Observational Cohort Study of Patients With Hormone Receptor-positive Metastatic Breast Cancer Treated With Palbociclib (Ibrance(Registered)) as Part of the United Kingdom Ibrance (Registered) Patient Program (IPP); the Real Outcomes Ibrance (Registered) Study (ROIS)
Conditions: HR+/HER2- Locally Advanced, Metastatic Breast Cancer
Sponsor: Pfizer

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12.11.2018
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X9001194 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 12 November  2018 
 
 
 
Pfizer Confidential 
Page 2 of 39 
and who switch treatment 1, 2 
and 3 years after palbociclib 
initiation, and median time to 
dose modification and treatment 
discontinuation (‘drug survival’). 
For patients who progress, to 
describe the 1st/2nd /3rd line of 
treatment after progression.  
• To describe overall survival and 
progression-free 
survival, 
response 
(complete 
response, 
partial response), stable disease. 
This includes estimating the 
proportion of patients achieving 
those endpoints at 1, 2 and 3 
years 
following 
palbociclib 
initiation; median survival, time 
to response and duration of 
response. In patients who respond 
to treatment, to describe partial 
response and complete response 
using “swimmer plots”. 
• To describe the occurrence of 
neutropenia during the first year 
post-initiation observation period. 
• To describe the occurrence of 
gastro-intestinal 
toxicity, 
including diarrhoea, nausea and 
vomiting during the first year 
post-initiation observation period. 
• To 
describe 
progression 
of 
clinical 
indicators, 
including 
biochemical 
and 
radiological 
indicators at each time-point 
available during the first year 
following palbociclib treatment 
initiation (e.g. full blood counts, 
liver function tests, bone profile). 
• To describe breast cancer related 
healthcare resource utilisation 
(hospital admissions, outpatient 
visits, calls to Cancer National 
Services and contacts with the 

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Final, 12 November  2018 
 
 
 
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Page 4 of 39 
1. TABLE OF CONTENTS 
 
1. TABLE OF CONTENTS .......................................................................................................4 
2. LIST OF ABBREVIATIONS ................................................................................................6 
3. RESPONSIBLE PARTIES ....................................................................................................8 
4. ABSTRACT ...........................................................................................................................9 
5. AMENDMENTS AND UPDATES .....................................................................................12 
6. MILESTONES .....................................................................................................................13 
7. RATIONALE AND BACKGROUND ................................................................................13 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................15 
9. RESEARCH METHODS ....................................................................................................16 
9.1. Study design ............................................................................................................16 
9.2. Setting ......................................................................................................................18 
9.2.1. Inclusion criteria .........................................................................................18 
9.3. Variables ..................................................................................................................18 
9.4. Data sources ............................................................................................................23 
9.5. Study size ................................................................................................................23 
9.6. Data management ....................................................................................................23 
9.6.1. Case Report Forms (CRFs) .........................................................................24 
9.6.2. Record Retention ........................................................................................25 
9.7. Data analysis ...........................................................................................................25 
9.8. Quality control .........................................................................................................27 
9.9. Limitations of the research methods .......................................................................27 
9.10. Other aspects .........................................................................................................28 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................28 
10.1. Patient Information ................................................................................................29 
10.2. Patient Consent ......................................................................................................29 
10.3. Patient Withdrawal ................................................................................................30 
10.4. Institutional Review Board (IRB)/Research Ethics Committee (REC) ................30 
10.5. Ethical Conduct of the Study ................................................................................30 

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Pfizer Confidential 
Page 6 of 39 
2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
IPP 
Ibrance® Patient Program 
ROIS 
Real Outcomes Ibrance® Study 
HR+ 
Hormone Receptor Positive 
BC 
Breast Cancer 
PFS 
Progression-Free Survival 
HER2(-) 
Human Epidermal Growth Factor 2 (Negative) 
MBC 
Metastatic Breast Cancer 
EU 
European Union 
NHS 
National Health Service 
NICE 
National Institute for Health and Care Excellence 
SMC 
Scottish Medicines Consortium 
UK 
United Kingdom 
CR 
Complete Response 
PR 
Partial Response 
OS 
Overall Survival 
AE 
Adverse Event 
CNS 
Cancer National Service 
AOS 
Acute Oncology Service 
IRB 
Institutional Review Board  
REC 
Research Ethics Committee 
CDK 
Cyclin-Dependent Kinase 
PALOMA 
Palbociclib Ongoing Trials in the Management of 
Breast Cancer 
US 
United States  
FDA 
Food and Drug Administration 
ENCePP 
European 
Network 
of 
Centres 
for 
Pharmacoepidemiology and Pharmacovigilance 

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Pfizer Confidential 
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GDPR  
General Data Protection Regulation 
ISPE 
International Society for Pharmacoepidemiology  
eCRF 
electronic Case Report Form 
NCRI 
National Cancer Research Institute 
Y 
Yes 
N 
No 
NCI-DCI 
National 
Cancer 
Institute 
- 
Deyo-Charlson 
Comorbidity Index  
CI 
Confidence Interval 
A&E 
Accident and Emergency 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDV 
Source Data Verification 
EMA 
European Medicines Agency 
GDPR 
General Data Protection Regulation 
MHRA 
Medicines and Healthcare products Regulation 
Regulatory Authority Agency 
SRSD 
Single Reference Safety Document 
STROBE 
Strengthening The Reporting of Observational 
studies in Epidemiology 
ICMJE 
International Committee of Medical Journal Editors 
 
 
 

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Pfizer Confidential 
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4. ABSTRACT 
Title: Observational cohort study of patients with hormone receptor-positive metastatic breast 
cancer treated with palbociclib (Ibrance®) as part of the United Kingdom Ibrance® Patient 
Program (IPP); the Real Outcomes Ibrance® Study (ROIS) 
Subtitle: the Real Outcomes Ibrance® Study (ROIS) 
Hormone receptor positive (HR+) breast cancer (BC) represents the largest therapeutic 
subtype of the disease, accounting for 60 to 65% of all malignant neoplasms of the breast. 
Palbociclib (Ibrance®) is a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 
(CDK4/6) which in clinical trial settings has been shown to increase progression-free 
survival (PFS) for patients with HR+, human epidermal growth factor 2-negative (HER2-) 
metastatic breast cancer (MBC). Palbociclib first received a European Union (EU) marketing 
authorisation in September 2016, to be commercialised as Ibrance® by Pfizer. Palbociclib 
was recommended for use with an aromatase inhibitor in patients with HR+/HER2- locally 
advanced and MBC in the National Health Service (NHS) in England by the National 
Institute for Health and Care Excellence (NICE) in November 2017 and by the Scottish 
Medicines Consortium (SMC) in December 2017. In order to provide access to palbociclib in 
the United Kingdom (UK) during the NICE/SMC appraisal period, the Ibrance® Patient 
Program (IPP) was initiated and run by Pfizer between April 2017 until a positive 
NICE/SMC appraisal in November 2017 (for England and Wales) or December 2017 (for 
Scotland).  
Pfizer are interested in the opportunity to collect data from patients who received palbociclib 
as part of the UK IPP, to better understand patients’ characteristics in a routine care setting, 
treatment persistence and dose management, clinical outcomes, and healthcare resource 
utilisation. This study will provide real-world evidence on patients’ clinical progression and 
experience of treatment with palbociclib in routine clinical settings in a UK context. 
Research question:  
What are the real-world treatment patterns, patients’ characteristics, clinical outcomes and 
healthcare resource utilisation associated with palbociclib treatment in the 3 years following 
initiation in United Kingdom patients with HR+/HER2- MBC treated as part of the IPP?  
 
Primary objectives:  
• To describe patient demographic and clinical characteristics at initiation of palbociclib. 
 
Secondary objectives 
• To describe treatment pattern (as per licence/IPP requirement); including the proportion 
of patients with dose modification and who switch treatment 1, 2 and 3 years after 
palbociclib initiation, and median time to dose modification and treatment 

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Pfizer Confidential 
Page 10 of 39 
discontinuation (‘drug survival’). For patients who progress, to describe the 1st /2nd /3rd 
line of treatment after progression.  
• To describe overall survival (OS) and progression-free survival (PFS), response 
(complete response [CR], partial response [PR]), stable disease. This includes estimating 
the proportion of patients achieving those endpoints at 1, 2 and 3 years following 
palbociclib initiation; median survival, time to response and duration of response. In 
patients who respond to treatment, to describe PR and CR using “swimmer plots”. 
• To describe the occurrence of neutropenia during the first year post-initiation observation 
period. 
• To describe the occurrence of gastro-intestinal toxicity, including diarrhoea, nausea and 
vomiting during the first year post-initiation observation period. 
• To describe progression of clinical indicators, including biochemical and radiological 
indicators at each time-point available during the first year following palbociclib 
treatment initiation (e.g. full blood counts, liver function tests, bone profile). 
• To describe BC related healthcare resource utilisation (hospital admissions, outpatient 
visits, calls to Cancer National Services and contacts with the Acute Oncology Service ) 
during the first year following palbociclib initiation. 
This is an observational cohort study with retrospective and prospective data collection to 
obtain medical data covering the 3 year period following palbociclib initiation.  
The study will be conducted in 8-9 NHS trusts across different regions within the UK (list of 
hospitals provided in Annex 1). In the hospitals selected for this study, approximately 250 
patients received palbociclib as part of the IPP out of a total of 846 women who received 
palbociclib in the UK.  Site selection was based upon a minimum of 15 patients being 
enrolled onto the IPP, except for one site selected) due to lead clinician’s membership in the 
steering committee.  Membership of the steering committee was based upon two criteria 1) 
membership of the National Cancer Research Institute (NCRI) MBC subcommittee and 2) 
had patients on the IPP.  All members of the steering committee meet this criteria.  The 
NCRI subcommittee is an independent committee from Pfizer, and Pfizer has no input into 
the committee as part of this study. 
Patients will be eligible for this study if: (1) they received ≥1 dose of palbociclib as part of 
the IPP at one of the selected hospitals; (2) at sites where the data is collected by external 
researchers, patients provide consent for an external researcher to access their medical 
records (for living patients only). Patients were eligible for the IPP if palbociclib was used in 
combination with an aromatase inhibitor and patients had previously untreated HR+/HER2- 
locally advanced or MBC.  
 
The following data will be collected from patients’ medical records: demographic 
characteristics at time of initiation, medical history prior to palbociclib initiation, clinical 

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Pfizer Confidential 
Page 11 of 39 
indicators of progression and response to treatment, occurrence of neutropenia and gastro-
intestinal toxicity post-palbociclib initiation, and healthcare resource utilisation. PFS and OS 
will be estimated for patients from the date of initiation of palbociclib. 
The analysis will be descriptive. Demographic characteristics and medical history will be 
described at the time of palbociclib initiation (baseline). Qualitative variables will be 
described by the absolute and relative (%) frequency of each class. Missing data will not be 
taken into account in the calculation of percentages (counts of missing observations will be 
included in a separate category). Quantitative variables will be described by their mean, 
standard deviation, median, 1st and 3rd quartiles, and extreme values (minimum and 
maximum), where applicable and the number of missing and non-missing values. The 
Kaplan-Meier method will be used to obtain estimates of median PFS, OS, CR, PR and time 
to discontinuation of palbociclib, with corresponding two-sided 95% confidence intervals.  
Completion of retrospective data collection is planned for the 1st of February 2019. 
Completion of the prospective data collection is planned for the 1st of February 2021. An 
interim report on descriptive characteristics of patients already enrolled into the study 
(primary objective) will be produced in January 2019. Delivery of a 1-year report on the 
analysis of patients with  1-year follow-up post-initiation period (primary and secondary 
objectives) is planned for the 1st of July 2019. An additional 3-year report on the analysis of 
patients with up to  3-year follow-up post-initiation period (primary and secondary 
objectives) may be provided in July 2021.  

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Pfizer Confidential 
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5. AMENDMENTS AND UPDATES 
Amendments must be made only by prior agreement between Pfizer, pH Associates and the 
Chief Investigator. The institutional review board (IRB)/research ethics committee (REC) 
must be informed of all amendments and give approval for substantial amendments. The 
Chief Investigator must send a copy of the approval letter from the REC/IRB to Pfizer. 
pH Associates, Pfizer, and the participating organisation(s) reserve the right to terminate 
participation in the study according to the study contract. pH Associates will notify the 
REC/IRB in writing of the study’s completion or early termination and send a copy of the 
notification to Pfizer and the Chief Investigator. 
 
Not applicable 
 
6. 

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Pfizer Confidential 
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6. MILESTONES 
 
Milestone 
Planned date 
Completion of feasibility assessment 
 
July 2018 
Start of data collection  
 
November 2018 for retrospective data 
collection 
February 2019 for prospective data 
collection 
End of data collection  
 
February 2019 for retrospective data 
collection 
February 2021 for prospective data 
collection 
Interim report on descriptive analysis of patients already 
enrolled into the study (primary objective) 
February 2019 
1-year report (primary and secondary objectives) 
 
01 of July 2019 [based on 1-year post 
initiation observation period, including all 
patients with up to 1-year follow-up post 
initiation] 
3-year report (primary and secondary objectives) 
 
01 of July 2021 [based on 3-year post 
initiation observation period, including all 
patients with up to 3 year follow-up post-
initiation] 
 
7. RATIONALE AND BACKGROUND 
BC is the most frequently occurring cancer in women and is a major public health problem, 
with 1.7 million new cases diagnosed globally in 2012, representing 25% of all incident 
cancer cases (1). In Europe, more than 464,000 new cases of BC were diagnosed in 2012. 
The UK incidence rate is the sixth highest in Europe, with around 54,900 new BC cases 
every year (2). HR+ BC represents the largest therapeutic subtype of the disease and 
accounts for over 80% of cases in the UK (4).  
Annually, approximately 6-7% of new BC cases present as de novo metastatic disease and 
approximately 30% of women with early BC go on to develop metastatic disease (2). 
Survival from BC largely depends on the stage at diagnosis; the 1-year survival is 100% for 
patients diagnosed at stage I, versus 63% for patients diagnosed at stage IV; and five-year 
survival is 99% and 15% respectively for stage I and IV (5,6). 

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Up until the addition of palbociclib, low survival rates reflected that current therapies were 
generally unsuccessful in treating MBC, and as such that there was a significant unmet need 
for the development of better treatment options (7). Traditional treatment selection for MBC 
is based on biomarkers including hormone receptor positivity and HER2 status, and 
individual patient and clinical characteristics that may include tumour burden, timing of 
disease recurrence, and the type of prior adjuvant therapies (8). HR+ BCs are generally 
receptive to hormonal therapy. However, their clinical benefit is limited in the case of 
patients with MBC who are diagnosed as HER2-  (9). Considering the multiple pathways 
involved in the hormone receptor network, targeting other components of pathologically 
activated intracellular signalling in BC has provided a direction for the development of novel 
therapies. The cyclin-dependent kinases (CDKs) are a large family of serine-threonine 
kinases that play an important role in regulating cell-cycle progression (10). The CDK4 and 
CDK6 inhibitors act at the transition from G1 phase of the cell cycle to S phase. This 
transition checkpoint is tightly controlled by the D-type cyclins and CDK4 and CDK6. When 
CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate the retinoblastoma-
associated protein. This suspends suppression of the E2 factor transcription factor family by 
the protein and ultimately allows the cell to proceed through the cell cycle and divide. In 
HR+ BC, cyclin D overexpression is common and loss of retinoblastoma-associated protein 
is rare, therefore making the transition checkpoint a potential therapeutic target. The CDK4 
and CDK6 inhibitors prevent progression through this checkpoint, leading to cell cycle arrest, 
and have changed the treatment landscape for patients with HR+/HER− MBC (11).  
 
Palbociclib, a CDK4/6 inhibitor, first received a EU marketing authorisation in September 
2016, to be commercialised as Ibrance® by Pfizer to be used in women in the first line 
setting as well as in those who have received prior endocrine therapy in combination with 
letrozole (an aromatase inhibitor)) or fulvestrant (an estrogen receptor down regulator) (12).  
 
Palbociclib was approved for use as first-line treatment of HR+/HER2− advanced BC in 
postmenopausal women, based on the phase II study Palbociclib Ongoing Trials in the 
Management of BC (PALOMA) PALOMA-1(13) and the phase III study PALOMA-2 (10). 
Palbociclib was approved for use with fulvestrant as second- or later-line treatment of 
HR+/HER2− advanced BC based on the phase III study PALOMA-3 (14,15).  In PALOMA-
1, median PFS was 20.2 months for the palbociclib-letrozole group versus 10.2 months for 
the placebo-letrozole group (hazard ratio [HR] for risk of progressing: 0.488, 95% 
confidence interval 0.319-0.748) (13); and In PALOMA-2, it was respectively 24.8 months 
versus 14.5 months (hazard ratio 0.58; 0.46 to 0.72) (10). In PALOMA-3, median PFS was 
9.5 months in the palbociclib-fulvestrant group versus 4.6 months in the placebo-fulvestrant 
(hazard ratio (HR): 0.46, 0.36-0.59)(14); and specifically for patients with prior resistance to 
hormonal therapy and visceral metastases, it was respectively 9.2 months versus 3.4 (HR, 
0.47; 0.35–0.61) (15). 
 
Palbociclib was recommended for use with an aromatase inhibitor in patients with locally 
advanced and MBC in the NHS in England by NICE in November 2017 and by the SMC in 
December 2017 (16,17). In order to provide access to palbociclib in the UK during the 

IBRANCE 
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NICE/SMC appraisal period, the IPP was run by Pfizer between April 2017 and November 
2017 for England and Wales, and December 2017 for Scotland. The IPP provided free access 
to treatment to NHS patients with previously untreated (or >12 month since discontinuation 
of  adjuvant or neoadjuvant treatment with a nonsteroidal aromatase inhibitor), HR+/HER2- 
MBC (18). 
 
Palbociclib and other CDK4/6 inhibitors have been generally well tolerated by patients. 
Based on pooled data from 3 randomised studies in patients who received palbociclib in 
combination with endocrine therapy (N=872), one most common side effect has been 
neutropenia soon after initiation of therapy which affects 80.6% of patients, including 10.1% 
experiencing grade 4 neutropenia and 1.6% experiencing febrile neutropenia (19). 
Palbociclib-induced neutropenia has also been shown to reverse rapidly with dose 
interruption and/or dose reduction (11). 
 
Several real-world observational studies focusing on the real-world treatment pattern of 
palbociclib have been conducted in the United States (US) since its approval by the US Food 
and Drug Administration (FDA) in February 2015 for patients with advanced or MBC 
(3,18,19). A retrospective observational study using a US electronic medical record database 
was conducted in 763 patients with advanced BC treated with palbociclib (8). More than two 
thirds (69.9%) of patients had a confirmed HR+/HER2- tumor. Of those, 612 (80.2%) 
received palbociclib concomitantly with letrozole. Mean follow up was 6.4 months and mean 
age at palbociclib initiation was 64 years. Dose reductions were observed in 20.1% of 
patients and 74.6% of patients had a neutropenic event during follow up (47.3% grade 3 and 
8.0% grade 4). In another US study in 1242 postmenopausal women with HR+/HER- MBC 
in the Symphony Health Solutions database, mean age at initiation of palbociclib was 62.7 
years and median follow-up was 8.7 months (20). During the 12-month post-index period, 
32–34% of patients reduced dose and 64–81% reduced or changed treatment.   
 
Pfizer are interested in the opportunity to collect data from patients who received palbociclib 
as part of the IPP, to better understand effectiveness and safety of palbociclib when used in 
routine care in a UK context, with a focus on treatment persistence and dose management, 
patients’ characteristics, clinical outcomes, and healthcare resource utilisation. This study 
will evaluate patients’ clinical progression and experience of treatment with palbociclib in 
routine clinical practice in the UK. This study may be of benefit to the NHS and patients in 
supporting assessments of the benefit of palbociclib in routine care; and will also help 
contextualise evidence on safety of palbociclib previously generated from the real-world 
studies in US populations.  
 
8. RESEARCH QUESTION AND OBJECTIVES 
What are the real-world treatment patterns, patients’ characteristics, clinical outcomes and 
healthcare resource utilisation associated with palbociclib treatment in the 3 years following 
initiation in UK patients with HR+/HER2- MBC treated as part of the IPP?  
 

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Primary objectives:  
 
• To describe patient demographic and clinical characteristics at initiation of palbociclib. 
Secondary objectives 
 
• To describe treatment pattern (as per licence/IPP requirement); including the proportion 
of patients with dose modification and who switch treatment 1, 2 and 3 years after 
palbociclib initiation, and median time to dose modification and treatment 
discontinuation (‘drug survival’). For patients who progress, to describe the 1st /2nd /3rd 
line of treatment after progression.  
To describe overall survival and progression-free survival, response (CR, PR), stable 
disease. This includes estimating the proportion of patients achieving those endpoints at 
1, 2 and 3 years following palbociclib initiation; median survival, time to response and 
duration of response. In patients who respond to treatment, to describe PR and CR using 
“swimmer plots”. 
 
• To describe the occurrence of neutropenia during the first year post-initiation observation 
period. 
 
• To describe the occurrence of gastro-intestinal toxicity, including diarrhoea, nausea and 
vomiting during the first year post-initiation observation period. 
 
• To describe progression of clinical indicators, including biochemical and radiological 
indicators at each time-point available during the first year following palbociclib 
treatment initiation (e.g. full blood counts, liver function tests, bone profile). 
 
• To describe BC related healthcare resource utilisation (hospital admissions, outpatient 
visits, calls to Cancer National Services (CNS) and contacts with the Acute Oncology 
Service (AOS)) during the first year following palbociclib initiation. 
 
9. RESEARCH METHODS  
The study is designed and will be conducted according to the requirements of the European 
Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; (22)) 
International Society for Pharmacoepidemiology (ISPE; (23)) guidance, European Union 
General Data Protection Regulation (GDPR; (24)) and national data protection legislation 
and regulations, as appropriate.  
9.1. Study design  
This study will be a UK-wide, multi-centre, non-interventional cohort study (Figure 1). The 
study will involve secondary use of hospital medical records (paper-based or electronic, as 

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appropriate), collected both retrospectively and prospectively, from patients’ medical 
records. Data will be collected for a maximum of 3 years following enrollment into the IPP.   
Consent from living patients will be required if data are collected by pH Associates. In that 
case, patients will be provided with information about the study and approached for consent 
by members of the direct care team, either by post or in person at a routine hospital visit. 
Since no consent can be obtained if the patient is deceased, identifiable medical records of 
deceased patients will be accessed for study data collection by the direct care team only, to 
preserve confidentiality and avoid bias arising from exclusion of deceased patients. 
 
Data will be collected retrospectively from the point of patient’s enrollment into the IPP until 
initial data collection, expected to take place between November 2018 and February 2019. 
Members of the direct care team, or researchers from pH Associates (for living patients 
only), will collect existing (retrospective) data from the medical records of eligible patients in 
an electronic case report form (eCRF).  
 
After the initial retrospective data collection, data will be collected prospectively up to a 
maximum of 3 years from enrollment in the IPP by members of the direct care team by 
updating the eCRF with any subsequent therapeutic and progression data available in the 
medical records until the end of the 3 year follow-up period.  
 
The palbociclib initiation date will be defined as the index date. The baseline period will 
extend from the date of diagnosis up to palbociclib initiation (index date). The post-initiation 
observation period will be defined as the period from the index date until the end of the 3 
year follow-up period. Patients will contribute data up to the time that they are lost to follow-
up (for example due to discharge, death or other reasons) or 3-year post-index observation 
period, whichever is sooner.  
 
Figure 1. Schematic of study design 
 
 
 

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9.2. Setting 
The study will be conducted in 8 or 9 NHS Trusts (See Annex 1).  Sites have been selected 
on the basis that:  
- 
They are geographically dispersed across the UK. 
- 
Their cancer service participated in the IPP. 
- 
They have appropriate and sufficiently trained personnel available locally to identify 
eligible patients and support the study delivery in accordance with applicable legal 
and regulatory requirements. 
- 
They treated at least 15 patients as part of the IPP, so that collectively the total 
number of patients across the selected sites approximates 250 patients. One site was 
also selected due to the lead clinician’s membership in the steering committee.  
Membership of the steering committee was based upon two criteria 1) membership of 
the National Cancer Research Institute (NCRI) MBC subcommittee and 2) had 
patients on the IPP.  All members of the steering committee meet this criteria.  The 
NCRI subcommittee is an independent committee from Pfizer, and Pfizer has no 
input into the committee as part of this study. 
- 
They have an interest in taking part in the study. 
 
9.2.1. Inclusion criteria 
All patients meeting the following eligibility criteria will be included in the study:  
  
• Patients enrolled into the IPP at one of the selected hospitals (see Annex 1 for IPP 
enrolment letter).   
• Patients who received ≥1 dose of palbociclib as part of the IPP at one of the selected 
sites. 
• For sites where data collection is performed by pH Associates, written informed consent 
will be required from living patients to access their medical records. 
• Patient aged ≥18 years old at enrollment into the IPP 
 
9.3. Variables 
The endpoints associated with each of the study objectives are described below, along with 
the variables that will be collected in order to address the objectives. Response options for 
each variable will be further detailed in the eCRF. A list of variables is available in Annex 2.  
 

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Endpoints to address the objective 
Variables required to address objective 
Primary objective: To describe patient demographic and clinical characteristics at initiation of 
palbociclib. 
• 
Demographic 
characteristics 
of 
patients, 
including summary measures of age, sex, 
ethnicity and menopausal status at initiation of 
palbociclib. 
• 
Summary measures of BC characteristics at 
the time closest prior to initiation of 
palbociclib: 
o recurrence,   stage and grade of 
disease, Ki-67 protein proliferation 
index, site of metastases,  lymph node 
involvement (including number of 
lymph 
nodes), 
oestrogen-receptor 
status, progesterone-receptor status, 
and HER2 status. 
• 
Duration of BC disease at initiation of 
palbociclib. 
• 
Treatment 
for 
BC 
diagnosis 
prior 
to 
palbociclib initiation. 
• 
Summary measures of relevant comorbidities 
diagnosed at or prior to initiation of 
palbociclib. 
• 
Palbociclib prescribed as on-label or off/label 
use according to Summary of Products 
Characteristics(19) 
 
• Sex (male / female). 
• Month and year of birth. 
• Ethnicity (categories to be defined in eCRF). 
• Menopausal status (Yes [Y]/No [N]). 
• For latest BC diagnosis prior to initiation of 
palbociclib: 
o Date of BC diagnosis. 
o Recurrence: 
Loco-regional, 
local, 
regional, distant, newly diagnosed.  
o Stage of disease: I, I, III, IV. 
o Grade of disease: 1,2, 3. 
o Biopsy results: Ki-67 proliferation 
index. 
o Site of metastases: lung, liver, other 
visceral, brain, bone, other non-
visceral. 
o   Lymph node involvement: Y/N, if Y 
report number of lymph nodes. 
o  Oestrogen-receptor status: Y/N. 
o Progesterone-receptor status: Y/N.  
o HER2 status: Positive/ Negative. 
• 
Treatment 
for 
BC 
diagnosis 
prior 
to 
palbociclib initiation :  
o (neo)-adjuvant 
chemotherapy: 
pathological 
complete 
response 
achieved Y/N, date start and date 
stopped. 
o Type 
of 
surgery: 
wide 
local, 
mastectomy. 
o (neo) adjuvant oestrogen therapy: date 
start and stopped. 
• Relevant comorbidities documented within 
baseline period (to include all individual 
components of the Deyo-Charlson comorbidity 
index from the National Cancer Institute [NCI-
DCI] (25)), to be further defined in full in the 
eCRF). 
Secondary objective: To describe treatment pattern (as per licence/IPP requirement); including the 
proportion of patients with dose modification and who switch treatment 1, 2 and 3 years after 
palbociclib initiation, and median time to dose modification and treatment discontinuation (‘drug 
survival’). For patients who progress, to describe the 1st /2nd /3rd line of treatment after progression.  

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• 
Summary measures of palbociclib treatment 
patterns, including: 
o Starting dose. 
o Proportion of patients with dose reductions 
at 1, 2 and 3 years after initiation. 
o Proportion of patients with palbociclib 
treatment discontinuation at 1, 2 and 3 years 
after initiation. 
o Mean (Standard Deviation [SD]) dose 
intensity over the course of treatment in 
patients 
who 
complete 
treatment 
of 
palbociclib 
o Median time to dose reduction in number of 
days (from start of treatment) and in terms 
of number of cycles (completed or 
interrupted).  
o Median time to dose increase in number of 
days (from start of treatment) and in terms 
of number of cycles (completed or 
interrupted); 
only 
in 
patients 
with 
previously reduced dose 
o Median time to palbociclib discontinuation 
(‘drug survival’) in number of days (from 
start of treatment) and in terms of number 
cycles (completed or interrupted).  
o Reasons for discontinuation. 
o 1st, 2nd and 3rd line of treatment after 
progression: number of patients prescribed 
each medication, dose, and length of 
treatment. 
• 
Description of the number of patients which 
are being prescribed as per posology of 
treatment (19):  
o Proportion of patients who complete a 
28-day cycle (21 days daily dose 
followed by 7 days off treatment). 
o Mean (SD) of completed 28 day 
cycles.  
o Proportion of patients co-administered 
letrozole at palbociclib initiation. 
o Proportion of patients co-administered 
fulvestrant at palbociclib initiation. 
 
• Palbociclib: date on initiation, initial dose, date 
of dose reduction, subsequent dose, dates of 
cycle initiation and completion, date of 
discontinuation (indicate whether last cycle is 
interrupted 
or 
completed), 
reasons 
for 
palbociclib dose reduction / increase / 
discontinuation. 
• Date of start and end of concomitant 
medication treatment: letrozole, fulvestrant, 
osteo-strengthening 
drugs 
(denosumab, 
zometa), other drugs. 
• First 3 lines of medication after palbociclib 
discontinuation: name, dose and length of 
treatment. 
Secondary objective: To describe overall survival and progression-free survival, response (CR, PR), 
stable disease. This includes estimating the proportion of patients achieving those endpoints at 1, 2 and 
3 years following palbociclib initiation; median survival, time to response and duration of response. In 
patients who respond to treatment, to describe PR and CR using “swimmer plots”. 

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• 
Proportion of patients at 1, 2 and 3 years 
following initiation of palbociclib who:  
o Are free from disease progression. 
o Are alive  
o Achieved PR  
o Achieved CR 
o Had stable disease 
• 
Median (95% confidence interval [CI]) :  
o PFS 
o OS 
o Time 
to 
achieving 
best 
overall 
response  
• 
Summary measures of duration of response 
(Kaplan-Meier analysis).  
• 
Representation of all radiological assessment 
of response (CR / PR / no response or stable 
disease / progressive disease) in patients 
responding to treatment (achieving CR or PR 
following initiation of palbociclib) using 
“swimmer plots”. 
  
• Date 
((DD/MM/YYYY) 
unless 
specified 
otherwise) of start and end of palbociclib. 
• Date of data collection. 
• Patient status at the end of data collection 
period (alive/dead): 
o Date of death / last clinic visit. 
o If not known (i.e. lost to follow-up), date of 
last recorded hospital visit. 
• Radiological assessments of response during 
the follow-up period: date of assessment and 
outcome (CR / PR / no response or stable 
disease / progressive disease), as documented 
by the local investigator. 
 
Secondary objective: To describe the occurrence of neutropenia during the first year post-initiation 
observation period. 
• 
For each cycle, proportion of patients at day 1 
into the cycle, day 15 into the cycle, day 22 
into the cycle (and number of patients 
assessed) who experience:  
o Neutropenia, overall and by grade. 
o Febrile neutropenia. 
• 
Summary measures of incidence of:  
o Neutropenia, overall and by grade. 
o Febrile neutropenia. 
 
• Incidence (Y / N) and date(s) of occurrence of 
neutropenia 
(by 
grade) 
and 
febrile 
neutropenia.  
   
Secondary objective: To describe the occurrence of gastro-intestinal toxicity, including diarrhoea, 
nausea and vomiting during the first year post-initiation observation period. 
• 
For each cycle, proportion of patients at day 1 
into the cycle, day 15 into the cycle, day 22 
into the cycle (and number of patients 
assessed) who experience Gastro-intestinal 
toxicity, including:  
o Diarrhoea 
o Nausea  
o Vomiting 
 
• 
Summary measures of incidence of:  
o Diarrhoea 
o Nausea  
o Vomiting 
Incidence (Yes / No) and date(s) of occurrence of 
gastro-intestinal toxicity, including:  
o Diarrhoea 
o Nausea  
o Vomiting 
 
   

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Secondary objective: To describe progression of clinical indicators, including biochemical and 
radiological indicators at each time-point available during the first year following palbociclib treatment 
initiation (e.g. full blood counts, liver function tests, bone profile). 
• Summary measures of full blood counts in the 
first year following initiation: haemoglobin, 
white cell counts, absolute neutrophil counts, 
platelet counts. 
• Summary measures of liver function tests in 
the first year following initiation: aspartate 
transaminase 
(also 
called 
aspartate 
aminotransferase), alanine transaminase (also 
called alanine aminotransferase), and alkaline 
phosphatase.  
• Summary measures of bone profile in the first 
year following initiation: calcium, phosphate. 
• Summary measures of radiological indicators 
in the first year following initiation: stable 
disease, progressive disease, CR/PR 
• Date and laboratory results as clinically 
indicated for each full blood count: pre-first 
cycle, on day 1 of each cycle of treatment, on 
day 15 into cycles 1 and 2 and day 22 if 
abnormal results at day 15. 
• Date and liver function test results for each test 
as above. 
• Date and bone profile results for each test. 
• Date and results of radiological examinations:  
stable disease, progressive disease, CR/PR 
Secondary objective: To describe BC-related healthcare resource utilisation (hospital admissions, 
outpatient visits and calls to CNS) during the first year following palbociclib initiation. 
• Summary measures of hospital admissions for 
each line of therapy, including:  
o Inpatient admissions per patient, including 
elective 
or 
non-elective 
and 
reasons 
(including day-case). 
o Length of stay per inpatient admission.  
o Emergency department visits per patient. 
o Outpatient visits per patient. 
• Summary of phone calls from patient to CNS. 
• Summary of contacts to AOS. 
 
• BC-related inpatient admission: dates, reason 
and duration (derived from dates of hospital 
entry and discharge) of hospitalisation: 
o Type: planned (elective) or Accident and 
Emergency (A&E). 
• BC-related outpatient admission: dates, reason.  
• Phone calls from patients to CNS: dates, 
reason. 
• Recorded contacts with AOS: dates, reason, 
type of contact (phone calls, visits). 
The following definitions will be implemented. PFS will be defined as the time from the date 
of palbociclib initiation to the date of first documented disease progression (i.e. mention of 
disease progression or mixed response in the medical records, e.g. due to evidence of a new 
site of disease, or increasing disease, after treatment initiation) or death. OS will be defined 
as the time from the date of palbociclib initiation until death from any cause. Time to 
achieving best overall response will be defined in patients who respond to treatment as the 
time from the date of palbociclib initiation until achievement of the best overall response: 
CR, or PR if CR is not achieved during follow-up. Duration of response will be defined as 
the time from the date CR or PR was first documented (whichever is recorded first) to the 
date of first documented disease progression or death from any cause (whichever occurs 
first). 

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9.4. Data sources  
Data for this study will be collected through retrospective and prospective patient chart 
review from 8-9 cancer services of NHS Trusts in the UK. A feasibility pilot for data 
collection will be carried out on 10 of the initial patients’ data collected.  These patients will 
be selected from one or two centres (dependent on the speed of data capture) to enable the 
data to be reviewed at the earliest opportunity. The purpose of this pilot will be to check the 
availability and quality of data that will be collected in the study, and to confirm the length of 
time required to collect the data.  
Data on patient demographic and clinical characteristics, treatment patterns, outcomes, 
healthcare resource use and AEs will be collected in deidentified-coded form, from paper 
based and/or electronic hospital medical records (as applicable at each site) by members of 
the patients’ direct care team or pH Associates.  
9.5. Study size 
This is a descriptive study and there is no a priori hypothesis specified. Therefore the sample 
size has been chosen pragmatically, based on the available patients from the IPP.  
  
Across the entire UK, 846 women received palbociclib as part of the IPP. In the sites selected 
for this study, approximately 250 patients (exact number will be updated after site 
confirmation and patient consent) received palbociclib as part of the IPP. All eligible patients 
within the selected sites will be recruited into the study.    
 
9.6. Data management  
Data management and handling of data will be conducted according to the study specific data 
management plan and in accordance with ENCePP/ISPE/ guidance and the General Data 
Protection Regulation and applicable national data protection legislation and regulations. 
Data for the study will be collected via an electronic data capture system using a standardised 
eCRF designed specifically for the study in accordance with this protocol. All data will be 
collected from hospital medical records by members of the NHS direct care team or an 
external researcher from pH Associates.  
 
Before the start of data collection, NHS staff collecting data from patients’ hospital medical 
records will be trained in data entry into the eCRFs by study management staff from pH 
Associates and consistency checks will be built into the eCRF to ensure data quality.  
 
Patients will be identified in all study records by a unique study code to link multiple study 
records for each participant  and preserve patient confidentiality. 
 
Data management for eCRFs will be carried out using MACRO™, a data management 
system which has a secure web-based data entry interface and is fully validated and 
compliant with the International Council for Harmonization E6 Good Clinical Practice 
guidelines, FDA Information Governance standard 21 Code of Federal Regulations Part 11 
and the EU Clinical Trials Regulation, and the UK Medicines and Healthcare products 

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Regulatory Agency requirements. The MACRO™ system has restricted access permissions 
for data entry and data management, and records an audit trail of all changes to data and 
activity in the system. Access to the study in MACRO™ will be restricted (by password 
protection) to only those members of staff directly involved with the study and assigned 
access permissions will control the level of access to that required for the role of each 
individual working on the study. If corrections are needed to an eCRF, queries will be raised 
in the electronic data capture system by the study data manager and these will be resolved by 
the responsible investigator (or designee) by reference to the source records or agreed 
assumptions. 
 
After obtaining the appropriate local approvals for data release, the deidentified data for this 
study will be collated and transferred securely to pH Associates, who will be the Data 
Processor for data management, analysis and reporting on behalf of Pfizer, the Data 
Controller. Pfizer will not have access to individual patient level data.After the initial 
retrospective data collection, data will be collected prospectively up to a maximum of 3 years 
from enrollment in the IPP by members of the direct care team by updating the eCRF with 
any subsequent therapeutic and progression data available in the medical records until the 
end of the 3 year follow-up period.  
 
9.6.1.  Case Report Forms (CRFs) 
As used in this protocol, the term eCRF should be understood to refer to an electronic data 
record. 
An eCRF is required and should be completed for each included patient.  The completed 
original eCRFs are the sole property of Pfizer and should not be made available in any form 
to third parties, except for authorised representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
eCRFs are securely stored at the study site in encrypted electronic form and will be password 
protected or secured in a locked room to prevent access by unauthorised third parties. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
eCRFs must be signed by the investigator or by an authorised staff member to attest that the 
data contained on the eCRFs are true.  Any corrections to entries made in the eCRFs or 
source documents must be dated, initialed, and explained (if necessary) and should not 
obscure the original entry. 
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the eCRFs must match those charts.  
In some cases, the eCRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the eCRF, and for which the eCRF will stand as the source document.  

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9.6.2.  Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, e.g., eCRFs and hospital records), all original signed 
informed consent documents, copies of all eCRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, and telephone call reports).  The records 
should be retained by the investigator according to local regulations or as specified in the 
clinical study agreement, whichever is longer.  The investigator must ensure that the records 
continue to be stored securely for so long as they are retained. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
9.7. Data analysis  
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a separate 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. 
Analyses will be performed by pH Associates using Stata (StataCorp LLC) and R. Data from 
all participating centres will be pooled for analysis. 
According to the objectives, descriptive statistics will be presented using data at 1 year (using 
retrospective data collected) or 2 and 3 years (using the prospective data as well as the 
retrospective data collected) following initiation of palbociclib. Clinical measurements will 
be presented at each time-point available, as described in section 7.3. The interim study 
report will only present results for objectives which are relevant to the 1-year follow-up 
period and the final report will present results for objectives which are relevant up to the 3-
year follow-up period.  
Descriptive statistics (numbers, percentages, means, standard deviations [SD], medians, 
quartiles, minimum, and maximum), as appropriate to the data collected, will be used to 
describe baseline demographic and clinical characteristics for the overall study. Treatment 
patterns and hospital admissions will also be reported using descriptive statistics. The 
frequency and proportion of patients experiencing a neutropenia, febrile neutropenia event; 

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and gastro-intestinal toxicity including diarrhea, nausea and vomiting, during follow-up, will 
be presented.  
Definitions will be implemented as described in section 9.3 Variables.  Patients who are 
known to be alive at the date of data collection (1-year for interim report and 3-year for full 
study report) will be censored at the date of data collection, and patients who are lost to 
follow-up will be censored on the date they were last known to be alive (e.g. date of last 
recorded hospital visit). Patients who are alive and free from disease progression at the date 
of data collection and those lost to follow-up will be censored on the date they were last 
known not to have disease progression (i.e. the date of last documented response 
assessment).  Patients remaining in CR or PR at the end of the post-initiation observation 
period or lost to follow-up will be censored on the date CR or PR was last documented.  
For the estimation of the proportion of patients alive, and free from disease progression, the 
denominator will be all patients known to be alive at the selected time-points (1 years, 2 
years and 3 years). For the estimation of the proportion of patients achieving PR, CR and 
with stable disease at the selected time-points (1 years, 2 years and 3 years), the denominator 
will be all patients with at least one assessment of response (CR / PR / no response or stable 
disease / progressive disease) in the past year. Estimation of time to achieving best overall 
response and duration of response; and representation using swimmer plots will be performed 
in patients who respond (achieve CR or PR during follow-up) only. 
Median PFS, OS, time to achieving best overall response, time to palbociclib dose 
modification and time to palbociclib discontinuation, and corresponding 95% CIs, will be 
estimated using Kaplan-Meier curves. Assessments of response (CR / PR / no response or 
stable disease / progressive disease ) in patients responding to treatment (achieving CR or PR 
following initiation of palbociclib) will be represented using “swimmer plots”. 
All percentages will be reported to the nearest whole number; therefore, in reporting study 
results in tables, figures and associated text, percentages may not add up to 100% due to 
rounding.  
Where dates are ambiguous because of missing day and/or months, standard imputation will 
be applied: where day is missing the 15th of the month will be assumed; where both day and 
month are missing the 1st of July will be assumed unless data collected is in 2017 (year of 
initiation of IPP) in which case the 15th of August will be assumed (midpoint as IPP was 
initiated in April 2017). Where other types of data are missing from the original medical 
record, the affected analyses will be conducted using only the results of those patients with 
data available and the number included in each analysis will be stated. The percentage of data 
missing will be reported for each study variable. The calculation of percentages will not 
contain the missing categories. Counts of missing observations will be presented in a separate 
category. 
 

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9.8. Quality control 
All data collectors will be provided with Data Collection Guidelines to facilitate consistent 
completion of the eCRF and will receive training in the requirements of the study protocol 
and correct completion of the eCRF prior to commencement of data collection. 
The accuracy and quality of data collection will be monitored by reference to source data 
(source data verification [SDV]).  
 
SDV will be performed on the complete dataset of a random sample of at least 10% of 
patients from each centre. Any issues identified by pH Associates relating to quality, 
accuracy or consistency of data collection will be discussed with the data collector concerned 
and further training provided by pH Associates if required. If any subsequent issues are 
identified related to quality, accuracy or consistency of data collection, a random check of a 
further 10% of data collected by that data collector will be undertaken. Should any further 
issues be identified, 100% SDV will be undertaken at the centre. It is the centre Investigator's 
responsibility to ensure the accuracy of the data entered in the CRFs. 
 
Where patient study data are collected by pH Associates, SDV will be performed by a pH 
Associates study monitor who did not collect data for that patient record. For patients whose 
entire dataset was collected by members of patients’ direct care team, a ‘back-to-back’ SDV 
will be performed with a member of the direct care team, as these patients will not have 
provided consent to their data being accessed by external researchers from pH Associates. 
This will involve the direct care team member at the centre reciting data from the patient 
notes to the pH Associates study monitor so that they can verify the data in the eCRF without 
the need to look directly at the identifiable source records.. All people performing SDV will 
be trained by pH Associates. 
 
All clinical data submitted will be checked for eligibility, completeness and accuracy by the 
pH Associates data management team using agreed manual and programmed validation 
checks and queries will be raised. Study centres will be required to co-operate with the data 
management team in the resolution of these queries.  
 
Analysis of the primary endpoint will be independently reviewed by a member of the Data 
Analysis team at pH Associates who was not involved in the analysis of the final study data. 
No additional analysis checks will be carried out. 
Investigators taking part in the study will have all required training for delivery of the study 
 
9.9. Limitations of the research methods 
• Comparisons of the results of this study with that of clinical trials and other real-
world studies may be limited due to the presence of several potential sources of bias.  
• Several sources of selection bias may be introduced in the study:  

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o At sites where data are collected by pH Associates, consent from living 
patients will be required; and consequently a low rate of consent amongst 
living patients may introduce an over-representation of deceased patients (for 
whom consent is not required) at those sites, and also compared to sites where 
consent is not required as all data are collected by the direct medical care 
team.  
o Patients were treated as part of routine care and therefore patients enrolled in 
this study may have more diverse characteristics than in a clinical trial setting 
(for example with regard to menopausal status, ER and PR status, HER2 
status), which may impact on the efficacy of palbociclib.  
o Patients will be recruited from larger centres enrolled in the IPP, which may 
differ from smaller centres in terms of demographic and clinical 
characteristics, and therefore may not be representative of all patients treated 
with palbociclib in routine care as part of the IPP.  
• Patients may be lost to follow-up due to the occurrence of AEs, lack of efficacy or 
other reasons, introducing attrition bias. However, the use of Kaplan-Meier curves 
will be used to obtain estimates of median PFS OS, CR, PR and this takes into 
account patient attrition. 
• Radiological results will be collected from medical notes recorded by radiologists 
who were unblended to patient’s treatment, introducing potential measurement bias.  
• The interpretation of data collected retrospectively will be dependent on the 
completeness and quality of the medical records and the reliability of the abstraction 
of data from the medical records. However, SDV will be employed to identify and 
correct abstraction errors. 
• This is a descriptive study and no analyses to control for confounding will be carried 
out; therefore, no definitive causal relationships between Ibrance® and study 
endpoints can be made. 
• At sites where data are collected by pH Associates, a low consent rate may diminish 
sample size and the target of 250 patients enrolled into the study may not be achieved. 
If <200 patients are recruited into the study, an expansion of the study to other sites 
involved in the IPP will be considered.   
9.10. Other aspects 
Not applicable. 
10. PROTECTION OF HUMAN SUBJECTS 
Not applicable 

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10.1. Patient Information  
All parties will comply with all applicable laws, including laws regarding the implementation 
of organisational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws.  
 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected or secured in a locked room to ensure that only authorised study staff 
members have access.  The study site will implement appropriate technical and 
organisational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorised parties will be identified by this single, patient-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the Clinical Study Agreement and applicable privacy laws. 
10.2. Patient Consent 
For deceased patients at the time of data collection, as this study involves deidentified 
structured or unstructured data sharing with researchers (the direct care team will produce 
deidentified research records from identifiable patients’ records to preserve confidentiality), 
which according to applicable legal requirements do not contain data subject to privacy laws, 
obtaining informed consent from patients by Pfizer is not required.   
For living patients at the time of data collection, the informed consent documents and any 
patient recruitment materials must be in compliance with local regulatory requirements and 
legal requirements, including applicable privacy laws. 
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/REC 
before use, and available for inspection. 
The investigator must ensure that each study patient or his or her legally acceptable 
representative is fully informed about the nature and objectives of the study, the sharing of 
data relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the patient’s personal data.  The investigator further must 
ensure that each study patient or his or her legally acceptable representative is fully informed 

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about his or her right to access and correct his or her personal data and to withdraw consent 
for the processing of his or her personal data. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed unless a waiver of 
informed consent has been granted by an IRB/REC.  The investigator will retain the original 
of each patient's signed consent document. 
10.3. Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons.  In any circumstance, every effort should be made to document 
patient outcome, if possible.  The investigator should inquire about the reason for withdrawal 
and follow-up with the patient regarding any unresolved adverse events.   
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
10.4. Institutional Review Board (IRB)/Research Ethics Committee (REC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(e.g., recruitment advertisements), if applicable, from the IRB/REC.  All correspondence 
with the IRB/REC should be retained in the Investigator File.  Copies of IRB/REC approvals 
should be forwarded to Pfizer.  
10.5. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in the Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology 
Practices issued by the International Society for Pharmacoepidemiology, European 
Medicines 
Agency 
(EMA) 
ENCePP 
Guide 
on 
Methodological 
Standards 
in 
Pharmacoepidemiology, and European Union  General Data Protection Regulation (GDPR).  
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
An AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have to have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.  The 
definition of an AE includes worsening of a pre-existing medical condition. A serious 
adverse event is any adverse drug reaction as defined above that:  

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• is fatal 
• is life threatening (places the subject at immediate risk of death) 
• requires in-patient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• other significant medical hazard. 
 
A serious adverse drug reaction is a serious adverse event that is considered related to the 
medicinal product. 
 
A hospitalisation meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a healthcare facility.  
“Other significant medical hazards” refer to important medical events that may not be 
immediately life-threatening or result in death or hospitalisation, but may jeopardise the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above.  Examples of such events could include allergic bronchospasm, 
convulsions, and blood dyscrasias, drug-induced liver injury, events that necessitate an 
emergency room visit, outpatient surgery, or other events that require other urgent 
intervention.  
All AEs related to any Pfizer product(s) shall be reported to Email Transmission: 
GBR.AEReporting@pfizer.com; Facsimile Transmission: 0800 015 6401 (toll free) 0845 
300 8032 (toll); Telephone Contact: 0845 300 8031 (toll free) 0845 300 8032 (toll); 
Address: Pfizer Pharmacovigilance, Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, 
Surrey KT20 7NS; by the Principal Investigator at each centre or pH Associates within 24 
hours of discovery or notification.  AE information must be recorded on the AE form emailed 
and/or faxed to  Email Transmission: GBR.AEReporting@pfizer.com; Facsimile 
Transmission: 0800 015 6401 (toll free) 0845 300 8032 (toll); Telephone Contact: 0845 
300 8031 (toll free) 0845 300 8032 (toll). 
Adverse drug reactions for non-Pfizer products should be notified by the Principal 
Investigator at each centre to the appropriate Marketing Authorisation Holder and/or to the 
Medicines and Healthcare Regulatory Authority (MHRA). 
All pregnancies occurring in female patients while taking Pfizer products, and all 
pregnancies occurring in female partners of male patients taking Pfizer products should be 
reported to Email Transmission: GBR.AEReporting@pfizer.com; Facsimile 
Transmission: 0800 015 6401 (toll free) 0845 300 8032 (toll); Telephone Contact: 0845 
300 8031 (toll free) 0845 300 8032 (toll); Address: Pfizer Pharmacovigilance, Pfizer 
Limited, Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS. 
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 AEs with 

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explicit attribution to any Pfizer drug that appears 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 adverse event 
monitoring  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 non-interventional study 
adverse event management report  and reported, within 24 hours of awareness, to 
Pfizer Safety using the non-interventional study 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 non-
interventional study adverse event monitoring Report Form. 
For these safety events with an explicit attribution to or associated with use of, respectively, a 
Pfizer product, the data captured in the medical record will constitute all clinical information 
known regarding these AEs.  No follow-up on related AEs will be conducted. 
All research staff members will complete the Pfizer requirements regarding training on the 
following:   “Your Reporting Responsibilities: Monitoring the Safety, Performance and 
Quality of Pfizer Products (Multiple Languages)” and any relevant Your Reporting 
Responsibilities supplemental training.  This training 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.   
 
11.1. Single Reference Safety Document 
The palbociclib Summary of Product Characteristics(19) will serve as the Single Reference 
Safety Document (SRSD) during the course of prospective data collection part of the study, 
which will be used by Pfizer safety to assess any safety events reported to Pfizer Safety by 
the investigator during the course of this study. The SRSD should be used by the investigator 
for prescribing purposes and guidance. 
 

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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The study will be reported according to the requirements of Strengthening the reporting of 
observational studies in epidemiology (STROBE)  (26). 
Authorship of publications arising from the study will follow the 2015 guidelines proposed 
by the International Committee of Medical Journal Editors (ICMJE) (27).).  All authors will 
meet the criteria for authorship, and all people who meet the criteria will be authors.  
Potential conflicts of interest will be disclosed.  All authors will have:  
• made substantial contributions to conception or design or acquisition of data, or 
analysis and interpretation of data; AND 
• participated in drafting the article or revising it critically for important intellectual 
content; AND  
• approved the final version to be published. 
Each author will meet all of these conditions and all individuals meeting these criteria will be 
authors.  Acquisition of funding, collection of data, or general supervision of the research 
group does not justify authorship.  Each author will have participated sufficiently in the work 
to take public responsibility for appropriate portions of the content. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.   
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 Non Interventional study protocol that the investigator becomes 
aware of. 
 
13. REFERENCES 
1.  
Cancer today [Internet]. [cited 2018 May 31]. Available from: 
http://gco.iarc.fr/today/home 
2.  
Breast cancer statistics [Internet]. Cancer Research UK. 2015 [cited 2018 May 31]. 
Available from: http://www.cancerresearchuk.org/health-professional/cancer-
statistics/statistics-by-cancer-type/breast-cancer 
3.  
Rugo HS, Diéras V, Gelmon KA, Finn RS, Slamon DJ, Martin M, et al. Impact of 
palbociclib plus letrozole on patient-reported health-related quality of life: results from 
the PALOMA-2 trial. Ann Oncol Off J Eur Soc Med Oncol. 2018 Apr 1;29(4):888–94.  

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4.  
Wishart GC, Greenberg DC, Chou P, Brown CH, Duffy S, Purushotham AD. Treatment 
and survival in breast cancer in the Eastern Region of England. Ann Oncol. 2010 
Feb;21(2):291–6.  
5.  
Cancer survival by stage at diagnosis for England (experimental statistics) - Office for 
National Statistics [Internet]. [cited 2018 Jun 7]. Available from: 
https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/condition
sanddiseases/bulletins/cancersurvivalbystageatdiagnosisforenglandexperimentalstatistic
s/adultsdiagnosed20122013and2014andfollowedupto2015 
6.  
National Cancer Registration and Analysis Service (NCRAS) [Internet]. GOV.UK. 
[cited 2018 Jun 7]. Available from: https://www.gov.uk/guidance/national-cancer-
registration-and-analysis-service-ncras 
7.  
Bonotto M, Gerratana L, Poletto E, Driol P, Giangreco M, Russo S, et al. Measures of 
Outcome in Metastatic Breast Cancer: Insights From a Real-World Scenario. The 
Oncologist. 2014 Jun 1;19(6):608–15.  
8.  
Kish JK, Ward MA, Garofalo D, Ahmed HV, McRoy L, Laney J, et al. Real-world 
evidence analysis of palbociclib prescribing patterns for patients 
with advanced/metastatic breast cancer treated in community oncology practice in the 
USA one year post approval. Breast Cancer Res BCR. 2018 May 2;20(1):37.  
9.  
Dalmau E, Armengol-Alonso A, Muñoz M, Seguí-Palmer MÁ. Current status of 
hormone therapy in patients with hormone receptor positive (HR+) advanced breast 
cancer. The Breast. 2014 Dec 1;23(6):710–20.  
10.  Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. Palbociclib and 
Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 17;375(20):1925–36.  
11.  CDK4/6 Inhibitors: Game Changers in the Management of Hormone Receptor–Positive 
Advanced Breast Cancer? | Cancer Network [Internet]. [cited 2018 Jun 5]. Available 
from: http://www.cancernetwork.com/breast-cancer/cdk46-inhibitors-game-changers-
management-hormone-receptorpositive-advanced-breast-cancer 
12.  European Medicines Agency - Human medicines - Ibrance [Internet]. [cited 2018 May 
31]. Available from: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/0038
53/smops/Positive/human_smop_001032.jsp&mid=WC0b01ac058001d127 
13.  Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-
dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus 
letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, 
advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet 
Oncol. 2015 Jan;16(1):25–35.  

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14.  Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im S-A, Masuda N, et al. Fulvestrant 
plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-
positive, HER2-negative metastatic breast cancer that progressed on previous endocrine 
therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 
randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425–39.  
15.  Turner NC, Finn RS, Martin M, Im S-A, DeMichele A, Ettl J, et al. Clinical 
considerations of the role of palbociclib in the management of advanced breast cancer 
patients with and without visceral metastases. Ann Oncol Off J Eur Soc Med Oncol. 
2018 Mar 1;29(3):669–80.  
16.  All Wales Medicines Strategy Group (AWMSG) - palbociclib (Ibrance) [Internet]. 
[cited 2018 May 22]. Available from: 
http://www.awmsg.org/awmsgonline/app/appraisalinfo/2392 
17.  Palbociclib (Ibrance®) is accepted for restricted use within NHS Scotland. [Internet]. 
Scottish Medicine Consortium. [cited 2018 May 15]. Available from: 
https://www.scottishmedicines.org.uk/medicines-advice/palbociclib-ibrance-
fullsubmission/ 
18.  McKee S. Pfizer offers Ibrance free to the NHS during NICE appraisal [Internet]. 2017 
[cited 2018 May 31]. Available from: 
http://www.pharmatimes.com/news/pfizer_offers_ibrance_free_to_the_nhs_during_nice
_appraisal_1192363 
19.  IBRANCE 75 mg hard capsules - Summary of Product Characteristics (SmPC) - (eMC) 
[Internet]. [cited 2018 Jun 28]. Available from: 
https://www.medicines.org.uk/emc/product/4449/smpc 
20.  Li N, Du EX, Chu L, Peeples M, Xie J, Barghout V, et al. Real-world palbociclib 
dosing patterns and implications for drug costs in the treatment of HR+/HER2- 
metastatic breast cancer. Expert Opin Pharmacother. 2017 Aug 13;18(12):1167–78.  
21.  Tang DH, Li N, Du EX, Peeples M, Chu L, Xie J, et al. First-line treatment disruption 
among post-menopausal women with HR+/HER2- metastatic breast cancer: a 
retrospective US claims study. Curr Med Res Opin. 2017;33(12):2137–43.  
22.  ENCePP Home Page [Internet]. [cited 2018 Jun 7]. Available from: 
http://www.encepp.eu/index.shtml 
23.  Resources - International Society for Pharmacoepidemiology [Internet]. [cited 2018 Jun 
7]. Available from: https://www.pharmacoepi.org/resources/guidelines_08027.cfm 
24.  European Union. General Data Protection Regulation [Internet]. 2018 May [cited 2018 
Apr 6]. Available from: http://eugdpr.org/the-regulation.html 

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ANNEX 3. ADDITIONAL INFORMATION 
Table 1. Dataset to be collected according to study time points 
Variables 
Study time points 
Baseline 
(From 
disease 
diagnosis 
to 
index 
date)  
Index date  
Post-
initiation 
observatio
n period  
Other  
Palbociclib treatment: date start, dose, 
date dose modified (new dose), date end 
and reason for end 
 
✓ 
✓ 
 
Date of birth (MM/YY) 
 
 
 
✓ 
M/F 
 
 
 
✓ 
Ethnicity (categories in eCRF) 
 
 
 
✓ 
Patient status at the end of data collection 
period (alive/dead) 
• 
date of death / last clinic visit 
• 
If not known (i.e. lost to follow-up), 
date of last recorded hospital visit. 
 
 
✓ 
 
Clinical response assessments during the 
follow-up period: date of assessment and 
outcome (complete response / partial 
response / no response or stable disease / 
progressive disease), as documented by 
the local investigator. 
 
 
✓ 
 
Date of data collection time points (to be 
specified in eCRF)  
 
 
✓ 
 
Menopausal status (Y/N) 
✓ 
 
 
 
BC Diagnosis: 
• 
 Date of diagnosis. 
• 
Primary / recurrent disease 
• 
Site, grade, biopsy (site biopsied, 
categories to be provided in eCRF), 
lymph node involvement, oestrogen-
receptor status, progesterone-receptor 
status, and HER2 status 
 
✓ 
 
 
 
Treatment for primary/ secondary BC:  
• 
(neo)-adjuvant 
chemotherapy: 
pathological 
complete 
response 
achieved Y/N, date start and date 
stopped 
• 
type 
of 
surgery: 
wide 
local, 
mastectomy 
• 
(neo)adjuvant oestrogen therapy: date 
✓ 
 
 
 

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Final, 12 November  2018 
 
 
 
Pfizer Confidential 
Page 38 of 39 
Variables 
Study time points 
Baseline 
(From 
disease 
diagnosis 
to 
index 
date)  
Index date  
Post-
initiation 
observatio
n period  
Other  
start and stopped 
 
Relevant 
comorbidities 
documented 
within baseline period (to include all 
individual components of the NCI-DCI, 
to be further defined in full in the eCRF). 
✓ 
 
✓ 
 
Date of start and end of concomitant 
medication 
treatment 
: 
letrozole, 
fulvestrant, 
osteo-strengthening 
drugs 
(denosumab, 
zometa), 
other 
 
(all 
medications to be included in eCRF) 
 
✓ 
 
✓ 
 
First 3 lines of medications after 
palbociclib discontinuation 
 
 
✓ 
 
Hemoglobin results to be extracted pre-
first cycle, on day 1 of each cycle of 
treatment, on day 15 into cycles 1 and 2 
and  day 22 if available 
✓ 
✓ 
✓ 
 
White cell counts to be extracted as above 
✓ 
✓ 
✓ 
 
Absolute 
neutrophil 
counts 
to 
be 
extracted as above 
✓ 
✓ 
✓ 
 
Platelet counts to be extracted as above 
✓ 
✓ 
✓ 
 
Aspartate transaminase levels to be 
extracted as above 
✓ 
✓ 
✓ 
 
Alanine 
transaminase 
levels 
to 
be 
extracted as above 
✓ 
✓ 
✓ 
 
Alkaline 
phosphatase 
levels 
to 
be 
extracted as above 
✓ 
✓ 
✓ 
 
Calcium levels to be extracted at pre-first 
cycle, then at each cycle, in the first year 
following initiation  
✓ 
✓ 
✓ 
 
Phosphate levels to be extracted as above 
✓ 
✓ 
✓ 
 
Calls from patient to CNS: dates and 
reason 
 
 
✓ 
 
BC-related 
inpatient 
admissions 
to 
hospital: 
planned 
(elective), 
A&E, 
reasons, duration (dates of entry and 
discharge) 
 
 
✓ 
 
BC-related outpatient admission: dates, 
reason  
 
 
 
✓ 
 

IBRANCE 
X9001194 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 12 November  2018 
 
 
 
Pfizer Confidential 
Page 39 of 39 
Variables 
Study time points 
Baseline 
(From 
disease 
diagnosis 
to 
index 
date)  
Index date  
Post-
initiation 
observatio
n period  
Other  
Progression: sites, dates 
 
 
✓ 
 
AE: Neutropenia (Y/N), date start and 
end, grade 
 
 
✓ 
 
AE: Febrile Neutropenia (Y/N), date start 
and end 
 
 
✓ 
 
AE: Diarrhoea (Y/N), date start and end, 
grade 
 
 
✓ 
 
AE: Nausea (Y/N), date start and end, 
grade 
 
 
✓ 
 
AE: Vomiting (Y/N), date start and end, 
grade 
 
 
✓ 
 
Death: date, cause 
 
 
 
✓ 
Note: All dates are DD/MM/YYYY for all patients, except for date of birth (MM/YY)