Retrospective, Multicenter, Observational Study to Evaluate Current Treatment Outcomes in Japanese Patients With Metastatic Renal Cell Carcinoma Treated With Avelumab Plus Axitinib as a First-line Therapy
Conditions: Renal Cell Carcinoma
Sponsor: Pfizer

Avelumab
B9991043 NON-INTERVENTIONAL STUDY PROTOCOL
Protocol version 2.0, 04 Novemver 2021
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Retrospective, Multicenter, Observational 
Study to Evaluate Current Treatment 
Outcomes in Japanese Patients With 
Metastatic Renal Cell Carcinoma Treated 
With Avelumab plus Axitinib as a First-line 
Therapy
Protocol number
B9991043
Protocol version identifier
Version 2.0
Date
04 Nov 2021
Active substance
Avelumab
Medicinal product
Avelumab (BAVENCIO®)
Research question and objectives
To describe the demographic and baseline
characteristics and treatment outcomes in 
patients with metastatic renal cell carcinoma 
(mRCC) treated with avelumab plus axitinib 
as a first-line therapy.
Author
 (NI study lead)
 
e-mail address : 
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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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................7
4. ABSTRACT...........................................................................................................................7
5. AMENDMENTS AND UPDATES.......................................................................................7
6. MILESTONES.......................................................................................................................8
7. RATIONALE AND BACKGROUND..................................................................................8
8. RESEARCH QUESTION AND OBJECTIVES ...................................................................9
8.1. Primary objective ......................................................................................................9
8.2. Secondary objectives.................................................................................................9
9. RESEARCH METHODS ......................................................................................................9
9.1. Study design ..............................................................................................................9
9.1.1. Primary endpoint ........................................................................................10
9.1.2. Secondary endpoints...................................................................................10
9.1.3. Definition of endpoints...............................................................................11
9.2. Setting......................................................................................................................11
9.2.1. Inclusion criteria .........................................................................................11
9.2.2. Exclusion criteria........................................................................................12
9.3. Variables..................................................................................................................12
9.3.1. Patient characteristics at baseline ...............................................................12
9.3.2. IMDC risk -related data at baseline............................................................12
9.3.3. Clinical outcome (Real-world PFS)............................................................13
9.3.4. Clinical outcome (OR)................................................................................13
9.3.5. Avelumab treatment (TTF).........................................................................13
9.3.6. Axitinib treatment (TTF) ............................................................................13
9.3.7. Corticosteroid treatment .............................................................................13
9.3.8. Pre-medication and treatment for infusion-related reaction of 
avelumab..........................................................................................................13
9.3.9. Second-line regimen after avelumab plus axitinib treatment .....................13
9.4. Data sources ............................................................................................................13
9.5. Study size ................................................................................................................13
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9.6. Data management....................................................................................................14
9.6.1. Electronic Case report forms (eCRFs)/Data collection tools 
(DCTs)/Electronic data record.........................................................................14
9.6.2. Record retention..........................................................................................14
9.6.3. Record disposal...........................................................................................15
9.7. Data analysis ...........................................................................................................15
9.7.1. Analysis Population....................................................................................15
9.7.2. Analysis Methods .......................................................................................15
9.7.3. Analysis of Primary Endpoints...................................................................15
9.7.4. Analysis of Secondary Endpoints...............................................................16
9.8. Quality control.........................................................................................................16
9.9. Limitations of the research methods .......................................................................16
9.10. Other aspects .........................................................................................................16
9.10.1. Report to the chief executive of the study site..........................................16
10. PROTECTION OF HUMAN SUBJECTS ........................................................................17
10.1. Patient information................................................................................................17
10.2. Patient consent.......................................................................................................17
10.2.1. For subjects who are alive and still visit the study site.............................17
10.2.2. Subjects who are alive and had been transferred to another medical 
facility ..............................................................................................................18
10.2.3. Subjects who are deceased........................................................................19
10.2.4. Handling of study results, etc. ..................................................................19
10.3. Patient withdrawal.................................................................................................20
10.3.1. Subjects who are alive and still visit the study site, or subjects who 
are alive and had been transferred to another medical facility ........................20
10.3.2. Subjects who are deceased........................................................................21
10.4. Institutional review board (IRB)/Independent ethics committee (IEC)................21
10.5. Ethical conduct of the study..................................................................................21
10.6. Predictable risks and benefits................................................................................21
10.6.1. Risk...........................................................................................................21
10.6.2. Benefits.....................................................................................................21
10.7. Conflicts of interest ...............................................................................................21
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10.8. Registration and publication of study....................................................................22
10.9. Secondary use of specimens and information obtained from subjects..................22
10.10. Responding to consultations from subjects and other related parties .................22
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS 
(AES)/ADVERSE REACTIONS .......................................................................................22
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........24
13. REFERENCES ..................................................................................................................24
14. LIST OF TABLES.............................................................................................................24
15. LIST OF FIGURES ...........................................................................................................24
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................24
ANNEX 2. ADDITIONAL INFORMATION.........................................................................24
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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
AEM
adverse event monitoring
BMI
body mass index
CI
confidence interval 
CR
complete response
CRP
C-reactive protein
CSA
clinical study agreement
DCF
data clarification form
DCT
data collection tool
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
IEC
Independent Ethics Committee
IMDC
International Metastatic RCC Database Consortium
irAE
Immune-related adverse event
IRB
Institutional Review Board
mRCC
metastatic renal cell carcinoma
NIS
non-interventional study
OR
objective response
PD-L1
programmed death ligand 1
PFS
progression-free survival
PD
progressive disease
PR
partial response
RCC
renal cell carcinoma
SAP
Statistical Analysis Plan
SD
stable disease
SD
standard deviation
TKI
tyrosine kinase inhibitor 
TNM
tumor-node-metastasis
TTF
time to treatment failure
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YRR
your reporting responsibilities
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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
List of Principal Investigators in this study will be prepared as Annex1.
4. ABSTRACT
Not applicable
5. AMENDMENTS AND UPDATES
Amendment 
number
Date
Protocol section(s) changed 
Summary of 
amendment(s)
Reason
2.0
25 Oct 2021
2. LIST OF ABBREVIATIONS, 
6. MILESTONES, 9.3. Variables, 
10.2.1. For subjects who are alive 
and still visit the study site, 10.2.2. 
Subjects who are alive and had 
been 
transferred 
to 
another 
medical facility, 10.2.3. Subjects 
who 
are 
deceased, 
10.2.4. 
Handling of study results, etc, 
10.2.4.1. Response to important 
findings and other information 
concerning the health of subjects, 
10.4. Institutional review board 
(IRB)/Independent 
ethics 
committee (IEC), 10.5. Ethical 
conduct of the study, 10.8. 
Registration and publication of 
study, 10.9. Secondary use of 
specimens 
and 
information 
obtained from subjects, ANNEX 
1. LIST OF STAND ALONE 
DOCUMENTS
2. Deleted the description
regarding UMIN-CTR, 6. 
changed the planned date 
of milestone, 9.1.2. delete 
“and/or”, 9.3. added the 
description that this study 
will not be collected 
human genome and gene 
information, 10.2.1. added  
"Handling of results and 
other information obtained 
from the study", 10.2.2. 
amended the name of the 
ethics guidelines, 10.2.3. 
amended the name of the 
ethics guidelines, 10.2.4. 
addded policy for the 
explanations of study 
results, etc., 10.2.4.1. 
added the description
regarding response to 
important findings and 
other information 
concerning the health of 
subjects, 10.4. added the 
method of review handling, 
10.5. amended the name of 
the ethics guidelines, 10.8. 
delete the description
regarding UMIN-CTR, 
10.9. added the details of 
methods of the handling 
secondary use, ANNEX 1. 
added "The responsible 
parties of the study"
2. to correct typos, 6. to 
amend the schedule, 9.1.2. to 
correct typos, 9.3. to clarify
that this study will not collect 
human genome and gene 
information, 10.2.1. because 
ethic guidelines has been 
revised, 10.2.2. because ethic 
guidelines has been revised, 
10.2.3. 
because 
ethic 
guidelines has been revised, 
10.2.4. 
because 
ethic 
guidelines has been revised, 
10.2.4.1. 
because 
ethic 
guidelines has been revised, 
10.4. because ethic guidelines 
has 
been 
revised, 
10.5. 
because ethic guidelines has 
been revised, 10.8. to correct 
typos, 10.9. to add the details, 
ANNEX 1. to correct typos
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6. MILESTONES
Milestone
Planned date
Observation period
from index date to 20 Jun 2021
Start of data collection
08 Sep 2021
End of data collection
31 Jan 2022
Analytical dataset lock
31 Jan 2022
Final study report
31 May 2022
7. RATIONALE AND BACKGROUND
Approximately 30,000 patients were diagnosed with renal cancer in Japan in 2017 1), and the
number of cases has been increasing annually since the 1980s.
Recently, the immunotherapeutic approaches have demonstrated clinical efficacy in several 
cancer types, and some immune checkpoint inhibitors have been approved for the treatment 
of renal cell carcinoma (RCC). One of them is avelumab, which is an anti-programmed death 
ligand 1 (PD-L1) antibody. In December 2019, avelumab plus axitinib combination therapy 
was approved as a first-line treatment for the unresectable or metastatic renal cell carcinoma 
(mRCC) in Japan. This is the first-line therapy approved in Japan that combines an immuno-
oncology drug with a tyrosine kinase inhibitor (TKI) to treat the patients with RCC.
Several clinical studies have been focused on this therapy for the treatment of RCC, but no 
real-world data have been collected in Japan. Therefore, the patient’s background, treatment 
status, and outcomes of avelumab plus axitinib combination therapy must be clarified in the
real-world clinical settings in Japan.
The Phase 3 JAVELIN Renal 101 trial was conducted to compare avelumab plus axitinib
combination therapy with sunitinib monotherapy in previously untreated patients with 
advanced RCC. The results showed that the progression-free survival (PFS) was significantly 
longer in patients who were treated with avelumab plus axitinib (median: 13.8 months; 95% 
confidence interval [CI]: 11.1 to inestimable months) than in those treated with sunitinib 
(median: 7.2 months; 95% CI: 5.7–9.7 months; hazard ratio for disease progression or death:
0.61; 95% CI, 0.47–0.79; P <0.001) 2). Therefore, more than a 1-year of follow-up period is
required to assess the real-world effectiveness of this combination therapy, such as PFS. 
Three studies with long-term follow-up periods were planned. In the present study, 
B9991043 is to evaluate the current treatment outcomes after a 1-year launch in patients with 
mRCC treated with avelumab plus axitinib as a first-line therapy. In the future, two other 
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observational studies will be conducted with follow-up periods of two and five years as per 
the plan.
8. RESEARCH QUESTION AND OBJECTIVES
To describe the demographic, baseline characteristics and treatment outcomes in patients 
with mRCC treated with avelumab plus axitinib as a first-line therapy.
8.1. Primary objective
To describe the demographic and baseline characteristics of patients with mRCC treated with
avelumab plus axitinib as a first-line therapy in a real-world clinical setting.
8.2. Secondary objectives
1) To evaluate the efficacy of avelumab plus axitinib combination therapy for patients 
with mRCC treated in Japan.
2) To describe clinical usage of corticosteroid for immune-related adverse events (irAE) 
during avelumab plus axitinib combination therapy period.
3) To describe pre-treatment and treatment for infusion-related reaction of avelumab.
4) To describe patterns of post progression subsequent treatments. 
9. RESEARCH METHODS 
9.1. Study design
This study is a multicenter, non-interventional, retrospective, medical chart review of patients 
with mRCC treated with avelumab plus axitinib as a first-line therapy in Japan between 20 
December 2019 and 20 December 2020. All decisions regarding clinical management and 
treatment of the participating patients were made by the investigator as part of standard care 
in real-world clinical setting and were not contingent upon the patient’s participation in the 
study. Data will be collected if available per study site.
!
Index date: The date of first prescription for avelumab plus axitinib between 20 
December  2019 (launch date) and 20 December 2020
!
Observation period: Patients will be followed from index date to 20 June 2021
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9.1.1. Primary endpoint
・Patient characteristics at baseline
–
Age
–
Sex
–
Body mass index (BMI)
–
Eastern Cooperative Oncology Group Performance Status (ECOG PS)
–
International Metastatic RCC Database Consortium (IMDC) risk score
–
Pathological diagnosis: Fuhrman grade, histological type, Sarcomatoid compornent
–
Tumor-node-metastasis (TNM) classification,
–
Number of metastatic organs and site of metastases
–
Complications
–
Nephrectomy
–
Renal function: estimated glomerular filtration rate (eGFR), proteinuria
–
C-reactive protein (CRP)
–
Smoking history
–
Concomitant drugs
9.1.2. Secondary endpoints
・Efficacy endpoint
–
Time to treatment failure (TTF) of avelumab plus axitinib as a first-line therapy
–
Real-world PFS
–
Objective response (OR)
・Avelumab-related endpoints
–
TTF
–
Discontinuation and interruption of avelumab
–
Reason for discontinuation and interruption
・Axitinib-related endpoints
–
TTF
–
Dose increase, dose reduction, discontinuation, and interruption of axitinib
–
Reason for dose increase, dose reduction, discontinuation, and interruption
・Corticosteroid-related endpoints 
–
Cumulative dose of corticosteroid for irAE during avelumab plus axitinib treatment
–
Duration of corticosteroid treatment for irAE during avelumab plus axitinib 
treatment
–
Number of corticosteroid administrations for irAE during avelumab plus axitinib 
treatment
・Infusion-related reaction-related endpoints
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–
Presence of pre-medication for potential infusion-related reaction of avelumab
–
Drugs of pre-medication for infusion-related reaction of avelumab
–
Presence of treatment for infusion-related reaction of avelumab
・Subsequent treatment-related endpoints
–
Drugs used after avelumab plus axitinib
9.1.3. Definition of endpoints
9.1.3.1. Time to treatment failure (TTF)
TTF is defined as the following:
!
TTF, defined as time from start of avelumab/axitinib treatment to end of treatment for
any cause earlier, including death.
9.1.3.2. Real-world PFS
Real-world PFS is defined as the following:
!
Real-world PFS, defined as time from start of avelumab/axitinib treatment to date of first 
disease progression (as clinically assessed by local investigator based on radiology, 
laboratory evidence, pathology, or other assessments) or death due to any cause, which 
ever came first
If there were no clinical records of death or disease progression, they were censored at 
the date of initiation of the next line of therapy for the patients undertaking two or more 
lines of therapy based on the record, or at their last visit date during the study period for 
the patients undertaking only one line of therapy based on the record.
9.1.3.3. Objective response (OR)
OR is defined as the following:
!
Complete or partial response as the best adjudication result (complete response [CR] > 
partial response [PR] > stable disease [SD] > progressive disease [PD], unknown) in a 
method complies with RECIST version. 1.1 tumor assessment as closely as possible in 
clinical practice by investigator’s judgment.
9.2. Setting
This study is a post-approval, company-sponsored, observational study.
9.2.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
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1）Diagnosed with mRCC based on the General Rule for Clinical and Pathological 
Studies on Renal Cell Carcinoma (4th Edition) before receiving avelumab plus 
axitinib as a first-line therapy;
2）Over 20 years of age at the time of mRCC diagnosis; 
3）Start treatment with avelumab plus axitinib as a first-line therapy for mRCC from 20 
December 2019 to 20 December 2020;
4）For patients who are still alive and have routine visits to the study site, evidence of a 
personally signed and dated informed consent document indicating that the patient 
has been informed of all pertinent aspects of the study.  For patients who are still 
alive and had been transferred to another hospital, evidence that the patient has been 
informed of all pertinent aspects of the study and oral or written informed consent is 
obtained.
5）Deceased patients are also included for inclusion criteria 1-3.
9.2.2. Exclusion criteria
There are no exclusion criteria for this study.
9.3. Variables
The following information will be collected in this study. Human genome and gene 
information will not be collected.
9.3.1. Patient characteristics at baseline
–
The following data regarding the patients characteristics will be collected at 
baseline: age, sex, BMI, ECOG PS, IMDC risk score, pathological diagnosis: 
Fuhrman grade, histological type, Srcomatoid compornent, Number of metastatic 
organs and site of metastases, TNM classification,complications, nephrectomy, renal
function: eGFR, proteinuria, CRP level, smoking history, and concomitant use of 
drugs. Patient characteristics to be collected at baseline include the most recent data 
prior to initial treatment with avelumab plus axitinib.
9.3.2. IMDC risk -related data at baseline
The following IMDC risk-related data will be collected:
1）<1 year from time of diagnosis to systemic therapy;
2）Karnofsky Performance Status <80%;
3）Hemoglobin < lower limit of normal;
4）Corrected calcium > upper limit of normal;
5）Neutrophils > upper limit of normal;
6）Platelets > upper limit of normal.
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9.3.3. Clinical outcome (Real-world PFS)
Definitions of Real-world PFS is defined in Section 9.1.3. The following data will be 
collected to determine the clinical outcomes: date of start of treatment, date of first disease 
progression or death due to any cause, whichever came first.
9.3.4. Clinical outcome (OR)
Definitions of OR is defined in Section 9.1.3. The following data will be collected to 
determine the clinical outcomes: tumor assessment (CR, PR, SD, PD, and unknown)
9.3.5. Avelumab treatment (TTF)
Definitions of TTF is defined in Section 9.1.3. The following avelumab treatment data will 
be collected: date of administration, actual and standard dosage, and reason for 
discontinuation and interruption.
9.3.6. Axitinib treatment (TTF)
Definitions of TTF is defined in Section 9.1.3. The following axitinib treatment will be 
collected: date of administration, reason for dose increase, dose reduction, actual and 
standard dosage, and reason for discontinuation and interruption.
9.3.7. Corticosteroid treatment
The following corticosteroid treatment data for irAE will be collected: date of treatment, 
drugs of corticosteroid, dose of corticosteroid, cumulative dose of corticosteroid, duration of 
treatment, and number of administrations during the treatment with avelumab plus axitinib.
9.3.8. Pre-medication and treatment for infusion-related reaction of avelumab
The following pre-medication and treatment data will be collected: Presence of pre-
medication, therapeutic drugs for infusion-related reaction of avelumab and presence of 
treatment for infusion-related reaction of avelumab.
9.3.9. Second-line regimen after avelumab plus axitinib treatment
The following second-line regimen data will be collected: medication after avelumab plus 
axitinib treatment.
9.4. Data sources 
As this is a retrospective study, all data will be collected from medical records at the 
participating study site. 
9.5. Study size
This study is descriptive study which aims to describe the demographic and baseline
characteristics of patients who were treated avelumab plus axitinib in first-line treatment for 
mRCC, rather than testing any pre-defined hypothesis. Since all the analyses will be 
descriptive, sample size calculations are not applicable.
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The expected number of patients will be approximately 70 patients in total, but the number 
should be considered flexible.
9.6. Data management 
Investigators will fill out electronic case report forms (eCRFs) based on the medical charts by 
electronic data capture (EDC). After the completion, eCRFs are transferred to a single 
electronic database. Only the de-identified and anonymized data are included.
When receiving a query from the sponsor on the completed eCRF (ie, Data Clarification
Form [DCF]), investigators will reconfirm the information on source documents, fill out the 
DCF as required, and submit the DCF.
9.6.1. Electronic Case report forms (eCRFs)/Data collection tools (DCTs)/Electronic 
data record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
An eCRF is required and should be completed for each included patient.  The completed 
original eCRFs are the sole property of Pfizer and should not be made available in any form 
to third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
eCRFs are securely stored at the study site in encrypted electronic form and will be password 
protected to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
eCRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the eCRFs are true.  Any corrections to entries made in the eCRFs or 
source documents must be dated, initialed, and explained (if necessary) and should not 
obscure the original entry.
The source documents are the hospital or the physician's chart.  In these cases, data collected 
on the eCRFs must match those charts. 
9.6.2. Record retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, eCRFs and hospital records), all original signed 
informed consent documents, copies of all eCRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to local regulations or as specified in the clinical 
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study agreement (CSA), whichever is longer.  The investigator must ensure that the records 
continue to be stored securely for so long as they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless Pfizer have expressly agreed to a different period of retention via a separate 
written agreement.  Record must be retained for longer than 15 years if required by 
applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
9.6.3. Record disposal
Study records must be disposed of appropriately according to each site regulation.
9.7. Data analysis
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.
9.7.1. Analysis Population
Will be provided in the SAP.
9.7.2. Analysis Methods
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile.
Qualitative variables will be summarized by frequency counts and percentages. 
For the time-to-event endpoints, eg, TTF and Real-world PFS, the Kaplan-Meier estimates 
(product-limit estimates) will be presented together with a summary of associated statistics 
including the median Real-world PFS time with 2-sided 95% CIs. In particular, the Real-
world PFS rate at several timepoints will be estimated with corresponding 2-sided 95% CIs. 
These endpoint will also be displayed graphically.
9.7.3. Analysis of Primary Endpoints
See Section 9.1.3. These endpoints will also be displayed graphically if necessary.
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9.7.4. Analysis of Secondary Endpoints
Efficacy Endpoints 
See Section 9.1.3. These endpoints will also be displayed graphically if necessary.
Other Secondary Endpoints
See Section 9.1.3. These endpoints will also be displayed graphically if necessary.
The SAP must be fixed before data lock. The final analysis will be performed after data lock
and may modify the plans outlined in the protocol.
9.8. Quality control
The sponsor will train investigators and study site staff with an onsite training visit or web-
training on the protocol, eCRFs, and any applicable study processes. Any new information 
relevant to the performance of this study will be forwarded to the investigator and study site 
staff during the study. Remote data monitoring will be conducted during the life of the study 
to ensure timely reporting of data, data integrity, and consistency. eCRFs for all included 
patients will be made available to the remote data monitor for review. The study sites will be 
queried and managed to request resolution to any issues that may arise during the course of 
the study.
9.9. Limitations of the research methods
•
This study is retrospective in nature so only existing data reported in patient records will 
be available. Variables that are often missing may affect estimation accuracy.
•
High-volume centers will be preferentially selected in this study, so site selection and 
outcome reporting bias may be included. For this reason, the study results may not 
reflect all Japanese clinical outcomes.
•
Evaluation of disease response may differ at each site, and measurement errors may be 
included in the estimated value.
9.10. Other aspects
9.10.1. Report to the chief executive of the study site
Each study site’s investigator shall report the following to the chief executive of the study 
site in writing:
1）Measurements to be revised in the protocol;
2）Progression of the study;
3）Termination, discontinuation, and interruption of the study.
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10. PROTECTION OF HUMAN SUBJECTS
10.1. Patient information
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code.
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal 
data, consistent with the clinical study agreement and applicable privacy laws.
10.2. Patient consent
10.2.1. For subjects who are alive and still visit the study site
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. The investigator, or a 
person designated by the investigator, will obtain written informed consent from each subject 
before any data is collected. The investigator will retain the original of each subject's signed 
consent form.
The informed consent form must be in compliance with local regulatory requirements and 
legal requirements. The informed consent form used in this study, and any changes made 
during the course of the study, must be prospectively approved by both the IRB/ IEC and 
Pfizer before use. Information to be provided to subjects:
1）Title of the study and the fact that approval of the chief executive of the study site 
has been given concerning its implementation. 
2）Names of the study site and the principal investigator [including names of the 
collaborative study site(s) and principal investigators of such collaborative study 
site(s), when the study is conducted collaboratively with other study site(s)];
3）Objectives and significance of the study;
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4）Method and time period of the study (including purpose of utilization of specimens 
or information acquired from the subject);
5）Reasons why asked to be enrolled in the study;
6）Burdens to be caused on the subjects and predictable risks and benefits;
7）The fact that subjects may withdraw their consent at any time even after they have 
given consent with regard to the study being commenced or continued (when it can 
be difficult to take measures that follow the withdrawal made by the study subject , a 
statement to that effect and the reason for the difficulty). 
8）The fact that the refusal or withdrawal of consent by a study subject with regard to 
the study is to be commenced or continued does not cause any disadvantage to such 
subject . 
9）Means to make information on the study public;
10）The fact that subjects can request and obtain or read the study protocol and 
documents concerning method of the study, to the extent it does not interfere the 
protection of personal information, of other subjects,  or the originality of the study, 
as well as the procedure to obtain or read such protocols and documents;
11）Handling of personal information (including process of anonymization, when 
anonymization is conducted);
12）Means for storage and disposal of specimens and information;
13）Status of study-related conflicts of interest of the study site, such as study fund 
resources as well as study-related conflicts of interest of each investigator, such as 
his/her individual income. 
14）Handling of results and other information obtained from the study.
15）Response to consultation made by subjects,  and other individuals concerned. 
16）When the study involves any financial expenditure on or remuneration for the 
subject, a statement to that effect and details of such;
17）When the study involves any invasiveness, whether compensation will be offered 
for study-related injury and details of such compensation. 
18）With respect to specimens and information acquired from the subject, when any of 
those may be utilized or provided to other study site(s) for future study that is not 
identified at the time of obtaining consent from the study subject, a statement to that 
effect and the contents of utilization assumed at the time of obtaining consent
19）When the study involves any invasiveness (not including minor invasiveness) and 
intervention, the fact that the monitor(s), the auditor(s), and IRB or IEC will be 
granted direct access to the specimens and information acquired from the subjects 
to the extent necessary, without violating the confidentiality of the subjects.
10.2.2. Subjects who are alive and had been transferred to another medical facility
In accordance with Chapter 4 “Informed Consent” of the “Ethical Guidelines for Life 
Science and Medical Research Involving Human Subjects”, it is not always necessary to 
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obtain written informed consent when existing information are to be provided to other 
medical facility, but the individual providing existing information shall obtain oral informed 
consent. 
In this study, it is not required to obtain written informed consent from the subjects who had 
been transferred to another medical facility. In case the subject’s data will be collected from 
another medical facility for this study, investigator must ask primary doctor who currently 
cares the patient at another hospital to obtain oral informed consent for the data collection. In 
addition, the conduct of this study will be disclosed, and the patients will be guaranteed an 
opportunity to refuse data collection for the patients.
10.2.3. Subjects who are deceased
In accordance with Chapter 4 “Informed Consent” of the “Ethical Guidelines for Life 
Science and Medical Research Involving Human Subjects”, the conduct of this study will be 
disclosed, and the subjects’ legally acceptable representatives will be guaranteed an 
opportunity to refuse data collection for the subjects.
The following data must be made public:
1）Purpose for which the data will be used;
2）Item of previously collected data;
3）Person responsible for data management;
4）Organization that will be providing data;
5）How to manage refusal—if the subject refuses participation in the study, their data 
cannot be used.   
10.2.4. Handling of study results, etc.
The principal investigator shall explain the following policy for the explanations of the study 
results, etc. to patients and obtain their consent.
(Policy for the explanations of study results, etc. )
With regard to the study results, etc., important findings, etc. concerning the health of 
patients including incidental findings (hereinafter referred to as "important findings, etc. 
concerning the health of patients"), will not be disclosed to patients individually, except for 
cases where not disclosing them would result in disadvantages to patients. Instead, the results 
will be published in the manner described in "10.8 Registration and publication of study".
10.2.4.1. Response to important findings and other information concerning the health of 
subjects
With regard to the explanation of important findings and other information on the health of 
subjects obtained throughout this study, the principal investigator shall confirm at the time of 
obtaining consent whether disclosure is required in advance. If disclosure is required, an 
explanation shall be provided. In doing so, the following items shall be considered:
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1)
Whether the results are sufficiently accurate and reliable as information to assess the 
health, etc., of subjects;
2)
Whether the results are important facts for the health, etc., of subjects;
3)
Whether the explanation of the results may significantly impede the proper conduct of 
the study.
If the subject does not wish to receive an explanation of the results obtained from this study, 
his or her wishes will be respected. However, even if the subject does not wish to receive an 
explanation of the results obtained from the study, and if it is known that the results will have 
a serious impact on the life of the subject, blood relatives, etc., and if there is an effective 
way to deal with the situation, the principal investigator shall seek opinions from the 
IRB/IEC regarding whether to give an explanation, and the details and method of the 
explanation after considering the following:
1)
Effect on the lives of study subjects and their blood relatives, etc.;  
2)
The availability of effective treatment and the health of study subjects;
3)
The possibility that blood relatives may be affected by the same disease;
4)
Description of the explanation of the results of the study at the time of informed consent.
Based on the opinions of the IRB or IEC, the principal investigator shall provide sufficient 
explanation to the subject, etc., and confirm the intention of the subject; if the subject still 
does not wish to receive the explanation, no explanation shall be provided.
If the subject does not give consent, the principal investigator will not, in principle, explain 
the results obtained from the study pertaining to the subject to anyone other than the subject. 
However, if a legally acceptable representative, blood relative, etc., of the subject wishes to 
receive an explanation of the results obtained from the study, etc., the principal investigator 
shall provide such explanation as necessary, after obtaining the opinions of the IRB/IEC as to 
whether such explanation is permissible, based on the reason for the request and the necessity 
of the explanation.
10.3. Patient withdrawal
10.3.1. Subjects who are alive and still visit the study site, or subjects who are alive and 
had been transferred to another medical facility
During the course of this study, the subject can withdraw his/her consent at any time. In any 
circumstance, every effort should be made to document patient outcomes, if possible. If the 
patient withdraws from the study and withdraws consent for disclosure of future information, 
no further evaluations should be performed and no additional data should be collected. The 
sponsor may retain and continue to use any data collected before withdrawal of consent.
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10.3.2. Subjects who are deceased
When the subjects’ legally acceptable representatives refuse to participate in the study during 
the study period, all of their data must be excluded from the analysis dataset. If the results of 
this study are disclosed on paper or conference at the time of refusal, the subject’s data 
cannot be excluded.
10.4. Institutional review board (IRB)/Independent ethics committee (IEC)
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents (e.g., informed consent forms if applicable) from the relevant IRBs/IECs. 
The IRB/IEC to which the review is requested shall be selected in accordance with the policy 
established by each medical institution, and the details of the review requesters shall be 
described in Annex 1. All correspondence with the IRB/IEC must be retained. Copies of 
IRB/IEC approvals must be forwarded to Pfizer. Pfizer Inc. and the principal investigator 
will respond appropriately to the information on the status of the review.
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; the study will follow generally accepted research 
practices described in the “Ethical Guidelines for Life Science and Medical Research 
Involving Human Subjects” issued by the Ministry of Health, Labour and Welfare.
10.6. Predictable risks and benefits
10.6.1. Risk
The subjects’ data will be collected retrospectively in this study, so there is no added risk to 
any individual subject.
10.6.2. Benefits
For individual subjects, there is no particular benefit because the study has a retrospective 
study design.
10.7. Conflicts of interest
This study will be performed with funding from Pfizer Inc. The investigators will review any
conflicts of interests that may affect the planning of this study or the interpretation of results 
by the IRB/IEC or the Conflicts of Interest Committee, according to the regulations of the 
study site. When the results of the study are published, accurate information will be disclosed 
by self-reporting in compliance with the guidelines of the academic society or journal used 
for publishing the results of the study.
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10.8. Registration and publication of study
Prior to implementation, this study and a summary were registered in the public database of 
ClinicalTrials.gov. Registered content will be properly updated without delay.
10.9. Secondary use of specimens and information obtained from subjects
The data obtained from this study may be used in other studies with different purposes, such 
as another study linked to this study or an integrated analysis (meta-analysis, etc.) with other 
research data. Such use will only be possible if another protocol is developed and approved 
by the IRB/IEC, and in such a case, information on the newly specified purpose of use, etc., 
shall be notified or disclosed to the subjects and the opportunity for refusal from the subjects, 
etc., shall be guaranteed, in principle, regarding the implementation of another study. In 
addition, the provision of information collected in this study from organizations or 
individuals outside of the responsible parties of this study shall be limited to cases in which 
Pfizer Inc. agrees. The ownership of rights, etc., arising from secondary use or provision to 
external parties shall be determined through consultation with Pfizer Inc. and the parties to 
which secondary use or provision is made.
Furthermore, the possibility of future secondary use or external provision of the collected 
information will be explained to the subjects at the time of their participation in this study, 
and their informed consent will be obtained.
10.10. Responding to consultations from subjects and other related parties
The principal investigator will set up a helpline for handling consultations about this study 
from subjects and other related parties. Information about each site helpline is included in the 
informed consent form and document related to opt-out.
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS (AEs)/ADVERSE 
REACTIONS
This study protocol requires human review of patient-level unstructured data; unstructured 
data refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol). Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE.
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows:
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• All serious and non-serious AEs with explicit attribution to any Pfizer drug that appear in 
the reviewed information must be recorded on the CapTool mini® and reported, within 24 
hours of awareness, to Pfizer Safety using the NIS AEM Report Form.
• Scenarios involving drug exposure, including exposure during pregnancy, exposure during 
breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy, and 
occupational exposure associated with the use of a Pfizer product must be reported, within 24 
hours of awareness, to Pfizer Safety using the NIS AEM Report Form.
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs. No follow-up on related AEs will be conducted.
All the demographic fields on the NIS AEM Report Form may not necessarily be completed, 
as the form designates, since not all elements will be available due to privacy concerns with 
the use of secondary data sources. While not all demographic fields will be completed, at the 
very least, at least one patient identifier (eg, gender, age as captured in the narrative field of 
the form) will be reported on the NIS AEM Report Form, thus allowing the report to be 
considered a valid one in accordance with pharmacovigilance legislation. All identifiers will 
be limited to generalities, such as the statement “A 35-year-old female...” or “An elderly 
male...” Other identifiers will have been removed.
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” may be documented in month/year (mmm/yyyy) format rather than identifying the 
actual date of occurrence within the month /year of occurrence in the day/month/year 
(DD/MMM/YYYY ) format.
All research staff members must complete the following Pfizer training requirements:
!
“Your reporting responsibilities (YRR) Training for Vendors Working on Pfizer Studies 
(excluding interventional clinical studies and non-interventional primary data collection 
studies with sites/investigators)”.
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by 
the trainee) as a record of completion of the training, which must be kept in a retrievable 
format. Copies of all signed training certificates must be provided to Pfizer.
Re-training must be completed on an annual basis using the most current Your Reporting 
Responsibilities training materials.
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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
The results of this study are not part of any regulatory submission. The results of this study 
will be submitted for abstracts and publications. The final output will be filed in Pfizer’s 
Global Document Management System upon final study completion. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.  
13. REFERENCES
1) National Cancer Center Cancer Information Service. Latest cancer statistics. Available 
at: https://ganjoho.jp/reg_stat/statistics/stat/summary.html, (reference data 2020-10-
01)
2) Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for 
Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-15. 
14. LIST OF TABLES 
None
15. LIST OF FIGURES
None
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
The responsible parties of the study
ANNEX 2. ADDITIONAL INFORMATION
Not applicable
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