AVENANCE - A Non-interventional Study to Provide Real-world Data on the Use of Avelumab as a Maintenance Treatment for Patients With Advanced or Metastatic Urothelial Carcinoma
Conditions: Urothelial Carcinoma
Sponsor: Pfizer

Avelumab
B9991045-AVENANCE NON-INTERVENTIONAL STUDY PROTOCOL
 V6.0 – 21 NOV 2022  
PFIZER CONFIDENTIAL  
CT24-WI-GL02-RF01 3.0 Non-Interventional Study Protocol Template For Primary Data Collection Study 02-
Nov-2020 
Page 1 of 42
Sponsor : Pfizer (SAS)
This study is being conducted as part of a joint development programme for Bavencio® 
between Pfizer and Merck.   
NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study information
Title
AVENANCE - A non-interventional study to 
provide real-world data on the use of avelumab as 
a maintenance treatment for patients with 
advanced or metastatic Urothelial Carcinoma
Protocol number
B9991045
Protocol version identifier
6.0
Date
November 21st 2022
Active substance
Avelumab
Medicinal product
BAVENCIO®
Research question and objectives
To generate clinical evidence on:
•
The characteristics of adv/mUC patients 
treated with avelumab
as maintenance 
treatment in the real-world setting. 
•
The effectiveness and safety of avelumab in 
the real-world setting. 
To 
describe 
patients’
characteristics 
and 
effectiveness of avelumab in different subgroups of 
interest.
The main subgroup of interest will be the patients 
with adv/mUC with histological variants.
Mains authors
Institut 
Cancerologie 
Strasbourg 
Europe, 
Strasbourg (ICANS).
 Pfizer France. 
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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS .......................................................................................................2 
2. LIST OF ABBREVIATIONS ................................................................................................4 
3. RESPONSIBLE PARTIES ....................................................................................................5 
4. ABSTRACT ...........................................................................................................................6 
5. AMENDMENTS AND UPDATES .....................................................................................10 
6. MILESTONES .....................................................................................................................12 
7. RATIONALE AND BACKGROUND ................................................................................12 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................13 
9. RESEARCH METHODS ....................................................................................................15 
9.1. Study design ............................................................................................................15 
9.1.1. Primary endpoint ........................................................................................16 
9.1.2. Secondary endpoints ...................................................................................16 
9.2. Setting ......................................................................................................................17 
9.2.1. Inclusion criteria .........................................................................................17 
9.2.2. Exclusion criteria ........................................................................................17 
9.3. Variables ..................................................................................................................18 
9.4. Data sources ............................................................................................................22 
9.5. Study size ................................................................................................................23 
9.6. Data management ....................................................................................................24 
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record ........................................................................................................24 
9.6.2. Record retention ..........................................................................................25 
9.7. Data analysis ...........................................................................................................26 
9.8. Quality control .........................................................................................................26 
9.9. Limitations of the research methods .......................................................................27 
9.9.1. Selection bias ..............................................................................................27 
9.9.2. Measures taken to reduce patients lost to follow-up and missing data .......27 
9.10. Other aspects .........................................................................................................28 
9.10.1. Archiving ..................................................................................................28 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................28 
10.1. Patient information ................................................................................................28 
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10.2. Patient consent .......................................................................................................29 
10.3. Patient withdrawal .................................................................................................29 
10.4. Institutional review board (IRB)/Independent ethics committee (IEC) ................30 
10.5. French National Medical Association (Conseil National de l’Ordre des 
Médecins, CNOM) ....................................................................................................30 
10.6. Data protection: French Data Protection Agency (Commission Nationale de 
l’Informatique et des Libertés [CNIL]) .....................................................................30 
10.7. Ethical conduct of the study ..................................................................................31 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................32 
11.1. Single reference safety document .........................................................................32 
11.2. Pharmacovigilance requirements ..........................................................................32 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........41 
13. REFERENCES ..................................................................................................................41 
14. LIST OF TABLES .............................................................................................................41 
15. LIST OF FIGURES ...........................................................................................................41 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................41 
ANNEX 2. ADDITIONAL INFORMATION .........................................................................42 
 
 
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B9991045-AVENANCE NON-INTERVENTIONAL STUDY PROTOCOL 
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2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
adv/Muc 
Locally advanced or metastatic urothelial carcinoma 
AE 
Adverse Event 
AEC 
Angiotensin-converting enzyme (ACE) 
AIS 
Anti-inflammatory steroids 
ATU 
Temporary Authorization for Use  
BSC 
Best Supportive Care  
ChT 
Chemotherapy 
CNIL 
French Data Protection Agency (Commission 
Nationale de l’Informatique et des Libertés) 
CNOM 
French National Medical Association (Conseil 
National de l’Ordre des Médecins) 
CPP 
Committee for the Protection of Persons (Comité de 
Protection des Personnes) 
CR 
Complete response 
DOR 
Duration Of Response 
DOT 
Duration Of Treatment 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ePRO 
Electronic Patient Reported Outcomes 
EQ-5D-5L 
EuroQoL – 5 dimensions 5 level 
FACT FBlSI-18 
Functional Assessment of Cancer Therapy - 
Bladder Symptom Index-18 
IRR 
Infusion related reaction 
NCCN 
National Comprehensive Cancer Network 
NSAIDs 
Non-steroidal anti-inflammatory drugs  
OS 
Overall Survival 
ORR 
Overall Response Rate  
PFS 
Progression Free Survival 
PD-L1 
Programmed death ligand1  
PPI 
Proton pump inhibitors 
PR 
Partial response 
Q 
Quadrimester 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
UC 
Urothelial Cancer 
VAS 
Visual analogue scale 
 
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B9991045-AVENANCE NON-INTERVENTIONAL STUDY PROTOCOL 
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3. RESPONSIBLE PARTIES 
Scientific Committee 
Name 
Title 
Affiliation 
Institut Cancerologie Strasbourg 
Europe, Strasbourg (ICANS) 
Institut Jean Godinot, Reims 
Centre Léon Bérard, Lyon 
Gustave Roussy, Villejuif 
CHU, Bordeaux 
HEGP, Paris 
Clinique Victor Hugo, Le Mans 
 
Scientific Committee coordinator 
Nom 
Title 
Affiliation 
Institut Cancerologie Strasbourg Europe, 
Strasbourg (ICANS) 
 
Study team  
Name 
Role 
Medical Team Leader Oncology - Pfizer 
Medical Advisor Oncology - Pfizer 
Medical Director Oncology - Merck 
Medical Advisor Oncology - Merck 
Real World Data Medical Manager - Pfizer 
NIS Project manager  - Pfizer 
NIS Lead - Pfizer 
Health economics manager - Pfizer 
Data management - Pfizer 
Statistical Lead - Pfizer 
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Avelumab 
B9991045-AVENANCE NON-INTERVENTIONAL STUDY PROTOCOL 
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4. ABSTRACT 
 
Title 
AVENANCE - A non-interventional study to provide real world data on the use of 
avelumab as a maintenance treatment for patients with advanced or metastatic 
Urothelial Carcinoma 
Main author 
 Institut Cancerologie Strasbourg 
Europe, Strasbourg (ICANS). 
 Pfizer France. 
Rationale 
On December 11th , 2020 the CHMP has adopted a positive opinion for avelumab as 
first line maintenance treatment of adult patients with locally advanced or metastatic 
urothelial carcinoma (adv/mUC) whose disease has not progressed with platinum-
based induction chemotherapy. Marketing authorization for avelumab use in 
adv/mUC was issued on January 21st, 2021 by European Medicine Agency. 
 
The early use in France of avelumab in maintenance treatment for adv/mUC patients 
in the setting of the ATU (since July 2020) is an opportunity to early collect real-
world data of avelumab in this indication. 
In addition to confirm the effectiveness and safety data provided by JAVELIN 
Bladder 100 study in routine clinical practice, this non-interventional study is an 
opportunity to generate effectiveness and safety data on different subgroups of 
interest. The main subgroup of interest will be the adv/mUC patients with 
histological variants. Few data are available on the efficacy of immunotherapy in 
histology variants of adv/mUC. 
Objectives 
Primary objective: to estimate Overall Survival (OS) of adv/mUC patients treated 
with avelumab in the real-world setting. 
Secondary objectives :  
• To describe patients’ characteristics: ECOG (0-4) at chemotherapy (ChT) 1st 
and avelumab initiation, sex, age, ChT regimens received in 1st line 
(Cis/Gem, Carbo/Gem, Cis/Carbo/Gem, MVAC regimens, others),  median 
number of ChT cycles received in 1st line, median time between the end of 
ChT 1st line and the start of avelumab, best response to 1st line chemotherapy 
(CR, PR, SD; CR-RP, SD), site and histology of the primary tumor (bladder, 
urethra or upper tract), site of baseline metastasis before ChT and avelumab 
(visceral vs non visceral), biological abnormalities (neutropenia, 
lymphopenia, impaired renal function, anemia), PD-L1 status and FGFR 
abnormality, Bajorin risk classification (0, 1, 2) evaluated before the start of 
090177e1a41aac13\Final\Final On: 28-Jul-2025 13:50 (GMT)
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B9991045-AVENANCE NON-INTERVENTIONAL STUDY PROTOCOL 
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ChT 1st line, use of concomitant treatments (corticosteroids/anti-
inflammatory 
steroids 
(AIS)/non-steroidal 
anti-inflammatory 
drugs 
(NSAIDs), 
angiotensin-II-receptor 
antagonists 
(sartans)/angiotensin-
converting enzyme (ACE) inhibitors, antibiotics, proton pump inhibitors 
(PPI)) at avelumab initiation, type of neoadjuvant and adjuvant treatments.  
• To estimate: Overall Survival from the start of ChT in 1st line, Progression 
Free Survival one and two (PFS1 and PFS2). Overall Response Rate (ORR), 
Duration Of Response (DOR) and Duration Of Treatment (DOT) while 
receiving avelumab. 
• To describe the pattern of progression while receiving avelumab. 
• To describe subsequent treatments and response to these treatments. 
• To describe the safety profile of avelumab. 
• To describe use of premedication (acetaminophen and antihistamine). 
• To describe Patient-Reported Outcomes (PROs) related to symptoms via the 
NCCN/FACT FBlSI-18 questionnaire and related to global health via the 
EQ-5D-5L questionnaire. This objective will be evaluated only among 
patients initiating avelumab after the start of the study. 
The primary and secondary objectives will be evaluated on the overall population 
and for prespecified subgroups. 
Design 
Multicenter ambispective (retrospective and prospective) non-interventional study 
of adv/mUC patients treated with avelumab, not impacting the treatment decision 
made by the treating physician and the medical management of treated patients. 
 
• All patients who initiated avelumab before the start of the study in the site 
will be included retrospectively. All patients are eligible: those under 
avelumab at inclusion, those who died before the start of the study, and those 
no longer treated with avelumab at the time of the study start.  
• Patients initiating the drug after the start of the study in the site will be 
prospectively included. 
 
Follow-up:  
The last patient prospectively included will be followed during 2 years. All other 
patients will be followed until death or until the end of the follow-up of the last 
patient prospectively included. 
Population  
Inclusion criteria 
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1. Patient ≥ 18 years of age 
2. Patient with locally advanced or metastatic urothelial carcinoma (irrespective of 
tumor histology) whose disease has not progressed (ongoing stable disease, partial 
response or complete response) following completion of first-line platinum-based 
chemotherapy and who has been (restrospective), is (retrospective and 
prospective), will be (prospective) treated with avelumab. 
3 For a patient alive at the moment of the inclusion in the study: the patient must 
be informed of the study, he/she must be given an information letter signed by the 
investigator and must not be opposed to the collection of his/her data 
For a patient who died before the inclusion in the study: the patient (during his 
lifetime) must not be opposed in writing to the collection of his data. 
4. Patient benefiting from a social security scheme according to local regulations 
Exclusion criteria 
5. For a patient alive at the moment of the inclusion in the study: patient without 
liberty, under tutelage, or unable to give oral consent. 
6. Patient enrolled in a prospective interventional clinical trial assessing an 
investigational product. 
Variables 
The following types of information will be collected:  
. Characteristics of patients and their cancer before avelumab initiation and previous 
treatments 
. Initiation of avelumab (date, premedication, biological exams) 
. Follow-up data (collect at inclusion and every 3 months until end of follow-up): 
avelumab administrations, tumoral responses, discontinuation, subsequent 
treatments, death 
. Patient reported outcome (PRO) : NCCN/FACT FBlSI-18 and EQ-5D-5L (at the 
time of avelumab initiation, at different time points after initiation if the patient is 
still treated with avelumab (6 weeks, 3 months, and every three months for up to 2 
years, tumor progression if so), and at avelumab discontinuation). 
Data sources 
The data of interest will be reported in electronic case report forms (eCRF) by the 
investigator site for each selected patient, at inclusion and regularly during follow-
up, on the basis of the data available in the patients’ medical records. 
In addition, two questionnaires will be completed by participants. 
Study size 
Target sample size is 600 patients. 
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Data analysis 
A detailed statistical analysis plan will be available before the database lock. 
 
The primary end point is the Overall Survival (OS). OS is defined as the time from 
the date of first injection of avelumab to the date of death due to any cause. Patients 
last known to be alive will be censored at date of last contact. OS will be summarized 
using the Kaplan-Meier method and displayed graphically. Confidence intervals 
(CIs) for the 25th, 50th and 75th percentiles will be reported.  
 
A first interim analysis (IA) will be performed 6 months after the inclusion of the 
1st patient and then every year for publication purposes. 
 
The data collected in the present study may also be analyzed together with data 
from other countries, to increase sample size to address with a higher precision for 
some of the study objectives. The details of this pooled analysis will be described 
in a separate analysis plan. 
Milestones 
Selection of investigating centers:     Q1 2021 
CPP submission:     January 2021 
Start of data collection (First patient First Visit):     Q2 2021 
End of data collection (Last Patient Last Visit):       Q4 2024 
Interim analysis 1: 
 Q2 2022 
Interim analysis 2: 
Q4 2022 
Interim analysis 3: 
Q4 2023 
Interim analysis 4: 
Q4 2024 
Final analysis and study report: 
Q1 2025 
 
 
 
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5. AMENDMENTS AND UPDATES 
 
Amendment 
number 
Date 
Protocol 
section(s) 
changed  
Summary of 
amendment(s) 
Reason 
1 / Protocol 
V3.0 
07-JUN-
2021 
 - Cover page 
 - 9.6.1 
 - 10.6 
Pfizer is jointly 
responsible of the 
processing of the personal 
data with Merck. 
This study is being 
conducted as part of a 
joint development 
programme for 
Bavencio® between 
Pfizer and Merck.   
 - 9.6.2  
 - 9.10.1 
Data storage period 
Clarification added 
 - 10.6 
 
The study comes within 
the scope of MR003 but 
also of MR004. 
Due to the retrospective 
part of the study. 
2 / Protocol 
V4.0 
 
25- 
NOV-
2021 
 
 -4 – 
ABSTRACT 
(inclusion 
criteria n° 3) 
 - information to person of 
trust not mandatory 
 - the patient must not be 
opposed in writing 
According to MR004 
9.2.1  
 - information to person of 
trust not mandatory 
 - the patient must not be 
opposed in writing 
According to MR004 
3 / Protocol 
V5.0 
29-
NOV-
2021 
11.2 (reporting 
period) 
Non serious AE reporting 
period is reduced to 90 
days after the last 
avelumab administration 
Exception request 
validated by Pfizer 
Pharmacovigilance 
Policy Committee 
4 / Protocol 
V6.0    
21-
NOV-
2022  
-4 – 
ABSTRACT 
(Study size) 
And  
9.5 Study Size 
 
 
 
Target sample size is 
increased to 600 patients 
 
 
 
 
 
 
Obtain the number of 
patients with variant 
initially planned 
 
 
 
 
 
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9.3 Variables  
 
 
 
 
 
 
And 
9.4 Data 
Sources 
 
 
 
 
 
 
* In order to validate the 
type of variants, 
anonymized anatomical 
pathology reports of the 
patients concerned will be 
collected and reviewed by 
the steering committee. 
For the patients presenting 
an 
UC 
with 
variant, 
anonymized 
anatomical 
pathology reports will be 
collected and stored in a 
dedicated directory in the 
eCRF. 
 
 
 
In order to confirm the 
histological type of the 
urothelial tumors of the 
patients included in the 
Avenance study, the 
scientific committee of 
the study wishes to 
review the anatomical 
pathology reports of 
these patients 
 
 
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 V6.0 – 21 NOV 2022  
 
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6. MILESTONES 
Table 1: study scheduled planning 
Milestone 
Planned date 
Selection of investigating centers  
Q1 2021 
CPP submission 
January 2021 
Start of data collection (First patient First Visit) 
Q2 2021 
End of data collection (Last Patient Last Visit) 
Q4 2024 
Interim analysis 1 
 Q2 2022 
Interim analysis 2 
Q4 2022 
Interim analysis 3 
Q4 2023 
Interim analysis 4 
Q4 2024 
Final analysis and study report 
Q1 2025 
 
7. RATIONALE AND BACKGROUND 
Urothelial Cancer (UC) accounts for approximately 90% of all cancer of urinary tract (bladder, 
upper urinary tract, urethra). About 11 000 patients are newly diagnosed with an urinary tract 
cancer each year in France1. Patients with metastatic UC have a dismal prognosis with a five-
year survival rate of only 5%. Platinum-based polychemotherapy regimen is currently the first-
line standard of care for patients with advanced/metastatic disease, but despite high initial 
response rates, durable and complete responses following first-line chemotherapy (ChT) are 
uncommon, and most patients will ultimately experience disease progression within nine 
months after initiation of treatment. 
Avelumab (MSB0010718C, BAVENCIO®) is a human Immunoglobulin G1 monoclonal 
antibody directed against the programmed death ligand1 (PD-L1).  
Avelumab in combination with Best Supportive Care (BSC) as a maintenance treatment had 
been evaluated versus BSC alone in a phase III randomized trial (JAVELIN Bladder 100) for 
locally advanced or metastatic Urothelial Carcinoma (adv/mUC) patients who have not 
progressed with first-line platinum-based chemotherapy2. The JAVELIN Bladder 100 study 
has demonstrated a significant 7.1-months improvement in median Overall Survival with 
Avelumab+BSC as first-line maintenance versus BSC alone, with a 31% reduction of the death 
risk in the overall population (hazard ratio = 0.69 (95% CI, 0.56, 0.86), p<0.001). The results 
of the JAVELIN Bladder 100 had been presented at ASCO 2020 and published in the New 
England Journal of Medicine on September 18th, 2020. 
 
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On June 30th, 2020, U.S. Food and Drug Administration approved avelumab for maintenance 
treatment of patients with locally advanced or metastatic Urothelial Carcinoma who have not 
progressed with first-line platinum-containing chemotherapy. 
 
On July 3rd, 2020 the French National Agency for Medicines and Health Products issued a 
cohort Temporary Authorization for Use (ATU) extension for avelumab in the first-line 
maintenance treatment of adult patients with locally advanced or metastatic Urothelial 
Carcinoma who have not progressed with first-line platinum-based chemotherapy and 
presenting an ECOG performance status of 0 or 1. 
 
On December 11th , 2020 the CHMP has adopted a positive opinion for avelumab as first line 
maintenance treatment of adult patients with locally advanced or metastatic urothelial 
carcinoma whose disease has not progressed with platinum-based induction chemotherapy. 
Marketing authorization for avelumab use in adv/mUC was issued on January 21st, 2021 by 
European Medicine Agency3. 
 
The early use in France of avelumab in maintenance treatment for adv/mUC patients in the 
setting of the the ATU is an opportunity to early collect real world data of avelumab in this 
indication. 
 
In addition to confirm the effectiveness and safety data provided by JAVELIN Bladder 100 
study in routine clinical practice this non-interventional study is an opportunity to generate 
effectiveness and safety data on different subgroups of interest. The main subgroup of interest 
will be the adv/mUC patients with histological variants. Few data are available on the efficacy 
of immunotherapy in histology variants of adv/mUC. 
 
 
8. RESEARCH QUESTION AND OBJECTIVES 
The study will generate clinical data on the characteristics of adv/mUC patients treated with 
avelumab and on the effectiveness and safety of avelumab in the real-world setting. 
Primary objective: to estimate Overall Survival (OS) of adv/mUC patients treated with 
avelumab in the real-world setting. 
Secondary objectives :  
• To describe patients’ characteristics: ECOG (0-4) at ChT 1st and avelumab initiation, 
sex, age, ChT regimens received in 1st line (Cis/Gem, Carbo/Gem, Cis/Carbo/Gem, 
MVAC regimens, others),  median number of ChT cycles received in 1st line, median 
time between the end of ChT 1st line and the start of avelumab, best response to 1st line 
chemotherapy (CR, PR, SD; CR-RP, SD), site and histology of the primary tumor 
(bladder, urethra or upper tract), site of baseline metastasis before ChT and avelumab 
(visceral vs non visceral), biological abnormalities (neutropenia, lymphopenia, 
impaired renal function, anemia), PD-L1 status and FGFR abnormality, Bajorin risk 
classification (0, 1, 2) evaluated before the start of ChT 1st line, use of concomitant 
090177e1a41aac13\Final\Final On: 28-Jul-2025 13:50 (GMT)

Avelumab 
B9991045-AVENANCE NON-INTERVENTIONAL STUDY PROTOCOL 
 V6.0 – 21 NOV 2022  
 
PFIZER CONFIDENTIAL  
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treatments (corticosteroids/anti-inflammatory steroids (AIS)/non-steroidal anti-
inflammatory 
drugs 
(NSAIDs), 
angiotensin-II-receptor 
antagonists 
(sartans)/angiotensin-converting enzyme (ACE) inhibitors , antibiotics, proton pump 
inhibitors (PPI)) at avelumab initiation, type of neoadjuvant and adjuvant treatments. 
• To estimate: Overall Survival from the start of ChT in 1st line, Progression Free 
Survival one and two (PFS1 and PFS2). Overall Response Rate (ORR), Duration Of 
Response (DOR) and Duration Of Treatment (DOT) while receiving avelumab. 
• To describe the pattern of progression while receiving avelumab. 
• To describe subsequent treatments and response to these treatments. 
• To describe the safety profile of avelumab. 
• To describe use of premedication (acetaminophen and antihistamine). 
• To describe Patient-Reported Outcomes (PROs) related to symptoms via the 
NCCN/FACT FBlSI-18 questionnaire and related to global health via the EQ-5D-5L 
questionnaire. This objective will be evaluated only among patients initiating avelumab 
after the start of the study. 
The primary and secondary objectives will be evaluated on the overall population and for 
prespecified subgroups. 
o Main subgroup of interest: histology (UC with variant; UC without variant). 
o Other subgroups of interest: ECOG at avelumab initiation (PS 0-1; PS ≥2), 
locally advanced  urothelial carcinoma versus metastatic urothelial carcinoma, 
previous ChT regimens (Cis/Gem, Carbo/Gem, Cis/Carbo/Gem, MVAC 
regimens, others), best response to 1st line chemotherapy (CR, PR, SD; CR+PR, 
SD), number of ChT cycles received in 1st line (˂ 4 cycles; ≥ 4 cycles and ≤ 6; 
˃ 6 cycles), site of baseline metastases before ChT (visceral vs non-visceral), 
patients with an early relapse on avelumab (progression at the first tumoral 
assessment) and patients with a long-term response to avelumab (4th quartile), 
delay between the end of ChT and the start of avelumab (˂ 4 weeks; between 4 
and 10 weeks; >10 weeks), ATU patients versus non ATU patients, site for the 
primary tumor (bladder, urethra, upper tract), PD-L1 status, FGFR abnormality, 
Bajorin risk classification evaluated before ChT 1st line (0, 1, 2), presence of 
biological anomalies (neutropenia, lymphopenia, impaired renal function, 
anemia), use of concomitant treatments (corticosteroids/AIS/NSAIDs, 
sartans/ACE inhibitors, antibiotics, PPI) at avelumab initiation. 
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9. RESEARCH METHODS 
9.1. Study design  
Multicenter ambispective (retrospective and prospective) non-interventional study of 
adv/mUC patients treated with avelumab, not impacting the treatment decision made by the 
treating physician and the medical management of treated patients (Figure 1). 
 
Inclusion period: expected 18 months to reach sample size. 
Target sample size is 600 patients. 
• All patients who initiated avelumab before the start of the study in the site will be 
included retrospectively. All patients are eligible: those under avelumab at inclusion, 
those who died before the start of the study, and those no longer treated with avelumab 
at the time of the study start.  
• Patients initiating the drug after the start of the study in the site will be prospectively 
included. 
 
Follow-up:  
The last patient prospectively included will be followed for 2 years. All other patients will be 
followed until death or until the end of the follow-up of the last patient prospectively included. 
 
Patients who started avelumab before the start of the study will be followed retrospectively, 
but also prospectively for those still alive at the beginning of the study. 
Follow-up visits will be made during the course of regular visits and/or hospitalisations. No 
additional visits or examinations are required by the protocol, as the study is observational: 
follow-up and treatment modalities will be at the sole discretion of the participating physician. 
Clinical data will be collected every three months after the inclusion in the study and until 
death or the end of the study: 24 months after the inclusion of the last prospective patient. 
Patients initiating avelumab after the start of the study (prospective part of the study) will 
complete PRO questionnaires : 1) at the time of avelumab initiation, 2) at different time points 
after initiation if the patient is still treated with avelumab (6 weeks, 3 months, and every three 
months for up to 2 years, tumor progression if so), 3) and at avelumab discontinuation. 
 
Number of sites: the study will be proposed to all sites participating to the ATU program, plus 
some additional centers expected to treat patients after the ATU period. Approximately 100 
sites are expected to participate to the study.  
 
 
 
 
 
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Figure 1. Study design 
9.1.1. Primary endpoint
OS: time between the first injection of avelumab and the date of death from any cause.  
9.1.2. Secondary endpoints 
•
OS from the start of the chemotherapy used in 1st line: time between the first injection
of the chemotherapy used in 1st line and the date of death from any cause. 
•
PFS1: time between the first injection of avelumab and the date of progression or death 
from any cause. Progression status will be defined according to RECIST 1.1.
•
PFS2: time between the first injection of avelumab and the date of progression or death 
from any cause during the 2nd line of treatment post-avelumab. Progression status will 
be defined according to RECIST 1.1. 
•
ORR: proportion of patients with a Complete Response or Partial Response as a best 
response during the avelumab treatment. Responses to treatment will be defined 
according to RECIST 1.1.
•
DOR: time between the beginning of the response and progression or death from any 
cause.
•
DOT: time between the first and last dose of avelumab. 
•
Patterns of progression under avelumab: metastatic sites and type of progression (new 
lesion(s)/progression of known lesion(s)). 
•
Subsequent treatments and response to these treatments: DOT, PFS, ORR and OS. 
•
Safety: AEs of any type, grade 3-4 AEs, AEs leading to interruption or discontinuation, 
AEs leading to death. 
End of 
study
Start of 
study
Start of early 
access (ATU)
Retrospective part
Prospective part
Inclusion period 
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• Premedications (acetaminophen and antihistamine): Proportion of patients who 
received a premedication at each injection of avelumab. Median number of cycles with 
premedication. To evaluate the correlation between infusion-related reactions and 
premedication. 
• Evolution of PROs NCCN/FACT FBlSI-18 and EQ-5D-5L scores during avelumab 
treatment. 
9.2. Setting 
The study will be proposed to all French centers where patients have been treated with 
avelumab in the setting of the ATU, plus some additional centers suitable to treat patients after 
the ATU period. 
All the eligible patients from the participating centers will be proposed to be included in the 
study. Regarding the ATU patients who died before the start of the study, families will be 
informed.  
9.2.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible to the study: 
1. Patient ≥ 18 years of age 
2. Patient with locally advanced or metastatic urothelial carcinoma (irrespective of tumor 
histology) whose disease has not progressed (ongoing stable disease, partial response or 
complete response) following completion of first-line platinum-based chemotherapy and who 
has been (restrospective), is (retropsectifve and prospective), will be (prospective) treated 
with avelumab. 
3. For a patient alive at the moment of the inclusion in the study : the patient must be informed 
of the study, he/she must be given an information letter signed by the investigator and must 
not be opposed to the collection of his/her data 
For a patient who died before the inclusion in the study : the patient (during his lifetime) 
must not be opposed in writing to the collection of his data. 4. Patient benefiting from a 
social security scheme according to local regulations 
9.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
5. For a patient alive at the moment of the inclusion in the study: patient without liberty, 
under tutelage, or unable to give oral consent. 
6. Patient enrolled in a prospective interventional clinical trial assessing an investigational 
product. 
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9.3. Variables 
Table 2 shows the information which will be collected in the study.  
 
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Table 2. Information collected in the study and timing of data collection 
Data elements 
Variables 
Timing of data collection 
Inclusion 6 weeks 
3 
months, 
then 
every 
three 
months 
until end 
of 
follow-
up  
Inclusion 
 
• Type of center 
• Eligibility criteria 
(inclusion/exclusion) 
• Date of provision of 
information letter 
X 
 
X 
Characteristics 
of patients and 
their 
cancer 
before 
avelumab 
initiation  
• Demographics : month and 
year of birth, sex  
• Patient 
and 
Cancer 
characteristics:  
. Localisation: upper/lower 
(bladder, 
urethra) 
urinary 
tract 
. 
Cancer 
characteristics: 
histological 
subtype 
including type of variant*, 
PD-L1 status and FGFR 
alteration with type of test 
and CPS score. 
• Localized cancer: date of 
diagnosis,  type of treatment 
(adjuvant/neoadjuvant), 
regimen, dates of start and 
end, number of ChT cycles, 
complete 
response 
if 
neoadjuvant. 
• Adv/mUC: date of diagnosis, 
stage at ChT initiation, 
metastatic sites at ChT 
initiation, Karnowski index 
and ECOG at ChT initiation, 
type of ChT regimen, dates of 
start and end, number of ChT 
X 
 
X 
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cycles, response at the end of 
ChT, date of start of partial or 
complete response if so. 
Initiation 
of 
avelumab 
 
• Patients 
characteristics 
: 
ECOG at initiation 
• Biological exam: neutrophil, 
lymphocyte, 
haemoglobin, 
creatinine clearance 
• Metastatic sites 
• Date of first administration, 
dose  
• Use of premedication 
(acetaminophen and 
antihistamine) 
X 
 
X 
Clinical 
Follow-up data  
 
• Avelumab administration 
. Date of each infusion, dose 
. 
Use 
of 
premedication 
(acetaminophen 
and 
antihistamine) 
• Tumoral 
response 
under 
avelumab 
. 
At 
inclusion 
(for 
retrospective data collection): 
tumoral evaluation (yes/no), 
best response since avelumab 
initiation, date of partial or 
complete response if so, date 
of progression if so with 
site(s) of progression and 
type (new or preexisting 
lesions). 
. Tumoral evaluation since 
last 
visit 
(yes/no, 
date), 
response (partial remission, 
complete 
remission, 
progression, stable disease, 
not evaluable), site(s) of 
progression if so and type 
(new or  preexisting lesions). 
• 
ECOG if the patient is still 
on avelumab 
• Avelumab discontinuation 
X 
 
X 
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. Temporary interruption(s) 
with reason and dates 
. Permanent discontinuation 
with reason and date 
• Subsequent treatments after 
avelumab discontinuation 
. 
Regimen 
and 
dates 
start/discontinuation 
. Best response, progression 
with date, 
• Death with date and cause 
• Lost to follow-up if so and 
date 
• Date of withdrawal if so 
Safety 
Adverse events (see section 11) 
X 
 
X 
Concomitant 
treatments 
Corticosteroids/AIS/NSAIDs, 
sartans/ACE inhibitors, 
antibiotics, PPI, if the patient is 
still on avelumab 
X 
 
X 
Patient 
reported 
outcome (PRO) 
 
Patients initiating avelumab after 
the start of the study will 
complete NCCN/FACT FBlSI-18 
and EQ-5D-5L questionnaires: 
1) at the time of avelumab 
initiation (baseline) 
2) at different time points 
after initiation if the 
patient is still treated 
with avelumab : 6 weeks, 
3 months, every three 
months for up to 2 years, 
tumor progression if so 
3) at avelumab 
discontinuation (whatever 
the reason is) 
X 
X 
X 
 
* In order to validate the type of variants, anonymized anatomical pathology reports of the 
patients concerned will be collected and reviewed by the steering committee. 
 
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9.4. Data sources  
The data of interest will be reported in an electronic case report forms (eCRF) by the 
investigator for each included patient, at inclusion and regularly during follow-up, on the basis 
of the data available in the patients’ medical records. A clinical study technician may help the 
investigator to enter the patient’s data in the eCRF.  
For the patients presenting an UC with variant, anonymized anatomical pathology reports will 
be collected and stored in a dedicated directory in the eCRF. 
Pfizer and Exystat, in charge of study data management, are responsible for the creation and 
maintenance of the eCRFs.  
No directly nominative data will be collected. During the individual set up of the investigator 
site, Pfizer will assign a 4-digit code to each site: this code corresponds to the site number.  
The patient number will comprise the site number (4 digits) followed by a 3-digit code assigned 
in ascending order of inclusion: for example, patient number 0009-002 corresponds to the 
second patient at site 9. The collected data will be confidential and covered by medical secrecy. 
In addition, two questionnaires (ePRO or paper) will be completed by participants who 
initiated avelumab after the beginning of the study:  
• NCCN/FACT FBlSI-18 (Functional Assessment of Cancer Therapy – Bladder Cancer 
Symptom Inventory) : The FBlSI-18 is a self-administered questionnaire to assess 
patient bladder cancer-specific symptoms using a ‘core’ set of questions a cancer site-
specific bladder subscale. Higher scores indicate a higher degree of bladder symptoms. 
• EQ-5D-5L (EuroQoL – 5 dimensions 5 level) : The EuroQol EQ-5D-5L is patient-
completed generic questionnaire consisting of 2 pages: the EQ-5D descriptive system 
and the EQ visual analogue scale (EQ VAS) :  
- 
The questionnaire (descriptive system) is designed to assess health status in terms 
of a single index value or utility score. It comprises five dimensions of health 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For 
each dimension, respondents select the statement that best describes their health on 
that day from five possible options of increasing levels of severity (no problems, 
slight problems, moderate problems, severe problems, and extreme problems).  
- 
The EQ VAS records the patient’s self-rated health on a vertical visual analogue 
scale, where the endpoints are labelled ‘The best health you can imagine’ and ‘The 
worst health you can imagine’. The VAS can be used as a quantitative measure of 
health outcome that reflect the patient’s own judgement. 
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9.5. Study size 
The primary endpoint is the Overall Survival (OS). In this non-interventional study, the 
objective is only descriptive and the sample size will rely on the precision of the estimate.  
The expected precision of the median survival time can be calculated using following 
assumptions: 
- 
Expected median Overall Survival time: 20 months. 
- 
Two-sided 95% Confidence Interval (CI).  
- 
Exponential Lifetime Percentile distribution (S(t)=e-t/29) with a median survival 
time of 20 months and a mean survival of 29 months. 
- 
Assuming the absence of right-censoring before the median survival and the 
occurrence of a single event for each event time. 
The different accuracies and CI for the median overall survival time can therefore be calculated 
as a function of sample sizes. Below accuracy and 95%CI for a median survival time of 20 
months: 
Total Sample 
 size 
Accuracy (total 
patients) 
Lower 
CI 
Upper CI 
400 
4,0 
18,3 
22,2 
433 
3,8 
18,3 
22,1 
467 
3,7 
18,4 
22,1 
500 
3,5 
18,4 
22,0 
533 
3,4 
18,5 
21,9 
567 
3,3 
18,5 
21,9 
600 
3,2 
18,6 
21,8 
667 
3,1 
18,7 
21,7 
800 
2,8 
18,8 
21,6 
1000 
2,5 
18,9 
21,4 
With 600 patients, the CI of OS is expected to be [18.6; 21.8] for a 3.2 months accuracy. 
A total of 47 variant patients for a total sample size of 600 patients will produce a two-sided 
95% confidence interval for the median survival time with a width equal to 12 months (PASS® 
version 15.0 validated with Nquery® version 8.3.1 - reference Mathews, Paul. 2010. Sample 
Size Calculations: Practical Methods for Engineers and Scientists. Mathews Malnar and 
Bailey, Inc.).  
 
With a total of 47 patients, the two-sided 95% CI associated to a median survival time of 20 
months will be [15.4 ; 27.4]. Of note the two-sided 95% CI for the whole sample (600 patients) 
will be [18.6 ; 21.8]. 
 
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9.6. Data management  
The data will be collected thanks to the software Cleanweb (from Telemedicine SA) and stored 
in a secured file storage server. The eCRF and the PROs data will be merged in the Cleanweb 
database.  
Only dedicated study personnel will have access to the database. 
A Data Management Plan will be drawn up to describe all of the Data Management activities 
carried out during the study, together with a Data Validation Plan, which will describe all of 
the coherence tests and listings of inconsistencies found during the study together with request 
messages for corrections sent to the participating investigator. This Data Management Plan 
must be approved by the sponsor before inclusions begin. 
The use of the e-CRF enables the pre-tests to be carried out (coherence tests performed online 
that enable an immediate correction of inconsistencies from the participating doctors), which 
will help to reduce the number of requests for correction. 
On a regular basis during the conduct of the study, the Data Manager will trigger the planned 
coherence tests. Incoherencies will be resolved online by the participating investigators or his 
delegates.  
Once all corrections have been made to the database and all the eCRFs signed by the 
investigators, the data manager will lock the database making the data available for the final 
statistical analysis. 
All the data management decisions will be documented in the data management issue log.  
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
The data of interest will be recorded in electronic format in a case report form (e-CRF). 
A e-CRF is required and should be completed for each included patient. The completed original 
e-CRFs will be sole property of Pfizer and Merck and should not be made available in any 
form to third parties, except for authorised representatives of Pfizer or Merck or appropriate 
regulatory authorities, without written permission from Pfizer and/or Merck. The investigator 
shall ensure that the e-CRFs are securely stored at the study site in encrypted electronic or 
paper format and are protected by a password or kept securely in a locked room in order 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 e-CRFs and any other data collection supports 
(source documents) and for ensuring that they are accurate, authentic/original, attributable, 
complete, consistent, legible, timely (contemporaneous), enduring, and available when 
required. The e-CRFs must be signed by the investigator or by an authorised member of the 
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research team in order to guarantee that the data contained on the e-CRFs are correct and 
complete. Any corrections to entries made in the e-CRF source documents must be dated, 
initialled by the author, and explained (if necessary) and should not obscure the original entry. 
In most cases the source documents are the hospital or the physician's record.  In these cases, 
data collected on the e-CRFs must match these records.  
In some cases, the e-CRF/e-PRO may also serve as the source document. In these cases, a 
document should be available at the investigator site or at Pfizer that clearly identifies those 
data that will be recorded on the e-CRF, and for which the e-CRF will stand as the source 
document.  
The e-PRO will be completed by those participants who chose to use this method to fill in data.  
Participants not wanting to use the e-PRO method may fill in the data concerning them using 
the same data collection forms in paper format. These paper forms will be entered in the study 
database by data entry operators appointed by the sponsor. 
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., CRFs/e-CRFs and hospital records), all original 
signed information letters, copies of all CRFs/e-CRFs, pharmacovigilance notification forms, 
source documents, detailed records of treatment dispensing, 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. 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 up to 2 years after the last publication of the results of 
the study or, failing any publication, up to the signature of the final report of the study and 
must then be archived for up to 20 years maximum or a duration in accordance with the existing 
regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, even 
if retention requirements have been met. 
Patient self-questionnaires may be directly completed in electronic format by the patients on 
the study ePRO. 
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Otherwise, hard copies of the completed patient self-questionnaires will be sent to Pfizer by 
the investigator site using secure follow-up envelopes. They will then be sent electronically by 
Pfizer via a secure site to the data management company for entry. 
9.7. Data analysis  
A detailed statistical analysis plan will be available before the database lock. 
 
All effectiveness analyses (except PRO analysis) will be performed on a Full Analysis Set 
(FAS) defined as all enrolled patients who received at least one injection of avelumab. 
“Enrolled" means a participant's, or his or her legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent/assent process 
and who meet all eligibility criteria. Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in the study, are not considered 
enrolled. 
 
The primary end point is the Overall Survival (OS). OS is defined as the time from the date of 
first injection of avelumab to the date of death due to any cause. Patients last known to be alive 
will be censored at date of last contact. OS will be summarized using the Kaplan-Meier method 
and displayed graphically. Confidence intervals (CIs) for the 25th, 50th (median) and 75th 
percentiles will be reported. In particular, six-months and one-year survival rate will be 
assessed with a 95%CI. 
 
A first interim analysis (IA) will be performed 6 months after the inclusion of the 1st patient 
and then every year for publication purposes. 
 
The data collected in the present study may also be analyzed together with data from other 
countries, to increase sample size to address with a higher precision some of the study 
objectives. The details of this pooled analysis will be described in a separate analysis plan. 
9.8. Quality control 
The quality of the data collected during the study will be ensured by: 
• 
The training of investigator teams during study set-up meeting (objectives and conduct 
of the study, protocol and e-CRF, logistics, pharmacovigilance procedures etc.) 
• 
Regular follow-up of investigators during the study (by telephone calls, emails and on-
site visits) 
• 
Control of data captured in the e-CRF (automated on-line control for key data and 
additional correction requests). All of these controls will be described in the Data 
Management Plan. 
 
Monitoring of participating centres  
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The investigators will be contacted throughout the study to ensure that they understand and 
follow the protocol and electronic questionnaire.  All the contacts will be documented. 
Depending on the progress of e-CRF completion, the CRA will carry out site monitoring visits. 
During these visits, the CRA will check the quality of data collected.  The CRA will also ensure 
that the investigator and the team responsible for the study in the centre have understood and 
followed the protocol, the existence of patients who have been included, that the data listed in 
the e-CRF are identical to the original data, checking that the site master file (SMF) is correctly 
maintained and confirming declaration of AEs to the Pfizer Pharmacovigilance Department.   
In order to do this, he/she will need to refer to the patients’ medical record. The investigators 
will therefore need to ensure that the CRA has access to the patients’ records.  The CRA 
involved in the monitoring procedures will not be involved in data collection.  The frequency 
of on-site visits will depend on the number of patients included in each centre. 
Key indicators of the good conduct of the study (number of active sites, number of included 
patients, number of follow-ups performed, number of queries, etc…) will be generated from 
the study database. This database can be used to edit study progress reports in order to manage 
site reminder letters. 
9.9. Limitations of the research methods 
9.9.1. Selection bias 
Centers selection  
Both specialized centers in adv/mUC management and non-specialized public and private 
centers have included patients in the avelumab ATU and will therefore be contacted to 
participate in the study. If the representativeness of the sample in relation to all patients treated 
with avelumab for adv/mUC in France over the study period cannot be guaranteed, this 
multicenter selection will make it possible to minimize this bias. 
In addition, the characteristics of participating centers and contacted centers will be compared 
(i.e local public hospitals, private centers, expert centers, university hospitals), and in case of 
difference, adjustment on the type of centers could be done to provide corrected estimates of 
primary and secondary endpoints as sensitivity analysis. 
Patients selection  
In order to limit the selection bias of study patients, participating centers will be asked to 
include retrospectively all eligible patients from their center who had already initiated a 
treatment with avelumab for adv/mUC, and for the prospective part of the study, to 
consecutively enroll all eligible patients after study set-up, until the planned number of patients 
have been included in the study. All patients who died before study set-up will be included, to 
avoid survival bias. 
9.9.2. Measures taken to reduce patients lost to follow-up and missing data 
Data will be collected from medical chart, which may lead to incomplete or missing 
information. As this study will not influence or modify usual practices, investigators will have 
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the possibility to note "not done", "not known" or "not applicable" in the e-CRF, facilitating 
the quantification of missing data.  In the event of missing data without one of these references 
being made, the CRA will endeavour to collect the corresponding information with the 
assistance of the investigator.  However, if the data remain missing at the time of the analysis, 
they will not be replaced and will be treated as such.   
In addition, the use of an e-CRF will limit data entry errors through automated online checks. 
Finally, training of the investigation teams to the e-CRF, as well as monitoring of data 
collection, will guarantee the quality of the information collected. 
If patients are lost to follow-up, the investigators will agree to call patients, one of their family 
circles or their general practitioner, in order to recover enough data in order to close the file.   
If any patients die, the doctor will investigate the cause of death. 
9.10. Other aspects 
9.10.1. Archiving 
The investigators will store the questionnaires for up to 2 years after the last publication of the 
results of the study or, failing any publication, up to the signature of the final report of the 
study and will then archive the questionnaires for up to 20 years maximum or a duration in 
accordance with the existing regulations.   
The study management centre will store and then archive all study-related documents for the 
same periods of time.   
After this period, all the documents will be returned to the study sponsor.   
 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information  
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any reports, 
publications, or other disclosures, except where required by applicable laws.  
 
The personal data will be stored at the study site in encrypted electronic and/or paper form and 
will be password protected or secured in a locked room to ensure that only authorized study 
staff have access. The study site will implement appropriate technical and organizational 
measures to ensure that the personal data can be recovered in the event of disaster.  In the event 
of a potential personal data breach, 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 
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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 
authorized 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 and other authorized 
parties 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 
The informed consent documents and any patient recruitment materials must be in compliance 
with local regulatory requirements and legal requirements, including applicable privacy laws. 
In the present French study, no signed consent is required. An information note signed by 
investigator is provided to the patient.  
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 institutional 
review board (IRB)/independent ethics committee (IEC) 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 
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. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/IEC.  If the investigator determines that 
a patient’s decisional capacity is so limited that he or she cannot reasonably be consulted, then, 
as permitted by the IRB/IEC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (e.g., minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (e.g., parent, 
spouse), and that the patient’s assent was obtained or waived.  If assent is obtained verbally, it 
must be documented in the source documents. 
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 
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outcome, if applicable.  The investigator would 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 pursuant to applicable local regulations. 
10.4. Institutional review board (IRB)/Independent ethics committee (IEC) 
This is a non-interventional study that does not modify in any way the usual medical 
management of the persons entering the study or compromise their physical or mental integrity 
or require any particular follow-up visit for the persons entering the study. All procedures are 
performed, and all products used in a usual way, without any additional or unusual diagnostic 
or monitoring procedure.  
Under these conditions, this study comes within the scope of application of Ordinance No. 
2016-800 of 16 June 2016 for research, article L1121-1, and the project must therefore be 
declared to the French National Agency for Medicines and Health Products Safety (Agence 
nationale de sécurité du medicament), and a submission made to the Committee for the 
Protection of Persons (CPP).  
The sponsor must obtain prior authorization for the study protocol, protocol amendments and 
patient information sheets, and all other significant documents (for example, advert to obtain 
recruits), where necessary, from the CPP.  
All correspondence with the CPP must be kept by the investigator.  
10.5. French National Medical Association (Conseil National de l’Ordre des Médecins, 
CNOM) 
In the context of article L.1453-7 et seq., in particular articles L.1453-10 and L.1453-11 of the 
Public Health Code (CSP), it is Pfizer's responsibility to submit the study for authorization to 
the CNOM.  
Indeed, the sponsor of the study must inform the CNOM of all financial aspects between the 
sponsor, the members of the scientific committee and the physicians participating in the study. 
In accordance with article L.4113-9 of the Public Health Code, it is the responsibility of each 
participating doctor to take the same steps with the Departmental Council of the Order to which 
he or she belongs. 
10.6. Data protection: French Data Protection Agency (Commission Nationale de 
l’Informatique et des Libertés [CNIL]) 
In accordance with law No. 78-17 of 6 January 1978 on Data Processing, Data Files and 
Civil Liberties as amended concerning the protection of individuals with regard to the 
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processing of personal data, this protocol will be subject to a declaration of compliance with a 
reference method to the French Data Protection Agency (CNIL).  
Taking into account the fact that the study comes within the scope of MR003 and MR004, the 
compliance commitments of Pfizer and Merck allows us to start without the opinion of the 
French Data Protection Agency (CNIL). 
10.7. Ethical conduct of the study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in 
• Guidelines for Good Pharmacoepidemiology Practices (GPP). Public Policy Committee, 
International Society of Pharmacoepidemiology. Pharmacoepidemiology and Drug Safety 
2016; 25:2-10. 
https://onlinelibrary.wiley.com/doi/full/10.1002/pds.3891 
 
• Good Practices for Outcomes Research issued by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR) 
http://www.ispor.org/workpaper/practices_index.asp 
 
• Good practices for real-world data studies of treatment and/or comparative effectiveness: 
Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence 
in health care decision making 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639372/ 
 
• International Ethical Guidelines for Epidemiological Studies issued by the Council for 
International Organizations of Medical Sciences (CIOMS) 
https://cioms.ch/shop/product/international-ethical-guidelines-for-epidemiological-studies/ 
 
• European 
Medicines 
Agency 
(EMA) 
European 
Network 
of 
Centers 
for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological 
Standards in Pharmacoepidemiology 
http://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml 
 
• The ENCePP Code of Conduct for scientific independence and transparency in the 
conduct of pharmacoepidemiological and pharmacovigilance studies 
http://www.encepp.eu/code_of_conduct/ 
 
• Food and Drug Administration (FDA) Guidance for Industry: Good Pharmacovigilance 
Practices and Pharmacoepidemiologic Assessment 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ 
ucm071696.pdf 
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• FDA Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting 
Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance 
s/UCM243537.pdf 
 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
11.1. Single reference safety document 
The current French Summary of Product Characteristics (SPC), will serve as the single 
reference safety document during the course 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 single reference safety document should be used by the investigator for prescribing 
purposes and guidance. 
11.2. Pharmacovigilance requirements 
 
PRIMARY DATA COLLECTION REQUIREMENTS (prospective part of the study) 
 
The table below summarizes the requirements for recording safety events on the e-CRF  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 drug exposure, including exposure during pregnancy, exposure during 
breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy, and 
occupational exposure.  These events are defined in the section “Definitions of safety events.”   
Safety event 
Recorded on the e-CRF   
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness 
SAE 
All 
All 
Non-serious AE 
All 
None  
Scenarios involving exposure 
to a drug under study, 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) 
Note: Any associated AE is 
reported together with the 
exposure scenario. 
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For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
(refer to section "Serious Adverse Events” below).  
Safety events listed in the table above must be reported to Pfizer within 24 hours of awareness 
of the event by the investigator regardless of whether the event is determined by the 
investigator to be related to avelumab.  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. 
For 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 e-CRF. In general, this will include a description of the AE in sufficient detail 
to allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any 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 serious adverse event reporting period begins at the time of  the patient’s 
first dose of avelumab or the time of the patient’s informed consent if s/he is being treated with 
avelumab at study start, and lasts through the end of the observation period of the study, or at 
least 90 calendar days following the last administration of a drug under study (whichever is 
longer); a report must be submitted to Pfizer Safety (or its designated representative) for any 
of the types of serious adverse events listed in the table above occurring during this period.  If 
a patient was administered a drug under study on the last day of the observation period, then 
the reporting period should be extended for 90 calendar days following the end of observation. 
 
For each patient, the non-serious AE collection period begins at the time of  the patient’s first 
dose of avelumab or the time of the patient’s informed consent if s/he is being treated with 
avelumab at study start, and lasts through 90 calendar days following the last administration 
of a drug under study. After the completion of the active study collection/reporting period of 
90-calendar days post-last administration of avelumab, through to the end of the observation 
period of two years, non-serious AEs are not collected on the e-CRF. 
 
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 
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changes his/her mind about participation), 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 SAE to be related to avelumab, 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 AE.  For 
AEs with a causal relationship to avelumab, 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 avelumab caused or contributed to an AE.  If the investigator’s final 
determination of causality is “unknown” and s/he cannot determine avelumab 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 avelumab 
did not cause the event, this should be clearly documented on the e-CRF and the NIS AEM 
Report Form.  
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 AEs include but are not limited to:   
• Abnormal test findings (see below for circumstances in which an abnormal test finding 
constitutes an AE); 
• Clinically significant signs and symptoms; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Lack of efficacy;  
• Drug abuse;  
• Drug dependency. 
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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. 
Abnormal test findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE 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 AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
Serious adverse events 
A SAE is any untoward medical occurrence in a patient administered a medicinal or nutritional 
product (including pediatric formulas) at any dose that: 
• Results in death; 
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• Is life-threatening; 
• Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute AEs); 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as a SAE unless the outcome is fatal within the safety reporting period.  
Hospitalization due to signs and symptoms of disease progression should not be reported as a 
SAE.  If the malignancy has a fatal outcome during the study or within the safety reporting 
period, then the event leading to death must be recorded as an AE and as a SAE with severity 
Grade 5. 
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 Pfizer 
product.  The terms “suspected transmission” and “transmission” are considered synonymous.  
These cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance (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.  
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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: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (e.g., environmental) avelumab, or the female becomes, or is found to be, 
pregnant after discontinuing and/or being exposed to avelumab (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). 
2. A male has been exposed, either due to treatment or environmental exposure to avelumab 
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. 
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If a study participant or study participant’s partner becomes, or is found to be, pregnant during 
the study participant’s treatment with avelumab, this information must be submitted to Pfizer, 
irrespective of whether an AE has occurred using the NIS AEM Report Form and the EDP 
Supplemental Form.  
In addition, the information regarding environmental exposure to avelumab in a pregnant 
woman (e.g., a patient 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:  
• 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 
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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. 
• 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 
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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. 
SECONDARY DATA SAFETY REPORTING REQUIREMENTS (retrospective part 
of the study) 
This study protocol requires human review of patient-level unstructured data; unstructured data 
refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database.  The reviewer is obligated to report adverse events 
(AEs) with explicit attribution to any Pfizer drug that appear in the reviewed information 
(defined per the patient population and study period specified in the protocol).  Explicit 
attribution is not inferred by a temporal relationship between drug administration and an AE, 
but must be based on a definite statement of causality by a healthcare provider linking drug 
administration to the AE. 
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows: 
• All serious and non-serious AEs with explicit attribution to any Pfizer drug that appear 
in the reviewed information must be recorded on the e-CRF and reported, within 24 
hours of awareness, to Pfizer Safety using the NIS AEM Report Form. 
• Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy, and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM Report 
Form. 
For these AEs with an explicit attribution or scenarios involving exposure to a Pfizer product, 
the safety information identified in the unstructured data reviewed is captured in the Event 
Narrative section of the report form, and constitutes all clinical information known regarding 
these AEs.  No follow-up on related AEs will be conducted. 
 
All research staff members must complete the following Pfizer training requirements:    
•  “YRR Training for Vendors Working on Pfizer Studies (excluding interventional 
clinical studies and non-interventional primary data collection studies with 
sites/investigators)”.  
These trainings must be completed by research staff members prior to the start of data 
collection.  All trainings include a “Confirmation of Training Certificate” (for signature by the 
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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.  
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
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. 
13. REFERENCES 
1.  
Estimations nationales de l’incidence et de la mortalité par cancer en France 
métropolitaine entre 1990 et 2018. Synthèse. Saint‑Maurice : Santé publique France, 2019. 20 
p.  http://www.santepubliquefrance.fr/ ; https://geodes.santepubliquefrance.fr/ #c=home ; 
http://lesdonnees.e‑cancer.fr/ ; https://www.e‑cancer.fr/. 
2.  
Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or 
Metastatic 
Urothelial 
Carcinoma. 
N 
Engl 
J 
Med. 
2020;383(13):1218-1230. 
doi:10.1056/NEJMoa2002788 
3.       https://www.pfizer.com/news/press-release/press-release-detail/european-commission-
approves-bavencior-avelumab-first-line 
 
14.  LIST OF TABLES  
Table 1: Study scheduled planning.  
Table 2: Information collected in the study and timing of data collection 
 
 
15. LIST OF FIGURES 
Figure 1: study design.  
 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
Number 
Title 
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1 
CRF V 2.0 du 25 MAR 2021 
2 
Information letter V3.0 du 07 JUN 2021 
3 
Questionnaire EQ-5D-5L  
4 
Questionnaire FACT FBlSI-18 
5 
Pregnancy form 
 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable 
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