UNDERSTANDING HEMOPHILIA A AND B DRUG DOSAGE ADMINISTRATION PATTERNS
Conditions: Hemophilia A, Hemophilia B
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study informations
Title
Understanding Hemophilia A and B Drug 
Dosage Administration Patterns
Protocol number
B1821056
Protocol version identifier
Version 1.1
Date of last version of protocol
04 April 2017
Active substance
B02BD09 – nonacog alfa
B02BD04 – coagulation Factor IX
B02BD31 – moroctocog alfa
B02BD02 – coagulation factor VIII
Medicinal product
Coagulation Factor VIII and Factor IX 
products
Research question and objectives
To compare the real world administration
patterns and resource utilization implications
of standard half-life (BeneFIX for 
hemophilia B, Xyntha and other standard 
half-life agents for hemophilia A) vs
extended half-life (Alprolix for hemophilia 
B, Eloctate and Adynovate for hemophilia 
A) agents for the treatment of hemophilia.
Authors
PhD
, 
PPD
PPD
PPD

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United States of America
, PhD
,
 
United States of America
, PhD
,
 
United Kingdom
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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TABLE OF CONTENTS
APPENDICES ...........................................................................................................................4
INVESTIGATOR SIGNATURE PAGE...................................................................................5
1. LIST OF ABBREVIATIONS................................................................................................6
2. RESPONSIBLE PARTIES....................................................................................................8
3. ABSTRACT...........................................................................................................................9
4. AMENDMENTS AND UPDATES.....................................................................................11
5. MILESTONES.....................................................................................................................11
6. RATIONALE AND BACKGROUND................................................................................11
7. RESEARCH QUESTION AND OBJECTIVES .................................................................12
8. RESEARCH METHODS ....................................................................................................12
8.1. Study design ............................................................................................................12
8.2. Setting......................................................................................................................12
8.2.1. Inclusion criteria .........................................................................................13
8.2.2. Exclusion criteria........................................................................................14
8.3. Variables..................................................................................................................14
8.4. Data sources ............................................................................................................16
8.5. Study size ................................................................................................................17
8.6. Data management....................................................................................................17
8.7. Data analysis ...........................................................................................................17
8.8. Quality control.........................................................................................................18
8.9. Limitations of the research methods .......................................................................19
8.10. Other aspects .........................................................................................................19
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................19
9.1. Participant Information and Consent.......................................................................19
9.2. Participant withdrawal.............................................................................................20
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............20
9.4. Ethical Conduct of the Study ..................................................................................20
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS (AE)/ADVERSE.......21
10.1. Adverse Event Reporting during Claims Assistance ............................................21
10.2. Guidance For Investigators AE Reporting during completion of 
Investigators Survey Questionnaire...........................................................................22

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10.3. Adverse Event Reporting Guidance for Patient and/or Caregiver Survey 
Responses ..................................................................................................................29
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........30
11.1. Publications by Investigators ................................................................................30
12. COMMUNICATION OF ISSUES ....................................................................................31
13. REFERENCES ..................................................................................................................32
14. LIST OF TABLES.............................................................................................................32
15. LIST OF FIGURES ...........................................................................................................32
APPENDICES
Appendix 1. LIST OF STAND ALONE DOCUMENTS .......................................................33
Appendix 2. FACTOR USE BEHAVIOR QUESTIONS........................................................34
Appendix 3. ENCePP checklist for study protocols................................................................34
Appendix 4. ANNEX 4. Additional information.....................................................................34

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INVESTIGATOR SIGNATURE PAGE
I have reviewed and approved Protocol B1821056. By signing below, I agree to abide by the 
terms of the protocol.
Signature: ______________________________
Name: _________________________________
Title: __________________________________
Institution: _____________________________
Date: __________________________________

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1. LIST OF ABBREVIATIONS
Abbreviation
Definition
AE
Adverse Event
AEM
Adverse Event Monitoring
ANOVA
Analysis of Variance
BV
Bivariate
CRF
Chart Review Form
EDP
Exposure During Pregnancy
FDA
Food and Drug Administration
GLM
General Linear Model
HAEM-A-QOL
Hemophilia-Specific Quality of Life Index for Adults
HAEMO-QOL
Hemophilia-Specific Quality of Life Index
ID
Identification
IRB / IEC
Institutional Review Board / Independent Ethics 
Committee
ISPOR
International Society for Pharmacoeconomics and 
Outcomes Research
MDE
Minimum Detectable Effect
MV
Multivariate
NIS
Non-interventional Study
OLS
Ordinary Least Squares
PI/Sub-PI
Primary Investigator/ Sub-Primary Investigator
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event

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SAS
Statistical Analysis System
SF-36
36 Item Short Form Health Survey
SF-10
10 Item Short Form Health Survey
SOPs
Standard Operating Procedures
SPSS
Statistical Package for the Social Sciences 
US
United States

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2. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Title
Affiliation
Address
 PhD
 
Outcomes and Evidence
Global Health and 
Value
Pfizer, Inc.
 
United States of 
America
 PhD
Outcomes and 
Evidence, Global 
Health and Value
Pfizer Limited
 
 
United 
Kingdom
, 
MTS, MD, MBA, 
FACS, FCCM
, Global 
Medical Affairs Lead, 
Hemophilia and 
Transplantation
Pfizer, Inc.
United States of 
America
, MD
US Medical Affairs
Rare Diseases Unit, 
Hematology
Pfizer, Inc.
United States of 
America
PhD
 Real 
World Data and 
Analytics, Global 
Health and Value
Pfizer, Inc.
 
United States of 
America
 
Dr.P.H.
Statistical Research and 
Data Science Center, 
Global Product 
Development
Pfizer, Inc.
 
United States of 
America
RPh.
Clinical Development 
Operations
Study Management
United States of 
America
 PhD
, Health 
Outcomes Research
 
Health Outcomes 
Research
 
Health Outcomes 
Research
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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3. ABSTRACT

Title: Understanding Hemophilia A and B Drug Dosage Administration Patterns. 
Version 4.0, 16 March 2017

Rationale and background: In recent years newer and extended half-life treatments 
(e.g. Alprolix, Eloctate, Adynovate) for hemophilia have been approved by the Food and 
Drug Administration (FDA). These newer, extended half-life treatments require less 
frequent administrations than standard half-life treatments (e.g. BeneFIX, Xyntha). 
However, little is known about the real world administration patterns for extended half-
life treatments in comparison to standard half-life treatments.

Research question and objectives: To compare the real world administration patterns 
and resource utilization associated with of standard half-life (e.g. BeneFIX for 
hemophilia B, Xyntha for hemophilia A) vs extended half-life (e.g. Alprolix for 
hemophilia B, Eloctate and Adynovate for hemophilia A) agents for the treatment of 
hemophilia in the U.S.

Study design: This will be a U.S. site-based study in which physician sites are recruited 
to participate in the study and enroll patients.  Participating physicians will conduct a 
chart review for their enrolled patients and these same patients will respond to a patient 
questionnaire online via a web survey.  In addition, these patients will be consented to 
supply their insurance claims data to Kantar Health study team for analysis. All survey 
questionnaires will be in English.

Population: Approximately 30 sites will participate in this study, with 300 patients 
enrolled (some caregivers expected if eligible patient is under 18 years of age).  The 
approximate distribution of patients by hemophilia type and treatment type is as follows:

Hemophilia A patients currently receiving Xyntha or another standard half-life treatment 
for at least six months (n=~75).

Hemophilia A patients currently receiving Adynovate or Eloctate for at least six months 
AND have been switched from a standard half-life treatment, and have been on the prior 
SHL treatment for at least six months (n=~75).

Hemophilia B patients currently receiving BeneFIX for at least six months (n=~75).

Hemophilia B patients currently receiving Alprolix for at least six months AND have 
been switched from BeneFIX, and have been on the prior BeneFIX treatment for at least 
six months (n=~75).

Variables: Include physician/practice characteristics, patient treatment pattern, patient 
demographics and patient clinical profile to be collected in the chart review form (CRF); 
patient demographics, clinical profile, physician-patient relationship, and quality of life 
reported outcomes to be collected in the patient/caregiver reported questionnaire; and 

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cost and utilization related to overall health and hemophilia management to be retrieved 
from claims data provided by patients/caregivers.

Data sources: Study data will come from three sources: (1) the patient/caregiver-
reported outcomes and treatment patterns collected in the form of an online survey, (2) 
the CRF by physicians collected in the form of an online survey, and (3) the data 
extracted from patient medical and pharmacy claims which will be received as paper files 
or pdf downloads.

Study size: This study will involve approximately 30 sites and approximately 300 
patients. Eligible sites will be activated on an ongoing basis and evaluated continuously 
as necessary to achieve cohort fulfillment.

Data analysis: Descriptive statistics (means, standard deviations, frequencies, 
percentages) will be used to characterize the physician and patient sample. Bivariate 
analyses using one-way Analysis of Variance (ANOVA) or chi-square tests will compare 
differences in demographics, health characteristics and outcomes (i.e., dosing, disease 
severity, health-related quality of life, healthcare resource use, costs) between standard 
half-life vs. extended half-life treatments separately for hemophilia A and hemophilia B 
patient cohorts. Generalized linear models (with appropriate link function and 
distribution) will be used to compare outcomes by treatment groups, adjusting for 
covariates.

Milestones: This study is estimated to take 18 months to complete with final report 
tentatively expected in late 2018.

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4. AMENDMENTS AND UPDATES
The protocol has been amended to incorporate the feedback received from the initial 
feasibility part of this study. Safety language has been amended to reflect the nature of data 
capture and participant interaction, and to ensure compliance with the required safety 
reporting Standard Operating Procedures (SOPs).
5. MILESTONES
Milestone
Planned date
Start of data collection 
April 2017
End of data collection
December 2017
Study Close Out
October 2018
6. RATIONALE AND BACKGROUND
Hemophilia A and B are chronic inherited bleedings disorders caused by an X-chromosome 
linked deficiency in coagulation factors.1 Although the incidence of hemophilia is relatively 
low, it imposes a high level of burden to sufferers, caregivers, and society.  As hemophilia 
requires lifetime treatment it is associated with substantial costs, particularly direct costs.  
Factor replacement therapy, used for both prophylaxis and on-demand therapy, is the 
mainstay of hemophilia treatment and has been estimated to cost more than $250,000 per 
adult in the United States.  Depending on the disease severity and treatment regimen, factor 
replacement products accounts for 45% to 93% of the total medical costs for hemophilia.2
Newer, extended half-life treatments for hemophilia have recently been approved by the 
FDA).  Alprolix is an extended half-life treatment that was approved by the FDA in March, 
2014 for hemophilia B.  And similarly, for hemophilia A, Eloctate was approved in 2014 and 
Adynovate in 2015.  These newer, extended half-life drugs require less frequent 
administrations than Pfizer’s BeneFIX (for hemophilia B) and Xyntha (for hemophilia A).   
Even a relatively small change in frequency of administration has the potential to translate 
into 50 or fewer infusions per year and a correspondingly smaller number of units infused per 
patient.  The expected advantages of fewer infusions from extended half-life products include 
greater patient compliance, less disruptions in daily activities and less reliance on others to 
help with infusions.1 However; these benefits are only realized if there is indeed fewer 
infusions associated with the extended half-life products compared with the standard half-life
products.  To date, little is known about real world administration patterns for extended half-
life treatments in comparison to standard half-life treatments.  Pfizer is seeking to understand 
whether   Alprolix , Eloctate, and Adynovate are being dosed more often than their labeling 
indicates, thus potentially costing payors and patients more money compared to traditional 
treatments, like BeneFIX and Xyntha.

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7. RESEARCH QUESTION AND OBJECTIVES
The study’s primary objective is to compare the dosing and resource utilization patterns of 
standard half-life treatments vs. extended half-life treatments for the management of 
hemophilia A and B

Specifically, the dosing and resource utilization patterns of Xyntha (or other standard 
half-life treatments) vs. Adynovate or Eloctate  will be assessed for treatment of 
hemophilia A

And similarly, the dosing and resource utilization patterns of BeneFIX (standard half-
life) vs. Alprolix (extended half-life) will be assessed for treatment of hemophilia B 
8. RESEARCH METHODS 
8.1. Study design
This study will be conducted as a prospective observational, cross-sectional epidemiological 
study in U.S. site-based clinical practice settings. Participating physicians / clinicians at 
approximately 30 sites will enroll approximately 300 patients for inclusion in the study.  
Participating patients – or their caregiver in the case of patients under the age of 18 - will be 
consented to participate.  After this consent occurs, the physicians will complete a 
retrospective chart review on each enrolled patient, entering their findings into a chart review 
form (CRF) online.  Patients will complete a one-time study questionnaire, which should take 
approximately 20 minutes to complete, by accessing a link online. The patient questionnaire 
will include self-report questions regarding patient demographics, clinical profile, treatment, 
and physician-patient relationship, along with several validated scales to assess health-related 
quality of life.  In addition, patients will submit their health insurance claims data to the study 
team for analysis. All survey questionnaires will be in English. All respondents will be 
provided remuneration for their participation.
8.2. Setting
The study will occur in a site-based clinical practice setting, meaning that patients will be 
recruited by physicians to participate in the study.  Eligible sites will be activated on an 
ongoing basis and evaluated continuously as necessary to achieve cohort fulfillment. Sites 
will identify patients according to criteria specified within protocol and patients will further 
be qualified within the web questionnaire. The Kantar Health research team will closely 
monitor patient enrollment between sites to ensure equal distribution across the four cohorts
is achieved. If needed, additional sites will be contracted and activated to meet total cohort
sample size. All physician and patient materials will be completed online via a web-link to a 
survey provided by Kantar Health.  

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8.2.1. Inclusion criteria
Physician/Clinician Participants
Participating sites must undergo a contracting procedure and agree to follow the study 
protocol as well as all terms of the study contract.  Participating sites will be led by a 
physician / clinician (e.g. nurse, nurse practitioner, physician assistant, etc.) who will serve as 
that site’s PI/sub-PI.  The participating PI/sub-PI must meet all the following inclusion 
criteria to participate in the study:

Must be a healthcare provider with at least 60% of time spent in direct patient care;

Board-certified or eligible with a Specialty in Hematology or Hematology-Oncology 
(if hematologist-oncologist, at least 10% practice is dedicated to treatment of 
hemophilia);

Currently manages at least 10 hemophilia A and/or B patients;

Must not be on the FDA debarment list.
Patient Participants
Participants must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:

Willing and able to provide informed consent.

Diagnosed with hemophilia A or B.

Current disease severity is either moderately severe or severe with a clotting factor 
level of ≤5%.

If suffering from hemophilia A, must be currently taking Xyntha (or another standard 
half-life treatment), Adynovate or Eloctate for at least six months. 

If currently taking Adynovate or Eloctate, must have been switched from a 
standard half-life treatment and had been on that prior treatment for at least six 
months.

If suffering from hemophilia B, must be currently taking BeneFIX or Alprolix for at 
least six months. 

If currently taking Alprolix, must have switched from BeneFIX and had been on 
that prior treatment for at least six months.

Infuse at least 3 times per month

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1. In the event of a caregiver responding on behalf of the patient, the above inclusion 
criteria will be applied for the patient for whom the caregiver is responding.  
8.2.2. Exclusion criteria
Patient Participants
Currently enrolled in a clinical trial and/or using investigational product for the treatment of 
his or her hemophilia 
8.3. Variables
Below is the current list of variables to be assessed in the in the study:
Physician Participants
Physician/Practice Characteristics

Primary medical specialty;

Board certification;

Percentage of time spent in direct patient care;

Percentage of their practice dedicated to the treatment of hemophilia;

Number of moderate to severe hemophilia A and B patients currently managed;

Number of hemophilia A and B patients currently participating in clinical trials;

Insurance plans accepted.
Patient Treatment Pattern

Current and previous hemophilia treatment;

Reasons for discontinuation;

Duration of treatment used;

Whether prescription was prophylaxis or on-demand;

Number of infusions per month prescribed;

Frequency of doctor visits for management of hemophilia.
Patient Clinical Profile 

Height and Weight;

Age of diagnosis;

Primary symptoms;

Disease severity;

Joint health score;

Comorbidities.

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Patient Participants:
Patient Demographics

Sex;

Age;

Race/ethnicity;

Marital status;

Household income;

Education;*

Employment status;*

Health insurance type;

Healthcare insurer;

Pharmacy insurer.
*In the case of caregivers responding, caregiver’s education and employment will also be 
collected.
Patient Clinical Profile 

Disease severity;

Clotting factor level.
Patient Treatment 

When are infusions done;

Number of infusions in a typical month;

Previous and current hemophilia treatments;

Duration of previous and current hemophilia treatments used;

Recent Factor Use Behavior;

Whether participated in clinical trials within the past 12 months.
Physician Patient Relationship 

Patient’s relationship with his/her physician in regards treatment decisions for 
hemophilia rated as either paternalistic, informative, interpretive, or deliberate 
depending upon which relationship description the patient selects.
Validated Scales for Health-Related Quality of Life 

36 Item Short Form Health Survey (SF-36 (adult)).3

10 Item Short Health Survey (SF-10 (caregiver reported for child)).4

Hemophilia-Specific Quality of Life Index for Adults (HAEM-A-QOL (adult)).5

Hemophilia-Specific Quality of Life Index (HAEMO-QOL (caregiver reported for 
child)).6

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Health Insurance Claims Data from Patients

Total services and healthcare costs (healthcare visits, factor).

Hemophilia-specific services and costs (healthcare visits, factor).
8.4. Data sources
This study will be conducted with physicians and patients in an online setting. Prior to 
participating, patients will be asked to provide their informed consent in order to proceed 
with the web surveys and provision of their health care insurance claims.
The physicians participating in this research will be asked to reference their patient medical 
records for each enrolled patient during their portion of the study.
There will be three sources of data for each patient (or caregivers of patients in the case of 
minor patients):
-
Patient responses to a web survey/questionnaire
-
Physician responses to a CRF concerning the same patient
-
Patients’ medical and pharmacy claims data obtained directly by the patient from their 
healthcare insurer and provided to Kantar Health via a secure, dedicated email 
address. 
No personal identifiable information will be captured in either the CRF or patient 
questionnaire. However, the medical claims component of the patient data may include 
confidential information. Therefore, we will ensure that all personal identifiable data are 
removed from the claims when the claims are received by Kantar Health. Once Kantar 
Health study staff receives claims via the dedicated email address, all identifying information 
(name, date of birth, or other individual identifiers) are redacted using mark-up application 
that puts a black bar over this data.  The claims document is then numbered with the patient’s 
anonymous study ID number and saved using the study ID number as the document name.  
The document is also password protected so that the redacting masks cannot be removed by 
other individuals.  All patient data will be reported in aggregate form and participants will 
only be identified by a random unique ID for reference. Kantar Health will not link any study 
data to personal information of any patient or physician participant. 
It is anticipated that claims data received will vary in type and degree of insurance data 
across different insurers. As such, the planned process is to extract some of the common 
variables as seen within sample claims such as date of service, carrier, provider type, service 
description, cost, and any procedural or diagnosis codes if present. The data will be entered 
and validated by Kantar Health. Final variable list and data format will be discussed with 
Pfizer prior to data entry. 

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8.5. Study size
The study will involve approximately 300 patients recruited from approximately 30 
participating sites.
This study will compare Xyntha vs. Eloctate /Adynovate among hemophilia A patients and 
Alprolix vs. BeneFIX among hemophilia B patients. For a mean difference comparing two 
independent means with the anticipated sample sizes (75 vs. 75; 150 total) with α=0.05, two-
sided, 80% power, the expected minimal detectable effect (MDE) would be Cohen’s d=0.46. 
This study with the anticipated sample size is powered to detect at least a moderate effect 
size.
8.6. Data management 
Study data will come from three sources: (1) the patient-reported outcomes and treatment 
patterns collected in the form of an online survey, (2) the CRF by physicians collected in the 
form of an online survey, and (3) the data extracted from patient medical and pharmacy 
claims which will be receive as paper files or pdf downloads.
Both patient and physician participants will be entering their survey responses via survey 
links that are unique to each participant so that each participant is identified by a random 
unique identification (ID) number. The database which houses the survey responses allows 
for direct exportation into statistical software (e.g., Statistical Package for the Social Sciences 
(SPSS), Statistical Analysis System (SAS), Stata).  Because each participant will be 
identified by a random unique ID number, the working data files will not contain any 
identifying information apart from the ID number. No identifying information (e.g. names, 
addresses, or other distinguishing information) will collected in the surveys will not be 
designed with such variables in mind. 
Regarding the claims data, a dedicated email address for receiving this data will be set up to 
receive this data directly from the patients (?) for this particular study to be accessed only by 
a select group of the research team at Kantar Health. Any personal identifiable data available 
in the claims, such as names, dates of birth, social security numbers, etc., will be omitted 
during data entry (performed through an external coding vendor) and all participants will 
only be identified by an assigned random unique ID for reference. Furthermore, the original 
claims data will be saved for 24 months after study completion and then backed up / 
destroyed according to Pfizer requirements.  The file containing claims data will be created 
in an agreed upon format between Pfizer and the Kantar Health. Data files provided to the 
broader Kantar Health research team or Sponsor will not include any personal identifying 
information as this information is either not collected or have been omitted/redacted as 
indicated above to preserve confidentiality. Details of data entry management are contained 
in the Data Management Plan.
8.7. Data analysis 
A detailed description of the analyses for this study will be provided in a statistical analysis 
plan (SAP). Below are the general statistical approaches we will implement.

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Descriptive Analyses
Descriptive statistics (means and standard deviations for continuous variables and 
frequencies and percentages for categorical variables) will be reported for all study measures 
on the total sample and subgroups. This analysis of the distributions will be a part of testing 
of model assumptions and will help inform the appropriate modeling techniques.
Bivariate Analyses
Bivariate (BV) comparisons and descriptives can help provide initial insight into the dosing, 
health-related quality of life, resource utilization, and cost patterns associated with different 
hemophilia treatments (standard half-life vs. extended half-life). BV comparisons, using chi-
square tests or one-way Analysis of Variance (ANOVA) for categorical and continuous 
variables, respectively, will be conducted for each hemophilia subgroup.  
The BV results will be used to feed into a more robust multivariable (MV) analysis to create 
a model to estimate health-related quality of life, resource utilization and costs, while 
controlling for covariates, associated with different hemophilia treatments.
Multivariable Analyses
Generalized Linear Models (GLM)
The type of GLM will be chosen on the basis of the distributions of the outcome variables of 
interest. For example, GLMs specifying a normal distribution and identity function will be 
used with mostly normally distributed variables (such as is typically the case with SF-36v2 
Health Related Quality of Life measures), whereas GLMs specifying a negative binomial 
distribution and log-link function will be used with highly positively skewed variables (such 
as is typically the case with healthcare resource utilization measures). Model fits will be 
examined to aid with model selection. For example, Poisson models may be attempted first, 
with highly skewed outcomes, but negative binomial models will also be tested to see if fits 
improve substantially when including the estimated relationship between mean and variance. 
Corrections to the standard errors will be implemented automatically to compensate for 
model underdispersion.  In the case of normal distributions, GLMs are recommended, as they 
are more robust than ordinary least squares (OLS) models to minor deviations from 
normality.  
8.8. Quality control
For this study, double data entry will be conducted for 15% of the total data entered. As there 
will be a total of 300 patients enrolled in the study, 45 patients’ responses will be randomly 
selected and all data for those patients will undergo double data entry in a separate excel file. 
Once all data is entered and double data entry has been completed, a comparison will be 
made within excel to address any discrepancies. If the error rate is higher than 10%, then 
100% of the data will be verified. Prior to data collection or data entry, consistency of 
database format will be confirmed for all data types.

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Details of the number of respondents chosen for data verification, how these were selected 
and the acceptable error level must be documented with the study documentation. Details of 
errors found, and what actions were taken following the discovery of these errors will be 
documented in the Data Entry Log. Of note, the only data entry activities for this study 
include entering the data from the patient’s medical claims data.
All of the patient’s medical claims data collected on paper will be stored on site at a Kantar 
facility in Toledo, Ohio. The data will be stored in a locked room that only the project team 
has access to. The data will be saved for 24 months after study completion and then backed 
up / destroyed according to Pfizer requirements. 
8.9. Limitations of the research methods
Subject responses may be influenced by recall and self-presentation biases which could 
introduce additional error. Therefore the design of the study was approached with the intent 
to maximize the external validity of the findings by requesting patient’s medical claims (as 
opposed to asking them to self-report their healthcare resource utilization for the past 12 
months, which will require recall and estimation) and obtaining real-world medical records 
data via the CRFs from physician report.  
8.10. Other aspects
Not applicable.
9. PROTECTION OF HUMAN SUBJECTS
9.1. Participant 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.
As this study will be conducted at participating sites, all sites will be thoroughly trained on 
the informed consent procedures for the study prior to beginning patient enrollment. Sites 
will be trained that each patient (or their caregiver) must autonomously consent to participate 
in the study prior to conducting the patient chart review or the patient participating in any 
study procedures.  In the case of minors ages 12-18, in addition to the parent/caregiver 
providing their informed consent, the minor will sign an assent document confirming their 
understanding and agreement of their role in the study.  Specifically, the minor will be 
informed that their parent/caregiver will be filling out a survey on the minor’s behalf as well 
as submitting the minor’s claims data and that the doctor will be performing a chart review of 
the minor’s medical chart.  The use of the assent form will verify that older minors – while 
not legally able to provide informed consent - are informed of the study procedures regarding 
their personal information, and respects their autonomy and privacy by allowing them to 
either agree or decline their participation on this basis.  The informed consent and assent 
forms used in this study, and any changes made during the course of the study, must be 
prospectively approved by both the IRB/IEC and Pfizer before use. Kantar Health will obtain 
central IRB review and approval for this study in the case of sites that allow central IRB 

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approval.  However, some participating sites may require their local site IRB review and 
approve the study and the consent documents per institution requirements.  In these cases, the 
participating site will use the relevant institution-specific informed consent template for the 
study, however all site-specific consent documents must be approved by Kantar Health and 
Pfizer prior to use.  In addition, sites may not make amendments to the informed consent 
documents with the approval of Pfizer and Kantar Health. 
9.2. Participant withdrawal
Participants 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 site investigator. In any circumstance, every 
effort should be made to document subject outcome, if possible. 
If the participant 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.
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
Kantar Health will be responsible for obtaining approval of the study protocol, protocol 
amendments, and informed consent forms, and other relevant documents, (e.g., recruitment 
advertisements), if applicable, from the IRB/IEC.  Copies of IRB/IEC approvals can
forwarded to Pfizer should sponsor want. Dependent upon the policies of each participating 
site, local IRB approval may be required at some of the sites whereas some sites are able to 
accept central IRB approval as the IRB of record for this study.  The site’s requirements for 
local or central IRB will be determined at the site contracting stage and agreed upon during 
the contracting process with each site.
9.4. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR). IRB approval will be collected from 
a central IRB or local IRB as described above prior to starting data collection.

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10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS (AE)/ADVERSE 
REQUIREMENTS
10.1. Adverse Event Reporting during Claims Assistance 
This study does not involve data collection of prospective, clinically adjudicated endpoints 
on individual patients.  There is no mechanism by which information on safety events for an 
individual patient will be captured by a study participant during the course of claims data 
collection; However, any information on a safety event inadvertently volunteered by a study 
participant during the course of this research must be reported as described as part of Your 
Reporting Responsibilities for contract research associations for non-interventional studies.
Further, routine communication with study participants via email or phone with the project 
team at Kantar Health is not expected during the conduct of the study.  However, it is 
possible that a study participant may provide information that could constitute a safety event 
(e.g., serious and non-serious AEs and/or scenarios involving exposure during pregnancy, 
exposure during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy and occupational exposure) to project team while in conversation about the survey 
for any other reason (e.g., seeking information about the purpose of the study).  In the event 
that a study participant in the study reports a safety event associated with the use of the Pfizer 
product, the project team will complete a non-interventional study (NIS) adverse event 
monitoring (AEM) Report Form and submit to Pfizer within 24 hours of becoming aware of 
the safety event.  Included in the completion of the NIS AEM Report Form is the study 
participant’s contact information as the reporter, as well as the contact information for the 
applicable  primary healthcare provider; complete contact information should be obtained so 
that, once the NIS AEM Report Form is transferred to Pfizer, the NIS AEM Report Form will 
be assessed and processed according to Pfizer’s standard operating procedures, including 
requests for follow-up regarding the safety event to the study participant, or as appropriate, 
the individual patient’s primary healthcare provider.
All members of the project team at Kantar Health 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 
the project team 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. In the event that study conduct will be longer than 1 year, re-training will 
be completed on an annual basis using the most current “Your Reporting Responsibilities” 
training materials.
Incidental collection of AE or Serious Adverse Events (SAE) for Non-Pfizer product 
information should NOT be reported to Pfizer Safety Database while reviewing data from 
any source 

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10.2. Guidance For Investigators AE Reporting during completion of Investigators 
Survey Questionnaire
The table below summarizes the requirements for recording safety events on the case report 
form and for reporting safety events on the non-interventional study (NIS) adverse event 
monitoring (AEM) Report Form to Pfizer Safety.  These requirements are delineated for 
three types of events: (1) serious adverse events (SAEs); (2) non-serious AEs (as applicable); 
and (3) scenarios involving exposure to a Pfizer product, including exposure during 
pregnancy, exposure during breast feeding, medication error, overdose, misuse, 
extravasation, and occupational exposure.  These events are defined in the section 
“Definitions of safety events”.  
Safety event
Recorded on the Case 
Report Form
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness
SAE
All (regardless of whether the 
event is determined by the 
investigator to be related to 
any Pfizer product)
Only events determined by 
the investigator to be related 
to a Pfizer product
Non-serious AE
All (regardless of whether the 
event is determined by the 
investigator to be related to 
any Pfizer product)
None
Scenarios involving exposure 
to a Pfizer product, including 
exposure during pregnancy, 
exposure during breast 
feeding, medication error, 
overdose, misuse, 
extravasation; lack of efficacy; 
and occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
All (regardless of whether 
associated with an AE) 
involving exposure to a 
Pfizer product
For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the adverse event and to assess whether it meets the criteria for classification 
as a SAE (see section "Serious Adverse Events” below) 
Safety events must be reported to Pfizer within 24 hours of awareness of the event by the 
investigator as described in the table above. In particular, if the SAE is fatal or life-
threatening, notification to Pfizer must be made immediately, irrespective of the extent of 
available event information. This timeframe also applies to additional new (follow-up) 
information on previously forwarded safety event reports. In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the events.

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For those safety events that are considered serious or that are identified in the far right 
column of the table above that are reportable to Pfizer within 24 hours of awareness, the 
investigator is obligated to pursue and to provide any additional information to Pfizer in 
accordance with this 24-hour timeframe. In addition, an investigator may be requested by 
Pfizer to obtain specific follow-up information in an expedited fashion.  This information is 
more detailed than that recorded on the case report form. In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information 
relevant to the event, such as concomitant medications and illnesses must be provided.  In the 
case of a patient death, a summary of available autopsy findings must be submitted as soon 
as possible to Pfizer or its designated representative.
Reporting period 
For each patient, the safety event reporting period begins at the time of the patient’s informed 
consent, which is obtained prior to the patient’s enrollment in the study, and lasts through the 
end of the observation period of the study; a report must be submitted to Pfizer Safety (or its 
designated representative) for any of the types of safety events listed in the table above 
occurring during this period. Most often, the date of informed consent is the same as the date 
of enrollment.  In some situations, there may be a lag between the dates of informed consent 
and enrollment.  In these instances, if a patient provides informed consent but is never 
enrolled in the study (e.g., patient changes his/her mind about participation, failed screening 
criteria), the reporting period ends on the date of the decision to not enroll the patient.  If the 
investigator becomes aware of a SAE occurring at any time after completion of the study and 
s/he considers the serious AE to be related to a Pfizer product, the SAE also must be reported 
to Pfizer Safety. 
Causality assessment
The investigator is required to assess and record the causal relationship.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of 
each adverse event.  For AEs with a causal relationship to a Pfizer product, follow-up by the 
investigator is required until the event and/or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment.  
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that a Pfizer product caused or contributed to an adverse event. If the 
investigator’s final determination of causality is “unknown” and s/he cannot determine 
whether a Pfizer product caused the event, the safety event must be reported within 24 hours. 
If the investigator cannot determine the etiology of the event but s/he determines that a Pfizer 
product did not cause the event, this should be clearly documented on the case report form 
and the NIS AEM Report Form. 

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DEFINITIONS OF SAFETY EVENTS
Adverse events
An AE is any untoward medical occurrence in a patient administered a medicinal product.  
The event need not necessarily have a causal relationship with the product treatment or 
usage.  Examples of adverse events include but are not limited to:  

Abnormal test findings (see below for circumstances in which an abnormal test 
finding constitutes an adverse event);

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease; 

Lack of efficacy; 

Drug abuse; 

Drug dependency.
Additionally, for medicinal products, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Off-label use; 

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure during breast feeding;

Medication error;

Occupational exposure.

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Abnormal test findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 
Test result is associated with accompanying symptoms, and/or
Test result requires additional diagnostic testing or medical/surgical intervention, and/or
Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or
Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
Serious adverse events
A serious adverse event is any untoward medical occurrence in a patient administered a 
medicinal or nutritional product (including pediatric formulas) at any dose that:
Results in death;
Is life-threatening;
Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute adverse events);
Results in persistent or significant disability/incapacity (substantial disruption of the ability 
to conduct normal life functions);
Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious.  The event may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 

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Pfizer product.  The terms “suspected transmission” and “transmission” are considered 
synonymous.  These cases are considered unexpected and handled as serious expedited cases 
by PV personnel.  Such cases are also considered for reporting as product defects, if 
appropriate.
Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, an event leading to an emergency room visit should be assessed for medical 
importance. 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. 
For example, the following reports of hospitalization without a medical AE are not to be 
reported. 
Social admission (e.g., patient has no place to sleep)
Administrative admission (e.g., for yearly exam)
Optional admission not associated with a precipitating medical AE (e.g., for elective 
cosmetic surgery)
Hospitalization for observation without a medical AE
Admission for treatment of a pre-existing condition not associated with the development of a 
new AE or with a worsening of the pre-existing condition (e.g., for work-up of persistent pre-
treatment lab abnormality)
Protocol-specified admission during clinical study (e.g., for a procedure required by the study 
protocol)
Scenarios necessitating reporting to Pfizer Safety within 24 hours 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below.
Exposure during pregnancy
An exposure during pregnancy (EDP) occurs if:

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A female becomes, or is found to be, pregnant either while receiving or having been  exposed 
to (e.g., environmental) a Pfizer product, or the female becomes, or is found to be, pregnant 
after discontinuing and/or being exposed to a Pfizer product (maternal exposure).
An example of environmental exposure would be a case involving direct contact with a 
Pfizer product in a pregnant woman (e.g., a nurse reports that she is pregnant and has been 
exposed to chemotherapeutic products).
A male has been exposed, either due to treatment or environmental exposure to a Pfizer 
product prior to or around the time of conception and/or is exposed during the partner 
pregnancy (paternal exposure).
As a general rule, prospective and retrospective exposure during pregnancy reports from any 
source are reportable irrespective of the presence of an associated AE and the procedures for 
SAE reporting should be followed.  
If a study participant or study participant’s partner becomes, or is found to be, pregnant 
during the study participant’s treatment with a Pfizer product, this information must be 
submitted to Pfizer, irrespective of whether an adverse event has occurred, must be submitted 
using the NIS AEM Report Form and the EDP Supplemental Form. 
In addition, the information regarding environmental exposure to a Pfizer product, in a 
pregnant woman (e.g., a subject reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) must be submitted using the NIS AEM Report 
Form and the EDP supplemental form. This must be done irrespective of whether an AE has 
occurred.  
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy, in addition, follow-
up is conducted to obtain information on EDP outcome for all EDP reports with pregnancy 
outcome unknown.  A pregnancy is followed until completion or until pregnancy termination 
(e.g., induced abortion) and Pfizer is notified of the outcome.  This information is provided 
as a follow up to the initial EDP report.  In the case of a live birth, the structural integrity of 
the neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) 
for termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (e.g., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

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Spontaneous abortion includes miscarriage and missed abortion;
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure to 
investigational product
Additional information regarding the exposure during pregnancy may be requested.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on 
preterm infants to identify developmental delays).  
In the case of paternal exposure, the study participant will be provided with the Pregnant 
Partner Release of Information Form to deliver to his partner.  It must be documented that the 
study participant was given this letter to provide to his partner.
Exposure during breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE. An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (e.g., vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an AE associated with such a 
drug’s administration, the AE is reported together with the exposure during breastfeeding.
Medication error
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer.  Such events may 
be related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use.  
Medication errors include:
Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or prescription on 
the part of the healthcare provider or the patient/consumer);
Confusion with regard to invented name (e.g., trade name, brand name).
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE:
Medication errors involving patient exposure to the product, whether or not the medication 
error is accompanied by an AE.

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Medication errors that do not involve a patient directly (e.g., potential medication errors or 
near misses).  When a medication error does not involve patient exposure to the product the 
following minimum criteria constitute a medication error report:
An identifiable reporter;
A suspect product;
The event medication error.
Overdose, Misuse, Extravasation
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE.
Lack of Efficacy
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product.
Occupational Exposure
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the 
investigator, irrespective of the presence of an associated AE/SAE.
10.3. Adverse Event Reporting Guidance for Patient and/or Caregiver Survey 
Responses
The patient questionnaire for this study will be completed online via a secure website.  The 
online surveys do not include questions that could potentially identify a safety event, nor 
does it provide a free text field where study participants could specify information that may 
constitute a safety event. Responses indicative of “bleeding” and / or “pain” reported through 
the patient completed closed item questionnaire < see ANNEX 2> are considered hemophilia 
events that are related to the condition of hemophilia, or directly as a consequence of the 
bleeding event and are not considered as an adverse event and reportable.
REQUIREMENTS
This study does not involve data collection on clinical endpoints on individual patients.  
There is no mechanism by which information on safety events for an individual patient will 
be captured by a study participant during the course of data collection; thus reporting of 
adverse events is not feasible in the data collection process.  However, any information on a 
safety event inadvertently volunteered by a study participant during the course of this 
research must be reported as described below.

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The survey CRF for this study will be completed online via a secure website.  The survey 
does not include questions that could potentially identify a safety event, nor does it provide a 
free text field where study participants could specify information that may constitute a safety 
event.  Further, routine communication with study participants via email or phone with the 
Programme staff is not expected during the conduct of the study.  However, it is possible that 
a study participant may provide information that could constitute a safety event (e.g., serious 
and non-serious AEs and/or scenarios involving exposure during pregnancy, exposure during 
breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy and 
occupational exposure) to Programme staff  while in conversation about the survey CRF for 
any other reason (e.g., seeking information about the purpose of the study).  In the event that 
a study participant in the study reports a safety event associated with the use of the Pfizer 
product, the Programme staff will complete a non-interventional study (NIS) adverse event 
monitoring (AEM) Report Form and submit to Pfizer within 24 hours of becoming aware of 
the safety event.  Included in the completion of the NIS AEM Report Form is the study 
participant’s contact information as the reporter, as well as the contact information for the 
applicable  primary healthcare provider; complete contact information should be obtained so 
that, once the NIS AEM Report Form is transferred to Pfizer, the NIS AEM Report Form will 
be assessed and processed according to Pfizer’s standard operating procedures, including 
requests for follow-up regarding the safety event to the study participant, or as appropriate, 
the individual patient’s primary healthcare provider..
All Programme staff 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 the Programme 
staff 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. 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Following the conclusion of patient recruitment, Kantar Health will provide Pfizer with a 
final summary report of the study findings. A summary will be made available to a 
participant upon request.
For all publications relating to the Study, Pfizer will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
11.1. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 

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unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-center study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
12. COMMUNICATION OF ISSUES
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 NI study protocol that the investigator becomes aware of.

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13. REFERENCES
1.
Knobe, Karin, and Erik Berntorp. "New treatments in hemophilia: insights for the 
clinician." Therapeutic advances in hematology (2012): 2040620712440007.
2.
Dalton, Dan R. "Hemophilia in the managed care setting." The American journal of 
managed care 21.6 Suppl (2015): s123-30.
3.
McHorney, C.A., Ware, J.E. Raczek, A.E. “The MOS 36-item Short Form Health 
Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and 
mental health constructs.” Medical Care (1993): 31, 247-263.
4.
Saris-Baglama, R. N., DeRosa, M. A., Raczek, A. E., Bjorner, J. B., & Ware, J. E. 
“Development, validation, and norming of the SF-10 for Children Health Survey 
[Abstract].” Quality of Life Research (2006): 15(S1), A-145
5.
von Mackensen S, Gringeri A & the Haem-A-QoL study Group. “Health-related 
Quality of Life in Adult Patients with Haemophilia – Assessment with a New Disease-
specific Questionnaire (Haem-A-QoL).” Journal Of Thrombosis and Haemostasis
(2005): 3(Sup1):P0813.
6.
von Mackensen S, Bullinger M; Haemo-QoL Group. “Development and testing of an 
instrument to assess the Quality of Life of Children with Haemophilia in Europe 
(Haemo-QoL).” Haemophilia (2004): 10(1):17-25.
14. LIST OF TABLES 
None
15. LIST OF FIGURES
None

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Amendment Version 1.1; 04 April 2017
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Appendix 1. LIST OF STAND ALONE DOCUMENTS
Number
Document 
reference 
number
Date
Title 
1
Appendix A
In design
Patient/Caregiver Informed Consent Form 
2
Appendix B
In design
Patient/Caregiver Questionnaire 
3
Appendix C
In design
Physician CRF

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Appendix 2. FACTOR USE BEHAVIOR QUESTIONS
In responding to this question, please think about what ‘you did’ / ‘the child with hemophilia
did’ over the past month.
For the factor replacement therapy ‘you use’ / ‘the child with hemophilia uses’ to prevent and 
control bleeds, over the past month, how many times did ‘you’ / ‘the child with hemophilia 
had to’ use an extra infusion for each of the following reasons?   
Felt pain which I thought was a bleed
Never
1 time
2 times
3 times
4 times or more
Bleeding episode 
Never
1 time
2 times
3 times
4 times or more
Wanted additional protection before 
engaging in a sport or other impact 
activity
Never
1 time
2 times
3 times
4 times or more
Want extra protection for some another 
reason
Never
1 time
2 times
3 times
4 times or more
Other reason not listed 
Never
1 time
2 times
3 times
4 times or more
Appendix 3. ENCePP checklist for study protocols
Not applicable
Appendix 4. ANNEX 4. Additional information
Not applicable