Safety and Effectiveness of Apixaban in Very Elderly Patients With NVAF Compared to Warfarin Using Administrative Claims Data
Conditions: Non-valvular Atrial Fibrillation
Sponsor: Pfizer

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Safety and effectiveness of apixaban in very elderly patients 
with NVAF compared to warfarin using administrative claims 
data 
 
 

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
 
Study information 
Title 
Safety and effectiveness of apixaban in very 
elderly patients with NVAF compared to 
warfarin using administrative claims data 
Protocol number 
B0661181 
Protocol version identifier 
Ver. 2.0 
Date 
10-AUG-2023 
Active substance 
B : Blood and blood forming organs 
B01: Antithrombotic agents 
B01A : Antithrombotic agents 
B01AF: Direct factor Xa inhibitors 
B01AF02: apixaban 
Medicinal product 
Eliquis (apixaban) 
Research question and objectives 
Japan is a very elderly society compared to 
other countries in Europe and the United 
States, and many patients are newly 
diagnosed with NVAF even in their 80’s or 
90’s. Most of these very elderly people have 
many complications and take many 
medications chronically as a result. In 
addition, many elderly patients have low body 
weight, sarcopenia, low ADL, frailty or frail-like 
characteristics, or high risk of falls. There has 
been much debate and inconclusive evidence 
on the value of anticoagulation for these very 
elderly patients with NVAF. 
ARISTOTLE study has shown that apixaban is 
superior or equivalent to warfarin in various 
populations including higher risk populations. 
However, there are few evidence, especially 
on safety and effectiveness of apixaban 
versus warfarin. 
 
Objectives 
To investigate safety and effectiveness of 
apixaban compared to warfarin in very elderly 
patients with NVAF. In addition to the absolute 

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age, effects on higher age-related risk factors 
on relative risk of apixaban to warfarin is also 
investigated. 
 
Author 
 
Pfizer Japan Inc., 
Shinjuku Bunka Quint Building 
3-22-7 Yoyogi, Shibuya-ku, Tokyo 151-8589, 
Japan 
 
PPD

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1. TABLE OF CONTENTS 
 
1 TABLE OF CONTENTS .................................................................................................. 4 
2 LIST OF ABBREVIATIONS ........................................................................................... 6 
3 RESPONSIBLE PARTIES ............................................................................................... 7 
4 PRINCIPAL INVESTIGATOR(S) OF THE PROTOCOLABSTRACT ............................ 8 
4.1 
Rationale and background: ............................................................................. 8 
4.2 
Study hypothesis and clinical questions .......................................................... 8 
4.3 
Study objectives ............................................................................................. 9 
4.4 
Study design: .................................................................................................. 9 
4.5 
Population ...................................................................................................... 9 
4.6 
Variables – include exposures, outcomes, and key co-variates ...................... 10 
4.7 
Data sources ................................................................................................. 11 
4.8 
Study size ..................................................................................................... 11 
4.9 
Data analysis ................................................................................................ 11 
4.10 
Milestones .................................................................................................... 11 
5 AMENDMENTS AND UPDATES ................................................................................ 11 
6 MILESTONES ............................................................................................................... 12 
7 RATIONALE AND BACKGROUND ............................................................................ 12 
8 RESEARCH QUESTION AND OBJECTIVES .............................................................. 13 
9 RESEARCH METHODS................................................................................................ 13 
9.1 
Study design ................................................................................................. 13 
9.2 
Endpoints ..................................................................................................... 14 
9.3 
Setting .......................................................................................................... 15 
9.3.1 
Inclusion criteria ............................................................................. 15 
9.3.2 
Exclusion criteria ............................................................................ 15 
 
 
9.5 
Variables ...................................................................................................... 17 
9.6 
Data sources ................................................................................................. 19 
CC
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9.7 
Study size ..................................................................................................... 19 
9.8 
Data management ......................................................................................... 19 
9.9 
Data analysis ................................................................................................ 19 
9.10 
Quality control ............................................................................................. 20 
9.11 
Limitations of the research methods ............................................................. 20 
9.12 
Other aspects ................................................................................................ 20 
10 PROTECTION OF HUMAN SUBJECTS....................................................................... 21 
10.1 
Patient information ....................................................................................... 21 
10.2 
Patient consent ............................................................................................. 21 
10.3 
Patient withdrawal ........................................................................................ 21 
10.4 
Institutional review board (IRB)/Independent ethics committee (IEC) .......... 22 
10.5 
Ethical conduct of the study.......................................................................... 22 
11 MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS.................................................................................................................. 22 
12 PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ........ 22 
13 REFERENCES ............................................................................................................... 22 
14 LIST OF TABLES .......................................................................................................... 22 
15 LIST OF FIGURES ........................................................................................................ 22 
16 ANNEX 1. LIST OF STAND ALONE DOCUMENTS .................................................. 23 
17 ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ................................... 23 
18 ANNEX 3. ADDITIONAL INFORMATION ................................................................. 23 
 
 

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2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADL 
Activity of daily living 
AF 
Atrial fibrillation 
CCI 
Charlson comorbidity index 
CV/MET 
Cardiovascular/Metabolism 
DPC 
Diagnosis Procedure Combination 
ICD 
International Statistical Classification of Diseases and 
Related Health Problems 
IPTW 
Inverse Probability Treatment Weighting 
MDV 
Medical Data Vision 
NVAF 
Non-valvular atrial fibrillation 
RWE 
Real world evidence 
 
 
 

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3. RESPONSIBLE PARTIES 
Name, 
degree(s) 
Title 
Affiliation 
Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name, degree(s) 
Job Title 
Affiliation 
Address 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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4. PRINCIPAL INVESTIGATOR(S) OF THE PROTOCOLABSTRACT 
• 
Title:  
• 
Safety and effectiveness of apixaban in very elderly patients with NVAF compared to 
warfarin using administrative claims data  
• 
Version 2.0, 10 AUG, 2023. 
 Pfizer 
Japan Inc. 
4.1. Rationale and background: 
Japan is a very elderly society compared to other countries in Europe and the United States, 
and there are many very elderly patients wth NVAF who are treated with any of anticoagulant 
and there are considerable number of patients who are newly diagnosed with NVAF even in their 
80’s and 90’s. Most of these very elderly people have many complications, including severe 
ones,  and take many medications chronically.In addition, many elderly patients have low body 
weight, sarcopenia, low ADL, frailty or frail-like characteristics, or high risk of falls. There has 
been much debate and inconclusive evidence on the value of anticoagulation for these very 
elderly patients with NVAF. 
ARISTOTLE study has shown that apixaban is superior or equivalent to warfarin in various 
populations including populations at higher risk. However, there are few studies in the real-world 
settings regarding very elderly patients who are at higher risk. 
4.2. Study hypothesis and clinical questions 
The ARISTOTLE study and various real-world evidence (RWE) have shown that apixaban is 
superior or equivalent to warfarin in safety and effectiveness profile. Subgroup analyses of the 
ARISTOTLE study suggested that superiority over warfarin could be consistent in most 
populations including high risk populations. Study hypothesis and clinical questions in this study 
is apixaban is superior to warfarin in both safety and effectiveness even in the very elderly 
patients with NVAF in the real-world settings. 
 The clinical question of this study is that apixaban has a superior effectiveness and safety 
profile compared to warfarin, even in very elderly patients who are at particularly high risk, such 
as those with 
, frail or frail patients, 
 
 
 
PPD
CCI
CCI

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4.3. Study objectives 
The objective of this study is to investigate safety and effectiveness of apixaban compared to 
warfarin in very elderly patients with NVAF. 
 
 
 
 
4.4. Study design: 
• 
This is a retrospective non-intervention observational study to evaluate the 
difference in safety and effectiveness between apixaban and warfarin using a database 
provided by Medical Data Vision Co. Ltd. (MDV Co. Ltd.). Eligible patients will be extracted 
from the database and allocated to the pre-defined cohorts based on the actual age, age of 
NVAF diagnosis and types of anticoagulant therapy.  
• 
Based on the age category and anticoagulants on the index date (a date when 
patients initiated an anticoagulant for prevention of stroke/SE), eligible patients will be 
allocated to some cohorts. Patient characteristics will be balanced by an Inverse probability 
of treatment weighting (IPTW) method, and risk of stroke/SE (primary effectiveness 
endpoint) and major bleeding (primary safety endpoint) will be compared. Hazard ratios and 
95% confident intervals will be calculated by using a COX proportional hazard method.  
• 
 
4.5. Population 
• 
Patients registered in the MDV database from 26 February, 2013 to 31 December, 2021 will 
be used. First, atients with a NVAF diagnosis and received apixaban or warfarin as an 
anticoagulant after the NVAF diagnosis will be identified and then among them only patients 
who are 80 or older when they initiated these medications.   
CCI

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4.6. Variables – include exposures, outcomes, and key co-variates 
• 
Following variables will be collected in this study at the index date (see 9.1 Study design for 
a definition of index date). 
• 
Items 
• 
definitions 
• 
roles 
• 
Gender 
• 
Male or female 
• Patient characteristics 
• 
 
 
 
 
• 
Timing of NVAF diagnosis 
• 
80-89 years 
• 
≥ 90 years 
• Patient characteristics 
• 
 
 
 
 
• 
Medications 
• Chronically prescribed medicines 
• Details are shown in the SAP 
• Patient characteristics 
• 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
• 
Stroke history 
• Previous diagnosis of cerebral 
infarction, cardiovascular 
embolism, hemorrhagic stroke, or 
TIM 
• Patient characteristics 
• 
 
CCI
CCI
CCI

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4.7. Data sources 
Medical Data Vision database, commercially available administrative claims database 
from hospitals introducing DPC (Diagnosis Procedure Combination) system, which 
comprises administrative data pertaining to approximately 39 million individuals (as of 2021 
Dec.) managed in the inpatient and outpatient settings. 
 
4.8. Study size 
All eligible patients will be used for the analysis. The number of patients to be used for 
the analysis was estimated in the preliminary feasibility check and we have confirmed that 
the statistical power may be sufficient to the analysis. 
Roughly estimated number of patients are as follows, 
• 
Male with NVAF: ≥ 80: 34,157 
• 
Female with NVAF: ≥ 80: 33,163 
The number of patients who are newly diagnosed with NVAF in 80-89 or ≥ 90 are not 
known. 
The dealied results of estimation of power calculation will be described in the Statistical 
Analysis Plan (SAP) 
4.9. Data analysis 
• The detailed methodology for data analysis is explained in the SAP.  
• For each age category, apixaban and warfarin cohorts whose patient characteristics are 
balanced by propensity score matching or IPTW methods will be created, and 
incidence rates of stroke/SE or major bleeding in each cohort and hazard ratios+ 95% 
confident intervals will be calculated. 
  
4.10. Milestones 
Data extraction from MDV database: Jun 30 – Jun 30, 2022 
Analysis: July.01 - Aug.31, 2023  
Completion of final study report: Sep.8, 2023 
Manuscript submission: Oct.31, 2023 
•  
5. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Protocol 
section(s) 
changed 
Summary of amendment(s) 
Reason 

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6. MILESTONES 
  
 
7. RATIONALE AND BACKGROUND 
Japan is a very elderly society compared to other countries in Europe and the United States, 
and there are many very elderly patients wth NVAF who are treated with any of anticoagulant 
and there are considerable number of patients who are newly diagnosed with NVAF even in their 
80’s and 90’s. Most of these very elderly people have many complications, including severe 
ones,  and take many medications chronically.In addition, many elderly patients have low body 
weight, sarcopenia, low ADL, frailty or frail-like characteristics, or high risk of falls. There has 
been much debate and inconclusive evidence on the value of anticoagulation for these very 
elderly patients with NVAF. 
ARISTOTLE study has shown that apixaban is superior or equivalent to warfarin in various 
populations including populations at higher risk. However, there are few studies in the real-world 
settings regarding very elderly patients who are at higher risk. 
1.1 
 22 
JUNE, 
2022 
4.10 
6 
 
Change the date; 
extraction from MDV 
database, start and end 
of data collection 
The scheduled Data 
extraction date has 
changed. 
2.0 
10 
AUG, 
2023 
4.5 
4.10 
6 
9.10 
Change the patient 
registration period 
 
Change the date of 
Milestones 
 
Change the data 
analyst 
The launch date of 
apixaban in Japan was 
considered for concurrent 
comparison with warfarin. 
And  the scheduled date 
FSR has changed. 
Milestone 
Planned date 
<Completion of feasibility assessment> 
28 Apr 2022 
Start of data collection  
30 Jun 2022 
End of data collection  
30 Jun 2022 
Final study report 
8 Sep 2023 

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8. RESEARCH QUESTION AND OBJECTIVES 
The ARISTOTLE study and various real-world evidence (RWE) have shown that apixaban is 
superior or equivalent to warfarin in safety and effectiveness profile. Subgroup analyses of the 
ARISTOTLE study suggested that superiority over warfarin could be consistent in most 
populations including high risk populations. Study hypothesis and clinical questions in this study 
is apixaban is superior to warfarin in both safety and effectiveness even in the very elderly 
patients with NVAF in the real-world settings. 
 The clinical question of this study is that apixaban has a superior effectiveness and safety 
profile compared to warfarin, even in very elderly patients who are at particularly high risk, such 
as those with 
, frail or frail patients, 
 
 
The objective of this study is to investigate safety and effectiveness of apixaban compared to 
warfarin in very elderly patients with NVAF. In addition to the absolute age, effects on higher 
age-related risk factors on relative risk of apixaban to warfarin is also investigated through 
subgroup analyses. 
 
 
9. RESEARCH METHODS  
9.1. Study design  
This is a retrospective non-intervention observational study to evaluate the difference in safety 
and effectiveness between apixaban and warfarin using a database provided by Medical Data 
Vision Co. Ltd. (MDV Co. Ltd.). Eligible patients will be extracted from the database and 
allocated to the pre-defined cohorts based on the actual age, age of NVAF diagnosis and types 
of anticoagulant therapy.  
Based on the age category and anticoagulants on the index date (a date when patients initiated 
an anticoagulant for prevention of stroke/SE), eligible patients will be allocated to some cohorts. 
Patient characteristics will be balanced by an Inverse probability of treatment weighting (IPTW) 
method, and risk of stroke/SE (primary effectiveness endpoint) and major bleeding (primary 
safety endpoint) will be compared. Hazard ratios and 95% confident intervals will be calculated 
by using a COX proportional hazard method.  
The following definitions will be used here 
• Index date: the date when warfarin or apixaban was initiated 
CCI
CCI

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• Baseline period: the 180 days before the index date 
• Cohorts:  
 Apixaban cohorts: patients who started an anticoagulant therapy with apixaban 
 Warfarin cohorts: patients who started an anticoagulant therapy with warfarin  
• Observational period: 
Follow-up period starts from the next day of the index date and ends depending on 
following outcomes which observed first.   
1. Major bleeding when the target outcome for the analysis is major bleeding. 
2. Composite of (ischemic or hemorrhagic) stroke and SE when the target outcome for 
the analysis is the composite endpoint. 
3. Any bleeding when the target outcome for the analysis is any bleeding. 
4. Discontinuation of the index OAC:  The index treatment will be "discontinued" if the 
index OAC is not prescribed within 45 days after prescription refill date (calculated 
from the last refill date plus days of supply) of the index OAC, even though the 
patient has >1 medical encounter records after more than 45 days following the 
prescription refill date. The supposed prescription refill date is regarded as the last 
day of the follow-up for discontinued patients. 
5. Switching from the index OAC:  The index treatment is regarded as "switched" if 
non-index OAC is prescribed within 45 days after prescription refill date of the index 
OAC when the patient has 1> medical encounter records after more than 45 days 
following the prescription refill date. The switched day is regarded as the last day of 
the follow-up for the switched patients. 
6. Withdrawal from the database:  The patients are regarded as “withdrawal” from the 
database if the index OAC is not prescribed within 45 days after prescription refill 
date of the index OAC and there is no data of the patient on the database after 
prescription refill date. The last medical encounter is regard as the last day of the 
follow-up for patients withdrawn from the database.  
9.2. Endpoints 
• 
Primary effectiveness endpoint: stroke/SE (a composite of ischemic stroke, hemorrhagic 
stroke and SE) 
• 
Primary safety endpoing: Major bleeding (any bleeding requiring hospitalization for 
treatment) 

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• 
Seconary effectiveness endpoint: 
 Cardiogenic embolic stroke 
 Ischemic stroke 
• 
Secondary safety endpoint: 
 Intracranial hemorrhage 
 Gastrointestinal bleeding 
 Intraocular bleeding 
9.3. Setting 
This study uses data from the MDV database, which includes the data used for both 
inpatient and outpatient insurance claims by hospitals according to the Diagnosis Procedure 
Combination (DPC) procedure. That is, medical information will be collected in the real-world 
settings. 
9.3.1. Inclusion criteria 
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study. 
1. 
Diagnosed with AF anytime in the baseline period or on the index date, also have definitive 
diagnosis of AF anytime in the baseline period, on the index date, or post-index period.  
2. 
Prescribed apixaban or warfarin on or after the day of AF diagnosis. The first observed 
prescription will be used to identify the patient’s index date and treatment cohort  
3. 
No use of the any OACs during the baseline period (the 180 days before the index date)  
4. 
Age of 18 years or older on the index date. 
5. 
Index date is at age 80 or older 
 
9.3.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. 
Having a diagnosis of valvular atrial fibrillation, post-operative atrial fibrillation, rheumatic atrial 
fibrillation or mechanical-valvular atrial fibrillation during the baseline and post-index period 
2. 
Having a cardiac surgery procedure record during the baseline period 

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3. 
Having a joint replacement procedure record during the baseline period 
4. 
Having a procedure of prosthetic heart valve during the baseline period 
5. 
Having a diagnosis of venous thromboembolism during the baseline period 
6. 
Female patients with pregnancy during the follow-up period 
7. 
Patients prescribed “off-label” doses of OACs (per Japanese package insert of each OAC) or patients 
treated with OAC but in “off-label” or “contraindicated” manners. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
C
C
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9.5. Variables 
Items 
definitions 
roles 
Gender 
Male or female 
Patient characteristics 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CC
I
CCI

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Medications 
 
 
The number of chronically prescribed medicine 
 
Patient characteristics 
Treated with  antiplatelet drug in baseline 
Defined using 
prespecified drug-specific 
codes: Yes or No 
Patient characteristics 
Treated with NSAIDs in baseline 
Defined using 
prespecified drug-specific 
codes: Yes or No 
Patient characteristics 
Treated with gastric secretion inhibitor in baseline 
Defined using 
prespecified drug-specific 
codes: Yes or No 
Patient characteristics 
Treated with statin-based drug in baseline 
Defined using 
prespecified drug-specific 
codes: Yes or No 
Patient characteristics 
Treated with anti-hypertensives in baseline  
Defined using 
prespecified drug-specific 
codes: Yes or No 
Patient characteristics 
Treated with anti-arrhythmics in baseline  
Defined using 
prespecified drug-specific 
codes: Yes or No 
Patient characteristics 
Treated with beta-blockers in baseline  
Defined using 
prespecified drug-specific 
codes: Yes or No 
Patient characteristics 
Procedures 
 
 
Cardioversion 
Defined using 
prespecified medical 
procedure codes: Yes or 
No 
Patient characteristics 
Cardiac ablation 
Defined using 
prespecified medical 
Patient characteristics 
CCI

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procedure codes: Yes or 
No 
 
9.6. Data sources  
The analysis will be based on administrative claims data provided from MDV Co. Ltd., a 
longitudinal database based on health insurance claims and medical records obtained from the 
hospitals in which the DPC payment system for utilization of both inpatient and outpatient 
hospital claims (percentage of inpatients is about 45%). The database provides claims data from 
450 hospitals (as of Sep.2021) using the DPC system for medical service claims (21% of general 
hospitals but 55% of general beds in Japan is under the DPC system) including approximately 
38 million patient data.  
9.7. Study size 
All eligible patients will be used for the analysis. The number of patients to be used for 
the analysis was estimated in the preliminary feasibility check and we have confirmed that 
the statistical power may be sufficient to the analysis. 
Roughly estimated number of patients are as follows, 
• 
Male with NVAF: ≥ 80: 34,157 
• 
Female with NVAF: ≥ 80: 33,163 
The number of patients who are newly diagnosed with NVAF in 80-89 or ≥ 90 are not 
known. 
The dealied results of estimation of power calculation will be described in the Statistical 
Analysis Plan (SAP) 
 
9.8. Data management  
Data will be securely provided by MDV Co. Ltd. All data have been structured and no 
development of new database and human review are not required. Provided data will be able to 
be used directly for the analysis.  
 
9.9. Data analysis  
Baseline patient demographic information will be compared among cohorts to be compared 
by appropriate tests (e.g., t-test, Mann Whitney-U test, chi-square test) based on the distribution 
of the measures.  
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 

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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. 
 
9.10. Quality control 
This study is a retrospective analysis using quality controlled structured data in a pre-existing 
database, and primary data collection will not be conducted. As for the data provided, quality of 
the data is guaranteed by MDV Co. Ltd., which has professional teams specialized in the 
maintenance and improvement of data quality. All these processes are consistently managed in-
house. All of operations for data management in MDV Co. Ltd. are conducted in accordance with 
standard operational procedures of MDV Co. Ltd. 
Data analysis will be conducted by Macromill Carenet, Inc. (Tokyo, Japan). The final results will 
be quality checked internally by Macromill Carenet according to their internal procedures. For 
quality assurance of analysis, they will conduct code review of all modules of program, 
descriptive statistics review of all variables and patients row data examination of all output 
results in a test phase. 
9.11. Limitations of the research methods 
• 
The data we will use are obtained from a claims database containing information provided 
by hospitals applying the flat-fee payment system, which are mostly large hospitals 
responsible for acute care. Therefore, a significant proportion of the patients included in the 
present analysis are likely in poorer health than the average population requiring 
hospitalization, possibly having more comorbidities and higher risk of stroke/SE and 
bleeding.  
• 
 
 
. 
 
9.12. Other aspects 
There is  slight duplicated analyses between and the current study and previously approved 
on-going study (named CER4 which will be investigated safety and effectiveness of apixaban 
compared to warfarin in bleeding-prone patients with NVAF) 
CCI

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• CER-4 is a study focused on the risk of bleeding in the bleeding-prone (with at least one 
risk factor for bleeding) population taking anticoagulants. On the other hand, the 
current study is to investigate the risk of developing Stroke / SE and bleeding in the 
very elderly people receiving anticoagulant therapy. Like this, study populations to be 
examined are at least in part similar but basically different. 
• Different, important unmet medical needs in Japan underlie these two studies. 
Anticoagulant therapy for patients at higher risk of bleeding and for very elderly 
patients are still critical unmet medical needs in Japan and these topics have been often 
discussed at the scientific meetings such as Japanese Circulation Society. 
• A part of analysis, safety and effectiveness in very elderly patients, is suplicatedly 
conducted in the two study because higher age is often considered as a risk of 
bleeding. 
 
 In contrast, in the current very 
elderly patients study, patients’ age is the main factor, and the effectiveness and safety 
of apixaban in the super-elderly will be investigated as the primary analysis. 
 
 
• Therefore, two studies are quite different in the purposes, underlying unmet medical 
needs to be met, populations to be investigated.  
 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information  
This study without human review of unstructured data involves data that exist in anonymized 
structured format and contain no patient personal information.   
10.2. Patient consent 
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required. 
 
10.3. Patient withdrawal 
Not applicable 
 
CCI
C
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10.4. Institutional review board (IRB)/Independent ethics committee (IEC) 
According to the Japanese regulations, this type of database study does not always need 
approval of IRB or IEC. This study is an actual survey and epidemiological study and will not  
submit protocol synopsis to IRB of Research Institute of Healthcare Data Science for protocol 
review and approval. 
10.5. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in CT24-WI-GL02-RF04 and references to any additional relevant guidance. 
 
11. 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. 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
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 investigator  is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately.   
If not, a part or all results of the study will be published in one of the peer-reviewed medical 
scientific journals. No design paper, progress reports and interim reports will be published 
elsewhere. 
 
13. REFERENCES 
14. LIST OF TABLES  
15. LIST OF FIGURES 
• 
 

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16. ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None 
17. ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable 
18. ANNEX 3. ADDITIONAL INFORMATION 
Not applicable