TREATMENT PATTERNS AND CLINICAL OUTCOMES AMONG PATIENTS RECEIVING PALBOCICLIB COMBINATIONS FOR HR+/HER2- ADVANCED/METASTATIC BREAST CANCER IN REAL WORLD SETTINGS
Conditions: Malignant Neoplasm of Breast
Sponsor: Pfizer

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TREATMENT PATTERNS AND CLINICAL OUTCOMES AMONG PATIENTS
RECEIVING PALBOCICLIB COMBINATIONS FOR HR+/HER2-
ADVANCED/METASTATIC BREAST CANCER IN REAL WORLD SETTINGS
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STUDY INFORMATION
Title
Treatment Patterns and Clinical Outcomes 
Among Patients Receiving Palbociclib 
Combinations For Hr+/Her2-
Advanced/Metastatic Breast Cancer in Real 
World Settings
Protocol number
A5481090
Protocol version identifier
Version 2.0
Date of last version of protocol
25 Nov 2019
Active substance
L01XE33
Palbociclib
Medicinal product
Ibrance (palbociclib)
Research question and objectives
To describe patient demographics, clinical 
characteristics, treatment patterns and clinical 
outcomes of adult female patients who have 
received palbociclib combination treatments in 
line with locally licensed indications in real 
world settings across multiple countries.
Primary objectives

To describe demographics and clinical 
characteristics of patients who have received 
palbociclib combination treatment in line 
with locally approved indications.

To describe adjuvant therapies received for 
the treatment of early or locally advanced 
breast cancer (Stages 0-IIIa).

To describe treatments received in the 
advanced/metastatic setting, before and after
palbociclib combination use.

To describe dosing and dose changes,
interruptions, delays and discontinuations

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associated with palbociclib use in clinical
practice.
•
To describe supportive therapies received by
patients while receiving palbociclib
combination treatments.
•
To determine in overall population and
defined subgroups, clinical outcomes
including (but not limited to):
•
Proportion of patients who are
progression free at specific intervals
(eg, 3, 6, 12, 18 months);
•
Objective response rate (ORR) -
depending on availability of follow-up 
data;
•
Proportion of patients alive after 1 and 
2 year post palbociclib combination
initiation (sample size permitting) -
depending on availability of follow-up 
data.
Author
, MSc
 
, MBA, BA
 
PPD
PPD
PPD
PPD
CCI

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TABLE OF CONTENTS
1. LIST OF ABBREVIATIONS................................................................................................6
2. RESPONSIBLE PARTIES....................................................................................................7
3. ABSTRACT...........................................................................................................................8
4. AMENDMENTS AND UPDATES.....................................................................................10
5. MILESTONES.....................................................................................................................11
6. RATIONALE AND BACKGROUND................................................................................12
7. RESEARCH QUESTION AND OBJECTIVES..................................................................13
8. RESEARCH METHODS ....................................................................................................15
8.1. Study Design ...........................................................................................................15
8.1.1. Core Medical Record Review.....................................................................16
8.1.2. German Interim Medical Record Review...................................................16
8.2. Setting......................................................................................................................17
8.2.1. Inclusion Criteria ........................................................................................18
8.2.2. Exclusion criteria........................................................................................19
8.3. Variables..................................................................................................................20
8.4. Data Sources............................................................................................................20
8.5. Study Size................................................................................................................21
8.6. Data Management....................................................................................................21
8.7. Data Analysis ..........................................................................................................22
8.8. Quality Control........................................................................................................24
8.9. Limitations of the Research Methods......................................................................24
8.10. Other Aspects ........................................................................................................25
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................25
9.1. Patient Information and Consent.............................................................................25
9.2. Patient Withdrawal..................................................................................................25
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ...............25
9.4. Ethical Conduct of the Study ..................................................................................25
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS ......................................................................................25

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11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........27
12. REFERENCES...................................................................................................................28
13. LIST OF TABLES AND FIGURES..................................................................................28

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1. LIST OF ABBREVIATIONS
Abbreviation  
Definition
ABC/MBC
advanced/metastatic breast cancer
AE
adverse events
AEM
adverse events monitoring
CDK
cyclin-dependent kinase
DFI
disease free interval
ECOG
eastern cooperative oncology group
eCRF
electronic case report forms
EMA
European Medicines Agency
EU
European Union
FTP
file transfer protocol
FTP
file transfer protocol
GPP
good pharmacoepidemiology practices
HER2-
human epidermal growth factor receptor 2 
negative
HR+
hormone receptor positive
IEC
Independent Ethics Committee
IRB
International Review Board
ISPE
International Society for 
Pharmacoepidemiology
LHRH
luteinizing hormone-releasing hormone 
NIS
non interventional study
ORR
objective response rate
PFS
progression free survival 
PHI
protected health information
SAP
statistical analysis plan
UK
United Kingdom
US
United States
CCI

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, Degree(s)
Title
Affiliation
Address
, 
MBA, BA
 
 
, MSc
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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3. ABSTRACT
Title: Treatment Patterns and Clinical Outcomes among Patients Receiving Palbociclib
Combinations for HR+/HER2- Advanced/Metastatic Breast Cancer in Real World Settings.
Rationale and background: Breast cancer is a major cause of cancer-related death 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 73% of all diagnosed breast cancers.  Palbociclib is a first in class CDK4/6 inhibitor 
that has been approved for use in HR+/HER- advanced/metastatic breast cancer (ABC/MBC) 
patients in a number of indications on the basis of efficacy demonstrated in three pivotal 
clinical trials; PALOMA-1 and PALOMA-2 (initial endocrine-based therapy) and 
PALOMA-3 (after progression following endocrine therapy). As a result of the recent 
approvals there is a need to understand the real world usage and clinical outcomes of patients 
receiving palbociclib in order to inform future treatment decisions. This study has been 
previously conducted in the US and Argentina with an additional ‘interim’ chart review 
conducted in Germany whereby no long term clinical outcomes were collected.
Research question and objectives: The primary objectives of this study are to describe the 
patient demographics, clinical characteristics, treatment patterns, and clinical outcomes of 
adult female patients who have received palbociclib combination treatments in line with 
locally licensed indications in real world settings across multiple countries.
Study design: This retrospective physician based medical record review will collect data from 
medical records of patients, who have received palbociclib combination in line with locally 
approved indications in 13 countries globally (data collection in four countries, US,
Argentina and “interim” German data in 2018 and Canada and Germany “core” data in 2019
have already been conducted). In countries where palbociclib has been on the market for a 
sufficient period of time and therefore sufficient follow-up data are available, a one-time 
review of patient’s medical records will be conducted. The study composed of two data 
collection phases, a core medical record review and an interim medical record review. The 
core study will be conducted across all markets whereby all variables collected, including 
sections relating to clinical outcomes (progression free rates, survival rates, best response 
etc.). The interim study will collect all data except the clinical outcomes due to lack of 
follow up time (ie, time since palbociclib approval was not long enough ago in some markets 
for sufficient follow up time to collect clinical outcomes data). The interim study was 
conducted in Germany in 2018 and is not planned for additional markets.
Population: Data will be collected from France, Italy, UK, Switzerland, Belgium, Spain, 
Netherlands, Portugal and Japan, with approximately 15-60 oncologists or gynecologists 
recruited per country.  To be eligible to participate physicians must have treated or be 
treating a minimum of 2 or more (dependent on country) HR+/HER2- ABC/MBC patients 
who meet the eligibility criteria for this study.  Each physician will complete between 
3-14 electronic case report forms (eCRFs).  Previously, data has been collected in the US

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(65 oncologists providing 652 eCRFs), Argentina (41/162), Canada (33/259) and Germany 
core (35/251).  In addition, an interim data collection was completed in Germany (whereby 
clinical outcomes were not collected due to lack of follow up data) with 42 physicians 
providing 257 eCRFs.  Including previous data collection in the US, Argentina, Germany and 
Canada, it is expected that approximately 476-486 physicians will be recruited, this will 
enable data to be collected for approximately 3131 patients overall.
Recruited physicians must go back in their records to the specific index date and select the 
next n number of eligible patient records from patients who have been treated with a 
palbocicib combination.  The ‘index date’ will be defined as 60 days after the physician first 
prescribed palbociclib + partner therapy following the availability of specific indication in 
the market.  To be eligible, patients must be female, aged 18 or over, have been diagnosed 
with HR+/HER2- ABC/MBC and must have received palbociclib combination in line with 
locally approved indications.  For the core study, patients must have initiated palbociclib 
with fulvestrant a minimum of three months, or palbociclib with letrozole/aromatase inhibitor 
a minimum of six months prior to data collection.
Variables: The variables assessed in this study will be patient demographics at the time of 
data collection, clinical characteristics, comorbid conditions, early and advanced breast 
cancer treatment history, palbociclib treatment patterns including dose changes, clinical 
outcomes (core medical record review only) and time since deceased (no. of days) if 
applicable.
Data sources: Patient medical records will be used as the data source.
Study size: For the core study up to approximately 476-486 physicians will be recruited, this 
will enable data to be collected for approximately 3131 patients.  Approximately 
30- 40 physicians will be recruited collecting 240-250 eCRFs each in Italy, France, Spain,
and the UK.  For Belgium and Netherlands, 15 physicians will be recruited collecting 
150 and 60 eCRFs per country respectively.  Approximately 20 physicians will be recruited 
in Switzerland collecting 100 eCRFs and 50 physicians recruited in Japan to complete 
approximately 150 eCRFs. Approximately 20 physicians will be recruited in Portugal 
collecting 100 eCRFs. For the US study 652 eCRFs were collected from 65 physicians, 
whilst in Argentina 162 eCRFs were collected from 41 physicians. For the German interim 
review 42 physicians were recruited with 257 eCRFs completed and for the German core 
study 35 physicias were recruited completing 251 eCRFs. In Canada, 33 physicians 
completed 259 eCRFs.
Data analysis: All analyses will be descriptive in nature. Categorical variables will be 
described using the number of observations, number and percent (%) in each category, and 
number of missing observations. Numeric variables will be described using the number of 
observations, mean and standard deviation, and minimum, maximum, median, interquartile 
range, and number of missing observations. Time to event will be described using a 
Kaplan-Meier chart or the median.

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Milestones: The medical record review data collection began in April 2017 and should be 
completed by 2019, however this will depend upon anticipated market approval dates and the 
required follow-up time for outcomes evidence. The US and Argentina data collection were 
completed in Q1 2018 with results and subsequent dissemination of data carried out 
throughout 2018. The German interim medical record review data collection was completed 
in October 2017.  The US and Argentina core report were completed in February 2018.  The 
Germany core and Canada data was completed in June 2019 with the results due for delivery 
by the end of 2019. Following completion of the core study in all additional markets, the 
final study report will be written and completed by Q2 2021.
4. AMENDMENTS AND UPDATES
Amendment 
Number
Date
Substantial or 
Administrative 
Amendment
Protocol 
Section(s) 
Changed
Summary of Amendment(s)
Reason
V1.0
May 06, 
2019
Administrative
1.
Addition of additional 
markets in which the research 
is being conducted in.
2.
New Pfizer HEOR project 
lead.
3.
Text amends referring to 
previous record reviews in the 
US, Argentina and Germany.
4.
Added in clarifying text as 
requested following Pfizer 
review to include information 
on additional markets, 
indications and more in depth 
information on methodology.
5.
Added references to 
guidelines on Protection of 
Human Subjects and AE 
reporting. Update safety 
language per the latest SOP.
v2.0
25 
November 
2019
6.
Increased sample sizes in 
Germany, Canada, UK, Italy, 
France, Japan, Belgium.
7.
Inclusion of Spain,– sample 
sizes and indications.
8.
Inclusion of countries 
Netherlands and Portugal.

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5. MILESTONES
Milestone
Planned date
Start of core data collection (US and Argentina data 
collection completed by January 2018)
April 2017
Start of German interim data collection
September 2017
End of German interim data collection
October 2017
Study Report: US and Argentina report
February 2018
Start of data collection – Canada, Germany (core))
June 2019
Start of data collection – Belgium, Italy, UK,
Switzerland, Japan
Q4 2019
Start of data collection – France, Spain, Netherlands, 
Portugal
Q1 2020
Study Report – All Countries (US, Argentina, Canada,
France, Germany, Italy, UK, Switzerland, Belgium, 
Spain, Netherlands, Portugal and Japan)
Q2 2021

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6. RATIONALE AND BACKGROUND
Breast cancer is the most common diagnosed cancer and the most common cause of 
cancer-related death in females worldwide.  There were 1.67 million new cases of breast 
cancer diagnosed globally in 2012, which equated to 12% of all diagnosed cancers. Out of 
these new cases 522,000 females died of the disease, which represented 15% of female 
deaths from cancer in 2012.1 There is a huge worldwide variation in breast cancer survival 
rates, ranging from 80% or more in North America, Sweden and Japan to 60% in 
middle-income countries and as low as 40% in low-income countries.2 Breast cancer 
survival rates have increased over the last 50 years, as relative survival increased from 
75.2% in 1975 to 90.6% in 2008.3 The 5 year survival rate for females with stage 0/I breast 
cancer is near to 100%, compared to that of Stage II and III, which are 93% and 72% 
respectively. Females who are diagnosed with metastatic or stage IV breast cancer have a 
much lower 5 year survival rate of 22%.4
An increased understanding of breast cancer has enabled enhanced profiling of different 
disease subtypes. Subtype classification is essential in order to decide on the appropriate 
treatment regime. Breast tumors are grouped according to the expression of hormone 
receptors (HR) and human epidermal growth factor receptor 2 (HER2). Overall HR status is 
the most important biomarker for breast cancer classification, as around 75% of all breast 
cancer tumors are HR positive (HR+). Tumors that are HR+ grow in response to increased 
levels of the hormones estrogen and progesterone. HR+ breast tumors are the most 
favorable, as they respond well to hormone therapies. In contrast HR- breast tumors do not 
respond well to hormone therapies. These tumors are known to be the most aggressive 
cancers, in regards to tumor size, grade, stage and patient outcome. HER2 positive (HER2+) 
breast tumors represent around 15% of all breast tumors. These tumors tend to be more 
aggressive and faster growing than HER2 negative (HER2-) tumors. HR+/HER2- breast 
cancer is the most common subtype diagnosed in the US. This subtype accounted for around 
73% of diagnosed breast cancer cases in 2010. Around 15-20% of breast tumors do not 
contain HR or HER2; these are known as triple negative breast cancers.5
Over the past few decades, hormonal therapies such as letrozole and fulvestrant have 
emerged as the preferred treatment for HR+ breast cancers. Following the success of the 
Phase II PALOMA-1 trial, the FDA granted accelerated approval of the CDK4/CDK6 
inhibitor palbociclib that causes cell cycle arrest to be used in combination with letrozole to 
treat advanced/metastatic HR+/HER2- post-menopausal breast cancer. The PALOMA-1 trial 
demonstrated median progression-free survival of 20.2 months for post-menopausal patients 
with advanced/metastatic HR+/HER- breast cancer receiving letrozole in combination with 
palbociclib vs. 10.2 months in patients receiving letrozole and placebo.6 The follow up 
Phase III PALOMA-2 trial demonstrated median progression free survival of 24.8 months for 
post-menopausal patients with advanced/metastatic HR+/HER- breast cancer receiving 
letrozole in combination with palbociclib vs. 14.5 months in patients receiving letrozole and 
placebo.7 The label has since been expanded to include any aromatase inhibitor in this 
indication.8

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In October 2016, palbociclib was granted approval to be used in combination with 
fulvestrant. This was following the success of the Phase III PALOMA-3 trial, conducted in 
patients with advanced/metastatic HR+/HER- breast cancer that had relapsed or progressed 
during endocrine therapy. The PALOMA-3 trial demonstrated a median progression-free 
survival of 10.8 months in those receiving fulvestrant in combination with palbociclib 
vs. 4.8 months in patients receiving fulvestrant with placebo.8
As a result of the recent approval of palbociclib, there is scarce information regarding how 
and when palbociclib combination is prescribed in routine clinical practice, and the outcomes 
associated with palbociclib use. Therefore, real world data on the characteristics, treatment 
patterns and clinical outcomes among patients receiving palbociclib combinations to treat 
HR+/HER- advanced/metastactic breast cancer (ABC/MBC) will provide valuable insight to 
help inform treatment decisions.
7. RESEARCH QUESTION AND OBJECTIVES
The primary objective of this real world study is to describe patient demographics, clinical 
characteristics, treatment patterns and clinical outcomes of adult female patients who have 
received palbociclib combination treatments in line with locally licensed indications in real 
world settings across multiple countries:
Canada/Argentina:

Palbociclib in combination with letrozole as early endocrine therapy to treat
advanced/metastatic HR+/HER2- post-menopausal breast cancer (CAN: May 2016,
ARG: December 2015).

Palbociclib in combination with fulvestrant for the treatment of females with
HR+/HER2- ABC/MBC with disease progression following endocrine therapy
(CAN: May 2017, ARG: August 2016). In pre- or perimenopausal females, the 
endocrine therapy should be combined with a luteinizing hormone-releasing hormone 
(LHRH) agonist.
Across the EU, Switzerland, US and Japan:

Palbociclib in combination with aromatase inhibitor as initial endocrine based therapy 
for the treatment of females with HR+/HER2- locally ABC/MBC (EMA: November 
2016, Switz: October 2017, US: Feb 2015, updated Mar 2017).

Palbociclib in combination with fulvestrant for the treatment of females with 
HR+/HER2- ABC/MBC who have received prior endocrine therapy 
(EMA: November 2016 Switz: March 2017). In pre- or perimenopausal females, the 
endocrine therapy should be combined with a luteinizing hormone-releasing hormone 
(LHRH) agonist.

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•
Palbociclib in combination with fulvestrant for the treatment of females with 
HR+/HER2- ABC/MBC with disease progression following endocrine therapy 
(US: Feb 2016).
•
In patients with inoperable or recurrent breast cancer, approved in combination for 
1L => Palbociclib + Letrozole, Approved in combination for 2nd line => Palbociclib + 
Fulvestrant (Japan).
Primary Objectives
•
To describe the demographic and clinical characteristics of patients who have 
received palbociclib combination treatments in line with locally approved indications.
•
To describe adjuvant therapies received for the treatment of early or locally advanced 
breast cancer (Stages 0-IIIa).
•
To describe treatments received in the advanced/metastatic setting, before and after 
palbociclib combination use.
•
To describe dosing and dose changes, interruptions, delays, and discontinuations 
associated with palbociclib use in clinical practice.
•
To describe supportive therapies received by patients while receiving palbociclib 
combination treatments.
•
To determine in overall population and defined subgroups, clinical outcomes 
including (but not limited to):
•
Proportion of patients who are progression free at multiple intervals (eg, 3, 6, 12, 
18 months);
•
Objective response rate (ORR) - depending on availability of follow-up data;
•
Proportion of patients alive 1 and 2 year post palbociclib combination 
initiation (sample size permitting) - depending on availability of follow-up data.
 
 
CCI

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8. RESEARCH METHODS
8.1. Study Design
This study will be conducted as a retrospective physician based medical record review of 
patients who have received palbociclib combination in line with locally approved indications.
In some countries data may be collected from patients receiving palbociclib combinations 
before the local reimbursement date, however patients must still be receiving palbociclib 
combinations in line with the approved indication. The study will comprise of a medical 
record review conducted in the US, Canada, Argentina, Italy, UK, France, Germany, 
Belgium, Switzerland, Spain, Netherlands, Portugal and Japan. The study design is 
outlined in Figure 1. The study has been previously conducted in the US, Argentina, Canada
with an additional ‘interim’ record review conducted in Germany (with a minimum of 
3 month follow up) whereby no long term clinical outcomes were collected. The core 
German study is now completed with clinical outcome data. 
Data collection will be online via electronic data capture using electronic case report form 
(eCRF).  Eligible physicians will be invited to complete an eCRF for up to between 
3-14 patients that meet the study criteria.  Each eCRF will take a minimum of 25 minutes to 
complete.  Patient eligibility will be confirmed by treating physicians.  In order to allow for a 
sufficiently long observational window, treating physicians will be asked to go back to a 
specific point in time, the index date, and sequentially select the medical records of the next 
‘n’ patients who meet the inclusion criteria.  The ‘index date’ will be defined as 60 days after 
the physician first prescribed palbociclib + partner therapy following the availability of 
specific indication in the market (eg, If palbociclib + letrozole was available Feb 1, 2015 in 
the US and the physician initiated a patient on palbociclib+ letrozole the next day, the index 
date will be April 2, 2015).  The index date will differ for the specific 
indications/combination partners if approved on different dates.
Study materials (ie, the CRF) will be subject to pilot testing with physicians followed by 
interviews to discuss the length, feasibility, ease of understanding and use, and the relevance 
to the objectives.
The advantage to a retrospective medical record review approach over a database analysis is 
that of being designed specifically to collect data that fulfils the study objectives.  Thus, it 
readily collects and informs on all key drug related clinical outcome measures of critical 
importance to this study, in a consistent manner, across countries.  The resulting data set 
enables direct comparisons across markets, delivering in turn greater confidence in the 
reliability of conclusions drawn from the research.  An additional advantage of this approach 
lies in the ability to obtain information that only the treating physician may be aware of, such 
as the reasons for treatment switches or discontinuations or more perceptive questions that 
rely on the physicians professional opinion.

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8.1.1. Core Medical Record Review
The core medical record review will capture data from approximately 3131 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.
The core medical record review has already been conducted in the US and Argentina in 2017
and for Germany (core) and Canada in Q3 2019.  Palbociclib has only been recently 
approved for use in the EU, therefore, additional European data collection in Belgium, Italy 
and the UK for the core medical record review will commence in Q4 2019 and for Spain, 
Netherlands, Portugal and France in Q1 2020. Similarly, data collection for Switzerland and 
Japan will commence Q4 2019, depending on the date of approval of palbociclib in each 
individual country. In some countries data may be collected from patients receiving 
palbociclib combinations before the local reimbursement date, however patients must still be 
receiving palbociclib combinations in line with the approved indication. In France patients 
must have initiated palbociclib combinations post- 01 Jan 2018 to avoid capturing any patient 
data for those receiving palbociclib combinations via an early access program. 
8.1.2. German Interim Medical Record Review
A German interim medical record review was conducted in Germany in October 2017.  This 
interim medical record review allowed for the collection of a number of baseline 
characteristics data.  This study had the same methodology as the core study and an almost 
identical eCRF, capturing demographics, clinical characteristics, disease history, treatment 
history and palbociclib dosing for patients receiving palbociclib combination treatment in 
line with the approved indications.  However, appropriate sections from the CRF relating to 
clinical outcomes associated with palbociclib combination were omitted from the interim 
eCRF (ie, ORR, CRF, progression free rates and survival rates).  A further full core medical 
review will be conducted in Germany in April 2019 in line with the methodology outline in
Section 8.1.1.

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Figure 1.
Study Design Depicting the Proposed Time Frame for the Medical Record 
Reviews
8.2. Setting
Upon study completion, data will be collected from 13 countries with approximately 
15-60 physicians (oncologists/gynecologists)1 recruited per country. Each physician will 
complete between 3-14 eCRFs (country and sample size dependent). Data will be collected 
retrospectively at a single point in time from patient medical records.
Initial screening questions/recruitment criteria will ensure the relevant physicians are selected 
and all other non-qualifying physicians will be excluded. In addition during physician 
recruitment a representative geographical split and private/public practice split will be sought 
where possible to ensure a representative sample.
                                                
1 Breast surgeons/general surgeons/gastro-surgeons may also be included as relevant treaters in Japan.

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To be eligible, physicians must have treated or be treating two or more
HR+/HER2- ABC/MBC patients who meet the eligibility criteria for the study. This will 
ensure that recruited physicians will be able to complete the minimum number of eCRFs 
required to participate in the study. Physicians are recruited by local fieldwork agencies in 
each market. The recruitment process occurs either via custom lists or a panel approach via 
telephone or email. In keeping with compliance, physicians must have previously stated 
their willingness to be contacted to participate in such research. Once physicians have been 
recruited, they must go back to a specific index date, defined in 8.1, and select the next n 
number of eligible patient records from patients who have been treated with a palbociclib 
combination. The consecutive approach to recruitment will be stressed to each participating 
physician to limit selection bias. Physicians will confirm patient eligibility.
Patient records must meet the following criteria to be eligible for the medical record reviews.
They must be female, aged 18 or older and they must have been diagnosed with 
HR+/HER2- ABC/MBC. Patients must have received palbociclib combination in line with 
country/locally approved indications. For the core record review, palbociclib and 
letrozole/aromatase inhibitor must have been initiated a minimum of 6 months prior to date 
of medical record review, and palbociclib and fulvestrant must have been initiated a 
minimum of 3 months prior to date of medical record review. This will permit the capture of 
meaningful clinical outcomes data. For the German interim record review, palbociclib was 
required to have been initiated a minimum of 3 months prior to data collection regardless of 
partner therapy.
A full list of the eligibility criteria can be found in 8.2.1.
In order to ensure that sufficient data is captured for each indication, indication quotas will be 
enforced. This will be determined on a country by country basis.
8.2.1. Inclusion Criteria
Physician inclusion criteria

Oncologist or gynecologist.2

Responsible for treating a minimum of ≥2-6 (depending on country) ABC/MBC 
patients who meet the eligibility criteria.

Agrees to participate in the study and complete the eCRFs within the data collection 
period.
                                                
2 Relevent treaters on a country level will be included.

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Patient inclusion criteria:

Female.

≥18 years old.

HR+/HER2- breast cancer diagnosis with confirmed metastatic or advanced disease.

Received palbociclib plus letrozole/aromatase inhibitor or palbociclib plus fulvestrant
in line with the licenced indication(s).

No prior or current enrolment in an interventional clinical trial for ABC/MBC.

Minimum of three months of follow up data since palbociclib with fulvestrant
initiation, or minimum of six months of follow up data since palbociclib with
letrozole/aromatase inhibitor initiation (core medical record review).

Minimum of three months of follow up data since palbociclib initiation (German 
interim medical record review only).

Inoperable or recurrent breast cancer (Japan only).
8.2.2. Exclusion Criteria
Physician exclusion criteria:

Qualified less than 2 years ago or more than 35 years ago.

Particpated in observational research for ABC/MBC in the last 3 months.

Have not prescribed either palbociclib plus fulvestrant or palbociclib plus aromatase 
inhibitor in line with the licenced indication(s).

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8.3. Variables
Table 1.
List of Study Variables
Variable
Role
Data source(s)
Operational definition
Patient demographics
Baseline 
Sub-group 
identifier
Patient records
Age, ethnicity, weight, height, biomarker 
status, family history of breast cancer.
Clinical characteristics
Baseline 
Sub-group 
identifier
Patient records
Patient status (alive/deceased), time since 
deceased (no. of days), time since initial BC 
diagnosis, time since ABC/MBC diagnosis, 
staging, node status, menopause status.  
ECOG/Karnofsky functional status, diagnosis 
for which palbociclib combination was 
prescribed, sites of metastases, de novo vs. 
recurrent disease, time from diagnosis 
palbociclib initiation.
Comorbid conditions
Baseline
Patient records
Comorbid conditions.
Early treatment history
Baseline 
Sub-group 
identifier
Patient records
Adjuvant treatments received since breast 
cancer diagnosis. Time since end of adjuvant 
treatment. Surgery/radiotherapy/neoadjuvant 
received.
Advanced treatment 
history
Baseline 
Sub-group 
identifier
Patient records
Treatments and supportive therapies received 
since metastatic/advanced HR+/HER2-
diagnosis. Duration of treatments. Reasons for 
regimen changes.
Palbociclib combination 
treatment
Exposure 
Sub-group 
identifier
Patient records
Starting dose, duration of treatment, changes in 
dose, interruptions, cycle delays and 
discontinuations.
Where possible reasons for change in 
treatment. Line of treatment.
Clinical outcomes (Core 
medical record review 
only)
Outcomes
Patient records
Proportion progression free, ORR, 
, PFS, 
1-yr and 2-yr survival in all patients and within 
specific subgroups.
8.4. Data Sources
The data source for both core and interim medical record reviews will be patient medical 
records.
CCI

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8.5. Study Size
Table 2.
Sample Size for Core Medical Record Review
Country
Approximate† Number of Physicians
Number of eCRFs
US (complete)
65
652
Argentina (complete)
41
162
Canada (complete)
33
259
UK
30-40
250
France
40
250
Germany interim (compelte)
42
257
Germany core (complete)
35
251
Italy
30
240
Belgium
15
150
Spain
40
250
Switzerland
20
100
Japan
50
150
Netherlands
15
60
Portugal
20
100
Total (approximate):
476-486
3131
†Actual no. physicians stated where data collection complete in US, AR, CAN, DE
The sample size above should be considered flexible, with scope to increase the sample size 
if feasible.  This will be assessed on a country by country basis.
The objectives do not state any hypotheses and therefore, do not require any statistical 
testing.  All the analyses will be descriptive and so sample size calculations are not required.
8.6. Data Management
Physician reported data from the eCRF will be transferred to a single electronic database.  All 
data will be de-identified and anonymized.  Incomplete data may be excluded from analysis 
following discussion with Pfizer.
De-identified raw data files will be transferred to Pfizer by a secure file transfer protocol 
(FTP) site.
Analyses will be conducted in STATA statistical software version 14.1 (StataCorp, 2016.  
Stata statistical software: Release 14.  College Station, TX, StataCorp LP).

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8.7. 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.
All analyses are to be descriptive and so all methods to be used will reflect this descriptive 
nature. The specific method that will be used depends on type of variable being analysed and 
those methods are:

Categorical variables – will be described using:

Number of observations (n);

Number and percent (%) within each category;

Number of missing observations.

Numeric variables – will be described using:

Number of observations (n);

Mean and Standard deviation;

Minimum, Maximum, Median and 1st and 3rd Quartiles;

Number of missing observations.

Time to event – will be described using:

A Kaplan-Meier chart that will visually estimate the distribution of times to some 
events, eg, progression, and will take into account those patients for which the 
event has not as yet occurred;

1-yr and 2-yr rates, median or some more appropriate percentiles if the median 
time is not reached in the sample.
The analyses will be conducted (using the methods above) in a number of phases, as already
detailed in the study design section.
1. Non EU countries – all variables (as shown in Section 8.3) will be described.

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2. EU countries – selected variables (all shown in Section 8.3 excluding clinical 
outcomes) will be described.
3. EU countries - all variables will be described.
Missing data will be excluded on a case by case basis and will not be imputed. This will 
mean that each table will not necessarily be based on the same number of patients.
Subgroup Analysis
Exploratory stratifications will be conducted to explore differences between line of therapy, 
demographics, treatments, clinical characteristics, baseline co-morbidities or ‘responders’ 
and ‘non-responders’ to treatment, however these will be only descriptive in nature. 
Responders and non-responders will be defined according to the best recorded response to 
palbociclib treatment.
Sample size permitting, additional stratifications may include:

Insurance type.

Eastern Cooperative Oncology Group (ECOG) Performance status.

Age.

Menopausal status.

De novo vs. recurrent disease.

Bone only disease.

Visceral vs. non-visceral metastases.

By primary site, eg, liver, lung.

Burden of metastases (eg, visceral involvement, multiple liver lesions, bilateral vs 
single lung involvement, presence of pleural effusion).

Duration of disease free interval (DFI).

Specific comorbidities.

Comorbidity index.

Prior endocrine treatment.

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
Treatment sequence.
8.8. Quality Control
To maximize data quality the following will be undertaken:

Provision of standardized instructions on study design, methodology and procedures:

Physicians will be contacted via email or telephone and an overview of the study
will be provided (detailing study objectives, patient inclusion criteria, correct
completion of eCRF and interview and any other logistical aspects of the study);

Follow-up with the physicians to ensure queries are resolved quickly.

The electronic materials will be tested thoroughly to ensure that all questions appear 
correctly on screen, allow easy interpretation/completion and that all routing and 
logic checks are working correctly. As such, there should be no missing data (given 
the online nature of the study, the physician will have to complete a question before 
he/she is able to move on the next) however, ‘don’t know or unknown’ will be valid 
responses.

There will be no monitoring visits or source data verification in this study.
8.9. Limitations of the Research Methods
A key limitation of a study of this nature is the reliance on accurate, complete eCRFs; which 
is dependent on the correct completion of the study materials and the availability of a 
detailed, complete patient records. We have outlined a number of important quality control 
steps to be taken as part of the study procedures to minimize the impact of this. Notably, to 
reduce the administrative burden on all physicians, the materials will be as short and 
user-friendly as possible.
The representativeness of the sample is limited to the consulting population for participation, 
who has been previously prescribed palbociclib combination in line with locally approved 
indications. We will not collect data from patients from non-participating physicians, thus 
introducing a potential selection bias. To minimize this multiple physicians will be recruited 
in each country from a diverse geographical spread and mixed private/public practice where 
possible. To eliminate any patient identification bias during data collection a systematic 
patient selection criteria will be included and stressed to each participating physician. This 
will be further defined in the eCRFs, but will take into account the date of palbociclib 
approval for each indication. Patients who received palbociclib prior to approval or off-label 
are not represented in this study.
Due to the observational design of the study, treatments received by patients may be subject 
to a channeling bias and thus must be interpreted with caution.

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8.10. Other Aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.  In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data.
This study will involve secondary data collection which will include human review of 
unstructured data. No protected health information (PHI) will be collected and all data will 
be de-identified. The research poses a minimal risk to patients, will not affect the rights or 
welfare of the patient and the study would not be feasible should informed consent be 
required. As a result, informed consent will not be sought for this study.
9.2. Patient Withdrawal
Not applicable.
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
The study will be submitted to a centralized independent IRB board in Europe for 
methodological review. In addition, a Western IRB exemption will be sought on the basis 
that the study will collect only secondary data, no protected health information (PHI) will be 
collected and all data will be de-identified.
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 Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE)
(https://www.pharmacoepi.org/resources/guidelines_08027.cfm). Compliant with the 
regulatory details outlines in the external guidance document CT24-WI_GL02-RF04 1.0.
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS REQUIREMENTS
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 

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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 eCRF 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:   

“YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”. 

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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.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
A global report will be provided on completion of the entire study with additional country 
specific reports provided in PowerPoint format as and when data collection is included in 
each market.  These reports will incorporate methodology, sample, tables of results and 
summaries. All documents used throughout the study will be contained within the report as 
appendices.
In addition to the two study reports, the following slide decks will be produced.

Country specific slide decks on completion of each market.

Final reports and publications per market requirement.

A global slide deck when the entire study is completed.
Additional country specific slide decks will be developed as needed. 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.
Communication of Issues
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.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of.

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12. REFERENCES
1.
Global cancer statistics | Centers for diseases control and prevention [Internet]. [cited 
2016 Sep 23]. Available from : http://www.cdc.gov/cancer/international/statistics.htm.
2.
Coleman MP et al. (2008). Cancer survival in five continents: a worldwide 
population-based study (CONCORD). Lancet Oncol, 9, 730–56.
3.
Breast cancer statistics | World Cancer Research Fund International [Internet]. [cited 
2016 Sep 23]. Available from: http://www.wcrf.org/int/cancer-facts-figures/data-
specific-cancers/breast-cancer-statistics.
4.
Breast cancer survival rates, by stage | American cancer society [Internet]. [Cited 2016 
Nov 30]. Available from: 
http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-survival-by-
stage.
5.
Dai X, Xiang L, Bai Z. Cancer Hallmarks, Biomarkers and Breast Cancer Molecular 
Subtypes. Journal of cancer. 2016; 7(10):1281-1294.
6.
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.
7.
FinnR, Martin M, Rugo H, et al. Palbociclib and letrozole in advanced breast cancer.
N Engl J Med. 2016;375:1925-1936.
8.
Full Prescribing Information, IBRANCE [Internet]. Food and Drug Administration; 
2017 [cited 2017 Apr 6]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf.
13. LIST OF TABLES AND FIGURES 
Table/Figure
Title
Page
Figure 1
Study Design Depicting the Proposed Time Frame for the 
Medical Record Reviews
17
Table 1
List of Study Variables
20
Table 2
Sample Size for Core Medical Record Review
21