A MULTI-CENTRE NON-INTERVENTIONAL STUDY TO DESCRIBE THE EARLY CLINICAL EXPERIENCE OF AVELUMAB USED AS MONOTHERAPY FOR THE FIRST-LINE MAINTENANCE TREATMENT OF ADULT PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA WHO ARE PROGRESSION-FREE FOLLOWING PLATINUM-BASED CHEMOTHERAPY
Conditions: Urothelial Cancer
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

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N O N -I N T E R V E N TI O N A L ( NI) S T U D Y P R O T O C O L  
  
C CI

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St u d y i nf or m ati o n  
Title   
A  M U L TI -C E N T R E  N O N -
I N T E R V E N TI O N A L S T U D Y T O  
D E S C RI B E T H E E A R L Y C LI NI C A L  
E X P E RI E N C E O F A V E L U M A B U S E D A S  
M O N O T H E R A P Y F O R T H E FI R S T -LI N E  
M AI N T E N A N C E T R E A T M E N T O F  
A D U L T P A TI E N T S WI T H L O C A L L Y  
A D V A N C E D O R M E T A S T A TI C  
U R O T H E LI A L C A R CI N O M A  W H O A R E  
P R O G R E S SI O N -F R E E F O L L O WI N G  
P L A TI N U M -B A S E D C H E M O T H E R A P Y   
Pr ot oc ol n u m ber   
B 9 9 9 1 0 4 7  
Pr ot oc ol versi o n i de ntifier   
Versi o n 1. 0  
D ate   
2 1 st J ul y 2 0 2 1  
Acti ve s u bst a nce   
L O 1 X C 3 1  
Me dici n al pr o d uct   
A vel u ma b   
Rese arc h q uesti o n a n d o bjecti ves   
T o u n dersta n d t he earl y cli nical e x perie nce 
of usi n g a vel u ma b as m o n ot hera p y f or first 
li ne ( 1 L) 
mai nte na nce treat me nt of a d ult 
patie nts wit h l ocall y a d va nce d or metastatic 
Ur ot helial 
Carci n o ma 
( U C) 
i ncl u di n g 
descri bi n g t he real -w orl d o verall s ur vi val 
(r w O S) i n patie nts w h o are pr o gressi o n-free 
f oll o wi n g plati n u m-base d c he m ot hera p y.     
A ut h or(s)   
 
 
 
 
  
1.  T A B L E O F C O N T E N T S  
1. T A B L E O F C O N T E N T S  ...................................................................................................... 2  
2. LI S T O F A B B R E VI A TI O N S  ............................................................................................... 5  
3. R E S P O N SI B L E P A R TI E S  ................................................................................................... 8  
4. A B S T R A C T  .......................................................................................................................... 8  
5. A M E N D M E N T S A N D U P D A T E S  .................................................................................... 1 3  
6. MI L E S T O N E S  .................................................................................................................... 1 5  
P P D

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7. RATIONALE AND BACKGROUND ............................................................................... 16 
8. RESEARCH QUESTION AND OBJECTIVES ................................................................. 17 
9. RESEARCH METHODS .................................................................................................... 18 
9.1. Study design ............................................................................................................ 18 
9.1.1. Setting ......................................................................................................... 19 
9.1.2. Inclusion criteria ......................................................................................... 19 
9.1.3. Exclusion criteria ........................................................................................ 20 
9.1.4. Study period ............................................................................................... 20 
9.1.5. Study follow-up time .................................................................................. 20 
9.2. Variables ................................................................................................................. 21 
9.2.1. Demographic and clinical characteristics ................................................... 23 
9.2.2. Treatment-related variables ........................................................................ 29 
9.2.3. Outcomes .................................................................................................... 31 
9.3. Data sources ............................................................................................................ 35 
9.4. Study size ................................................................................................................ 35 
9.5. Data management.................................................................................................... 36 
9.5.1. Case report forms (CRFs)/Electronic data record ...................................... 36 
9.5.2. Record retention ......................................................................................... 36 
9.6. Data analysis ........................................................................................................... 37 
9.6.1. Descriptive analysis .................................................................................... 37 
9.6.2. Overall and progression-free survival ........................................................ 37 
9.6.3. Treatment patterns ...................................................................................... 37 
9.7. Quality control ........................................................................................................ 38 
9.8. Limitations of the research methods ....................................................................... 38 
9.8.1. Selection bias and study representativeness ............................................... 38 
9.8.2. Missing or erroneous data .......................................................................... 38 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................ 39 
10.1. Patient information................................................................................................ 39 
10.2. Patient consent ...................................................................................................... 39 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) ................ 40 
10.4. Ethical conduct of the study .................................................................................. 40 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE  ............... 40 
REACTIONS ...................................................................................................................... 40 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ....... 41 
13. REFERENCES .................................................................................................................. 43 
14. LIST OF TABLES ............................................................................................................ 44 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS ......................................................... 44 
ANNEX 2. ADDITIONAL INFORMATION ........................................................................ 45 
 

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2. LIST OF ABBREVIATIONS  
Abbreviation  
Definition  
AE(s)  
Adverse event(s)  
AEM  
Adverse event monitoring   
BSC  
Best supportive care  
CAG  
Confidentiality Advisory Group  
CSA  
Clinical study agreement  
CSR  
Clinical study report  
CPS  
Combined positive score  
CRF  
Case report form  
EAMS  
Early Access to Medicines Scheme  
EC  
European Commission  
ECOG  
Eastern Cooperative Oncology Group  
eCRF  
Electronic case report form  
EDC  
Electronic data capture  
EHR  
Electronic Health Record  
EMA  
European Medicines Agency  
EU  
European Union  
FDA  
Food and Drug Administration  
HRA  
Health Research Authority  
IEC  
Independent ethics committee  
IgG1  
Immunoglobulin G1  

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IRB  
Institutional review board  
 
IRAS  
Integrated research application system  
IQR  
Inter-quartile range  
JB100  
JAVELIN Bladder 100  
NHS  
National Health Service  
NIS  
Non-interventional study  
PD-L1  
Programmed death-ligand 1  
QMS  
Quality management system  
rwTTNT  
Real-world time to next treatment  
rwOS  
Real-world overall survival  
rwPFS  
Real-world progression-free survival  
rwTTD  
Real-world time to discontinuation  
REC  
Research ethics committee  
R&D  
Research and Development  
SDV  
Source data verification  
SACT  
Systemic anti-cancer therapy  
SAP  
Statistical analysis plan  
SOP  
Standard operating procedure  
TCC  
Transitional cell carcinoma  
UC  
Urothelial carcinoma  
UK  
United Kingdom  

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USA  
United States of America  
YRR  
Your reporting responsibilities   
1L  
First-line   
2L  
Second-line   
  
  
  
 

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3.  R E S P O N SI B L E P A R TI E S  
Pri nci p al I n vesti g at or(s) of t he Pr ot oc ol  
N a me, de g ree(s)   
J o b Title   
Affili ati o n   
A d d ress   
  
S p o ns or Pr ot oc ol A ut h ors  
4.  A B S T R A C T  
Title   
A m ulti -ce ntre n o n -i nter ve nti o nal st u d y ( NI S) t o descri be t he earl y 
cli nical e x perie nce of a vel u ma b use d as m o n ot hera p y f or t he first -li ne 
mai nte na nce treat me nt of a d ult patie nts wit h l ocall y a d va nce d or 
metastatic U C w h o are pr o gressi o n -free f oll o wi n g plati n u m-base d 
c he m ot hera p y.  
P P D
P P D

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Rationale and 
background  
Bladder cancer is the 11th most common cancer in the United Kingdom 
(UK). Patients with advanced or metastatic UC are usually offered a 
platinum-based chemotherapy. Avelumab is a human monoclonal 
antibody which, as demonstrated in the JAVELIN Bladder 100 (JB100) 
trial, is associated with a median overall survival gain of 7.1 months 
when used as maintenance therapy in combination with best supportive 
care (BSC) compared with BSC only. The drug has been approved by the 
Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) for monotherapy for the first-line maintenance treatment 
of adult patients with locally advanced or metastatic UC who are 
progression-free following platinum-based chemotherapy. Access to the 
drug has initially been facilitated by the Early Access to Medicines 
Scheme (EAMS) programme in the UK since September 2020. There is 
now a need for UK-specific early clinical and outcome data in patients 
treated with avelumab for this indication in routine clinical care.  
Research 
question and 
objectives  
The primary objective of this study is to estimate real-world overall 
survival (rwOS) in a real-world cohort of patients treated with avelumab 
monotherapy for the first-line maintenance treatment of adult patients 
with locally advanced or metastatic UC who are progression-free 
following platinum-based chemotherapy.  
The secondary objectives are:  
1. To describe the clinical and demographic characteristics of the 
study population  
2. To estimate real-world progression-free survival (rwPFS)  
3. To describe treatment characteristics of 1L anti-cancer therapies 
received prior to the initiation of avelumab as 1L maintenance 
therapy  
4. To describe treatment patterns after initiation of avelumab as 1L 
maintenance therapy  
5. To describe the adverse events (AEs) explicitly attributed to 
avelumab in a real-world population  
6. To describe real-world all-cause associated healthcare resource 
burden associated with avelumab therapy   

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Study design  
A multi-centre NIS with both a retrospective chart review and 
prospective follow-up of patients conducted in selected secondary/tertiary 
care centres of the UK National Health Service (NHS). The study will be 
entirely conducted using records obtained in routine clinical care and will 
not involve contact with patients.  
Confidential Advisory Group (CAG) and appropriate ethics permission 
will be obtained before commencing the study.  
Population  
Patients must meet all the following criteria to be eligible for inclusion 
in the study:  
1. Patients with a diagnosis of locally advanced or metastatic UC, either 
de novo or relapsed   
2. Patients received 1L platinum-based chemotherapy and had stable 
disease, partial response, or complete response to this treatment  
3. Patients received avelumab as indicated as a monotherapy for the 
first-line maintenance treatment of adult patients with locally 
advanced or metastatic UC who are progression-free following 
platinum-based chemotherapy   
4. Patients aged ≥18 years on the date that they commenced avelumab  
Patients meeting any of the following criteria will be excluded from the 
study:  
1. Patients whose hospital records are not available for review  
2. Patients who are receiving an investigational medicinal product as 
part of a clinical trial at the time of maintenance therapy with 
avelumab  
Variables  
Variables to be collected include:  
Demographic and clinical characteristics of the study population, at 
selected time points, including: 
o Age at diagnosis and at avelumab initiation 
o Diagnostic details on UC  
o Eastern Cooperative Oncology Group (ECOG) performance  
            status   
o Cigarette smoking history 
  
Treatment characteristics prior to avelumab initiation, including:  
o Systemic anti-cancer therapy (SACT) regimen received  

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o Number of platinum-based chemotherapy cycles received since 
initial diagnosis  
o Number of distinct platinum-based chemotherapies received  
o Time from completion of 1L SACT to avelumab initiation 
o  Response to 1L therapy  
  
Treatment characteristics from avelumab initiation, including:  
o Duration of avelumab treatment  
o Time to second-line (2L) therapy  
o SACT regimen received as 2L therapy  
o Number of cycles received as 2L therapy  
o Time from initiation of avelumab to treatment discontinuation   
o High dose systemic steroid treatment following initiation of 
avelumab  
Adverse events explicitly attributed to avelumab treatment:  
o AE diagnosis 
o Outcome of AE  
o Classification as either serious or non-serious AE  
o Results in hospitalisation or prolongation of hospitalisation  
o Is life threatening  
o Resulted in death  
o Persistent or significant incapacity  
o Congenital anomaly/birth defect in any offspring  
o Other important medical event that may require medical or 
surgical intervention to avoid any of the above criteria  
o AEs leading to administration adjustments or discontinuation of 
avelumab  
o AEs leading to systemic steroid treatment  
  
All-cause associated healthcare resource burden:  
o Accident and emergency visits o Hospitalisations o Duration of 
hospitalisation  

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Data sources  
A total of 8-12 NHS centres will be selected for this study and each of 
them will be required to identify a minimum of 6 patients identified in 
sequential order from the first eligible patient treated at the site according 
to prespecified criteria. Data on patient and treatment characteristics as 
well as events and outcomes will be extracted from patient medical 
records and hospital charts from participating NHS sites using electronic 
case report forms (eCRF).   
Study size  
We aim to include approximately 100 patients into the study and follow 
them up for treatment patterns, events and endpoints in the study for up to 
24 months per patient.   
 
Data analysis  
Clinical and demographic characteristics, treatment characteristics, 
toxicity and AEs will be analysed descriptively, where continuous 
variables will be described using the mean (with standard deviation) 
and/or the median (with inter-quartile range, IQR) and categorical 
variables will be described using number and percentage. rwOS, rwPFS, 
time to next treatment (rwTTNT) and time to discontinuation (rwTTD) 
will be analysed using time to event analysis. Survival curves and 
median survival times will be estimated using Kaplan-Meier methods.   
Milestones  
Study commencement: August 2021  
Study completion: December 2024  
Final study report: January 2025  
 
 

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M E R C K S E R O N O C O N FI D E N TI A L   
P a ge 1 3  of 4 5   
5. A M E N D M E N T S A N D U P D A T E S  
  
A me n d me nt 
n u m ber   
D ate  
Pr ot oc ol 
secti o n(s)  
c h a n ge d  
S u m m ar y of 
a me n d me nt(s)  
Re as o n  
 1  
 
3 0/ 0 6/ 2 0 2 3  
 All 
secti o ns  
 C ha n ges of me nti o ns 
of Pfizer t o Merc k 
Ser o n o , c ha n ge i n 
a ut hr os hi p, 
p har mac o vi gila nce 
re p orti n g  
C ha n ge of s p o ns or 
t o Merc k Ser o n o  
beca use of  t he 
Merc k -Pfizer 
Allia nce 
ter mi nati o n o n 
A vel u ma b  
 2  
 
3 0/ 0 6/ 2 0 2 3  
Secti o n 3 –  
Res p o nsi ble 
a ut h ors  
 Re m o val of Pfizer 
a ut h or a n d re placi n g 
t he pre vi o us Merc k 
Ser o n o  a ut h or wit h 
t he c urre nt st u d y lea d 
 
 C ha n ge of s p o ns or 
t o Merc k Ser o n o 
beca use of  t he 
Merc k Ser o n o -
Pfizer Allia nce 
ter mi nati o n o n 
A vel u ma b  
3  
3 0/ 0 6/ 2 0 2 3  Secti o n 4 & 
6  - 
Milest o ne  
U p date t o t he data 
c ollecti o n e n d date 
fr o m N o ve m ber 2 0 2 3 
t o J u ne 2 0 2 4 
 
U p date of  re p ort date 
fr o m J u ne 2 0 2 4 u ntil 
Ja n uar y 2 0 2 5 
We e x pect t he last 
patie nt e nr olle d t o 
c o m plete 2 4 
m o nt hs f oll o w u p 
b y e n d of J u ne 
2 0 2 4, t his will p us h 
t he fi nal st u d y 
re p ort till Ja n uar y 
2 0 2 5  
4  
3 0/ 0 6/ 2 0 2 3  Secti o n 
1 0. 4 –  
Et hical 
c o n d uct 
Re placi n g me nti o ns 
of ‘c o ntr olle d 
d oc u me nt pertai ni n g 
t o Pfizer’ wit h Merc k 
Ser o n o c o ntr olle d 
d oc u me nts  
We will be usi n g 
Merc k Ser o n o  
c o ntr olle d 
d oc u me nts  
5  
3 0/ 0 6/ 2 0 2 3  Secti o n 1 1  
Re placi n g t he Pfizer 
s pecific d oc u me nt 
na me  ‘NI S A d verse 
E ve nt M o nit ori n g 
( A E M) Re p ort F or m’ 
We will be usi n g 
Merc k Ser o n o ’s 
A d verse E ve nt 
Re p ort Fr o m . 
 
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with ‘NIS Adverse 
Event (AE) Report 
Form  
 
Replacing ‘Your 
Reporting 
Responsibilities 
Training’ by ‘Merck 
PV Responsibilities 
Training’ or similar 
Merck Serono local 
training  
 
 
 
 
Training reference 
updated to a Merck 
Serono one   
  
 

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6. MILESTONES  
  
Milestone  
Planned date  
Completion of feasibility assessment  
August 2021  
Ethics approval  
August 2021  
Start of data collection   
November 2021  
End of data collection   
June 2024  
Interim report 1  
November 2022  
Study progress report 1  
On the 1-year anniversary of  
receiving ethical approval in the  
UK  
Final study report  
January 2025 
  

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7. RATIONALE AND BACKGROUND  
Urothelial carcinoma, also known as transitional cell carcinoma (TCC) arises from the 
transitional epithelium in the urinary system and is the most commonly occurring bladder 
cancer (1). Risk factors for UC include cigarette smoking, older age, being of male sex, being 
Caucasian, genetic susceptibility, having a family history, chronic bladder infections as well 
as arsenic and chemical exposure (2). Patients usually present with haematuria, difficulty 
urinating, pelvic pain, bone pain and unintentional weight loss (3).   
  
There were 10,233 new incident cases of invasive bladder cancer (ICD-10 code C67) annually 
in the UK 2015-2017, with 5,485 deaths annually between 2016-2018. Bladder cancer is the 
11th most common cancer in UK, and the 10th most common cause of cancer death in the UK. 
When diagnosed at its earliest stage, more than 9 in 10 (95%) people with bladder cancer will 
survive their disease for one year or more, compared with more than 1 in 3 (36%) people when 
the disease is diagnosed at the latest stage (4). Five-year age-standardised survival is 53% for 
all patients, ranging from 79% for stage I to 41% for stage III patient (5). Five-year survival 
data for stage IV patients in the UK are not available but data from the United States of America 
(USA) report that 5-year relative survival decreases to 37% if it has spread to regional lymph 
nodes, and to 6% if it has spread to a more distant site (6).   
  
Treatment success depends on how early the patient is diagnosed and treated. In early stage 
UC, surgical resection is the course of action, while advanced or metastatic UC is treated with 
chemotherapy. In the UK, cisplatin-based chemotherapy is offered. If cisplatin-based 
chemotherapy is unsuitable, carboplatin in combination with gemcitabine is offered among 
Programmed death-ligand 1 (PD-L1) negative patients, and atezolizumab or carboplatin in 
combination with gemcitabine is offered for PD-L1 positive patients. 2L treatment depends on 
prior treatment and includes platinum-based chemotherapy, checkpoint inhibitors or BSC (7,8).  
  
In June 2020, the FDA approved avelumab for maintenance treatment in patients with locally 
advanced or metastatic UC that have not progressed with 1L platinum-containing 
chemotherapy (9). In January 2021, the European Commission (EC) approved avelumab as a 
monotherapy for the 1L maintenance treatment of adult patients with locally advanced or 
metastatic UC who are progression-free following platinum-based chemotherapy (10). 
Avelumab is a human monoclonal Immunoglobulin G1 (IgG1) antibody that targets the 
immunomodulatory cell surface ligand protein, PD-L1. The JB100 trial was designed to be a 
randomized, multicentre and open label study conducted to understand the efficacy of 
avelumab. Maintenance therapy with avelumab in addition to BSC showed improved overall 
survival compared to BSC alone in patients with advanced UC whose cancer had not 
progressed following 1L platinum-based chemotherapy (11,12). Overall survival at 1 year was 
71% in the avelumab group and 58% in the control group, with a hazard ratio for death reported 
at 0.69 (95% confidence interval, CI, 0.56 – 0.86, p=0.001). Median overall survival was 21.4 
months in the avelumab group vs. 14.3 months in the control group and median progression 

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free survival was 3.7 months vs. 2.0 months, respectively. Patients received avelumab 
following a treatment-free interval of four to ten weeks after receipt of four to six cycles of 
chemotherapy with gemcitabine plus cisplatin or carboplatin. AEs of any grade occurred in 
98.0% of patients in the avelumab group and 77.7% in the control group (13).   
  
This NIS aims to understand clinical outcomes of patients treated with avelumab as 
monotherapy for the 1L maintenance treatment of locally advanced or metastatic UC who are 
progression-free following platinum-based chemotherapy, in a real-world setting in the UK.  
8. RESEARCH QUESTION AND OBJECTIVES  
  
The purpose of this NIS is to describe the early clinical real-world outcomes of patients treated 
with avelumab as monotherapy for the 1L maintenance treatment of locally advanced or 
metastatic UC who are progression-free following platinum-based chemotherapy. As from 
September 2020, patients in the UK meeting the UC indication have been provided access to 
avelumab via EAMS. This study aims to investigate patients who received avelumab in 
secondary/tertiary care in the UK through either the EAMS or through NHS commissioning. 
The primary objective of this study is to compare overall real-world survival with overall 
survival reported by the JB100 clinical trial (13). Detailed objectives have been ratified by 
three NHS medical oncologists with an academic interest in UC to ensure feasibility in the 
real-world setting, are as follows:  
  
Among all adult patients with locally advanced or metastatic UC who are progression-free 
following platinum-based chemotherapy and are treated with avelumab as a 1L maintenance 
therapy:  
  
Primary Objective  
1. To estimate rwOS in a real-world cohort of patients treated with maintenance avelumab 
for locally advanced or metastatic UC  
  
Secondary objectives  
1. To describe the demographic and clinical characteristics of this cohort at first diagnosis 
of UC, diagnosis of locally advanced or metastatic disease and at avelumab treatment 
initiation  
  
2. To estimate real-world rwPFS from initiation of avelumab  
  
3. To describe treatment characteristics of the anti-cancer therapies received for locally 
advanced or metastatic UC prior to the initiation of avelumab as a 1L maintenance 
therapy   
  
4. To describe treatment patterns after initiation of avelumab as a 1L maintenance therapy  

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5. To describe the AEs explicitly attributed to avelumab in a real-world population  
  
  
6. To describe real-world all-cause associated healthcare resource burden associated with 
avelumab therapy   
  
  
  
9. RESEARCH METHODS   
9.1. Study design   
This is a multi-centre, UK-based, NIS, with both a retrospective chart review and prospective 
follow-up of patients. Data collected as part of routine care entered into electronic patient 
records and paper-based charts will be extracted from records of adult patients with locally 
advanced or metastatic UC whose disease has not progressed following 1L platinum-based 
chemotherapy, and are treated with avelumab as a 1L maintenance therapy. Detailed 
information on the setting, the inclusion and exclusion criteria of patients, the study period and 
follow-up are described below.  
  
The primary outcome of interest is rwOS and secondary outcomes include rwPFS and rwTTD. 
Other variables of interest include demographic, clinical and treatment characteristics. 
Outcome and variable definitions are described in detail in section 9.   
  
This is a NIS because there will be no patient contact and only clinical data collected in routine 
clinical care will be collected and analysed as part of this study. No study visits, examinations, 
laboratory tests or procedures will be mandated. No changes to routine patient management 
are expected to occur as a result of a patient’s inclusion in the study.  
  
  
  

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Figure 1. Schematic of the study design  
9.1.1. Setting  
This study is to be conducted in secondary/tertiary care centres of the UK NHS. In the UK, 
avelumab is indicated as monotherapy for the 1L maintenance treatment of adult patients with 
locally advanced or metastatic UC who are progression-free following platinum-based 
chemotherapy.   
  
The study aims to recruit approximately 100 patients treated with avelumab with follow-up for 
up to 24 months after avelumab initiation. Among all centres who have registered patients as 
treated with avelumab, we will select 8-12 centres for participation ensuring a good 
geographical spread and instruct centres to extract data from 6-12 patients per centre. Potential 
participating hospitals will be subject to a site feasibility assessment to ensure eligible sites 
have the required number of patients, access to data and capacity to take part in this study. Data 
collection will commence after the appropriate ethics and research and development (R&D) 
approvals have been obtained and the site is fully initiated.   
  
Centres will be provided with clear instructions on how to identify patients and extract their 
data. They will be instructed to extract patients in chronological order of avelumab initiation 
(earliest first) to avoid selection bias and to ensure consistency in the recruitment methodology 
across the participating research sites. Centres will be requested to recruit 6-12 patients each 
so that the geographical spread of patients across centres is maintained.   
  
9.1.2. Inclusion criteria  
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study:  

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1. Patients with a diagnosis of locally advanced or metastatic UC, either de novo or 
relapsed   
2. Patients received 1L platinum-based chemotherapy and had stable disease, partial 
response, or complete response to this treatment  
3. Patients received avelumab as indicated as a monotherapy for the first-line maintenance 
treatment of adult patients with locally advanced or metastatic UC who are progression-
free following platinum-based chemotherapy   
4. Patients aged ≥18 years on the date that they commenced avelumab  
9.1.3. Exclusion criteria  
Patients meeting any of the following criteria will not be included in the study:  
1. Patients whose hospital records are not available for review  
2. Patients who are part of a clinical trial testing an investigational medicinal product at 
the time of maintenance therapy with avelumab  
  
9.1.4. Study period  
The data collection period will start November 2021 with retrospective identification of 
patients first treated with avelumab since September 2020. It is anticipated that by July 2021 
fewer than 100 patients will have been treated with avelumab in the UK across NHS sites 
participating in this study. Therefore, the patient identification window and subsequent follow 
up window would need to be extended by prospective identification of patients up to the time 
point the 100th patient is entered. After identification of all patients, periodic data collection of 
treatment and outcome data for all identified patients will run until 24 months has elapsed since 
the avelumab initiation date for each patient, with the data collection component of the study 
being completed shortly after 24 months since the latest initiation date in the study.  
  
9.1.5. Study follow-up time  
Follow-up time will be defined as the time from avelumab initiation date (the ‘index date’) 
until the end of follow-up (defined as the earliest of; death, being lost to follow up, 24 months 
post avelumab-initiation, end of study period or censoring as defined per each objective, see 
below Table 1).   
  
Reasons for loss to follow-up would include emigration and transition into private healthcare 
settings. For patients who are identified as lost to follow-up, records will be censored at the 
last available record or end of study, whichever is earlier.   
  

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Follow-up time for the primary and secondary outcomes is defined below.   
Table 1. Follow-up time for outcomes  
Outcome  
Follow-up start date  
Follow-up end date until event defined as 
below, or censoring at the earliest of the 
following outcomes:  
rwOS  
Date of avelumab initiation  
Endpoint of interest: survival   
Censoring of follow-up at the earliest of:  
• 
Death  
• 
Lost to follow-up  
• 
24 months after avelumab initiation  
  
rwPFS  
Date of avelumab initiation  
Endpoint of interest: the earliest of progression 
or death  
Censoring of follow-up at the earliest of:  
• 
Progression*  
• 
Death  
• 
Lost to follow-up  
• 
24 months after avelumab initiation  
  
rwTTNT  
Date of last dose of 1L SACT 
treatment  
Endpoint of interest: initiation of avelumab  
  
Given that only patients who initiated 
avelumab in this study are included, no other 
censoring endpoints need to be defined.  
  
rwTTD  
Date of avelumab initiation  
Endpoint of interest: earliest of discontinuation 
of avelumab or death  
Censoring of follow-up at the earliest of:  
• 
Discontinuation of avelumab  
• 
Death   
• 
Lost to follow-up  
• 
24 months after avelumab initiation  
  
*Progression is defined as any event identified either through radiological scans or other 
assessment judged by a clinician to be progression  
  
9.2. Variables  
Variables and their operational definitions are defined in the tables below. Further definitions 
of variables will be included in the statistical analysis plan (SAP). The operational definitions, 

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e.g. the definition of progression, might be updated in the SAP to reflect the availability of 
routinely collected data in patient records.  

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9.2.1. Demographic and clinical characteristics   
  
Table 2. Variable definitions for demographic and clinical characteristics  
Variable  
Role  
Time of measurement  
Operational definition  
Objective 1: demographic and clinical characteristics at first diagnosis of UC  
Age at initial diagnosis  
Demographic and  
clinical characteristics   
First diagnosis of UC  
Derived using date of birth and date of 
initial UC diagnosis  
Date of initial diagnosis  
Demographic and  
clinical characteristics  
First diagnosis of UC  
As recorded:  
• Day/Month/Year of diagnosis  
Stage at initial diagnosis  
Demographic and  
clinical characteristics  
First diagnosis of UC  
As recorded:  
• 
Stage 0a  
• 
Stage 0is  
• 
Stage I  
• 
Stage II  
• 
Stage IIIA  
• 
Stage IIIB  
• 
Stage IVA  
• 
Stage IVB  
Primary tumour site  
Demographic and  
clinical characteristics  
First diagnosis of UC  
As recorded:  
• 
Bladder  
• 
Not-bladder  
  

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Sex  
Demographic and  
clinical characteristics  
First diagnosis of UC  
As recorded:  
• 
Male  
• 
Female  
 
Variable  
Role  
Time of measurement  
Operational definition  
 
 
 
• Not known  
  
Objective 1 (continued): demographic and clinical characteristics at diagnosis of locally advanced or metastatic UC  
Age at diagnosis  
Demographic and  
clinical characteristics   
At 
locally 
advanced 
or 
metastatic UC diagnosis  
Derived from date of birth and date of 
stage IV UC diagnosis   
Date of locally advance or 
metastatic UC diagnosis   
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis  
As recorded:  
• Day/Month/Year of diagnosis  
Stage of UC  
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis  
As recorded  
• 
Stage III  
• 
Stage IVA  
• 
Stage IVB  
Histology  
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis (or if 
not 
available, 
at 
initial 
diagnosis, where applicable)   
  
As recorded:  
• 
Benign  
• 
Papillary urothelial neoplasm of low 
malignant potential  
• 
Malignant  
• 
Undifferentiated carcinoma  

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PD-L1 status  
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis (or if 
not 
available, 
at 
initial 
diagnosis, where applicable)   
  
• 
PD-L1 test (present or not recorded)  
• 
Type of antibody testing used or not 
recorded  
• 
PD-L1 positive or negative or not 
recorded  
ECOG performance status  
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis  
As recorded (0-5)  
 
Variable  
Role  
Time of measurement  
Operational definition  

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• 0 = Fully active, able to carry on all 
pre-disease performance without 
restriction  
• 1 = Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary  
nature, e.g., light housework, office 
work  
• 2 = Ambulatory and capable of all self-
care but unable to carry out any work 
activities. Up and about more than 50% 
of waking hours  
• 3 = Capable of only limited self-care, 
confined to bed or chair more than  
50% of waking hours  
• 4 = Completely disabled. Cannot carry 
on any self-care. Totally confined to 
bed or chair  
• 5 = Dead   
De novo/newly relapsed  
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis (and 
look-back period from initial 
diagnosis)  
As recorded:  at locally advance or 
metastatic UC diagnosis:  
• 
De novo disease  
• 
Newly relapsed  
• 
Unknown  
When patients are classified as newly 
relapsed stage IV; the following details 
will be described: 
 • Previous stage  
 

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Variable  
Role  
Time of measurement  
Operational definition  
 
 
 
• Histological subtype   
Time from previous diagnosis to relapse  
Site of metastases  
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis  
Sites of metastases as recorded in the 
records:  
•    lymph nodes  
• 
bone  
• 
lung  
• 
liver  
• 
peritoneum  
• 
other, as specified  
• 
Unknown  
Time from first diagnosis  
Demographic and  
clinical characteristics  
At 
locally 
advanced 
or 
metastatic UC diagnosis  
Time between date of initial diagnosis 
and diagnosis of locally advanced or 
metastatic UC diagnosis  
Prior surgical resection of 
primary UC  
Demographic and  
clinical characteristics  
Look-back window (between  
initial diagnosis and at locally 
advanced or metastatic UC  
diagnosis)  
As recorded  
Prior 
adjuvant/neoadjuvant 
systemic therapy  
Demographic and  
clinical characteristics  
Look-back window (between  
initial diagnosis and at locally 
advanced or metastatic UC  
diagnosis)  
• 
Yes  
• 
No  
  

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Cigarette smoking history  
Demographic and  
clinical characteristics  
Look-back window (at locally 
advanced or metastatic UC  
diagnosis)  
As recorded  
• 
Current smoker  
• 
Former smoker  
• 
Never smoker  
• 
Unknown  
  
Variable  
Role  
Time of measurement  
Operational definition  
Previous history of non             
muscle invasive bladder 
cancer  
Demographic and  
clinical characteristics  
Look-back window (prior to 
locally advanced or metastatic 
UC diagnosis)  
As recorded  
• 
Yes  
• 
No  
  
Objective 1 (continued): demographic and clinical characteristics at avelumab treatment initiation  
Age at avelumab initiation  
Demographic and  
clinical characteristics  
At avelumab treatment 
initiation  
Derived from date of birth and date of 
avelumab initiation  
ECOG performance status  
Demographic and  
clinical characteristics  
At avelumab treatment 
initiation  
As recorded (0-5). For definitions of each 
category, see above  

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9.2.2. Treatment-related variables   
  
Table 3. Variable definitions of treatment-related variables  
 
Variable  
Role  
Time of measurement  
Operational definition  
Number 
of 
patients 
switching 
between 
different platinum-based 
chemotherapies   
  
Treatment pattern 
prior to avelumab 
initiation  
Look-back window  
(between locally advanced 
or metastatic UC diagnosis 
and avelumab initiation)  
Patients will be described as switching treatment if they 
receive a different therapy in comparison to their initial 
treatment during the period between initial treatment and 
avelumab initiation (avelumab not included). The 
number of patients switching from initial platinum-based 
chemotherapy initiated after locally advanced or 
metastatic UC diagnosis will be described for each 
different therapy after switch  
Variable  
Role  
Time of measurement  
Operational definition  
Objective 3: Treatment characteristics of anti-cancer therapies received for locally advanced or metastatic UC prior to initiation 
of avelumab  
SACT regimen received   
Treatment pattern 
prior to avelumab 
initiation  
Look-back window  
(between locally advanced 
or metastatic UC diagnosis 
and avelumab initiation)  
Unique SACT regimen reported as initial therapy after 
locally advanced or metastatic UC diagnosis (inclusive)  
Number of cycles of 
platinum-based 
chemotherapy received   
Treatment pattern 
prior to avelumab 
initiation  
Look-back window  
(between locally advanced 
or metastatic UC diagnosis 
and avelumab initiation)  
Number of cycles of platinum-based chemotherapy 
received since locally advanced or metastatic UC 
diagnosis  

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rwTTNT from completion 
of 1L SACT  
  
Treatment pattern 
prior to avelumab 
initiation  
Look-back window  
(between locally advanced 
or metastatic UC diagnosis 
and avelumab initiation)  
Time between completion of 1L SACT (derived from 
date of last SACT cycle) and date of initiation of 
avelumab  
See also Table 1.   
Response to 1L therapy  
Treatment pattern 
prior to avelumab 
initiation  
Look-back window  
(between locally advanced 
or metastatic UC diagnosis 
and avelumab initiation)  
Response to 1L therapy as reported by the clinician will 
be described at the end of 1L therapy according to the 
following categories:  
• Complete response  
• 
Partial response  
• 
Stable disease  
  
Objective 4: Treatment patterns after initiation of avelumab as 1L maintenance therapy:  
Duration 
of 
treatment 
with avelumab  
Treatment pattern  
from avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Will be derived based on the date of avelumab initiation 
(index date) and the last date of avelumab treatment. The 
last day of avelumab treatment will be calculated based 
on the last recorded date of avelumab treatment received 
+ 14 days. A gap of 30 consecutive days of no treatment 
with avelumab will be used to establish the last recorded 
date of avelumab treatment received.  
  
 
Variable  
Role  
Time of measurement  
Operational definition  
Time interval between 
start of avelumab and  
start of 2L therapy  
  
Treatment pattern 
from avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Time interval will be derived using the dates of avelumab 
initiation and initiation of first regimen of 2L therapy. 
This parameter will be calculated only among patients 
who go on to receive 2L therapy after avelumab initiation  

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Number of patients who 
receive 2L therapy  
Treatment pattern  
from avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Number of patients who received 2L therapy after 
initiating avelumab  
Number of patients who 
discontinue 
avelumab 
and start 2L therapy  
Treatment pattern 
from avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Number of patients who discontinue avelumab and 
subsequently receive 2L therapy  
SACT regimen received 
as 2L therapy  
Treatment pattern  
from avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Among the number of patients receiving 2L therapy, 
unique SACT regimen reported as 2L therapy after 
avelumab initiation any time during follow-up  
Number of SACT cycles 
received as 2L therapy  
Treatment pattern  
from avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Number of cycles received as 2L therapy after avelumab 
initiation   
rwTTD from initiation of 
avelumab  
  
  
Treatment pattern  
from avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Time between avelumab initiation until the earliest of:  
• 
Date of discontinuation (a gap of 30 days without 
treatment with avelumab will be used to establish a 
patient as having discontinued avelumab)  
• 
Having a subsequent systemic therapy regimen  
• 
Date of death from any cause  
See Table 1 for other censoring points  
High 
dose 
systemic 
steroid use  
Treatment from  
avelumab  
initiation  
Between avelumab  
initiation and end of follow-
up  
Name of systemic steroid used  
Dose of systemic steroid  
Start and stop dates  
Reason for treatment (if recorded)  
9.2.3. Outcomes   
  
Table 4. Outcome variables definitions  
Variable  
Role  
Time of measurement  
Operational definition  

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Primary objective: Estimation of overall survival  
rwOS  
Patient outcome  
From avelumab initiation to 
end of follow-up  
Time between avelumab initiation until date of death 
from any cause  
See table 1 for other censor endpoints  
  
rwOS will be reported at 6-monthly intervals and at the 
end of the study.  
 
Objective 2: Estimation of progression-free survival  
rwPFS  
Patient outcome  
From avelumab initiation to 
end of follow-up  
Time between avelumab initiation until earliest of:  
• 
Date of first progression   
• 
Date of death from any cause   
See Table 1 for other censor endpoints  
  
rwPFS will be reported at 6-monthly intervals and at the 
end of the study.  
  
Progression will be determined based on progression 
being referenced in a clinician and/or radiology report, 
as described by an electronic health record (EHR) study 
(14).   
A proxy for progression could also be established as 
the earliest of death or start of new SACT after 
avelumab initiation  
 
Variable  
Role  
Time of measurement  
Operational definition  
Objective 5: To describe the adverse events attributed to avelumab in a real-world population  

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Adverse events explicitly 
attributed to avelumab  
Patient outcome  
From avelumab initiation to 
end of follow-up  
Any AE with explicit attribution to avelumab as noted 
in the clinical records. 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.  
  
• 
AE diagnosis  
• 
Outcome of AE  
• 
Classification as either serious or non-serious AE  
o Results in hospitalisation or prolongation of 
hospitalisation  
o 
Is life threatening  
o 
Resulted in death  
o 
Persistent or significant incapacity  
o 
Congenital anomaly/birth defect in any offspring 
o Other important medical event that may require 
medical or surgical intervention to avoid any of the 
above criteria  
• 
AEs discontinuation of avelumab  
• 
AEs leading to systemic steroid treatment  
  
Objective 6: To describe real-world all-cause associated healthcare resource burden associated with avelumab therapy  
Variable  
Role  
Time of measurement  
Operational definition  

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All-cause healthcare 
resource burden  
Health care 
resource outcomes  
From avelumab initiation to 
end of follow-up  
Mean and median number, per patient, of the following: 
• 
Accident and emergency visits   
• 
Hospitalisations  
• 
Duration of hospitalisation (days)  
  

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9.3. Data sources  
Data will be extracted from patient medical records and hospital charts from participating NHS 
sites using eCRF. A study information pack will be shared with R&D departments in the 
hospital. Only after each site has been initiated will data be collected by the study teams directly 
from patient medical records (paper and/or electronic) and hospital charts. Centres will be 
provided with clear instructions on how to identify patients and extract their data. Centres will 
be requested to recruit 6-12 patients each so that the geographical spread of patients across 
centres is maintained. They will be instructed to extract these patients in chronological order 
of avelumab initiation (earliest first) to avoid selection bias and to ensure consistency in the 
recruitment methodology across the participating research sites.   
eCRFs will be developed for use in this study using an electronic data capture (EDC) system 
called INES with the help of three therapy areas experts. INES is a fit-for-purpose EDC system 
that has been used in over 2,000 studies and survey-based projects. The web-based system can 
be accessed by the NHS using a multitude of internet browsers. In addition to the eCRF, a data 
management plan will be constructed.  
9.4. Study size  
We aim to enter 100 patients into the study with a maximum follow-up of 24 months per 
patient. Based on the JB100 trial, 1-year overall survival in the avelumab-treated group was 
71% and median overall survival was 21.4 months (13). In our anticipated study population of 
100 patients we would therefore expect 29 deaths by 12 months and >50 deaths by 24 months 
of follow-up. We have estimated the number of survivors by 12 and 24 months of follow-up, 
with the corresponding overall survival estimate and its 95% CI, based on 80, 100 and 120 
patients included in the study in the table below.  
  
Table 5. Estimated overall survival with 95% CI at 12 and 24 months of follow-up from  
avelumab initiation  
  
At 12 months  
At 24 months  
Number of  
patients 
in 
the study  
Number of 
survivors  
Estimate 
of OS(a)  
95% CI (c)  
Number of 
survivors  
Estimate of 
OS(b)  
95% CI(c)  
  
  
  
  
  
  
  
80  
57  
71%  
60-81%  
38  
48%  
36-59%  
100  
71  
71%  
61-80%  
48  
48%  
38-58%  
120  
85  
71%  
62-79%  
58  
48%  
39-58%  
(a) Based on 1-year survival of 71.3% from trial  
(b) Based on 2-year survival of 48.0% (estimated from (13)) (c) 
Based on Clopper-Pearson exact method for binomial probability  
  
  

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9.5. Data management   
9.5.1. Case report forms (CRFs)/Electronic data record  
As used in this protocol, the term CRF should be understood to refer to an online, eCRF that 
will be built in the INES EDC system.  
An eCRF is required and should be completed for each included patient. The completed 
original eCRFs are the sole property of Merck Serono and should not be made available in any 
form to third parties, except for authorised representatives of Merck Serono or appropriate 
regulatory authorities, without written permission from Merck Serono. The investigator shall 
ensure that the eCRFs will only be accessible to authorised staff members to prevent access by 
unauthorised third parties.  
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the eCRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
eCRFs must be signed by the investigator or by an authorised staff member to attest that the 
data contained on the eCRFs are true and accurate. Any corrections to entries made in the 
eCRFs or source documents must be dated, initialised, and explained (if necessary) and should 
not obscure the original entry.  
In this study, the source documents are the hospital or the physician's charts.  In these cases, 
data collected on the eCRFs must match those source documents.   
9.5.2. Record retention  
To enable evaluations and/or inspections/audits from regulatory authorities or Merck Serono 
or its agents, the investigator agrees to keep records, including the identity of all participating 
patients (sufficient information to link records, e.g., CRFs and hospital records), copies of all 
CRFs, safety reporting forms, source documents, detailed records of treatment disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, and 
telephone call reports).  The records should be retained by the investigator according to local 
regulations or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.  
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), Merck Serono should be prospectively notified.  
The study records must be transferred to a designee acceptable to Merck Serono, such as 
another investigator, another institution, or to an independent third party arranged by Merck 
Serono.   

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Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless Merck Serono have expressly agreed to a different period of retention via a 
separate written agreement.  Record must be retained for longer than 15 years if required by 
applicable local regulations.   
The investigator must obtain Merck Serono's written permission before disposing of any 
records, even if retention requirements have been met.  
9.6. Data analysis   
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a SAP, which will be dated, filed, and maintained by the sponsor.  The SAP 
may modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment.  
The SAP will include detailed tables shells and example data visualisation of the analysis. A 
brief overview of the planned analysis is below.  
9.6.1. Descriptive analysis   
Clinical and demographic characteristics, treatment characteristics and toxicity and AEs will 
be analysed descriptively, where continuous variables will be described using the mean (with 
standard deviation) and/or the median (with IQR) and categorical variables will be described 
using number and percentage.   
9.6.2. Overall and progression-free survival  
Real-world OS and PFS will be analysed using time to event analysis. The definitions of these 
outcomes are provided in Table 1. Survival curves will be estimated using Kaplan-Meier 
methods and median (and IQR) time to event will be estimated with rwOS and rwPFS as 
endpoints. The number of patients who have not experienced the outcome and estimated 
survival probability (with 95% CI) will also be described at 6-monthly intervals post diagnosis 
until the end of follow-up. Censoring in analysing each individual outcome will be described 
in detail in the SAP.  
9.6.3. Treatment patterns  
In addition to the description of treatment characteristics, rwTTD and rwTTNT will be 
analysed using time to event analysis. Survival curves will be estimated using Kaplan-Meier 
methods and median (and IQR) time to event will be estimated with rwTTD and rwTTNT as 
endpoints. Table 1 describes the censoring endpoints. Healthcare resource utilisation  
Healthcare resource burden (specifically number of all- cause hospitalisations, and duration of 
hospital stay, A&E admissions) will be reported. As reason for hospitalisation is harder to 
extract and subject to misclassification, only all-cause hospitalisation will be analysed.   

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9.7. Quality control  
At the study level, all aspects of the study design and management from study document 
preparation (protocol, Questionnaire, SAP, reports) to ongoing site management will be 
conducted within the framework of the IQVIA Quality Management System (QMS) and in 
accordance to IQVIA and/or Merck Serono’s SOPs.  
  
According to these policies and procedures, a Data Management and Data Monitoring plan for 
the study will be developed and executed, which will include quality control on study 
management and centre management.  
  
9.8. Limitations of the research methods  
  
9.8.1. Selection bias and study representativeness  
The study aims to collect information on patients treated with avelumab, initially as part of the 
EAMS, and further to include other NHS sites treating patients with avelumab through NHS 
commissioning. The EAMS closed on 21st January 2021 once the marketing authorisation from 
the European Medicines Agency was granted and the EAMS extension was put in place in the 
interim until a funding decision was made.  
  
There is a potential selection bias that could be introduced by only including the participating 
EAMS and EAMS extension NHS sites, as they might differ compared to other NHS sites (e.g. 
being centres of excellence), this is a limitation of this study.  Additionally, the geographies of 
the participating NHS sites are spread throughout the UK, aimed at maximising 
representativeness of the study population.   
  
It is anticipated that most patients to be included in the study will already have initiated 
avelumab by the time the study is started and that only a minority of patients will be identified 
after the study has started at the centre. For most patients, therefore, demographic and treatment 
characteristics will be retrospectively assessed based on existing records and for a minority, 
prospectively. There is a potential for prospectively assessed data to be of different (higher) 
quality and/or completeness if a centre being aware that the avelumab-treated patients are part 
of a study changes medical record keeping practices or if the centre extracts data in real-time. 
While this is difficult to assess, it can be partially circumvented by extracting patient records 
retrospectively at periodic intervals, even if they are created after initiation of the study.   
  
9.8.2. Missing or erroneous data   
Due to variability in hospital record keeping practices, not all variables are expected to be 
available in the electronic medication records and medical charts. Whilst the primary objective 
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some other variables are more likely to be missing than others. Site monitoring, and where 
required, source data verification (SDV) will also aim to reduce and minimise the collection of 
erroneous data.  
  
  
10. PROTECTION OF HUMAN SUBJECTS  
10.1. Patient information   
All parties will comply with all applicable laws, including laws regarding the implementation 
of organisational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any reports, 
publications, or other disclosures, except where required by applicable laws.   
  
The personal data will be stored at the study site in encrypted electronic and/or paper form and 
will be password protected or secured in a locked room to ensure that only authorised study 
staff have access.  The study site will implement appropriate technical and organisational 
measures to ensure that the personal data can be recovered in the event of disaster.  In the event 
of a potential personal data breach, the study site shall be responsible for determining whether 
a personal data breach has in fact occurred and, if so, providing breach notifications as required 
by law.  
To protect the rights and freedoms of natural persons with regard to the processing of personal 
data, when study data are compiled for transfer to Merck Serono and other authorised parties, 
patient names will be removed and will be replaced by a single, specific, study numerical code, 
based on a numbering system defined by the study sponsor.  All other data transferred to Merck 
Serono or other authorised parties will be non-identifiable 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, 
Merck Seronowill maintain high standards of confidentiality and protection of patients’ 
personal data consistent with the CSA and applicable privacy laws.  
10.2. Patient consent  
At the time of entry of patients into the study, it is likely that some patients may have died or 
be receiving end of life care.  Therefore, to avoid the potential of biasing the study cohort 
towards that of a survivor cohort, and to avoid causing any unnecessary distress to the family 
and next of kin of deceased patients or patients receiving end of life care, no consent will be 
sought as part of this study.  
An application to the CAG has been made to waive the need for seeking informed consent from 
all patients on the grounds of the abovementioned concerns. Therefore, no patients or their next 
of kin will be informed about the use of their data or consent sought as part of this study.  

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10.3. Institutional review board (IRB)/Independent ethics committee (IEC)  
There must be prospective approval of the study protocol, protocol amendments, and other 
relevant documents from the relevant IRBs/IECs.  All correspondence with the IRB/IEC must 
be retained. Copies of IRB/IEC approvals must be forwarded to Merck Serono 
An application for ethical review by the Health Research Authority (HRA) Research Ethics 
Committee (REC) using the Integrated Research Application System (IRAS) platform will be 
made for this study. HRA approval is the process by which the NHS will assess aspects of 
governance and legal compliance, as well as the independent REC opinion, provided through 
the UK research ethics service. It replaces the need for local checks of legal compliance and 
related matters by each participating organisation in England.  
10.4. 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 Merck Serono’s controlled medical documents. 
11. MANAGEMENT AND  
REPORTING OF  
ADVERSE  
EVENTS/ADVERSE  
REACTIONS   
This study protocol requires human review of patient-level unstructured data; unstructured data 
refer to verbatim medical data, including text-based descriptions and visual depictions of 
medical information, such as medical records, images of physician notes, neurological scans, 
X-rays, or narrative fields in a database. The reviewer is obligated to report AEs with explicit 
attribution to any Merck Serono 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 NIS Adverse Events (AE) Report Form to 
Merck Serono Safety are as follows:  
• 
All serious and non-serious AEs with explicit attribution to any Merck Serono drug 
that appear in the reviewed information must be recorded on the CRF and reported, 
within 24 hours of awareness, to Merck Serono Safety using the NIS AE Report Form.   
  
o This is inclusive of any adverse events or known toxicities that is explicitly 
attributed to any first-line chemotherapy regimen observed where a component 
of that chemotherapy regimen is marketed by Merck Serono.  
  
• 
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 Merck Serono product 

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must be reported, within 24 hours of awareness, to Safety using the NIS AE Report 
Form.   
  
o This is inclusive of any off-label prescribing of any Merck Serono marketed 
medicinal products.  
For these AEs with an explicit attribution or scenarios involving exposure to a Merck Serono 
product, the safety information identified in the unstructured data reviewed is captured in the 
Event Narrative section of the report form, and constitutes all clinical information known 
regarding these AEs. No follow-up on related AEs will be conducted.  
All the demographic fields on the NIS AE Report Form may not necessarily be completed, as 
the form designates, since not all elements will be available due to privacy concerns with the 
use of secondary data sources. While not all demographic fields will be completed, at the very 
least, at least one patient identifier (e.g., gender, age as captured in the narrative field of the 
form) will be reported on the NIS AE Report Form, thus allowing the report to be considered a 
valid one in accordance with pharmacovigilance legislation. All identifiers will be limited to 
generalities, such as the statement “A 35-year-old female...” or “An elderly male...” Other 
identifiers will have been removed.  
Additionally, the onset/start dates and stop dates for “Illness”, “Study Drug”, and “Drug Name” 
may be documented in month/year (mmm/yyyy) format rather than identifying the actual date 
of occurrence within the month/year of occurrence in the day/month/year (DD/MMM/YYYY ) 
format.   
All research staff members must complete the following Merck Serono training requirements:  
• “Merck PV Responsibilities Training” or similar a Merck Serono local training.   
These trainings must be completed by research staff members prior to the start of data 
collection. All trainings include a “Confirmation of Training Certificate” (for signature by the 
trainee) as a record of completion of the training, which must be kept in a retrievable format. 
Copies of all signed training certificates must be provided to Merck Serono.   
Re-training must be completed on an annual basis using the most current Merck PV 
Responsibilities Training.” All certificates of training completion must be stored in the study 
master file (SMF) . 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS  
Upon completion of this study, the aggregated results will be interpreted and discussed in a 
clinical study report (CSR) within 12 months after the completion of the last patient’s follow 
up period. This CSR will contain a description of the objectives of the study, the methodology, 
results, and conclusions. The completed eCRFs, the final study output and CSR will remain 

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the confidential property of Merck Serono and may not be released to unauthorized people in 
any form (publication or presentations) without express written approval from Merck Serono.   
An annual study progress report will be submitted to the IEC on a yearly basis following the 
initial ethical approval of the study.  
We will publish the summary details and results of the NIS as per guidance within the 
Association of the British Pharmaceutical Industry’s Code of Practice and Merck Serono’s 
SOP. Further dissemination of the study findings may also be made, including abstracts and 
posters to scientific and medical conferences, as well as other scientific publications as decided 
by Merck Serono .  
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 Merck Serono 
product, Merck Serono should be informed immediately.    
  
  
  
  
  
  
 

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13. REFERENCES  
1. 
What Is Bladder Cancer? [Internet]. [cited 2021 Jun 16]. Available from: 
https://www.cancer.org/cancer/bladder-cancer/about/what-is-bladder-cancer.html  
2. 
Bladder Cancer Risk Factors [Internet]. [cited 2021 Jun 16]. Available from: 
https://www.cancer.org/cancer/bladder-cancer/causes-risks-prevention/risk-factors.html  
3. 
Bladder cancer - Symptoms [Internet]. nhs.uk. 2018 [cited 2021 Jun 17]. Available from: 
https://www.nhs.uk/conditions/bladder-cancer/symptoms/  
4. 
Bladder cancer statistics [Internet]. Cancer Research UK. 2015 [cited 2021 Jun 16]. 
Available 
from: 
https://www.cancerresearchuk.org/health-
professional/cancerstatistics/statistics-by-cancer-type/bladder-cancer  
5. 
Cancer survival in England - adults diagnosed - Office for National Statistics [Internet]. 
[cited 
2021 
Jun 
16]. 
Available 
from: 
https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/condition 
sanddiseases/datasets/cancersurvivalratescancersurvivalinenglandadultsdiagnosed  
6. 
Survival Rates for Bladder Cancer [Internet]. [cited 2021 Jun 17]. Available from:  
https://www.cancer.org/cancer/bladder-cancer/detection-diagnosis-
staging/survivalrates.html  
7. 
Overview | Atezolizumab for untreated PD-L1-positive locally advanced or metastatic 
urothelial cancer when cisplatin is unsuitable | Guidance | NICE [Internet]. NICE; [cited  
2021 Jun 16]. Available from: https://www.nice.org.uk/guidance/ta492  
8. 
1 Recommendations | Bladder cancer: diagnosis and management | Guidance | NICE 
[Internet]. 
NICE; 
[cited 
2021 
Jun 
22]. 
Available 
from: 
https://www.nice.org.uk/guidance/ng2/chapter/1-Recommendations  
9. 
Research C for DE and. FDA approves avelumab for urothelial carcinoma maintenance 
treatment. FDA [Internet]. 2020 Jul 1 [cited 2021 Jan 29]; Available from:  
https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-
avelumaburothelial-carcinoma-maintenance-treatment  
10. Bavencio - News | Merck global [Internet]. [cited 2021 Feb 24]. Available from: 
https://www.merckgroup.com/en/news/bavencio-1l-uc-eu-approval-25-01-2021.html  
11. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma | 
NEJM 
[Internet]. 
[cited 
2021 
Jun 
16]. 
Available 
from: 
https://www.nejm.org/doi/full/10.1056/NEJMoa2002788  

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12. Pfizer. A phase 3, multicenter, multinational, randomized, open-label, parallel-arm study 
of avelumab (msb0010718c) plus best supportive care versus best supportive care alone 
as a maintenance treatment in patients with locally advanced or metastatic urothelial 
cancer whose disease did not progress after completion of first-line platinum containing 
chemotherapy [Internet]. clinicaltrials.gov; 2021 Apr [cited 2021 Jun 14].  
Report No.: NCT02603432. Available from:  
https://clinicaltrials.gov/ct2/show/NCT02603432  
13. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab 
Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 
[Internet]. 2020 Sep 24 [cited 2021 Jan 29];383(13):1218–30. Available from:  
https://doi.org/10.1056/NEJMoa2002788  
14. Griffith SD, Tucker M, Bowser B, Calkins G, Chang C (Joe), Guardino E, et al.  
Generating Real-World Tumor Burden Endpoints from Electronic Health Record Data:  
Comparison of RECIST, Radiology-Anchored, and Clinician-Anchored Approaches for 
Abstracting Real-World Progression in Non-Small Cell Lung Cancer. Adv Ther 
[Internet]. 2019 Aug 1 [cited 2021 Feb 5];36(8):2122–36. Available from: 
https://doi.org/10.1007/s12325-019-00970-1  
  
  
14. LIST OF TABLES   
Table 1. Follow-up time for outcomes ...............................................................................20 
Table 2. Variable definitions for demographic and clinical characteristics...........................21  
Table 3. Variable definitions of treatment-related variables ................................................25  
Table 4. Outcome variables definitions ..............................................................................28 
Table 5. Estimated overall survival with 95% CI at 12 and 24 months of follow-up from 
avelumab initiation .................................................................................31  
  
  
LIST OF FIGURES  
Figure 1. Schematic of the study design .............................................................................18  
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS  
None  
  
  
 

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ANNEX 2. ADDITIONAL INFORMATION  
Not applicable.