A Panel-Based Chart Review Study to Examine the Effects of Axitinib Dose Reduction and Interruption for Adverse Event Management Among Patients Receiving First-Line Axitinib in Combination With Immune-Oncology Drugs for the Treatment of Advanced Renal Cell Carcinoma
Conditions: Renal Cell Carcinoma
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Title
A Panel-Based Chart Review Study to Examine the 
Effects of Axitinib Dose Reduction and Interruption 
for Adverse Event Management among Patients 
Receiving First-Line Axitinib in Combination with 
Immune-Oncology Drugs for the Treatment of 
Advanced Renal Cell Carcinoma
Protocol number
A4061097
Protocol version identifier
Version 1.0
Date of last version of protocol
19 October 2020
Active substance
Not applicable 
Medicinal product
Axitinib (INLYTA®) 
Research question and objectives
To assess how dose reductions or treatment 
interruptions related to axitinib can be implemented 
to manage and resolve adverse events occurring 
among patients with advanced renal cell carcinoma 
treated with first-line axitinib in combination with 
avelumab or pembrolizumab
Country(-ies) of study
United States
Author
, PharmD, MSc
 
235 E 42nd Street
New York, NY 10017
 
, MSc, MBA
Pfizer, Inc.
Pfizer Hellas 243 Messoghion Ave. 15451 N. 
Psychico, Athens, Greece
PPD
PPD
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, ScD, MPH
 
PPD
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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................6
4. AMENDMENTS AND UPDATES.......................................................................................6
5. MILESTONES.......................................................................................................................6
6. RATIONALE AND BACKGROUND..................................................................................6
7. RESEARCH QUESTION AND OBJECTIVES ...................................................................7
8. RESEARCH METHODS ......................................................................................................9
8.1. Study Design .............................................................................................................9
8.2. Setting........................................................................................................................9
8.2.1. Inclusion Criteria ..........................................................................................9
8.2.2. Exclusion Criteria.......................................................................................10
8.3. Variables..................................................................................................................10
8.3.1. Physician Characteristics............................................................................10
8.3.2. Baseline Patient Characteristics..................................................................10
8.3.3. Characterization of AEs..............................................................................13
8.3.4. Management Strategies for AEs .................................................................13
8.4. Data Sources............................................................................................................14
8.4.1. Pilot Test.....................................................................................................15
8.5. Study Size................................................................................................................15
8.6. Data Management ...................................................................................................15
8.7. Data Analysis ..........................................................................................................16
8.7.1. Analysis of Physician and Patient Characteristics......................................16
8.7.2. Analysis of AEs ..........................................................................................16
8.7.3. Description of Management Strategies for AEs.........................................16
8.7.4. Analysis of Resolution of AEs ...................................................................16
8.8. Quality Control........................................................................................................16
8.9. Limitations of the Research Methods......................................................................17
8.10. Other Aspects ........................................................................................................18
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................18
9.1. Patient Information and Consent.............................................................................19

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9.2. Patient Withdrawal..................................................................................................19
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............19
9.4. Ethical Conduct of the Study ..................................................................................19
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................19
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........20
12. REFERENCES ..................................................................................................................21
13. LIST OF FIGURES ...........................................................................................................24
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................24
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .........................................24
ANNEX 3. ADDITIONAL INFORMATION.........................................................................24

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse event
AEM
Adverse event monitoring
AG
Analysis Group, Inc.
AIDS
Acquired immune deficiency syndrome
AJCC
American Joint Committee on Cancer
CHF
Congestive heart failure
COPD
Chronic obstructive pulmonary disease
CTCAE
Common Terminology Criteria for Adverse Events
CVD
Cerebrovascular disease
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
FDA
Food and Drug Administration 
GPP
Guidelines for Good Pharmacoepidemiology Practices
IRB
Institutional Review Board
IEC
Independent Ethics Committee
IMDC
International Metastatic Renal Cell Carcinoma 
Database Consortium 
IO
Immuno-oncology 
IQR
Interquartile range
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and 
Outcomes Research
MSKCC
Memorial Sloan Kettering Cancer Center 
NCI
National Cancer Institute
NIS
Non-interventional study
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1 
RCC
Renal cell carcinoma
SD
Standard deviation
STROBE
Strengthening the Reporting of Observational Studies 
in Epidemiology
US
United States
VEGF
Vascular endothelial growth factor

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, Degree(s)
Title
Affiliation
Address
, 
PharmD, MSc
Pfizer, Inc.
235 E. 42nd St.
New York, NY 10017
 
, MSc, 
MBA
 
Pfizer, Inc.
Pfizer Hellas 243 
Messoghion Ave. 
15451 N. Psychico, 
Athens, Greece
, 
MPH, ScD
Dr 
, 
MD
 
4. AMENDMENTS AND UPDATES
NONE.
5. MILESTONES
Milestone
Planned Date
Start of data collection 
30 November 2020
End of data collection
31 January 2021
Final study report
31 July 2021
6. RATIONALE AND BACKGROUND
An estimated 400,000 new cases of kidney cancer, of which renal cell carcinoma (RCC) 
accounts for approximately 90%, are diagnosed worldwide every year.1-3 RCC comprises 
2-3% of all adult malignancies with an estimated 63,000 incident cases and 14,000 deaths 
from RCC annually in the United States (US).4 The exact cause of RCC is not well 
understood, but inherited and acquired mutations in oncogenes, such as von Hippel-Lindau, 
fumarate hydratase, and folliculin genes, may cause kidney cells to become cancerous. 
Obesity, hypertension, smoking, occupational exposure to toxic compounds such as cadmium 
and asbestos, and male gender are potential risk factors for triggering the genetic 
mutations,1,2 but many gene changes are random idiopathic events. Due to the lack of early 
symptoms and clinical indications of disease, up to 30% of patients with RCC are diagnosed 
with advanced or metastatic disease.5 Prognosis is poor among advanced RCC patients, with 
5-year survival rates of approximately 8%.6 The burden of advanced RCC is projected to 
grow with the aging population and increasing prevalence of risk factors for RCC, such as 
obesity and hypertension.2,3
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During the last decade, targeted therapies, which are agents that target the vascular 
endothelial growth factor (VEGF), the VEGF receptor, or the mammalian target of 
rapamycin, became standard of care for patients with advanced RCC.7 Since 2005, several 
targeted therapies have been approved for the treatment of advanced RCC in the US, 
including axitinib (Inlyta®), sunitinib (Sutent®), bevacizumab (Avastin®), sorafenib 
(Nexavar®), pazopanib (Votrient®), cabozantinib (Cabometyx®, Cometriq®), everolimus 
(Afinitor®), and temsirolimus (Torisel®).7,8 Targeted therapies have been associated with 
improved progression-free survival and overall survival, favorable side effect profiles, and 
improved health-related quality of life.9-15
Yet, recent advancements in immuno-oncology (IO) therapeutic agents have changed the 
treatment paradigm for advanced RCC. IO therapies work by blocking immune checkpoints 
(eg, programmed death-1 [PD-1]/PD-ligand 1 [PD-L1]) and restoring tumor-specific 
T-cell-mediated immune responses,16,17 and have demonstrated antitumor activity and 
durable responses in patients with advanced RCC.18,19 Specifically, the KEYNOTE-426 trial 
demonstrated that treatment-naïve advanced RCC patients who were treated with axitinib in 
combination with pembrolizumab had significantly longer overall survival, progression-free 
survival, and objective response rate compared to sunitinib,20 leading to US Food and Drug 
Administration (FDA) approval of axitinib in combination with pembrolizumab for first-line 
advanced RCC treatment in April 2019. In addition, the JAVELIN Renal 101 trial showed 
significantly longer progression-free survival among advanced RCC patients who received 
avelumab plus axitinib than with sunitinib in first-line,21 leading to FDA approval of axitinib 
in combination with avelumab for first-line advanced RCC treatment in May 2019.
While axitinib has generally demonstrated a favorable tolerability profile in real-world 
studies,22,23 there is currently limited information on the real-world adverse event (AE) 
profile of axitinib in combination with IO therapies. In addition, the effect of dose reductions 
and treatment interruptions used to manage and resolve AEs occurring among patients with 
advanced RCC who use axitinib in combination with IOs is not well understood. Given this 
gap in the literature, AG will conduct a physician panel-based chart review to describe how 
dose reductions or treatment interruptions related to axitinib (in combination with IO therapy 
including avelumab or pembrolizumab) can be implemented to potentially manage and 
resolve AEs occurring among patients with advanced RCC. In this way, the study could help 
demonstrate that AEs associated with axitinib may be mitigated without excess use of 
healthcare resource use or additional treatment burden to patients beyond modifications 
related to axitinib.
7. RESEARCH QUESTION AND OBJECTIVES 
The specific objectives of the study are as follows:
1. Describe incident AEs experienced among patients with advanced RCC who received 
first-line axitinib in combination with IO therapies.

Type and seriousness of AEs (ie, diarrhea, fatigue, hypertension, nausea, 
palmar-plantar erythrodysesthesia [hand-foot syndrome]).

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
Proportion of patients who experienced repeated AEs.

Time from treatment initiation to AE onset, overall and by type and seriousness of 
AEs. 
2. Among patients with advanced RCC who developed incident AEs while receiving 
first-line axitinib in combination with IO therapies, characterize and describe 
management strategies for AEs, stratified by type and seriousness of AEs. 

Proportion of patients who used each of the following management strategies:

No action for axitinib and IO therapy;

No action for axitinib, but treatment modification for IO therapy (ie, treatment 
interruption, treatment discontinuation);

Axitinib dose reduction, but no action for IO therapy;

Axitinib treatment interruption, but no action for IO therapy;

Axitinib treatment discontinuation, but no action for IO therapy;

Axitinib dose reduction, and treatment modification for IO therapy;

Axitinib treatment interruption, and treatment modification for IO therapy;

Axitinib treatment discontinuation, and treatment modification for IO therapy.

Average axitinib dose reduction (absolute and percentage change), where 
applicable.

Duration of treatment interruption, where applicable.
3. Assess the frequency of and time to AE resolution (from AE onset and initiation of 
management strategy, separately) among patients with advanced RCC who developed 
incident AEs while receiving first-line axitinib in combination with IO therapies
according to different management strategies implemented, stratified further by type 
and seriousness of AEs, as allowed by sample size. 
The above objectives will also be conducted for repeated AEs of the same type.

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8. RESEARCH METHODS
8.1. Study Design
A retrospective physician panel-based chart review study in the US will be conducted. The 
index date will be defined as the initiation of first-line axitinib (used in combination with 
IO therapy) on or after May 2019, which marks FDA approval of axitinib in combination 
with avelumab for first-line advanced RCC treatment. The baseline period will be defined as 
the 12-month period prior to the index date. The observation period will be defined as the 
time from index date to the earliest of initiation of a second line therapy, death, loss to 
follow-up, or date of chart abstraction. During the observation period, onset, management, 
and resolution of AEs will be assessed. The study design scheme is depicted in Figure 1.
Figure 1.
Study Design Scheme
8.2. Setting
8.2.1. Inclusion Criteria
Physicians meeting the following criteria will be invited to participate in the chart review 
study:

Specialty in oncology.

Access to complete medical records for at least one patient with advanced RCC who 
meets the patient eligibility criteria.
Eligible oncologists will be asked to select up to three patients meeting the following criteria 
for inclusion in the chart review study:

Confirmed diagnosis with advanced RCC.

Treated with first-line axitinib/IO combination therapy at or after diagnosis.

Experienced at least one AE (ie, diarrhea, fatigue, nausea, hypertension, and 
palmar-plantar erythrodysesthesia [hand-foot syndrome]) while treated with 
axitinib/IO combination therapy.
Earliest of initiation of 
second line therapy, death, 
loss to follow-up, or date of 
chart abstraction
Index date
Initiation of first-line axitinib used in 
combination with IO therapy
(May 2019 or later)
Baseline period 
(12 months)
Observation period 

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
Age 18 years or older at the time of advanced RCC diagnosis.

Initiated axitinib/IO combination therapy at least 3 months prior to the start date of 
medical chart abstraction to ensure sufficient follow-up time. 
In the event that an oncologist has more than three eligible patients, the electronic case report 
form (eCRF) will have an underlying program that requires the oncologist to select patient 
charts based on a randomized sequence of letters. Specifically, the program will produce a 
random letter and request the oncologist to pull the first eligible patient chart with the last 
name that corresponds to the random letter. If there are no eligible patients whose last name 
begins with the first letter in the sequence, then the next letter in the order of the sequence 
will be shown. The random process will repeat for each new patient chart to be completed by 
the oncologist, until chart abstraction is completed for three eligible patients or until the 
physician has identified all eligible patients.
8.2.2. Exclusion Criteria
There are no exclusion criteria for this study.
8.3. Variables
The following variables will be collected in an eCRF.
8.3.1. Physician Characteristics
The following variables will be collected once for each physician participating in the study:

Geographic region (ie, Northeast, Midwest, South, West, Other).

Practice setting (ie, academic-based, community-based).

Practice size (ie, solo [1 physician], small [2-10 physicians], medium 
[11-50 physicians], large [≥51 physicians]).

Years in practice since completion of oncology training (ie, <1 year, 1-5 years, 
6-10 years, 11-20 years, >20 years).

Total number of unique advanced RCC patients seen per year.

Percentage of advanced RCC patients prescribed first-line axitinib in combination 
with IO therapies in the past year.
8.3.2. Baseline Patient Characteristics
The following variables, to the extent they are available, will be assessed during the baseline 
period or on the index date:

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Demographics

Month and year of birth (to calculate age at time points of interest).

Sex (ie, male, female).

Weight.

Height.

Race/ethnicity (ie, American Indian or Alaska Native, Asian, Black or African 
American, Hispanic or Latino, Native Hawaiian or other Pacific Islander, White, 
Other).

Insurance type (ie, employer, private/non-group, Medicaid, Medicare, military, 
uninsured, other).
Clinical characteristics

Date of advanced RCC diagnosis.

Date of first-line axitinib/IO combination therapy initiation.

IO agent used in combination with axitinib treatment.

Initial dose of axitinib.

Histological type (ie, non-clear cell, clear cell).

Sarcomatoid differentiation.

Nephrectomy status.

Number of metastatic sites and site locations.

TNM stage according to American Joint Committee on Cancer (AJCC) staging 
system.

Nodal status.

Fuhrman grade.

Largest tumor size.

Necrosis status of the primary tumor (ie, macroscopic, microscopic).

Microvascular invasion.

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
Comorbidities used to derive the NCI Comorbidity Index:

Acquired immunodeficiency syndrome (AIDS);

Acute myocardial infarction;

Cerebrovascular disease (CVD);

Chronic obstructive pulmonary disease (COPD);

Congestive heart failure (CHF);

Dementia;

Diabetes;

Diabetes with complications;

History of myocardial infarction;

Mild liver disease;

Moderate/severe liver disease;

Paralysis (hemiplegia or paraplegia);

Peptic ulcer disease;

Peripheral vascular disease;

Renal disease;

Rheumatologic disease.

Eastern Cooperative Oncology Group (ECOG) performance status.

Variables to calculate prognostic risk score (ie, Memorial Sloan Kettering Cancer 
Center [MSKCC] risk or International Metastatic Renal Cell Carcinoma Database 
Consortium [IMDC] risk).

Time from RCC diagnosis to initiation of first-line treatment;

Karnofsky performance status;

Serum hemoglobin level;

Correct calcium level;

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
Neutrophil count;

Platelet count.
8.3.3. Characterization of AEs
The following variables, to the extent they are available, will be assessed during the 
observation period:

Type of AE, as defined by Common Terminology Criteria for Adverse Events 
(CTCAE): 

Diarrhea, characterized by an increase in frequency and/or loose or watery bowel 
movements;

Fatigue, characterized by a state of generalized weakness with a pronounced 
inability to summon sufficient energy to accomplish daily activities;

Nausea, characterized by a queasy sensation and/or the urge to vomit;

Hypertension (new and worsening), characterized by a pathological increase in 
blood pressure;

Palmar-plantar erythrodysesthesia (hand-foot syndrome), characterized by 
redness, marked discomfort, swelling, and tingling in the palms of the hands or 
the soles of the feet.

Serious AE. 

As specified by the FDA, an AE is considered serious when the patient outcome 
is: death, life-threatening, hospitalization (either initial admission or prolongation 
of hospitalization), disability or permanent damage, or congenital anomaly/birth 
defect.

Date(s) of AE onset.

Date(s) of AE resolution.
8.3.4. Management Strategies for AEs
The following variables, to the extent they are available, will be assessed during the 
observation period:

Type of management strategy:

No action for axitinib and IO therapy;

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
No action for axitinib, but treatment modification for IO therapy (ie, treatment 
interruption, treatment discontinuation);

Axitinib dose reduction, but no action for IO therapy;

Axitinib treatment interruption, but no action for IO therapy;

Axitinib treatment discontinuation, but no action for IO therapy;

Axitinib dose reduction, and treatment modification for IO therapy;

Axitinib treatment interruption, and treatment modification for IO therapy;

Axitinib treatment discontinuation, and treatment modification for IO therapy.

Treatment modification for axitinib: 

Date(s) of dose reduction;

Modified dosage of axitinib;

Date(s) when treatment was halted and reinitiated;

Date(s) treatment was discontinued.

Treatment modification for IO therapy: 

Date(s) when treatment was halted and reinitiated;

Date(s) treatment was discontinued.
8.4. Data Sources
AG will contract with a physician panel vendor, Medefield America Limited LLC, to 
conduct an oncologist panel-based medical chart review in the US. Medefield has access to a 
large panel of physicians in a wide range of geographic locations. Oncologists will be 
recruited based on their medical specialty and selected for the study based on the eligible 
criteria. Each oncologist will complete eCRFs for up to three patients, with each chart review 
taking approximately 30 minutes to complete. The study will be double-blinded (physicians 
will be blinded to study sponsor and study sponsor will be blinded on physicians recruited to 
participate).
Oncologists will abstract data from medical charts of eligible patients using an online eCRF, 
which AG and the physician panel vendor will jointly develop specifically for this study. 
Medefield will set up a web-based portal with consistency checks, quality control, and 
validation processes built into the eCRF to ensure data quality. To capture all relevant 
information necessary for the study objectives, the eCRF may include both structured 

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(eg, multiple choice, select all options that apply) and unstructured fields (eg, open-ended 
responses).
8.4.1. Pilot Test
Prior to launch of data collection, a pilot test will be conducted with up to three oncologists, 
who will be abstracting data from patient charts. The purpose of the pilot test is to ensure that 
the questions in the eCRF are clear and interpreted correctly by the oncologists. Oncologists 
participating in the pilot test will have the ability to comment on the questions they do not 
fully understand and to provide suggestions on improving the questions. The pilot test will 
also help ensure that key data elements are contained in patient charts, such that key data 
elements of this study could be obtained in a reliable manner through the patient chart 
abstraction.
Upon completion of the pilot test, AG will clean and analyze the data in order to evaluate 
their adequacy and quality for addressing the study objectives. Further discussions with 
Pfizer will take place to discuss these findings and potential updates to the eCRF. Changes to 
the eligibility criteria as well as alternative analytical approaches that are more suitable for 
the available data may also be considered. Based on this assessment, the study protocol and 
the eCRF may be updated as needed. 
8.5. Study Size
Approximately 200 oncologists may be recruited by the physician panel vendor to abstract 
medical charts. AG anticipates to obtain data from the medical charts of 400-600 patients 
with advanced RCC. No formal sample size computation was performed as all statistical 
analyses are descriptive in nature and no hypotheses are being tested. 
8.6. Data Management 
This study will collect de-identified data. No patient identifiable information including names 
or medical record number will be collected in the eCRF. For variables that may contain 
potentially identifiable information such as number of years in practice, ranges or categories 
will be used rather than collecting specific values. Furthermore, physicians extracting the 
data will not retain a decoding key so that the data cannot be linked back to an individual. 
Lastly, the identity of physicians participating in this study will not be known to AG, 
Medefield, or Pfizer. 
De-identified data collected from the physicians by the physician panel vendor will be 
transferred to AG over a secured and encrypted network for analysis, and stored in secure 
servers accessible only by designated personnel working on the project within AG. The 
minimum retention time will meet the strictest standard applicable for the study, as dictated 
by the applicable guidelines or applicable laws or regulations.

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8.7. Data Analysis 
8.7.1. Analysis of Physician and Patient Characteristics
Baseline patient demographic and clinical characteristics will be summarized overall and by 
type of IO therapy given in combination with axitinib. In addition, physician characteristics 
will be described. Continuous variables will be summarized with mean (± standard deviation 
[SD]) and median (interquartile range [IQR]) values, while categorical variables will be 
summarized with frequency distributions. 
8.7.2. Analysis of AEs 
Type and seriousness of AEs will be tabulated and described using frequency and 
proportions, separately by type of therapy (ie, type of IO therapy given in combination with 
axitinib). In addition, the proportion of patients who experienced repeated AEs of the same 
type will be summarized overall and by type of AE. For each type and seriousness of AE, 
time from index date to onset of AEs will be summarized using means (± SD) and medians 
(IQR). Furthermore, the time between the first AE and the first repeated AE of the same type 
will be calculated.
8.7.3. Description of Management Strategies for AEs
Among patients with advanced RCC who developed AEs while receiving axitinib/IO 
combination therapy, descriptive analyses will be conducted to characterize management 
strategies used for AEs including repeated AEs of the same type, overall and by type and 
seriousness of the AEs. Frequencies and proportions will be used to describe the various 
management strategies related to axitinib and other therapies (eg, IO agents). The proportion 
of patients using multiple management strategies will also be described. Among patients 
whose AEs were managed with axitinib dose reduction, the average dose reduction will be 
described using the absolute and percentage change. Duration of treatment interruption will 
be summarized using means (± SD) and medians (IQR). 
8.7.4. Analysis of Resolution of AEs
The proportion of patients achieving resolution of AEs will be described, overall and by type 
and seriousness of the AEs. The time to resolution from AE onset and from initiation of 
management strategy will be calculated for all AEs experienced including repeated AEs. The 
time to resolution of AE (from the onset of AE and from the initiation of management 
strategies) will be separately estimated using Kaplan-Meier analysis; median time to event 
will be reported. Analyses will be conducted separately by type of management strategy. 
8.8. Quality Control
Data quality processes will occur at multiple times during the study. 
Data collection consistency checks: During the data collection phase, the eCRF will include 
automatic consistency checks such as date validation rules and checks to prevent entry of 
values outside of an expected range.

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Documentation and diagnostics applied to computer code development: The primary 
programmer at AG will be responsible for creating and documenting all project-specific 
code, including comments as to why changes are made over the course of the project. In 
addition to evaluating diagnostic output independently, the programmer will evaluate this 
output with the entire project team before results tables are generated.
Independent code review: A second programmer will be assigned to a project for the 
purpose of performing code review. The code review programmer will work with the primary 
programmer to confirm that code is written with correct syntax and generates results as 
specified in the analysis plan. Issues identified by the code reviewer will be documented and 
resolved.
Validation of study results: AG will validate the results tables to confirm that results are 
consistent across analysis tables and that the results make sense from a “real-world” 
perspective. Specifically, the AG team will closely review and audit all results tables for
accuracy. Moreover, AG will check to make sure that all results are aligned with expectations 
and findings from the literature.
Peer review of final deliverables: In addition to the AG study team reviewing all final 
reports before delivery, an internal, peer reviewer will also be assigned to evaluate final 
products. This peer reviewer will examine the final results and reports to ensure concordance 
among all final documents as well as to evaluate content for consistency.
8.9. Limitations of the Research Methods
Several limitations should be considered when interpreting findings from this study.

There is potential for measurement error in data collection, and the use of a 
standardized, pilot-tested eCRF with data validation checks will address this to some 
extent. Overall, the quality of data is limited by how well information was recorded in 
the patients’ medical charts. 

To protect physician and patient anonymity, the collected data cannot be audited 
against medical records and queries on the accuracy of data entries cannot be 
conducted. Erroneous data entries can be detected by checking inconsistent responses, 
but may result in the inability to use certain data points. 

There may be missing information if data have not been recorded in a systematic
manner by physicians over time; collecting information on physician characteristics 
can help understand if missingness is related to physician practice. In addition, AEs 
never reported to a physician (ie, if they were self-resolved without seeking care), or 
events not recorded or misclassified in the medical charts, will not be captured. As 
such, the proportion of management strategies for AEs would only apply to AEs that 
require healthcare intervention.

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
The study is subject to self-reporting bias, including social desirability bias. To 
minimize the potential for this bias, study materials will emphasize that participation 
in the survey is anonymous.

This study is subject to potential selection bias as physicians who elect to participate 
may differ from those who decline to participate. Demographic and practice 
characteristics will be presented to describe the sample of physicians enrolled in this 
study and may be compared to national reports describing similar physician 
characteristics (eg, Kantar healthcare reports) to provide insight into the 
generalizability of results.
Despite these limitations, retrospective chart review studies using a panel-based approach are 
less resource-intensive than prospective cohort studies, allowing for the creation of detailed 
datasets with information on patient characteristics tailored to specific research questions. 
Using a physician panel provides direct insight into patient medical history and clinical 
course, and allows the possibility of supplementing data with physician knowledge when 
information is not well recorded in patient charts.
8.10. Other Aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
This is a retrospective medical records review study where data collected will be strictly 
de-identified and will not be traceable back to individual subjects. No subject identifiers will 
be requested in this study in order to protect subject interests. In addition, the study is 
double-blinded (physicians will be blinded to study sponsor and study sponsor will be 
blinded on physicians recruited to participate). Therefore, it will not be possible to identify 
the patient or physician from the data used for this study. 
Only de-identified aggregated data will be presented in the final study report.
Compliance with Pfizer and regulatory standards provides assurance that the rights, safety, 
and well-being of subjects participating in non-interventional studies are protected 
(consistent with the principles that have their origin in the Declaration of Helsinki) and that 
the study data are credible and responsibly reported.
This study was designed and shall be implemented and reported in accordance with the 
Guidelines for Good Pharmacoepidemiology Practices (GPP) of the International Society for 
Pharmacoepidemiology (ISPE),24 the STROBE (Strengthening the Reporting of 
Observational Studies in Epidemiology) guidelines,25 and with the ethical principles laid 
down in the Declaration of Helsinki. 

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9.1. Patient Information and Consent
The study will be conducted entirely using retrospective medical records. Informed consent 
is not expected to be required in this study as the data collected does not contain personal 
identifiers. 
9.2. Patient Withdrawal
Not applicable.
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
AG will submit all required materials, including the protocol and the CRF to a central 
Institutional Review Board (IRB), and make any requested changes to obtain final IRB 
approval prior to commencement of data collection. 
9.4. Ethical Conduct of the Study
This 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 Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR).
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study is not classified as a PASS because no new safety information will be found due 
to also the small sample size, as specified on page 15, compared to the overall number of 
patients treated in the USA (approximately 28,000) with axitinib monotherapy or in 
combination with IOs.
This study requires physicians participating in the study to review patient-level medical 
charts, which include 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. Physicians who review medical charts are obligated to report AEs with 
explicit attribution to any Pfizer drug(s) 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.
Reporting of safety events on the NIS adverse event monitoring (AEM) Report Form to 
Pfizer Safety will be the responsibility of individual physicians, and the requirements are as 
follows:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be reported, within 24 hours of awareness, 
to Pfizer Safety using the NIS AEM Report Form.

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
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 medical charts 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.   
Following the completion of data collection, Medefield will provide AG with a data export. 
Within 24 hours of receiving the data export, AG will prepare a line listing of all serious and 
non-serious AEs associated with Pfizer products as reported by physicians in the eCRF to be 
forwarded to Pfizer. Since data collected in the study will be strictly de-identified and will 
not be traceable back to individual subjects or participating physicians, not all demographic 
fields will be available. However, at least one physician identifier (eg, qualifications) and at 
least one patient identifier (eg, gender, age) will be provided as a part of the line listing, thus 
allowing it to be considered valid in accordance with pharmacovigilance legislation. 
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug 
Name” will be documented in month/year (mm/yyyy) format.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Assuming Pfizer protocol approval by October 2020, the final study report will be completed 
and is estimated to be available in July 2021.
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. 

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13. LIST OF FIGURES
Figure 1.
Study Design Scheme.................................................................................9
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None. 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.
ANNEX 3. ADDITIONAL INFORMATION
Not applicable.