DEMOGRAPHICS, PATIENT CHARACTERISTICS, TREATMENT PATTERNS AND CLINICAL OUTCOMES OF PATIENTS TREATED WITH PALBOCICLIB IN A REAL LIFE SETTING IN ISRAEL
Conditions: Metastatic Breast Cancer
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
Demographics, patient characteristics, treatment 
patterns and clinical outcomes of patients treated 
with Palbociclib in a real life setting in Israel
Protocol number
A5481160
Protocol version identifier
4
Date
30 August 2022
Active substance
L01XE33 (Palbociclib)
Medicinal product
Ibrance (Palbociclib)
Research question and objectives
To describe patient demographics, clinical 
characteristics, clinical outcomes and treatment 
patterns of adult breast cancer patients who have 
initiated palbociclib combination treatment as 
per the national basket of health services in 
January 2018 until August 2020 for all lines of 
therapy. 
New follow up to 30 June 2022
Author
Dr.
 
Pfizer Pharmaceuticals Israel Ltd.
P.O.Box 12133, 9 Shenkar St.
Herzliya Pituach, Israel 4672509
 Professor 
 
 
Dr.
PPD
PPD
PPD
PPD
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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.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................5
3. RESPONSIBLE PARTIES....................................................................................................7
4. AMENDMENTS AND UPDATES.......................................................................................8
5. MILESTONES.......................................................................................................................8
6. RATIONALE AND BACKGROUND..................................................................................8
7. RESEARCH QUESTION AND OBJECTIVES ...................................................................8
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. Demographic characteristics at baseline (from structured electronic 
database): .........................................................................................................16
8.3.2. Clinical and health related characteristics at baseline: ...............................16
8.3.3. Treatment patterns:.....................................................................................17
8.3.4. Cancer related variables:.............................................................................17
8.3.5
.
Clinical outcomes for palbociclib (analysed separately by therapy line):..18
8.4. Data sources ............................................................................................................18
8.5. Study size ................................................................................................................18
8.6. Data management....................................................................................................18
8.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data 
record ...............................................................................................................19
8.6.2. Record retention..........................................................................................19
8.7. Data analysis ...........................................................................................................20
8.8. Quality control.........................................................................................................20
8.9. Strength and limitations of the research methods ...................................................20
8.10. Other aspects .........................................................................................................21
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................21
9.1. Patient information..................................................................................................21
9.2. Patient consent.........................................................................................................21

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9.3. Institutional review board (IRB)/Independent ethics committee (IEC)..................22
9.4. Ethical conduct of the study....................................................................................22
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................22
Human Review of Structured Data ................................................................................23
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........23
12. REFERENCES ..................................................................................................................24
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................24
ANNEX 2. ADDITIONAL INFORMATION.........................................................................28

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ABC/MBC
advanced/metastatic breast cancer
AE
adverse events
AEM
adverse events monitoring
AI
aromatase inhibitor
ANOVA
analysis of variance
ATC
anatomical therapeutic chemical
BMI
body mass index
CDK
cyclin-dependent kinase
CDK4/6-I
cyclin-dependent kinase 4 and 6 inhibitors
CI
confidence internal
CIOMS
council for international organizations of medical 
sciences
CKD
chronic kidney disease
COPD
chronic obstructive pulmonary disease
CPT
current procedural terminology
CRF
case report form
CVD
cardiovascular disease
DCT
data collection tool
ECOG
Eastern Cooperative Oncology Group
ER+
Estrogen receptor positive
FDA
food and drug administration
gBRCAm
germline breast cancer gene mutation
GIS
geographic information systems
HER2
human epidermal growth factor receptor 2
HER2-
human epidermal growth factor receptor 2 negative
HMO
health maintenance organization
HR
hormone receptor
HR+
hormone receptor positive
ICD-9
international classification of diseases ,ninth revision
IEC
independent ethics committee
IQR
interquartile range
IRB
international review board
ISPOR
international society for pharmacoeconomics and 
outcomes research
K-M
kaplan-meier (curve)
MHS
Maccabi Healthcare Services
N
number
NIS
non-interventional study
CCI
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PDF
portable document format
PR+
progesterone receptor positive
RWE
real-world evidence
SD
standard deviation
SES
socioeconomic status
TTNT
time to next treatment
USA
united sates of america
YRR
your reporting responsibilities

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
Dr
 PhD
Senior Medical 
Advisor, 
NI Study Lead of 
the protocol
Pfizer 
Pharmaceuticals 
Israel Ltd. 
9 Shenkar St. 
Hertzelia, Israel
 
Bpharm, MSc
Epidemiologist, 
sub-investigator of 
the protocol
 
 
 
 
Israel
Dr 
MD
Head Oncologist
 
 Israel
Prof
 
PHD MHA
 
Principal 
Investigator of the 
protocol
 
 
 
 
Israel
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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4. AMENDMENTS AND UPDATES
5. MILESTONES
Milestone
Planned date
Start of data collection 
08 November 2020
End of data collection
30 June 2022
Final study report
31 December 2022
6. RATIONALE AND BACKGROUND
Breast cancer is a major cause of mortality in females worldwide. Hormone receptor positive (HR+)
and human epidermal growth factor receptor 2 negative (HER2-) breast cancer is the most 
commonly diagnosed subtype accounting for around 75% of all diagnosed breast cancers1. 
Palbociclib is a first in class cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that has been
approved for use in HR+/HER2- advanced/ metastatic breast cancer (ABC/ MBC) patients in a
number of indications on the basis of efficacy demonstrated in 3 pivotal clinical trials; PALOMA-1
and PALOMA 2 (initial endocrine-based therapy) and PALOMA-3 (after progression following
endocrine therapy) 2,3. As a result of the recent approvals there is a need to understand the real world 
usage and clinical outcomes of patients receiving CDK4/6 inhibitors, including palbociclib, in order
to inform future treatment decisions. 
There is high level of screening and awareness for breast cancer in Israel. Palbociclib was included 
in the national health basket and therefore reimbursed since January 2018 in all lines of treatment, 
according to the labeling. 
Although there is Real-World Evidence (RWE) on palbociclib published from the USA, Argentina, 
Germany and Italy 4,5,6 there is no awareness of RWE with palbociclib  coming from Israel.
7. RESEARCH QUESTION AND OBJECTIVES
Primary Objective: To describe patient demographics, clinical characteristics, clinical outcomes and 
treatment patterns of adult breast cancer patients who have initiated palbociclib combination 
treatment as per the national basket of health services in January 2018 until August 2020 for all lines 
of therapy.  Extended follow up for treatment patterns to 30th June 2022.
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8. RESEARCH METHODS 
8.1. Study design
This is a population based retrospective database study that will include patients with metastatic, 
HR+/ HER2- breast cancer and who initiated first  or subsequent lines of treatment with palbociclib. 
Data will be available from Maccabi Healthcare Services (MHS) database in Israel for patients who 
received approval for treatment with palbociclib since 01 January 2018  until 31 August 2020.
Treatment amendment and extension:Treatment lines will be rerun for the same patient cohort for an 
additional year and a half of follow-up to 30 June 2022.
The database review followed by  a medical record review will capture data from approximately 
500-700 patients on demographics, clinical characteristics, disease history, treatment history, 
palbociclib dosing, clinical outcomes and post-palbociclib combination therapy treatment data. The 
study will be descriptive in nature therefore no control or comparator groups will be included.
8.2. Setting
Patients (age ≥18 years) will be identified from MHS purchase data between 01 July 2017 until 31 
August 2020. 
Index date will be defined as date of initiation of palbociclib treatment.
Patient records must meet the following criteria to be eligible for the medical record reviews. 
Patients must be at least 18 years of age at index date and they must have been diagnosed with 
HR+/HER2- ABC/ MBC. Patients must have received palbociclib combination in line with Israel
approved indications. A minimum of 6 months follow up of palbociclib combination therapy  prior 
to date of medical record review will be necessary for inclusion. This will permit the capture of 
meaningful clinical outcomes data. Patients will be followed through the end of the observation 
period, date of death or left the health maintenance organization (HMO).
A full list of the inclusion criteria can be found in Section 9.2.1.
8.2.1. Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the study:
1. A diagnosis of metastatic breast cancer, based on the National/MHS cancer registry.
2. Newly diagnosed metastatic breast cancer patients and newly treated with palbociclib within 6 
months of diagnosis, in any line of treatment in the metastatic setting.
3. Available data on palbociclib treatment for at least 6 months.
4. Continuous healthcare plan enrolment in MHS for at least one year before index date.
5. At least 18 years of age at index date.
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8.2.2. Exclusion criteria
Patients meeting any of the following criteria will not be included in the study:
1. Patients that initiated HER2 inhibitors.
8.3. Variables
The following variables will be collected from the MHS electronic database and non-structured data 
extracted from PDF files of patient data:
Variable
Source
Role in 
study
Period of 
measurement
Reporting 
phase
Operational 
definition
Demographic and Clinical and health related characteristics at baseline
PatID
MHS 
structured 
data
Data linkage
Not 
reported 
Unique patient 
identifier used to 
link clinical records. 
This information 
will not be disclosed 
to the study 
sponsor.
Gender
MHS 
structured 
data
Baseline 
characteristic
Prior medical 
history
Reported
Male/Female
Age
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Patient's age (in 
years) at index date.
Age groups
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Groups such as <50 
versus ≥50
Body mass index 
(BMI)
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Median 
(Interquartile Range 
- IQR)
BMI groups
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Underweight 
(BMI<18.5), normal 
(BMI 18.5-24.9), 
overweight (BMI 
25-25.9), obese 
(BMI ≥30), missing
Smoking history
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Ever smoker, never 
smoker, unknown.

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Menopausal 
status
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Pre-, peri- or post-
menopausal
Region of 
residence
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
North, South, 
Central region
Socioeconomic 
status
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Based on a points 
system, categorized 
as low (1-4), 
medium (5-6), high 
(7-10)
Co-morbidities
MHS 
validated 
registries
Baseline 
characteristic
Baseline
Reported 
For cardiovascular 
disease, 
cerebrovascular 
disease, stroke, 
congestive heart 
failure, diabetes 
mellitus, chronic 
kidney disease, 
hypertension, 
Chronic obstructive 
pulmonary disease 
(COPD).
Variable
Source
Role in 
study
Period of 
measurement
Reporting 
phase
Operational 
definition
Chronic diseases
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
Depression as 
defined by ICD-9 
codes.
Deyo-Charlson 
Comorbidity 
index 
MHS 
structured 
data and 
MHS 
validated 
registries
Baseline 
characteristic
Baseline
Reported 
Co-medications
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
At least 2 purchases 
within 3 months 
prior to index date.
Genetic 
counselling for 
gBRCAm
(germline Breast 
Cancer gene 
mutation) 
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
yes/no

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Genetic testing 
for gBRCAm 
performed
MHS 
structured 
data
Baseline 
characteristic
Baseline
Reported 
yes/no
Death
MHS 
structured 
data
Endpoint
After index 
date
Death is captured 
from National 
Insurance Data
Disease Characteristics
Date of initial 
breast cancer 
diagnosis
National 
cancer 
registry
Baseline 
characteristic
Baseline
Reported 
Records may be 
incomplete
Histology
Extracted 
from PDF 
patient 
data files
Baseline 
characteristic
Baseline
Reported 
Location of 
metastases
Extracted 
from PDF 
patient 
data files
Baseline 
characteristic
Baseline
Reported 
Bone, brain, lymph 
nodes, ovary, 
visceral
Visceral/non 
visceral status
Extracted 
from PDF 
patient 
data files
Baseline 
characteristic
Baseline
Reported 
Non-visceral, 
visceral (lungs, 
liver), bone only
Eastern 
Cooperative 
Oncology Group 
(ECOG) 
performance 
status at 
diagnosis
Extracted 
from PDF 
patient 
data files
Baseline 
characteristic
Baseline
Reported 
Grouped as 0-1, 2, 
3-4, 
unknown/missing
Molecular status 
data: performed 
HER2/ HR tests
Extracted 
from PDF 
patient 
data files
Baseline 
characteristic
Baseline
Reported
yes/no
Hormone 
sensitivity
Extracted 
from PDF 
patient 
data files
Baseline 
characteristic
Baseline
Reported 
primary or 
secondary resistance
Variable
Source
Role in 
study
Period of 
measurement
Reporting 
phase
Operational 
definition
Progression of 
disease from 
imaging
Extracted 
from PDF 
patient 
data files
Baseline 
characteristic
Baseline
Reported 
Treatment Characteristics

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Index treatment 
regimen 
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Reported 
Palbociclib 
combination 
treatment -
combination with 
aromatase inhibitor 
or fulvestrant.
Lines of therapy
MHS 
structured 
data and 
PDF 
patient 
data files.
Treatment 
characteristic
Study 
observation 
period
Reported
Identified according 
to the sequence of 
dispensed 
medications.
Median duration 
of each line of 
therapy
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Reported
Duration in weeks 
or months between 
the start and stop of 
each line of therapy 
will be reported as 
mean (SD) and 
median (IQR)
Number of 
cycles of index 
treatment
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Reported
Mean (SD) and 
Median (IQR)
Index palbociclib 
treatment dose
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Reported
Mean (SD) and 
Median (IQR)
Index palbociclib
treatment dose 
schedule change
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Reported
Proportion of 
patients with dose 
changes
Date of 
treatment 
initiation
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Not 
Reported 
First date will be 
used if a regimen 
consists of more 
than one drug given 
on different dates.
Index treatment 
end date
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Not 
Reported 
Date of final 
treatment for each 
drug or regimen. It 
is possible that the 
patient's treatment 
stop date is not 
documented if the 
patient dies, is lost 
to follow up or is 
still on therapy. The 
final treatment date 
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study date will be 
uses, whichever is 
earliest.
Variable
Source
Role in 
study
Period of 
measurement
Reporting 
phase
Operational 
definition
Post-palbociclib 
treatment 
duration
MHS 
structured 
data
Clinical 
Outcomes 
Study 
observation 
period
Not 
Reported
The regimen 
received by patients 
following 
discontinuation 
from the palbociclib 
treatment.
The duration (in 
weeks) between the 
start and stop of the 
post-palbociclib 
treatment. Findings 
will be summarized 
as the mean (± SD) 
and median (range) 
of values.
Proportion of 
patients who 
progress/ do not 
progress
MHS 
structured 
data and 
PDF 
patient 
data files.
Clinical 
Outcomes
Study 
observation 
period
Reported
Using imaging files, 
the proportion of 
patients who 
progress and do not 
progress from the 
index treatment 
until 6, 12 and 24 
months will be 
summarized as the 
count and 
percentage of the 
following:
Patients with 
ongoing index 
treatment
Patients who died 
following index 
treatment
Patients who 
advanced to a 
subsequent 
treatment
Patients who did not 
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subsequent 
treatment for 
unknown reasons 
Time to 
chemotherapy 
after palbociclib 
treatment
MHS 
structured 
data
Clinical 
Outcomes
Study 
observation 
period
Reported
Time to 
chemotherapy 
(Kaplan Meier 
method median 
(95% CI)) from end 
of index treatment 
and start of 
chemotherapy. 
Summary of 
number of events 
and censored 
patients at 6, 12, 18, 
24 months.
Time to next 
treatment 
(TTNT)
MHS 
structured 
data
Treatment 
characteristic
Study 
observation 
period
Reported
TTNT will be 
defined as the 
interval (in weeks or 
months) between 
the start of the index 
treatment date and 
the date of the next-
line treatment. 
Patients who did not 
advance to the next 
treatment will be 
censored on the 
study end date or 
death, whichever 
occurs first.
Kaplan-Meier (K-
M) method with 
95% CI and 
summary tables of 

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8.3.1. Demographic characteristics at baseline (from structured electronic database):

Patient demographics: age, age group and gender.

Region of residence (North, Central, South).  

Socioeconomic status (SES): based on a score ranked with 1 (lowest) to 10 derived for 
commercial purposes by Points Location Intelligence using geographic information systems 
(GIS) and data such as expenditures related to retail chains, credit cards and housing. This 
score is highly correlated with SES measured by the Central Bureau of Statistics1. SES will 
be categorized into low (1-4), medium (5-6) and high (7-10). 
8.3.2. Clinical and health related characteristics at baseline:

Body mass index (BMI) will be categorized using standard cut-points 2.

Baseline chronic diseases will be identified using previously validated MHS automated 
chronic disease registries for the following co-morbidities: diabetes 3, cardiovascular disease 
(CVD) 4, chronic kidney disease (CKD) 5 , hypertension 6, COPD, other patient relevant 
condition (if applicable) e.g. depression.

Deyo-Charlson Comorbidity index (using validated MHS patient registries where available).

Co-medications – Minimum of  2 purchases within the 3 months period prior to index date.

Menopausal status.
events and censored 
patients at 6, 12, 18, 
24 months.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
Cancer history will be obtained from National Cancer Registry 7 data available through 2015 
and MHS cancer registry data which draws from pathology reports and diagnoses linked to 
cancer medication approvals through 2017.

Smoking status (ever/never/unknown) will be obtained from the MHS database and/or 
physician reports.

Genetic counselling for germline BRCA mutation carried out yes/no.

Testing for germline BRCA mutation carried out yes/no.
8.3.3. Treatment patterns:

Number (N) (%) patients receiving first, second- and third-line treatments by drug name and 
therapeutic group, median duration of each line of therapy, and number of cycles for each 
line of therapy. Treatment lines are defined according to the sequence of dispensed 
medications, with information captured both from pharmacy database (for medications 
approved by the HMO), and from hospital medical records (including information on 
medications provided by private insurance and clinical studies) using the following 
algorithm. Any drug purchased within 1 month of a new line is considered part of that line. 
Cessation of a drug from a combination regimen is considered the same line as the patient is 
not receiving additional treatment. Cessation is likely due to tolerance issues or adverse 
effects although we do not know the reason as our data is from purchase data. 
Addition of a new drug to a current regimen is considered a new treatment line.

Index treatment regimen - palbociclib combination partner: Aromatse Inhibitors (AI) or 
fulvestrant; Subsequent therapy per lines of therapy.

Dosing and dose changes, interruptions, delays, and discontinuations associated with 
palbociclib therapy.

Treatment lines will be rerun for extended follow up to 30 June 2022.
8.3.4. Cancer related variables:
These variables will extracted from patient PDF files/ letters sent to MHS from the physician.

Date of initial breast cancer diagnosis.

Histology.

Location of metastases: bones, brain, visceral, lymph nodes, other.

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
ECOG performance status at diagnosis.

Molecular status data: performed HER2/ HR tests (yes/no).

Hormone sensitivity: primary or secondary resistance.

Progression of disease from imaging.
8.3.5. Clinical outcomes for palbociclib (analysed separately by therapy line):

N (%) progression at 6, 12 and 24 months.

Duration of treatment on palbociclib (Median time on treatment).

Time on treatment for subsequent line of therapy.

Time to chemotherapy after palbociclib treatment.
8.4. Data sources
Data will be extracted from the Maccabi Health Services (MHS) database. MHS is a nationwide 
health plan (payer-provider) representing a quarter of the population in Israel. The MHS database 
contains longitudinal data on a stable population of 2.2 million people since 1993 (with <1%/year 
moving out). Data are automatically collected and include comprehensive laboratory data from a 
single central lab, full pharmacy prescription and purchase data, and extensive demographic data on 
each patient. MHS uses the International Classification of Diseases, Ninth Revision, Clinical 
Modification (ICD-9-CM) coding systems as well as self-developed coding systems to provide more 
granular diagnostic information beyond the ICD codes. Medications are coded according to the 
Israeli coding system with translations to Anatomical Therapeutic Chemical (ATC) coding system 
wherever available. Procedures are coded using Current Procedural Terminology (CPT) codes.
8.5. Study size
Sample size calculations are not applicable as this is a descriptive study. The expected number of 
patients eligible for the study is about 500-700 patients.
8.6. Data management 
Part of the data will be collected from the main database, such as demographics, comorbidities, 
systemic therapy (not including chemotherapy like cisplatin or carboplatin), date of death. Data that 
is not available in the main database such as tumor characteristics (stage of disease, histology), 
chemotherapy (cisplatin, carboplatin), response (from imaging results), biomarker status, metastases 
site, Eastern Cooperative Oncology Group (ECOG) results, and discontinuation will be extracted 
through additional chart review from medical letters in PDF format by trained data extractors. 
Extracted data will be recorded in an electronic case report form created for this study using 
Microsoft Access Database. All data is anonymous and does not leave the MHS system.
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SPSS version 24 and R data processing and statistical software will be used.
8.6.1. Case report forms (CRFs)/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.
A CRF is required and should be completed for each included patient.  The completed original CRFs
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. MHS shall ensure that the CRFs are securely stored at Maccabi Research & 
Innovation Institute in encrypted electronic and/or paper form and will be password protected or 
secured in a locked room to prevent access by unauthorized third parties.
MHS has ultimate responsibility for the collection and reporting of all clinical, safety, and laboratory 
data entered on the CRFs 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 CRFs must be signed MHS or by 
an authorized staff member to attest that the data contained on the CRFs are true.  Any corrections to 
entries made in the CRFs 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 
CRFs must match those charts. 
8.6.2. Record retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, MHS agrees to 
keep all study-related records, including the identity of all participating patients (sufficient 
information to link records, e.g., CRFs and physician records), copies of all CRFs, safety reporting 
forms, source documents, detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (e.g., letters, meeting minutes, and telephone call reports).  The records 
should be retained by MHS according to local regulations or as specified in the research agreement, 
whichever is longer.  MHS must ensure that the records continue to be stored securely for so long as 
they are retained.
If MHS becomes unable for any reason to continue to retain study records for the required period, 
Pfizer should be prospectively notified.  The study records must be transferred to a designee 
acceptable to Pfizer.
Study records must be kept for a minimum of 15 years after completion or discontinuation of the 
study, unless MHS and 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.  
MHS must obtain Pfizer's written permission before disposing of any records, even if retention 
requirements have been met.

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8.7. Data analysis 
Data will consist of structured data from the MHS electronic database and non-structured data 
extracted from PDF files of patient data. Data validation will be performed and consist of quality 
control checks for appropriate values, logical sequences and quantity of missing values. Missing data 
will be identified and reported in the results tables as percentages for all variables. If there is a large 
amount of missing or illogical data, a decision to include,  exclude or impute that variable will be 
subsequently made based on the study sponsor’s decision.
Descriptive analyses will be conducted to evaluate the demographic, clinical and treatment 
characteristics overall, as well as for each of the study cohorts. Results will be reported in aggregate. 
Categorical variables (eg, ECOG performance status) will be reported as frequency and percentage. 
Continuous variables such as age will be reported as mean, (standard deviation) and median (Inter 
quartile range). In the case of missing observations, the number and percentage of missing values 
will be reported. Chi-square testing will be used to assess associations between categorical variables 
when patient counts for single cells within the results tables are greater or equal to 5. When 
distribution cannot be assumed to be Chi-square, then Fisher’s exact test will be used. Depending on 
normality, analysis of variance (ANOVA)/t-tests or Kruskall-Wallis tests will be used for continuous 
variables. An alpha level of 0.05 will be the primary criterion for statistical significance of this 
study.
Time from treatment initiation until progression  (as determined in the patient record) and drug 
discontinuation will be determined for the calculation of median time on treatment.
Duration of treatment on palbociclib, Time on treatment for subsequent line of therapy and Time to 
chemotherapy after palbociclib treatment and
 
 
Plots will be generated. Patients are censored at end of study or left MHS.
Sub- analyses will be carried out for palbociclib.
All analyses will be conducted using IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: 
IBM Corp, and a P value < 0.05 is considered statistically significant. 
8.8. Quality control
Quality control checks on MHS data are built into the “Clicks” physician visit management system 
and further quality control is carried out by the BI department.
8.9. Strength and limitations of the research methods
In general the study will be prone to selection bias and misclassification errors due to its 
observational design. Another potential limitation of the study could be the level of missing data. 
The possibility of selection bias is minimized because the study aims to include all metastatic breast 
cancer patients treated at MHS during a specified time period. In order to minimize the bias due to 
secondary data extraction from existing medical records, appropriate quality checks will be done by 
the analytical team. These checks include, but are not limited to, examination of missing and out of 
range values, comparison of data estimates to established norms, use of appropriate statistical 
methods to counteract the bias, wherever possible. Data cleaning procedures will be implemented 
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and updated at each data export and a review of clinical charts will be planned. A uniform handling 
of data that is conflicting, ambiguous, missing, or unknown will be performed. No statistical 
imputation of missing data is planned.  
The study population and practice patterns captured in this study are from one health care provider 
and may not be representative of the country’s breast cancer patient population and treatment 
practices. Therefore, the generalizability of the results may be limited. Small number of patients in 
certain stratification groups may result in wide CIs for estimates generated during the analyses. 
ECOG performance status, which is likely predictive of anti-cancer treatment and 
 
 Due to the descriptive nature of the study 
no inferences regarding casualty can be drawn from the results. 
8.10. Other aspects
Not applicable
9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient information 
All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures to ensure protection of patient personal data.  Such measures 
will include omitting patient names or other directly identifiable data in any reports, publications, or 
other disclosures, except where required by applicable laws. 
Patient personal data will be stored at Maccabi Research & Innovation Institute in encrypted 
electronic and/or paper form and will be password protected or secured in a locked room to ensure 
that only authorized study staff have access. MHS 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, MHS 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, any patient names 
will be removed and will be replaced by a single, specific, numerical code.  All other identifiable 
data transferred to Pfizer or other authorized parties will be identified by this single, patient-specific 
code. In case of data transfer, Pfizer will maintain high standards of confidentiality and protection of 
patients’ personal data consistent with the research agreement and applicable privacy laws.
9.2. Patient consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, obtaining informed consent from patients by Pfizer is not required and exemption will 
be received from the ethics committee.
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9.3. 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 study will 
be conducted per approval of the Maccabi Research Committee and the local Institutional Review 
Boards.
All correspondence with the IRB/IEC must be retained.  Copies of IRB/IEC approvals must be 
forwarded to Pfizer.
9.4. Ethical conduct of the study
The study will be conducted in accordance with legal and regulatory requirements, as well as with 
scientific purpose, value and rigor and follow generally accepted research practices described in:

Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR) 
http://www.ispor.org/workpaper/practices_index.asp 

International Ethical Guidelines for Epidemiological Studies issued by the Council for 
International Organizations of Medical Sciences (CIOMS)

Food and Drug Administration (FDA) Guidance for Industry: Good Pharmacovigilance 
Practices and Pharmacoepidemiologic Assessment

Israeli Ministry of Health regulation 14 – Medical trials in Human subjects
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/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:

All serious and non-serious AEs with explicit attribution to any Pfizer drug that appear in the 
reviewed information must be recorded on the data collection tool 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.

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
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 (e.g., 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.”
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. 
Human Review of Structured Data 
This study involves data that exist as structured data by the time of study start. In these data sources, 
individual patient data are not retrieved or validated, and it is not possible to link (i.e., identify a 
potential association between) a particular product and medical event for any individual.  Thus, the 
minimum criteria for reporting an adverse event (AE) (i.e., identifiable patient, identifiable reporter, 
a suspect product, and event) cannot be met.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
A report will be provided on completion of the entire study in a Word format. This report will 
incorporate methodology, sample, tables of results and summaries. All documents used throughout 
the study will be contained within the report as appendices. Results of this study may be submitted to 
conferences and journals for publication. As per Pfizer’s requirements, the project will only be 
considered complete upon delivery of the full study report and close of all study publications. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable competent 
authority in any area of the world, or if MHS 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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12. REFERENCES
1. Dai X, Xiang L, Bai Z. Cancer Hallmarks, Biomarkers and Breast Cancer Molecular 
Subtypes. Journal of cancer. 2016; 7(10):1281-1294.
2. McCain M. First-in-Class CDK4/6 Inhibitor Palbociclib Could Usher in a New Wave of 
Combination Therapies for HR+, HER2− Breast Cancer. PharmTher.2015 Aug;40(8):511-20
3. FinnR, Martin M, Rugo H, et al. Palbociclib and letrozole in advanced breast cancer. N Engl 
J Med. 2016;375:1925-1936
4. G. Taylor-Stokes et al. Treatment patterns and clinical outcomes among patients receiving 
palbociclib in combination with an aromatase inhibitor or fulvestrant for HR+/HER2-
advanced/metastatic breast cancer in realworld settings in the US: Results from the IRIS 
study. The Breast 43 (2019) 22e27
5. Waller et al. Real World Treatment With Palbociclib in Argentina: IRIS Study. J Global 
Oncol. 2019 May;5
6. Michelino De Laurentiis et al. Real-world treatment patterns and clinical outcomes among 
women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings 
in Italy and Germany. Cancer Research, Volume 80, Issue 4 Supplement, pp. P3-11-25. 
7. Israel Centeral Bureau of Statistics. 1995 Census of Population and Housing Jerusalem: 
1998.
8. BMI Classification [database on the Internet]. 2006 [cited 2014]. Available from: 
http://apps.who.int/bmi/index.jsp?introPage=intro_3.html.
9. Chodick G, Heymann AD, Shalev V, Kookia E. The epidemiology of diabetes in a large 
Israeli HMO. Eur J Epidemiol. 2003;18:1143-6.
10. Shalev V, Chodick G, Goren I, Silber H, Kokia E, Heymann AD. The use of an automated 
patient registry to manage and monitor cardiovascular conditions and related outcomes in a 
large health organization. Int J Cardiol. 2011;152(3):345-9. Epub 2010/09/10.
11. Coresh J, Turin TC, Matsushita K, Sang Y, Ballew SH, Appel LJ, et al. Decline in estimated 
glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. 
JAMA. 2014;311(24):2518-31. Epub 2014/06/04.
12. Weitzman D, Chodick G, Shalev V, Grossman C, Grossman E. Prevalence and factors 
associated with resistant hypertension in a large health maintenance organization in Israel. 
Hypertension. 2014;64(3):501-7.
13. Israel Center for Disease Control. Israel national cancer registry. Jerusalem, Israel: Ministry 
of Health.
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
1. Baseline demographic and clinical characteristics of patients diagnosed with metastatic 
breast cancer 2018-2019 split by Palbociclib as first-, second- or third line (n=XX).
First 
Line
Second 
Line
Third 
Line
Total
n=XXX

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Demographic Variables
Age 
median (IQR)
<65
>=65
Gender 
male
female
Region of residence
Central
North
South
Socioeconomic status*
low
medium
high
Clinical Variables
Deyo-Charlson Comorbidity 
Index (without malignancy 
or HIV)
mean (SD)
0
1
2
3
≥4
Co-morbidities
Diabetes mellitus
Cardiovascular 
disease
Stroke
Congestive heart 
failure
Hypertension
Chronic kidney 
disease

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Chronic 
obstructive 
pulmonary 
disease
Other (e.g. 
depression)
Co-medications
Smoking
Ever smoker 
Never smoker
Unknown
BMI
Menopausal status
Pre/Peri 
menopausal
Postmenopausal
Genetic counselling for 
gBRCAm
Yes
No
Testing for gBRCAm
Yes
No
2. Cancer related characteristics of patients with breast cancer at baseline
First 
Line
Second 
Line
Third 
Line
Total
(n)
Histology
Location of 
metastases
Brain
Bone

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3. Time on Palbociclib treatment
Line of 
treatment 
(first-, 
second- or 
third line)
N
Number 
(%) 
discontinued
Median 
time on 
treatment 
(95% 
CI), 
months
% on
treatment 
at 3 
months
% on 
treatment 
at 6 
months
% on 
treatment 
at 12 
months
% on 
treatment 
at 24 
months
Log 
rank P 
value
4. Palbociclib treatment patterns
Visceral
Lymph nodes
Other
ECOG
0-1
2
3-4
Unknown/missing
Hormone 
sensitivity
Primary
Secondary
Molecular status 
data: performed 
HER2 / HR tests
HR+ [Estrogen Receptor 
positive (ER+), 
Progesterone Receptor 
positive (PR+) or both]
HER2+

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ANNEX 2. ADDITIONAL INFORMATION
Not applicable
Line of 
treatment 
(first-, 
second- or 
third line)
Combination 
partner: AI 
or 
Fulvestrant
Number 
(%) of 
dose 
reductions 
from 
125mg to 
100mg
Number 
(%) of dose 
reductions 
from 
100mg to 
75mg
Number 
(%) of 
dose 
reductions 
from 
125mg to 
75mg
Number (%) 
of dose 
Interruptions
Number (%) of 
discontinuations