Infliximab-Pfizer Biosimilar Post-Marketing Database Study
Conditions: Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Psoriasis
Sponsor: Pfizer

Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
CT24-WI-JPN-GPSP01-RF10 6.0 Non-Interventional Study Protocol Template for Post-marketing Database 
Study 01-Nov-2023
Page 1 of 51
Infliximab-Pfizer Biosimilar Post-Marketing Database Study
NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Pfizer Japan Inc.
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.
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
CT24-WI-JPN-GPSP01-RF10 6.0 Non-Interventional Study Protocol Template for Post-marketing Database 
Study 01-Nov-2023
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Study information
Title
Infliximab-Pfizer Biosimilar Post-Marketing 
Database Study
Protocol number
B5371010
Protocol version identifier
Version 4
Date
28 June 2024
Active substance
Infliximab-Pfizer Biosimilar
Medicinal product
PF-06438179
Research question and objectives
The research question is to evaluate the important 
safety outcome events in patients with rheumatoid 
arthritis, ulcerative colitis, Crohn’s disease, or 
psoriasis who have received Infliximab-Pfizer 
Biosimilar compared to those patients who have 
received Remicade from December 1, 2018 through 
November 30, 2023.
The primary objective is to evaluate the incidence rate 
of serious infections overall in patients with 
rheumatoid arthritis, ulcerative colitis, Crohn’s 
disease, or psoriasis who have received Infliximab-
Pfizer Biosimilar compared to those patients who 
have received Remicade.
Secondary objectives are as follows,

to evaluate the incidence rate of serious 
infections in patients in each disease subcohort 
who have received Infliximab-Pfizer Biosimilar 
compared to those patients who have received 
Remicade.

to evaluate the incidence rate of tuberculosis, 
serious blood disorder, interstitial pneumonia, 
and malignancy overall in patients with 
rheumatoid arthritis, ulcerative colitis, Crohn’s 
disease, or psoriasis who have received 
Infliximab-Pfizer Biosimilar compared to those 
patients who have received Remicade.

to evaluate the incidence rate of tuberculosis, 
serious blood disorder, interstitial pneumonia, 
and malignancy in patients in each disease 
subcohort, who have received Infliximab-Pfizer 
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I nfli xi ma b-Pf izer Bi osi milar
B 5 3 7 1 0 1 0 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
Versi o n 4 , 2 8 J u ne 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -J P N-G P S P 0 1 -R F 1 0 6 . 0 N o n-I nter ve nti o nal St u d y Pr ot oc ol Te m plate f or P ost-mar keti n g Data base 
St u d y 0 1- N o v -2 0 2 3
P a ge 3 of 5 1
Bi osi milar c o m pa re d t o t h ose patie nts w h o ha ve 
recei ve d Re mica de.
A ut h or
, P h D
Pfizer R & D Ja pa n
, P h D
Pfizer R & D Ja pa n
 P h D
Pfizer R & D Ja pa n
0 9 0 1 7 7 e 1 a 1 0 b 0 1 8 6\ Fi n al\ Fi n al O n: 2 7- J u n- 2 0 2 4 0 3: 4 3 ( G M T)
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
CT24-WI-JPN-GPSP01-RF10 6.0 Non-Interventional Study Protocol Template for Post-marketing Database 
Study 01-Nov-2023
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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................4
2. DEFINITION OF TERMS ....................................................................................................6
3. LIST OF ABBREVIATIONS................................................................................................7
4. RESPONSIBLE PARTIES....................................................................................................8
5. ABSTRACT...........................................................................................................................9
6. AMENDMENTS AND UPDATES.....................................................................................12
7. MILESTONES.....................................................................................................................14
8. RATIONALE AND BACKGROUND................................................................................14
9. RESEARCH QUESTION AND OBJECTIVES .................................................................16
9.1. Safety Specifications...............................................................................................16
9.2. Research question and study objective....................................................................17
10. RESEARCH METHODS ..................................................................................................17
10.1. Study design ..........................................................................................................17
10.2. Setting....................................................................................................................17
10.2.1. Study period (data period) ........................................................................18
10.2.2. Definitions of exposure and control, and the defining information..........18
10.2.3. Inclusion criteria .......................................................................................19
10.2.4. Exclusion criteria......................................................................................19
10.2.5. Flow chart .................................................................................................19
10.3. Variables................................................................................................................20
10.3.1. Definition of outcomes and defining information ....................................20
10.3.2. Covariate, and the defining information...................................................22
10.4. Data sources ..........................................................................................................22
10.4.1. Overview of the health information database used in this study..............22
10.4.2. Validation .................................................................................................22
10.5. Study size ..............................................................................................................22
10.6. Data analysis .........................................................................................................26
10.7. Quality control.......................................................................................................27
10.8. Limitations of the research methods .....................................................................27
10.9. Other aspects .........................................................................................................28
11. PROTECTION OF HUMAN PARTICIPANTS ...............................................................28
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
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Study 01-Nov-2023
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11.1. Patient information................................................................................................28
11.2. Patient consent.......................................................................................................28
11.3. Institutional review board (IRB)/Ethics committee (EC)......................................28
11.4. Ethical conduct of the study..................................................................................29
12. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................29
13. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........29
14. SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR 
REPORTING OF STUDY IMPLEMENTATION STATUS AND EVALUATION 
OF OBTAINED RESULTS TO THE PMDA ....................................................................30
15. ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON 
THE STUDY RESULTS AND CRITERIA FOR DETERMINATION OF THE 
INITIATION.......................................................................................................................30
16. ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION...........................30
17. NAME, ADDRESS AND OUTSOURCED OPERATIONS OF THE PERSON 
WHO WAS CONTRACTED WITH THE OPERATIONS ...............................................30
18. REFERENCES ..................................................................................................................31
19. LIST OF TABLES.............................................................................................................31
20. LIST OF FIGURES ...........................................................................................................31
ANNEX 1. LIST OF STANDALONE DOCUMENTS ..........................................................31
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................31
ANNEX 3. ADDITIONAL INFORMATION.........................................................................31
APPENDIX. ORGANIZATIONAL SYSTEM FOR POST-MARKETING 
SURVEILLANCE ..............................................................................................................32
ATTACHMENT 1. OUTCOME DEFINITIONS ...................................................................33
1. Serious infections .......................................................................................................33
2. Tuberculosis ...............................................................................................................33
3. Serious blood disorder................................................................................................33
4. Interstitial pneumonia.................................................................................................36
5. Malignancy.................................................................................................................37
ATTACHMENT 2. DISEASE CODE LIST ...........................................................................38
ATTACHMENT 3. DRUG LIST ............................................................................................49
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
CT24-WI-JPN-GPSP01-RF10 6.0 Non-Interventional Study Protocol Template for Post-marketing Database 
Study 01-Nov-2023
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2. DEFINITION OF TERMS
Not applicable
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
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Study 01-Nov-2023
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3. LIST OF ABBREVIATIONS
Abbreviation
Definition
BCG
Bacille de Calmette et Guérin
CD
Crohn's Disease
DMARDS
Disease Modifying Anti-Rheumatic Drugs
DPC
Diagnosis Procedure Combination
EC
Ethics Committee
ICD
International Classification of Diseases
IgG1
Immunoglobulin G1
IPTW
Inverse Probability of Treatment Weighting
IRB
Institutional Review Board
ISO
International Organization for Standardization
MDV
Medical Data Vision
MHLW
Ministry of Health, Labour and Welfare
PFSB
Pharmaceutical and Food Safety Bureau
PMDA
Pharmaceuticals and Medical Devices Agency
RA
Rheumatoid Arthritis
RMP
Risk Management Plan
SAP
Statistical Analysis Plan
TNFα
Tumor Necrosis Factor Alpha
UC
Ulcerative Colitis
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
CT24-WI-JPN-GPSP01-RF10 6.0 Non-Interventional Study Protocol Template for Post-marketing Database 
Study 01-Nov-2023
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4. RESPONSIBLE PARTIES
The Japan Good Post Marketing Study Practice Officer
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
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Study 01-Nov-2023
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5. ABSTRACT
Title: Infliximab-Pfizer Biosimilar Post-Marketing Database Study
Principal Investigators:
Hiroyuki Hashimoto, Pfizer R&D Japan
Yoshiomi Nakazuru, Pfizer R&D Japan
Yoichi Ii, Pfizer R&D Japan
Rationale and Background: 
Based on results from the clinical development program, safety specifications for additional 
pharmacovigilance activities have been identified. Additional pharmacovigilance activities 
will be performed through comparisons of the occurrence of the safety specifications 
especially for serious infections, tuberculosis, serious blood disorder, interstitial pneumonia, 
and malignancy between Infliximab-Pfizer Biosimilar and the innovator (Remicade) by using 
an electronic health care database. Since it has not been reported that the safety is 
significantly different between the indications of Remicade, the evaluation will be mainly 
performed in the overall four diseases, and the evaluation of each disease will be also 
performed in disease subcohorts.
Research Question and Objectives: 
The research question is to evaluate the important safety outcome events in patients with 
rheumatoid arthritis, ulcerative colitis, Crohn’s disease, or psoriasis who have received 
Infliximab-Pfizer Biosimilar compared to those patients who have received Remicade from 
December 1, 2018 through November 30, 2023.
The primary objective is to evaluate the incidence rate of serious infections overall in patients 
with rheumatoid arthritis, ulcerative colitis, Crohn’s disease, or psoriasis who have received 
Infliximab-Pfizer Biosimilar compared to those patients who have received Remicade.
Secondary objectives are as follows,

to evaluate the incidence rate of serious infections in patients in each disease subcohort 
who have received Infliximab-Pfizer Biosimilar compared to those patients who have 
received Remicade.

to evaluate the incidence rate of tuberculosis, serious blood disorder, interstitial 
pneumonia, and malignancy overall in patients with rheumatoid arthritis, ulcerative 
colitis, Crohn’s disease, or psoriasis who have received Infliximab-Pfizer Biosimilar 
compared to those patients who have received Remicade.
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
CT24-WI-JPN-GPSP01-RF10 6.0 Non-Interventional Study Protocol Template for Post-marketing Database 
Study 01-Nov-2023
Page 10 of 51

to evaluate the incidence rate of tuberculosis, serious blood disorder, interstitial 
pneumonia, and malignancy in patients in each disease subcohort, who have received 
Infliximab-Pfizer Biosimilar compared to those patients who have received Remicade.
Study Design: This is an observational cohort study. 
Population: The study population includes individuals who have a diagnosis of rheumatoid 
arthritis, ulcerative colitis, Crohn’s disease, or psoriasis and have been exposed to 
Infliximab-Pfizer Biosimilar or the innovator (Remicade) with a planned study period 
between December 1, 2018 and November 30, 2023. 
Outcome events: Serious infections, tuberculosis, serious blood disorder, interstitial 
pneumonia, malignancy
Data Source: The source population for the study sample will be patients from the Medical 
Data Vision (MDV) database; a hospital-based claims database in Japan that consists of 
outpatient and inpatient data from hospitals using the diagnosis procedure combination 
(DPC) system.
Study Size: The number of exposed to Infliximab-Pfizer Biosimilar patients would be 
expected about 1,000 patients for all 4 indications (rheumatoid arthritis, ulcerative colitis, 
Crohn's disease and psoriasis). The number of comparator (Remicade) patients would be 
expected to be about 9 times as large as the number of exposed patients.
Data Analysis: 
Three analysis sets will be defined as follows to evaluate the relative risks of Infliximab-
Pfizer Biosimilar to Remicade. 

The full analysis set will include all patients who are considered eligible by the inclusion 
and exclusion criteria in Section 10.2.3 and Section 10.2.4.

The comparative analysis set will be a subset of the full analysis set who are new users. 
That is, patients switching from non-Pfizer Infliximab Biosimilar or Remicade to Pfizer-
Infliximab Biosimilar will be excluded. Also, patients switching from any Infliximab 
Biosimilar to Remicade will be excluded.

The comparative matched analysis set will be a subset of the comparative analysis set 
that includes all patients matched between Infliximab-Pfizer Biosimilar and Remicade. 
Each patient from the Infliximab-Pfizer Biosimilar group will be matched to two patients 
from the Remicade group based on the propensity score.
For each analysis set, the incidence rate of each outcome event (serious infections, 
tuberculosis, serious blood disorder, interstitial pneumonia, and malignancy) will be 
calculated for Infliximab-Pfizer Biosimilar and Remicade group for the main cohort and for 
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Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
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Study 01-Nov-2023
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each disease subcohort (rheumatoid arthritis, ulcerative colitis, Crohn’s disease, or psoriasis). 
The incidence rate will be estimated by counting the number of events in the numerator and 
dividing by the total person-time of observation in the denominator.
The following comparative analyses will be carried out to assess the relative incidence of 
these events using the comparative analysis set and comparative matched analysis set. Crude
hazard ratios and rate ratios will be calculated including 95% confidence intervals with 
Remicade as the reference group. Crude rate differences will be calculated including 95% 
confidence intervals (the risk of Infliximab-Pfizer Biosimilar - the risk of Remicade).
Two types of analyses based on propensity score will be conducted. First is the Inverse 
Probability of Treatment Weighting (IPTW) method based on the comparative analysis set. 
Second is the method based on matched analysis based on the comparative matched analysis
set.
For the IPTW analysis, adjusted hazard ratios, rate ratios, and rate differences will be 
calculated based on weights based on the propensity score. Hazard ratios will be calculated 
by Cox proportional hazard model. Rate ratios and rate difference will be calculated by a 
Poisson regression model accounting for different duration on treatment.
For the matched analysis, adjusted hazard ratios, rate ratios, and rate differences will be 
calculated by using the following models. Hazard ratios will be calculated by Cox 
proportional hazard model. Rate ratios and rate difference will be calculated by a Poisson 
regression model accounting for different duration on treatment.
Milestones: The study period is from 1 December 2018 through 30 November 2023. The 
start of data collection for the final analysis is on 1 December 2023 (the date when data 
extraction begins). The end of data collection is on 28 February 2024 (the date when the 
analytic dataset is completely available). The final study report submission will be on 31 July 
2025.
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I nfli xi ma b-Pf izer Bi osi milar
B 5 3 7 1 0 1 0 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
Versi o n 4 , 2 8 J u ne 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -J P N-G P S P 0 1 -R F 1 0 6 . 0 N o n-I nter ve nti o nal St u d y Pr ot oc ol Te m plate f or P ost-mar keti n g Data base 
St u d y 0 1- N o v -2 0 2 3
P a ge 1 2 of 5 1
6. A M E N D M E N T S A N D U P D A T E S
Versi o n 
I de ntifier
D ate
A m e n d me nt 
T y pe 
(s u bst a nti al or 
a d mi nistr ati ve)
Pr ot oc ol Secti o n(s) 
C h a n ge d
S u m m ar y of 
A m e n d me nt(s)
Re as o n
Ver. 4
2 8 J u ne
2 0 2 4
S u bsta ntial
1 0. 3. 2. C o variate, a n d 
t he defi ni n g i nf or mati o n
Descri pti ve u p date
fr om Bi ol o gics 
(e xcl u di n g I nfli xi ma b-
Pfizer Bi osi milar) t o 
Bi ol o gics (e xcl u di n g 
a n y I nfli xi ma b 
pr o d ucts)
In or der t o 
c o n d uct a nal ysis 
c orrectl y
A T T A C H M E N T 1. 
O U T C O M E 
D E FI NI TI O N S
3. Seri o us bl o o d dis or der
Ta ble A 1 - 3-1. Basic 
C o n diti o ns a n d 
A d diti o nal C o n diti o ns 
f or Bl o o d Dis or der 
( Pa nc yt o pe nia) t o be 
Use d i n t his St u d y
A d diti o nal C o n diti o n 4
C orrecti o n of dr u g 
na me a n d dr u g c o de
Descri pti o n 
u p dates d ue t o 
ty p o
A T T A C H M E N T 2. 
DI S E A S E C O D E LI S T
Ta ble A 2 -1. Disease 
C o de List f or I nfecti o n
U p date of d isease co de 
list
A T T A C H M E N T 2. 
DI S E A S E C O D E LI S T
Ta ble A 2 -5. Disease 
C o de List f or 
Mali g na nc y
U p date of d isease co de 
list
A T T A C H M E N T 3. 
D R U G LI S T
Ta ble A 3 -5. List of 
Bi ol o gics
Re m o val of I nfli xi ma b 
fr o m t he list t o ali g n 
wit h t he descri pti ve 
u p date i n 1 0. 3. 2
I n or der t o 
c o n d uct a nal ysis 
c orrectl y
Ver. 3
3 1 Ja n uar y
2 0 2 4
A d mi nistrati ve
1 7. N A M E, A D D R E S S 
A N D O U T S O U R C E D 
O P E R A TI O N S O F T H E 
P E R S O N W H O W A S 
C O N T R A C T E D WI T H 
T H E O P E R A TI O N S
A d diti o n of  t he 
o uts o urce ve n d or
Selecte d t he 
ve n d or f or 
statistical 
a nal ysis
0 9 0 1 7 7 e 1 a 1 0 b 0 1 8 6\ Fi n al\ Fi n al O n: 2 7- J u n- 2 0 2 4 0 3: 4 3 ( G M T)
C CI

I nfli xi ma b-Pf izer Bi osi milar
B 5 3 7 1 0 1 0 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
Versi o n 4 , 2 8 J u ne 2 0 2 4
P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -J P N-G P S P 0 1 -R F 1 0 6 . 0 N o n-I nter ve nti o nal St u d y Pr ot oc ol Te m plate f or P ost-mar keti n g Data base 
St u d y 0 1- N o v -2 0 2 3
P a ge 1 3 of 5 1
A P P E N DI X. 
O R G A NI Z A TI O N A L 
S Y S T E M F O R P O S T -
M A R K E TI N G 
S U R V EI L L A N C E
U p date of t he 
or ga nizati o n str uct ure
A d mi nistrati ve 
c ha n ge
Ot her
U p date of t he f o oter 
i nf or mati o n
Re visi o n of t he 
pr ot oc ol 
te mplate
Ver. 2
3 0 Oct o ber 
2 0 2 3
S u bsta ntial
St u d y i nf or mati o n
Descri pti ve u p date t o 
Ali g n wit h c o ver title
A d mi nistrati ve 
c ha n ge
3. LI S T O F 
A B B R E VI A TI O N S
Descri pti ve 
u p date( A d diti o n a n d 
deleti o n)
A d mi nistrati ve 
c ha n ge
5. A B S T R A C T
Title
Descri pti ve u p date t o 
Ali g n wit h c o ver title
A d mi nistrati ve 
c ha n ge
5. A B S T R A C T
Data A nal ysis a n d 
Milest o nes
Descri pti ve u p date f or 
c ha n ges i n t he a nal ysis 
pla n a n d milest o ne
7. MI L E S T O N E S
Deleti o n of pla n ne d
i nteri m a nal ysis date
1 0. 3. 2. C o variate, a n d 
t he defi ni n g i nf or mati o n
Descri pti ve u p date f or 
c ha n ges i n t he a nal ysis 
pla n
1 0. 6. Data a nal ysis
Descri pti ve u p date f or 
c ha n ges i n t he a nal ysis 
pla n
1 0. 8. Li mitati o ns of t he 
researc h met h o ds
A d diti o n of t he 
descri pti o n t hat 
c o m paris o ns will be 
ma de re gar dless of t he 
n u m ber of acc u m ulate d 
cases, a n d li mitati o n 
re gar di n g t he 
i nter pretati o n of t he 
res ults of c o m paris o n 
i n t he case w here t he 
c o m paris o n is 
c o n d ucte d wit h o ut 
ac hie vi n g t he tar get 
sa m ple size.
1 1. 3. I nstit uti o nal re vie w 
b oar d (I R B)/ Et hics 
c o m mittee ( E C)
Descri pti ve u p date f or 
t he secti o n title a n d 
e x pressi o n.
Descri pti o n 
u p dates
A T T A C H M E N T 3. 
D R U G LI S T
Descri pti ve u p date f or 
c ha n ges i n t he a nal ysis 
pla n a n d milest o ne
Descri pti o n 
u p dates
Ver. 1
2 6 Oct o ber 
2 0 2 2
N A
N A
N A
N A
0 9 0 1 7 7 e 1 a 1 0 b 0 1 8 6\ Fi n al\ Fi n al O n: 2 7- J u n- 2 0 2 4 0 3: 4 3 ( G M T)
C CI

Infliximab-Pfizer Biosimilar
B5371010 NON-INTERVENTIONAL STUDY PROTOCOL
Version 4, 28 June 2024
PFIZER CONFIDENTIAL
CT24-WI-JPN-GPSP01-RF10 6.0 Non-Interventional Study Protocol Template for Post-marketing Database 
Study 01-Nov-2023
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7. MILESTONES
Milestone
Planned date
Timing to finalize the study protocol
26 October 2022
Start of data collection for final analysis
1 December 2023
End of data collection for final analysis
28 February 2024
Final study report
31 July 2025
8. RATIONALE AND BACKGROUND
Infliximab-Pfizer Biosimilar is a follow-on biologic to Remicade (the reference product). It 
consists of a chimeric immunoglobulin G1 (IgG1) monoclonal antibody that binds with high 
affinity to the human tumor necrosis factor alpha (TNFα). Biosimilarities between 
Infliximab-Pfizer Biosimilar and Remicade have been established through analytical, 
structural and functional tests and non-clinical and clinical studies in accordance with the 
Guidelines for the Quality, Safety, and Efficacy Assurance of Follow-on Biologics from 
Ministry of Health, Labour and Welfare (PFSB/ELD Notification No. 0304007 dated March 
4, 2009), therefore, the treatment for rheumatoid arthritis, ulcerative colitis, Crohn’s disease 
and psoriasis has been approved on 2 July 2018 and launched 10 December 2018, the 
treatment for refractory uveoretinitis has been approved on 22 April 2020 and the treatment 
for ankylosing spondylitis has been approved on 14 October 2020.
During the review process of J-NDA approval, it was pointed out from the regulatory 
authority that it is important to confirm a broad safety profile in clinical practice for 
biosimilars in drug use investigations etc. as information available based on clinical studies 
by approval is limited. Clinical studies were conducted to show similarity between 
Infliximab-Pfizer Biosimilar and Remicade-EU in patients with RA, however there is no 
safety data in patients with indications other than RA in clinical study. Therefore, it was also 
pointed out that concerning indications of infliximab for which clinical studies have not been 
conducted, it is important to prove not only the safety but also the efficacy by conducting 
drug use investigations, etc. Therefore, Pfizer planned drug use investigations to confirm the 
safety and efficacy and this database study to confirm the safety for rheumatoid arthritis, 
ulcerative colitis, Crohn’s disease, and psoriasis as shown in the RMP. Among safety 
specifications of additional pharmacovigilance activities for the four indications, Pfizer 
selected serious infections, tuberculosis, serious blood disorder, interstitial pneumonia, and 
malignancy as safety specifications evaluated in pharmacovigilance activities using a hospital 
based claims database since it was considered feasible to collect information in the database 
study and would be valuable to provide the information with both Infliximab-Pfizer 
Biosimilar and Remicade. Since it has not been reported that the safety is significantly 
different between the indications of Remicade, the evaluation will be mainly performed in 
the overall four diseases (indicated conditions; rheumatoid arthritis, ulcerative colitis, 
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Crohn’s disease, and psoriasis), and the evaluation of each disease will also be performed in 
disease subcohorts as secondary objective.
According to the Notification for 'Procedures for developing Post-marketing Study Plan’ 
(Pharmaceuticals and Medical Device Agency 23 Jan 2018), when there are multiple 
research questions for a single product, studies are selected depending upon each approach. 
In these instances, feasible studies to respond to multiple research questions may be 
investigated as needed, taking into account the feasibility of implementing the respective 
studies together. To make it feasible to deal with multiple research questions together by one 
study, this database study will be conducted to evaluate one representative safety 
specification as the primary outcome event which is the most appropriate to compare with 
Remicade based on the possibility of collecting the sufficient number of occurrences and 
evaluate the other outcome events as a secondary objective.
These outcome events will be measured in both Infliximab-Pfizer Biosimilar and Remicade 
exposed-patients, and the occurrence of these events are expected to be similar. There are 
five safety specifications for this database study, but serious infections, which can expect the 
greatest number of subjects based on historical studies, will be the primary safety
specification, and others will be secondary specifications from the viewpoint of 
comparability.
This study will be conducted based on the following GPSP Ordinance: 
“MHLW Ordinance on the Standards for Post-marketing Studies and Clinical Trials of 
Medical Products” (MHLW Ordinance No. 171, dated 20 Dec 2004), “Enforcement of 
the MHLW Ordinance on the Standards for Post-marketing Studies and Clinical Trials of 
Medical Products” (PFSB Notification No. 1220008, dated 20 Dec 2004), “Questions and 
Answers (Q & A) on the MHLW Ordinance on the Standards for Postmarketing Studies 
and Clinical Trials of Medical Products” (Office Memorandum, dated 25 Mar 2005), 
“Guidelines on the Method for Conducting Post-marketing Study, etc. of Prescription 
Drugs” (PFSB/ELD Notification No. 1027001, dated 27 Oct 2005), “Enforcement of the 
MHLW Ordinance on the Standards for Post-marketing Safety Control of Medicinal 
Products, Quasi-medicinal Products, Cosmetics, and Medical Devices and Enforcement 
of the MHLW Ordinance on the Partial Revision of the MHLW Ordinance on the 
Standards for Post-marketing Studies and Clinical Trials of Medical Products” (PFSB 
Notification No. 0311-7, dated 11 Mar 2013), “MHLW Ordinance on the Amendments of 
Related Cabinet Orders in accordance with the Law Partially Revising the 
Pharmaceutical Affairs Law, etc. and Enforcement of the Law Partially Revising the 
Pharmaceutical Affairs, Law, etc. and on the Amendments of Related Cabinet Orders in 
accordance with the Enforcement of the Cabinet Order on Transitional Measures” 
(Article 14, Partial Revision of the MHLW Ordinance on the Standards for Post-
marketing Studies and Clinical Trials of Medical Devices) (MHLW Ministerial 
Ordinance No. 87, dated 30 Jul 2014), “MHLW Ordinance for Partial Amendments of the 
MHLW Ordinance on the Standards for Post-Marketing Surveillances and Clinical Trials 
of Medical Products (Partial Amendments of the MHLW Ordinance on the Standards for 
Post-Marketing Surveillances and Clinical Trials of Medical Products)” (MHLW 
Ordinance No. 116, dated 26 Oct 2017), “Promulgation of the MHLW Ordinance for 
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Partial Amendments of the MHLW Ordinance on the Standards for Post-Marketing 
Surveillances and Clinical Trials of Medical Products (Related to the MHLW Ordinance 
on the Standards for Post- Marketing Surveillances and Clinical Trials of Medical 
Products)” (PSEHB Notification No. 1026-1, dated 26 Oct 2017), “MHLW Ordinance on 
the Amendments of Related Cabinet Orders in accordance with enforcement of the Law 
Partially Revising the Law on Ensuring Quality, Efficacy, and Safety of Pharmaceutical 
Products and Medical Devices (Partial Revision of the MHLW Ordinance on the 
Standards for Post-marketing Studies and Clinical Trials of Pharmaceutical Products)” 
(MHLW Ordinance No. 155, dated 31 Aug 2020), About the confirmation method of the 
implementation status of the Post-marketing Database Studies using the DB survey 
management tool in the compliance inspection of pharmaceutical products and 
regenerative medical products (PMDA/CRS Notification No. 1111002, dated 11 Nov 
2021), “Points to note on the Reliability assurance for Post-marketing Database Studies 
Medical Products” (PSEHB Notification No. 0221-1, dated 21 Feb 2019), “Questions and 
Answers (Q & A) on the Reliability assurance for Post-marketing Database Studies 
Medical Products” (Office Memorandum, dated 19 Jun 2019), “Guidelines for the 
Conduct of Pharmacoepidemiological Studies in Drug Safety Assessment with Medical 
Information Databases” (dated 31 Mar 2014), “Basic principles on the utilization of 
health information databases for Post-Marketing Surveillance of Medical Products” 
(PSEHB/PED Notification No. 0609-8, PSEHB/SD Notification No. 0609-4, dated 9 Jun 
2019), “Contents and format of a study protocol for Post-marketing Database Study” 
(dated 23 Jan 2018), “Risk Management Plan Policy” (PFSB/SD Notification No. 0411-1 
/ -2, dated 11 Apr 2012), “Procedures for Developing Post-marketing Study Plan 
(originally published as Procedures for Developing Post-marketing Study Plan by PMDA 
in January 2018)” (PSEHB/PED Notification No. 0314-4, PSEHB/SD Notification No. 
0314-4, dated 14 Mar 2019), “Development and Publication of Risk Management Plan” 
(Joint PSEHB/DED Notification No. 0318-2 and PSEHB/SD Notification No. 0318-1, 
dated 18 Mar 2022), “Questions and Answers (Q & A) on Risk Management Plans” 
(Office Memorandum, dated 18 Mar 2022), and “Pharmacovigilance Planning” 
(PFSB/ELD Notification No. 0916001, PFSB/SD Notification No. 0916001, dated 16 
Sep 2005).
9. RESEARCH QUESTION AND OBJECTIVES
9.1. Safety Specifications
Important Identified Risks: serious infections, tuberculosis, serious blood disorder, interstitial 
pneumonia 
Important Potential Risks: malignancy
Important Missing Information: None
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9.2. Research question and study objective
The research question is to evaluate the important safety outcome events in patients with 
rheumatoid arthritis, ulcerative colitis, Crohn’s disease, or psoriasis who have received 
Infliximab-Pfizer Biosimilar compared to those patients who have received Remicade from 
December 1, 2018 through November 30, 2023.
In this database study, based on the incidence rate of the safety specifications in the historical 
clinical studies (serious infections: 2.8%; tuberculosis, serious blood disorder, interstitial 
pneumonia, and malignancy: less than 1%), serious infections is set as the primary safety 
specification, and tuberculosis, serious blood disorder, interstitial pneumonia, and 
malignancy are set as secondary safety specification to show no significant difference in 
safety concerns between Infliximab-Pfizer Biosimilar and Remicade. 
The primary objective is to evaluate the incidence rate of serious infections overall in patients 
with rheumatoid arthritis, ulcerative colitis, Crohn’s disease, or psoriasis who have received 
Infliximab-Pfizer Biosimilar compared to those patients who have received Remicade.
Secondary objectives are as follows,

to evaluate the incidence rate of serious infections in patients in each disease subcohort 
who have received Infliximab-Pfizer Biosimilar compared to those patients who have 
received Remicade.

to evaluate the incidence rate of tuberculosis, serious blood disorder, interstitial 
pneumonia, and malignancy overall in patients with rheumatoid arthritis, ulcerative 
colitis, Crohn’s disease, or psoriasis who have received Infliximab-Pfizer Biosimilar 
compared to those patients who have received Remicade.

to evaluate the incidence rate of tuberculosis, serious blood disorder, interstitial 
pneumonia, and malignancy in patients in each disease subcohort , who have received 
Infliximab-Pfizer Biosimilar compared to those patients who have received Remicade.
10. RESEARCH METHODS 
10.1. Study design 
To meet the study objectives, an observational cohort study using a hospital-based claims
database in Japan will be performed (Figure 2).
10.2. Setting
The source population for the study sample will be patients from the Medical Data Vision 
(MDV) database; a hospital-based claims database in Japan that consists of outpatient and 
inpatient data from hospitals using the diagnosis procedure combination (DPC) system. Data 
collection of MDV database started from April 2008. As of August 2020, the MDV database 
included information on more than 32 million patients from 419 hospitals which covers 
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approximately 24% of acute-care hospitals using the DPC system. Data variables include 
hospitalization and discharge information, patient information, inpatient and outpatient 
medications, medical practices, inpatient and outpatient diagnoses, and laboratory results. 
Currently, more than 150 studies have already been published which includes more than 10 
safety evaluating studies.
10.2.1. Study period (data period)
The planned study period is anticipated to be from December 1, 2018 through November 30, 
2023. Individuals with the index date (Figure 1 and related explanation) in this study period 
will be included in the study. This 5-year period might be extended if insufficient number of 
exposed (Infliximab-Pfizer Biosimilar) patients. 
Figure 1.
Schematic of Cohort Entry
10.2.2. Definitions of exposure and control, and the defining information
Provisional index date is defined as the first recorded Infliximab-Pfizer Biosimilar or 
Remicade during the 5-year period. The final index date is determined by the 90-day look-
back period and the treatment group allocation as follows: 
1. All subjects treated with Infliximab-Pfizer Biosimilar that meet the 90-day look-
back criteria will be included in the “exposed” group. This definition includes 
patients switching from non-Pfizer Infliximab Biosimilar or Remicade to 
Infliximab-Pfizer Biosimilar.
Five years Study Period
90-day look-back period
Index Date
Follow-up time
Begins on the Index Date
Diagnosis of 
disease 
indication
1. Assessment of indicated disease diagnosis
2. Assessment of prevalent safety outcomes
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2. All patients not meeting the former criteria but meet the 90-day look-back criteria 
for Remicade and without prior use of Infliximab Biosimilar will be included in 
the “control” group.
No patient will be included in both treatment groups.
10.2.3. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Have at least 90 days of look-back period
2. Have diagnostic code of indicated diseases (rheumatoid arthritis, ulcerative colitis, 
Crohn’s disease, or psoriasis) in the 90-day look-back period. Patients with >1 indication 
will be summarized as a separate group from each sub-cohort. An inpatient or outpatient 
visit assigned a diagnosis code consistent with either rheumatoid arthritis, ulcerative 
colitis, Crohn’s disease, or psoriasis using ICD-10 coding:
!
Rheumatoid arthritis: M05, M06
!
Ulcerative colitis: K51
!
Crohn’s disease: K50 
!
Psoriasis (Psoriasis vulgaris, Psoriasis arthropica, Pustular psoriasis and Psoriatic 
erythroderma): L40 
3. 15 years of age or older at the time of index date 
10.2.4. Exclusion criteria
Patients with pre-existing safety outcome event during the 90-day look-back period will be 
excluded from the study cohort for that specific outcome event as this study is observing 
incident cases(see Section 10.6).
10.2.5. Flow chart
Figure 2 is the flow chart of the study B5371010. Main cohort is defined as overall 
population who meet the inclusion and exclusion criteria in section 10.2.3 and 10.2.4.
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Figure 2.
Flow chart of the study B5371010
10.3. Variables
10.3.1. Definition of outcomes and defining information
There are five safety outcome events in this study that will be identified using multiple 
coding systems in the database: serious infections, tuberculosis, serious blood disorder, 
interstitial pneumonia, and malignancy. 
In this database study, based on the incidence rate of the safety specifications in the historical 
clinical studies (serious infections: 2.8%; tuberculosis, serious blood disorder, interstitial 
pneumonia, and malignancy: less than 1%), serious infections is set as the primary safety 
specification, and tuberculosis, serious blood disorder, interstitial pneumonia, and 
malignancy are set as secondary safety specifications.
Definition of five safety outcome events (serious infections, tuberculosis, serious blood 
disorder, interstitial pneumonia, and malignancy) are shown in the appendix. Outcome events 
are defined based on medical practice, guidelines, etc.
Outcome (acute) events: serious infections, tuberculosis, serious blood disorder, interstitial 
pneumonia:
Remicade
Infliximab-Pfizer Biosimilar 
Disease subcohorts (Rheumatoid Arthritis, Ulcerative Colitis, Crohn’s Disease, Psoriasis) 
will be created by using main cohort.
Patients with >1 indication will be summarized as a separate group from each sub-cohort.
MDV Database
(From Dec. 1, 2018 to 
Nov 30, 2023)
Meet inclusion and exclusion criteria
Main cohort
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The observation of these outcome events is expected to occur in an acute time period 
following any exposure. Maximum dosing interval of Remicade is every 8 weeks in the 
package insert based on overall evaluation of clinical trials. The package insert also indicates 
that the blood concentration of Remicade was maintained in clinical studies. Furthermore, as 
a biologic, almost all patients will not use other biologics within 8 weeks after last dose 
which is approximately 60 days. Therefore, a 60 day risk window after exposure will be 
utilized from the last dose received. An incident event occurring during the 60 day risk 
window will be counted in the numerator for the analysis and the person-time will accrue 
until the first occurrence of an event, the end of the 60 day risk window, date of switch 
treatment, death, or the end of study period (Figure 3).
Figure 3.
Observation Time for Study Patients with Acute Events
Outcome (latent) event: malignancy:
The observation of a latent outcome event like a malignancy requires additional 
considerations. A 60 day risk window may not be sufficient follow-up time to observe an 
incident event with long latency. As a result, this study will analyze malignancy differently 
compared to the acute outcome events by extending follow-up time until the first incident 
event, death, end of the study period, or loss to follow-up. The primary analysis will utilize 
an ever-exposed approach whereby a person will always be considered exposed to the initial 
treatment. All malignancy will be reported in the primary analysis even those that occur after 
the day of initial treatment. Sensitivity analyses will be considered that truncate events during 
specified risk periods (60 days) associated with information known about the occurrence of 
malignancies. Patients switching between Infliximab-Pfizer and Remicade is likely to be 
excluded from this sensitivity analysis.
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10.3.2. Covariate, and the defining information
Indicated disease, Information on sociodemographic characteristics (sex, age at the index 
date), medical history (Yes or No in the 90-day look-back period: Cerebrovascular disease, 
Chronic pulmonary disease, Diabetes, Liver disease, Renal disease, or Dementia), and prior 
medications (Yes or No in the 90-day look-back period: Methotrexate [RA], DMARDS other 
than methotrexate [RA], Amino salicylate [CD, UC], Immunosuppressant (Steroid), 
Immunosuppressant (non-steroid), Biologics (excluding any Infliximab products), Janus 
kinase inhibitor, or Anti-tuberculosis) will be collected from the database as available. This 
information will be used for the study analysis as appropriate. Disease code list and drug list 
are included in ATTACHMENT 2. DISEASE CODE LIST and ATTACHMENT 3. DRUG 
LIST, respectively. These lists will be updated to latest version at the analysis, if needed.
10.4. Data sources 
The source population for the study sample will be patients from the Medical Data Vision 
(MDV) database; a hospital-based claims database in Japan that consists of outpatient and 
inpatient data from hospitals using the diagnosis procedure combination (DPC) system. The 
detailed information is described in section 10.2.
10.4.1. Overview of the health information database used in this study
The quality of the data provided is managed by MDV through the oversight of their in-house 
data maintenance and quality improvement teams. All of these processes are consistently 
managed in-house. MDV have also been certified ‘ISO27001’. MDV will extract the data 
which met the inclusion and exclusion criteria in section 10.2.3 and 10.2.4 by their standard 
operating procedures and provide them to Pfizer.
10.4.2. Validation
For serious infection, the primary outcome of this study, outcome definition was based on the 
results from a published validation study1. The validation study was planned in consultation 
with PMDA to evaluate the validity of the algorithm definition for malignant tumor and for 
serious infections using the MDV database, a Japanese administrative healthcare database. In 
this study, an optimal algorithm from the validation study was adopted, where the optimality 
was based on both the positive predictive value and pseudo sensitivity.
For other secondary outcomes (tuberculosis, serious blood disorder, interstitial pneumonia, 
and malignancy), outcome definitions were based on medical viewpoints with reference to 
medical practices and clinical guidelines.
10.5. Study size
The number of exposed to Infliximab-Pfizer Biosimilar patients would be expected about 
1,000 patients for all 4 indications (rheumatoid arthritis, ulcerative colitis, Crohn's disease 
and psoriasis). The number of comparator (Remicade) patients would be expected to be about 
9 times as large as the number of exposed patients. The following sample size rationale was 
calculated based on the assumption that the number of patients in Remicade cohort is at least 
twice as large as that in Infliximab-Pfizer Biosimilar considering the inclusion and exclusion 
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criteria. Also, the rationale focuses on the precision of estimates achieved with these sample 
sizes with additional information on possibility of detection large differences such as 2 or 3 
times in terms of risk ratios.
Incidence proportion for serious infection is 3% and incidence proportions for the other 
safety specifications in this Database study is 0.5% are assumed based on a 54-week clinical 
study. It was evaluated the probabilistic properties of the risk ratio and the risk difference 
with Infliximab-Pfizer Biosimilar and Remicade (1: 2 patients).
For serious infection, when the number of patients is 300 in Infliximab-Pfizer Biosimilar 
group, if the true incidence proportion of Infliximab-Pfizer Biosimilar is 9 % (3 times higher 
than Remicade), as shown in Table 1, the probabilities that the estimate of risk ratio exceeds 
2 and 3 are calculated as 91.5 % and 49.3 %, respectively. And, the estimate of risk ratio is 
distributed within 1.85 to 5.17 with 90% probability. Moreover, the lower limit of the 95% 
confidence interval of the risk ratio exceeds 1 with probability of 96.1 %. When we focus on 
the risk difference (Table 2), the estimate of risk difference is distributed within 0.0317 to 
0.0900 with 90% probability, and the lower limit value of the 95% confidence interval 
exceeds 0 with probability of 96.1 %. In addition, the range where the entire 95% confidence 
interval is included with 90 % probability is 0.0018 to 0.1332, and the width of the range was 
0.1314.
For the other events with 0.5% incidence proportion, when the number of patients is 1000 in 
Infliximab-Pfizer Biosimilar group, if the true incidence proportion of Infliximab-Pfizer 
Biosimilar is 1.5 % (3 times higher than Remicade), as shown in Table 1, the probabilities 
that the estimate of risk ratio exceeds 2 and 3 are calculated 84.4 % and 48.6 %, respectively. 
And, the estimate of risk ratio is distributed within 1.50 to 6.67 with 90 % probability. 
Moreover, the lower limit of the 95% confidence interval of the risk ratio exceeds 1 with 
probability of 79.3 %. When we focus on the risk difference (Table 2), the estimate of risk 
difference is distributed within 0.0030 to 0.0170 with 90 % probability, and the lower limit 
value of the 95% confidence interval exceeds 0 with probability of 79.3 %. In addition, the 
range where the entire 95% confidence interval is included with 90 % probability is –0.0031 
to 0.0281, and the width of the range was 0.0312.
Based on the above, it is possible to detect the increase of the risk appropriately, it is 
reasonable to estimate to include 1000 patients for all 4 indications in the database. Also, it is 
possible to detect the increase of serious infection appropriately, it is reasonable to be 
estimated to be included 300 patients for all 4 indications in the database.
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Table 1.
The probabilistic properties of the risk ratio with infliximab BS Pfizer and the innovator (1: 2 patients) d)
The number of patients
True incidence proportion
Estimate of risk ratio (RR)
Probability that the 
lower limit of the 95% 
confidence interval of 
the risk ratio exceeds 1
c)
(%)
Pfizer
Innovator
Pfizer
Innovator
ratio
Pr(RR>2)a)
(%)
Pr(RR>3) a)
(%)
Interval in which RR 
lies with 90% 
probability b)
300
600
0.03
0.03
1
3.8
0.5
(0.4615, 1.8889)
3.1
0.06
0.03
2
48.2
11.0
(1.1429, 3.5556)
56.8
0.09
0.03
3
91.5
49.3
(1.8490, 5.1667)
96.1
1000
2000
0.03
0.03
1
0.0
0.0
(0.6667, 1.4118)
2.4
0.06
0.03
2
49.5
1.2
(1.4795, 2.6804)
96.5
0.09
0.03
3
99.4
49.6
(2.2973, 3.9574)
100.0
0.005
0.005
1
9.6
2.3
(0.3077, 2.4000)
3.1
0.010
0.005
2
50.1
17.8
(0.8750, 4.5000)
36.8
0.015
0.005
3
84.4
48.6
(1.5000, 6.6667)
79.3
a) Pr(RR>2) and Pr(RR>3) shows the probabilities that the estimate for risk ratio exceed 2 and 3, respectively. 
b) Interval was defined as 5-percentile and 95-percentile of point estimate.
c) The 95% confidence interval was calculated by using Miettinen-Nurminen method based on score statistics.
d) Based on 10000 times simulations. When the number of cases for infliximab BS Pfizer and the innovator were 0, they were excluded from the calculation. 
Regarding the confidence interval, even when RR is 0 or infinity, it is excluded from the calculation.
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Table 2.
The probabilistic properties of the risk difference with infliximab BS Pfizer and the innovator (1: 2 patients) d)
The number of 
patients
True incidence proportion
Interval in which risk 
difference lies with 
90% probability a)
Probability that the 
lower limit of the 95% 
confidence interval of 
the risk difference 
exceeds 0 (%)b)
Range in which 95% confidence 
interval of the risk difference is 
include with 90% probabilityb), c)
Pfizer
Innovator
Pfizer
Innovator
difference
Range
Width of 
the range
300
600
0.03
0.03
0
(–0.0200, 0.0200)
3.1
(–0.0411, 0.0516)
0.0927
0.06
0.03
0.03
(0.0050, 0.0567)
56.8
(–0.0200, 0.0940)
0.1140
0.09
0.03
0.06
(0.0317, 0.0900)
96.1
(0.0018, 0.1332)
0.1314
1000
2000
0.03
0.03
0
(–0.0110, 0.0110)
2.4
(–0.0228, 0.0258)
0.0486
0.06
0.03
0.03
(0.0160, 0.0440)
96.5
(0.0014, 0.0627)
0.0613
0.09
0.03
0.06
(0.0440 , 0.0760)
100.0
(0.0267, 0.0977)
0.0710
0.005
0.005
0
(–0.0045, 0.0045)
3.1
(–0.0094, 0.0128)
0.0223
0.010
0.005
0.005
(–0.0010, 0.0110)
36.8
(–0.0064, 0.0207)
0.0271
0.015
0.005
0.010
(0.0030, 0.0170)
79.3
(–0.0031, 0.0281)
0.0312
a) Interval was defined as 5-percentile and 95-percentile of point estimate.
b) The 95% confidence interval for risk difference was calculated by using Miettinen-Nurminen method.
c) Lower of the range was defined as 5-percentile of lower limit of 95 % confidence interval on simulations. Upper of the range was defined as 95-percentile of 
upper limit of 95 % confidence interval on simulations.
d) Based on 10000 times simulations. When the number of cases for infliximab BS Pfizer and the innovator were 0, they were excluded from the calculation.
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10.6. Data analysis 
Three base analysis sets will be defined as follows to evaluate the risks of Infliximab-Pfizer 
Biosimilar to Remicade. Specifically, hazard ratio, rate ratio, and rate difference will be 
examined together in comprehensive fashion to evaluate the overall safety profile. Any 
inconsistency in results among the three measures will be examined for its cause.

The full analysis set will include all patients who are considered eligible by the inclusion 
and exclusion criteria in Section 10.2.3 and Section 10.2.4.

The comparative analysis set will be a subset of the full analysis set who are new users. 
That is, patients switching from non-Pfizer Infliximab Biosimilar or Remicade to Pfizer-
Infliximab Biosimilar will be excluded. Also, patients switching from any Infliximab 
Biosimilar to Remicade will be excluded.

The comparative matched analysis set will be a subset of the comparative analysis set 
that includes all patients matched between Infliximab-Pfizer Biosimilar and Remicade. 
Each patient from the Infliximab-Pfizer Biosimilar group will be matched to two patients
from the Remicade group based on the propensity score. The propensity score will be 
based on indicated disease, sex, age at the index date, calendar year-month of the index 
date, medical history, and prior medications (see Section 10.3.2).
For assessment of each outcome event (serious infections, tuberculosis, serious blood 
disorder, interstitial pneumonia, and malignancy), a subset of each base analysis set that 
excludes patients with the same outcome event during the 90-day look-back period will be 
used. One set of propensity score will be used for all outcomes.
For each analysis set, the incidence rate of each outcome event will be calculated for 
Infliximab-Pfizer Biosimilar and Remicade group for the main cohort and for each disease 
subcohort (rheumatoid arthritis, ulcerative colitis, Crohn’s disease, or psoriasis). The 
incidence rate will be estimated by counting the number of subjects with event in the 
numerator and dividing by the total person-time of observation in the denominator. For the 
outcome events: serious infections, tuberculosis, serious blood disorder, and interstitial 
pneumonia; the person-time will accrue until the first occurrence of an event, the end of the 
60-day risk window, date of switch treatment, death, or the end of study period. For the 
malignancy outcome, the person-time will accrue until the first incident event, death, end of 
the study period, or loss to follow-up (Section 10.3.1). 
The following comparative analyses will be carried out to assess the relative incidence of 
these events using the comparative analysis set and comparative matched analysis set. Crude 
hazard ratios and rate ratios will be calculated including 95% confidence intervals with 
Remicade as the reference group. Crude rate differences will be calculated including 95% 
confidence intervals (the risk of Infliximab-Pfizer Biosimilar - the risk of Remicade). Hazard 
ratios and its 95% confidence intervals will be calculated by Cox proportional hazard model 
using treatment (Infliximab-Pfizer Biosimilar or Remicade) as a factor. Confidence intervals 
for rate ratios and rate differences will be calculated based on the formulas, 
b
a
1
1
∀
and 
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2
2
R
P
PT
b
PT
a
∀
where a, b: cases of Infliximab-Pfizer Biosimilar and Remicade; PTP, 
PTR: person-time of observation of Infliximab-Pfizer Biosimilar and Remicade, for the 
standard error of the logarithm of the incidence rate ratio and the rate difference, 
respectively2.
Two types of analyses based on propensity score will be conducted. First is the Inverse 
Probability of Treatment Weighting (IPTW) method based on the comparative analysis set 
(primary analysis). Second is the method based on matched analysis based on the 
comparative matched analysis set. 
For the IPTW analysis, adjusted hazard ratios, rate ratios, and rate differences will be 
calculated based on weights based on the propensity score as same as the score used in the 
matched analysis. Hazard ratios will be calculated by Cox proportional hazard model. Rate 
ratios and rate difference will be calculated by a Poisson regression model accounting for 
different duration on treatment. In each of the previous analyses, treatment (Infliximab-Pfizer 
Biosimilar or Remicade) will be included as a factor. Distribution of propensity scores and 
weights will be examined prior to the analyses.
For the matched analysis, adjusted hazard ratios, rate ratios, and rate differences will be 
calculated by using the following models. Hazard ratios will be calculated by Cox 
proportional hazard model. Rate ratios and rate difference will be calculated by a Poisson 
regression model accounting for different duration on treatment. In each of the previous 
analyses, treatment (Infliximab-Pfizer Biosimilar or Remicade) will be included as a factor.
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 the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment.
10.7. Quality control
This study is a retrospective cohort study using quality-controlled data in a pre-existing 
database, and primary data collection will not be conducted. The quality of the data provided 
is managed by MDV through the oversight of their in-house data maintenance and quality 
improvement teams. All of these processes are consistently managed in-house. MDV have 
also been certified ‘ISO27001’.
10.8. Limitations of the research methods
This study has several limitations. 
First, the potential data source, MDV, is an acute-care hospital-based database. Therefore, 
severe cases of disease are more likely to be captured than mild or moderate cases of disease 
which can be treated in other non-hospital settings. As a result, the disease, exposure, and 
outcome assessment may not be generalizable to all of Japan. Second, patients may seek care 
outside the hospital where the primary disease diagnosis and treatment occurred; thus, not all 
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I nfli xi ma b-Pf izer Bi osi milar
B 5 3 7 1 0 1 0 N O N -I N T E R V E N TI O N A L S T U D Y P R O T O C O L
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P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -J P N-G P S P 0 1 -R F 1 0 6 . 0 N o n-I nter ve nti o nal St u d y Pr ot oc ol Te m plate f or P ost-mar keti n g Data base 
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o utc o mes will be rec or de d. T his is li kel y  t o res ult i n a n u n deresti mate i n t he a bs ol ute 
i nci de nce f or all o utc o mes b ut is li kel y t o be n o n-differe ntial w he n c o m pari n g I nfli xi ma b -
Pfizer Bi osi milar t o Re mica de. T hir d, M D V has i n patie nt a n d o ut patie nt prescri pti o n 
i nf or mati o n, b ut d osi n g i nf or mati o n ma y n ot be acc urate. F o urt h, t he i nf or mati o n of pri or 
vacci nati o n s uc h as H z oster, p ne u m oc occ us or B C G f or t u berc ul osis, t hese i nf or mati o n of 
ot her i nstit uti o ns ca n't be c ollecte d, s o t he p ossi bilit y  of data c ollecti n g is q uite rare. Fift h, as 
a h os pital-base d data base, patie nt hist or y  f or patie nts ca n be li mite d w hic h pre ve nts ca pt uri n g 
a hist or y of mali g na nc y. T his ma y res ult i n ca pt uri n g pre vale nt o utc o mes i n t he o bser vati o n 
peri o d as o p p ose d t o i nci de nt o utc o mes a n d t h us o veresti mati n g t he i nci de nce. H o we v er, t his 
li mitati o n is li kel y t o be n o n-differe ntial w he n c o m pari n g I nfli xi ma b-Pfizer Bi osi milar t o 
Re mica de. Si xt h, M D V pri maril y  ca pt ures data fr o m ac ute-care h os pitals dia g n oses of 
mali g na nc y  ma y be li mite d (i m m ortal ti me bias). T his is li kel y t o res ult i n a n u n deresti mate 
i n t he a bs ol ute i nci de nce, b ut it is li kel y t o be n o n-differe ntial w he n c o m pari n g I nfli xi ma b -
Pfizer Bi osi milar t o Re mica de. Se ve nt h, w hile ca ncer a n d deat h re gistries e xist, ca pa bilities 
t o li n k wit h a n o n ymize d M D V data is n ot p ossi ble li miti n g t he a bilit y t o i de ntif y all ca ncer 
cases. Ei g ht h , t he met h o ds liste d t o defi ne o utc o mes ma y n ot be t he m ost s pecific i ncl u di n g 
n o n- vali date d o utc o mes a n d n o n-a dj u dicate d o utc o mes; t heref ore, t he res ults c o ul d be a n 
o veresti mate of t he tr ue ris ks. Fi nall y , alt h o u g h t his st u d y was i nitiall y pla n ne d t o be 
c o n d ucte d wit h 3 0 0 patie nts f or seri o us i nfecti o n a n d 1 0 0 0 patie nts f or t he ot her o utc o mes at 
t he c o ncl usi o n of f oll o w- u p w h o ha ve recei ve d I nfli xi ma b-Pfizer Bi osi milar, f oll o wi n g a 
o n 1 1- J ul y-2 0 2 3 t hat i ncl u de d stat us of e x pecte d n u m ber of patie nts, t he 
pla n was re vise d. I n t he u p date pla n c o m parati ve a nal y ses will be c o n d ucte d re gar dless of 
acc u m ulati o n of t he n u m ber of patie nts wit h a n u n dersta n di n g t hat, if t he st u d y  size is s maller 
t ha n i n t he i nitial pla n, t he statistical precisi o n of esti mati o n will be re d uce d. In s uc h a case, 
t he i nter pretati o n of t he res ults will be ma de caref ull y.
1 0. 9. Ot her as pects
N ot A p plica ble
1 1. P R O T E C TI O N O F H U M A N P A R TI CI P A N T S
1 1. 1. P atie nt i nf or m ati o n 
T his st u d y i n v ol ves data t hat e xist i n dei de ntifie d/a n o n ymize d str uct ure d f or mat a n d c o ntai n 
n o patie nt pers o nal i nf or mati o n. 
1 1. 2. P atie nt c o nse nt
As t his st u d y  i n v ol ves dei de ntifie d/a n o n ymize d str uct ure d data, w hic h acc or di n g t o 
a p plica ble le gal re q uire me nts d o n ot c o ntai n data s u bject t o pri vac y  la ws, o btai ni n g i nf or me d 
c o nse nt fr o m patie nts b y Pfizer is n ot re q uire d.
1 1. 3. I nstit uti o n al re vie w b o ar d (I R B)/ E t hics c o m mittee ( E C)
I n t his st u dy, t he re vie w b y t he I nstit uti o nal Re vie w B oar d (I R B)/ Et hics C o m mittee ( E C) is 
n ot esse ntial. 
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11.4. Ethical conduct of the study
This study is included in the scope of application of the “Good Post-Marketing Study 
Practice” (Ordinance of Ministry of Health, Labour and Welfare No. 171 of December 20, 
2004) and the MHLW Ordinance in the section 8. RATIONALE AND BACKGROUND and 
will be conducted in accordance with legal and regulatory requirements, as well as with 
scientific purpose, value, and rigor.
12. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves data that exist as structured data by the time of study start.
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (i.e., identify a potential association between) a particular product and 
medical event for any individual. Thus, the minimum criteria for reporting an adverse event 
(AE) (i.e., identifiable patient, identifiable reporter, a suspect product, and event) cannot be 
met. 
13. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Information obtained in this study shall be used to report Ministry of Health, Labour and 
Welfare (MHLW), Pharmaceuticals and Medical Devices Agency (PMDA), Pfizer Inc. 
which is the corporate parent of marketing authorization holder (or sponsor) of this study, 
and the group companies, or regulatory agency in other countries. And also, it shall be used 
for application of re-examination (including Japan Periodic Safety Report), re-evaluation, 
preparation of material for proper use information of this drug, publications and activities for 
information service. Also, Pfizer could disclose the study results to provide information for 
proper use, as needed, on www.clinicaltrials.gov (ClinicalTrials.gov), as presentations at 
academic conferences, as manuscripts, and so on. 
Data obtained in this study will be reported to the MHLW pursuant to the Pharmaceutical 
and Medical Device Act; pertinent to which, data may be publicly posted in MHLW's 
"Pharmaceutical and Medical Device Safety Information" and "Pharmaceuticals and Medical 
Devices Information Website (http://www.info.pmda.go.jp) as an aggregated data or other 
relevant information. Furthermore, results may also be disclosed if the MHLW is required to 
disclose such information in accordance with the "Act on Access to Information Held by 
Administrative Organs" (Law No. 42 dated May 14, 1999); provided that in no personal 
information be subject to such disclosure, nor will it be posted or disclosed in any form or 
shape. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the party responsible for collecting data 
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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.
14. SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR 
REPORTING OF STUDY IMPLEMENTATION STATUS AND EVALUATION OF 
OBTAINED RESULTS TO THE PMDA
At the time of submission of regular report: once a year from approval to the submission of 
the final report, due to evaluate safety information and report to PMDA.
15. ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE 
STUDY RESULTS AND CRITERIA FOR DETERMINATION OF THE INITIATION
Review the risk management plan (RMP), including the following matters, will be reviewed 
at the time of each milestone.
!
Whether or not to change the contents of the implementation plan, including whether 
there are additional elements to the Safety Specifications.
!
Whether or not to formulate risk minimization measures for new elements of the Safety 
Specifications
16. ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION
Regarding the organizational system in the study, refer to the APPENDIX.
17. NAME, ADDRESS AND OUTSOURCED OPERATIONS OF THE PERSON WHO 
WAS CONTRACTED WITH THE OPERATIONS
Company name: Pfizer R&D Japan 
Address: Shinjuku Bunka Quint Bldg., 3-22-7, Yoyogi, Shibuya-ku, Tokyo
Scope of the outsourced operations: Draft of study planning and operations 
Company name: EPS Corporation
Address: 2-23 Shimomiyabicho, Shinjuku-ku, Tokyo
Scope of the outsourced operations: Statistical analysis
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18. REFERENCES
1. Nishikawa A, Yoshinaga E, Nakamura M, et al. Validation Study of Algorithms to 
Identify Malignant Tumors and Serious Infections in a Japanese Administrative 
Healthcare Database, Annals of Clinical Epidemiology 2022;4(1):20–31
2. Kenneth J. Rothman. Epidemiology. An introduction. 2nd Edition, Oxford University 
Press, 2012.
19. LIST OF TABLES 
Table 1.
The probabilistic properties of the risk ratio with infliximab BS Pfizer and the 
innovator (1: 2 patients) 
Table 2.
The probabilistic properties of the risk difference with infliximab BS Pfizer 
and the innovator (1: 2 patients) 
20. LIST OF FIGURES
Figure 1.
Schematic of Cohort Entry
Figure 2.
Flow chart of the study B5371010
Figure 3.
Observation Time for Study Patients with Acute Events
ANNEX 1. LIST OF STANDALONE DOCUMENTS
None
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable
ANNEX 3. ADDITIONAL INFORMATION
Not applicable
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P FI Z E R C O N FI D E N TI A L
C T 2 4 -WI -J P N-G P S P 0 1 -R F 1 0 6 . 0 N o n-I nter ve nti o nal St u d y Pr ot oc ol Te m plate f or P ost-mar keti n g Data base 
St u d y 0 1- N o v -2 0 2 3
P a ge 3 2 of 5 1
A P P E N DI X. O R G A NI Z A TI O N A L S Y S T E M F O R P O S T -M A R K E TI N G 
S U R V EI L L A N C E
Or g a niz ati o n al str uct ure c h art
List of rele v a nt de p art me nts
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ATTACHMENT 1. OUTCOME DEFINITIONS
1. Serious infections
Those to which the Additional Condition 1 applies in addition to the following Basic Conditions are 
defined serious infections.
The onset date of outcome is the date of hospitalization described in the Basic Conditions.
Table A1-1. Basic Conditions and Additional Conditions of Outcome Definition of Serious 
Infection to be Used In this Study
Condition
Description
Basic Condition
Patients with a date of hospitalization due to infection and definitive 
diagnosisa
Additional 
Condition 1
Patients to whom immune/infection test and other related tests (category 
code D) have been performed between 1 month before hospitalizationb and 
during hospitalization
a ICD-10 codes of infections are listed in the disease code list (Attachment)
b Including the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
2. Tuberculosis
Those to which the Additional Condition 1 applies in addition to the following Basic Conditions are 
defined tuberculosis.
The onset date of outcome is the date of drug prescription described in the Additional Condition 1.
Table A1-2. Basic Conditions and Additional Conditions of Outcome Definition of 
Tuberculosis to be Used in this Study
Condition
Description
Basic Condition
Patients with a definitive diagnosisa of tuberculosis
Additional 
Condition 1
Patients prescribed an anti-tuberculosis agent (drugs in Therapeutic 
Category Code 616 or 622) in the month of hospital visit for tuberculosis or 
the following month of the date of hospitalizationb
a ICD-10 codes of tuberculosis are listed in the disease code list (Attachment)
b Including the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
3. Serious blood disorder
Serious blood disorders are defined as diseases that are relevant to pancytopenia, granulocytopenia, 
thrombocytopenia, or anemia.
In addition to the following Basic Condition, diseases that are relevant to any of the Additional 
Conditions (1, 2, 3, 4, 5, or 6) are defined pancytopenia.
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The onset date of outcome is the date of hospitalization described in the Basic Conditions.
Table A1-3-1. Basic Conditions and Additional Conditions for Blood Disorder 
(Pancytopenia) to be Used in this Study
Condition
Description
Basic Condition
Patients with a date of hospitalization due to pancytopenia and a 
definitive diagnosisa
Additional Condition 1
Patients receiving blood transfusion (Category Code 920) within the 
following month of the date of hospitalization for pancytopeniab
Additional Condition 2
Patients prescribed antibiotics or antifungals (ATC code J01 or J02) 
within the following month of the date of hospitalization for 
pancytopeniab
Additional Condition 3
Patients prescribed granulocyte colony-stimulating factors (National 
Health Insurance drug price list [first 7 digits]: 3399405, 3399406, 
3399407, 3399408, 3399409, 3999410 or 3999411) within the 
following month of the date of hospitalization for pancytopeniab
Additional Condition 4
Patients prescribed antithymocyte globulin (National Health Insurance 
drug price list [first 7 digits]: 6399423) or ciclosporin (National Health 
Insurance drug price list [first 7 digits]: 3999004 or 3999406) for 
immunosuppressive therapy within the following month of the date of 
hospitalization for pancytopeniab
Additional Condition 5
Patients prescribed anabolic hormones (drugs in Therapeutic Category 
code 244) within the following month of the date of hospitalization for 
pancytopeniab
Additional Condition 6
Patients prescribed thrombopoietin receptor agonists (National Health 
Insurance drug price list [first 7 digits]: 3999028 or 3999430) within 
the following month of the date of hospitalization for pancytopeniab
a ICD-10 codes of pancytopenia are listed in the disease code list (Attachment)
b Including the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
In addition to the following Basic Condition, diseases that are relevant to any of the Additional 
Conditions (1, 2, or 3) are defined granulocytopenia.
The onset date of outcome is the date of hospitalization described in the Basic Conditions.
Table A1-3-2. Basic Conditions and Additional Conditions for Blood Disorder 
(Granulocytopenia) to be Used in this Study
Condition
Description
Basic Condition
Patients with a date of hospitalization due to granulocytopenia and a 
definitive diagnosisa
Additional Condition 1
Patients prescribed antibiotics or antifungals (ATC code J01 or J02) 
within the following month of the date of hospitalization for 
granulocytopeniab
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Table A1-3-2. Basic Conditions and Additional Conditions for Blood Disorder 
(Granulocytopenia) to be Used in this Study
Condition
Description
Additional Condition 2
Patients prescribed granulocyte colony-stimulating factors (National 
Health Insurance drug price list [first 7 digits]: 3399405, 3399406, 
3399407, 3399408, 3399409, 3999410 or 3999411) within the 
following month of the date of hospitalization for granulocytopeniab
Additional Condition 3
Patients for whom the immunological test (Category Code D012) or the 
microbiological test (Category Code D017-D023) has been calculated 
within the following month of the date of hospitalization for 
granulocytopeniab
a ICD-10 codes of granulocytopenia are listed in the disease code list (Attachment)
b Including the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
In addition to the following Basic Condition, diseases that are relevant to any of the Additional 
Conditions (1, 2, 3 or 4) are defined thrombocytopenia.
The onset date of outcome is the date of hospitalization described in the Basic Conditions.
Table A1-3-3. Basic Conditions and Additional Conditions for Blood Disorder 
(Thrombocytopenia) to be Used in this Study
Condition
Description
Basic Condition
Patients with a date of hospitalization due to thrombocytopenia and a 
definitive diagnosisa
Additional Condition 1
Patients receiving blood transfusion (Category Code 920) within the 
following month of the date of hospitalization for thrombocytopeniab
Additional Condition 2
Patients prescribed adrenocorticosteroids (drugs in Therapeutic 
Category Code 245) within the following month of the date of 
hospitalization for thrombocytopeniab
Additional Condition 3
Patients prescribed immunoglobulin (ATC code J06B) within the 
following month of the date of hospitalization for thrombocytopeniab
Additional Condition 4
Patients for whom anti-platelet antibody test (Receipt Computerized 
Code: 160039710) is performed within the following month of the date 
of hospitalization for thrombocytopeniab
a ICD-10 codes of thrombocytopenia are listed in the disease code list (Attachment)
b Including the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
In addition to the following Basic Condition, diseases that are relevant to any of the Additional 
Conditions (1, 2, 3, 4, 5, 6, or 7) are defined anemia.
The onset date of outcome is the date of hospitalization described in the Basic Conditions.
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Table A1-3-4. Basic Conditions and Additional Conditions for Blood Disorder (Anemia) 
to be Used in this Study
Condition
Description
Basic Condition
Patients with a date of hospitalization due to anemia and a definitive 
diagnosisa
Additional Condition 1
Patients receiving blood transfusion (Category Code 920) within the 
following month of the date of hospitalization for anemiab
Additional Condition 2
Patients prescribed erythropoiesis factors or hypoxia inducible factor 
prolyl hydoxylase (HIF-PH) inhibitors (ATC code B03XA) within the 
following month of the date of hospitalization for anemiab
Additional Condition 3
Patients prescribed glucocorticoid (ATC code H02AB) within the 
following month of the date of hospitalization for anemiab
Additional Condition 4
Patients prescribed immunoglobulin (ATC code J06B) within the 
following month of the date of hospitalization for anemiab
Additional Condition 5
Patients prescribed methylthioninium (Receipt Computerized Code: 
622402701) is performed within the following month of the date of 
hospitalization for anemiab
Additional Condition 6
Patients prescribed ascorbic acid (drugs in Therapeutic Category Code 
314) within the following month of the date of hospitalization for 
anemiab
Additional condition 7
Patients receiving plasma exchange therapy (Category Code J039) 
within the following month of the date of hospitalization for anemiab
a ICD-10 codes of anemia are listed in the disease code list (Attachment)
b Including the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
4. Interstitial pneumonia
Those to which the following Basic Condition, Additional Condition 1 and Additional Condition 2 as 
well as Additional Condition 3 or Additional Condition 4 apply are defined as interstitial pneumonia.
The onset date of outcome is the date of test conduct described in the additional condition 1.
Table A1-4. Basic conditions and additional conditions of outcome definition of interstitial 
pneumonia to be used in this study
Condition
Description
Basic Condition
Patients with a definitive diagnosisa of interstitial pneumonia
Additional Condition 1
Patients who have undergone imaging/imaging test (Category Code E) 
in the month of hospital visit or the month of the date of hospitalization 
for interstitial pneumoniab
Additional Condition 2
Patients who have undergone interstitial pneumonia marker test 
(Category Code D007) or drug lymphocyte stimulation test (Category 
Code D016) in the month of hospital visit or the following month of the 
date of hospitalization for interstitial pneumoniab
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Table A1-4. Basic conditions and additional conditions of outcome definition of interstitial 
pneumonia to be used in this study
Condition
Description
Additional Condition 3
Patients prescribed adrenocortical steroids (drugs in Therapeutic 
Category Code 245) or antifibrotic agents (Receipt Computerized 
Code: 620008559, 622439201 or 622439301) in the month of hospital 
visit or the following month of the date of hospitalization for interstitial 
pneumoniab
Additional Condition 4
Patients who have undergone tests to differentiate from infection 
(Category Code D012, D017,D018,D019,D020,D021,D022,D023) or 
tests related to transbronchial lung biopsy (Category Code D302 or 
D415) within the month of hospital visit or the following month of the 
date of hospitalization for interstitial pneumoniab
a ICD-10 codes of interstitial pneumonia are listed in the disease code list (Attachment)
bIncluding the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
5. Malignancy
Those to which the Additional Condition 1 applies in addition to the following Basic Conditions are 
defined malignancy.
The time point of the onset of outcome is the month of hospital visit when the definitive diagnosis 
described in the Basic Condition is made.
Table A1-5. Basic Conditions and Additional Conditions of Outcome Definition of 
Malignancy to be Used in this Study
Condition
Description
Basic Condition
Patients with a definitive diagnosisa of malignancy
Additional Condition 1
Patients who have undergone imaging/imaging test (Category Code E) 
in the month of hospital visit or within 1 month before or after the date 
of hospitalization for malignancyb
a ICD-10 codes of malignancy are listed in the disease code list (Attachment)
bIncluding the day of hospitalization
ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision
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ATTACHMENT 2. DISEASE CODE LIST
Table A2-1. Disease Code List for Infection
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Intestinal infectious diseases
A00-A09
A00.1, A01.2, A01.3, A02.8, A03.2, A03.8, 
A06.6, A07.0, A07.3
Tuberculosis
A15-A19
A15.3, A15.5, A15.7-A15.9, A16.0, A16.1, 
A17.1, A17.9, A19.0. A19.1, A19.8
Certain zoonotic bacterial 
diseases
A20-A28
A20.0-A20.3, A20.7, A20.8, A21.1, A21.7, 
A21.8, A22.2, A22.8, A23.0-A23.3, A23.8, 
A24.2-A24.4, A25.0, A26.8, A26.9, A28.9
Other bacterial diseases
A30-A49
A30.0, A30.1, A30.3, A30.8, A32.0, A34, 
A36.1, A36.2, A37.0, A37.1, A37.8, A39.3, 
A40.8, A43.8, A44.1, A44.8
Infections with a 
predominantly sexual mode 
of transmission
A50-A64
A56.2, A56.8, A60.9, A63.8
Other spirochetal diseases
A65-A69
A66.0, A66.3-A66.9, A67, A68.0, A69.8
Other diseases caused by 
chlamydiae
A70-A74
A71.0
Rickettsioses
A75-A79
A75.0, A75.1, A77.0, A77.3, A77.9, A79.0
Viral infections of the CNS
A80-A89
A80.0-A80.2, A80.4, A81.9, A82.1, A83.1-
A83.3,
A83.5, A83.6, A83.8, A83.9, A84, A87.8, 
A88.8, A89
Arthropod-borne viral fevers 
& viral hemorrhagic fevers
A90-A99
A92.1-A92.4, A93.0-A93.2, A95, A96, A98.0-
A98.4, A98.8
Viral infections characterized 
by skin & mucous membrane 
lesions
B00-B09
B04, B05.3, B05.4, B08.8
Viral hepatitis
B15-B19
B16.0, B16.1, B17.0, B18.0, B18.8, B19.0
HIV disease
B20-B24
B20.1, B20.5, B20.7-B20.9, B21.3, B21.7-
B21.9, B22.7, B23.1, B23.2
Other viral diseases
B25-B34
B27.8, B33.4
Mycoses
B35-B49
B35, B36.2, B36.3, B38.3, B38.4, B38.7, B38.8,
B39.0, B39.3-B39.5, B40.7-B40.9, B41, B42.0,
B43.1, B43.8, B45.8, B46.2, B46.8, B48.1, 
B48.2
Protozoal diseases
B50-B64
B50.8, B51.0, B51.8, B52.0, B52.8, B53.1, 
B53.8, B55.0, B55.9, B56, B57.0, B57.1, 
B57.3-B57.5, B60.0, B64
Helminthiases
B65-B83
B65.0, B66.2, B67.1-B67.3, B67.6, B69.0, 
B69.1, B69.8, B70.1, B71.0, B71.8, B72, B73, 
B74.1-B74.4, B76.1, B76.8, B77.0, B81.3, 
B81.8, B83.3, B83.4, B83.9
Pediculosis, acariasis & other 
infestations
B85-B89
B87.1-B87.3, B87.8, B87.9, B88.2, B88.8
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Table A2-1. Disease Code List for Infection
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Sequelae of infectious & 
parasitic diseases
B90-B94
B92, B94.2, B94.8, B94.9
Other infectious diseases
B99
-
Hemophagocytic syndrome, 
infection- associated
D76.2
-
Other histiocytosis syndromes
D76.3
-
Immunodeficiency following 
hereditary defective response 
to Epstein-Barr virus
D82.3
-
Thyroiditis
E06.0, E06.1, 
E06.9
-
Inflammatory diseases of the 
CNS
G00-G06
G01, G02, G03.8, G04.1, G05
Demyelinating diseases of the 
CNS
G36.0, G37.0, 
G37.4
-
Geniculate ganglionitis
G51.1
-
Mononeuritis multiplex
G58.7
-
Hereditary and idiopathic 
neuropathy, unspecified
G60.9
-
Polyneuropathy, unspecified
G62.9
-
Disorders of eyelid, lacrimal 
system and orbit
H00-H06
H00.1, H01.1, H01.8, H01.9, H02, H03, H04.1,
H04.2, H04.5, H04.6, H04.8, H04.9, H05.2-
H05.5, H05.8, H05.9, H06
Disorders of conjunctiva
H10.0, H10.2, 
H10.4
-
Corneal ulcer
H16.0
-
Other keratitis
H16.8
-
Unspecified keratitis
H16.9
-
Other iridocyclitis
H20.8
-
Chorioretinal inflammation, 
unspecified
H30.9
-
Other specified retinal 
disorders
H35.8
-
Purulent endophthalmitis
H44.0
-
Unspecified disorder of globe
H44.9
-
Optic neuritis
H46
-
Diseases of external ear
H60-H61
H60.4, H60.5, H60.8, H61.1-H61.3, H61.8, 
H61.9
Diseases of middle ear and 
mastoid
H65-H73
H67, H68.1, H69, H70.8, H71, H72, H73.9
Vestibular neuronitis
H81.2
-
Labyrinthitis
H83.0
-
Disorders of acoustic nerve
H93.3
-
Acute rheumatic fever
I00-I01
I01.1, I01.8, I01.9
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Table A2-1. Disease Code List for Infection
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Other forms of heart disease
I30, I31, I33, 
I38, I40, I51.4, 
I51.8,
I31.2, I31.3
Diseases of arteries, arterioles 
and capillaries
I71.2, I71.4, 
I72.9, I74.0, 
I77.6
-
Diseases of veins, lymphatic 
vessels & lymph nodes, NOC
I80.9, I88, I89.1
I88.8
Acute upper respiratory 
infections
J00-J06
J01.8
Influenza and pneumonia
J09-J18
J10.0, J10.8, J16.8, J17, J18.2
Other acute lower respiratory 
infections
J20-J22
J20.7, J21.8
Other diseases of upper 
respiratory tract
J30-J39
J30, J32.8, J33, J34.1-J34.3, J35.3, J35.9, J38.0-
J38.6, J39.3, J39.9
Chronic lower respiratory 
diseases
J40-J44
J41.8, J43, J44.0, J44.1, J44.9
Suppurative & necrotic 
conditions of lower 
respiratory tract
J85-J86
-
Pleural effusion, NOC
J90
-
Diseases of mediastinum, 
NOC
J98.5
-
Disorders of diaphragm
J98.6
-
Diseases of oral cavity, 
salivary glands and jaws
K05.0-K05.3, 
K05.5,
K06.8, K07.6, 
K10.2,
K10.3, K11.2, 
K11.3,
K12.0-K12.3, 
K13.0, K14.0, 
K14.2
-
Diseases of oesophagus, 
stomach & duodenum
K20, K22.1, 
K29.1, K29.7-
K29.9, K31.8
-
Diseases of appendix
K35.3, K35.8, 
K36, K37
-
Noninfective gastroenteritis 
& colitis, unspecified
K52.9
-
Other diseases of the 
intestines
K57.1, K57.3, 
K57.9, K61, 
K62.6, K62.8
-
Peritonitis
K65.0, K65.8, 
K65.9
-
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Table A2-1. Disease Code List for Infection
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Other inflammatory liver 
diseases
K75.0, K75.1, 
K75.9
-
Disorders of gallbladder, 
biliary tract & pancreas
K81.0, K81.1, 
K81.9, K83.0, 
K85.0, K85.9
-
Other postprocedural 
disorders of digestive system, 
NOC
K91.8
-
Infections of the skin and 
subcutaneous tissue
L00-L08
L00, L01.1, L04.1-L04.3, L04.8, L05, L08.1, 
L08.8
Other dermatitis
L30.3, L30.9
-
Pustulosis palmaris et 
plantaris
L40.3
-
Cicatricial alopecia [scarring 
hair loss]
L66.3, L66.4
-
Other follicular disorders
L73.1, L73.2, 
L73.9
-
Other eccrine sweat disorders
L74.8
-
Other disorders of the skin 
and subcutaneous tissue
L89.9, L98.0
-
Pyogenic arthritis
M00
M00.8
Spondylopathies
M46.2, M46.3,
M46.5, M46.9, 
M47.2
-
Infective myositis
M60.0
-
Other soft tissue disorders
M71.1, M72.6, 
M72.8
-
Osteomyelitis
M86
M86.4
Glomerular diseases
N00.9, N01.7, 
N01.9, N05.9
-
Renal tubulo-interstitial 
diseases
N10, N12, 
N15.1, N15.9
-
Other specified disorders of 
kidney and ureter
N28.8
-
Other diseases of urinary 
system
N30.2, N30.3,
N30.8, N30.9, 
N32.3, N34.0-
N34.2, N36.1, 
N39.0
-
Diseases of male genital 
organs
N41.0-N41.2, 
N41.9, N45.0, 
N45.9,
N48.1, N48.2, 
N49.1, N49.2, 
N50.0
-
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Table A2-1. Disease Code List for Infection
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Inflammatory disorders of 
breast
N61
-
Inflammatory diseases of 
female pelvic
   organs 
N70-N77
N73.6, N73.8, N73.9, N74, N75.0, N75.9, 
N76.8
Infections of genitourinary 
tract in pregnancy
O23
O23.3
Maternal care for (suspected) 
damage to fetus from viral 
disease in mother
O35.3
-
Infection of amniotic sac and 
membranes
O41.1
-
Complications predominantly 
related to the puerperium
O85, O86, O91
O86.8
Other obstetric conditions, 
NOC
O98.3, O99.5
-
Gangrene, NOC
R02
-
Pleurisy
R09.1
-
Post-traumatic wound 
infection, NOC
T79.3
-
Complications of surgical and 
medical care, NOC
T81.4, T82.6, 
T82.7,
T83.5, T84.5, 
T84.6, T84.7, 
T85.7
-
Nishikawa A, Yoshinaga E, Nakamura M, et al. Validation Study of Algorithms to Identify Malignant 
Tumors and Serious Infections in a Japanese Administrative Healthcare Database. Annals of Clinical 
Epidemiology 2022;4(1):20–31. Cited from SUPPLEMENTARY INFORMATION in 
https://doi.org/10.37737/ace.22004. (Accessed: June 11, 2024)
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Table A2-2.
Disease Code List for Tuberculosis
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Respiratory tuberculosis, 
bacteriologically and histologically 
confirmed
A15
-
Respiratory tuberculosis, not confirmed 
bacteriologically or histologically
A16
-
Tuberculosis of nervous system
A17
-
Tuberculosis of other organs
A18
-
Miliary tuberculosis
A19
-
Source: “Statistical Classification of Disease, Injuries and Causes of Death” Ministry of Health, Labour 
and Welfare (mhlw.go.jp)
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Table A2-3-1. Disease Code List for Serious Blood Disorder (Pancytopenia)
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Other aplastic anemias
D61
-
Source: “Statistical Classification of Disease, Injuries and Causes of Death” Ministry of Health, Labour 
and Welfare (mhlw.go.jp)
Table A2-3-2. Disease Code List for Serious Blood Disorder (Granulocytopenia)
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Agranulocytosis
D70
-
Source: “Statistical Classification of Disease, Injuries and Causes of Death” Ministry of Health, Labour 
and Welfare (mhlw.go.jp)
Table A2-3-3. Disease Code List for Serious Blood Disorder (Thrombocytopenia)
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Purpura and other haemorrhagic 
conditions
D69
-
Source: “Statistical Classification of Disease, Injuries and Causes of Death” Ministry of Health, Labour 
and Welfare (mhlw.go.jp)
Table A2-3-4. Disease Code List for Serious Blood Disorder (Anemia)
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Anemia due to enzyme disorders
D55
-
Acquired hemolytic anaemia
D59
-
Other anemias
D64
-
Methemoglobinemia
D74
-
Source: “Statistical Classification of Disease, Injuries and Causes of Death” Ministry of Health, Labour 
and Welfare (mhlw.go.jp)
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Table A2-4.
Disease Code List for Interstitial Pneumonia
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Acute drug-induced interstitial lung 
disorders
J70.2
-
Chronic drug-induced interstitial 
lung disorders
J70.3
-
Drug-induced interstitial lung 
disorders, unspecified
J70.4
-
Acute respiratory distress syndrome
J80
-
Pulmonary edema
J81
-
Pulmonary eosinophilia, not 
elsewhere classified
J82
-
Other interstitial pulmonary diseases
J84
-
Source: “Statistical Classification of Disease, Injuries and Causes of Death” Ministry of Health, Labour 
and Welfare (mhlw.go.jp)
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Table A2-5. Disease Code List for Malignancy
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
HIV disease resulting in 
Kaposi sarcoma
B21.0
-
HIV disease resulting in 
Burkitt lymphoma
B21.1
-
HIV disease resulting in 
other types of non-
Hodgkin lymphoma
B21.2
-
Malignant neoplasms of 
lip, oral cavity and 
pharynx
C00-C14
C00.5, C02.3, C02.4, C02.8, C04.8, C05.8, C06.8,
C08.8, C09.8, C10.8, C11.8, C13.8, C14.2, C14.8
Malignant neoplasms of 
digestive organs
C15-C26
C16.8, C17.3, C17.8, C18.8, C21.2, C21.8, C24.8, 
C26.0, C26.8
Malignant neoplasms of 
respiratory and 
intrathoracic organs
C30-C39
C31.8, C32.8, C38.8, C39
Malignant neoplasms of 
bone and articular 
cartilage
C40-C41
C40.8, C40.9, C41.8
Melanoma and other 
malignant neoplasms of 
skin
C43-C44
C44.8
Malignant neoplasms of 
mesothelial and soft tissue
C45-C49
C45.7, C46.0-C46.8, C47.8, C48.8, C49.8
Malignant neoplasm of 
breast
C50
-
Malignant neoplasms of 
female genital organs
C51-C58
C51.8, C54.8, C57.1-C57.8
Malignant neoplasms of 
male genital organs
C60-C63
C60.8, C63.8
Malignant neoplasms of 
urinary tract
C64-C68
C67.8, C68.1, C68.8, C68.9
Malignant neoplasms of 
eye, brain and other parts 
of CNS
C69-C72
C69.5, C69.8, C69.9, C71.8, C72.2, C72.8
Malignant neoplasms of 
thyroid and other 
endocrine glands
C73-C75
C75.8, C75.9
Malignant neoplasms of 
ill-defined, secondary and 
unspecified sites
C76-C80
C76.7, C76.8
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Table A2-5. Disease Code List for Malignancy
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Malignant neoplasms, 
stated or presumed to be 
primary, of lymphoid, 
hematopoietic and related 
tissue
C81-C96
C82.5, C84.9, C85.7, C86.4, C88.7, C88.9, C92.6, 
C92.8, C93.7, C95.7, C96.7, C96.9
In situ neoplasms
D00-D09
D01.5, D01.7, D02.4, D03.2, D03.4, D03.5, 
D04.8, D05.7, D06.7, D07.6, D09.1, D09.3, D09.7
Neoplasms of uncertain or 
unknown behaviour
D37-D48
D38.6, D39.9, D40.9, D41.7, D41.9, D43.7, 
D43.9, D44.2, D44.6, D46.0, D46.7, D47.9
Other histiocytosis 
syndromes
D76.3
-
Other chronic pain
R52.2
-
Poisoning by 
antineoplastic and 
immunosuppressive drugs
T45.1
-
Nishikawa A, Yoshinaga E, Nakamura M, et al. Validation Study of Algorithms to Identify Malignant Tumors 
and Serious Infections in a Japanese Administrative Healthcare Database. Annals of Clinical Epidemiology 
2022;4(1):20–31. Cited from SUPPLEMENTARY INFORMATION in https://doi.org/10.37737/ace.22004.
(Accessed: June 11, 2024)
Table A2-6.
Disease Code List for Indicated disease
Disease/procedure
ICD-10 code(s)
version 2013
Exceptions
Rheumatoid arthritis
M05, M06
-
Ulcerative colitis
K51
-
Crohn’s disease
K50
-
Psoriasis (Psoriasis vulgaris, Psoriasis 
arthropica, Pustular psoriasis and 
Psoriatic erythroderma)
L40
-
Source: “Statistical Classification of Disease, Injuries and Causes of Death” Ministry of Health, Labour 
and Welfare (mhlw.go.jp)
Table A2-7.
Disease Code List for Comorbidity disease (Covariate)
Disease/procedure
ICD-10 code(s)
Exceptions
Cerebrovascular disease
G45.x, G46.x, H34.0, I60.x–I69.x
-
Chronic pulmonary disease
I27.8, I27.9, J40.x–J47.x, J60.x–
J67.x, J68.4, J70.1, J70.3
-
Diabetes
E10.0, E10.1, E10.6, E10.8, 
E10.9, E11.0, E11.1, E11.6, 
-
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E11.8, E11.9, E12.0, E12.1, 
E12.6, E12.8, E12.9, E13.0, 
E13.1, E13.6, E13.8, E13.9,
E14.0, E14.1, E14.6, E14.8, E14.9
E10.2–E10.5, E10.7, E11.2–
E11.5, E11.7, E12.2–E12.5, 
E12.7, E13.2– E13.5, E13.7, 
E14.2–E14.5, E14.7
Liver disease
B18.x, K70.0–K70.3, K70.9,
K71.3–K71.5, K71.7, K73.x, 
K74.x, K76.0, K76.2–K76.4, 
K76.8, K76.9, Z94.4 I85.0, I85.9, 
I86.4, I98.2, K70.4, K71.1, K72.1, 
K72.9, K76.5, K76.6, K76.7
-
Renal disease
I12.0, I13.1, N03.2–N03.7, 
N05.2– N05.7, N18.x, N19.x, 
N25.0, Z49.0– Z49.2, Z94.0, 
Z99.2
Dementia
F00.x–F03.x, F05.1, G30.x, G31.1
-
Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and 
ICD-10 administrative data. Med Care. 2005;43:1130-9.
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ATTACHMENT 3. DRUG LIST
Table A3-1. List of DMARDS
GENERAL NAME
Actarit
Auranofin
Bucillamine
Iguratimod
Leflunomide
Methotrexate
Mizoribine
Penicillamine
Salazosulfapyridine
Sodium Aurothiomalate
Tacrolimus Hydrate
Table A3-2. List of Amino salicylate
GENERAL NAME
Mesalazine
Salazosulfapyridine
Table A3-3. List of Immunosuppressant (Steroid)
GENERAL NAME
Betamethasone
Betamethasone Acetate/Betamethasone Sodium Phosphate
Betamethasone Sodium Phosphate
Cortisone Acetate
Dexamethasone
Dexamethasone Palmitate
Dexamethasone Sodium Phosphate
Hydrocortisone
Hydrocortisone Sodium Succinate
Methylprednisolone
Methylprednisolone Acetate
Prednisolone
Prednisolone Sodium Succinate
Triamcinolone
Triamcinolone Acetonide
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Table A3-4. List of Immunosuppressant (non-steroid)
GENERAL NAME
Apremilast
Azathioprine
Carotegrast methyl
Ciclosporin
Mercaptopurine Hydrate
Tacrolimus Hydrate
Table A3-5. List of Biologics
GENERAL NAME
Abatacept(Genetical Recombination)
Adalimumab(Genetical Recombination)
Bimekizumab(Genetical Recombination)
Brodalumab(Genetical Recombination)
Certolizumab Pegol(Genetical Recombination)
Etanercept(Genetical Recombination)
Golimumab(Genetical Recombination)
Guselkumab(Genetical Recombination)
Ixekizumab(Genetical Recombination)
Ozoralizumab(Genetical Recombination)
Risankizumab(Genetical Recombination)
Sarilumab(Genetical Recombination)
Secukinumab(Genetical Recombination)
Tildrakizumab(Genetical Recombination)
Tocilizumab(Genetical Recombination)
Ustekinumab(Genetical Recombination)
Vedolizumab(Genetical Recombination)
Table A3-6. List of Janus kinase inhibitor
GENERAL NAME
Baricitinib
Filgotinib Maleate
Peficitinib Hydrobromide
Tofacitinib Citrate
Upadacitinib Hydrate
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Table A3-7. List of Anti-tuberculosis
GENERAL NAME
Aluminoparaaminosalicylate Calcium Hydrate
Bedaquiline Fumarate
Calcium Paraaminosalicylate Hydrate
Cycloserine
Delamanid
Enviomycin Sulfate
Ethambutol Hydrochloride
Ethionamide
Isoniazid
Isoniazid Sodium Methanesulfonate Hydrate
Kanamycin Sulfate
Pyrazinamide
Rifabutin
Rifampicin
Streptomycin Sulfate
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