AN OBSERVATIONAL REAL-WORLD STUDY OF THE SYSTEMIC TREATMENT OF WELL-DIFFERENTIATED, UNRESECTABLE OR METASTATIC, PROGRESSIVE PANCREATIC NEUROENDOCRINE TUMOURS (PNET): A STUDY OF MORBIDITY AND MORTALITY AT 2 YEARS
Conditions: Pancreatic Neuroendocrine Tumor, Well Differentiated and Progressive
Sponsor: Pfizer

  
Novartis Pharma S.A.S. 
Rueil-Malmaison 
France 
 
Pfizer S.A.S 
23, 25, Avenue du Dr Lannelongue 
75668 PARIS Cedex 14 
 
Study protocol 
 
“An observational real-world study of the systemic treatment of 
well-differentiated, unresectable or metastatic, progressive 
pancreatic neuroendocrine tumours (pNET): a study of morbidity 
and mortality at 2 years” 
OPALINE 
 
 
Sponsors 
Novartis pharma S.A.S and Pfizer S.A.S 
Document type 
Observational study protocol 
Version 13 
 17th July 2018 
 
 
 
 
 
 
 
 

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Table of contents 
Rationale for the amendment .................................................................................................... 4 
Summary of the protocol ........................................................................................................... 5 
1. 
Abbreviations ...................................................................................................................... 9 
2. 
Introduction ...................................................................................................................... 11 
3. 
Objectives of the study ...................................................................................................... 15 
3.1. 
Primary objective ................................................................................................................ 15 
3.2. 
Secondary objectives ........................................................................................................... 15 
4. 
Nature of the study ........................................................................................................... 16 
5. 
Study plan ......................................................................................................................... 17 
5.1. 
Patient selection ................................................................................................................... 17 
5.1.1. 
Inclusion criteria .......................................................................................................................... 17 
5.1.2. 
Exclusion criteria: ....................................................................................................................... 18 
5.1.3. 
Recruitment of doctors and patients ............................................................................................ 18 
5.2. 
Study design ......................................................................................................................... 18 
5.2.1. 
Schedule and duration of the study ............................................................................................. 18 
5.2.2. 
Data collection ............................................................................................................................ 19 
6. 
Study monitoring and quality control .............................................................................. 23 
6.1. 
Set up and monitoring......................................................................................................... 23 
6.2. 
Quality control ..................................................................................................................... 23 
6.3. 
Scientific Committee ........................................................................................................... 24 
7. 
Pharmacovigilance ........................................................................................................... 25 
8. 
Data Processing ................................................................................................................ 36 
8.1. 
Determining the sample size ............................................................................................... 36 
8.2. 
Data management ................................................................................................................ 38 
8.2.1. 
Case report form and data collection ........................................................................................... 39 
8.2.2. 
Data retention .............................................................................................................................. 39 
8.3. 
Statistical analysis ............................................................................................................... 40 
8.3.1. 
Population and variables analysed .............................................................................................. 40 
8.3.2. 
Analysis of the objectives ........................................................................................................... 41 
9. 
Limitations of the study .................................................................................................... 42 
9.1. 
Selection bias ........................................................................................................................ 42 
9.1.1. 
Representativeness of enrolled patients....................................................................................... 42 
9.1.2. 
Patients lost to follow up during the study .................................................................................. 43 
9.1.3. 
Left truncation and left censoring ............................................................................................... 43 
9.2. 
Measurement bias ............................................................................................................... 43 
9.3. 
Missing data ......................................................................................................................... 44 
9.4. 
Confounding factors ............................................................................................................ 44 
9.5. 
Study size .............................................................................................................................. 44 
10. 
Schedule of the study .................................................................................................... 45 
11. 
Regulatory considerations ............................................................................................ 45 
11.1. 
Declaration to the CNOM (French doctors’ professional association) ....................... 46 

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11.2. 
Financial agreement ........................................................................................................ 46 
11.3. 
Declarations to the CCTIRS (French consultative committee on data processing in 
healthcare research) and the CNIL (French data protection commission) ............................... 46 
11.4. 
Document for the patient ................................................................................................ 47 
11.4.1. 
Patient information ...................................................................................................................... 47 
11.4.2. 
Consent ........................................................................................................................................ 48 
11.4.3. 
Early withdrawal of the patient ................................................................................................... 48 
11.5. 
Agreement with participating doctors ........................................................................... 49 
11.6. 
Archiving .......................................................................................................................... 49 
12. 
Final report and publication of the results .................................................................. 49 
13. 
List of documents/Material issued to participating doctors ........................................ 49 
14. 
References ..................................................................................................................... 51 
15. 
APPENDICES .............................................................................................................. 53 
15.1. 
APPENDIX 1: Information letter for the patient and consent form .......................... 53 
15.2. 
APPENDIX 2: Non-Inclusion Register .......................................................................... 55 
 
 

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Rationale for the amendment 
 
 
• 
Revision to section 7 “Pharmacovigilance” in respect of new Novartis internal rules 
(Procedures). The investigator’s obligations remain unchanged, only the internal Novartis 
rules concerning the management of cases have been changed. 
• 
Two sections have been added concerning the management of data further to compliance 
with the GDPR: General Data Protection Regulation. (Sections 8.2.1 and 8.2.2). 
• 
Three sections have been added concerning provision of patient information further to 
compliance with the GDPR: General Data Protection Regulation. (Sections 11.4.1 to 11.4.3). 
• 
Two sections have been added concerning the French law known as Jardé’s law and the MR-
003: Regulatory considerations (Section 11 and 11.3). 
• 
Changes have been made to the register (version 15 dated 17/07/2018) to ensure that all of 
the patients identified have been included in the study and that the non-inclusion register 
does not have to be completed. 
• 
The information line has been updated in the non-inclusion register (version 15 dated 
17/07/2018): phone number to call for any information: 0800 940 170. 
• 
Changes have been made to the CRF (version 15 dated 17/07/2018) to remove grade 0, to 
allow a visit without tumour assessment to be entered, to add the statement NK (not known) 
for certain data and to add clarifications to the “anticipated end of study form” page in the 
event of death. The list of abbreviations has been updated: The abbreviation “NK” (not 
known) has been added. 
• 
In section 9, Limitations of the study, one type of bias has been added, and in section 8.3, 
Statistical Analysis, the version of SAS used has been clarified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Summary of the protocol 
Nature of the study:  
This is an observational, descriptive, prospective (partially retrospective), multicentre study carried 
out in France in adult patients treated for a well-differentiated, unresectable or metastatic, 
progressive pancreatic neuroendocrine tumour. The study will be carried out in sites involved in the 
management of neuroendocrine tumours of the pancreas. The inclusion phase is 28 months with 
prospective monitoring of 24 months. 
Title:  
“An observational real-world study of the systemic treatment of well-differentiated, unresectable or 
metastatic, progressive pancreatic neuroendocrine tumours (pNET): a study of morbidity and 
mortality at 2 years”- OPALINE. 
Study medication:  
Treatment 
for 
well-differentiated, 
unresectable 
or 
metastatic, 
progressive 
pancreatic 
neuroendocrine tumours (pNET). Two treatment groups will be set up: the “targeted therapies” 
group with two sub-groups for Everolimus (AFINITOR®) and Sunitinib (SUTENT®); and the “other 
treatments” group with four sub-groups: chemotherapy, somatostatin analogues, interferon alpha 
and radionuclide therapy. 
Objectives:  
- 
Primary objectives: to describe the real-world outcome of adult patients treated (targeted 
therapies and other treatments) for a well-differentiated, unresectable or metastatic, 
progressive pancreatic neuroendocrine tumour in terms of morbidity and mortality at 2 
years (by describing progression-free survival, overall survival and safety). 
- 
Secondary objectives:  
o To describe the characteristics of the population of adult patients treated for a well-
differentiated, unresectable or metastatic, progressive pancreatic neuroendocrine 
tumour 
o To describe the management of patients treated for pNET 
Population concerned:  
- 
Number of patients: 150 patients in total  
- 
Inclusion criteria: Adult patients treated for well-differentiated, unresectable or metastatic, 
progressive pNET before initiation of the treatment chosen by the investigator 
- 
Exclusion criteria: Patients with a diagnosis of poorly differentiated neuroendocrine 
carcinoma or adeno-neuroendocrine carcinoma, patients who have already received a 
targeted therapy (everolimus or sunitinib) in a previous line of therapy (patient in 

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rechallenge), patients on their fifth or higher line of systemic treatment, patients who refuse 
to give their consent 
 
Method and duration of observation 
The study will be carried out in sites involved in the management of neuroendocrine tumours of the 
pancreas. These sites will be identified from a database of doctors specialised in oncology, 
gastroenterology and endocrinology built up as part of this study by the two sponsors. Patients who 
meet the eligibility criteria will be invited to enrol in the study until the required number is met, and 
each patient may only be enrolled once in the study. The patient’s therapeutic management will not 
be altered by taking part in the study and it will follow the recommendations made in a 
Multidisciplinary Team Meeting (MDTM) in accordance with good practice guidelines. 
The inclusion phase is 28 months.  
All patients may be included who are seen for a consultation or hospitalisation and start (incident 
cases) or have already started at the time of inclusion (as long as the treatment has been initiated by 
the recruiting site; these are prevalent cases) a systemic treatment that is either targeted therapy 
with sunitinib or everolimus or another treatment of either chemotherapy, somatostatin analogues, 
radionuclide therapy or interferon alpha as a first, second, third or fourth line therapy. The patients 
will be prospectively monitored for the whole duration of the study (24 months of follow-up) starting 
from inclusion in the study.  
Data will only be collected retrospectively for the ‘prevalent case’ patients (those who started 
treatment before the enrolment visit), so that data from treatment initiation onward is recorded. 
Safety data will be collected for ‘prevalent case’ patients as described in the following paragraph and 
in paragraph 7: pharmacovigilance. The monitoring data will be collected at the tumour assessment 
visits that are carried out in practice around every 2-3 months, and are separate from any treatment 
interruptions, changes or discontinuation that may be needed. 
Origin and nature of the data collected:  
The patients who start treatment at enrolment (‘incident’ cases) will have indirectly nominative 
medical data collected prospectively on enrolment and throughout their follow-up. The following 
information will be collected: 
o Social and demographic characteristics 
o Characteristics of patients at the start of their treatment: comorbidities and medical 
history, ECOG performance status 
o A description of the disease: initial diagnosis, localisation of metastases at the start of 
treatment, symptoms of functioning disease at the start of treatment, most recently 
performed radiology examinations 
o Description of the treatment line started at the time of enrolment: targeted therapies or 
other 
treatments, 
date 
of 
initiation, 
dose 
and 
treatment 
regimen, 
monotherapy/combined treatment  
o Description of previous treatments 
o Description of changes to the dose/treatment regimen or discontinued treatment 

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o Tumour assessments 
o Safety (see paragraph 7: pharmacovigilance) 
 
The patients who started treatment before enrolment (‘prevalent’ cases) will have indirectly 
nominative medical data collected retrospectively on enrolment, then prospective data collected 
throughout their follow-up. The following information will be collected: 
Retrospectively: 
o Social and demographic characteristics 
o Characteristics of patients at the start of their treatment: comorbidities and medical 
history, ECOG performance status 
o A description of the disease: initial diagnosis, localisation of metastases at the start of 
treatment, symptoms of functional disease at the start of treatment, most recently 
performed radiology examinations 
o Description of the treatment line ongoing at the time of enrolment: targeted therapies 
or 
other 
treatments, 
date 
of 
initiation, 
dose 
and 
treatment 
regimen, 
monotherapy/combined treatment  
o Description of previous treatments 
o Description of any dose changes or treatment interruptions since initiation of treatment 
o Safety (see paragraph 7: pharmacovigilance):  
 If the treatment ongoing at enrolment is Everolimus:  
- Adverse events clearly related to Everolimus that occurred between starting 
treatment and enrolment 
- Adverse events clearly related to a Pfizer product that occurred between starting 
the first line of treatment for the illness and enrolment 
 For all other treatments ongoing at enrolment (Sunitinib, chemotherapy, 
somatostatin analogues, interferon alpha or radionuclide therapy):  
- Adverse events clearly related to a Pfizer product that occurred between starting 
the first line of treatment for the illness and enrolment. 
 Prospectively: 
o Description of any dose changes or treatment interruptions   
o Tumour assessments 
o Safety (see paragraph 7: pharmacovigilance) 
Data analysis:  
All tests will be carried out using a type I error risk of α =5%. 
The descriptive analysis of the qualitative and ordinal variables will consist of the number and 
frequency of each category with a confidence interval of 95%, and the number of missing data. The 
quantitative variables will be presented in table form showing the overall population and that of 
each sub-group of patients analysed: total numbers, mean and median, standard deviation, 
confidence interval, and the number of missing data. The estimate of progression-free survival and 
overall survival will be made using the Kaplan-Meier method. The survival S(t) function will be the 

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probability that the event of interest (progression or death respectively) does not occur before the 
date t.  
The survival rates will be estimated and presented for each of the groups of interest: 
- 
Targeted therapy group (with an estimate for the everolimus and sunitinib sub-groups) 
- 
Other treatments group (with estimates for the sub-groups if there are sufficient total 
numbers) 
It is important to note that statistical comparisons in the strictest sense between the different 
treatment groups in this observational study are not appropriate due to the expected bias and 
because the groups are not comparable at enrolment (treatments not assigned randomly). If, 
however, comparisons are envisaged, a Cox multivariate model will be used in order to adjust for 
patient characteristics that may potentially be associated with the type of treatment received and 
with survival that could be liable to skew the estimates (confounding factors, effect modification).  
Calculation of the number of patients needed:  
The calculation of the number of patients needed is based on the primary objective of describing 
morbidity and mortality evaluated specifically in terms of progression-free survival and overall 
survival. The calculation is based on the expected precision of the estimate of median survival 
(confidence interval).  
In view of: 
- 
The target population, estimated at 150-170 cases per year, 
- 
The prevalence of the treatment groups of interest and the need to stratify enrolments 
across the treatment sub-groups, 
- 
The criteria for inclusion in the study (exclusion of patients on their 5th or higher treatment 
line), 
A total of 150 patients enrolled over a period of around 2 years seems to be a realistic target. The 
inclusion of 150 patients in total would allow the median survival (progression-free or overall) to be 
estimated with a precision of around 8%.  
It should be noted that in the analyses of the sub-groups (targeted therapies, other treatments) the 
median will be estimated with less precision since the total numbers in each stratum will be lower. 
For example, if we assume a balanced distribution of patients between the targeted therapies and 
other treatments groups, or 75 patients per group, precision will be 11%. 
 
 

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1. 
Abbreviations 
 
(S)AE 
(Serious) Adverse Event 
AEM 
Adverse Event Monitoring 
MA 
Marketing Authorisation 
ANSM 
Agence Nationale de Sécurité du Médicament et des produits de santé 
[French national agency for the safety of medicines and health products] 
CRA 
Clinical Research Associate 
COPD 
Chronic Obstructive Pulmonary Disease  
CCTIRS 
Comité Consultatif sur le Traitement de l’Information dans le domaine de la 
recherche en Santé [consultative committee on data processing in 
healthcare research] 
CNIL 
Commission Nationale de l’Informatique et des Libertés [French data 
protection commission] 
CNOM 
Conseil National de l’Ordre des Médecins [French doctors’ professional 
association] 
EC 
Ethics Committee 
(e)CRF 
(electronic) Case Report Form 
CRO: 
Contract Research Organization  
SC 
Scientific Committee 
CSP 
Code de la Santé Publique [French public health code] 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
ENETS 
European Neuroendocrine Tumour Society 
EORTC 
European Organisation for Research and Treatment of Cancer 
GTE 
Groupe d’étude des Tumeurs Endocrines [Endocrine tumour study group] 
HAS 
Haute Autorité de Santé [French health authority] 
CI 
Confidence Interval 
MRI 
Magnetic Resonance Imaging 
NK 
Not Known 
NIS 
Non-Interventional Study 
SAP 
Statistical Analysis Plan 
PASS 
Post Authorization Safety Study 
PET scan 
Positron Emission Tomography 
PFS 
Progression Free Survival 
RMP 
Risk Management Plan 
PV 
Pharmacovigilance 
QLQ-C30 
Quality of Life Questionnaire-Core 30 
MDTM 
Multidisciplinary Team Meeting 
RECIST 
Response Evaluation Criteria In Solid Tumours 
CT 
Computed Tomography 
CRT 
Clinical Research Technician 
TNCD 
Thésaurus National de Cancérologie Digestive [French thesaurus of 
gastrointestinal oncology] 
NET 
Neuroendocrine tumour grading system 
pNET 
Pancreatic neuroendocrine tumour 
WHO 
World Health Organization  

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2. 
Introduction 
Epidemiology 
The standardised incidence ratios over the world population of well-differentiated pancreatic 
neuroendocrine tumours (pNET) are 0.19 in men and 0.12 in women (sex ratio 1.6) per 100,000 
people per year(1), meaning they account for only a small proportion (2.8 %) of all pancreatic cancers 
(2-6). Since pNET patients have higher survival rates than those with pancreatic adenocarcinoma, the 
prevalence of pNET is greater, estimated at 10% of pancreatic cancers. 
In France, the incidence of pancreatic cancer is estimated at around 10,000 new cases per year (7). 
One type of presentation is known as functioning pNET, in which digestive hormones are produced 
and symptoms connected with this secretion occur, while the other more common type is non-
functioning pNET without hormone secretion and corresponding symptoms. It is estimated that 60 - 
90% of pNET are non-functioning (8, 9) and that 85% of pancreatic neuroendocrine tumours are well-
differentiated. The degree of differentiation of the tumour is based on the 2010 WHO NET grading 
system (10): well-differentiated tumours (grade 1 and 2) as against poorly differentiated tumours 
(grade 3). The management of these patients varies according to the degree of differentiation.  
 
Prognosis  
In the Yao et al study (3), the overall median survival of patients with pNET was 38 months and the 5-
year survival rate was 43%. In a French study (1) the survival rate was 61.3% at 1 year and 44.2% at 5 
years. The same trends could be seen in an English study (11) with a survival rate at 1 year estimated 
at 64.7% and 38.6% at 5 years.  
The factors for a poorest prognosis are in particular the type and localisation of metastases, the 
tumour grade, the degree of differentiation and age over 40 years (3, 12). The criteria for assessing 
the prognosis for pNET are set out in the table below (drawn from the publication of the ENETS 
consensus (9)): 
 
 
Table 1 – Criteria for assessing the prognosis of endocrine pancreatic neoplasms 

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Therapeutic management 
The criteria for choice of management are extension of the tumour locally, how much disease 
progression is seen and symptoms.  
There are “anti-secretory” treatments for functioning disease consisting in particular of somatostatin 
analogues for VIPoma, glucagonoma and insulinoma (which can also be effective against the 
tumour). 
In localised forms, surgery is the gold standard curative treatment. In well-differentiated, localised, 
small tumours <2cm, treatment abstention may be justified with simple monitoring only, especially if 
the surgery proposed is a Whipple’s procedure (pancreaticduodenectomy) and if the tumour is well-
defined, rather than recourse to surgery which does remain the gold standard curative treatment.  
In locally advanced or metastatic forms the following “anti-cancer” treatments are used (13-15): 
- 
Hepatic (chemo)embolization, which is a good palliative option for patients who are not 
candidates for surgery (16) 
- 
Chemotherapy: proven efficacy in well-differentiated pancreatic tumours (e.g. a 
combination of streptozotocin and 5-FU and/or doxorubicin with an objective response 
rate of around 35-40% (17-19))  
 
Somatostatin analogues 
- 
Interferon alpha: 42% show symptomatic response (secretions) and 11% show tumour 
reduction 
- 
Radionuclide therapy with radiolabelled somatostatin analogues 
 
The following figure shows a treatment algorithm used in patients with pancreatic neuroendocrine 
tumours and based on the degree of differentiation (figure from publication (20)). 
 
Figure 1 - Therapeutic algorithm for patients with well-differentiated and poorly differentiated pancreatic 
neuroendocrine tumours 
 
 
 

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Targeted therapies are systemic treatments that offer a new therapeutic option. There are two 
treatments that have shown efficacy in the therapeutic management of patients with unresectable 
pNET in placebo-controlled clinical trials (21, 22), particularly on a primary outcome measure of 
progression-free survival (PFS): sunitinib and everolimus. PFS was defined as the time between 
randomisation and the date of first documented disease progression or death, irrespective of the 
cause. The absolute gain in PFS was 5.9 months for sunitinib and 6.4 months for everolimus. The 
secondary outcome measures for both drugs were overall survival (defined as the time between 
randomisation and death irrespective of cause), the objective response percentage according to the 
RECIST criteria, the duration of response, safety and quality of life based on the EORTC QLQ-C30 
scale (for sunitinib). Adverse effects were observed with a higher frequency in the everolimus and 
sunitinib groups than in the placebo groups.  
On the basis of these trials, applications to extend the indications have been granted by the health 
authorities for both products.  
 
Justification for the study 
In an opinion of 21st September 2011 (23) concerning an extended indication for sunitinib to the 
treatment of well-differentiated, unresectable or metastatic, progressive pancreatic neuroendocrine 
tumours in adults, the transparency commission asked for data that would allow them to look at the 
impact of sunitinib based on a register of well-differentiated, unresectable or metastatic, progressive 
pancreatic neuroendocrine tumours in adults, in comparison with other treatments. Based on these 
data, the outcomes of treated patients in terms of morbidity and mortality at two years would be 
able to be described. 
In an opinion of 28th March 2012 (24) concerning an extended indication for everolimus to the 
treatment of well or moderately differentiated, unresectable or metastatic, progressive 
neuroendocrine tumours of pancreatic origin in adults, the transparency commission asked for data 
that would allow them to look at the impact of everolimus from a register of well-differentiated, 
unresectable or metastatic, progressive pancreatic neuroendocrine tumours in adults, in comparison 
with other treatments. Based on these data, the course of treated patients in terms of morbidity and 
mortality at two years would be able to be described. 
In order to respond to the requests from the authorities, the two pharmaceutical companies 
(Novartis and Pfizer) firstly approached the Groupe d’étude des Tumeurs Endocrines (GTE, Endocrine 
Tumours Study Group)1 to explore whether it would be feasible to use their data and to look at the 
possibility of grafting a study on to the existing GTE endocrine tumours register. However, due to 
major problems with using the data from this register to respond specifically to the request from HAS 
(the type of data collected being basically epidemiological, the timeframe and the difficulties with 
collecting data), this option was rejected. 
 
 
                                                     
 
1 http://www.fichiergte.com/ 

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Furthermore, it would not be possible to compare the two treatments (everolimus, sunitinib) to each 
other and to other treatments from a statistical perspective. This is because the population size 
needed for a statistically significant comparison based on, for example, the criterion of mortality, 
would take over 6 years of recruitment to reach (if 4 treatment groups were compared, with the 
hypothesis of a 20% relative reduction in mortality, and 250 patients needed per group, so 1000 
patients2) given that the target population is estimated at 150 patients per year. Furthermore, it was 
important to consider that at the same time there are a number studies in France recruiting from the 
same limited population (at least four studies known of) which would have an even greater effect on 
the feasibility and potential for inclusion. 
These issues and the similarity of the two study requests made by HAS led the two pharmaceutical 
companies to consider a single observational study, estimating the impact on morbidity and 
mortality at 2 years of well-differentiated, unresectable or metastatic, progressive pancreatic 
neuroendocrine tumours (pNET) in adults.  
 
In order to answer the questions from HAS, two broad groups of treatments were decided upon:  
- 
The “targeted therapies” group, made up of two sub-groups: 
o Everolimus (AFINITOR®) 
o Sunitinib (SUTENT®) 
- 
The “other treatments” group, made up of four sub-groups of the most commonly 
prescribed treatments:  
o Chemotherapy 
o Somatostatin analogues 
o Interferon alpha 
o Radionuclide therapy 
Local treatments (chemoembolization, radiofrequency ablation etc.) and surgery were 
excluded in order to ensure sufficient population numbers to meet the objectives. 
 
 
 
                                                     
 
2 Case set out in detail as sent by Novartis to HAS in a letter of 7th March 2012 

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3. 
Objectives of the study 
 
3.1. 
Primary objective 
The primary objective of this observational study is to describe the real-world outcomes in adult 
patients treated (targeted therapies and other treatments) for a well-differentiated, unresectable or 
metastatic, progressive pancreatic neuroendocrine tumour in terms of morbidity and mortality at 2 
years. The following parameters will be assessed in order to meet this objective: 
• 
Rate of progression-free survival at 2 years. Progression-free survival is defined as the time 
between the start of treatment (of the treatment line ongoing at the time the patient was 
enrolled in the study) and the date of the first disease progression or death, irrespective of 
the cause. 
• 
Overall survival at 2 years. Overall survival is defined as the time between the start of 
treatment (of the treatment line ongoing at the time the patient was enrolled in the study) 
and death, irrespective of the cause. 
• 
Safety of the treatments (targeted therapies and other treatments) defined by instances of 
treatment discontinuation and the reasons, adverse events (graded according to the 
‘Common Terminology Criteria for Adverse Events’ (CTCAE) version 4.0 of May 2009), and 
any complications of adverse events. 
 
3.2. 
Secondary objectives 
This study will also enable us to meet the following secondary objectives:  
• 
To describe the characteristics of the population of adult patients treated for a well-
differentiated, unresectable or metastatic, progressive pancreatic neuroendocrine tumour 
• 
To describe the management of patients with well-differentiated, unresectable or 
metastatic, progressive pancreatic neuroendocrine tumours and treated with targeted 
therapies and other treatments (types of treatment, treatment regimens and prescription 
modalities) 
 
 
 

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4. 
Nature of the study 
This is a national observational, descriptive, prospective (partially retrospective), multicentre study 
carried out in France in adult patients treated for a well-differentiated, unresectable or metastatic, 
progressive pancreatic neuroendocrine tumour.  
The study will be carried out in sites involved in the management of neuroendocrine tumours of the 
pancreas.  
These sites will be identified from a database of doctors specialised in oncology, gastroenterology 
and endocrinology built up as part of this study by the two sponsors. Patients who meet the 
eligibility criteria will be invited to enrol in the study until the required number is met, and each 
patient may only be enrolled once in the study. The patient’s therapeutic management will not be 
altered by taking part in the study and it will follow the recommendations made in a Multidisciplinary 
Team Meeting (MDTM) in accordance with good practice guidelines. 
The inclusion phase is 28 months and will enable us to prospectively include patients seen for a 
consultation or hospital admission during the inclusion phase and treated by targeted therapies 
(Everolimus or Sunitinib) or by another treatment (one of those defined as part of this study: 
chemotherapy somatostatin analogues, radionuclide therapy or interferon alpha), for which the 
following apply: 
- 
Treatment is started as first, second, third or fourth line treatment at the time of 
enrolment in the study with a change of treatment line being defined as a change of drug 
or combination thereof (incident cases) 
- 
The treatment ongoing at inclusion was started as a first, second, third or fourth line 
therapy prior to enrolment in the study as long as treatment was started at the same site 
that is enrolling the patient in the study (prevalent cases) 
The patients will be prospectively monitored for the whole duration of the study (24 months of 
follow-up) starting from inclusion in the study. The monitoring visits will take place during the 
patient's usual consultations for tumour assessment carried out at the site (around every 2-3 
months), separately from any treatment interruptions, changes or discontinuation that may be 
needed. 
The study will also consist of a retrospective and/or prospective data collection phase, depending on 
whether patients are prevalent or incident cases, concerning their cancer treatment at the time of 
their enrolment in the study (Table 2, § 5.2.2 "Data collection"). 
The study data will be collected via an electronic case report form (eCRF) by either the doctors or the 
Clinical Research Associates (CRA)/Clinical Research Technicians (CRT) at the enrolment and 
monitoring visits.  
 
 
 
 

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5. 
Study plan 
5.1. 
Patient selection 
Each doctor participating in the study will have to include all consecutive patients seen at the site 
who meet all the inclusion and exclusion criteria until the numbers required for each sub-group have 
been reached (targeted therapies group, other treatments group) and the total number for the study 
has been met at a national level.  
In order to ensure that inclusion adheres to this consecutive pattern, a non-inclusion register 
(appendix 2) will be set up. Eligible patients who are not enrolled in the study must be recorded in 
this register throughout the inclusion phase and/or until the expected number of patients has been 
reached. Only minimal characteristics will be recorded: sex, age of patient, ECOG performance status 
and reason for non-inclusion. 
 
Within the inclusion phase a maximum of 75 patients treated with “other treatments” irrespective of 
treatment line will be observed, and a minimum of 75 patients treated with “targeted therapies” 
irrespective of treatment line, of which 35 patients minimum treated with sunitinib and 35 patients 
treated with everolimus. It should be noted that on 15th September 2017, recruitment will end even 
if sufficient numbers of patients for the “other treatments” and “targeted therapies” cohort have not 
been recruited. 
 
5.1.1. 
Inclusion criteria 
Patients who meet all of the following criteria can be enrolled: 
1. 
Patients over the age of 18 years 
2. 
Patients treated with a targeted therapy (sunitinib, everolimus), or by other treatments 
(interferon, or radionuclide therapy, or chemotherapy or a somatostatin analogue)* for: 
*patients who are started on a 1st, 2nd ,3rd or 4th line of treatment (targeted therapy or other 
treatment) at the time they are enrolled (incident cases) or patients whose 1st, 2nd, 3rd or 4th 
line of treatment is ongoing as long as this treatment was started at the site that is enrolling 
the patient in the study (prevalent cases); a change of treatment line is defined as a change of 
drug or combination thereof.  
- 
a neuroendocrine tumour of the pancreas, that is unresectable or metastatic and confirmed 
by histology, 
- 
well-differentiated, 
- 
with disease progression prior to initiation of treatment in the investigator’s opinion (clinical 
or radiological progression),  
3. 
Patients who have been informed about the study design and have signed the informed 
consent form. 
Patients who are participating in another observational study can still be enrolled. Moreover, it will 
be important to enrol patients from clinical trials since the follow-up bias this could entail (connected 
to the schedule and terms of follow-up imposed by the trial) will have less impact than selection bias, 
which could lead to this study only including patients who are not eligible for clinical trials. However, 
in order to identify and categorise patients into the different groups of interest, patients 
participating in a clinical trial will be able to be included if they are in a treatment arm in the trial 
with a treatment that has been validated with an MA (Marketing Authorisation) and by the TNCD 

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(Thésaurus National de Cancérologie Digestive; French thesaurus of gastrointestinal oncology) based 
on the versions of December 2013, if the clinical trial is not double blinded and if patients are not 
included in the placebo arm in a placebo-controlled trial.  
5.1.2. 
Exclusion criteria: 
The following patients may not be included in the study: 
1. 
Patients with a diagnosis of poorly differentiated neuroendocrine carcinoma or adeno-
neuroendocrine carcinoma. 
2. 
Patients receiving a targeted therapy (everolimus or sunitinib) that they have already received 
in an earlier treatment line (patient in rechallenge). 
3. 
Patients who refuse to give consent. 
4. 
Patients on their fifth or higher line of systemic treatment.  
5. 
Patients participating in a clinical trial with a treatment that is not validated by an MA and by 
the TNCD in the versions of December 2013. 
6. 
Patients who have been randomised to the placebo arm in a placebo-controlled trial or who 
are in a double-blind clinical trial. 
It is important to limit the number of lines of systemic treatment to four because some pNET 
patients on their 5th line may have up to a 12-year history of treatment. Data collection would be 
neither feasible nor reliable (information bias). Moreover, it will also be important to standardise the 
sample of patients as far as possible, and targeted therapies are rarely prescribed beyond the first 
four treatment lines. 
 
5.1.3. 
Recruitment of doctors and patients 
The study will be offered to sites involved in the management of pNET (from a database of doctors 
specialised in oncology, gastroenterology and endocrinology) built up as part of this study by the two 
sponsors.  Doctors will be recruited by a specialist Service Provider under contract to Novartis 
Pharma and Pfizer. The study will be open to the greatest number of sites in order to have a 
representative group of doctors participating and to have the greatest potential for enrolments in 
the study (in view of the limited numbers of potential patients). 
The doctors who agree to participate will form the population of participating doctors. 
After completing training for the study, each doctor participating must include patients seen 
consecutively for consultations or hospital admissions who meet all of the eligibility criteria. In order 
to reduce selection bias, doctors must enrol patients consecutively and exhaustively, until the overall 
required numbers for the study nationally are achieved, by sub-group and by treatment line in the 
targeted therapies group.  
 
5.2. 
Study design 
5.2.1. 
Schedule and duration of the study 
Doctors who are specialists in oncology, gastroenterology or endocrinology working at sites involved 
in the management of patients with pNET will be invited to recruit patients for the study. After 

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agreeing to the study protocol, the participating doctor has 28 months to recruit the planned 
number of patients.  
In order to answer the questions from HAS, two broad groups of treatments will be formed:  
- 
The “targeted therapies” group, made up of two sub-groups: 
o Everolimus  
o Sunitinib  
- 
The “other treatments” group, made up of four sub-groups of the most commonly 
prescribed treatments:  
o Chemotherapy 
o Somatostatin analogues 
o Interferon alpha 
o Radionuclide therapy 
- 
Either a first, second, third or fourth line of treatment will be started at the time of 
enrolment, or the patient will already be on a first, second, third or fourth line of 
treatment before enrolment in the study (as long as the treatment was started at the 
site that is enrolling the patient in the study), with a change of line defined as a change 
of drug or combination thereof. 
Within the inclusion phase a maximum of 75 patients treated with “other treatments” irrespective of 
treatment line will be observed and a minimum of 75 patients treated with “targeted therapies” 
irrespective of treatment line, of which a minimum of 35 patients will be treated with sunitinib and 
35 with everolimus. It should be noted that on 15th September 2017, recruitment will end even if 
sufficient numbers of patients for the “other treatments” and “targeted therapies” cohort have not 
been recruited. 
The participating doctors will consecutively and exhaustively enrol (until the number of patients 
expected by the site is reached) all patients treated either with a targeted therapy or “other 
treatment” who meet the study inclusion criteria, and each patient may only be enrolled once in the 
study. Once all sites have been opened and trained, the inclusion phase is estimated at 28 months.  
These patients will be prospectively monitored throughout the whole duration of study follow-up 
(which is 24 months from the time of enrolment in the study) at their usual consultations for tumour 
assessment at the sites (or approximately every 2/3 months), which are separate from any treatment 
interruptions, changes or discontinuation that may be needed. There will be no consultations 
scheduled by the protocol of this observational study, with the methods of treatment and follow-up 
remaining those that are judged appropriate by the doctor.  
 
Figure 2 Overall study design 
 
5.2.2. 
Data collection 
The data will be collected in an electronic case report form (eCRF). Patients will be indirectly 
identified by a number that is for the study only (a combination of the site number and patient 
number). 

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6. 
Study monitoring and quality control 
6.1. 
Set up and monitoring 
The study will be set up by a specialist Service Provider (CRO) under contract to Novartis Pharma and 
Pfizer. All of the documents required to participate will be sent to each doctor. 
The monitoring and logistics of the study will be the remit of a specialist Service Provider under 
contract to Novartis Pharma and Pfizer. This provider will deliver centralised management of the 
various documents for the participating doctors (verification, entry). A database specifically to 
manage the monitoring of the study will be developed through which regular editing of the study 
progress reports will be possible. 
6.2. 
Quality control 
Data will be monitored, quality controlled, entered and analysed by the service provider specialised 
in data management and processing who are under contract to Novartis Pharma and Pfizer. 
- 
Data will be monitored, quality controlled, entered and analysed by the service provider 
specialised in data monitoring, management and processing in observational studies in line 
with current best practice, under contract to Novartis Pharma SAS and Pfizer SAS.  
- 
Requests for additional information and/or corrections may be addressed (by sending an 
electronic form) to the participating doctors if any information is missing or unclear for the 
purposes of the data validation plan.  
 
This study will be subject to enhanced monitoring with two components: 
- 
Throughout the study, the doctors will be contacted by specially trained staff from the 
Service Provider under contract to Novartis Pharma and Pfizer in order to make sure that 
they have understood the protocol and the electronic case report form, and that they are 
following the protocol. Each one of these contacts will be documented. 
- 
On-site quality control of data will be carried out based on a sample of 10% of active sites. 
The active sites for quality control will be chosen at random at the end of the inclusion 
phase. Before this is set up, a quality control plan will be drafted by the Service Provider and 
discussed with the study Scientific Committee.  
 
Clinical Research Associates at the specialised Service Provider under contract to Novartis Pharma 
and Pfizer will be required to check on site that the enrolled patients exist, the quality of the data 
collected and that the data transferred into the data collection form are identical to the source 
data (a small amount of clinically relevant and important data will be checked as defined in advance 
in agreement with the Scientific Committee). This information will be checked by the clinical research 
associates directly accessing the patient’s file. The patient will have been informed in advance of this 
and agreed to it (Appendix 1: information letter for the patient and consent form).  
A report on the quality control visits will be drafted by the Service Provider and presented to the 
Scientific Committee for analysis and advice on any corrective action that needs to be taken. The 
Scientific Committee may decide that a further quality control campaign should be carried out.  

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6.3. 
Scientific Committee 
A scientific committee has been set up to monitor this study. Its role is to define and validate the 
methodology of the study and the ways in which the study is to be carried out, and to review and 
validate the statistical analysis report. If there are anomalies in the process of checking data, the 
committee will look at all measures judged to be necessary to improve data quality. The committee 
will play a part in communicating the results of the study. 
It is made up as follows: 
 
Clinical experts 
 
 
Doctor 
, 
 
 
 
 
Doctor 
, 
 
 
 
 
Epidemiology expert 
 
 
Professor 
, epidemiologist - 
 in gastroenterology and gastrointestinal 
oncology, 
 
 
 
Statistics expert 
 
 
Professor 
, 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Furthermore, if the serious adverse event is fatal or life-threatening, the Pfizer/Novartis 
Pharmacovigilance Departments must be notified immediately, including whatever information is 
available about the adverse event. This time frame also apples to any new (follow-up) information 
concerning adverse event or serious adverse event notifications that have already been submitted. In 
the rare situations in which the investigator is not immediately informed that an adverse event has 
occurred, the investigator must enter the adverse event or serious adverse event in the electronic 
CRF within 24 hours of becoming aware of it, and the time when he/she first became aware of this 
adverse event must be recorded. 
In the case of adverse events considered to be serious or that fit into the right column of the table 
above entitled “Declared to pharmacovigilance” which need to be declared to the Pfizer/Novartis 
pharmacovigilance departments within 24 hours of becoming aware of them, the investigator must 
seek and provide all additional information to Pfizer/Novartis within this 24-hour time frame. 
Furthermore, Pfizer/Novartis can ask an investigator to urgently obtain specific additional follow-up 
information. This information may be more detailed than what has been logged in the study case 
report form. In general, this information will include a sufficiently detailed description of the adverse 
event for a complete medical assessment of the case, and an independent judgement on whether 
there is a causal link. All relevant information pertaining to the event, such as concomitant 
treatments or illnesses, must be provided. If the patient dies, a summary of the available autopsy 
results must be sent to Pfizer/Novartis or to the approved representative as soon as possible. 
 
 
Note:  For any death entered in the electronic CRF without an associated SAE being declared, the 
Pfizer/Novartis Pharmacovigilance Departments will be notified immediately and the investigator will 
be asked for additional information. 
 
Notification period 
For each patient, the period for notification of adverse events begins from the time when the patient 
receives the first dose of the study medication or from the date when the patient gives his/her 
informed consent if he/she has already been exposed to the study medication, and it ends at the end 
of the observation phase of the study, which is a minimum of 28 calendar days after the last 
administration of the study medication; the process for declaring the different types of adverse 
events to the Pfizer/Novartis Pharmacovigilance departments or approved representative during this 
period are listed in table 4 above. If the patient receives the study medication on the last day of the 
observation phase, the notification period will be extended by 28 calendar days after the end of the 
observation phase. Usually, the date when the consent form is signed will correspond to the date 
that the patient is enrolled in the study. 
In some cases, they may be a delay between the date that the consent form is signed and the date of 
enrolment in the study. 
In cases in which the patient gives his/her consent but is never enrolled in the study (for example: 
the patient changes his/her mind about participating; does not meet the screening criteria), the 
notification period ends on the date when the decision is made not to include the patient. 
 

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If the investigator becomes aware of a serious adverse event occurring at any time after the end of 
the observation phase that he/she considers to be related to a study medication, this serious adverse 
event must also be declared to the Pharmacovigilance department at Pfizer.  
If an SAE, non-serious AE or specific scenario occurs after the end of the observation phase, it only 
needs to be declared to the pharmacovigilance department at Novartis, by fax or by e-mail, if the 
investigator suspects a causal link with the study medication(s). 
 
 
Assessing causality 
The investigator must assess causality and report on it. The investigator must obtain sufficient 
information to determine the causality of every adverse event. For AE considered to be related to a 
study medication, the investigator must monitor these events until resolution or stabilisation of the 
event and/or of any sequelae to the extent deemed to be acceptable by the investigator, and with 
the approval of Pfizer/Novartis of this assessment. 
The investigator's assessment of causality is the determination of whether there is a reasonable 
possibility that a study medication could have caused or contributed to an adverse event. If the final 
determination of causality is unknown and the investigator is unable to determine whether a study 
medication has caused the event, then the adverse event (Pfizer) or serious adverse event (Novartis) 
must be reported within 24 hours. 
 
If the investigator is unable to determine the aetiology of the event but he/she has determined that 
no study medication was the cause of the event, this must be clearly stated on the case report form 
and the non-interventional study adverse event monitoring form (Pfizer) or non-interventional study 
serious adverse event monitoring form (Novartis). 
 
 
DEFINITION OF AN ADVERSE EVENT 
Adverse events 
An adverse event is an unwanted medical effect occurring in a patient who has been administered a 
medication. The event does not necessarily have to be causally linked to the treatment or usage. The 
same definition applies to medical devices and to nutritional products (including formulations for 
babies or young children [henceforth designated by “paediatric formulation”]). Examples of adverse 
events include the following from this non-exhaustive list:  
• 
Abnormal test results (see below for the circumstances in which an abnormal test result 
constitutes an AE) 
• 
Clinically significant signs and symptoms 
• 
Change to results on a clinical examination 
• 
Hypersensitivity 
• 
Lack of efficacy  
• 
Abusive use  

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• 
Dependence 
In addition, for medications, this can include signs or symptoms resulting from: 
• 
Overdose 
• 
Withdrawal 
• 
Misuse  
• 
Use outside the indications of the MA (marketing authorisation)  
• 
Interactions with other medications 
• 
Extravasation 
• 
Exposure during pregnancy 
• 
Exposure during breastfeeding 
• 
Medication errors 
• 
Occupational exposure 
 
Abnormal test results 
The following criteria are used to determine whether an abnormal result on an objective test should 
be reported as an adverse event: 
• 
The test result is associated with symptoms, and/or 
• 
The test result leads to additional diagnostic investigations or a medical/surgical 
intervention, and/or 
• 
The test result leads to a change of dosage, withdrawal from the study, administration of an 
additional and significant concomitant treatment, or another treatment, and/or 
• 
The test result is considered to be an adverse event by the investigator or the sponsor 
Simply needing to repeat an abnormal test, in the absence of the above conditions, does not 
constitute an adverse event. Any abnormal test result that turns out to be due to an error does not 
need to be reported as an adverse event. 
 
Serious adverse events 
A serious adverse event is defined an unwanted medical effect occurring in a patient receiving a 
medication or nutritional product, regardless of the dose, that: 
• 
Leads to death  
• 
Is life-threatening 
• 
Requires hospitalisation of the patient or prolongs a hospitalisation (see below for the 
circumstances in which this does not constitute an adverse event) 
• 
Leads to a persistent or significant incapacity (substantial disruption to the ability to conduct 
acts of daily living)  
• 
Leads to a congenital anomaly or birth defect 
Progression of the malignancy over the course of the study (including signs and symptoms of 
progression) must not be reported as a serious adverse event, unless this results in death during the 
study or during the adverse events notification period. Hospitalisation due to the signs and 

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symptoms of disease progression must not be reported as a serious adverse event. If the malignancy 
results in death during the study or adverse events notification period, then the event leading to 
death must be recorded as an adverse event, and as a grade 5 serious adverse event. 
An event will be defined as a medically important event on the basis of medical and scientific 
judgement. A medically important event is not immediately life-threatening and/or does not lead to 
death or hospitalisation. However, if it is established that the event may jeopardise the patient 
and/or require an intervention in order to avoid the outcomes outlined above, the medically 
important event must be reported as serious.  
For example, this category of medically important events would include allergic bronchospasm 
requiring intensive care in the emergency department or at home, blood dyscrasias, convulsions that 
do not lead to hospitalisation, or even the development of dependence on a medication or abuse of 
a medication. 
Moreover, any suspected transmission of an infectious agent, whether pathogenic or not, by a 
Pfizer/Novartis product is considered to be a serious adverse event. This kind of event may be 
suspected based on clinical symptoms or examination results indicating an infection in a patient 
exposed to a Pfizer/Novartis product. The terms “suspected transmission” and “transmission” are 
considered to be synonyms. 
These cases are considered to be unexpected and must be managed as serious cases by the 
Pfizer/Novartis Pharmacovigilance departments. These cases may also be reported as a product 
defect, if applicable. 
 
Hospitalisation 
Hospitalisation is defined as any initial admission (even one lasting under 24 hours) in a healthcare 
establishment or any prolongation to an admission. 
An admission also includes a transfer within the hospital to an intensive care unit (for example, from 
the psychiatric ward to a medical ward, from a medical ward to a coronary intensive care unit, from 
the neurology ward to a tuberculosis care unit). 
Attending the emergency department does not necessarily constitute a hospitalisation; however, an 
event that leads to an attendance at the emergency department must be considered to be medically 
important. 
A hospitalisation in the absence of an adverse event does not constitute an adverse event in itself 
and does not need to be declared. For example, the following reasons for hospitalisation without AE 
do not need to be declared:  
• 
Social admission (for example, the patient has no accommodation) 
• 
Administrative admission (for example, for an annual examination) 
• 
Elective admission with no causative AE (for example, for a scheduled cosmetic surgery 
intervention) 
• 
Hospitalisation for observation in the absence of an AE  

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• 
Admission for treatment of a pre-existing condition that is not associated with either the 
development of a new AE or with the pre-existing condition worsening (for example, for 
assessment further to persistent abnormal results on laboratory tests that pre-date the 
treatment) 
• 
Admission scheduled in the protocol during the clinical study (for example, for an act that is 
required by the study protocol) 
Situations that must be declared to the Pfizer and Novartis Pharmacovigilance Departments within 
24 hours during pregnancy and following the same guidelines as for an adverse event in the other 
situations (except when the criteria for a serious adverse event are met, in which case it must be 
declared within 24 hours). 
These are situations involving exposure to a medication, including exposure during pregnancy via the 
mother or father with or without the outcome being known, exposure during breastfeeding, 
medication errors, dispensing errors, medication administration errors or accidental exposure to a 
medication, overdose, misuse, abuse, interaction with another medication or a food, lack of efficacy, 
off-label use, withdrawal or rebound symptoms, extravasation and occupational exposure. Some of 
these situations are described below. 
 
 

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Exposure during pregnancy (or prenatal exposure) 
Exposure during pregnancy occurs if: 
1. A woman becomes pregnant or discovers she is pregnant while she is receiving or has been 
exposed to a study medication (for example, environmental exposure), or a woman becomes 
pregnant or discovers that she is pregnant after stopping and/or having been exposed to a study 
medication (maternal exposure); 
An example of environmental exposure would be a case in which a pregnant woman had direct 
contact with a study medication (for example, a nurse reporting that she is pregnant and has 
been exposed to chemotherapy products). 
2. A man has been exposed to a study medication, either as part of treatment or by environmental 
exposure, before or around the time of conception and/or he has been exposed during his partner’s 
pregnancy (paternal exposure). 
As a general rule, cases of prospective and retrospective exposure during pregnancy, irrespective of 
the source, need to be declared whether there is an associated adverse event or not, following the 
reporting procedure for serious adverse events. 
If a female patient in the study or the female partner of a male patient in the study becomes 
pregnant or discovers she is pregnant during treatment with the study medication, the investigator 
must declare this information to the Pfizer/Novartis Pharmacovigilance Departments, whether or not 
this has resulted in an adverse event, and complete the non-interventional studies adverse event 
monitoring form and also the “Exposure during pregnancy” form. 
Furthermore, information relating to the environmental exposure to a study medication of a 
pregnant woman (for example, a patient reports that she is pregnant and she has been exposed to a 
cytotoxic product by inhalation or after accidentally spilling it) must be declared to the 
Pfizer/Novartis Pharmacovigilance Departments, whether or not this has resulted in an adverse 
event, by completing the non-interventional studies adverse event monitoring form and also the 
“Exposure during pregnancy” form. 
The information sent must include the predicted date at which the pregnancy will reach full-term 
(see below for information concerning the term of pregnancy). 
Follow-up must be set up in order to obtain general information about the pregnancy. 
Furthermore, follow-up must be set up to obtain information about the outcome of the pregnancy in 
all cases that are subject to a notification of exposure during pregnancy for which the outcome is 
unknown.  
A pregnancy must be monitored until it reaches full term or until termination of the pregnancy (for 
example, elective termination of the pregnancy), and Pfizer/Novartis must be informed of the 
outcome.  
This information will be provided as a follow-up to the initial report of exposure during pregnancy. If 
the outcome is a birth, the newborn can be assessed at that point for anomalies or defects.  
If the pregnancy ends in termination, the reason must be specified and, if clinically possible, the 
foetus must be assessed for anomalies or defects by means of a visual inspection (unless the results 

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of tests carried out before the procedure have led to the conclusion of a congenital anomaly and the 
results have been declared). 
If the outcome of the pregnancy meets the criteria for an SAE (for example, an extra-uterine 
pregnancy, spontaneous abortion, intrauterine foetal death, neonatal death or congenital anomaly 
[in a live birth, aborted foetus, intrauterine foetal death or neonatal death]), the procedures for 
declaring an SAE must be followed. 
Additional information on pregnancy outcomes that must be reported as SAE:  
• 
Spontaneous abortion includes miscarriage and missed miscarriage; 
• 
Neonatal deaths that occur in the months following the birth must be declared, regardless 
of the cause, as SAE. Furthermore, the death of a young infant aged over 1 month must be 
declared as an SAE when the investigator deems that the death of the young infant is linked 
or possibly linked to exposure to the study medication. 
Additional information on the exposure during pregnancy may be requested. Monitoring of cases in 
which the outcome is birth will be treated on a case by case basis (for example, monitoring of infants 
born pre-term in order to identify any developmental delays). 
In cases of paternal exposure, an information form for pregnant partners will be given to the patient 
participating in the study for his partner. It must be documented that this form has been given to the 
patient participating in the study to be passed on to his partner. 
 
Exposure during breastfeeding 
Cases of exposure during breastfeeding must be reported, regardless of whether there is an 
associated AE. 
A notification of exposure during breastfeeding must not be submitted when a Pfizer/Novartis 
product is specifically indicated for use in breastfeeding women (e.g. vitamins) and it has been 
administered in line with the MA. 
However, if the baby presents with an associated AE on administration of such a product, the AE 
must be declared as exposure during breastfeeding. 
 
Medication error 
A medication error is understood to be any unintended error in prescription, dispensing or 
administration of a medication that may lead to inappropriate medication use or patient harm while 
the medication is in the control of a healthcare professional, patient or consumer. Such events may 
be related to professional practice, healthcare products, or procedures and systems, including: 
prescribing, order communication, product labelling, packaging and nomenclature, compounding, 
dispensing, distribution, administration, education, monitoring and use.  
Medication errors include: 
• 
Near-misses, whether or not these involve a patient directly (for example, inadvertent or 
mistaken administration, which is the accidental use of the product outside of its 
indication or prescription by a healthcare professional or a patient/consumer) 
• 
Confusion concerning the name of a product (for example, trade name, brand name). 

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The investigator must declare the following medication errors to the Pfizer/Novartis 
Pharmacovigilance Departments, regardless of whether there is an associated AE/SAE: 
• 
Medication errors involving patient exposure to the product, regardless of whether the 
medication error is accompanied by an adverse event or not. 
• 
Medication errors that do not directly involve a patient (for example, potential 
medication errors or near-misses). When a medication error does not involve patient 
exposure to the product, the following are the minimum criteria for a case of medication 
error: 
- 
Identifiable notifier 
- 
Suspected product 
- 
Medication error 
 
Overdose, Misuse, Extravasation 
Cases of overdose, misuse and extravasation associated with the use of a Pfizer/Novartis product 
must be declared to the Pfizer/Novartis Pharmacovigilance Departments by the investigator, 
regardless of whether there is an associated AE/SAE or not. 
 
Lack of efficacy 
Cases of lack of efficacy of a Pfizer/Novartis product must be declared to the Pfizer/Novartis 
Pharmacovigilance Departments by the investigator, regardless of whether there is an associated 
AE/SAE or not; or indication for a Pfizer/Novartis product. 
 
Occupational exposure 
Cases of occupational exposure to a Pfizer/Novartis product must be declared to the Pfizer/Novartis 
Pharmacovigilance departments by the investigator, regardless of whether there is an associated 
AE/SAE or not. 
The serious or non-serious adverse event monitoring form must be sent by fax within 24 hours to the 
Novartis Pharmacovigilance Department on the following number: 01 55 47 68 00 or to the Pfizer 
Pharmacovigilance Department on the following number: 01 70 74 57 33. 
 
As part of the enhanced monitoring of specific risks as defined in the Risk Management Plans for 
AFINITOR (Afinitor RMP, V 9/8) and for SUTENT (SUTENT RMP V14.0) respectively, the 
Novartis/Pfizer Pharmacovigilance Departments may need to send to the doctor or to any other 
involved healthcare professional a targeted questionnaire about these events and this will need to 
be returned to the Novartis/Pfizer Pharmacovigilance Department once it has been completed.  
 
Collection and declaration of adverse events to Pharmacovigilance departments – Retrospective 
data  
This protocol also requires the investigator (or an individual under the investigator’s responsibility) to 
carry out a review of so-called “unstructured” patient data: unstructured data is medical data, 
including written or visual descriptions of medical information such as medical files, doctors’ notes, 
neurological tests, radiography, or “comments” fields in a database.  

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The person in charge of this review must enter on the electronic CRF all serious and non-serious 
adverse events (AE) that are clearly related to a Pfizer medication or to Everolimus that may appear 
in the data that are reviewed (defined by patient population and by the specific study phase of the 
protocol), if they meet the conditions for retrospective declaration of (S)AE as defined in § 5.2.2 of 
the protocol, i.e.: 
 If the treatment ongoing at enrolment is Everolimus, enter the following in the electronic 
CRF so that the CRO in charge of the study can submit a declaration to the 
Pharmacovigilance departments:  
- (S)AE(s) clearly related to Everolimus that occurred between starting Everolimus and 
enrolment. 
- (S)AE(s) clearly related to a Pfizer product that occurred between starting the first line 
treatment for the illness and enrolment 
 For all other treatments ongoing at enrolment (Sunitinib, chemotherapy, somatostatin 
analogues, radionuclide therapy or interferon alpha), retrospective declaration in the 
electronic CRF is required, so that the CRO in charge of the study can submit a declaration to 
the Pfizer Pharmacovigilance Department, in the following cases:  
 
- (S)AE(s) clearly related to a Pfizer product that occurred between starting the first 
treatment line for the illness and enrolment. 
The temporal relationship between administration of the medication and the adverse event cannot 
be used as the basis for a judgement of whether the event can be attributed to the medication, and 
instead this must be founded on a health professional making an unquestionable determination of 
causality that will establish a link between the medication and the AE. 
All serious and non-serious adverse events as well as specific situations that need to be declared to 
the pharmacovigilance departments that are identified based on the data examined must, if they 
meet the conditions for retrospective declaration of (S)AE, be recorded in the electronic CRF.  
These events will be declared to the Pharmacovigilance Departments of Pfizer and Novartis directly 
via the eCRF (there is no need for any additional submission) using the NIS AEM Report Form and 
following the requirements applicable to the reporting of adverse events to the pharmacovigilance 
departments concerned: 
• All serious and non-serious adverse events must be declared to the Pharmacovigilance 
Departments concerned as follows:  
- Serious and non-serious adverse events clearly related to a Pfizer medication will be reported 
to the Pfizer Pharmacovigilance Department by the CRO within 24 hours of the event coming 
to light (entered on the electronic CRF by the investigating site)  
- Serious and non-serious adverse events clearly related to everolimus will be reported to the 
Novartis Pharmacovigilance Department by the CRO within 24 hours of the event coming to 
light (entered on the electronic CRF by the investigating site)  
  
•  Situations involving exposure during pregnancy via the mother or father in which the outcome is 
unknown must be declared to the Pharmacovigilance Departments within 24 hours of the event 
coming to light: 

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- For exposure to a Pfizer product: report to Pfizer Pharmacovigilance Department  
- For exposure to everolimus: report to Novartis Pharmacovigilance Department  
• Situations concerning exposure during breastfeeding, medication errors, dispensing errors, 
medication administration errors or accidental exposure to a medication, overdose, misuse, 
abuse, interaction with another medication or food, lack of efficacy, off-label use, withdrawal or 
rebound symptoms, extravasation or occupational exposure associated with the use of a Pfizer 
product or everolimus must be declared to the Pharmacovigilance Departments concerned as 
follows:  
- All situations associated with use of a Pfizer medication will be reported to the Pfizer 
Pharmacovigilance Department within 24 hours of the situation coming to light  
- All situations associated with use of everolimus will be reported to the Novartis 
Pharmacovigilance Department within 24 hours of the situation coming to light  
 
For adverse events clearly related to or associated with the use of a Pfizer product/everolimus, the 
data entered in the medical file will constitute all of the known clinical information concerning these 
adverse events. There will be no follow-up concerning these adverse events. 
 
All members of staff at the CRO in charge of monitoring the study must meet the requirements of 
Pfizer and Novartis in terms of training in: “Your Reporting Responsibilities: Monitoring the Safety, 
Performance and Quality of Pfizer Products (Multiple Languages)” (Pfizer) and 5 P training, which is 
validated through a specific test in “Management of local interventional studies - DVL.OC.P.0002 
(Novartis)” as well as any other additional training deemed to be useful. This training will be provided 
to all CRO staff before the study begins. All training will include a "certificate of training" (signed by 
the person trained) as confirmation, and this must be kept in an accessible format. Copies of all 
signed training certificates must be provided to Pfizer and to Novartis.  
 
 
8. 
Data Processing 
8.1. 
Determining the sample size 
Calculating how many patients to include 
The calculation of the number of patients needed is based on the primary objective of describing 
morbidity and mortality evaluated specifically in terms of progression-free survival and overall 
survival. 
The calculation is based on the expected precision of the estimate of median survival (confidence 
interval).  
An estimate of the variance of S(t) (Kaplan Meier estimator) is given using Greenwood's formula: 
 
 

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While the study is ongoing, the original documents will be stored at the premises of the specialised 
service provider under contract to Novartis Pharma and Pfizer, and will only be accessible to 
authorised persons. They will then be sorted into archiving boxes and sent directly to the company in 
charge of archiving for Novartis Pharma and Pfizer. 
 
8.2.1. 
Case report form and data collection 
Where the term is used in this protocol, CRF (Case Report Form) must be understood as 
referring to a hard copy or electronic copy of data, or both, depending on the method of 
data collected used in the study. 
In this study, the data of interest will be recorded in a case report form in electronic format 
(e-CRF). 
A CRF is required and must be completed for each enrolled patient. The original and duly 
completed CRF are the sole property of the Sponsors and must not be disclosed to any third 
parties, irrespective of their nature, with the exception of representatives authorised by the 
Sponsors or competent regulatory authorities, without the written authorisation of the 
Sponsors. The participating doctor must ensure that the CRF are stored securely on the 
study site in an encrypted electronic form and/or hard copy and will be password protected 
or kept safely in a locked room in order to ensure they are not accessed by unauthorised 
third parties. 
The participating doctor has ultimate responsibility for the collection and notification of all 
clinical, safety and laboratory test data entered on the e-CRF and any other data collection 
resource (source documents), and for ensuring the data is correct, authentic, original, 
unquestionable, complete, consistent, legible and available (if necessary).  
The CRF must be signed by the participating doctor or by an authorised staff member in 
order to guarantee the authenticity of the data entered on the CRF. All corrections made to 
the data entered on the CRF or source documents must be dated, initialled and explained (if 
necessary) and must not mask the original entry. 
In the majority of cases, the source documents are the hospital or doctor’s records. In these 
cases, the data collected in the CRF must correspond to the data in these records. 
In some cases, the CRF may also be the source document. In these cases, a document 
available on-site and from the Sponsors must clearly identify the data that have been 
recorded in the CRF, and for which data the CRF is the source document. 
8.2.2. 
Data retention 
In order to allow the regulatory authorities or Sponsors to perform evaluations and/or 
inspections/audits, the investigator agrees to retain the records, including the identities of 
all participating patients (sufficient information to make the link with the records, for 
example the CRF and hospital records), all original signed informed consent forms, copies of 
all CRF, pharmacovigilance notification forms, source documents, detailed records of 
treatment distribution and sufficient documentation of relevant correspondence (for 
example, letters, minutes of meetings and records of telephone calls). These records must 
be kept by the participating doctor in line with local regulations or in accordance with the 
specifications in the study contract, whichever is the longer.  

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The participating doctor must ensure that the records continue to be stored securely for as 
long as he/she is required to be retain them. 
If the participating doctor is no longer able to retain the study records for the required 
period for any reason whatsoever (for example: retirement, relocation), the participating 
doctor must inform the Sponsors. The study records must be transferred to a designated 
person with the prior approval of the Sponsors, such as another participating doctor, 
another institution or an independent third party designated by the Sponsors.  
The participating doctor's records must be retained for a minimum of 15 years after the end 
of the study (last visit of last patient) or interruption to it or for longer if required by local 
regulations. The participating doctor must obtain prior written authorisation from the 
Sponsors to disclose any records, even if the retention requirements have been met. 
 
8.3. 
Statistical analysis 
The statistical analysis plan will be set out by the service provider instructed by Novartis Pharma and 
Pfizer and it will be validated with the members of the scientific committee before analysis begins. 
8.3.1. 
Population and variables analysed 
8.3.1.1. 
Analysis methods 
The software SAS® (version 9.1 or later, SAS Institute, North Carolina USA) will be used for the 
analysis. 
The descriptive analysis of the qualitative and ordinal variables will consist of the number and 
frequency of each category with a confidence interval of 95%, and the number of missing data. The 
quantitative variables will be described in terms of totals, mean and median, standard deviation, 
confidence interval and the number of missing data.  
The overall survival and progression-free survival data will be described using Kaplan Meier curves. 
Median survival will be estimated and presented with a CI 95%. 
As far as possible, graphic representations will be presented with the results of the analyses. 
The association measures between two variables (univariate analyses other than comparisons of the 
sub-groups of interest) will use the usual methods.  The association between two qualitative 
variables will be measured using Pearson’s chi-squared test. If a condition for validity is not met, the 
correction for continuity will be used (Yates chi-squared test) as long as there is a logical possibility of 
regrouping the categories. The mean values of the quantitative variables will be compared using 
Student’s t-test with and without the hypothesis of equal variance. The equality of variance will be 
estimated using Levène's test and a diagnosis of normality will be assessed based on the appearance 
of histograms and Shapiro-Wilk test results.  
The total number of missing values for each variable analysed will be given in the results table. The 
key data will be set as compulsory fields in the electronic CRF in order to manage the proportion of 
missing data, and if necessary imputation techniques will be used. 

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8.3.1.2. 
Representativeness of doctor and patient samples 
The participating doctors will be described. Comparisons will be made between doctors who have 
participated actively in the study (included at least one patient) and doctors who were not active or 
who refused to participate. Patients who are lost to follow-up during the study (who leave the study 
with no information on whether or not treatment was continued or on death) will be compared to 
the patients who are monitored until the event date (progression, death or end of treatment) or the 
end date of 2 years. 
 
8.3.2. 
Analysis of the objectives 
8.3.2.1. 
Analysis of the primary objective 
The primary objective of this observational study is to describe the real-world outcomes of adult 
patients treated (with targeted therapies and other treatments) for a well-differentiated 
unresectable or metastatic progressive pancreatic neuroendocrine tumour in terms of morbidity and 
mortality at 2 years. 
The following parameters will be assessed in order to meet this objective: 
• 
Rate of progression-free survival at 2 years. Progression-free survival is defined as the time 
between the start of treatment (of the treatment line ongoing at the time the patient was 
enrolled in the study) and the date of the first documented disease progression or death, 
irrespective of the cause. 
• 
Rate of overall survival at 2 years. Overall survival is defined as the time between the start of 
treatment (of the treatment line ongoing at the time the patient was enrolled in the study) 
and death, irrespective of the cause. 
 
Progression-free survival and overall survival will be estimated using the Kaplan-Meier method. The 
survival S(t) function will be the probability that the event of interest (progression or death 
respectively) does not occur before the date t. This function will be represented in a graph using a 
survival curve that will include 95% confidence intervals, estimated using Rothman’s formula.  
Survival until progression will be estimated taking into account the date of initiation (of the 
treatment line ongoing at enrolment of the patient) of the targeted therapy or other treatment (as 
defined in this study) and the event date, i.e. the date of progression or of death. Patients with no 
event or who are lost to follow-up will be censored at the last date they are known to be alive. 
Overall survival will be estimated considering the date of origin to be the date of initiation (of the 
treatment line ongoing at enrolment of the patient) of the targeted therapy or other treatment, and 
the event date to be the date of death. Patients with no event or who are lost to follow-up or alive at 
the end of the study will be censored at the last date they are known to be alive.  
 
 
These survival rates will be estimated and presented for each of the groups of interest: 
- 
Targeted therapy group (with an estimate for the everolimus and sunitinib sub-groups) 

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- 
Other treatments group (with estimates for the sub-groups if there are sufficient total 
numbers) 
 
It is important to note that statistical comparisons in the strictest sense between the different 
treatment groups in this observational study are not appropriate due to the expected bias and 
because the groups are not comparable at enrolment (treatments not assigned randomly). If, 
however, comparisons are envisaged, a multivariate Cox model will be used in order to adjust for 
patient characteristics that may potentially be associated with the type of treatment received and 
survival and that could be liable to skew the estimates (confounding factors, effect modification). 
• 
Safety of the treatments (targeted therapies and other treatments) during the prospective 
phase of the study, defined by instances of treatment discontinuation and the reasons for 
this, adverse events (graded according to the ‘Common Terminology Criteria for Adverse 
Events’ (CTCAE) version 4.0 of May 2009), and any complications of adverse events. 
The proportion of patients for whom adverse events are reported (total proportion and proportion 
reporting grades 3 or 4 adverse events) will be estimated as well as the proportion who stop 
treatment due to an inability to tolerate it. 
 
8.3.2.2. 
Analysis of secondary objectives 
The analysis of secondary objectives will be purely descriptive and will use the usual methods as set 
out in 7.3.1.1. It will be presented in detail in the final statistical analysis plan. 
 
9. 
Limitations of the study 
This protocol has been set out in a way that best meets the objectives set for this observational study 
and to respond to the request from HAS. However, it does have some limitations that must be 
discussed and that will need to be taken into account when the study is implemented and the results 
are being used. 
9.1. 
Selection bias 
It is fundamental that the study sample should be as representative as possible of the target 
population in order for the study results to be able to be extrapolated to the target population. The 
representativeness of the sample depends on internal validity (precision of estimates and selection 
criteria for the study population – the patients) and on external validity (plan and sampling 
fluctuation).  
9.1.1. 
Representativeness of enrolled patients 
Once again there is a potential selection bias in observational studies. It is inevitable that patients 
will be consciously selected for or excluded from enrolment by doctors. Participating doctors will be 
asked to include the first patients that meet the eligibility criteria in a sequential and exhaustive 
manner until the numbers for each sub-group have been reached (targeted therapies group, other 
treatments group) and the total number for the study at a national level, in order to reduce this bias. 

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In order to ensure that inclusion adheres to this consecutive pattern, a non-inclusion register 
(appendix 2) will be set up. Eligible patients who are not included in the study must be recorded in 
this register throughout the inclusion phase and/or until the expected number of patients has been 
reached. Only minimal characteristics will be recorded: sex, year of birth, ECOG performance status 
and reason for non-inclusion. 
Moreover, it will be important to enrol in this study patients participating in clinical trials (under 
certain conditions set out in section 4.1.1) since the follow-up bias this could entail (connected to the 
schedule and terms of follow-up imposed by the trial) will have less impact than selection bias, which 
could lead to this study only including patients who are not eligible for clinical trials.  
A decision has also been made to restrict the inclusion of patients by excluding all patients who have 
received 5 or more lines of treatment. The reason for this is that, although this criterion restricts and 
filters the study population, it will allow the sample of patients treated for pNET that we wish to 
assess in this study to be standardised as far as possible. In fact, pNET patients have often received 
very different sequences/lines of treatment because there is no validated sequence. By standardising 
the sample, we will therefore ensure that the descriptions for the treatment sub-groups are valid 
and if appropriate, based on these previous treatment lines. 
9.1.2. 
Patients lost to follow up during the study 
There will be a particular focus on patients who leave the study, or who the investigator does not see 
again for a visit due to the observational nature of the study (the frequency of visits for patient 
follow-up can vary from one doctor to another). For patients who are lost to follow-up, a last 
visit/anticipated end of study questionnaire will be completed by the investigator. The statistical 
analyses will compare the characteristics of the enrolled patients who participate in the whole 
duration of the study with the enrolled patients who were later lost to follow-up and/or left the 
study. 
9.1.3. 
Left truncation and left censoring 
For prevalent case patients who have started their current treatment before enrolment in the study, 
there is left truncation bias due to the fact that it is impossible to include deceased patients in the 
study. Prevalent case patients all lead to left censoring bias due to the absence of retrospectively 
recorded tumour assessments. 
These types of bias will be taken into account in the analysis of overall survival and progression-free 
survival through use of a statistical method that will be detailed in the statistical analysis plan. 
  
9.2. 
Measurement bias 
On the face of it, there should be minimal measurement bias, especially since the objectives are 
basically descriptive and the patients will be included and data collected prospectively. However, 
there may be measurement bias for the patients who have started treatment (targeted therapy or 
other treatment) before inclusion in the study. The reason for this is that for these patients’ data will 
be collected retrospectively up to the date that the current treatment line was started where the 
primary objectives of estimating progression-free survival and overall survival rates are concerned. 
Nonetheless, the information collected (progression/response, current treatment) are key data in 
the monitoring of the patient and must be logged in the patients’ records. Furthermore, the specific 

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retrospective data collected concerning response and treatment will only include the treatment line 
ongoing at enrolment. This is because the only information required about any previous treatment 
lines is the number of lines and the corresponding treatment regimens (not detailed). 
The estimate of progression-free survival will be less accurate than if it were from a clinical trial 
because of the intervals between assessment visits, which follow real-world practices and are 
scheduled less frequently than in clinical trials. Equally, the assessment of progression/response will 
be based on the investigator’s judgement (which will be based on the RECIST criteria). 
 
9.3. 
Missing data 
Data will be recorded on the electronic CRF. Use of this tool will mean that missing data is minimised 
in the first place because it consists of drop-down lists and compulsory fields, validated by the 
Scientific Committee. 
Furthermore, the approach to managing missing data, which is especially important in the context of 
longitudinal studies, will be discussed and methodology will be validated in the analysis plan. 
 
9.4. 
Confounding factors 
Confounding by indication is expected in this observational study in which a treatment is chosen 
from a number of possible options and not at random; instead it is selected by the investigator based 
on the characteristics of the patient, their illness and their previous treatments. A statistical 
comparison in the strictest sense of the impact of treatments for pNET in terms of morbidity and 
mortality is not appropriate in this study since there is a high exposure to confounding factors. It is 
for this reason that the study has been designed to describe the impact on morbidity and mortality in 
each treatment group (targeted therapies, other treatments) independently.  
If, however, comparisons are envisaged, a multivariate Cox model will be used in order to adjust for 
patient characteristics that may potentially be associated with the type of treatment received and 
survival and that could be liable to skew the estimates (confounding factors, effect modification). 
 
9.5. 
Study size 
Pancreatic neuroendocrine tumours are an orphan disease. The target population is estimated at 150 
patients per year. In this study, the calculation of study size must find a balance between the 
statistical calculations and the feasibility of the study. Therefore, according to the data available, a 
total of 150 patients enrolled over a period of around 2 years seems to be a realistic target. The 
inclusion of 150 patients in total would allow the median survival (progression-free or overall) to be 
estimated with a precision of around 8%. It should be noted that in the analyses of the sub-groups 
(targeted therapies, other treatments) the median will be estimated with less precision since the 
total numbers in each stratum will be lower.  
It is also important to emphasise that these simulated calculations (beyond taking into account the 
practical and real feasibility of recruiting patients) are based on the primary objective of describing 
morbidity and mortality evaluated specifically through progression-free survival and overall survival. 
The calculations have not been carried out with the objective of drawing a comparison. This is 
because the population size needed for a statistically significant comparison based on, for example, 

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the criterion of mortality, would take over 6 years of recruitment to reach (if 4 treatment groups 
were compared, with the hypothesis of a 20% relative reduction in mortality, and 250 patients 
needed per group, so 1000 patients) given that the target population is estimated at 150 patients per 
year.  
 
10. 
Schedule of the study 
The study is scheduled to be set up once the necessary regulatory approvals have been obtained, 
which will be September 2014 at the earliest.  
All of the patients recruited by sub-group (targeted therapies and other treatments) and by type of 
treatment for the targeted therapies group (everolimus and sunitinib) will be monitored by the 
specialised service provider under contract to Novartis Pharma and Pfizer. 
 
As stipulated in paragraph 10 “Schedule of the study” of version 11 of the protocol dating from 1st 
July 2016, if at the end of the two years of the inclusion phase the total population has not been 
reached or if the recruitment target of one of the sub-groups has not been reached, the Scientific 
Committee will be asked to decide whether recruitment for the study should continue or not, and 
how it should be carried out. 
On 20th April 2017 (3 weeks before the end of the 2-year inclusion phase), neither the total target 
population nor the sub-group target had been reached and they would not be reached by 12th May 
2017 (end date of the 2-year inclusion phase).  
As a result, on 24th April 2017, there was a meeting between the Scientific Committee and the 
pharmaceutical companies Pfizer and Novartis. After a reminder of the context, the timelines and the 
progress report of the study, the scientific committee agreed that the target of including a total of 
150 patients was feasible and realistic. A decision was therefore made firstly to extend the 
recruitment phase until 15th September 2017 and secondly that there would be no further extension 
after that date. 
If the total recruitment target (150 patients) and the cohort recruitment targets for the “other 
treatments” (at least 75 patients) and “targeted therapies” groups (at least 35 patients on 
everolimus and 35 patients on sunitinib) were reached before 15th September 2017, inclusions 
would be stopped.  
 
11. 
Regulatory considerations 
 
This study does not fall under the scope of French law n° 2006-450 of 18th April 2006 concerning 
research or law n° 2004-806 of 9th August 2004 article 88 chapter II article L1121-1 so there is no 
requirement to submit the plan to the Agence Nationale de Sécurité du Médicament et des produits 
de santé (ANSM, French national agency for the safety of medicines and healthcare products), or to 
an Ethics Committee (EC). 
Ruling n° 2016-800 of 16th June 2016 concerning research involving human subjects states in article 
8 that studies properly declared or authorised by the date at which the implementation decree (of 
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force could continue for five years in accordance with the legislation that was initially applicable to 
them. 
At the end of this 5-year period, they would need to be assessed again by an Ethics Committee and, if 
necessary, by ANSM under conditions set out in the French public health code. 
The OPALINE study received an opinion before 16th November 2016 and will end within the 5-year 
period set out above, meaning that substantial amendments to this study are not within the 
jurisdiction of an Ethics Committee and these will be managed in accordance with the applicable 
texts. 
 
11.1. 
Declaration to the CNOM (French doctors’ professional association) 
Since doctors participating in this study are remunerated, the study protocol and the participating 
doctors’ financial contract will be submitted for an opinion to the Conseil National de l’Ordre des 
Médecins (CNOM; article L.4113-6 of the French public health code) by Novartis Pharma and Pfizer. 
Novartis Pharma and Pfizer will also submit the financial contracts for the members of the Scientific 
Committee to CNOM for an opinion. 
Each participating doctor will receive a copy of the contract along with a letter from Novartis Pharma 
and Pfizer stipulating that the financial contract has been submitted to CNOM and since the 
timeframe of 2 months has expired, the opinion from CNOM is deemed to be favourable. A copy of 
this letter will need to be sent to each doctor's regional branch of CNOM along with a copy of the 
financial contract (articles L.4113-9, L.4113-10, L.4163-10 of the French public health code). 
11.2. 
Financial agreement 
The doctors participating in the study commit to following the protocol as it is written. 
This is a contractual agreement and a financial agreement is submitted by Novartis Pharma and 
Pfizer before a doctor agrees to participate. This agreement sets out the planned remuneration for 
participating doctors. 
11.3. 
Declarations to the CCTIRS (French consultative committee on data 
processing in healthcare research) and the CNIL (French data protection 
commission) 
Since this study requires personal data to be collected for the purposes of research in the field of 
healthcare, it comes under the scope of chapter IX of the French data protection law of 6th January 
1978, amended. It has been submitted to the Comité consultatif sur le traitement de l’information en 
matière de recherche dans le domaine de la santé (CCTIRS, consultative committee on data 
processing in healthcare research) for an opinion and to the Commission Nationale Informatique et 
Libertés (CNIL, French data protection commission) to request authorisation. 
Since this study is no longer the jurisdiction of CCTIRS as of 5th May 2017, the date when the ruling 
was made concerning the creation of the Comité d’Expertise pour les Recherches, les Etudes et les 
Evaluations dans le domaine de la Santé (CEREES, French Committee for expertise in research, 
studies and assessments in the field of healthcare) in line with French law n° 2016-41 concerning 
modernisation of the healthcare system of 26th January 2016 and the implementation decree of 

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Jardé’s law n° 2016-1537 of 16th November 2016, the departments of the ministry for research no 
longer have jurisdiction over analysing corrections made to research studies. 
However, in accordance with French data protection law 78-17 of 6th January 1978, amended by law 
2004-801 of 6th August 2004 concerning the protection of private persons with regard to their 
personal data, the protocol has been assessed for compliance with a reference methodology, and the 
Sponsors have made a subsequent declaration of compliance to CNIL.  
This means that the data collected will correspond strictly to the field of application of the CNIL 
reference methodology MR-003 and the Sponsors commit to following this methodology, which will 
be added to the study documents. 
The use of indirectly nominative data (patients identified by a number following the order of entry 
into the study) is justified because there will be a need to send requests for additional information to 
the participating doctors after the questionnaires have been received and entered in order to 
guarantee the quality of the data, and if checks are needed in the event of a dispute on 
computerisation of the data, the investigator will be able to identify patients from whom data needs 
to be collected at a later stage. 
The doctors will have to fill in and keep a correlation table so that they can return to the patient’s file 
by their entry number in the study and respond to these requests.  
Under the French data protection law of 6th January 1978, amended, the patient will be informed of 
his/her right to access, object to and seek corrections to data recorded as part of this study, and that 
this right may be exercised at any time through his/her doctor. 
Nominative information concerning the participating doctors will be declared and the doctors will be 
informed in the financial agreement of their rights to access, object to and seek corrections to this 
information. 
11.4. 
Document for the patient  
In accordance with French data protection law of 6th January 1978, amended, the patient will be 
informed in writing of the nature and objective of the study, as well as his/her right to access, object 
to and seek corrections to the data collected as part of this study (see Appendix 1: Patient 
information). 
11.4.1. Patient information 
All parties will comply with the legislation in force, in particular through the implementation 
of organisational and technical measures to ensure that patients’ personal data is protected. 
These measures will consist of the omission of patient names and other data that will allow 
them to be identified directly from all reports, publications and any other disclosures, with 
the exception of the requirements imposed by the legislation in force. 
Personal data will be stored at the study site (in an encrypted electronic form and/or hard 
copy) and will be password protected and/or kept securely in a room locked with a key in 
order to ensure that only authorised study staff can access them. Each participating site will 
put in place appropriate technical and organisational measures to ensure that personal data 
can be recovered in the event of a loss. In the event of a potential breach of personal data, 
the participating site will be responsible for determining whether this breach has actually 
occurred and, if so, to make such notifications as are required by law. 

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In order to protect the rights and freedoms of private persons with regard to their personal 
data, when the study data are compiled for submission to the Sponsors and other agreed 
parties, patient names will be removed and replaced with a unique and specific numeric 
code using a numbering system that will be defined by the Sponsors.  
All other data that allows patients to be identified that is to be sent to the Sponsors or to 
other agreed parties will be identified by this unique code that is specific to each patient. 
Each participating doctor’s site will keep a confidential list of patients that have participated 
in the study with a link between the numeric codes for each patient and their true identity.  
If the data is transferred, the Sponsors will ensure compliance with high levels of 
confidentiality and a protection of patients’ personal data, in accordance with the provisions 
of the study contract and the laws in force on the protection of privacy. 
11.4.2. Consent 
The consent forms and all material intended for patient recruitment must comply with local 
regulatory and legislative requirements, in particular the laws in force concerning the 
protection of privacy. 
The informed consent forms used for the process of obtaining informed consent and all 
materials for patient recruitment must be examined and approved by the Sponsors, 
approved by an Ethics Committee (EC) (if applicable) before they are used, and they must be 
available for inspection. 
The participating doctor must ensure that all patients in the study are fully informed about 
the nature and objectives of the study, how data connected to the study will be 
communicated and any risks associated with their participation, in particular the risks 
associated with the processing of patients’ personal data.  
The participating doctor must also ensure that all patients in the study are fully informed 
about their rights to access and correct their personal data, and to withdraw their consent 
for their personal data to be processed. 
The participating doctor, or a person designated by the participating doctor, will obtain the 
written informed consent of every patient before any action specifically connected to the 
study is carried out. The participating doctor will keep the original informed consent form of 
each of his/her patients. 
11.4.3. Early withdrawal of the patient 
Patients can withdraw from the study early at any time at their own request, or they can be 
excluded at any time at the discretion of the participating doctor or the sponsors for reasons 
of safety, behaviour or administrative issues. In all cases, every effort must be made to 
document the outcome of the patient, if possible. The participating doctor must ask about 
the reason for early withdrawal and any follow-up of all unresolved adverse events.   
If the patient withdraws from the study early, and also withdraws his/her consent for any 
future information to be disclosed, no further assessment may be carried out and no 

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additional data may be collected. The sponsors will be able to keep and continue to use all 
data collected before the patient withdrew his/her informed consent. 
 
11.5. 
Agreement with participating doctors 
This protocol will be presented to prospective participating doctors before they are asked to confirm 
whether they will participate. Participation will be confirmed by signing the financial agreement 
offered by Novartis Pharma and Pfizer. 
In accordance with article R.5120 of the French public health code, doctors and all persons invited to 
work on this study will be held under professional confidentiality with regard to the way the study is 
carried out, the people participating and the results obtained. Without the prior agreement of the 
sponsors, they may not give information about the study to anyone other than the Health 
Authorities. 
11.6. 
Archiving 
 
The study data collection forms will be archived in hard copy by Novartis Pharma and Pfizer for 15 
years. 
12. 
Final report and publication of the results 
An analysis report of the results will be sent to the participating doctors. 
The process for scientific publication of the results, and the authors participating in these 
publications and communications, will be defined by Novartis Pharma and Pfizer who will retain the 
copyright at an international level to all significant publications, including translations into other 
languages.  
The scientific committee will play a part in communicating the results of the study. Novartis Pharma 
and Pfizer also reserve the right to: 
- 
Use the study results for the purposes of any regulatory procedure, on their own behalf or 
on behalf of subsidiaries 
- 
Present the results in their medical information about medications 
- 
Distribute printed copies of publications 
Nobody may make use of these rights without the prior written agreement of Novartis Pharma and 
Pfizer. 
 
13. 
List of documents/Material issued to participating doctors 
The following documents will be issued to each participating doctor: 
- 
The financial agreement in triplicate (one for the regional branch of CNOM, one for Novartis 
Pharma and Pfizer, one for the doctor to keep) 
- 
The opinion from CNOM or in the event of a tacit favourable opinion, a copy of the letter 
stating that the financial agreement has been submitted to CNOM for approval and, if 

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applicable, all correspondence between CNOM and the pharmaceutical companies further to 
submission of the file 
- 
A copy of the scientific protocol 
- 
A study data collection form and an information letter (CNIL wording) and consent form for 
each patient recruited. 
 
 
 
 

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14. 
References 
 
1. 
Lepage C, Bouvier AM, Phelip JM, Hatem C, Vernet C, Faivre J. Incidence and management of 
malignant digestive endocrine tumours in a well defined French population. Gut. 2004;53(4):549 53. 
Epub 2004/03/16. 
2. 
Delaunoit T, Neczyporenko F, Rubin J, Erlichman C, Hobday TJ. Medical management of 
pancreatic neuroendocrine tumors. The American journal of gastroenterology. 2008;103(2):475 83; 
quiz 84. Epub 2007/11/22. 
3. 
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after 
"carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the 
United States. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2008;26(18):3063 72. Epub 2008/06/21. 
4. 
Yao JC, Phan AT, Jehl V, Shah G, Meric Bernstam F. Everolimus in advanced pancreatic 
neuroendocrine tumors: the clinical experience. Cancer research. 2013;73(5):1449 53. Epub 
2013/02/26. 
5. 
David M, Lepage C, Jouve JL, Jooste V, Chauvenet M, Faivre J, et al. Management and 
prognosis of pancreatic cancer over a 30 year period. British journal of cancer. 2009;101(2):215 8. 
Epub 2009/07/02. 
6. 
Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors 
(PNETs): incidence, prognosis and recent trend toward improved survival. Annals of oncology : 
official journal of the European Society for Medical Oncology / ESMO. 2008;19(10):1727 33. Epub 
2008/06/03. 
7. 
Hospices civils de Lyon, Institut de veille sanitaire, Institut national du cancer, Francim, 
Institut national de la santé et de la recherche médicale. Projections de l'incidence et de la mortalité 
par cancer en France en 2010. Rapport technique. 2010 [cited 2013]; Available from: 
http://www.invs.sante.fr/applications/cancers/projections2010/rapport projections nationales can
cer 2010.pdf. 
8. 
Vinik AI, Raymond E. Pancreatic neuroendocrine tumors: approach to treatment with focus 
on sunitinib. Therapeutic advances in gastroenterology. 2013;6(5):396 411. Epub 2013/09/05. 
9. 
Falconi M, Bartsch DK, Eriksson B, Kloppel G, Lopes JM, O'Connor JM, et al. ENETS Consensus 
Guidelines for the management of patients with digestive neuroendocrine neoplasms of the 
digestive system: well differentiated pancreatic non functioning tumors. Neuroendocrinology. 
2012;95(2):120 34. Epub 2012/01/21. 
10. 
Rindi G, Arnold R, Bosman F, Capella C, Klimstra D, Klöppel G, et al. Nomenclature and 
classification of neuroendocrine neplasms of the digestive system 
 WHO classification of tumours of the digestive system Bosman FT, Carneiro F, Hruban RH, Theise D, 
eds International Agency for Research Cancer 2010:13 142010. 
11. 
Lepage C, Rachet B, Coleman MP. Survival from malignant digestive endocrine tumors in 
England and Wales: a population based study. Gastroenterology. 2007;132(3):899 904. Epub 
2007/03/27. 
12. 
Bilimoria KY, Talamonti MS, Tomlinson JS, Stewart AK, Winchester DP, Ko CY, et al. 
Prognostic score predicting survival after resection of pancreatic neuroendocrine tumors: analysis of 
3851 patients. Annals of surgery. 2008;247(3):490 500. Epub 2008/04/01. 
13. 
Chanson P, Ducreux M. [Biotherapy of neuroendocrine tumors]. La Revue du praticien. 
2002;52(3):280 4. Epub 2002/04/03. Biotherapie des tumeurs neuro endocrines. 

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14. 
Ducreux M, Baudin E, Schlumberger M. [Treatment strategy of neuroendocrine tumors]. La 
Revue du praticien. 2002;52(3):290 6. Epub 2002/04/03. Strategie de traitement des tumeurs neuro
endocrines. 
15. 
Pavel M, Baudin E, Couvelard A, Krenning E, Oberg K, Steinmuller T, et al. ENETS Consensus 
Guidelines for the management of patients with liver and other distant metastases from 
neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 
2012;95(2):157 76. Epub 2012/01/21. 
16. 
Steinmuller T, Kianmanesh R, Falconi M, Scarpa A, Taal B, Kwekkeboom DJ, et al. Consensus 
guidelines for the management of patients with liver metastases from digestive (neuro)endocrine 
tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2008;87(1):47 62. 
Epub 2007/12/22. 
17. 
Delaunoit T, Ducreux M, Boige V, Dromain C, Sabourin JC, Duvillard P, et al. The doxorubicin
streptozotocin combination for the treatment of advanced well differentiated pancreatic endocrine 
carcinoma; a judicious option? European journal of cancer (Oxford, England : 1990). 2004;40(4):515
20. Epub 2004/02/14. 
18. 
Fjallskog ML, Granberg DP, Welin SL, Eriksson C, Oberg KE, Janson ET, et al. Treatment with 
cisplatin and etoposide in patients with neuroendocrine tumors. Cancer. 2001;92(5):1101 7. Epub 
2001/09/26. 
19. 
Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, doxorubicin, 
and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic 
endocrine carcinomas. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2004;22(23):4762 71. Epub 2004/12/01. 
20. 
Delbaldo C, Faivre S, Dreyer C, Raymond E. Sunitinib in advanced pancreatic neuroendocrine 
tumors: latest evidence and clinical potential. Therapeutic advances in medical oncology. 
2012;4(1):9 18. Epub 2012/01/10. 
21. 
Raymond E, Hammel P, Dreyer C, Maatescu C, Hentic O, Ruszniewski P, et al. Sunitinib in 
pancreatic neuroendocrine tumors. Targeted oncology. 2012;7(2):117 25. Epub 2012/06/05. 
22. 
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced 
pancreatic neuroendocrine tumors. The New England journal of medicine. 2011;364(6):514 23. Epub 
2011/02/11. 
23. 
Haute Autorité de Santé. Avis de la commission de la transparence SUTENT. 2011 [cited 
2013]; 
Available 
from: 
http://www.has sante.fr/portail/upload/docs/application/pdf/2011
10/sutent
ct 10136.pdf. 
24. 
Haute Autorité de Santé. Avis de la commission de la transparence AFINITOR. 2012 [cited 
2013]; 
Available 
from: 
http://www.has sante.fr/portail/upload/docs/application/pdf/2012
04/afinitor 28032012 avis ct11775.pdf. 
 
 

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15. 
APPENDICES 
15.1. 
APPENDIX 1: Information letter for the patient and consent form 
Document unchanged since version 9.3 of the protocol 
- PATIENT INFORMATION - 
Dear Sir/Madam, 
 
Your doctor is inviting you to participate in a national observational study in France that is being 
carried out in response to a request from the Health Authorities. This study, named Opaline, is being 
carried out for research purposes in patients with a neuroendocrine tumour of the pancreas. The aim 
of this study is to describe the care and outcome of adult patients in France who, like you, have a 
neuroendocrine tumour of the pancreas.  
Your doctor wishes to collect some information about your disease, treatments that you are 
receiving and have received in the past, and the safety of these treatments. The data that will be 
collected in this study will allow us to describe the care and outcome of your illness.  
These data will be taken from your medical records and will concern the following: 
- 
Demographic data and characteristics at the time of enrolment (medical history, treatments) 
- 
Imaging examinations (assessments of the tumour)  
- 
The outcome of your illness 
- 
Treatments 
- 
Side effects 
Your doctor will complete a questionnaire with your medical information when you are enrolled in 
the study and then again at each of your usual follow-up appointments for a period of two years. 
This study is not a clinical trial, which means that if you participate there will be no additional or 
different treatments or examinations from those that you receive or will have to receive as part of 
your usual care and there is no risk. If your doctor loses contact with you during the study, he/she 
may have to attempt to contact you by telephone, email, letter or another means. 
You are free to agree or refuse to participate in this study and this will have no effect on your 
continued medical care that your doctor provides. You can decide to stop participating at any time, 
and this will in no way influence the quality of the care that your doctor provides. Your role in this 
project will be to give your agreement to your doctor for him/her to complete the questionnaires. 
You will not need to do anything else.  
 
If you agree to participate:  
The study has been set up by the pharmaceutical companies Novartis and Pfizer in response to a 
request from the Health Authorities. As part of the process of entering the data, ensuring that the 
study is good quality and following the schedule, your doctor may entrust someone else who will be 
held to professional confidentiality with accessing your medical records and the collection of the 
medical data required by the protocol. The data collected are strictly confidential and only the 
medical team, persons duly instructed by the research sponsor or any other person invited to work 
on the study will be able to access them, and strictly for the purposes of the task assigned to them. 
Your medical data that are collected as part of this study will be processed by computer and sent to 
the pharmaceutical companies Novartis and Pfizer under conditions that will guarantee they remain 
secure and confidential. You will be identified in the files by a patient number and there will be no 
mention of your first name or surname.  
 

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If you refuse to participate:  
Your doctor will have to complete a document with some data about you: sex, year of birth, your 
general health. No other information about you will be recorded. You have the right to refuse to 
allow this minimal information to be recorded; simply inform your doctor. 
Your refusal to participate in the study will not have any impact on your usual medical follow-up. You 
will continue to receive care and follow-up as usual from your doctor.  
 
We thank you in advance for your cooperation with this epidemiological research and we remain at 
your disposal if you need any further information. 
 
The scientific committee and the medical team responsible for the Opaline study. 
 
PATIENT CONSENT 
 
I agree that the data recorded during this research may be subject to computerised processing by the 
pharmaceutical companies Novartis and Pfizer or their behalf. 
I am free to agree or refuse to participate in this observational study and this will have no effect on 
my continued medical care that my doctor provides. 
By adding my signature below, I agree voluntarily to participate in this observational study under the 
conditions set out in the information letter and I give the abovementioned parties direct access to 
my medical records. 
I have taken note that my right of access, as laid down in the law of 6th January 1978 relating to data 
protection (article 39), can be exercised at any time via the doctor who is treating me as part of this 
research and who knows my identity. I will be able to exercise my right to seek corrections and to 
object through this same doctor. 
I will receive a signed copy of the information letter.  
 
PATIENT 
 
(Section to be completed by the patient) 
 
 
SURNAME:……………………………………………………… 
FIRST NAME:……………………………………………….. 
DATE:……………………………………………………. 
SIGNATURE:…………………………………………... 
 
INVESTIGATING DOCTOR 
 
(Section to be completed by the doctor 
obtaining consent) 
 
SURNAME:……………………………………………………… 
FIRST NAME:……………………………………………….. 
DATE:……………………………………………………. 
SIGNATURE:…………………………………………... 
 
 
 
 

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15.2. 
APPENDIX 2: Non-Inclusion Register 
Document amended in version 13 of the protocol 
 
 
 
Non-Inclusion Register 
Version 15 of 17th July 2018 
 
 
 
OBJECTIVES OF THE NON-INCLUSION REGISTER 
The non-inclusion register will allow for a comparison of patients who are included in the OPALINE study 
with patients who are not included. 
This comparison will allow for an evaluation of selection bias and its impact on how representative the 
study population is. 
This means that there will be no barrier to full use and publication of the statistical results. 
 
GUIDELINES FOR COMPLETION OF THE NON-INCLUSION REGISTER 
The non-inclusion register needs to be completed during the inclusion phase of the OPALINE study for all 
adult patients who meet the inclusion and exclusion criteria but who do not wish to participate in the 
study 
 
We remain at your disposal for any further information on: 
0800 940 170 (free from a landline) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The data collected in this document will be declared to CNIL. Under the provisions of articles 34 and subsequent articles of the French data 
protection law of 6th January 1978, amended, you have a right to access, seek corrections to and removal of data through the 
pharmaceutical company Pfizer. 
 
 

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Date: |___|___||___|___||_2_|_0_|___|___| 
 
 
 
 
 

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Summary 
 
1. 
Data collected .................................................................................. Erreur ! Signet non défini. 
2. 
Enrolment visit ................................................................................. Erreur ! Signet non défini. 
2.1 Checking eligibility criteria .......................................................................... Erreur ! Signet non défini. 
2.2 Social and demographic characteristics ....................................................... Erreur ! Signet non défini. 
2.3 Characteristics of patients on initiation of the current treatment line or treatment line 
initiated at enrolment ...................................................................................... Erreur ! Signet non défini. 
2.4 History of the illness ................................................................................... Erreur ! Signet non défini. 
2.5 Treatment line ongoing at the enrolment visit ............................................. Erreur ! Signet non défini. 
2.6 Safety – onset of adverse events (recorded retrospectively) ........................ Erreur ! Signet non défini. 
3. 
Tumour assessment visit ................................................................... Erreur ! Signet non défini. 
3.1 Tumour assessment .................................................................................... Erreur ! Signet non défini. 
3.2 Clinical parameters ..................................................................................... Erreur ! Signet non défini. 
3.3 Therapeutic management since last tumour assessment.............................. Erreur ! Signet non défini. 
3.4 Safety – onset of adverse events ................................................................. Erreur ! Signet non défini. 
4. 
Anticipated end of study form ........................................................... Erreur ! Signet non défini. 
5. 
Adverse  events recording module  (recorded prospectively) .............. Erreur ! Signet non défini. 
6. 
AE reporting form ............................................................................. Erreur ! Signet non défini. 
 
 

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RADIONUCLIDE THERAPY screen - Treatment initiation 
For all cases of treatment with radionuclide therapy initiated on the day of enrolment or before the enrolment visit 
(treatment line ongoing) 
Treatment with radionuclide therapy initiated as:  
 
 Monotherapy 
 
 Combination therapy with: 
 
 
 A somatostatin analogue 
Please state:   Octreotide 
 
 Lanreotide 
 
 Other treatment, please state:  1) ___________ 
 
 
 
2) ___________ 
 
Date of initiation:  /  /  (DD/MM/YYYY) 
 
Place of treatment:     France 
 
 Netherlands 
 
 Switzerland 
 
 Other, please state: __________ 
 
Number of treatments administered since initiation:  
 
Radioisotope:  
 Lutetium 
 
 
 Indium 
 
 
 Ytrium 
 
 
 

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If the treatment has been continued since the last documented visit 
SUNITINIB screen – Treatment continued 
EVEROLIMUS screen – Treatment continued 
CHEMOTHERAPY screen – Treatment continued 
INTERFERON ALPHA screen – Treatment continued 
SOMATOSTATIN ANALOGUE screen – Treatment continued 
RADIONUCLIDE THERAPY screen – Treatment continued 
 
If the treatment has been started since the last documented visit 
SUNITINIB screen – New treatment line 
EVEROLIMUS screen – New treatment line 
CHEMOTHERAPY screen – New treatment line 
INTERFERON ALPHA screen – New treatment line 
SOMATOSTATIN ANALOGUE screen – New treatment line 
RADIONUCLIDE THERAPY screen – New treatment line 
 
 
 

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Best response to treatment when patient last seen 
 Complete response 
 
 
 Stable disease 
 Partial response 
 
 
 Disease progression 
Date of the last disease assessment:  /  /  (DD/MM/YYYY) 
 
 
 

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Appendix AE reporting form 
Non-interventional study adverse events reporting form   
For internal usage by Pfizer /Novartis 
AE declaration number (please state if known) 
Premises n°  
Date of declaration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
0 
  
  
 
0 
0 
0 
0 
0 
0 
 
  
PROTOCOL/STUDY NUMBER 
 
SITE NUMBER 
 
 
PATIENT IDENTITY NUMBER 
Study title:       
 Initial declaration      
 Follow-up declaration 
Country of onset of the event: France 
Patient 
details 
Age        
 Male 
 Female 
Height      
 cm 
Weight      
 kg 
Ethnic origin:  
  No requirement to enter in accordance with local regulation   
If 
patient 
deceased: 
Date of death       
Cause(s) of death           
Determined by autopsy: Y 
    N 
   Unknown 
 
If yes, cause of death determined by autopsy:       
 
Patient medical history  
 None  
 
 Unknown 
State the relevant medical history below. Include other diseases present at the time of the 
event and pre-existing conditions. If more space is needed, use copies of this page.  
Disease (please state) 
Date 
of 
onset 
End 
date 
Tick here if 
ongoing 
Relevant details 
Include surgical interventions and dates 
      
      
      
 
      
      
      
      
 
      
      
      
      
 
      
      
      
      
 
      
Study medication (brand name and 
generic name) formulation, route of 
administration, indication 
Tick 
if 
the 
medication is by  
Dose 
Units 
Frequency 
Date 
of 
onset 
End 
date 
Tick here if 
ongoing 
Pfizer 
Novarti
s
      
 
 
      
      
      
      
      
 
      
 
 
      
      
      
      
      
 
      
 
 
      
      
      
      
      
 
      
 
 
      
      
      
      
      
 
Treatments received in the 28 days preceding the onset of the AE 
In the 28 days preceding the onset of the AE, did the patient receive at least one dose of 
Sunitinib? 
Yes 
No 
In the 28 days preceding the onset of the AE, did the patient received at least one dose of a 
Pfizer study product (other than Sunitinib)? 
Yes 
No 
 NK 
In the 28 days preceding the onset of the AE, did the patient receive at least one dose of 
Everolimus? 
Yes 
No 
In the 28 days preceding the onset of the AE, did the patient receive at least one dose of 
Octreotide? 
Yes 
No 
Concomitant medications 
 None   
 Unknown 
State below any concomitant medications taken in the two weeks preceding the onset of the event. 
Exclude all medications that were only administered over two weeks before the event, and any 
medication used to treat the event or taken after onset of the event. If more space is needed, use copies 
of this page. 
Name of the medication (brand 
and generic names)  
Reason for use 
Administration route 
Date 
of 
onset 
End 
date  
Tick here if 
ongoing 
      
      
      
      
      
 
      
      
      
      
      
 
      
      
      
      
      
 
      
      
      
      
      
 

Novartis Pharma S.A.S. – Pfizer S.A.S 
 
Page 88 of 90 
Observational study protocol 
final version of 17/07/2018 
 
Protocol V13 final version of 17th July 2018 
 
 
Relevant tests 
State only the results of tests relevant to confirmation of the adverse event(s), for example blood tests or 
diagnostic imaging. If more space is needed, use copies of this page. 
Test 
Date 
Result 
Units 
Normal values 
Min                        Max     Comments 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
Version 5.0_FR, August 2016 
 Page ___ of ___ 
Confidential Pfizer/Novartis 
 
 
 
Non-interventional study adverse events reporting form   
For internal usage by Pfizer /Novartis 
AE declaration number (please state if known) 
Premises n°  
Date of declaration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
0 
  
  
 
0 
0 
0 
0 
0 
0 
 
  
PROTOCOL/STUDY NUMBER 
 
SITE NUMBER 
 
 
PATIENT IDENTITY NUMBER 
ADVERSE 
EVENTS 
(if 
more 
than 
two, 
please 
use 
copies 
of 
this 
page) 
State 
the 
diagnosis 
if 
known 
rather 
than 
symptoms 
or 
signs 
Designation 
of 
the 
adverse event  
Date of  
onset:  
Was the event serious?                                 
 Yes  
 No  
If yes, please state the serious event criteria below:   
Serious event criteria (tick all that apply): 
 Death 
 Life threatening  
 Hospitalisation/prolonged existing hospitalisation 
 Persistent/significant incapacity/disability  
 Congenital anomaly/birth defect 
 Medically important event 
Status on the date of 
reporting or of death:  
 Resolution 
        } 
 Resolution with sequelae     }  
 Resolution ongoing  
 Not resolved 
 Unknown 
Is there a reasonable possibility that the event may have been 
linked to a study medication? 
 Yes   
 No 
If yes, please state the study medication:   
           
 
 
Is there a reasonable possibility that the event may have been 
linked to a concomitant medication? 
 Yes   
 No 
If yes, please state the concomitant medication:   
           
 
Last step taken in response to the event(s); please state 
medication name: 
      
      
Date 
of 
resolution: 
      
Designation 
of 
the 
adverse event  
Date of  
onset:  
Was the event serious?                                 
 Yes  
 No  
If yes, please state the criteria for seriousness below:   
Serious event criteria (tick all that apply): 
 Death 
 Life threatening  
 Hospitalisation/prolonged existing hospitalisation 
 Persistent/significant incapacity/disability  
 Congenital anomaly/birth defect 
 Medically important event 
Status on the date of 
reporting or of death:  
 Resolution 
        } 
 Resolution with sequelae     }  
 Resolution ongoing  
 Not resolved 
 Unknown 
Is there a reasonable possibility that the event may have been 
linked to a study medication? 
 Yes   
 No 
If yes, please state the study medication:   
           
 
 
Is there a reasonable possibility that the event may have been 
linked to a concomitant medication? 
 Yes   
 No 
If yes, please state the concomitant medication:   
           
 
Last step taken in response to the event(s); please state 
medication name: 
      
      
Date 
of 
resolution: 
      

Novartis Pharma S.A.S. – Pfizer S.A.S 
 
Page 89 of 90 
Observational study protocol 
final version of 17/07/2018 
 
Protocol V13 final version of 17th July 2018 
 
 
Study medication 
Concomitant medication 
Study medication 
Concomitant medication 
      
 
      
 
      
 
      
 
  Stopped (temporarily or 
permanently, 
or 
administration deferred) 
  Dose reduced     
  Dose increased   
  No change to dose 
  Unknown 
  None taken  
  Stopped (temporarily or 
permanently, 
or 
administration deferred) 
  Dose reduced     
  Dose increased   
  No change to dose 
  Unknown 
  None taken  
  Stopped (temporarily o
permanently, 
o
administration deferred) 
  Dose reduced     
  Dose increased   
  No change to dose 
  Unknown 
  None taken  
  Stopped (temporarily or 
permanently, 
or 
administration deferred) 
  Dose reduced     
  Dose increased   
  No change to dose 
  Unknown 
  None taken  
Did an AE/SAE develop again on reintroduction of the 
medication?      
 Yes     
 No      
 Unknown     
 Not applicable         
If yes, which medication?        
Did an AE/SAE develop again on reintroduction of the medication?      
 Yes     
 No      
 Unknown     
 Not applicable         
If yes, which medication?        
Version 5 0_FR, August 2016 
 Page ___ of ___ 
Confidential Pfizer/Novartis 
Non-interventional study adverse events reporting form   
For internal usage by Pfizer /Novartis 
AE declaration number (please state if known) 
Premises n°  
Date of declaration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
0 
  
  
 
0 
0 
0 
0 
0 
0 
 
  
PROTOCOL/STUDY NUMBER 
 
SITE NUMBER 
 
 
PATIENT IDENTITY NUMBER 
 
 
Description of the event 
 
State all information not given elsewhere on the form relating to the circumstances, chronology, diagnosis and treatment of the event(s). If 
more space is needed, use copies of this page. 
                

Novartis Pharma S.A.S. – Pfizer S.A.S 
 
Page 90 of 90 
Observational study protocol 
final version of 17/07/2018 
 
Protocol V13 final version of 17th July 2018 
 
 
 
Reporter’s comments:       
Reporter: 
      
      
            -         -         
                              First name 
Surname (Please write in BLOCK CAPITALS) 
Date: DD-MM-YYYY 
Address: 
      
       /      
      
       
                            Street 
Town 
Postcode 
Country 
Telephone:       
Fax:       
Email:       
 
Name 
of 
participating 
doctor: 
__________________________________  
Signature of participating doctor/doctor's representative:   
Date participating doctor/representative became aware of the event:    -         -     DD-MM-YYYY 
Send this form to Pfizer within 24 hours of becoming aware of the event or immediately in the event of death or a life-threatening 
SAE. 
INCLUDE ALL RELEVANT INFORMATION ON THE FORM. DO NOT ATTACH SOURCE DOCUMENTS. 
Version 5 0_FR, August 2016 
 Page ___ of ___ 
Confidential Pfizer/Novartis