all diagnoses and procedures 
(up to 14 each) found on the service records.

The Inpatient Services Table contains the individual claims that are summed to create 
the inpatient admission records. An admission identifier on both the Inpatient
Admissions and the Inpatient Services Tables identifies the claims that make up each
admission record.

The Outpatient Services Table comprises services that were rendered in a doctor’s
office, hospital outpatient facility, or other outpatient facility.

The Facility Header Table contains the header records from facility claims for
inpatient and outpatient services, including full diagnosis information.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 24

The Outpatient Pharmaceutical Claims Table contains outpatient prescription drug
data from multiple sources, including mail-order data. Each record includes National
Drug Code (NDC), therapeutic class, ingredient cost, dispensing fee, copayment,
deductible, total gross payment, and other data elements.

The RED BOOK™Supplement contains RED BOOK variables that enhance
prescription drug analyses.  These variables are linked to the Outpatient
Pharmaceutical Claims Table by NDC.

The Annual Enrollment Summary Table provides a single record per year for each
enrollee, showing enrollment start and end dates and, for some demographic 
variables, the most prevalent demographic and plan information; for other variables,
monthly values are included.

The Enrollment Detail Table provides a single record per month of enrollment for 
each enrollee, with detailed demographic information.

The Population Aggregate Table provides average counts of the covered (insured)
population to use for rate-supported analysis.  The counts are recorded by several
demographic variables (eg, age group, gender, region, etc.).

The MarketScan Medicare Supplemental Database contains the healthcare experience 
of individuals with Medicare supplemental insurance paid for by employers. Both the
Medicare-covered portion of payment (represented as Coordination of Benefits 
Amount, or COB) and the employer-paid portion are included in this database. The
tables that make up the Medicare Supplemental Database are the same as those that 
make up the Commercial Database.
Claims are not included in the database until they have been adjudicated; there is a lag of 
approximately six months after the close of a calendar year or a quarter between services
provided and their inclusion in the Research Databases. However, the Early View Database 
has a 90-day lag that includes paid amounts for 100 percent of prescription drugs,
approximately 85 percent of physician office visits, and approximately 70 percent of hospital
claims.
The MarketScan Early View Database includes all of the components found in the standard 
MarketScan Commercial and Medicare Supplemental Databases. It includes standardized
inpatient, outpatient, pharmaceutical, and health-plan enrollment data. The MarketScan
Early View Database captures healthcare services incurred up to 90 days before data release 
and includes only adjudicated claims. However, the medical component of care for some 
patients will not be complete, since some claims (particularly inpatient claims) take longer to 
be adjudicated. Because this study is examining only comorbidities prior to and treatments
during or prior to tofacitinib initiation fully adjudicated claims are not required and all 
available data will be used including Commercial, Medicare Supplemental, and Early View 
Databases.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 25
8.8. Study Size
The sample size for this study is fixed by the duration of the observation window. No formal 
sample size computation was performed.  All patients who meet inclusion/exclusion criteria 
will be included in the analyses.
8.9. Data Management 
The MarketScan Research Databases comply with both the spirit and the letter of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  The MarketScan Databases
meet the criteria for a limited-use dataset and contain none of the data elements prohibited by
HIPAA for limited-use datasets.
8.10. Data Analysis
8.10.1. Primary Objective
•
To compare RA-related costs among patients treated with tofacitinib (IR, XR and 
combined groups) to patients treated with each of the bDMARDs (individually, as 
well as to TNFi and to non-TNFi  each combined as groups).
 
For the descriptive analysis, 12-month RA-related cost measures will be 
presented per patient during the baseline and follow-up periods. The change in health care 
cost from baseline to follow-up will be identified. In addition, total RA-related health care 
cost will be presented in each of the months of the baseline and follow-up.  
 
8.10.2. Secondary Objectives
•
Explore the differences in demographic and clinical characteristics between patients
treated with tofacitinib vs. each individual bDMARD.
For this objective descriptive analysis will be conducted.  
•
Compare treatment patterns including dosing, concomitant medication use, 
adherence, persistence and switching with tofacitinib vs. each individual bDMARD.
For this objective, treatment patterns will be summarized across the cohorts of interest.
CCI
CCI
CCI
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 26
•
Compare all-cause and RA-related health care utilization of patients treated with
tofacitinib vs. each individual bDMARD.
For this objective descriptive analysis will be conducted.
•
Compare all-cause healthcare costs for patients treated with tofacitinib vs. each
individual bDMARD.
For this objective descriptive analysis will be conducted
 
 
•
Compare medication effectiveness among patients treated with tofacitinib vs. each 
individual bDMARD.
Medication effectiveness at one year will be examined by the medication cohorts of interest
using patients who have at least 1 year of follow-up. For this objective descriptive analysis
will be used, 
 
 
CCI
CCI
CCI
C
C
I

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 27
8.10.3. Descriptive Analysis
All study variables, including pre- and post-index measures, will initially be analyzed 
descriptively.  In general, numbers and percents will be provided for dichotomous and
polytomous variables, while means, medians, and standard deviations will be provided for
continuous variables. Missing or unavailable data will not be imputed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 28
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 29
 
 
 
 
 
 
 
 
 
  
 
 
CCI
C
C
I

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 30
8.12. Quality Control
This is a retrospective study, so issues of quality control at study sites, eg, data queries, do
not apply.  Analyses are programmed according the specifications in the protocol, and if
applicable, the statistical analysis plan and documented in a programming plan. Final
deliverables are reviewed and verified by a second, independent programmer who may also
perform double programming.  All quality checks are documented in the programming plan.
8.13. Limitations of the Research Methods
8.13.1. Claims
Limitations that are general to claims database analyses and specific to this study should be
noted. First, diagnosis of autoimmune conditions will be identified using ICD-10-CM
diagnosis codes, which are subject to potential miscoding. Second, the baseline period for
this study will be 12 months long.  Therefore, patients treated with a bDMARD in the
baseline can be considered to be continuing users of bDMARD therapy; however, patients 
with no bDMARD use in the baseline may have just been off therapy for the 12 months prior. 
Lastly, this study will include an examination of medication effectiveness at 1 year among all
bDMARD users. Effectiveness will be measured using a validated algorithm; however, the
algorithm was not validated for all medications being included. Specifically, tofacitinib was
approved for treatment of RA after the algorithm was developed. This study will include
consultation with physicians to determine if the algorithm is valid for all study medications
or if modifications need to be implemented.
8.14. Other Aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
9.1. 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.
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, any patient names will be removed and will be replaced by a single, specific, 
numerical code.  All other identifiable data transferred to Pfizer or other authorized parties 
will be identified by this single, patient-specific code. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with Truven Marketscan and applicable privacy laws.
9.2. Patient Consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required.  

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 31
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
IRB is not required for this study as it uses commercially available de-identified secondary
data sources and is considered exempt from the requirements for “human subjects research”
in the US.
9.4. 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 CT24-WI-GL02-RF04 and the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR).
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS
This study involves data that exist as structured data by the time of study start or a 
combination of existing structured data and unstructured data, which will be converted to 
structured form during the implementation of the protocol solely by a computer using 
automated/algorithmic methods, such as natural language processing.
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (ie, identify a potential association between) a particular product and medical 
event for any individual.  Thus, the minimum criteria for reporting an adverse event (AE) (ie,
identifiable patient, identifiable reporter, a suspect product, and event) cannot be met.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
For all publications relating to the Study, Pfizer will comply with recognized ethical
standards concerning publications and authorship, including Section II - “Ethical
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
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 party responsible for collecting data 
from the participant 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.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 32
12. REFERENCES
 
2.
Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, Januel JM, Sundararajan V. 
Updating and validating the Charlson comorbidity index and score for risk adjustment 
in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 
2011;173(6):676-82.
3.
Bayliss EA, Ellis JL, Shoup JA, Zeng C, McQuillan DB, Steiner JF. Association of 
patient-centered outcomes with patient-reported and ICD-9-based morbidity measures. 
Ann Fam Med 2012;10(2):126-33.
4.
Curtis, J.R., et al., Derivation and preliminary validation of an administrative claims-
based algorithm for the effectiveness of medications for rheumatoid arthritis. Arthritis 
Res Ther, 2011. 13(5): p. R155.
5.
Oladapo, et. al. Medication Effectiveness with the Use of Tumor Necrosis Factor 
Inhibitors Among Texas Medicaid Patients Diagnosed with Rheumatoid Arthritis. 
Journal of Managed Care Pharmacy. 657 – 67. Vol. 20, No. 7. July 2014
6.
US Department of Labor, Bureau of Labor Statistics. Consumer Price Index. Medical 
Care. Series ID: CUUR0000SAM. Washington, DC: U.S. Dept. of Labor, Bureau of 
Labor Statistics. http://data.bls.gov/cgi-bin/surveymost?cu
7.
Frytak JF, Henk JH, et al. Health Services Utilization Among Alzheimer’s Patients:
Evidence from Managed Care. Alzheimer’s and Dementia. 2008; 4(5):361-67.
C
C
I

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 33
13. LIST OF TABLES 
TABLE 1.
EXCLUSIONARY DIAGNOSES...................................................................12
TABLE 2.
ADHERENCE AND DOSE ESCALATION CRITERIA...............................19
14. LIST OF FIGURES
None.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 34
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 35
ANNEX 2. LIST OF RA TREATMENTS
Drug codes will be refreshed based on latest data.  That is, use the dictionaries to obtain the 
most comprehensive lists of NDC and HCPCS codes.  

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 36
ANNEX 3. LIST OF CONVENTIONAL SYNTHETIC DMARDS
Drug codes will be refreshed based on latest data.  That is, use the dictionaries to obtain the most 
comprehensive lists.  Examples are displayed below.
Generic Names
J-codes
NDC
Hydroxychloroquine
n/a
Please look-up in “redbook.”
Methotrexate
J8610, J9250, J9260
Leflunomide
n/a
Sulfasalazine
n/a
Other Medications:
Chloroquine
J0390
Proprietary codes (based on 
groupings of NDC codes by
generic name) will be used to 
identify these drugs from
pharmacy claims.
Combos
n/a
Cyclosporine
J7502, J7515, J7516,
C9438, J7503, 
K0121,
K0122, K0418
Thalidomide
n/a
Azathioprine
J7500, J7501, C9436, 
K0119, K0120
Cyclophosphamide
J8530, J9070, J9080,
J9090, J9091, J9092,
J9093, J9094, J9095,
J9096, J9097, C9420,
C9421
Auranofin
n/a
Aurothioglucose
J2910
Gold Sodium 
Thiomalate
J1600
Penicillamine
n/a
Tacrolimus
J7507, J7525, C9006, 
J7508
Minocycline
J2265

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 37
ANNEX 4. LIST OF OTHER MEDICATIONS
Drug codes will be refreshed based on latest data.  That is, use the dictionaries to obtain the 
most comprehensive lists.  Examples are displayed below.
Medication 
HCPCS, if applicable
Glucocorticoids^
betamethasone
J7624
budesonide
cortisone
J0810
dexamethasone
J1094, J1095,
J1100, J8540,
Q0137,
Q0138,
S0173
Fludrocortisone
hydrocortisone
methylprednisolone
J1020, J1030,
J1040, J2920,
J2930, J7509
prednisolone
J1680, J2640, J2650, J7510
prednisone
J1690, J7506, K0125
triamcinolone
J3300, J3301, J3302, J3303
NSAID
J1885
Opioids
^Proprietary codes (based on groupings of NDC codes by generic name) will
also be used to identify these drugs from pharmacy claims

Tofacitinib
A3921305 NON-INTERVENTIONAL STUDY PROTOCOL
Final Version 1.2, 6 December 2019
PFIZER CONFIDENTIAL
Page 38
ANNEX 5. CONSUMER PRICE INDEX VALUES
Use the following values of yearly averaged CPI (source: 
http://data.bls.gov/cgi-bin/surveymost?cu U.S. Medical Care, 1982-84=100 
- CUUR0000SAM)
Year
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
AVERAGE
2016
454.175 458.295 458.620 459.994 461.230 462.075 464.164 468.379 469.154 469.230 469.333 469.447 463.675
2017
471.700 474.546 474.561 473.582 473.512 474.360 476.126 476.869 476.485 477.121 477.198 477.802 475.322
2018
481.060 482.897 483.984 484.034 484.853 486.019 485.193 484.172 484.708 485.269 486.886 487.409 484.707
2019
490.204 491.227 492.306 493.331 494.928 495.563 497.687 500.916 501.468 506.100
496.373