An Active Surveillance to Monitor the Real World Safety in Indian Patients Prescribed Nintedanib for the Treatment of Locally Advanced, Metastatic or Locally Recurrent Non Small Cell Lung Cancer (NSCLC) of Adenocarcinoma Tumor Histology After First Line Chemotherapy
Conditions: Non-small Cell Lung Cancer
Sponsor: Boehringer Ingelheim

ABCD
 
Active Surveillance Protocol
 
Document Number:
c13593217-03
BI Study Number:
1199.272
BI Investigational
Product(s):
Nintedanib
Title:
An active surveillance to monitor the real world safety in Indian 
patients prescribed nintedanib as per approved Indian Label for 
the treatment of locally advanced, metastatic or recurrent non-
small cell lung cancer (NSCLC) of adenocarcinoma tumour 
histology after first-line chemotherapy.
Protocol version 
identifier:
4.0
Date of last version of 
protocol:
19 July 2018
PASS:
Yes
EU PAS register 
number:
EUPAS17078
Active substance:
Nintedanib
Medicinal product:
Nintedanib Capsules 150mg
Nintedanib Capsules 100mg
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
To evaluate real-world safety of nintedanib in Indian patients 
with non small cell lung cancer of adenocarcinoma histology
after first line of chemotherapy.
Country(-ies) of study:
India
Author:
Marketing authorisation 
holder(s):
MAH contact person:

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EU-QPPV:
Signature of EU-QPPV:
(The signature of the EU-QPPV is provided electronically)
Date:
04 Jun 2021
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Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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2.
TABLE OF CONTENTS
 
......................................................................................................... 1
2.
TABLE OF CONTENTS....................................................................................... 3
4.
RESPONSIBLE PARTIES.................................................................................... 6
6.
AMENDMENTS AND UPDATES..................................................................... 19
7.
MILESTONES..................................................................................................... 52
8.
RATIONALE AND BACKGROUND................................................................ 53
9.
RESEARCH QUESTION AND OBJECTIVES ................................................. 54
10.
RESEARCH METHODS .................................................................................... 55
10.1
STUDY DESIGN............................................................................................ 55
10.3
VARIABLES .................................................................................................. 59
10.3.1
Exposures ................................................................................................ 59
10.3.2
Outcomes................................................................................................. 59
10.4
DATA SOURCES........................................................................................... 62
10.5
SAMPLE SIZE ............................................................................................... 62
10.6
DATA MANAGEMENT................................................................................ 62
10.7
DATA ANALYSIS......................................................................................... 62
10.7.1
Analyses of outcome events.................................................................... 63
10.7.2
Interim analyses....................................................................................... 63
10.8
QUALITY CONTROL................................................................................... 64
10.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 64

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10.10 OTHER ASPECTS ......................................................................................... 64
10.10.1
Informed consent, data protection, study records ................................... 64
10.10.1.1
Study approval, patient information, and informed consent....................64
10.10.1.2
Data quality assurance .............................................................................65
10.10.1.3
Records ....................................................................................................65
10.10.1.4
Statement of confidentiality.....................................................................65
11.
PROTECTION OF HUMAN SUBJECTS .......................................................... 67
12.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 68
12.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 68
12.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 69
12.3
REPORTING TO HEALTH AUTHORITIES................................................ 71
13.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 72
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 74
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 75
ANNEX 3. CHILD PUGH CLASSIFICATION OF HEPATIC IMPAIRMENT........ 82

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4.
RESPONSIBLE PARTIES
Contact details and the list of all investigators will be kept in a stand-alone document.

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6.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or update
Reason
1
28 
Sep 
2016
Section 1
Change in page numbers 
Boehringer Ingelheim contact details
Incorporation of 
additional text
Address for 
regulatory 
communication
Section 2
DCGI, ECOG and EOT included in 
the list of abbreviations
Section 3
Boehringer Ingelheim contact details
Address for 
regulatory 
communication
Section 4
Amend from:
An active surveillance to monitor the 
real world safety of nintedanib in 
Indian patients for the treatment of 
locally advanced, metastatic or 
locally recurrent non-small cell lung 
cancer (NSCLC) of adenocarcinoma 
tumour histology after first-line 
chemotherapy.
Amend to:
An active surveillance to monitor the 
real world safety in Indian patients 
prescribed  nintedanib for the 
treatment of locally advanced, 
metastatic or recurrent non-small cell 
lung cancer (NSCLC) of 
adenocarcinoma tumour histology 
after first-line chemotherapy.
For more clarity
Section 4, 
9.1
Amend from:
In addition, 100 consecutive NSCLC
patients of adenocarcinoma 
histology who have progressed after 
first line chemotherapy and are 
planned to be treated with single 
agent docetaxel will also be 
registered from the same centres 
during the same time period.
For more clarity

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Amend to:
In addition, 100 consecutive locally 
advanced, metastatic or recurrent 
NSCLC patients of adenocarcinoma 
histology who have progressed after 
first line chemotherapy and are 
planned to be treated with single 
agent docetaxel will also be 
registered from the same centres 
during the same time period.
Amend from:
“Patients who will be prescribed 
nintedanib will have follow up 
visits”
Amend to:
“Patients who will be prescribed 
nintedanib are suggested to have 
further visits”
Section 4, 
9.2.2
Under inclusion criteria for patients 
initiating nintedanib: 
Amend from:
Patients who are newly prescribed 
nintedanib according to the package 
insert.
Amend to:
Patients ≥18 years of age with 
locally advanced and/or metastatic 
NSCLC of stage IIIB or IV, or 
recurrent NSCLC and 
adenocarcinoma histology after 
relapse or failure of first line of 
chemotherapy who are newly 
prescribed nintedanib according to 
the package insert. 
Amend from:
Patients with further follow-up  
possible with participating physician 
during the planned period of active 
surveillance
Amend to:
Patients in whom further 
visit/contact is possible during the 
planned period of active surveillance
Add: 
For more clarity

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Patients in whom information 
mentioned under section 9.2.2.2 is 
available
Under exclusion criteria for patients 
initiating nintedanib:
Add:
Patients who are positive for EGFR 
mutations and ALK rearrangements
Under inclusion criteria for patients 
planned to be treated with single 
agent docetaxel
Amend from:
In addition for the assessment of 
baseline characteristics,100 
consecutive NSCLC patients of 
adenocarcinoma histology who have 
progressed after first line 
chemotherapy and are planned to be 
treated with single agent docetaxel 
will be enrolled from the same 
centres/settings and timeframe.
Amend to:
In addition for the assessment of 
baseline characteristics,100 
consecutive locally advanced, 
metastatic or recurrent NSCLC 
patients of adenocarcinoma 
histology who have progressed after 
first line chemotherapy and are 
planned to be treated with single
agent docetaxel will be enrolled 
from the same centres/settings and 
timeframe.
Under exclusion criteria for patients 
planned to be treated with single 
agent docetaxel
Amend from:
Willingness to provide informed 
consent to collect the baseline 
characteristics
Amend to:
Willingness to provide informed 
consent to collect the information 
mentioned under section 9.2.2.2

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Section 4, 
9.1, 
Flowchart, 
9.2.2.1, 
9.2.2.3,  
9.3.3, 9.4, 
9.7, 9.7.1, 
11.2,
“Baseline visit” changed to “visit 1” 
“follow-up visits” changed to 
“further visits”
For more clarity
Section 4, 
9.2.2.2, 
9.3.3
Under NSCLC related variables
Amend from:
Stage of the disease (Stage IIIB or 
IV), for stage IV: location of 
metastases; Brain metastases at visit 
1
Amend to:
Locally advanced/metastatic/ 
recurrent disease; stage of the 
disease; for stage IV- location of 
metastases; brain metastases at visit 
1
For more clarity
Section 4
Protocol amendment date added. 
Change in timelines
Timelines 
changed 
according to the 
anticipated date 
of availability of 
commercial 
stocks
Flowchart
“Before the start of drug 
administration”-  deleted
“Date of start administration” 
changed to “Drug administration”. 
Foot note # added to explain the 
dosage and timing of administration 
of nintedanib. 
Foot note 1 changed from 
“Pregnancy status will be recorded at 
the baseline and follow up  visits” to 
“Starting dose of docetaxel should 
be recorded in eCRF and source 
notes” 
Foot note 2 updated to clarify that 
height should be collected at 
baseline visit only.
Asterix * added to vital signs and 
For more clarity

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physical examination 
Foot note $ added in docetaxel 
flowchart to elucidate that starting 
dose of docetaxel should be recorded 
in eCRF and source notes. 
Section 9.1
Amend from:
“Patients who will be prescribed 
nintedanib will have follow up 
visits”
Amend to:
“Patients who will be prescribed 
nintedanib are suggested to have 
further visits”
Section 9.1
Collection of safety information 
telephonically for patients who are 
lost to follow up.
In order to 
minimise missed 
data
Section 
9.3.2
Amend from:
Percentage of patients who require 
dose reductions (nintedanib and 
docetaxel, docetaxel 
discontinuations)
Amend to:
Percentage of patients who require 
nintedanib dose reductions and 
discontinuations due to adverse 
events
To collect 
additional safety 
information on 
discontinuations 
for nintedanib 
due to adverse 
events. Since it is 
an active 
surveillance of 
nintedanib 
information on 
docetaxel 
discontinuations 
will not be 
collected
Section 
9.3.3
In the section on thrombotic risk –
“start date, stop date/ongoing, please 
specify” added
For more clarity
Section 
9.7.2
Amended from:
Interim analyses  will be performed 
for the purpose of creating periodic 
safety update reports to the local 
authority (every 6 to 12 months 
depending on the time from the 
approval).
Amended to:
No interim analysis is planned for 
this active surveillance
PSURs will be 
submitted at 
regular intervals. 
Submission of 
PSUR will not 
require interim 
analysys.

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Section 
9.10.1.1
Amend from:
The  review by Drug controller 
general of India (DCGI), the 
approval of Institutional Review 
Board (IRB) or Ethics Committee 
will be sought before the start of this 
active surveillance.  
Amend to:
In addition to  review and approval 
by Drug controller general of India 
(DCGI), the approval of Institutional 
Review Board (IRB) or Ethics 
Committee will be sought as per the 
institutional procedures before the 
start of this active surveillance.  
To comply with 
the institutional 
procedures 
Section 
9.10.1.1
Amended from:
The Investigator must sign (or place 
a seal on) and date the informed 
consent form.
Amended to:
The Investigator must sign and date 
the informed consent form.
Investigator sign 
is required on 
ICF
Section 
9.10.1.4
Amend from:
Data generated as a result of this 
active surveillance need to be 
available for inspection on request 
by the participating physicians, the 
sponsor’s representatives, by the 
IRB / IEC and the regulatory 
authorities.
Amend to:
Data generated as a result of this 
active surveillance need to be 
available for inspection on request 
by the sponsor’s representatives, by 
the IRB / IEC and the regulatory 
authorities.
The data will be 
available for 
inspection by the 
sponsor’s 
representatives, 
by the IRB / IEC 
and the 
regulatory 
authorities.
Section 
11.2
Amend from:
The following must be collected by 
the investigator in the CRF from first 
intake of nintedanib at scheduled 
visits and within 28 days (inclusive) 
after last intake in patients exposed 
to nintedanib (= end of study)
For more clarity

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Amend to:
The following must be collected by 
the investigator in the CRF from 
signing the informed consent 
onwards at scheduled visits and 
within 30 days (inclusive) after last 
intake in patients exposed to 
nintedanib (= follow up visit)

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Number
Date
Section of 
study 
protocol
Amendment or update
Reason
2
19
Jul
2018
Section 1
Change in page numbers 
Update in Protocol version, version date 
and Author
Administra
tive change
Section 1 & 
Section 5
An active surveillance to monitor the real 
world safety in Indian patients prescribed 
nintedanib as per approved Indian Label
for the treatment of locally advanced, 
metastatic or recurrent non-small cell lung 
cancer 
(NSCLC) 
of 
adenocarcinoma 
tumour 
histology 
after 
first-line 
chemotherapy.
Administra
tive update 
for better 
clarity
Section 3
Abbreviation of MAH added
Administra
tive update 
for better 
clarity
Section 5: 
&
Section 8:
Rationale 
and 
Background
Although about 70% of patients initially 
achieve clinical remission or disease 
stabilisation 
with 
first-line 
platinum-
containing therapy, nearly all have disease 
progression and need second line therapy
further lines of therapies. Currently in 
India, docetaxel, pemetrexed, erlotinib 
and 
immunotherapeutic 
drugs 
like 
nivolumab, 
pembrolizumab 
and 
atezolizumab are approved second line 
treatments
for NSCLC patients who 
progress on first line chemotherapy in 
non-small cell lung cancer (NSCLC) in 
India 
consist 
of 
monotherapy 
with 
docetaxel, erlotinib, or pemetrexed. The 
median overall survival for all these 
second line treatments is approximately 8 
– 13 months. Therefore, tThere is still a 
high unmet need for new effective 
treatments for these patients. second line
treatments for patients with NSCLC.
The proposed active surveillance aims to 
collect the real world safety data of 100 
patients at twenty (20) selected centres 
who will be prescribed treated with
Administra
ti ve update 
for better
clarity.

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nintedanib & docetaxel per the approved 
Indian label within first two years from 
the date of commercial availability of 
drug in India (23rd January 2017)or until 
a maximum of two years whichever occurs 
first at selected centres.

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Section 5: 
&
Section 9:
Research 
question 
and 
objectives
This active surveillance aims to collect the 
safety data of include 100 consecutive 
NSCLC patients with adenocarcinoma 
histology who will be prescribed treated 
with nintedanib per the approved Indian 
label within two years from the date of 
the commercial availability of the drug 
in India (23rd January 2017).or until a 
maximum of two years whichever occurs 
first. The objective is to look at the safety 
of nintedanib in the real world setting.
Administra
ti ve update 
for better
clarity.
Section 5: 
&
Section 
10.1:
Study 
design
100 NSCLC patients treated with 
nintedanib per the approved Indian 
label will be enrolled in this active 
surveillance. They are classified into 
following groups:
An active surveillance based on newly 
collected data.
Group A.
Patients 
who 
started 
treatment with nintedanib 
& docetaxel after  23rd
January, 2017 and have 
discontinued the drug at 
the time of participation in 
the active surveillance.
Group B.
Patients 
who 
started 
treatment with nintedanib 
& docetaxel after 23rd 
January, 2017 and are 
continuing the drug at the 
time of participation in the 
active surveillance .
Group C.
Patients who have been 
newly 
prescribed 
nintedanib & docetaxel at 
the time of participation in 
the active surveillance.
In addition 100 locally advanced, 
metastatic or recurrent non-small cell 
lung 
cancer 
(NSCLC) 
of 
adenocarcinoma 
tumour 
histology 
treated with single agent docetaxel in the 
second after the first line chemotherapy
therapy will also be enrolled. They are 
classified into following groups:
To include 
the 
retrospecti
ve patient 
data

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single agent and docetaxel treated.)
The 
medical 
records 
of 
patients 
belonging to Group A and B will be 
evaluated to see if any ADRs or SAEs 
have occurred in the nintedanib & 
docetaxel arm during the duration of 
the treatment and up to 30 days 28 days 
after the last intake of the drug. Group 
B and Group C patients  are suggested 
to have further visits according to the 
clinical practice (approximately every 3 
weeks when given along with docetaxel 
and approximately every 4
weeks 
thereafter till the discontinuation of 
nintedanib); and an additional follow up 
visit up to 30 days 28 days after the last 
dose of nintedanib. At each visit, all 
ADRs associated with nintedanib and 
SAEs will be recorded and reported as 
per section 12.2.  There may be 
unscheduled 
visits 
between 
the 
scheduled visits. All ADRs and SAEs 
will 
also 
be 
collected 
at 
these 
unscheduled visits and entered into the 
eCRF. For nintedanib treated patients, 
certain information (e.g. co-medications, 
see flowchart) will also be collected at 
further and unscheduled visits (if 
available), as the status may change 
over the time. 
In case the patient is lost to follow up 
(patients not contactable for further 
visits), the site should attempt to contact 
the 
patient 
or 
patient’s 
relative 
telephonically to gather the information 
on the vital status and record it in the 
eCRF. 
Additionally, 
whenever 
the 
investigator becomes aware of  SAEs 
and/or any ADRs occurring in an 
enrolled 
patient, 
before 
individual 
patient’s end of study, it needs to be 
reported as per section 12.2. Patients 
who have taken at least one dose of 
nintedanib will be included in the safety 
analysis.This active surveillance will 
include 100 consecutive patients with 

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2. Patients who are positive for EGFR 
mutations or ALK rearrangements
Registration period:
This active surveillance will include 100 
NSCLC 
patients, 
treated 
with 
Nintedanib & Docetaxel (classified as 
Group A, B and C, see section 10.1) per 
the inclusion & exclusion criteria within 
two years from the date of the 
commercial availability of the drug in 
India (23rd January 2017). In addition, 
100 NSCLC patients who treated with 
single agent docetaxel (classified as 
Group I, II and II, see section 10.1) at 
the same centres and during the same 
time frame will also be included. The 
patient registration will continue until it is 
confirmed that 100 patients treated with 
nintedanib are included and that baseline 
characteristics of 100 additional patients 
(or as many patients as in the nintedanib 
group if <100) planned to be treated with 
single agent docetaxel are collected from 
the same centres during the same time 
frame, or until a maximum of two years, 
whichever occurs first. Patients who have 
taken at least one dose of nintedanib and 
have minimum of one further visit will be 
considered eligible to be included in the 
safety analysis.
Patient registration method:
At each study site, I In accordance with 
the inclusion & exclusion criteria, 100 
NSCLC patients who have been newly 
prescribed treated with nintedanib & 
docetaxel (classified as Group A, B and 
C, see section 10.1) according to the 
approved Indian label will be registered in 
a 
consecutive 
manner. 
In 
addition  
consecutive 
100 
locally 
advanced, 
metastatic or recurrent NSCLC patients of 
adenocarcinoma histology planned to be

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treated 
with 
single 
agent 
docetaxel 
(classified as Group I, II and III, see 
section 10.1) in the second after the first 
line therapy, from the same sites and 
during the same time period, will also be 
registered. The first patient enrolled at a 
given site should be in the nintedanib & 
docetaxel group. Once a patient is 
enrolled into the nintedanib & docetaxel 
group, the site team is suggested to enrol 
the next eligible patient, who had 
initiated/will be initiating single agent 
docetaxel at the same site in the 
docetaxel group.
Previous first line therapies and their 
duration
(platinum based or non
platinum based, and more specifically, 
previous treatment with bevacizumab)
End of registration
The patient registration will continue till 
100 consecutive patients treated with 
nintedanib & docetaxel after during the 
first two years, starting from the date of
commercial availability of the product 
drug in India (23rd January 2017), are 
included; and their safety data are 
collected till the drug discontinuation of 
the drug with an additional follow up 
visit up to 30 28 days after the last 
intake of the drug. or up to two years 
after the availability of nintedanib in India 
if less than 100 patients are included and 
baseline characteristics of 100 patients (or 
as many patients as in the nintedanib group  
if <100) planned to be treated with single 
agent docetaxel are collected from the 
same sites during the same time frame.
Baseline characteristics of 100 NSCLC 
patients 
treated 
with 
single 
agent 
docetaxel, at the same sites during the 
same period, will also be collected.
Section 5: 
Exposure to nintedanib will be estimated Administra

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Section 5: 
&
Section 
10.5
Sample 
Size
100 NSCLC patients who have initiated 
or will initiate nintedanib & docetaxel 
according to the approved Indian label 
(classified as Group A, B and C, see 
section 10.1) will be enrolled in this 
safety surveillance program. The sample 
size of 100 is as per the request from the 
regulatory 
agency.This 
active 
surveillance will be conducted up to the 
100 consecutive patients treated with 
nintedanib after commercial availability of 
the product in India per the approved label 
are included or up to two years after this 
availability of nintedanib in India if less 
than 
100 
patients 
eligible 
in 
the 
participating centres. The sample size of 
100 is a regulatory requirement.
In 
addition 
100 
consecutive 
locally 
advanced, metastatic or recurrent NSCLC 
patients of adenocarcinoma histology who 
have progressed after the first line 
chemotherapy and are planned to be were / 
are being treated with/ newly prescribe 
have initiated or will initiate d with
single agent docetaxel
(classified as 
Group I, II and II, see section 10.1) at 
the same centres and during the same 
time frame will also be included will be 
enrolled. The baseline characteristic of 
these patients will be recorded at visit 
1and they will not be followed.
To include 
the 
retrospecti
ve patient 
data and to 
provide 
better 
clarity.
Section 5: 
&
Section 
10.7
Data 
Analysis
The patients, who have taken at least one 
dose of nintedanib and have at least one 
further visit, will be included in the safety 
analysis.
The 
baseline 
characteristics 
of 
100 
consecutive NSCLC patients who are 
planned to be treated with single agent 
docetaxel in the second after the first line 
chemotherapy will be used to compare 
the patients profile with the nintedanib & 
docetaxel users and will assist to put the 
safety data of nintedanib into perspective.
Administra
tive update 
to provide 
better 
clarity.

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Any patient who meets at least one of the 
following criteria is treated as ineligible 
for all safety analyses: 
No further visit data are available
No r Required registration procedure is
was not followed
No valid site contract is available
Analyses of outcome events
In general, safety analyses will be 
descriptive in nature, and will be based on 
BI standards, and will focus on any 
suspected all ADRs
and  SAEsserious 
AEs and AEs leading to death.
To this end, all SAEs occurring between
first intake of nintedanib + docetaxel 
prescribed at baseline/ visit 1 and within 
30 days up to 28 days (inclusive) after the 
last 
intake
of 
nintedanib
will 
be 
considered ‘treatment emergent’.
The grading of adverse events ADRs and  
SAEs will be done by using Common 
Terminology Criteria for Adverse Events 
version 4 (CTCAE v4).
Interim analysis
No interim analysis is planned for this 
active surveillance program; however 
status report will be submitted to DCGI 
at the end of two years from the start of 
marketing of the drug in India.
Flowchart
FLOW 
CHART 
FOR 
PATIENTS 
TREATED WITH NINTEDANIB IN 
COMBINATION WITH DOCETAXEL: 
FOR 
PATIENTS 
PRESCRIBED 
NINTEDANIB 
IN 
COMBINATION 
WITH DOCETAXEL.
Time:- ## Approximately every 3 weeks 
Title 
of 
flow chart 
updated for 
better 
clarity

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with docetaxel and approximately every 4
weeks thereafter; a or at discontinuation 
(EOT)Visit 2 6
Time:- Visit 6 onwards, End of treatment; 
Follow up visit (End of treatment + 30 
days 28 days)
Item:- Updated according to the deletions 
in the time frame.
##Evaluation time points/visit schedules 
are approximate and are same for all types 
of patients (i.e. Group A, B and C patients 
mentioned under section 10.1). Collected 
data should be reported as those to the 
closest available visit. Group A patients, 
data will be collected retrospectively from 
their medical records. For Group B 
patients, 
data 
will 
be 
collected  
retrospectively from their medical records 
till the date of start of their participation in 
this active surveillance and prospectively 
thereafter. For Group C patients, data will 
be collected prospectively. There may be 
unscheduled visits between the scheduled 
visits. All ADRs and SAEs will also be 
collected at these unscheduled visits and 
entered into the eCRF. In case the patient 
is lost to follow up (patients not 
contactable for further visits), the site 
should attempt to contact the patient or 
patient’s relative telephonically to gather 
the information on the vital status and 
record it in the eCRF. at & s;ss will be 
reported as per.
# The administered dose of nintedanib should 
be recorded in the eCRF and source 
documents.
FLOW 
CHART 
FOR 
PATIENTS 
TREATED 
WITH 
SINGLE 
AGENT 
DOCETAXEL: 
FOR PATIENTS PRESCRIBED SINGLE 
AGENT DOCETAXEL
#For Group I and II patients (see section 
10.1), baseline data will be collected 

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retrospectively from their medical records 
at visit 1.
Section 
10.9
Limitations 
of the 
Research 
Methods
The scientific objective of this active 
surveillance program
is to obtain an 
estimate of the occurrence of ADRs and 
AEs (serious and fatal)SAEs in NSCLC 
patients prescribed nintedanib & docetaxel
per the approved Indian label in the real 
world setting. For retrospective data, 
there may be a possibility of missed 
information on adverse events. For 
patients followed prospectively, loss to 
follow up, loss of information and recall 
bias could impose limitations. Since only 
the cohort treated with nintedanib & 
docetaxel
will be followed up, it is 
impossible to assess the safety of nintedanib 
compared to other drugs. The possible 
selection bias will be minimized by 
enrolling all nintedanib & docetaxel 
treated patients (discontinued, ongoing 
and newly prescribed) from the date of 
commercial availability of the drug (23rd 
January 
2017) 
at 
selected 
centres
including 
consecutive 
patients; 
and 
potential channeling channelling bias will 
be assessed by recording the baseline 
characteristics of a comparator group of 100 
additional patients who are planned to be 
were/are
treated 
with 
single 
agent 
docetaxel in the second line after the first 
line therapy at same center during the 
same timeframe.However, other factors 
may impose limitations such as loss to 
follow up, information and recall bias.
Administra
tive update 
to provide 
better 
clarity.
Study approval, patient information, and 
informed consent:
Prior to patient participation in this active 
surveillance 
study,
written 
informed 
consent must be obtained from each patient 
(or 
the 
patient’s 
legally 
accepted 
representative) according to the regulatory 
and legal requirements of India (applicable 
for 
Group 
B/C 
and 
Group 
II/III 
patients).
The 
Investigator 
must 
give 
a 
full 
Administra
tive update 
to provide 
better 
clarity.

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explanation to the participants of this active 
surveilance 
surveillance
regarging
regarding the collection of the safety data 
at specific time points to the participants.
Section 11:
Protection 
of human 
subjects
There is no need for a clinical trial type
insurance to ensure the of well-being and 
rights of participants because since this is 
an active surveillance program of the 
patients prescribed nintedanib per the 
approved label in the real world setting
and there is no risk of an experimental 
treatment. There is no regulation or 
requirement for ensuring the well being 
and rights of participants.
Administra
tive update 
to provide 
better 
clarity.
Section 
12.2:
Adverse 
event and 
serious 
adverse 
event 
collection 
and 
reporting
all All ADRs (serious and non serious)
associated with nintedanib
All  SAEs serious and fatal AEs in patients 
exposed to nintedanib
All ADRs and AEs (serious and fatal) 
SAEs including those persisting after study 
completion must be followed up until they 
are 
resolved, 
have 
been 
sufficiently 
characterized, or no further information can 
be obtained.
Expedited Reporting of AEs and Drug 
Exposure During Pregnancy
Additionally, 
below 
mentioned 
information will also be collected for 
subjects identified under Group A and 
Group B during retrospective review of 
existing medical records
Administra
tive update 
to provide 
better 
clarity.
Section 13: 
Plans for 
disseminati
ng and 
communica
ting study 
results
A final report summarizing the results of the 
study and the analysis will be submitted to 
the Indian regulatory agency at the end of 
the active surveillance program And also 
final report will be submitted  in re
examination documents.
Administra
tive update 
to provide 
better 
clarity.

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Number
Date
Section of 
study 
protocol
Amendment or update
Reason
3
04
Jun
2021
Section 5
Abstract 
Milestones
& 
Section 7
  Milestones
3rd Protocol amendment: Actual
date added.
First patient in/  Start of data 
collection: Actual date updated.
Dates  updated:
-
Last patient out/ End of data 
collection 
-
Final report/ Final report of 
study results
Dates updated 
inline with the 
current study 
status.
Section 8
Rationale and 
background
& 
Section 14
Refrences
Unpublished references (U02-
1482, U11-1947)  have been 
replaced with a published 
reference (P14-16851).
Thus, rendering section 14.2 as
not applicable.
Provision of
applicable
published
reference.
Section 5
Abstract 
Population
&
Section 10.2.2 
               
Selection of 
population
Inclusion and exclusion criteria 
for patients being treated with 
nintedanib & docetaxel:
-
Exclusion criteria
1. Patients who were previously 
treated with nintedanib.
2. Patients who are positive for 
EGFR mutations or ALK 
rearrangements
3. Patients who are participating 
in a clinical trial.
Inclusion and exclusion criteria 
for patients being treated with 
single agent docetaxel:
-
Exclusion criteria
1. Patients who were previously 
treated with docetaxel.
Exclusion 
criteria # 2 
removed to align 
the use of 
Nintedanib with 
the current 
medical practice.
Exclusion 
criteria # 2 
removed to align 
the use of 
Docetaxel with 
the current 
medical practice.

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2. Patients who are positive for 
EGFR mutations or ALK 
rearrangements
3. Patients who are participating 
in a clinical trial.
Section 5
Abstract
Population
&
Section 10.2.2 
            
Selection of 
population
Inclusion and exclusion criteria 
for patients being treated with 
nintedanib & docetaxel:
-
Exclusion criteria
Amend from:
3. Patients who are participating 
in a clinical trial. 
Amend to:
2. Patients who are participating 
in a clinical trial. (Past 
participation in a clinical study is 
allowed so long as the 
participation ceased 30 days 
before the first dose of nintedanib 
or docetaxel)
Inclusion and exclusion criteria 
for patients being treated with 
single agent docetaxel:
-
Exclusion criteria
Amend from:
3. Patients who are participating 
in a clinical trial. 
Amend to:
2. Patients who are participating 
in a clinical trial. (Past 
participation in a clinical study is 
Text in bracket 
added to provide 
better clarity 
about the 
exclusion 
criteria.

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allowed so long as the 
participation ceased 30 days 
before the first dose of nintedanib 
or docetaxel)
Flow chart for 
patients 
treated with 
nintedanib in 
combination 
with docetaxel
Section 10.3.2
Outcomes
Section 
10.2.2.1
Registration 
period
Section 10.2.2
Selection of 
population
Date of last administration 
(treatment discontinuation) is 
included to be collected at
‘Approximately every 3 weeks 
with docetaxel and approximately 
every 4 weeks thereafter; or at 
discontinuation (EOT)’.
Amend from:
How to assess and report AEs 
including the definitions are 
described in section 11.
Amend to:
How to assess and report AEs 
including the definitions are 
described in section 12.
In addition, 100 NSCLC patients  
who treated with single agent
docetaxel……..
Inclusion and exclusion criteria 
for patients treated with single 
agent docetaxel:
-Inclusion criteria:
1. Patients in whom it is possible 
to obtain voluntary informed 
consent from either from the 
patient or………..
Typographical & 
grammatical 
errors rectified.

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Section 11
Protection of 
human 
subjects
There is no need for a clinical trial 
insurance to ensure the of well-
being and………..
Section 5 
Abstract
Rationale and 
background
Section 5 
Abstract
Research 
question and 
objectives
Amend from:
The proposed active surveillance 
aims to collect the real world 
safety data of 100 patients treated 
with nintedanib & docetaxel per 
the approved Indian label within 
two years from the date of 
commercial availability of drug in 
India (23rd January 2017) at 
selected centres.
Amend to:
The proposed active surveillance 
aims to collect the real world 
safety data of 100 patients treated 
with nintedanib & docetaxel per 
the approved Indian label within 
two years from the date of 
commercial availability of drug in 
India (23rd January 2017) or as 
mentioned in the study approval 
letter issued by the DCGI at 
selected centres.
Amend from:
This active surveillance aims to 
collect the safety data of 100 
NSCLC 
patients 
with 
adenocarcinoma histology treated 
with nintedanib per the approved 
Indian label within two years from 
the 
date 
of 
the 
commercial 
availability of the drug in India 
(23rd January 2017).
Amend to:
This active surveillance aims to 
For better clarity.

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Section 8
Rationale And 
Background
Section 9
Research 
Question And 
Objectives
collect the safety data of 100 
NSCLC 
patients 
with 
adenocarcinoma histology treated 
with nintedanib per the approved 
Indian label within two years from 
the 
date 
of 
the 
commercial 
availability of the drug in India 
(23rd 
January 
2017) 
or 
as 
mentioned in the study approval 
letter issued by the DCGI.
Amend from:
The proposed active surveillance 
aims to collect the real world 
safety data of 100 patients at 
selected 
centres 
treated 
with 
nintedanib per the approved label 
within two years from the date of 
commercial availability of drug in 
India (23rd January 2017).
Amend to:
The proposed active surveillance 
aims to collect the real world 
safety data of 100 patients at 
selected 
centres 
treated 
with 
nintedanib per the approved label 
within two years from the date of 
commercial availability of drug in 
India (23rd January 2017) or as 
mentioned in the study approval 
letter issued by the DCGI. 
Amend from:
This active surveillance aims to 
collect the safety data of  100 
NSCLC patients with 
adenocarcinoma histology treated 
with nintedanib per the approved 
Indian label within 2 years from 
the date of commercial 

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10.2.2.1
Registration 
period
availability of the drug in India 
(23rd January 2017).
Amend to:
This active surveillance aims to 
collect the safety data of  100 
NSCLC patients with 
adenocarcinoma histology treated 
with nintedanib per the approved 
Indian label within 2 years from 
the date of commercial 
availability of the drug in India 
(23rd January 2017) or as 
mentioned in the study approval 
letter issued by the DCGI.
Amend from:
This active surveillance will 
include 100 NSCLC patients, 
treated with Nintedanib &
Docetaxel (classified as Group A, 
B and C, see section 10.1) per the 
inclusion & exclusion criteria 
within two years from the date of 
the commercial availability of the 
drug in India (23rd January 2017).
Amend to:
This active surveillance will 
include 100 NSCLC patients, 
treated with Nintedanib &
Docetaxel (classified as Group A, 
B and C, see section 10.1) per the 
inclusion & exclusion criteria.
within two years from the date of 
the commercial availability of the 
drug in India (23rd January 2017).

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10.2.2.2
End of 
registration
10.7.2
Interim 
Analyses
Amend from:
The patient registration will 
continue till 100 patients treated 
with nintedanib and docetaxel 
during the first two years, starting 
from the date of commercial 
availability of the drug in India 
(23rd January 2017), are included; 
and their……………….
Amend to:
The patient registration will 
continue till 100 patients treated 
with nintedanib and docetaxel 
during the first two years, starting 
from the date of commercial 
availability of the drug in India 
(23rd January 2017) or as 
mentioned in the study approval 
letter issued by the DCGI, are 
included; and their……………..
Amend from:
No interim analysis is planned for 
this active surveillance program; 
however status report will be 
submitted to DCGI at the end of 
two years from the start of 
marketing of the drug in India.
Amend to:
No interim analysis is planned for 
this active surveillance program; 
however status report will be 
submitted to DCGI at the end of 
two years from the start of 
marketing of the drug in India or 

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as mentioned in the study 
approval letter issued by the 
DCGI.
12.2
Adverse event 
and serious 
adverse event 
collection and 
reporting
Expedited reporting of AEs and 
Drug exposure during Pregnancy
Amend from:
In specific occasions the 
Investigator could inform the 
Sponsor upfront via telephone. 
This does not replace the 
requirement to complete and fax 
the NIS AE form.
Amend to:
In specific occasions the 
Investigator could inform the 
Sponsor upfront via telephone. 
This does not replace the 
requirement to complete and send 
the NIS AE form.
To be in line 
with the the 
current practice.
12.2
Adverse event 
and serious 
adverse event 
collection and 
reporting
‘Exemption of disease progression 
from AE reporting’ added.
Safety analysis 
will focus on 
nintedanib safety 
profile.
Section 5
Abstract 
Study design
& 
Flow chart for 
patients 
treated with 
nintedanib in 
combination 
with docetaxel
Below mentioned text added:
Disease progression of the 
underlying malignancy reflects 
the natural course of the disease. 
As such it is exempted from 
reporting as a (S)AE. Progression 
of the subject's underlying 
malignancy will be recorded on 
the appropriate pages of the 
(e)CRF only and will not be 
reported on the NIS AE Form.
To be in line 
with section 
12.2, Exemption 
of disease 
progression from 
AE reporting

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Section 10.1
Study design
Section 5
Abstract 
Flow chart for 
patients 
treated with 
nintedanib in 
combination 
with docetaxel
Collection of adverse drug 
reactions (serious and non-
serious) and adverse events 
(serious and fatal) for Visit 1 is 
included.
To be in line 
with the section 
12.2
Annex 2
ENCePP 
Checklist for 
Study 
Protocol
An updated ENCePP Checklist for 
Study Protocol (Revision 4) is 
incorporated in place of Revision 
2.
Current version 
of ENCePP 
checklist  
incorporated. 

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7.
MILESTONES
Milestone
Planned Date
Final protocol
26 April 2016
1st Protocol amendment
28 September 2016
2nd Protocol Amendment
19 July 2018
3rd Protocol Amendment
04 Jun 2021
Start of data collection
30 June 2017
End of data collection
31 December 2022
Registration in the EU 
PASS register
EUPAS17078 (05-Jan-2017)
Final report of study results
31 May 2023

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8.
RATIONALE AND BACKGROUND
Lung cancer is the leading cause of cancer deaths worldwide (R12-1150). Most patients are 
diagnosed with advanced or metastatic disease and although about 70% of patients initially 
achieve clinical remission or disease stabilisation with first-line platinum-containing therapy, 
nearly all have disease progression and need further lines of therapies. Currently in India, 
docetaxel, 
pemetrexed, 
erlotinib 
and 
immunotherapeutic 
drugs 
like 
nivolumab, 
pembrolizumab and atezolizumab are approved  for NSCLC patients who progress on first 
line chemotherapy. The median overall survival for all these second line treatments is 
approximately 8-13 months. There is a high unmet need for new effective second-line 
treatments for patients with NSCLC after first line chemotherapy.
Nintedanib is a small-molecule tyrosine kinase inhibitor. It is an indolinone derivative that 
blocks the kinase activity of the fibroblast growth factor receptors (FGFR) 1-3, the platelet 
derived growth factor receptors (PDGFR) α and β, and the vascular endothelial growth factor 
receptors (VEGFR) 1-3 (P14-16851) In a pivotal trial phase III trial 1199.13, nintedanib in 
combincation with docetaxel significantly prolonged progression free survival (PFS) in the 
overall patient population. The final overall survival (OS) analysis in the predefined 
population of adenocarcinoma patients showed a statistically significant improvement in OS 
which translated into a 17% reduction in the risk of death compared to placebo. Median OS 
was improved in a clinically meaningful way, from 10.3 months with placebo to 12.6 months 
in the nintedanib arm, representing a 22% improvement in median OS (P13-13353) (P13-
13346)
., made an application for the grant of permission to 
import and market nintedanib soft gelatin 100 and 150 mg capsules. The proposal of the firm 
was deliberated in the Subject Expert Committee (SEC) where the global and subgroup 
analysis report of 114 Indian subjects (Nintedanib 58, Placebo 56) was presented. Of these 59 
Indian adencarcinoma patients, 30 subjects were on nintedanib and 29 subjects were on 
placebo. Regulators were concerned about the need for dose reduction in 31% of Indian 
patients treated with nintedanib in the 1199.13 study and some other safety concerns related 
to deaths and discontinuation in the Indian subgroup exposed to nintedanib. During the SEC 
meeting on 29th September 2015, the SEC members were convinced about the efficacy and 
safety of nintedanib but requested the company to perform an active surveillance of 100 
patients using the drug for a period of two years from the date of marketing the drug. The 
proposed active surveillance aims to collect the real world safety data of 100 patients at 
selected centres treated with nintedanib per the approved label within two years from the date 
of commercial availability of drug in India (23rd January 2017) or as mentioned in the study 
approval letter issued by the DCGI. 

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9.
RESEARCH QUESTION AND OBJECTIVES
This active surveillance aims to collect the safety data of  100 NSCLC patients with 
adenocarcinoma histology treated with nintedanib per the approved Indian label within 2 
years from the date of commercial availability of the drug in India (23rd January 2017) or as 
mentioned in the study approval letter issued by the DCGI. The objective is to look at the 
safety of nintedanib in the real world setting. 

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treatment and up to  28 days after the last intake of the drug. Group B and Group C patients  
are suggested to have further visits according to the clinical practice (approximately every 3 
weeks when given along with docetaxel and approximately every 4 weeks thereafter). An 
additional follow up visit will be conducted up to to  28 days after the last dose of nintedanib. 
At each visit, all ADRs associated with nintedanib and SAEs will be recorded and reported as 
per  section 12.2.  Disease progression of the underlying malignancy reflects the natural 
course of the disease. As such it is exempted from reporting as a (S)AE. Progression of the 
subject's underlying malignancy will be recorded on the appropriate pages of the (e)CRF only 
and will not be reported on the NIS AE Form. There may be unscheduled visits between the 
scheduled visits. All ADRs and  SAEs will also be collected at these unscheduled visits and 
entered into the eCRF. For nintedanib & docetaxel treated patients, certain information (e.g. 
co-medications, see flowchart) will also be collected at further and unscheduled visits (if 
available), as the status may change over the time.
In case the patient is lost to follow up (patients not contactable for further visits), the site 
should attempt to contact the patient or patient’s relative telephonically to gather the 
information on the vital status and record it in the eCRF. Additionally, whenever the 
investigator becomes aware of unexpected SAEs and/or any ADRs occurring in an enrolled 
patient, before individual patient’s end of study, it needs to be reported as per section 12.2. 
Patients who have taken at least one dose of nintedanib will be included in the safety analysis.
As this is an active surveillance of patients treated with nintedanib in the real world, no 
specific treatment is mandated or withheld from the patients. The choice of adjunct treatment 
(e.g. radiotherapy) must be according to the regular medical practice and at the discretion of 
the physician. The assignment of the patient to nintedanib or any other treatment falls within 
current practice and prior to the decision to talk to the patient about the study, so that the 
decision to prescribe nintedanib is clearly separated from the decision to include the patient in 
this active surveillance. The decision of treatment, including the intended duration of 
treatment, is at the discretion of the physician providing care for the patient.

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characteristics of 100 NSCLC patients treated with single agent docetaxel will be used to 
compare the patients profile with the nintedanib & docetaxel users and will allow us to put 
the safety data of nintedanib into perspective. Whenever patient profiles differ between those 
treated with combination of nintedanib and docetaxel and single agent docetaxel, cautious 
interpretation is required when comparing with the nintedanib treated populations from other 
trials / registries.
Any patient who meets the following criteria is treated as ineligible for safety analyses: 
 Required registration procedure was not followed
10.7.1
Analyses of outcome events
All outcome events are based on reported AE data which will be handled according to BI 
standards (see the section below).
Safety
In general, safety analyses will be descriptive in nature, and will be based on BI standards, 
and will focus on all ADRs and SAEs.
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To this 
end, all AEs occurring between first intake of nintedanib + docetaxel prescribed at baseline/
visit 1 and up to 28 days (inclusive) after the last intake of nintedanib will be considered 
‘treatment emergent’. An AE is considered to be an ADR if either the physician who has 
reported the AE or the sponsor assesses its causal relationship as ‘related’. The grading of 
ADRs and  SAEs will be done by using Common Terminology Criteria for Adverse Events 
version 03 (CTCAE v03)
The incidence and grading of AEs will be tabulated by system organ class and preferred term
for overall 
 
. 
No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard.
Descriptive statistics will be calculated for laboratory tests, vital signs and physical 
examination.
10.7.2
Interim analyses
No interim analysis is planned for this active surveillance program; however status report will 
be submitted to DCGI at the end of two years from the start of marketing of the drug in India
or as mentioned in the study approval letter issued by the DCGI.

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10.8
QUALITY CONTROL
All processes will be conducted according to BI PMS, NISnd and if applicable PASS SOPs. 
Appropriate records and documents will be stored based on all relevant SOPs and these 
processes are checked by internal self-check.
10.9
LIMITATIONS OF THE RESEARCH METHODS
The scientific objective of this active surveillance program is to obtain an estimate of the 
occurrence of ADRs and SAEs in NSCLC patients prescribed nintedanib & docetaxel per the 
approved Indian label in the real world setting. For retrospective data, there may be a 
possibility of missed information on adverse events. For patients followed prospectively, loss 
to follow up, loss of information and recall bias could impose limitations. Since only the 
cohort treated with nintedanib & docetaxel will be followed up, it is impossible to assess the 
safety of nintedanib compared to other drugs. The possible selection bias will be minimized 
by enrolling all nintedanib & docetaxel treated patients (discontinued, ongoing and newly 
prescribed) from the date of commercial availability of the drug (23rd January 2017) at 
selected centres; patients and potential channelling bias will be assessed by recording the 
baseline characteristics of a comparator group of 100 additional patients who were/are treated 
with single agent docetaxel after the first line therapy at same center during the same 
timeframe.
10.10
OTHER ASPECTS
10.10.1
Informed consent, data protection, study records
The active surveillance will be carried out in compliance with the protocol, and the latest 
revision of the Declaration of Helsinki, as well as the Guidelines for Good 
Pharmacoepidemiological 
Practice 
(GPP) 
from 
Epidemiological 
Society 
for 
Pharmacoepidemiology (ICPE), 
 guideline, 
Guideline on good pharmacovigilance practice, relevant BI SOPs and relevant local 
regulations.  
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the patient’s treating physician.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this active surveillance will be described in the contract. As a general rule, no results should 
be published prior to finalization of the Study Report.
10.10.1.1
Study approval, patient information, and informed consent
In addition to review and approval by Drug controller general of India (DCGI), the approval 
of Institutional Review Board (IRB) or Ethics Committee will be sought as per the 
institutional procedures before the start of this active surveillance.  
Prior to patient participation in this active surveillance, written informed consent must be 
obtained from each patient (or the patient’s legally accepted representative) according to the 
regulatory and legal requirements of India (applicable for Group B/C and Group II/III 

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patients). Each signature must be personally dated by each signatory and the informed 
consent and any additional patient-information form must be retained by the Investigator as 
part of the study records. A signed copy of the informed consent and any additional patient 
information must be given to each patient or the patient’s legally accepted representative.
The Investigator must give a full explanation of this active surveillance regarding the 
collection of the safety data at specific time points to the participants. The Investigator 
obtains written consent of the patient’s own free will with the informed consent form after 
confirming that the patient understands the contents. The Investigator must sign and date the 
informed consent form.
10.10.1.2
Data quality assurance
Automatic checks at data entry will reduce the error while entering data. A quality assurance 
audit/inspection of this active surveillance may be conducted by the sponsor, sponsor’s
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the study related files and correspondence, and the 
informed consent documentation.
10.10.1.3
Records
Electronic data capture (EDC) will be used to gather the data.
10.10.1.3.1 Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. Data 
reported on the eCRF must be consistent with the source data or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer records. 
Current medical records must also be available.
10.10.1.3.2 Direct access to source data and documents
The Investigator / institution will permit monitoring, audits, IRB/IEC review and regulatory 
inspection, providing direct access to all source data/documents related to this active 
surveillance program.
CRF/eCRF and all source documents, including progress notes and copies of laboratory and
medical test results must be available at all times for review. 
The Clinical Research Associate (CRA)/on site monitor and auditor may review all 
CRF/eCRF, and written informed consents.
10.10.1.4
Statement of confidentiality
Individual patient’s medical information obtained as a result of this active surveillance
program is considered confidential and disclosure to third parties is prohibited with the 
exceptions noted below. Patient confidentiality will be ensured by using patient identification 
code numbers.

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Data generated as a result of this active surveillance program need to be available for 
inspection on request by the sponsor’s representatives, by the IRB / IEC and the regulatory 
authorities.

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11.
PROTECTION OF HUMAN SUBJECTS
There is no need for a clinical trial insurance to ensure the well-being and rights of 
participants since this is an active surveillance program of the patients prescribed nintedanib 
per the approved Indian label in the real world setting and there is no risk of an experimental 
treatment. 

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12.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
12.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalisation, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Adverse Event of Special Interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this 

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study, e.g. the potential for AEs based on knowledge from other compounds in the same 
class. 
No AESIs have been defined for this active surveillance.
12.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection and Reporting of AEs
The design of this active surveillance is of non-interventional nature and the study is 
conducted within the conditions of the approved marketing authorisation. Sufficient data 
from controlled interventional trials are available to support the evidence on the safety and 
efficacy of the studied BI drug. For this reason the following AE collection and reporting 
requirements have been defined.
The following must be collected by the investigator in the CRF from signing the informed 
consent onwards at scheduled visits and within 28 days (inclusive) after last intake in patients 
exposed to nintedanib (= follow up visit)
-
All ADRs associated with nintedanib
-
All SAEs in patients exposed to nintedanib
All ADRs and SAEs including those persisting after study completion must be followed up 
until they are resolved, have been sufficiently characterized, or no further information can be 
obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event:
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced

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•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on Common terminology criteria for adverse 
events version 03 (CTCAE v03)
The intensity of adverse events should be classified and recorded according to the above 
referenced definition  in the e-CRF.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken nintedanib, the investigator must report any drug exposure during 
pregnancy, which occurred in a female subject or in a partner to a male subject to the Sponsor 
by means of Part A of the Pregnancy Monitoring Form. The outcome of the pregnancy 
associated with the drug exposure during pregnancy must be followed up and reported by 
means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the follow up visit. Additionally, below mentioned 
information will also be collected for subjects identified under Group A and Group B during 
retrospective review of existing medical records: 

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Type of Report
Timeline
All SAEs in patients exposed to nintedanib
Immediately within 24 hours
All non-serious ADRs associated with 
nintedanib
In 7 calendar days
All pregnancy monitoring forms
In 7 calendar days
The rules for adverse event reporting exemptions as outlined below apply.
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and send the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages and the NIS AE form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
the Nintedanib according to the local regulatory requirements for spontaneous AE reporting 
at the investigator’s discretion by using the locally established routes and AE report forms. 
The term AE includes drug exposure during pregnancy, and, regardless of whether an AE 
occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and benefit.
Exemption to Adverse Events reporting 
Disease progression of the underlying malignancy reflects the natural course of the disease. 
As such it is exempted from reporting as a (S)AE. Progression of the subject's underlying 
malignancy will be recorded on the appropriate pages of the (e)CRF only and will not be 
reported on the NIS AE Form. Death due to disease progression is also to be recorded on the 
appropriate (e)CRF page and not on the NIS AE Form. However, when there is evidence 
suggesting a causal relationship between Nintedanib and the progression of the underlying 
malignancy, the event must be reported as a SAE on the NIS AE Form and on the (e)CRF. 
The exempted event is disease progression (other MedDRA preferred terms include 
malignant neoplasm progression and neoplasm progression).
12.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to the 
local and international regulatory requirements.

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13.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The progress reports and final reports will be submitted in Indian Periodic Safety Update 
Report (PSUR). A final report summarizing the results of the study and the analysis will be 
submitted to the Indian regulatory agency at the end of the active surveillance program

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
1. 
Not applicable 
Not applicable
Contact details and 
the list of all 
investigators

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMEA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 4)
Adopted by the ENCePP Steering Group on 15/10/2018
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology, which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example, in the case of an innovative study design). In this case, the
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). The Checklist is a supporting document and does not replace the 
format of the protocol for PASS presented in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

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Study title: An active surveillance to monitor the real world safety in Indian
patients prescribed nintedanib as per approved Indian Label for the treatment of locally 
advanced, metastatic or recurrent non-small cell lung cancer (NSCLC) of 
adenocarcinoma tumour histology after first-line chemotherapy.
EU PAS Register® number: 17078
Study reference number (if applicable): BI Study Number: 1199.272
Section 1: Milestones
Yes
No
N/A
Section
Number
1.1
Does the protocol specify timelines for 
7
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Progress report(s)
1.1.4 Interim report(s)
1.1.5 Registration in the EU PAS Register®
1.1.6 Final report of study results.
Comments:
Section 2: Research question
Yes
No
N/
A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in 
the risk management plan, an emerging safety issue)
8
2.1.2 The objective(s) of the study?
9
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
10.2.2
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
Comments:
1Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2Date from which the analytical dataset is completely available.

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Section 3: Study design
Yes
No
N/
A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, other design) 
10.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
10.4
3.3
Does the protocol specify measures of 
occurrence? (e.g., rate, risk, prevalence)
10.7
3.4
Does the protocol specify measure(s) of 
association? (e.g. risk, odds ratio, excess risk, rate ratio, 
hazard ratio, risk/rate difference, number needed to harm 
(NNH))
10.7
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
12
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
10.1
4.2
Is the planned study population defined in terms 
of:
4.2.1 Study time period
10.1
4.2.2 Age and sex
10.2.2
4.2.3 Country of origin
1
4.2.4 Disease/indication
9
4.2.5 Duration of follow-up
10.1
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
10.2.2
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/
A
Section
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured?
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure)
10.2.2.2
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)

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Section 5: Exposure definition and measurement
Yes
No
N/
A
Section
Number
5.3
Is exposure categorised according to time 
windows?
5.4
Is intensity of exposure addressed? 
(e.g. dose, duration)
5.5
Is exposure categorised based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
5.6
Is (are) (an) appropriate comparator(s) 
identified?
10.1
Comments:
Section 6: Outcome definition and measurement
Yes
No
N/
A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
10.3.2
6.2
Does the protocol describe how the outcomes
are defined and measured? 
10.3.2
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, use of 
validation sub-study)
6.4
Does the protocol describe specific outcomes 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease or treatment, compliance, disease 
management)
Comments:
Section 7: Bias
Yes
No
N/
A
Section
Number
7.1
Does the protocol address ways to measure 
confounding? (e.g. confounding by indication)
10.3.3
7.2
Does the protocol address selection bias? (e.g. 
healthy user/adherer bias)
10.9
7.3
Does the protocol address information bias?
(e.g. misclassification of exposure and outcomes, time-
related bias)
10.9
Comments:

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Section 8: Effect measure modification
Yes
No
N/A
Section
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect) 
10.3.3
Comments:
Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
10.3.1
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
10.3.2
9.1.3 Covariates and other characteristics?
10.3.3
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose, number of days of supply prescription, daily 
dosage,  prescriber)
10.3.1
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
10.3.2
9.2.3 Covariates and other characteristics?
(e.g. age, sex, clinical and drug use history, co-morbidity, 
co-medications, lifestyle)
10.3.3
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD), Medical Dictionary for Regulatory 
Activities (MedDRA))
10.7.1
9.3.3 Covariates and other characteristics?
9.4
Is a linkage method between data sources
described? (e.g. based on a unique identifier or other)
Comments:
Section 10: Analysis plan
Yes
No
N/
A
Section
Number
10.1 Are the statistical methods and the reason for 
their choice described? 
10.7
10.2 Is study size and/or statistical precision 
estimated?
10.7

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Section 10: Analysis plan
Yes
No
N/
A
Section
Number
10.3 Are descriptive analyses included?
10.7
10.4 Are stratified analyses included?
10.5 Does the plan describe methods for analytic 
control of confounding?
10.6 Does the plan describe methods for analytic 
control of outcome misclassification?
10.7 Does the plan describe methods for handling 
missing data?
10.7.1
10.8 Are relevant sensitivity analyses described?
Comments:
Section 11: Data management and quality 
control
Yes
No
N/
A
Section
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
10.4
10.10
11.2 Are methods of quality assurance described?
10.10.1.2
11.3 Is there a system in place for independent 
review of study results? 
Comments:
Section 12: Limitations
Yes
No
N/
A
Section
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
10.9
12.1.2 Information bias?
10.9
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods).
10.9
12.2 Does the protocol discuss study feasibility?
(e.g. study size, anticipated exposure uptake, duration of 
follow-up in a cohort study, patient recruitment, precision of 
the estimates)
10.1
Comments:

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Section 13: Ethical/data protection issues
Yes
No
N/
A
Section
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
10.10.1
13.2 Has any outcome of an ethical review procedure 
been addressed?
10.10.1
13.3 Have data protection requirements been 
described?
10.10.1
Comments:
Section 14: Amendments and deviations
Yes
No
N/
A
Section
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
6
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/
A
Section
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
13
15.2 Are plans described for disseminating study 
results externally, including publication?
13
Comments:

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ANNEX 3. CHILD PUGH CLASSIFICATION OF HEPATIC 
IMPAIRMENT 
Assessment 
Degree of abnormality 
Score
Score
Encephalopathy
None 
Moderate 
Severe
1
2
3
Ascites
Absent 
Slight
Moderate
1
2
3
Bilirubin (mg/dL)
<2
2.1-3
>3
1
2
3
Albumin (g/dL)
>3.5
2.8-3.5
<2.8
1
2
3
Prothrombin Time (seconds 
> control)
0-3.9
4-6
>6
1
2
3
Total Score
Group
Severity
5-6
A
Mild
7-9
B
Moderate
10-15
C
Severe

 
 
 
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