OBSERVATOIRE NATIONAL D'UTILISATION D'INFLECTRA™ EN VIE RÉELLE.
Conditions: Crohn Disease, Ulcerative Colitis, Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriatic Arthritis
Sponsor: Pfizer

ReFLECT<Infliximab> 
<C1231004> NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment no. 3 Version 6.0 final of 22/June/2018 
  
Pfizer Internal data. Confidential. 
Page 1 of 60 
 
 
This document contains confidential information which is the property of Pfizer PFE France (Pfizer Group). 
Unless otherwise indicated in writing, by accepting or revising this document, you accept to keep this 
information confidential and to not copy it or to disclose it to other persons (except when applicable law so 
requires) or to not use it for unauthorised purposes. In an eventual real or suspected violation of this 
obligation, Pfizer PFE France (Pfizer Group) must be notified immediately. 
 
 
 
 
A NON-INTERVENTIONAL STUDY PROTOCOL (NI) 
 
Information on the study 
 
Title 
ReFLECT 
National Observatory on use of Inflectra® under real-life conditions. 
Protocol number 
C1231004 
Identifier of protocol 
version  
Amendment NO. 3 - Version  6.0 final 
Date of latest version of 
the protocol  
22/June/2018 
Active substance 
Infliximab 
Medicinal product 
Inflectra® 
Question and 
objectives of the 
study  
Primary Objective 
To describe under real-life conditions of use: 
- 
The response to treatment, 
- 
The profile of patients treated with Inflectra® 
Secondary objectives 
- 
To describe in routine practice: 
o The conditions for use of Inflectra® 
o The safety and tolerability to Inflectra® 
- 
To determine factors predictive of response to treatment 
- 
To describe the profile of immunogenicity of Inflectra® 
- 
To measure anxiety, stress and patient mistrust at time of 
announcement of switch and impact of the psychological profile 
on patient follow-up in terms of efficacy, safety and continuation 
of the biosimilar product 
- 
To evaluate the course of anxiety and of stress of patients after 
the switch 
Author 
Pfizer PFE France 

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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................... 2 
1. RESPONSIBLE PARTIES .................................................................................................... 6 
2. SUMMARY ........................................................................................................................... 8 
3. AMENDMENT ................................................................................................................... 15 
4. DECISIVE STAGES ........................................................................................................... 15 
5. JUSTIFICATION AND CONTEXT ................................................................................... 16 
5.1. Medical Context ........................................................................................... 16 
5.2. Rationale of the Observatory ....................................................................... 17 
5.3. Treatment ..................................................................................................... 17 
5.3.1. Description ................................................................................................. 17 
5.3.2. Therapeutic indications in the setting of the study ..................................... 17 
5.3.3. Posology and administration ...................................................................... 19 
5.3.4. Concomitant treatments .............................................................................. 20 
6. OBJECTIVES OF THE STUDY ........................................................................................ 20 
6.1. Primary objective ......................................................................................... 20 
6.2. Secondary objectives.................................................................................... 21 
7. ASSESSMENT END POINT .............................................................................................. 21 
7.1. Primary assessment end points .................................................................... 21 
7.2. Secondary assessment end points ................................................................ 22 
8. STUDY METHODS ............................................................................................................ 23 
8.1. Study ............................................................................................................ 23 
8.1.1. Recruitment of participating centres .......................................................... 23 
8.1.2. Set up of the centres by the CRO ............................................................... 24 
8.1.3. Recruitment of patients .............................................................................. 24 
8.1.4. Study schedule ............................................................................................ 25 
8.1.5. Tentative study schedule ............................................................................ 25 
8.2. Context ......................................................................................................... 26 
8.2.1. Inclusion criteria ......................................................................................... 26 
8.2.2. Non-inclusion criteria ................................................................................. 26 
8.2.3. Exclusion criteria ........................................................................................ 26 
8.2.4. Study withdrawal ........................................................................................ 26 

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8.3. Variables ................................................................................................................. 27 
8.3.1. Data at inclusion ......................................................................................... 27 
8.3.2. Follow-up visit data .................................................................................... 28 
8.3.3. Data on withdrawals from study ................................................................ 29 
8.4. Sources of data ........................................................................................................ 30 
8.5. Study size ................................................................................................................ 30 
8.6. Data management .................................................................................................... 31 
8.6.1. Case report form and data collection .......................................................... 33 
8.6.2. Data storage ................................................................................................ 33 
8.6.3. Channel of CRFs ........................................................................................ 34 
8.6.4. Construction of the database ...................................................................... 34 
8.6.5. Control of data ............................................................................................ 35 
8.6.6. Access of data ............................................................................................. 35 
8.6.7. Locking of the database .............................................................................. 35 
8.6.8. Data management report ............................................................................ 35 
8.7. Data analysis ........................................................................................................... 35 
8.7.1. Statistical Method ....................................................................................... 35 
8.7.2. General methodology ................................................................................. 36 
8.7.3. Descriptive analysis .................................................................................... 36 
8.7.4. Primary assessment end points ................................................................... 36 
8.7.5. Secondary assessment end points ............................................................... 37 
8.7.6. Schedule of analyses .................................................................................. 39 
8.8. Quality control ........................................................................................................ 39 
8.8.1. Set up of participating doctors .................................................................... 39 
8.8.2. Logistics and monitoring of participating centres ...................................... 39 
8.8.3. Quality and accuracy of data ...................................................................... 40 
8.9. Limits of methods of research ................................................................................. 40 
8.10. Other aspects ......................................................................................................... 41 
8.10.1. Data collection .......................................................................................... 41 
8.10.2. Archiving .................................................................................................. 41 
9. PROTECTION OF PATIENTS .......................................................................................... 41 
9.1. Information of the patient ....................................................................................... 41 

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9.2. Consent.................................................................................................................... 43 
9.3. Early discontinuation by a patient ........................................................................... 44 
9.4. Regulatory aspects .................................................................................................. 44 
9.4.1. Committee for the Protection of Persons (CPP)/Public Health Code law “2004-
806 of 9 August 2004” ..................................................................................... 44 
9.4.2. French National Council of Doctors .......................................................... 44 
9.4.3. Data protection: National Commission on Data Processing and Freedoms 
“CNIL” ............................................................................................................ 45 
9.5. Ethical conduct of study .......................................................................................... 45 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS ................................... 46 
10.1. Requirements in terms of pharmacovigilance ....................................................... 46 
10.2. Period of reporting ................................................................................................ 48 
10.3. Evaluation of causal relationship .......................................................................... 49 
10.4. Definition of an adverse event .............................................................................. 49 
10.4.1. Adverse event ........................................................................................... 49 
10.4.2. Serious adverse events .............................................................................. 50 
10.5. Situations requiring reporting to Pfizer Pharmacovigilance within 24 hours. ...... 52 
10.6. Single reference document on safety .................................................................... 55 
11. PLANS ON COMMUNICATION OF STUDY RESULTS ............................................. 55 
11.1. Scientific committee ............................................................................................. 55 
11.2. Access to source data ............................................................................................ 56 
11.3. Confidentiality ...................................................................................................... 56 
11.4. Property of data ..................................................................................................... 56 
11.5. Communication and publication ........................................................................... 56 
11.6. . Communication of problems ............................................................................... 57 
11.7. Financing of the Study .......................................................................................... 57 
12. REFERENCES .................................................................................................................. 58 
13. LIST OF TABLES ............................................................................................................. 60 
14. LIST OF FIGURES ........................................................................................................... 60 
ANNEX 1. ADVERSE EVENT REPORT FORM ................................................................. 60 
 ANNEX 2. PREGNANCY FOLLOW-UP AND CHILDBIRTH FOLLOW-UP FORM ..... 60 
 ANNEX 3. SEVERITY RATING SCALE ............................................................................ 60 

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 ANNEX 4. CONSENT FROM A MINOR PATIENT .......................................................... 60    
ANNEX 5. CONSENT FROM A MAJOR PATIENT ........................................................... 60 
 ANNEX 6. RHEUMATOLOGY CRF ................................................................................... 60 
 ANNEX 7. GASTRO-ENTEROLOGY CRF ........................................................................ 60 
 ANNEX 8. SUMMARY OF PRODUCT CHARACTERISTICS ......................................... 60 
 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
6-MP 
6-mercaptopurine 
AE 
Adverse event 
AZA 
Azathioprine 
BMI 
Body Mass Index 
CCTIRS 
Consultative Committee for Data processing in Scientific Research 
CDEIS 
Crohn's Disease Endoscopic Index of Severity 
CEPS 
Economic Committee on Health Products 
CNIL 
National Commission on Data Processing and Freedoms 
CNOM 
French National Medical Council  
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
DMARD 
Disease-modifying anti-rheumatoid drug 
DNA 
Deoxyribonucleic  acid 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration (US) 
HAS 
French National Authority for Health 
IgG 
type G immunoglobulin 
MA 
Marketing Authorisation 
NYHA 
New York Heart Association 
RA 
Rheumatoid arthritis 
SAE 
Serious adverse event 
SmPC 
Summary of Product Characteristics 
TNF 
Tumour Necrosis Factor 
UCEIS 
Ulcerative Colitis Endoscopic Index of Severity 

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<C1231004> NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment no. 3 Version 6.0 final of 22/June/2018 
  
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3. AMENDMENT 
 
French-specific protocol  
Amendment 
number 
Date 
Substantial or 
administra- 
tive  
amendment 
Section(s) 
changed in 
protocol 
Summary of 
amendment(s
) 
Reason  
Initial protocol 
Version 2.0 
19 April 
2016 
NA 
NA 
NA 
NA 
Amendment 
no. 1 
Version 3.1 
23 August 
2016 
Administrative 
All 
- Pfizer Template 
- Updating of 
PV paragraph 
Updating 
in 
conformity 
with 
Pfizer procedures. 
Amendment 
No. 2 
Version 4.0 
20/Nov/2017 Administrative 
All 
Change to 
participating 
doctors and 
schedule 
Amendment 
No. 3 
Version 6.0 
22/June/2018 Non-
substantial 
All 
- 
Addition of 
data on 
stress, 
anxiety, and 
mistrust  
- 
Addition of 
two new 
members in 
the scientific 
committee  
- 
Updating 
of RGPD 
(General 
Regulatio
n on Data 
Protection  
New 
scientific 
publications  
Possible protocol amendments will be reported to the CNIL and to the CNOM. Each participating 
doctor should be informed of each change to the protocol and agree to comply with the protocol and 
its amendments, which are an integral part of the protocol.  
 
 
4. DECISIVE STAGES 
The decisive stages are presented in the following. 
Decisive stage 
Planned date 
Recruitment of doctors 
End of May 2016 
Start of data collection: 
- 
1st patient included 
September 2016 

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- 
Last patient included 
December 2018 
End of data collection: 
- 
1st patient included 
September 2018 
- 
last patient included 
December 2020 
Interim report  
Each year starting from December 2016 
Study final report 
At latest January 2021 
 
 
5. JUSTIFICATION AND CONTEXT 
The objective of this non-interventional study is to describe under real-life conditions of use, the 
response to treatment, as well as the profile of patients treated with Inflectra® 
 
5.1. Medical Context 
Although combined in the same category, auto-immune diseases are of a highly heterogeneous 
nature: over 80 of them exist [1]. In 2009, the world-wide prevalence of auto-immune diseases was 
8% [2]. The pathophysiological mechanisms at the origin of these diseases are heterogeneous also: 
genetic factors, environmental and immunological factors can be involved. For example, psoriatic 
arthritis is characterised by specific mutations, while auto-antibodies can be detected in rheumatoid 
arthritis [1]. Psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease and 
ulcerative colitis are classified among inflammatory type auto-immune diseases. In 2013, almost 
431,000 persons in France were suffering from a long-duration disorder (ALD) associated with one 
of these diseases for which, therefore, they received total reimbursement of expenditures associated 
with their disease [3]. One of the characteristics of inflammatory auto-immune diseases is an 
increase in levels of Tumour Necrosis Factor alpha (TNF-α). Therefore, TNF-α inhibition is to be 
considered in treatment of the diseases. It is in this manner that infliximab acts. This monoclonal 
antibody binds to the soluble and transmembrane forms of TNF-α receptors, thus preventing 
interaction with the ligand. This results in blockade of activation of cellular signalling pathways 
responsible for production and release of cytokines. The result is a decrease in the immune and 
inflammatory responses [1,4]. 
Infliximab, initially marketed under the name Remicade™, was approved by the US Food and Drug 
Administration Agency (FDA) for treatment of Crohn’s disease in August 1998 [5] and was 
authorised in Europe in 1999. Today, Remicade™ is also indicated in treatment of psoriasis, of 
ulcerative colitis, of ankylosing spondylitis, of RA and of psoriatic arthritis. Inflectra®, the first 
biosimilar of Remicade™, was approved by the European Commission in 2013 [4]. Inflectra® has 
been developed in conformity with European requirements and can be considered as a therapeutic 
alternative to Remicade™ [6]. In fact, its equivalence to Remicade™ 

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has been demonstrated in a clinical study conducted on 606 patients with RA and in a 
pharmacokinetic study conducted on patients with ankylosing spondylitis [4]. In a phase III 
randomised trial, 73.4% of patients treated with Inflectra® showed an improvement of at least 20% 
in symptoms of RA based on the ACR20 score at 30 weeks versus 69.7% of patients treated with 
Remicade™. In this same study, 42.3% of patients in the Inflectra® group showed an improvement 
of symptoms of at least 50% in comparison to 40.6% of patients in the Remicade™ group. 
Comparable data on safety and tolerability between the two groups confirmed the equivalence of 
Inflectra® to Remicade™. Furthermore, there was no significant difference concerning the 
immunogenicity profile at 54 weeks between the two treatments, and the impact of anti-medicinal 
product antibodies on efficacy and safety was also comparable. Based on bioequivalence with 
Remicade™, the indications for Inflectra® have been expanded to all indications of Remicade™ 
[4]. 
 
5.2. Rationale of the Observatory  
In 2013, European sales of Remicade™ amounted to almost 2 billion euros [7]. The introduction of 
the first biosimilar for Remicade™ on the European market may enable the European health systems 
to generate over 20 billion euros of savings between now and 2020 [8]. The introduction of 
Inflectra® on the European market therefore has a definite economic advantage. Beyond the 
economic aspect, it would be useful to collect data on use of Inflectra® under real-life conditions, 
data which currently do not exist.  
The present observatory has been set up in order to achieve this objective and to collect data on the 
use of Inflectra® under real-life conditions.  
Moreover, and as with other biotherapies indicated in management of psoriasis, the French National 
Authority for Health (HAS) has requested that the follow-up of a cohort representative of patients 
with psoriasis be set up. For this purpose, the decision has been taken to become part of an ongoing 
register, the PSOBIOTEQ register, dedicated to patients with psoriasis. In order to avoid having two 
competing studies, patients with psoriasis therefore will not be included in the present observatory.  
Lastly, patient mistrust with respect to biosimilars in general, and in particular, at time of the switch 
from the reference biological treatment to its biosimilar product and their impact on follow-up of 
patients in terms of the nocebo effect have been the subject of recent publications (16-17). This new 
problem requires that elements of response be provided with the aid of observational prospective 
data. 
5.3. Treatment  
5.3.1. Description 
Inflectra® (infliximab) is a medicinal product biosimilar to Remicade™. It is an IgG1 human-
murine chimeric monoclonal antibody produced in murine hybridoma cells by recombinant DNA 
technique. Inflectra® is marketed as a powder for solution to be diluted for infusion is the dose of 
100 mg. 
 
5.3.2. Therapeutic indications in the setting of the study  
The therapeutic indications of Inflectra® in adults which are considered in the setting of the study 
are described in the SmPC as follows: 

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• Rheumatoid arthritis: Inflectra®, in combination with methotrexate, is indicated for 
reduction of signs and symptoms, but also improvement of functional capacities in: 
o Adult patients with active disease when the response to DMARDs, including 
methotrexate, has been inappropriate; 
o Adult patients with active, severe, and progressive disease, not previously treated 
with methotrexate nor with other DMARDs. 
In these populations of patients, slowing of joint destruction, measured by X-rays, has 
been demonstrated. 
• Crohn’s disease: Inflectra® is indicated in: 
o Treatment of moderate to severe active Crohn’s disease in adult patients who have 
not responded in spite of appropriate and well-conducted treatment with a 
corticosteroid and/or an immunosuppressant; or in whom this treatment is contra-
indicated or is poorly tolerated;  
o Treatment of fistulising active Crohn’s disease in adult patients who have not 
responded in spite of appropriate and well-conducted conventional treatment 
(including antibiotics, surgical drainage and immuno-suppressant therapy).  
• Ulcerative colitis: Inflectra® is indicated in treatment of active, moderate to severe 
ulcerative colitis in adult patients who have not responded adequately to conventional 
treatment consisting of corticosteroids and 6-mercaptopurine (6-MP) or azathioprine 
(AZA), or in whom this treatment is poorly tolerated or contra-indicated.  
• Ankylosing spondylitis: Inflectra® is indicated in treatment of active, severe ankylosing 
spondylitis in adults who have not responded adequately to conventional treatment. 
• Psoriatic arthritis: Inflectra® is indicated in treatment of active and progressive psoriatic 
arthritis in adult patients when the response to previous treatment with DMARDs has been 
inadequate. Inflectra® should be administered  
o In combination with methotrexate 
o Or alone in patients who have shown intolerance to methotrexate or in whom 
methotrexate is contra-indicated. 
In conformity with conditions of the SmPC, the indications for Inflectra® in children are: 
• Crohn’s disease: Inflectra® is indicated in treatment of severe, active Crohn’s disease in 
children and adolescents 6 to 17 years of age, who have not responded to conventional 
treatment consisting of a corticosteroid, an immuno-modulator and first-line nutritional 
treatment; or in whom these treatments are poorly tolerated or contra-indicated. Infliximab 
has been studied solely in combination with immuno-suppressant conventional treatment. 
• Ulcerative colitis: Inflectra® is indicated in treatment of severe, active ulcerative colitis in 
children and adolescents 6 to 17 years of age, who have not responded adequately to 
conventional treatment consisting of corticosteroids and 6-MP or AZA, or in whom these 
treatments are poorly tolerated or are contra-indicated.  

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5.3.3. Posology and administration 
This observational study does not have the aim of changing or influencing medical practices 
concerning prescription and use of Inflectra®. Patients will be managed according to the usual 
practice of each centre.  
In conformity with the SmPC, treatment with Inflectra® should be initiated under control of 
qualified doctors experienced in diagnosis and treatment of RA, of inflammatory bowel disease 
(IBD), of ankylosing spondylitis and of psoriatic arthritis. Inflectra® should be administered by 
intravenous dosing. Infusions of Inflectra® should be administered by qualified healthcare 
professionals experienced in detecting any infusion-related complication. Patients treated with 
Inflectra® should receive the patient leaflet, as well as the treatment reporting card. 
 
The dosages for Inflectra® in adults are described as follows in the SmPC: 
• Rheumatoid arthritis: 3 mg/kg administered in intravenous infusion followed by additional 
infusions of 3 mg/kg at weeks 2 and 6 after the first infusion and then every 8 weeks. 
Inflectra® should be administered in combination with methotrexate. 
Available data suggest that a clinical response usually is obtained within 12 weeks of 
treatment. If a patient obtains an inadequate response or no longer responds after this period, 
a dose increase by increments of about 1.5 mg/kg can be considered, up to a maximum of 
7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg, as often as every 4 
weeks, can be considered. If an adequate response is obtained, patients should be maintained 
at the dose or the frequency of administration selected. Continuation of this treatment should 
be reconsidered attentively in patients for whom no therapeutic benefit has been 
demonstrated during the first 12 weeks of treatment or after adjustment of the dose.  
 
• Active, moderate to severe Crohn’s disease: 5 mg/kg administered by intravenous 
infusion, followed by an additional infusion of 5 mg/kg 2 weeks after the first infusion. If a 
patient does not respond after 2 doses, no additional treatment with infliximab should be 
administered. In responder patients, alternative strategies for continuation of treatment are 
as follows:  
o Maintenance therapy: an additional infusion of 5 mg/kg at week 6 after the initial 
dose, followed by infusions every 8 weeks, or  
o Re-administration: an infusion of 5 mg/kg if signs and symptoms of the disease 
recur.  
• Fistulised active Crohn’s disease: 5 mg/kg administered by intravenous infusion, followed 
by additional infusions of 5 mg/kg at weeks 2 and 6 after the first infusion. If the patient does 
not respond after 3 doses, no additional treatment with infliximab should be administered. 
In responder patients, alternative strategies for continuation of treatment are as follows: 
o Maintenance therapy:  additional infusions of 5 mg/kg every 8 weeks or 

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o Re-administration: infusion of 5 mg/kg if signs and symptoms of the disease recur 
followed by infusions of 5 mg/kg every 8 weeks 
• Ulcerative colitis: 5 mg/kg administered by intravenous infusion, followed by additional 
infusions of 5 mg/kg at weeks 2 and 6 after first infusion, and then every 8 weeks.  
• Ankylosing spondylitis: 5 mg/kg administered by intravenous infusion, followed by 
additional infusions of 5 mg/kg at weeks 2 and 6 after first infusion, and then every 6 to 8 
weeks. If a patient does not respond at week 6, no additional treatment with infliximab should 
be administered. 
• Psoriatic arthritis: 5 mg/kg administered by intravenous infusion, followed by additional 
infusions of 5 mg/kg at weeks 2 and 6 after first infusion, and then every 8 weeks. 
• Re-administration for Crohn’s disease and rheumatoid arthritis: if signs and symptoms 
of the disease recur, infliximab can be re-administered within the 16 weeks following the 
last infusion. In clinical studies, delayed onset hypersensitivity reactions have been 
infrequent and have occurred after intervals without infliximab of less than 1 year. Safety 
and efficacy of re-administration after an infliximab-free interval of more than 16 weeks 
have not been established. 
• Re-administration for ulcerative colitis and psoriatic arthritis: Safety and efficacy of re-
administration, other than every 8 weeks, are not established.  
• Re-administration for ankylosing spondylitis: Safety and efficacy of re-administration, 
other than every 6 to 8 weeks, have not been established. 
 
The dosages of Inflectra® in children are described as follows in the SmPC: 
• Crohn’s disease: 5 mg/kg administered by intravenous infusion, followed by additional 
infusions of 5 mg/kg at weeks 2 and 6 after the first infusion, and then every 8 weeks. 
• Ulcerative colitis: 5 mg/kg administered by intravenous infusion, followed by additional 
infusions of 5 mg/kg at weeks 2 and 6 after the first infusion, and then every 8 weeks.  
 
5.3.4. Concomitant treatments 
Considering that this study is observational and does not aim to change medical practice, no measure 
to be taken is required concerning use of concomitant treatments. Doctors are asked to refer to the 
SmPC of Inflectra® to ensure safety of patients. 
 
6. OBJECTIVE OF THE STUDY 
6.1. PRIMARY OBJECTIVE 
The primary objective is to describe under real-life conditions of use:  
• Response to treatment,  
• Profile of patients treated with Inflectra® 

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6.2. Secondary objectives 
The secondary objectives are: 
• To describe in routine practice: 
o The conditions for use of Inflectra® 
o The safety of Inflectra® 
• To determine factors predictive of response to treatment 
• To describe the immunogenicity of Inflectra® 
• To measure anxiety, stress and mistrust of patients at time of announcement of a switch 
and impact of psychological profile on follow-up of patients in terms of efficacy, safety 
and continuation of the biosimilar product 
• To assess the outcome of anxiety and of stress of patients after the switch 
 
7. ASSESSMENT END POINT 
7.1. Primary assessment end points 
Response to treatment will be described indirectly and expressed by the per cent of patients without 
therapeutic failure during the 2 years’ follow-up. Therapeutic failure is defined as permanent 
discontinuation of Inflectra® because of intolerance and/or permanent discontinuation of Inflectra® 
due to lack of response to treatment based on the doctor’s assessment.  
The response to treatment will be described in the general population, but also in adults and in 
children. It will also be described based on severity of disease, assessed by specific rating scales of 
each disease and assessed by the doctor.  
 
The profiles of adult patients and of paediatric patients who received prescription of Inflectra® 
will be described based on information collected by the participating doctor during the inclusion 
visit. The following data will be collected:  
• Characteristics of patients 
o Age, 
o Sex, 
o Weight, height, 
o Contraception, if applicable 
o Pre-treatment assessment prior to initiation of anti-TNFα therapy 
• In adults, in the indication for which Inflectra® is prescribed: 
o Gastroenterology: Crohn’s disease, ulcerative colitis 
o Rheumatology: psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis 
• In children and adolescents, indication for which Inflectra® is prescribed: 
o Gastroenterology: Crohn’s disease, ulcerative colitis 
• Date of diagnosis of the disease 
• Severity of the disease: (annex 3) 
o Assessed by the participating doctor on the 3-point Likert scale: “mild”, “moderate” 
or “severe”. 
o Described by the specific activity index of the disease: 
▪ Rheumatoid arthritis: ACR or DAS28 

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▪ Ankylosing spondylitis: BASDAI or BASFI 
▪ Psoriatic arthritis: ACR or DAS28 
▪ Ulcerative colitis: Mayo score/PUCAI for paediatric patients/UCEIS 
▪ Crohn’s disease: Harvey-Bradshaw index/CDEIS 
• For patients who discontinue the biotherapy for which they are treated to initiate treatment 
with Inflectra®, characteristics of this switch will be described as follows: 
o Previous biotherapy 
o Reason for which the switch was performed 
o Dates of first and last administration of previous biotherapy 
o Number of doses administered for the previous biotherapy 
o Last dose administered of previous biotherapy  
o Response of patient to the previous biotherapy 
 
In conformity with new recommendations of the French health authorities (May 2016), patients 
naïve for infliximab or treated with Remicade™ can be treated with infliximab biosimilar product. 
 
7.2. Secondary assessment end points 
Data on prescription of Inflectra® during the 2 years’ follow-up: 
• Date of administration 
• Posology or dose administered  
• Duration of infusion  
• Duration of monitoring of patient in the hospital after administration 
• Treatment phase: induction/maintenance/re-administration 
• Concomitant treatments: corticosteroids/disease-modifying anti-rheumatoid drugs 
DMARDs/immuno-suppressants/5-aminosalicylic acid derivative/alkalising 
agents/biotherapy 
Tolerability to treatment will be expressed by the per cent of adverse events (AE) reported. The 
nature, severity and seriousness of each AE will be described. Adverse events specific to Inflectra® 
will be also be sought and described.  
Statistical analysis will be performed in order to determine factors predictive of response to 
Inflectra®. Factors tested will be chosen among data collected and are detailed in the paragraph 
“statistical analyses” (page 35). 
Maintenance under treatment will be determined at end of follow-up of each patient.  
The immunogenicity profile of Inflectra® will be described by serum assay measurement of 
infliximab residual serum levels (IRL) and anti-infliximab antibody levels. 
 
Data related to stress, anxiety and to mistrust (solely in patients who have been informed of a 
switch from infliximab of reference to Inflectra®) will be as follows: 
o Cook-Medley Questionnaire (8 items), also called the cynical mistrust rating scale 

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o GAD7 Questionnaire (7 items) 
o Questionnaire on stress perceived related to switch (3 items) 
In order to measure the impact of announcement of a switch on duration of treatment and per cent 
discontinuation of treatment, patients will be categorised depending on their psychological profile 
at time of switch:  
o For anxiety: 
o GAD>7 versus GAD<8 
o Or raw values in GAD7 score 
o For mistrust: 
o Median in Cook-Medley questionnaire (>median: propensity to mistrust 
<median confidence in another person) 
o Or raw values in Cook-Medley score 
o For stress: 
o Median in questionnaire on stress (>median:  stress present <median stress absent) 
o Or raw values of scores in the questionnaire on stress 
 
8. STUDY METHODS 
8.1. Study  
This observational, prospective, national, multi-centre study is aimed at eligible patients in whom 
Inflectra® is prescribed in conformity with the conditions contained in the SmPC, in one of the 
participating centres. The hospitals which take part in the study are part of the French hospital 
establishments which have referenced Inflectra®. 
 
Total duration of the study is estimated to be 4 years: 2 years’ inclusion period and 2 years’ follow-
up per patient. If needed, duration of the inclusion period can be modified.  
 
Pfizer PFE France (Pfizer Group), sponsor of the study, has entrusted the logistics of conduct to the 
CRO Axonal-Biostatem (92000, Nanterre). 
All members of the staff of the CRO in charge of follow-up of the study are required to complete 
Pfizer requirements in terms of training in: “Your Reporting Responsibilities: Monitoring the Safety, 
Performance and Quality of Pfizer Products (version in force)” (Pfizer) as well as all additional 
training considered useful. Such training will be provided at all members of staff of the CRO prior 
to start of the study. All trainings include a “certificate of training” (signed by the person trained) as 
the certificate of training, which should be kept in accessible format. Copies of all training 
certificates signed should be provided by Pfizer. 
 
8.1.1. Recruitment of participating centres 
All rheumatologists, gastroenterologists and internists practicing in a public or private hospital 
which have referenced Inflectra® will be invited to take part in this study. 

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Prior to start of the study, the departments concerned in these hospitals will be informed by postal 
mail of the set up of the observatory. Selection of centres which desire to participate will be 
performed.  
 
8.1.2. Set up of centres by the CRO 
A contract will be established for each participating doctor. Prior to set up of the centre performed 
by phone by a CRA in the CRO, a kit containing the protocol, the information leaflet and consent 
form, the register of non-inclusion, the study early permanent discontinuation forms and adverse 
event reporting forms will be sent to centres. 
 
8.1.3. Recruitment of patients 
Except for patients with psoriasis, all patients for whom Inflectra® is prescribed in conformity with 
conditions of the SmPC in one of the participating centres will be included in this study, unless they 
explicitly express their refusal concerning access to their medical dossier and to collection of their 
personal data. Doctors who prescribe Inflectra® in participating centres must systematically give 
patients the information leaflet. Patients who accept that their personal medical data be collected for 
purposes of this study will notify their agreement by signing the consent form. For minor patients, a 
decision on participation in this study will be left to one of their legal guardians.  
 
We estimate that about 1,200 patients will be treated with Inflectra® during the 24 months of the 
recruitment period (600 patients over 12 months). 
 
After a centre is set up, all patients receiving the administration of Inflectra® and who satisfy 
screening criteria are eligible to participate in the study. It is at time of this administration that 
patients will be invited to participate and that they will sign the consent form. Consent must be 
signed at latest prior to the discharge of the patient from the hospital. Both patients initiating 
Inflectra® and patients already under treatment with Inflectra® are eligible. 
 
The participating doctor or the team in charge of the study will give to eligible patients and who 
have accepted to participate in this study by signature of the consent form, self-questionnaires as 
well as an envelope, in order to be completed. After completing it, the patient should then place the-
questionnaire in a sealed envelope and then give it to the participating doctor or team in charge of 
the study. 
The sealed envelope containing the patient’s completed self-questionnaires will be sent by the 
participating doctor or the team in charge of the study, to the CRO in charge of the study, via a 
dedicated transporter.  
 
The participating doctor or the team in charge of the study will not be made aware of responses to 
the self-questionnaires. 
 
In each centre, a paper register will be made available to participating doctors in order to list patients 
eligible but who have not been included: reason for non-inclusion, age, sex and disease. Only an 
order number will be used to designate these patients in the manner so that they cannot be identified.  

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At the end of the study, this list will be recovered by the CRA. Patients not included will be compared 
to patients included based on characteristics reported, in order to verify the absence of a selection 
bias or of an inclusion bias.  
 
8.1.4. Study schedule  
 
Inclusion 
Month 6 
Month 12 
Month 18 
Month 24 
At each 
infusion 
Distribution of the information 
leaflet 
X 
Verification of inclusion and non-
inclusion criteria 
X 
Description of patient profile  
X 
Description of conditions 
for use of Inflectra® 
X 
X 
X 
X 
Assessment of response to 
treatment  
X 
X 
X 
X 
Description of tolerability to 
treatment  
X 
X 
X 
X 
Description of immunogenicity 
profile of Inflectra® 
X 
X 
X 
X 
X 
Cook-Medley* Questionnaire 
X 
GAD7 Questionnaire* (7-item) 
X 
X 
Questionnaire on stress* 
X 
X 
X 
*: solely in patients who have been informed of the switch from infliximab reference to Inflectra® 
 
8.1.5. Tentative study schedule 
The tentative study schedule at time of regulatory submission is as follows: 
• Submission to the CTIRS: early February 2016 
• Submission to the CNIL: end of April 2016 
• Submission to the CNOM; June 2016 
• Set up of centres: September 2016 
• Inclusion period: October 2016 – December 2018 
• End of follow-up of patients: December 2020 
• Interim analysis: Each year starting from December 2016 
• Final analysis: December 2020 
• Interim clinical report: Each year starting from December 2016 
• Final clinical report: January 2021 

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8.2. Context 
8.2.1. Inclusion criteria 
- 
Adult patients treated with Inflectra® on day of inclusion, whatever the treatment phase or adult 
patients who have been informed of the switch from infliximab reference to Inflectra®, in one 
of the following indications and in conformity with the SmPC: Crohn’s disease, ulcerative 
colitis, rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis.  
- 
Paediatric patients (children and adolescents 6 to 17 years of age) treated with Inflectra®, 
whatever the treatment phase, from the time that Inflectra® is prescribed in conformity with the 
indications mentioned in the SmPC: Crohn’s disease or ulcerative colitis.  
- 
Patients (or their legal representatives) who have received information (oral and written) 
concerning the study and who accept to participate.  
- 
Patients who gave their agreement for access to their clinical data and to their medical dossier 
by signing the consent form. Patients should sign the consent form at latest prior to their 
discharge from the hospital (first administration of Inflectra® after inclusion in the study). 
 
8.2.2. Non-inclusion criteria 
- 
Patients who refuse access to their medical dossier for collection of their personal medical 
data. 
- 
Patients not treated with Inflectra®. 
- 
Patients treated with Inflectra® for psoriasis. 
- 
Patients with a history of hypersensitivity to infliximab, to other murine proteins or to one of 
the excipients of Inflectra®. 
- 
Patients with tuberculosis or presenting with any other severe infection such as sepsis, an 
abscess or an opportunistic infection.  
- 
Patients presenting with moderate to severe heart failure (NYHA III/IV) 
 
8.2.3. Exclusion criteria 
Patients included who withdraw their consent will be excluded from the study. They will decide if 
their personal medical data collected may be used in the interim analysis and in the final analysis in 
so far as the latter have not been performed at time of their withdrawal from the study. 
 
8.2.4. Study withdrawal  
Reasons for withdrawal from the study will be indicated in the page of the e-CRF planned for 
this purpose. The date of end of study visit will be noted.  
Study withdrawals prior to scheduled end of follow-up will be classified according to the following 
categories:  
- 
Patient lost to follow-up 
- 
Non-compliance with study procedures (inclusion or non-inclusion criteria not complied with)  

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- 
Withdrawal from study desired by patient (if yes, specify reason invoked by patient) 
- 
Withdrawal from study for an adverse event which resulted in discontinuation of treatment (if 
yes, specify type) 
- 
Serious adverse event which resulted in discontinuation of treatment (if yes, specify type) 
- 
Death (cause and date) 
- 
Other reason (if yes, specify) 
 
8.3. Variables 
The e-CRF is the tool for data collection which will make it possible to achieve the objectives of 
the study. Data will be collected from time of inclusion up to end of study, scheduled end or not.  
 
8.3.1. Data at inclusion 
Characteristics of patients will be collected and recorded in the electronic case report form (eCRF) 
during the inclusion visit: 
• Age, sex, weight, height or body mass index (BMI) if available, smoker (yes/no), 
contraception if applicable 
• Indication for which Inflectra® is prescribed: Crohn’s disease/ulcerative colitis/rheumatoid 
arthritis/ ankylosing spondylitis/psoriatic arthritis/other, to be specified 
• Date or year of diagnosis  
• Severity of the disease: 
o Mild/moderate/severe  
o Specific activity index of the disease 
• For patients initiating treatment with Inflectra®, a pre-treatment assessment prior to 
initiation of anti-TNFα: completed/not completed 
• For patients already under treatment with Inflectra®, date of first prescription of Inflectra® 
• Previous treatments: corticosteroids/immuno-suppressants/biotherapy/surgery/other 
(yes/no/unknown; if yes, list) 
o Patient naïve for biotherapy (never before treated with biotherapy): yes/no; if not, 
specify:  
▪ Previous 
biotherapy 
prescribed: 
anti-TNFα 
(infliximab/adalimumab/etanercept/golimumab/ 
Rituximab), 
selective 
immuno-suppressant 
(vedolizumab/abatacept), 
interleukin 
inhibitor 
(anakinra/ustekinumab/tocilizumab), Anti-integrin (Vedolizumab) other 
(specify) 
▪ Dates of first and of last administration of the previous biotherapy 
▪ Number of doses administered of previous biotherapy  
▪ Last dose administered of previous biotherapy  
▪ If the previous biotherapy is not Inflectra® (switch), reason for which 
treatment has been changed in favour of Inflectra®: no response with 
previous treatment/insufficient response with previous treatment/problem of 
tolerability with previous treatment/other  
• Results of immunogenicity, if available: 

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o Reason and date of assay 
o Infliximab residual serum levels (IRL), 
o Anti-infliximab antibody serum levels 
 
• Data relating to stress, anxiety and to mistrust (solely in patients who have been informed 
of a switch from infliximab of reference to Inflectra®): 
o Cook-Medley Questionnaire (8 items), so-called cynical mistrust rating scale  
o GAD7 Questionnaire (7 items) 
o Questionnaire on stress perceived relating to switch (3 items) 
 
8.3.2. Follow-up visit data 
Data collected and recorded in the eCRF every 6 months: 
• Data concerning each administration of Inflectra®: 
o Administration performed: yes/no, if yes specify: 
▪ Date of administration 
▪ Posology or dose administered  
▪ Duration of infusion 
▪ Duration of monitoring of patient in the hospital after administration 
▪ Treatment phase: induction/maintenance/re-administration 
o Concomitant treatments: 
▪ Corticosteroids 
▪ Disease-modifying anti-rheumatic treatments (DMARDs) 
▪ 5-aminosalicylic acid derivatives 
▪ Immuno-suppressant agents 
▪ Alkylating agents 
▪ Biotherapy 
o Adverse events including adverse events of specific interest related to Inflectra®: 
▪ Infusion-related reactions, including acute and delayed onset 
hypersensitivity reactions 
▪ Infections including serious infections, tuberculosis, opportunistic 
infections, hepatitis B 
▪ Congestive heart failure,  
▪ Intestinal and perianal abscess 
▪ Malignant disorders, leukaemias, lymphomas 
▪ Demyelinating disorders  
▪ Lupus syndrome, disseminated lupus erythematosus  
▪ Hepatobiliary disorders 
▪ Sarcoidosis, sarcoidosis-like reactions 
o Situations involving exposure to one of the study medicinal products, including: 
o Exposure in pregnancy,  
o Exposure in breastfeeding  
o Medicinal product errors, 
o Cases of an overdose, 

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o Cases of misuse, 
o Extravasation,  
o Lack of efficacy,  
o Occupational exposure 
 
• Immunogenicity results, if available: 
o Infliximab residual serum levels (IRL), 
o Anti-infliximab antibody serum levels 
• Patient status: 
o In remission: yes/no o 
Lost to follow-up: yes/no o 
Deceased: yes/no 
o The patient discontinued his/her treatment with Inflectra® permanently: yes/no 
o Severity of the disease: 
▪ According to the doctor’s assessment: mild/moderate/severe  
▪ According to specific activity index of the disease 
In case of death, permanent discontinuation of Inflectra® or patient lost to follow-up, please 
complete the early permanent discontinuation form. 
 
If the patient withdrew consent concerning access to his/her medical dossier and collection of 
personal data, please complete the early permanent discontinuation form.  
 
Data collected at time of each infusion (solely in patients who have been informed of a switch 
from infliximab reference to Inflectra®) 
o GAD7 Questionnaire (7 items) 
 
Data collected at 6 months and one year (solely in patients who have been informed of a switch 
from infliximab reference to Inflectra®) 
o Questionnaire on stress perceived relating to the switch (3 items) 
 
 
8.3.3. Data on withdrawals from study 
The early withdrawal from study form should be completed with the following elements: 
• Reason and date of withdrawal from study: 
o Patient died, date of death  
o Patient lost to follow-up, date of last contact  
o Withdrawal of consent regarding access to medical dossier and collection of data, date 
of withdrawal of consent  
o Permanent discontinuation of treatment with Inflectra®: 
▪ Specify: discontinuation of treatment with an anti-TNFα/switch to another 
infliximab (Remicade™/Remsima ™)/switch to another biotherapy. 
▪ Reason for discontinuation of treatment with Inflectra®: no response with 
Inflectra®/insufficient response with Inflectra®/problem of tolerability with 
Inflectra® 
/ Inflectra® is no longer available in the hospital/patient is stable in 
remission/other, specify  

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▪ Date of permanent discontinuation of treatment with Inflectra® 
 
In case of problems of tolerability with Inflectra® or of death, please complete the adverse 
event/serious adverse event report form (annex 1). 
 
 
8.4. Sources of data  
Data of interest will be recorded in a case report form in electronic format (eCRF). If necessary, a 
clinical study technician may assist the participating doctor in patient data entry in the eCRF. For 
each patient included, the participating doctor is asked to collect data in the eCRF at the inclusion 
visit and then at least every 6 months during the 2 years of follow-up. At each connection to the 
eCRF, all data of interest in the previous 6 months will be recorded, including all information 
describing administrations of Inflectra®. For this purpose, an automatic reminder message will be 
sent to doctors a few days before planned date of connection.  
The CRO service provider is responsible for creation and maintenance of eCRFs. Only the first letter 
of the patient’s surname and first letter of his/her first name will be recorded in the eCRF. No data 
marked by a patient name will be collected. At time of individual set up of a centre, the CRO will 
assign a 3-figure composite code to each centre: this code corresponds to the centre number.  
The patient number will consist of the centre number (out of 4 figures) followed by a 3 figure code 
assigned in increasing order to inclusions: for example, patient number 0009002 corresponds to 
second patient in centre 9. Data collected will be confidential and covered by medical secret.  
 
8.5. Size of study 
In conformity with new recommendations by the French health authorities (May 2016), patients 
naïve for therapy or treated with Remicade™ can be treated with Inflectra®. Based on current 
prescribing data, it is estimated that about 1,200 patients will be treated with Inflectra® during the 
two years corresponding to the inclusion period (600 patients over 12 months). 
Calculation of sample size is based on accuracy of the estimate with a confidence interval for each 
proportion of patients treated with Inflectra®. The number of patients required depends on the 
expected per cent, the necessary accuracy and the alpha risk.  
In the absence of data available under real-life conditions, in the most unfavourable hypothesis, i.e.: 
a proportion of 50% with a 95% two-sided confidence interval, the following formula makes it 
possible to calculate the sample size necessary based on proportion (p) and accuracy (i) as follows:  
 
 
 
 
 
Proportion 

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Proportion 
Accuracy 
10% 
20% 
30% 
40% 
50% 
±2.5% 
553 
983 
1291 
1475 
1536 
±3.0% 
384 
683 
896 
1024 
1067 
±3.5% 
282 
502 
658 
753 
784 
±4.0% 
216 
384 
504 
576 
600 
±4.5% 
171 
304 
398 
455 
474 
±5.0% 
138 
246 
323 
369 
384 
±5.5% 
114 
203 
267 
305 
317 
±6.0% 
96 
171 
224 
256 
267 
±6.5% 
82 
145 
191 
218 
227 
 
Based on the applied formula, 1,200 patients would make it possible to have an accuracy of between 
2.5% and 3.0% in the treatment responder rate. 
 
Concerning the objective related to stress and to anxiety: the per cent of treatment discontinuations 
at one year is estimated at 25%, whatever the level of anxiety. The Nocebo effect is included in this 
percentage for about 10% and may differ depending on level of anxiety.  
Thus, the following hypotheses are considered:  
o Per cent discontinuation of treatment at one year: 25% 
o Per cent discontinuation in anxious patients (GAD>7): 30% 
o Per cent discontinuation in non-anxious patients (GAD<8): 20% 
o Missing data in discontinuation of treatment due to patients lost to follow-up: 10% 
A sample size of 300 patients (150 GAD>7 and 150 GAD<8) is necessary in order to calculate a 
95% two-sided confidence interval of the odds ratio of the variable treatment discontinuation not 
containing the value 1. Therefore, under these hypotheses, the odds ratio may be 0.58 and its 
confidence interval [0.35; 0.99]. By taking into account 10% missing data, 300/0.9=330 patients 
will have to be included after implementation of amendment no. 3. Thus, 330 adult patients having 
been informed of a switch from infliximab reference to Inflectra® will have to be included to achieve 
this secondary objective (Pass software version 15.0.4). The inclusion period may be changed 
depending on the progression of inclusions in order to achieve this objective. 
 
8.6. Data management  
A Data Management plan will be drafted which will describe all activities of Data Management 
performed during this study, as well as a Data Validation Plan which will describe all tests of 
consistency, obvious corrections (SECs) and listings of inconsistencies performed in this study, as 
well as messages of requests for corrections sent to the participating doctor which have to be 
approved by the Sponsor prior to start of inclusions. 

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Use of the e-CRF makes it possible to use pre-tests (tests of consistency executed online which 
enable to immediately correct differences between participating doctors) enables to decrease the 
number of requests for correction. 
Once the pages have been entered and monitored, the Data Manager will initiate execution of tests 
of consistency programmed under Clinsight® version 7.0, inconsistencies will be resolved by 
participating doctors online. 
Once all possible corrections have been made to the database, the Data Management Report written 
by the Data Manager and a request for authorisation of locking of the database by the Sponsor. Once 
the database has been locked, the final version of the Data Management Report and a certificate 
confirming locking of the database will be sent to the Sponsor.  
 
 
 
8.6.1. Case report form and data collection  
 
 
As used in the protocol, the term CRF (Case Report Form) should be taken as referring to a paper 
medium or to an electronic record of data, or both, depending on method of data collection used in 
this study.  
Data of interest will be recorded in a case report form in electronic format (e-CRF). 
A CRF is required and should be completed for each patient included. Original CRFs duly completed 
are the exclusive property of Pfizer and must not be made available to any third parties in whatever 
form except to authorised representatives of Pfizer or of the competent regulatory authorities, 
without written authorisation from Pfizer. The participating doctor must ensure that the CRFs are 
kept in a secure manner on the study site in encrypted electronic or paper form and will be password 
protected or secured in a locking room to prevent access by unauthorised third parties.  
The participating doctor is responsible in the last resort for collection and reporting of all clinical 
data, safety and tolerability and biological data between the CRF and any other medium for data 
collection (source documents) and make certain that they are accurate, authentic, original, 
attributable, complete, consistent, legible and available (if necessary).  
The CRF should be signed by the participating doctor or by an authorised member of staff to ensure 
the authenticity of data entered in the e-CRF. All corrections made to documents entered in the e-
CRF or source documents must be dated, initialled and explained (if necessary) and must not conceal 
the original data entered.  
In the majority of cases, source documents are comprised of hospital dossiers or of the doctor’s 
dossiers. In this case, data collected in the e-CRF should correspond to these dossiers.  

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In certain cases, the CRF can also be used as a source document. In such a case, a document available 
on-site and at Pfizer should clearly identify the data which will be recorded in the e-CRF and for 
which the CRF will comprise the source document. 
 
 
8.6.2. Data storage  
In order to enable evaluations and/or inspections/audits by the regulatory authorities or by Pfizer, 
the investigator agrees to keep the dossiers, including the identity of all participating patients 
(sufficient information to establish the link with the dossiers, for example, CRF[/ORD] and hospital 
dossiers), all signed original informed consent documents, copies of all CRFs, pharmacovigilance 
report forms, source documents, detailed dossiers on treatment allocation and adequate 
documentation of relevant correspondence (for example, letters, meeting minutes and phone call 
reports). Dossiers should be kept by the participating doctor in conformity with local regulation or 
according to specifications of an agreement established for the study according to the longest 
duration.  
The participating doctor should ensure that dossiers continue to be stored in a secure manner for as 
long as they have to be stored.  
If the participating doctor is no longer able, for whatever reason, to continue to keep the study 
dossiers during the required period (for example: if he/she retires, or if the participating doctor 
moves away from the site), the participating doctor should inform Pfizer. The study dossiers should 
be transferred to a person designated after acceptance by Pfizer, such as another participating doctor, 
another institution or to an independent third party designated by Pfizer PFE France (Pfizer Group). 
The participating doctor’s dossiers should be kept for a minimum duration of 15 years after the end 
(last visit of last patient) or discontinuation of the study or for longer if necessary, whenever local 
regulations so require. The participating doctor should obtain written authorisation from Pfizer 
before disclosing the contents of any dossier, even if requirements for storage have been satisfied. 
8.6.3. Channel of CRFs 
Data collected from a participating doctor at time of inclusion and of follow-up visits of patients 
will be recorded directly by the participating doctor in the eCRF of the study.  
Adverse events will be collected via the eCRF by doctors at consultations on usual follow-up, for 
all patients in the study. Whenever applicable, requests for additional information from the PFIZER 
PFE France pharmacovigilance department (Pfizer Group) will be sent to the person who reported 
the event (participating doctor). All reports (initial and follow-up reports) will be collected via the 
centre number and the patient number. 

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Self-questionnaires, as well as an envelope will be given to patients by the participating doctor or 
the team in charge of the study in order to be completed. They should then be given in a sealed 
envelope to the participating doctor or the team in charge of the study.  
The sealed envelope containing completed patient self-questionnaires will be sent by the 
participating doctor or the team in charge of the study, to the CRO in charge of the study, via a 
dedicated transporter. 
 
 
8.6.4. Construction of the database 
An annotated questionnaire will be prepared by the CRO in charge of data management. This 
document will contain the names of tables and names of variables. Each variable will be associated 
with its type, its length, and its possible format. The annotated questionnaire will be submitted to 
Pfizer PFE France (Pfizer Group) for validation. 
The CRO then will build a database using its own software. The structure of the database will be 
documented and verified on listings by comparing the attributes of variables in the database with 
specifications recorded in the annotated questionnaire.  
Prior to entry of real data, the structure of the database and the data entry screens will be tested and 
validated in agreement with Standard Operating Procedures of the CRO and those of Pfizer PFE 
France (Pfizer Group). To do this, fictitious questionnaires will be completed and entered. Validation 
will be done by a case-by-case review on listing of these data and then on their comparison with data 
recorded in the questionnaires. A validation report will be written and sent to Pfizer PFE France 
(Pfizer Group). The final structure of the database should be submitted to Pfizer PFE France (Pfizer 
Group) for validation prior to data entry of real data. 
An audit file will be created in order to record all changes made to the database. The original data, 
the modified data, the date and time of the change, the person who made the change and the reason 
for the change will be recorded in the audit file. Functioning of the audit file will be tested by the 
change to fictitious data. A report will be written and sent to Pfizer PFE France (Pfizer Group). 
 
 
8.6.5. Control of data  
A list of controls of consistency enabling detection of inconsistencies and of aberrant responses 
present in questionnaires will be edited by the CRO and validated by Pfizer. Such controls will be 
scheduled with the CRO’s own software and then tested with fictitious data. These fictitious data 
and documentation relating to tests will be kept in the study binder by the CRO and available for 
review by Pfizer PFE France firm (Pfizer Group). 

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After data entry, controls will be executed continuously, a specific request for each inconsistency 
will be generated electronically by the data control system. In order to limit the number of requests 
to submit to participating doctors, a guide to obvious corrections prepared by the CRO and validated 
by Pfizer may be compiled.  
The CRO will make available the documentation on data control upon simple request from Pfizer 
PFE France (Pfizer Group). Periodic progress reports on data control will be edited by the CRO and 
sent to Pfizer PFE France (Pfizer Group). 
 
 
8.6.6. Access to data 
The databases and servers on which they are stored will be located in locking facilities. Only staff 
dedicated to the study will have access to the databases.  
 
 
8.6.7. Locking of database 
Locking of the database will be performed only after data entry, data control and possible coding 
have been completed by the CRO. Locking of the database will be performed in agreement with the 
Pfizer PFE France procedure (Pfizer Group). After validation by Pfizer PFE France (Pfizer Group), 
the database will be locked by the CRO and ready for statistical analysis. 
 
 
8.6.8. Data management report 
A data management report will be edited by the CRO after locking of the database and sent to Pfizer 
PFE France (Pfizer Group). 
 
 
8.7. Data analysis  
Statistical analyses will be performed by a CRO under the responsibility of Pfizer PFE France (Pfizer 
Group). 
The detailed methodology of statistical analysis of data collected in the setting of the study will be 
documented in the statistical analysis plan (SAP), which will be dated, recorded and administered 
by Pfizer PFE France (Pfizer Group). The SAP can modify the plans described in the protocol; all 
major changes to definitions of the primary assessment end point or of their analyses will be reflected 
in a protocol amendment. 
 
8.7.1. Statistical Method 
The statistical analyses will be performed by the CRO Service Provider independently of Pfizer PFE 
France firm (Pfizer Group). 

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A statistical analysis plan (SAP) will be complied after approval of the protocol and validated before 
locking of the database. This document will present a comprehensive list of analyses which will be 
performed, as well as the methodologies used and rules on derivations of variables. This document 
will have value as a reference for statistical analyses.  
 
8.7.2. General methodology 
Quantitative data will be described by their sample size, their mean, standard deviation, median and 
their range.  
Qualitative data will be described by their sample size and their per cent. 95% two-sided confidence 
intervals will be provided whenever considered relevant. Missing data will not be taken into account 
in calculation of per cents.  
The statistical tests will be two sided with a 5% risk of error.  
Since the primary objectives of this study are descriptive, no imputation of missing data is planned 
if only for certain dates (missing days will be replaced by 15 and missing months by 6). 
No readjustment of visits is planned.  
Sub-group analyses will be performed for each objective, by differentiating adult and paediatric 
populations. 
Moreover, all analyses will be repeated in the sub-group of patients who have been informed of a 
switch from infliximab reference to Inflectra®. 
 
8.7.3. Descriptive analysis 
General characteristics of patients, as well as characteristics of prescribing doctors at time of 
inclusion will be described. In criteria available, subjects who accepted to participate will be 
compared to those who refused. Withdrawals from study will also be described and will be illustrated 
in the study flowchart.  
 
8.7.4. Primary assessment end points 
• Response to treatment: 
Response to treatment will be described indirectly and expressed by per cent of patients who are not 
in therapeutic failure during the 2 years’ follow-up. Therapeutic failure is defined as permanent 
discontinuation of Inflectra® because of intolerance (an adverse event related to Inflectra®) and/or 
permanent discontinuation of Inflectra® because of absence of a response to treatment according to 
the doctor’s assessment (see chap. 7.1). The per cent of patients without a therapeutic failure will be 
described with its 95% confidence interval, overall and then by the following sub-groups: 
 
- 
Paediatric and adult population  
- 
The indication for which InflectraTM was prescribed 
- 
Severity of the disease according to the Likert scale 
- 
The activity index specific for each disease  
- 
Level of anxiety 
 
• Profiles of patients 

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The demographic characteristics (such as: age, sex, etc.), clinical (duration of the disease, diseases, 
co-morbidity, previous treatments, etc.) will be described by differentiating paediatric and adult 
populations.  
Special attention will be paid to the sub-population of patients who are in a therapeutic switch (as 
defined in chap. 7.1). 
Profiles of patients as described in the abovementioned will be produced in this sub-population by 
adding the duration of previous biotherapy, the number of doses administered, the time between the 
last dose and initiation of InflectraTM, as well the patient’s response.  
If sample sizes so permit, this sub-population will be described according to the following: 
- 
Previous biotherapy used 
- 
Reasons for the switch  
- 
Patient’s level of anxiety  
 
8.7.5. Secondary assessment end points 
• Conditions on use of Inflectra® 
Data relating to prescription (posology/dose, duration of infusion, duration of monitoring, post-
treatment, treatment phase and concomitant treatment) will be described at each time: D0, M6, M12, 
M18 and M24 and overall according to the following sub-groups:  
- 
Paediatric and adult population  
- 
Indication for which InflectraTM was prescribed 
- 
Severity of the disease according to the Likert scale 
- 
The activity index specific for each disease  
The cumulative doses and durations of treatment will be presented and also described.  
• Safety and tolerability to Inflectra® 
At the outset, coding of AE will be performed according to the MedDRA dictionary. 
The following tables will be presented according to adult and paediatric populations:  
- 
Proportion of patients who reported at least one AE 
- 
Proportion of patients who reported at least one un SAE 
- 
Proportion of patients who reported at least one specific AE (as described in chap. 8.2) 
A description of AEs will be performed based on:  
- 
Paediatric or adult population  
- 
Seriousness (mild, moderate, severe) 
- 
Relation with InflectraTM 
- 
Severity  
- 
Type of disease  
- 
Duration of disease  
- 
Naïve of therapy characteristics of the patient with respect to biotherapies 
- 
Responder status or not  
An individual listing of AEs and specific AEs (description, type, date of start and date of end, 
intensity, treatment, etc.) will be provided. 
• Factors predictive of response to treatment 
For each indication, factors predictive of response to treatment will be analysed by a logistic 
regression model. Univariate analysis will be performed in order to select factors which then will 

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be taken into account in the multi-variate model. The following list presents non-exhaustively 
certain variables which may be tested: 
- 
Demographic data 
o Age, 
o Sex, 
o BMI, 
o Smoker status  
- 
Clinical and laboratory data 
o Severity (described qualitatively and quantitatively), 
o Duration of the disease,  
o Concomitant treatments,  
o History of treatment with a biotherapy,  
o History of treatment with infliximab, 
o Infliximab residual serum level (IRL) after 14-week induction therapy in patients 
treated for acute episodes,  
o anti-infliximab antibody serum levels after 14-week induction therapy in patients 
treated for acute episodes  
o Cumulative dose 
o Duration of treatment with InflectraTM 
o Anxiety profile of patient  
o Cynical mistrust rating scale  
o Stress score 
 
• Inflectra® immunogenicity profile 
IRL and anti-infliximab antibody levels will be described at each time and according to:  
- 
Dose or posology administered 
- 
Naïve status for biotherapy 
- 
Indication 
- 
Severity of the disease  
 
• Data relating to stress, anxiety and to mistrust (solely in patients who have been informed 
of a switch from infliximab of reference to Inflectra®): 
A detailed plan of analysis will present the analyses relating to these data. 
 
GAD7 questionnaire is an anxiety state questionnaire with 7 items on the experience of the last 
two weeks.  
 
The patient’s anxiety profile will be defined as follows: GAD (Anxious >7; not anxious <8) 
The best categorisation may be chosen with methods of sensitivity/specificity with the variable 
discontinuation of treatment.  
 
The outcome (absolute difference of scores from time of inclusion visit) over time of GAD7 scores 
will be analysed with a repeated measure mixed model of analysis of covariance including at least 
as explanatory variables the initial value, as well as the variable for stopping of treatment 

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at one year (or 2 years). The LS Means will be estimated at each time in this model with their 95% 
two-sided confidence interval. The time x discontinuation of treatment interaction will also be 
explored in this model. For patients anxious at the outset (score>7), the time necessary for return to 
a non-anxious state (GAD≤7) will be analysed with analysis of survival methodology.  
 
The Cook-Medley 8-item questionnaire, also called cynical mistrust scale will be described and 
may also be correlated with the GAD7 questionnaire, as well as the response and duration of 
treatment.  
 
The questionnaire on stress perceived with relation to a switch to the biosimilar contains three 
questions and the score is obtained by addition of the three scores (on emotional reactivity, 
syndrome of repetition and tendency to avoidance) in order to obtain an overall score. This score 
may be correlated with the GAD7 questionnaire, as well as response and duration of treatment. 
The outcome of scores at the 3 times will be analysed as for GAD7. Since this questionnaire has 
not been validated, a working validation may be planned (sensitivity to change, etc.).  
 
 
8.7.6. Schedule of analyses 
It is planned to perform several interim analyses, mainly descriptive, based on data collected 
throughout the duration of the study. The final analysis will be performed when the study has been 
completed with all data collected.  
 
 
8.8. Quality control  
8.8.1. Set up of participating doctors 
Participating doctors will be asked to participate in this study. This participation will be evidenced 
by signature of the financial agreement. Upon validation of the latter, a visit to set up on-site or by 
phone will be organised by the Clinical Research Associate in order to present the study and all 
afferent documents to the participating doctor, as well as to members of his/her staff that will have 
been designated, if applicable.  
 
 
8.8.2. Logistics and monitoring of participating centres  
Throughout this study, participating doctors will be contacted in order to ensure their understanding 
and compliance with the protocol and of the electronic questionnaire. All contacts will be 
documented.  
If the sponsor considers it necessary, in light of the progress in completing eCRFs, CRAs may 
perform monitoring visits on-site. During these visits, CRAs from the CRO will check the quality 
of data collected. In order to do this, they should refer to the patient’s medical dossiers. Participating 
doctors therefore should ensure that the CRAs can have access to patient dossiers  
 

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The CRAs involved in monitoring procedures do not intervene in data collection. The frequency of 
on-site visits will depend on the number of patients included in each centre.  
 
Key indicators in proper conduct of the study (number of active centres, number of patients included, 
number of follow-ups performed, etc.) will be generated using the study database. This database will 
enable to edit study progress reports which will enable to manage reminders from centres. 
 
 
8.8.3. Quality and accuracy of data 
The participating doctor will be responsible for collection and reporting of all clinical data, safety 
and laboratory data entered in the eCRF and/or other forms of data collection (source documents), 
and must make certain that they are accurate, authentic, attributable to the patient, complete, 
consistent, legible, contemporaneous and available if needed.  
In order to enable controls and/or audits by the regulatory authorities or by PFIZER PFE France 
(Pfizer Group), the participating doctor agrees to keep registers, including the identify of all 
participating patients (sufficient information to connect dossiers (ex.: eCRF and hospital medical 
dossiers). The participating doctor will keep all original informed consent forms, copies of reports 
of adverse events, source documents, and medical results leading to therapeutic decisions. 
 
 
8.9. Limits of methods of research  
This protocol has been built in a manner so as to best achieve the objectives set for this observational 
study. However, it has certain limits which should be discussed and taken into account at time of 
implementation of the study and utilisation of results, such as for example: 
Measures taken to limit patient’s lost to follow-up and missing data  
Since this study does not aim to influence or to modify usual practices, participating doctors will 
have the ability to note “not done” or “not applicable” in collection of data. In case of missing data, 
without one of these notations, the CRA will make every effort to collect corresponding information 
with the aid of the participating doctor. Nevertheless, if data are still missing at time of the analysis, 
they will not be replaced and they will be processed such as the following:  
In case of patients lost to follow-up, the participating doctors will accept to call the patient, one of 
their family members or their family doctor in order to retrieve sufficient data to close the dossier.  
In case of death, the doctor will investigate its cause. 

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8.10. Other aspects 
8.10.1. Data collection  
After signature of the contract and a visit to set up the study, the participating doctors and each 
person participating in the centre, should return to the CRO the form on awareness of the protocol, 
the certificate of training in the eCRF and the certificate of training in pharmacovigilance. 
Participating doctors will then receive the web link with their identifier and their access code number 
to the e-CRF. 
These codes are personal, each person participating in the centre will receive his/her identifier and 
his/her code number. 
The participating doctors will complete the questionnaire for each patient included at time of regular 
consultations scheduled when such consultations coincide with the study visits. A one-month time 
period before and after the theoretical date will be tolerated for visits to be entered in the eCRF. 
If the patient discontinues the study during the follow-up, the doctor will complete the end of study 
questionnaire and will provide the reason for withdrawal from the study (Section -). 
Participating doctors agree to exhaustive collection of data for each patient.  
 
 
8.10.2. Archiving 
Participating doctors will keep questionnaires up to 15 years after the last visit of the last patient 
The study management centre will keep all documentation related to the study up to 15 years after 
last visit of the last patient.  
Then, all documents will be returned to the sponsor of the study.  
 
 
9. PROTECTION OF PATIENTS 
9.1. Information of the patient 
 
 
All parties will comply with legislation in force, in particular, by implementation of organisation 
and technical measures in order to ensure protection of personal data of patients. These measures 
will include the omission of names of patients or of other data enabling to identify them directly in 
all reports, all publications and all other disclosures, except for requirements imposed by legislation 
in force.  
Personal data will be stored on the study site (in encrypted electronic and/or paper format) and will 
be password protected and/or secured in a locking room in order to ensure that only authorised   

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study staff has access to it. The participating centre will set up appropriate technical and 
organisational measures in order to ensure that personal data may be retrieved in case of an accident. 
In the eventuality of a potential violation of personal data, the participating centre will be responsible 
for determining if this violation has really occurred and if so, to perform the notifications required 
by law.  
In order to protect the rights and freedoms of physical persons with regard to processing of personal 
data, when study data are compiled in order to be transferred to Pfizer and to other certified parties, 
names of patients will be removed and replaced by a unique, specific numerical code, based on a 
numbering system defined by Pfizer. 
All other data enabling identification of patients which will be transferred to Pfizer or to other 
certified parties will be identified by this specific unique code for each patient. The centre of the 
participating doctor will retain a confidential list of patients who participated in the study, with a 
link between the numerical codes for each patient and the actual identity of each of them.  
In case of transfer of data, Pfizer will maintain high standards of confidentiality and of protection of 
personal data of patients, in conformity with conditions of the contract established for the study and 
laws on protection of personal data.  
 
 
9.2. Consent 
Consent documents and all materials intended for recruitment of patients must comply with 
regulatory requirements and local legislation, in particular, laws in force on respect of personal data.  
Informed consent documents used in the process for obtaining informed consent and all materials 
enabling recruitment of patients must be examined and approved by Pfizer, approved by the 
Committee for the Protection of Persons (CPP- Ethics Committee) (if applicable) prior to their use 
and should be available for their inspection. 
 
The participating doctor must ensure that all patients in this study or their legal representative or 
relative(s) or parent(s) or legal guardian(s) (when this involves a minor) are fully informed of the 
nature and the objectives of the study, of communication of data related to the study and of possible 
risks associated with their participation, in particular, risks associated with processing of a patient’s 
personal data.  
 
The participating doctor must ensure that all patients in this study or their legal representative or 
their relative(s) or parent(s) or legal guardian(s) (when it involves a minor) are fully informed of 
their rights of access and of correction of their personal data and of their right of withdrawal of 
consent for processing of their personal data.  

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When consent is obtained from a legal representative/parent) or from a patient’s legal guardian, the 
consent of the patient (affirmative agreement) must then be obtained when the patient is able to 
provide consent according to modalities determined by the CPP (if applicable). If the participating 
doctor determines that the decision-making capacity of a patient is too limited so that he/he, in 
particular, may be consulted then, if this is authorised by the CPP (if applicable) and in conformity 
with regulatory requirements and local registration, an exemption from patient consent is possible 
by mentioning in the source documentation the reason why consent was not obtained.  
 
If the patient does not provide his/her own consent, the source documents should mention why the 
patient did not provide consent (for example, a minor, an adult with impaired decision-making 
capacity), how the participating doctor determined that the person signing the consent form was the 
patient’s legal representative, the relationship between the signatory of the consent form and the 
patient participating in the study (for example, parent, spouse) and the fact that consent from the 
patient was obtained or that an exemption was granted. If consent is obtained orally, it should be 
documented in the source documents.  
 
If the study includes minors who reach the age of adulthood during this study, as defined by local 
legislation, they should repeat their consent in their capacity as adults in order to remain in the study. 
If inclusion of emancipated minor children is authorised by study criteria relating to age, the CPP 
(if applicable) and local legislation, they should provide documentation of their civil state in order 
to provide their consent without the permission of a parent or of a legal guardian.  
 
The participating doctor, or a person designated by the participating doctor, will obtain written 
informed consent from each of the patients, or from the patient’s legal representative, from one or 
both parents, or from the legal guardian and consent of the patient is applicable before any specific 
part of the study is performed. The participating doctor will retain the original informed consent 
document from each patient.  
 
 
9.3. Early discontinuation by a patient  
Patients can withdraw early from this study at any time at their own request or they can be excluded 
from it at any time at the discretion of the participating doctor or the sponsor for reasons of safety, 
behaviour or administrative problems. In all cases, every effort should be made to document the 
outcome of the patient, if possible. The participating doctor should inquire to find the reason for the 
early withdrawal and follow-up of the patient regarding all unresolved adverse events.  
If a patient withdraws early from the study and he/she also withdraws his/her consent for disclosure 
of future information, no other assessment should be performed and no additional data should be 
collected. The sponsor can keep and continue to use all data collected prior to the so-called 
withdrawal of informed consent.  

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9.4. Regulatory aspects 
9.4.1. Committee for the Protection of Persons (CPP -Ethics Committee)/Public Health 
Code Law “2004- 806 of 9 August 2004” 
This is an observational study which does not change in any manner the usual medical management 
of persons entering into the study, does not produce any change to physical or psychological integrity 
and does not require a specific follow-up visit for persons entering in this study. All procedures are 
performed and products are used as usual, with no additional or unusual procedure for diagnosis or 
follow-up.  
Under these conditions, this study does not fall within the scope of application of the law of 
programme no. 2006-450 of 18 April 2006 for research nor under law no. 2004-806 of 9 August 
2004 article 88 chapter II article L1121-1 and therefore the project does not come under the heading 
of submission to the French National Agency for Medicines and Health Products Safety (ANSM), 
nor to the Committee for the Protection of Persons (Ethics Committee - CPP). 
Regulation no. 2016-800 of 16 June 2016 relating to research involving the human person stipulates 
in its article 8 that research regularly reported or authorised as of date of entry in force of the 
application decision (application decision of the so-called Jardé law no. 2016-1537 of 16 November 
2016) continued during five years in conformity with legislation which was initially applicable to 
them. 
At the end of this 5-year period, they will be subject to another examination by the Committee for 
the Protection of Persons (CPP-Ethics Committee), and if applicable, by ANSM (French National 
Agency for Medicines and Health Products Safety under conditions stipulated by the public health 
code.  
In the case in point, for an opinion which was delivered prior to 16 November 2017, the Committee 
for the Protection of Persons (Ethics Committee (CPP) is not competent for substantial changes 
involving this project. 
 
 
9.4.2. French National Council of Doctors 
Participating doctors and scientific committee experts will be compensated for their participation in 
this study. The study protocol and the financial agreements will be submitted to the French National 
Medical Council, section H (article L4113-6 of the Public Health Code and articles R4113-104 and 
R4113-105). 
Each participating doctor and scientific expert must send to the Departmental Board of the Medical 
Council a copy of his/her contract (articles L4113-9, L4113-10 and L4163-10 of the Public Health 
Code).  

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9.4.3. Data protection: National Commission on Data Processing and 
Freedoms “CNIL” 
In conformity with law 78-17 of 6 January 1978 relating to data processing, files and freedoms as 
modified by law 2004-801 of 6 August 2004 relating to protection of physical persons with regard 
to processing of personal data, this protocol has been the subject of a request for an opinion from 
the Consultative Committee on data processing in the area of research in the field of health 
(CCTIRS). Upon receipt of a favourable opinion from this committee, the computer file used in 
order to conduct the present study has been the subject of a request for authorisation from the 
National Commission on Data Processing and Freedoms (CNIL). This computer file can be 
implemented only upon receipt of authorisation from the CNIL.  
Since this involves the potential competence of the Consultative committee on data processing in 
the area of research in the field of health (CCTIRS) which was eliminated on 5 May 2017, the date 
of the decision which mentioned creation of a Committee of Experts for Research, Studies and 
Evaluations in the field of Health (CEREES) in application of French law no. 2016-41 in 
modernisation of the health system of 26 January 2016, and the decision on application of the so-
called Jardé law no. 2016-1537 of 16 November 2016, the departments of the minister of research 
are no longer competent to analyse corrections made to research projects.  
Also, in conformity with law 78-17 of 6 January 1978 relating to data processing, files and freedoms 
as modified by law 2004-801 of 6 August 2004 relating to protection of physical persons with regard 
to processing of personal data, the protocol has been the subject of a declaration of conformity with 
a reference methodology to the National Commission on Data Processing and Freedoms (CNIL). 
Data collected will correspond strictly to the field of application of the methodology of reference 
MR-003 of CNIL and Pfizer agrees to follow this methodology, which will be added to the study 
documents.  
 
 
9.5. Ethical conduct of the study 
The study will be conducted in conformity with legal and judicial requirements, as well as the 
objective, the scientific value and rigour and in compliance with generally accepted research 
practices described in the recommendations on Good pharmaco-epidemiological practices (GPP) 
published by the International Society for Pharmaco-epidemiology (ISPE), recommendations  on 
Good epidemiology practice (GEP) published by the International Epidemiological Association 
(IEA), Good practices of research on results published by the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR), the international ethical recommendations 
for epidemiological research published by the Council for International Organizations of Medical 
Sciences (CIOMS), the European network of centres of pharmaco-epidemiology and 
pharmacovigilance (ENCePP) and the  European Medicines Agency (EMA),  

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the Guide of methodological standards in pharmaco-epidemiology, and guidance of the FDA for 
industry: 
Good 
pharmacovigilance 
and 
pharmaco-epidemiological 
assessment 
(Good 
Pharmacovigilance and Pharmacoepidemiologic Assessment), directives of the Food and Drug 
Administration (FDA) and for the pharmaceutical industry and staff of the FDA: Good practice of 
conduct and of reporting of pharmaco-epidemiological safety studies using all electronic medical 
data, guidelines for industry: Measures of outcome noted by the patient: Use in development of 
medical products to support the labelling of the label and/or equivalent.  
 
 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS  
10.1. Requirements in terms of pharmacovigilance 
The following table summarises the requirements for recording of adverse events in the electronic 
case report and for reporting adverse events via the adverse event report form of non-interventional 
studies in Pfizer pharmacovigilance (NIS AEM Report Form). These requirements are defined by 
three types of events:  
(1) Serious adverse events (SAE) 
(2) Non-serious adverse events (AE) (if applicable), and  
(3) Situations involving exposure to a medicinal product, including exposure in pregnancy, 
exposure in breastfeeding, medicinal product errors, overdose, misuse, extravasation, 
and occupational exposure. These events are defined in the section entitled “Definition 
of an adverse event”.  

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Adverse events must be reported to Pfizer within 24 hours after the participating doctor becomes 
aware of the event, whether the event has been considered as related or not to the study medicinal 
product by the participating doctor.  
In particular, if the serious adverse event is fatal or life-threatening, the event should be reported to 
Pfizer immediately, whatever the information available on the adverse event. This time period also 
applies to all new information (follow-up) relating to reports of adverse events previously sent. In 
rare cases, where the participating doctor is not immediately informed of the outcome of an adverse 
event, the participating doctor should report the event within 24 hours after he/she became aware of 
it and provide information on the time when he/she became aware of this adverse event for the first 
time.  
For adverse events considered as serious or identified in the right column of the abovementioned 
table which are to be reported to Pfizer within 24 hours of awareness of them, the participating 
doctor is required to look for and provide all information to Pfizer in conformity with this time 
period of 24 hours. Furthermore, Pfizer can request to obtain urgently from the participating doctor 
specific additional information on follow-up. Such information can be more detailed than that 
reported in the study case report. Generally, such information will include a sufficiently detailed 
description of the adverse event in order to enable a complete medical evaluation of the case and an 
independent determination of the possible causal relationship. All relevant information regarding 
the event such as concomitant treatments or disorders must be provided. In case of death of a patient, 
a summary of available results of an autopsy should be sent as soon as possible to Pfizer or to its 
certified representative. 
10.2. Period of reporting 
For each patient, the period of reporting of adverse events starts with the time when the patient 
received the first dose of the study medicinal product or from the date on which the patient provided 
his/her informed consent if he/she has already been exposed to the study medicinal product and ends 
with the end of the period of observation of the study, i.e. at least at the end of a period of 28 calendar 
days after the last dose of the medicinal product of the study. A report should be sent the PFIZER 
Pharmacovigilance or its certified representative for all types of adverse events listed in the 
abovementioned table and which occurred during this period. If the patient received the study 
medicinal product on the last day of the observational period, the period of reporting will be extended 
28 calendar days after the end of the observational period.  
In cases where the patient provided his/her consent but was never included in the study (for example: 
the patient changed his/her mind on participation; failure in screening criteria), the period of 
reporting ends with date of decision on non-inclusion of the patient.  

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If the participating doctor becomes aware of a serious adverse event which occurred at any time 
after the end of the observational period and that he/she considers related to a study medicinal 
product, this serious adverse event should also be reported to the Pfizer Pharmacovigilance 
department. 
10.3. Evaluation of causal relationship 
The participating doctor must assess and report the causal relationship. For all adverse events, 
sufficient information must be obtained by the participating doctor in order to determine the causal 
relationship of each adverse event. For AE considered as related to a study medicinal product, the 
participating doctor is required to perform follow-up until resolution or stabilisation of the event 
and/or of its sequelae at a level considered acceptable by the participating doctor and that Pfizer 
agrees with this evaluation.  
The evaluation of the causal relationship by the participating doctor is the determination of the fact 
that a reasonable possibility exists that a study medicinal product has caused or contributed to an 
adverse event. If final determination of the causal relationship is “unknown” and that the 
participating doctor cannot determine if a study medicinal product has caused the event, then the 
event should be reported within 24 hours.  
If the participating doctor cannot determine the aetiology of the event, but that he/she has determined 
that no study medicinal product was the cause of the event, this should be clearly mentioned in the 
case report form and in the adverse event report form in non-interventional studies.  
10.4. Definition of an adverse event 
10.4.1. Adverse event 
An adverse event is any untoward manifestation which occurs in a patient in whom a medicinal 
product was administered and the event does not necessarily have a causal relationship with this 
treatment or its use. Examples of adverse events include, without this list being limited to, the 
following:  
a. Abnormal test results (see in the following for circumstances in which an abnormal test result 
constitutes an AE); 
b. 
Clinically significant symptoms and signs, 
c. 
Changes to results of a clinical examination,  
d. 
Hypersensitivity reactions,  
e. 
Progression/worsening of an underlying disorder; 
f. 
Lack of efficacy;  
g. 
Medicinal product abuse;  
h. 
Medicinal product dependence.  
 
Furthermore, for medicinal products, they can include signs or symptoms resulting: 

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a. 
From an overdose; 
b. 
From withdrawal;  
c. 
From misuse;  
d. 
From off-label use (off-label use in the Marketing Authorisation); 
e. 
Medicinal product interactions;  
f. 
Of extravasation; 
g. 
Of exposure in pregnancy;  
h. 
Of exposure during breastfeeding;  
i. 
Of a medicinal product error; 
j. 
Of occupational exposure. 
 
Abnormal test results 
Criteria enabling to determine if an abnormal result of an objective test must be reported as 
an adverse event are as follows:  
• The test result is associated with symptoms, and/or  
• The test result requires additional diagnostic investigation or medical/surgical intervention, 
and/or 
• The test result leads to a change in posology or to withdrawal of a patient from the study, the   
administration of a significant additional concomitant treatment or to another treatment, 
and/or 
• The test result is considered as an adverse event by the participating doctor or the sponsor.  
The simple repetition of an abnormal test result, in the absence of one of the abovementioned 
conditions, does not constitute an adverse event. Any abnormal test result which proves to result 
from an error does not need to be reported as an adverse event. 
10.4.2. Serious adverse events 
A serious adverse event is defined as any untoward manifestation in a patient receiving a medicinal 
product or a nutritional product, whatever the dose, or using a medical device, and:  
• Which causes death;  
• Is life-threatening;  
• Requires hospitalisation of the patient or prolongation of hospitalisation (see following for 
circumstances in which this does not constitute an adverse event);  
• Results in permanent or important disability or incapacity (important alteration of capacity 
to perform actions of daily life); 
• Results in a congenital anomaly or a malformation.  

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An event will be defined as a medically important event based on medical and scientific judgement. 
A medically important event may not be immediately life-threatening and/or resulting in death or 
hospitalisation. However, if it is established that the event can be life-threatening and/or require an 
intervention in order to avoid one of the abovementioned outcomes, the medically important event 
must be reported as serious.  
Events which, for example, enter into this category of medically important events are allergic 
bronchospasm requiring intensive care in a hospital emergency room or in the patient’s home, 
bleeding disorders, seizures which have not resulted in hospitalisation, or development of medicinal 
product dependence or medicinal product abuse.  
Furthermore, all suspicion of transmission of an infectious agent, pathogenic or not, by a Pfizer 
product is considered as a serious adverse event. This event can be suspected by clinical symptoms 
or test results indicating an infection in a patient exposed to a Pfizer product. The terms “suspicion 
of transmission” and “transmission” are considered as synonymous. 
Such cases are considered as unexpected and should be managed as serious cases by the Pfizer 
Pharmacovigilance department. These cases can also be reported as a product defect, if applicable. 
Hospitalisation 
Hospitalisation is defined as any initial admission (even for a duration of less than 24 hours) in a 
health establishment or any prolongation of an admission. 
An admission also includes the transfer within the hospital to an intensive care unit (for example, 
from a psychiatry department to a medical department, from a medical department to the coronary 
care unit, from the neurology department to a medical unit for tuberculosis). 
A consultation in the emergency room does not necessarily constitute a hospitalisation; however, an 
event which leads to a consultation in the emergency room (ER) should be evaluated as medically 
important.  
A hospitalisation in the absence of an adverse event does not constitute an adverse event in itself 
and does not require to be reported. For example, the following reasons for hospitalisation without 
AE that are not be reported.  
• Social admission (for example, the patient has no place to sleep) 
• An administrative admission (for example, for an annual check-up) 
• An optional admission not associated with a triggering AE (for example, for a scheduled 
cosmetic surgery procedure)  
• Hospitalisation for observation in the absence of an AE 

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• Admission for treatment of a pre-existing condition not associated with development of a 
new AE nor worsening of a pre-existing condition (for example, for an assessment following 
persistence of abnormal laboratory test data pre-existing prior to treatment) 
• Admission planned by the protocol during a clinical study (for example, for a procedure 
required by the study protocol).  
 
10.5. Situations requiring reporting to Pfizer Pharmacovigilance within 24 hours. 
Situations involving exposure in pregnancy, exposure during breastfeeding, a medicinal product 
error, an overdose, misuse, extravasation, lack of efficacy and occupational-related exposure are 
described in the following. 
Exposure in pregnancy (or exposure in utero) 
 
Exposure in pregnancy occurs if: 
1. A woman becomes pregnant or it turns out that she is pregnant while she is receiving or is 
exposed to a medicinal product of the study (for example, environmental exposure), or a 
woman becomes pregnant or it turns out that she is pregnant after having discontinued and/or 
having been exposed to the medicinal of the study (maternal exposure); 
An example of environmental exposure would be a case involving direct contact with a Pfizer 
product in a pregnant woman (for example, a nurse reports that she is pregnant and has been 
exposed to chemotherapy products).  
2. A man has been exposed, in the setting of a treatment or of environmental exposure to a 
medicinal product of the study before or around the period of conception and/or has been 
exposed during pregnancy of his partner (paternal exposure). 
Generally, cases of prospective and retrospective exposure during pregnancy, whatever the source, 
are to be reported, whether a concomitant adverse event is present or not, according to the procedure 
for reporting serious adverse events.  
If a female patient in the study or the partner of a male patient in the study becomes pregnant or it 
turns out that she is pregnant during treatment of a patient in the study with a medicinal product in 
the study, the participating doctor must report this information to Pfizer, whether an adverse event 
has occurred or not, by completing the adverse event report form for non-interventional studies, as 
well as the additional form “Exposure in pregnancy”.  
Furthermore, information relating to environmental exposure to a medicinal product of the study of 
a pregnant female patient (for example, a patient reports that she is pregnant and that she has been 
exposed to a cytotoxic product by inhalation or after accidentally spilling the product) must be 
reported to Pfizer, whether an adverse event has occurred or not, by completing the adverse event 
report form for non-interventional studies, as well as the additional form “Exposure in pregnancy”.

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The information sent should include the planned date of term of pregnancy (in the following for 
information concerning term of pregnancy). 
Follow-up should be implemented in order to obtain general information on pregnancy.  
Furthermore, follow-up should be initiated to obtain information on the outcome of pregnancy for all 
cases which are the subject of reporting of exposure in pregnancy whose outcome is unknown.  
A pregnancy should be followed up to term or up to termination of pregnancy (for example, voluntary 
termination of pregnancy) and Pfizer must be informed of its outcome.  
This information will be provided as follow-up to the initial report on exposure in pregnancy. In case 
of the birth of a baby, the structural integrity of the neonate can be evaluated at time of birth.  
In case of termination of pregnancy, the reason must be specified and, if possible clinically, the 
structural integrity of the foetus must be evaluated by visual inspection (unless results of tests 
performed prior to the procedure have concluded in a congenital anomaly and these results have been 
reported).  
If the outcome of pregnancy corresponds to criteria of an SAE (for example, an ectopic pregnancy, a 
spontaneous abortion, foetal death in utero, neonatal death, a congenital anomaly [for a live birth, an 
aborted foetus, foetal death in utero, or neonatal death]), procedures for reporting SAE must be 
followed.  
Additional information on the outcome of pregnancy which are reported as an SAE are as follows:  
• A spontaneous abortion which includes a miscarriage and retention of the foetus;  
• Neonatal death which occurs within a month after birth must be reported, whatever the causal 
relation as an SAE. Furthermore, the death of an infant more than 1 month of age must be 
reported as a SAE when the participating doctor assesses the death of the baby of a very 
young age as related or possibly related to exposure to the studied product. 
 
Additional information on exposure in pregnancy can be requested. Follow-up on outcome at birth 
will be processed on a case-by-case basis (for example, follow-up of pre-term neonates of low 
gestational age in order to identify developmental retardation). 
In case of paternal exposure, a form for reporting information intended for pregnant partners will be 
given to the patient participating in the study for his partner. It must be documented that this 
document has been given to the patient participating in this study for transmission to his partner.  
Exposure during breastfeeding 

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Situations of exposure during breastfeeding must be reported, independently of existence of an 
associated AE.  
Reporting of exposure during breastfeeding should not be performed when a Pfizer product 
specifically indicated for use in a breastfeeding woman (ex.: vitamins) is administered in agreement 
with the MA.  
However, if the infant presents an AE associated with administration of a such a medicinal product, 
the AE must be reported with exposure during breastfeeding.  
Medicinal product error 
 
A medicinal product error means any unintentional error in prescribing, dispensing or administration 
of a medicinal product, which can cause or lead to inappropriate use of a medicinal product or to 
harm for the patient while the latter is under the control of the healthcare professional, the patient or 
the consumer. These events can be related to professional practice, the products, the procedures and 
to systems in particular: prescribing, transmission of an order; product information, packaging and 
nomenclature of the product, composition, dispensing, distribution, administration, training in the 
product, monitoring and use.  
Medicinal product errors include:  
a. Near-accidents, involving or not a patient directly (for example, inadvertent administration/error, 
which is accidental use of a product outside of the indication or the prescription by a healthcare 
professional or a patient/consumer); 
b. Confusion concerning the name of the patient (for example, commercial name, tradename);  
The participating doctor must report the following medicinal product errors to Pfizer, independently 
of existence of a concomitant AE/SAE: 
a. Medicinal product errors involving exposure of a patient to the product, whether the medicinal 
product error is accompanied by an adverse event or not.  
b. Medicinal product errors not involving a patient directly (for example, potential errors or near 
adverse events). Whenever a medicinal product error does not involve exposure of a patient to a 
product, the following minimal criteria comprise a case of a medicinal product error:  
- 
An identifiable reporting party; 
- 
A suspect product;  
- 
A medicinal product error. 
Overdose, Misuse, Extravasation 

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Cases of an overdose, misuse and extravasation associated with use of a Pfizer product must be 
reported to Pfizer by the participating doctor, independently of existence of a concomitant AE/SAE. 
 Lack of efficacy 
Cases of lack of efficacy of a Pfizer product should be reported to Pfizer by the participating doctor 
independently of the existence of a concomitant AE/SAE or of indication of a Pfizer product.  
Occupational exposure 
Cases of occupational exposure to a Pfizer product should be reported to Pfizer by the participating 
doctor independently of existence of a concomitant AE/SAE.  
 
 
10.6. Single reference document on safety 
The reference document to use during this study is the Summary of Product Characteristics (SmPC) 
in force in France. 
This single reference document on safety should be used by the participating doctor for prescribing 
information and recommendations.  
 
 
11. PLANS ON COMMUNICATION OF STUDY RESULTS 
Pfizer and the scientific committee aggress to send the study results to all doctors who participated 
in the study.  
The list of participating doctors will be systemically associated in all publications.  
At least one communication and one publication are planned at end of study.  
 
11.1. Scientific committee 
A qualified, multi-disciplinary Scientific Committee has been set up for the study. It consists of 2 
rheumatologists and 2 gastroenterologists who participated in drafting of the protocol and in its 
validation and who will participate in validation of the statistical analysis plan and in drafting of the 
clinical report. The scientific committee also has the mission of proposing and/or of validating 
changes 
to 
the 
protocol 
once 
the 
study 
is 
ongoing. 
 

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11.2. Access to source data 
Source data means all documents or an original object enabling to prove the existence or accuracy 
of data or of a fact recorded during the study, in particular, medical dossiers of patients included.  
Participating doctors will make available documents and individual data strictly necessary to data 
collection in the setting of the study, follow-up of the study, quality control and an audit of a 
biomedical research study, the disposition of persons having access to documents in conformity with 
legislative and regulatory conditions in force (articles L.1121-3 and R.5121-13 of the public health 
code). 
 
 
11.3. Confidentiality 
In conformity with legislative conditions in force (articles L.1121-3 and R.5121-13 of the public 
health code), persons with direct access to source data will take all necessary precautions in order to 
ensure confidentiality of information relating to investigational medical devices, a research study, 
persons who are subjects in it and, in particular, concerning their identity as well as the results 
obtained. Such persons, in the same capacity as participating doctors themselves, are subject to 
professional secrecy. 
During the research study or at its end, data collected on persons who are subjects in it and sent to 
the sponsor by participating doctors (or all other specialised participants) will be made anonymous. 
In any case, they must not clearly reveal the names of persons concerned nor their address. 
No data by name concerning the patient will be collected.  
The sponsor (or its representative) will make certain that each person who is a subject in the research 
study has given his/her agreement for access of individual data concerning him/her and strictly 
necessary in quality control of the study. 
 
11.4. Property of data 
PFIZER PFE France (Pfizer Group) will retain the right of property of all forms in the case reports, 
data analyses and reports which result from this study.  
 
11.5. Communication and publication 
All information obtained based on this study will be considered as confidential, up until the analysis 
and final review by PFIZER PFE France (Pfizer Group) and by members of the scientific committee 
have been performed.  
Results of this study can be edited or presented by members of the scientific committee after revision 
and agreement of PFIZER PFE France (Pfizer Group), and such that the confidential  

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information or industrial property is not disclosed. Prior to publication or presentation, a copy of the 
final text should be sent by members of the scientific committee to Pfizer PFE France (Pfizer Group), 
for comment. Such comments will aim to ensure the scientific content of publications and/or 
presentations proposed and to ensure that the data and the material relating to products and activities 
of PFIZER PFE France (Pfizer Group) receive a just, precise and reasonable presentation.  
 
 
11.6. Communication of problems 
In the eventual case of prohibition or a restriction imposed (for example, suspension of the study) 
by a competent authority responsible in whatever region of the world, or if the participating doctor 
becomes aware of new information which could influence the evaluation of benefits and risks of a 
PFIZER PFE France (Pfizer Group) product, PFIZER PFE France (Pfizer Group) must immediately 
be informed of it.  
Furthermore, the participating doctor will immediately inform PFIZER PFE France (Pfizer Group) 
of all urgent measures of safety taken by the participating doctor in order to protect patients in this 
study against all immediate hazard and all serious violations of this protocol of a non-interventional 
study for which the participating doctor is aware of.  
 
 
11.7. Financing of the Study  
Conduct of this observatory is paid for by PFIZER PFE FRANCE (PFIZER GROUP). 

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12. REFERENCES 
1. Cho J, Feldman M. Heterogeneity of autoimmune diseases: pathophysiologic 
insights from genetics and implications for new therapies. Nature Medicine 2015; 
21:730-738 
2. Cooper G., Bynum M., Somers E. Recent insights in the epidemiology of autoimmune 
diseases: improved prevalence estimates and understanding of clustering of diseases. Journal 
of Autoimmunity 2009; 33(3-4):197-207 
3. Assurance Maladie. Répartition et taux pour les principales maladies (CIM-10) des 
personnes en affection de longue durée (ALD 30 ou 31) au 31 décembre 2013 pour le 
régime général (population prévalente), caractéristiques d’âge et de sexe (tableau III). 
(Medical Insurance Fund. Distribution and rates for the main disorders (ICD-10) persons 
with long-duration disorders (ALD 30 or 31) as of 31 December 2013 for the general plan 
(prevalent population), characteristics of age and sex (table III). Available on 
http://www.ameli.fr/l-assurance-maladie/statistiques-et-publications/donnees- 
statistiques/affection-de-longue-duree-ald/prevalence/frequence-des-ald-au-31-12-2013.php 
(consulted in September 2015). 
4. EMA. Inflectra Assessment Report. EMA/CHMP/589422/2013. Available on: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- 
_Public_assessment_report/human/002778/WC500151490.pdf (consulted in September 2015) 
5. "Infliximab Product Approval Information - Licensing Action". Drugs@FDA. U.S. 
Food and Drug Administration (FDA). Retrieved 2009-11-14 
6. Weise M, Bielsky MC, Smet K et al. Biosimilars: what clinicians should know. 
Blood. 2012; 120: 5111-5117. 
7. Merck and Co, 2013 Annual Report, available on: 
http://www.merck.com/investors/financials/form-10-k-2013.pdf (consulted in June  
2015) 
8. Haustein R, Millas C, Hoer A et al. Saving money in the European healthcare 
systems with biosimilars. Generics and Biosimilars Initiative Journal. 2012; 1(3-4): 
120-6. 
9. ACR, available on http://www.rhumato.info/cours-revues2/115-polyarthrite- 

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rhumatoide/1699-evaluation-de-la-polyarthrite-rhumatoide (consulted in December 
2015) 
10. DAS28, available on http://www.rhumatologie.asso.fr/03-Services/instruments- 
pratiques/DAS28.html (consulted in December 2015) 
11. BASDAI, available on: http://www.asas-group.org/clinical-instruments.php?id=04 
(consulted in November 2015) 
12. BASFI, available on: http://www.asas-group.org/clinical-instruments.php?id=04, 
(consulted in November 2015) 
13.Harvey Bradshaw Index, available on: http://www.gastroenterologue-poitiers.fr/wp- 
content/uploads/media/pdf/mici/memo/fiche_08.pdf (consulted in November 2015) 
14.Mayo score, available from: 
http://www.gastro.medline.ch/Services_et_outils/Scores_cliniques/Scores_cliniques.php#ev
a l Accessed November 2015 
15.PUCAI, available from: http://www.bespghan.be/docs/PUCAI.pdf Accessed 
novembre 2015 
16. N. W. Boone et al The nocebo effect challenges the non-medical infliximab switch 
in practice European Journal of Clinical Pharmacology (2018) 
17. Mourad F. Rezk et al Treatment Outcomes with Biosimilars: Be Aware of the Nocebo 
Effect Rheumatol Ther (2017) 4:209–218 
18. ANSM: Etat des lieux sur les médicaments biosimilaires. May 2018 

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13. LIST OF TABLES 
No table of contents entries found. 
14. LIST OF FIGURES 
 
 
ANNEX 1. ADVERSE EVENT REPORT FORM   
ANNEX 2. PREGNANCY FOLLOW-UP AND CHILDBIRTH FOLLOW-UP FORM    
ANNEX 3. SEVERITY RATING SCALE 
ANNEX 4. CONSENT FROM A MINOR PATIENT 
ANNEX 5 CONSENT FROM AN ADULT PATIENT 
ANNEX 6. RHEUMATOLOGIST CRF 
ANNEX 7. GASTROENTEROLOGIST CRF 
ANNEX 8. SUMMARY OF PRODUCT CHARACTERISTICS