Assessment of Real-World Outcomes Associated With Afatinib (Gilotrif) Use in Patients With Solid Tumors Harboring NRG1 Gene Fusions
Conditions: Non-squamous, Non-Small Cell Lung Cancer
Sponsor: Boehringer Ingelheim

 
 
 
001-MCS-90-124_RD-01 (4.0) 
TITLE PAGE 
Protocol for non-interventional studies based on existing data 
TITLE PAGE 
Document Number: 
<document number> 
BI Study Number: 
CTMS 1200.335 
BI Investigational 
Product(s): 
Gilotrif® (afatinib) 
Title: 
Assessment of Real-World Outcomes Associated with 
Afatinib (Gilotrif) Use in Patients with Solid Tumors 
Harboring NRG1 Gene Fusions 
Protocol version 
identifier: 
v1.0 
Date of last version of 
protocol: 
N/A 
PASS: 
No 
EU PAS register 
number: 
Active substance: 
Afatinib 
Antineoplastic agents, tyrosine kinase inhibitors 
ATC code: L01XE13 
Medicinal product: 
Gilotrif 40 mg, 30 mg, 20 mg  
Product reference: 
20 mg: NDC: 0597-0141-30 
30 mg: NDC: 0597-0137-30 
40 mg: NDC: 0597-0138-30 
Procedure number: 
Joint PASS: 
Research question and 
objectives: 
Research Questions: 
1. What are the characteristics of patients with NRG1 
gene fusion-positive solid tumors treated with 
afatinib, and what are the characteristics of those 
treated with another systemic therapy? 
Study Objectives: 
1. To describe the demographic and clinical 
characteristics of patients with NRG1 gene fusion-
positive solid tumors treated with afatinib and of 
patients with NRG1 gene fusion-positive solid tumors 
treated with other systemic therapy. 

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2. To calculate the ORR and DOR among patients with 
NRG1 gene fusion-positive solid tumors treated with 
afatinib and among patients with NRG1 gene fusion-
positive solid tumors treated with other systemic 
therapy 
3. To estimate PFS (and TOT, TTP) among patients with 
NRG1 gene fusion-positive solid tumors treated with 
afatinib and among patients with NRG1 gene fusions 
treated with other systemic therapy 
4. To estimate OS among patients with NRG1 gene 
fusion-positive solid tumors treated with afatinib and 
among patients with NRG1 gene fusion-positive solid 
tumors treated with other systemic therapy 
5. To describe the incidence and severity of adverse 
events (AEs) among patients with NRG1 gene fusion-
positive solid tumors while on treatment with afatinib 
or other systemic therapy 
Country(-ies) of 
study: 
United States 
Authors: 
Marketing 
authorization 
holder(s): 
 
MAH contact person: 
Date: 
8-MAY-2020 
 
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This document may not - in full or in part - be passed on, reproduced, published or 
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1. TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................. 1 
1. TABLE OF CONTENTS ............................................................................................ 3 
2. LIST OF ABBREVIATIONS ..................................................................................... 5 
3. 
RESPONSIBLE PARTIES .................................................................................... 7 
4. 
ABSTRACT ........................................................................................................... 9 
5. 
AMENDMENTS AND UPDATES ..................................................................... 15 
6. 
MILESTONES ..................................................................................................... 16 
7. 
RATIONALE AND BACKGROUND ................................................................ 17 
8. 
RESEARCH QUESTIONS AND OBJECTIVES ............................................... 18 
9. 
RESEARCH METHODS .................................................................................... 19 
9.1 
STUDY DESIGN ............................................................................................ 19 
9.2 
SETTING ........................................................................................................ 19 
9.2.1 
Provider/Site/Patient Selection ................................................................ 20 
9.3 
VARIABLES .................................................................................................. 21 
9.3.1 
Exposures ................................................................................................ 21 
9.3.2 
Outcomes ................................................................................................. 21 
9.3.3 
Covariates ................................................................................................ 24 
9.4 
DATA SOURCES ........................................................................................... 25 
9.4.1 
Source Documents ................................................................................... 25 
9.4.2 
Dataset and Records ................................................................................ 26 
9.5 
STUDY SIZE .................................................................................................. 26 
9.6 
DATA MANAGEMENT ................................................................................ 26 
9.7 
DATA ANALYSIS ......................................................................................... 27 
9.8 
QUALITY CONTROL ................................................................................... 27 
9.8.1 
eCRF Functionality Testing .................................................................... 28 
9.8.2 
Data Validation ....................................................................................... 28 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 29 
9.10 
OTHER ASPECTS ......................................................................................... 30 
9.11 
SUBJECTS ...................................................................................................... 30 
9.11.1 
Cases ........................................................................................................ 30 
9.11.2 
Controls ................................................................................................... 31 
9.12 
BIAS ................................................................................................................ 31 
10 
PROTECTION OF HUMAN SUBJECTS .......................................................... 32 

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11 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 33 
11.1 
Definitions of adverse events .......................................................................... 33 
11.2 
Adverse event and serious adverse event collection and reporting................. 34 
11.2.1 
Collection of AEs .................................................................................... 34 
11.3 
Reporting to health Authorities ....................................................................... 37 
12 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ............................................................................................................ 38 
13 
REFERENCES .................................................................................................... 39 
13.1 
PUBLISHED REFERENCES ......................................................................... 39 
13.2 
UNPUBLISHED REFERENCES ................................................................... 39 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 40 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 41 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 48 
 

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2. LIST OF ABBREVIATIONS  
1L 
First-line (therapy) 
AACR 
American Association for Cancer Research 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate aminotransferase 
BI 
Boehringer Ingelheim Pharmaceuticals 
 
 
CI 
Confidence interval 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Event 
Del19 
exon 19 deletion mutation 
DOCB 
Duration of clinical benefit 
DOR 
Duration of response  
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
EGFR+ 
EGFR mutation-positive 
EHR 
Electronic Health Record 
EMR 
Electronic Medical Record 
FAE 
Fatal adverse event 
FDA 
United States Food & Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
HER2 
human epidermal growth factor receptor-2 
HER3 
human epidermal growth factor receptor-3 
IMA 
Invasive mucinous adenocarcinoma 
IRB 
Institutional Review Board 
ISPE 
International Society for Pharmacoepidemiology 
L858R 
exon 21 point mutation 
MMR 
Mismatch Repair Genes 
MSI 
Microsatellite Instable 
NIS 
Non-interventional study 
NSCLC 
Non-small cell lung cancer 
NRG1 
Neuregulin-1 
 
 
ORR 
Overall response rate 
OS 
Overall survival 
PHI 
Protected Health Information 
PFS 
Progression-free survival 
PD 
Progressive disease 
PR 
Partial response  
PS 
Performance Status 

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RECIST 
Response Evaluation Criteria In Solid Tumors  
RCT 
Randomized controlled trial 
RWE 
Real-world evidence 
SAE 
Serious adverse event 
SD 
Stable disease 
SE 
Standard Error 
SJS 
Stevens Johnson Syndrome 
STROBE 
Strengthening the Reporting of Observational Studies in Epidemiology 
TEN 
Toxic Epidermal Necrolysis 
TKI 
Tyrosine kinase inhibitor 
TOT 
Time on treatment 
TTF 
Time to treatment failure 
TTP 
Time to progression 
US 
United States 
 

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3. RESPONSIBLE PARTIES  
 
Principal/Co-
Investigators 
Clinical Investigators 
 
and Senior Medical 
  
 
 
Team 
 Medicine 
 
 
Senior Global Medical Advisor 
Study Statistician 
Project 
 
Project 
 
Research
 
Consultant, 
 
Clinical Analyst 

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Regulatory Affairs 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. ABSTRACT 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Gilotrif® 
 
Name of active ingredient: 
afatinib 
Antineoplastic agents, tyrosine 
kinase inhibitors 
ATC code: L01XE13 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision date: 
17 March 2020 
CTMS 
1200.335 
1.0 
17 March 2020 
Title of study: 
Assessment of Real-World Outcomes Associated with Afatinib 
(Gilotrif) Use in Patients with Solid Tumors Harboring NRG1 Gene 
Fusions 
Rationale and 
background: 
The first neuregulin 1 (NRG1) fusion was reported by Fernandez-
Cuesta et al in 2014 when they identified five CD74-NRG1 fusions in 
invasive mucinous adenocarcinoma (IMA). Multiple tumor types with 
NRG1 fusions have been described, including other lung, renal, head 
and neck, pancreatic, breast, ovarian, uterine, and prostate. The CD74-
NRG1 fusion provides an extracellular anchor for the epidermal growth 
factor (EGF) domain of NRG1 to bind to ErbB3 (HER3), leading to 
HER3 heterodimerization and activation of downstream signaling 
pathways resulting in oncogenesis. As such, targeted treatment with 
inhibitors of this pathway represents a possible therapeutic strategy. 
Afatinib, a pan-ErbB inhibitor, has been evaluated in preclinical 
models and in several case reports in patients with tumors harboring 
NRG1 fusions who have achieved durable benefit with afatinib. NRG1 
fusions are rare, with an estimated overall frequency of ~0.2% to 0.8% 
across solid tumors and have a reported prevalence of up to 31% in 
lung IMA, making prospective clinical trials challenging.  
Obtaining real-world data describing the real-world outcomes 
associated with afatinib in patients with NRG1 fusion-positive solid 
tumors is valuable, and such data may be used in supplemental 
applications for label expansion requests to the U.S. FDA and other 
agencies. 

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Research 
question and 
objectives: 
Research Questions: 
1. What are the characteristics of patients with NRG1 gene fusion-
positive solid tumors treated with afatinib, and what are the 
characteristics of those treated with another systemic therapy? 
Study Objectives: 
1. To describe the demographic and clinical characteristics of 
patients with NRG1 gene fusion-positive solid tumors treated 
with afatinib and of patients with NRG1 gene fusion-positive 
solid tumors treated with other systemic therapy. 
2. To calculate the ORR and DOR among patients with NRG1 
gene fusion-positive solid tumors treated with afatinib and 
among patients with NRG1 gene fusion-positive solid tumors 
treated with other systemic therapy 
3. To estimate PFS (and TOT, TTP) among patients with NRG1 
gene fusion-positive solid tumors treated with afatinib and 
among patients with NRG1 gene fusions treated with other 
systemic therapy 
4. To estimate OS among patients with NRG1 gene fusion-
positive solid tumors treated with afatinib and among patients 
with NRG1 gene fusion-positive solid tumors treated with other 
systemic therapy 
5. To describe the incidence and severity of adverse events (AEs)  
among patients with NRG1 gene fusion-positive solid tumors 
while on treatment with afatinib or other systemic therapy 
Study design: 
This retrospective cohort study will be conducted via a multi-site 
medical chart review of patients with NRG1 gene fusion-positive solid 
tumors. Two cohorts of patients will be identified: the first includes 
any patient with NRG1 gene fusion-positive solid tumors who has 
received afatinib in any line of therapy (afatinib cohort). The second 
includes any patient with NRG1 gene fusion-positive solid tumors who 
has not received afatinib in any line of therapy (other systemic therapy 
cohort). All patients must have initiated treatment after 01/01/2017 and 
before 03/31/2020. To remove potential bias, patients who died prior to 
3 months following treatment initiation are still eligible. Data 
collection is anticipated to occur in Q3/Q4 of 2020, allowing for a 
minimum follow-up of approximately 3 months. Demographics, 
clinical characteristics, safety, and clinical outcomes (ORR, DOR, 
DOCB, TOT, TTP, PFS, OS, and AEs will be described for both 
patient cohorts.  

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Population: 
Inclusion Criteria 
 Adults, 18 years of age or older, at the time of diagnosis with 
any solid tumor. 
 Confirmed NRG1 gene fusion in any solid tumor.  
 Initiated afatinib or other systemic therapy (in any line of 
therapy) for treatment of a solid tumor with NRG1 gene fusion 
on or after 01/01/2017 and before 03/31/2020. 
 Followed up for ≥3 months after initiation of afatinib or other 
systemic therapy (unless deceased prior to 3 months of follow-
up). 
Exclusion Criteria 
 Treatment with any TKI/ErbB-directed therapy other than 
afatinib  
 
 
Variables: 
The primary exposure of interest is treatment with afatinib. Two 
unmatched cohorts of patients will be created: the afatinib-treated 
cohort includes patients with an NRG1 gene fusion who received 
afatinib in any line of therapy; the second cohort includes any patient 
with an NRG1 gene fusion who had never received afatinib prior to the 
date of data collection. Demographic and clinical characteristics (e.g., 
sex, age, payer type, US region, race/ethnicity, tumor 
type/characteristics, comorbidities, ECOG PS, NRG1 gene fusion 
testing [e.g., timing, lab/location, results/partner], tumor-specific 
testing of interest [e.g., EGFR]) will be described in each cohort of 
patients. Clinical outcomes to be measured in this study include ORR, 
DOR, DOCB, TOT, TTP, PFS, OS, and AEs.  

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Data sources: 
De-identified, patient-level data will be obtained from providers in the 
 who 
will complete an eCRF for eligible patients. 
 
will recruit providers from 
 to participate. 
 is a community 
of over 7,000 oncologists, hematologists and urologists from across the 
U.S., with varying levels of time in practice, from practices both within 
and outside of group purchasing organizations. A subset of this 
provider group (~800) participates in retrospective observational 
research studies. All provider participation in the study is voluntary.  
 
Providers will abstract clinical and treatment related data as available 
from the patient’s EHR from the time of diagnosis of their primary 
malignancy through the last date of follow-up with the patient or death. 
Providers will complete an eCRF for all eligible patients and will begin 
data abstraction with the first eligible patients, subsequently selecting 
consecutive patients moving forward. Required data elements are 
specified in the study inclusion/exclusion criteria; non-required data 
elements may be missing/unknown. Providers may abstract data into 
the eCRF for both patients they personally managed/treated or those 
managed/treated by other providers within their practice.  
Providers are compensated for their time completing data abstraction 
into the eCRF only after subsequent data verification, as necessary. No 
source documents will be provided to 
 for verification; however, 
 will require duplicate data entry for a sample of patients’ initial 
data collection to verify data point accuracy. 

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Study size: 
The total target number of patients is up to120 patients, including up to 
70 patients with an NRG1 gene fusion-positive solid tumor treated with 
afatinib and up to 50 patients with an NRG1 gene fusion-positive solid 
tumor who had not received afatinib at the time of data collection. The 
target number of patients was based on the results of a pilot feasibility 
study conducted by 
 with Boehringer Ingelheim (BI). 
 
In December 2019, 
 conducted outreach to approximately 800 
providers in 
 to inquire as to the number of patients with NRG1 
gene fusion-positive solid tumors treated with afatinib whom they had 
personally managed or who were cared for at their practice. Providers 
were presented with similar inclusion criteria as those described above. 
In total, 12 oncologists completed short eCRFs describing a total of 108 
patients. Of those, 67 (62%) were treated with afatinib and 41 (38%) 
had not received afatinib. 
 
Based on the feasibility study, 
 will target up to 70 afatinib-
treated patients with NRG1 gene fusion-positive solid tumors and up to 
50 patients with NRG1 gene fusion-positive solid tumors who had not 
received afatinib. Although the feasibility study did not identify this 
number of patients, further recruitment of non-responders to the survey 
invitation will be used to achieve the target number of patients planned 
for this study. In lieu of a comparative analysis between the afatinib-
treated and non-afatinib treated patients are exploratory, the precision 
of estimates involving 70 patients in the afatinib-treated cohort would 
be associated with a standard error of any bivariate response variable 
between 6.0% and 13.9%.  

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Data analysis: 
Demographic and clinical characteristics will be reported via 
descriptive analyses, including counts and frequencies for dichotomous 
and categorical variables, while measures of centrality (mean, median) 
and spread (min, max, standard deviation, interquartile range, as 
appropriate) will be used for continuous variables. These 
characteristics will be described at the time of initial diagnosis of 
advance/metastatic disease and at the time of initiation of each line of 
therapy received. 
For disease response, the point estimate for ORR and associated 95% 
confidence interval will be calculated for each cohort. The Kaplan-
Meier method will be used to estimate any time to event outcome 
including DOR, DOCB, TOT, TTP, PFS, and OS to account for any 
right censoring (e.g., patient had not discontinued therapy, patient had 
not progressed or died).  
Given the small number of patients targeted for study inclusion and 
anticipated differences in baseline characteristics between afatinib-
treated and patients treated with other systemic therapies, statistical 
comparisons are not planned. In lieu of statistical comparisons between 
cohorts, the non-afatinib cohort will provide context for interpreting 
results among those treated with afatinib. Specifically, this context 
includes what patients with NRG1 gene fusions not treated with 
afatinib look like, how they are managed and treated, and what their 
clinical outcomes look like. The non-afatinib cohort will provide a 
broader understanding of NRG1 gene fusions among patients with solid 
tumors, for which limited evidence currently exists.  
Incidence and severity of AEs will be summarized and displayed in 
number/percentage. All safety endpoints will be analysed descriptively. 
 
Milestones: 
Task 
Start Date 
Internal approval of study synopsis 
March 2020 
Internal approval of study protocol 
May 2020 
Submission of study protocol to FDA 
May 2020 
FDA feedback received 
June 2020 
Finalization of protocol 
July 2020 
IRB submission and review 
July 2020 
Recruitment & data collection 
Q3/Q4 2020 
Demographics & clinical characteristics 
November 2020 
Outcomes assessment 
November 2020 
Final report  
December 2020 
 

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5. AMENDMENTS AND UPDATES 
None 

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6. MILESTONES 
Milestone 
Planned Completion Date  
Internal approval of study synopsis 
March 2020 
Internal approval of study protocol 
May 2020 
Submission of study protocol to FDA 
May 2020 
FDA feedback received 
June 2020 
Finalization of protocol 
July 2020 
IRB submission and review 
July 2020 
Recruitment & data collection 
Q3/Q4 2020 
Demographics & clinical characteristics 
November 2020 
Outcomes assessment 
November 2020 
Final report 
December 2020 

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7. RATIONALE AND BACKGROUND 
The epidermal growth factor receptor (EGFR) signaling pathway regulates apoptosis and 
proliferation in normal cells. An EGFR family component of the of tyrosine kinase ligands, 
neuregulin-1 (NRG1), induces the proliferation, differentiation, and survival of cells in 
epithelial, neuronal, and myocytic tissue types, among others. The first NRG1 fusion was 
reported by Fernandez-Cuesta et al. in 2014 when they identified five CD74-NRG1 fusions in 
invasive mucinous adenocarcinoma (IMA).[1] The CD74-NRG1 fusion provides an 
extracellular anchor for the epidermal growth factor (EGF) domain of NRG1 to bind to ErbB3 
(HER3) leading to HER3 heterodimerization and activation of downstream signaling pathways 
leading to oncogenesis.[2] As such, targeted treatment with inhibitors of this pathway 
represents a possible therapeutic strategy. Afatinib, a pan-ErbB inhibitor has been evaluated in 
preclinical models[3] and in several case reports in patients with tumors harboring a NRG1 
fusions that achieved durable benefit with afatinib.[4-6]  
 
NRG1 fusions are rare, with an estimated overall frequency of ~0.2% across solid tumors[7] 
and have a reported prevalence of up to 31% in lung IMA[8] making prospective clinical trials 
challenging. In addition to IMA, other tumor types with NRG1 gene fusions that have been 
described include cholangiocarcinoma (0.8% of cases tested), thyroid cancer (0.7%), ovarian 
cancer (0.5%), pancreatic cancer (0.4%), non-small cell lung cancer (NSCLC; 0.3%), breast 
cancer (0.2%), sarcomas (0.2%), and sinonasal teratocarcinoma,[9] as well as renal cell 
carcinoma, head and neck cancer, uterine cancer, and prostate cancer.[10] While the incidence 
of NRG1 gene fusions is only around 0.2% of all solid tumors, this represents approximately 
3,500 new cases per year.  
 
Results presented at the American Association for Cancer Research (AACR) Annual Meeting 
2019 showed tarloxotinib to be active against NRG1 gene fusion cancers, irrespective of site 
of origin. It is believed that afatinib may have similar activity across sites of cancer associated 
with NRG1 gene fusions. Recent case reports presented some of the first evidence that patients 
with NRG1 gene fusions who were treated with afatinib had durable responses.[5] While the 
first reports emerged in lung cancer,[5] further research has implicated other solid tumors.[6] 
These findings indicate that malignancies associated with NRG1 gene fusions may benefit from 
treatment with afatinib. 
 
Afatinib (Gilotrif®) was initially approved in 2013 by the U.S. Food & Drug Administration 
(FDA) for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR 
exon 19 deletions or exon 21 (L858R) substitution mutations; this indication was broadened in 
2018 to include non-resistant EGFR mutations. Additionally, afatinib was approved in 2016 
for the treatment of patients with metastatic squamous NSCLC progressing after platinum-
based chemotherapy. Obtaining real-world data describing the real-world outcomes associated 
with afatinib use in patients with NRG1 fusion-positive across a range of solid tumors may be 
used in supplemental applications for label expansion requests to the FDA and other agencies. 
This study aims to provide real-world evidence on the real-world clinical outcomes associated 
with afatinib use among patients with NRG1 gene fusions across a range of solid tumors, as 
well as real-world data among patients with NRG1 gene fusions treated with other systemic 
therapies.  
 
 

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8. RESEARCH QUESTIONS AND OBJECTIVES 
Limited data on durable responses in patients with NRG1 gene fusion-positive solid tumors 
have been reported with afatinib. Beyond these data, no comprehensive evaluation has been 
conducted of patients harboring NRG1 gene fusions treated with afatinib or other systemic 
therapy, in any line of therapy, to describe patient characteristics and clinical outcomes 
associated with afatinib use. This study aims to answer these questions by achieving the 
objectives stated below. As this study is descriptive in nature, no a priori hypothesis will be 
tested. 
 
Research Questions: 
1. What are the characteristics of patients with NRG1 gene fusion-positive solid tumors 
treated with afatinib, and what are the characteristics of those treated with another 
systemic therapy?  
Study Objectives: 
1. To describe the demographic and clinical characteristics of patients with NRG1 gene 
fusion-positive solid tumors treated with afatinib and of patients with NRG1 gene 
fusion-positive solid tumors treated with other systemic therapy. 
2. To calculate the ORR and DOR among patients with NRG1 gene fusion-positive solid 
tumors treated with afatinib and among patients with NRG1 gene fusion-positive solid 
tumors treated with other systemic therapy 
3. To estimate PFS (and TOT, TTP) among patients with NRG1 gene fusion-positive 
solid tumors treated with afatinib and among patients with NRG1 gene fusions treated 
with other systemic therapy 
4. To estimate OS among patients with NRG1 gene fusion-positive solid tumors treated 
with afatinib and among patients with NRG1 gene fusion-positive solid tumors treated 
with other systemic therapy 
5. To describe the incidence and severity of AEs among patients with NRG1 gene 
fusion-positive solid tumors while on treatment with afatinib or other systemic 
therapy 
 
 
 

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9. RESEARCH METHODS 
9.1 STUDY DESIGN 
This is a non-interventional, retrospective, US, multi-site, cohort study based on existing data 
from medical records of patients with NRG1 gene fusion-positive solid tumors treated with 
afatinib or other systemic therapy. Two cohorts of patients will be identified. The first includes 
any patient with NRG1 gene fusion-positive solid tumors who has received afatinib in any line 
of therapy (afatinib cohort) between 01/01/2017 and 03/31/2020. The second includes any 
patient with NRG1 gene fusion-positive solid tumors who has not received afatinib in any line 
of therapy (other systemic therapy cohort) during the same period and no history of afatinib 
use. Follow-up will include at least 3 months after initiation of afatinib or other systemic 
therapy, unless a patient died prior to 3 months of follow-up.  
 
In total, up to 120 patients with NRG1 gene fusion-positive solid tumors will be selected for 
this study, of whom up to 70 will be afatinib-treated and up to 50 will be treated with other 
systemic therapy. Study objectives are to describe these patients and calculate the ORR in each 
group, as well as to estimate PFS, TOT, TTP, OS, DOR, and DOCB along with describing the 
incidence and severity of AEs among patients in the two cohorts. Data to be collect through 
this medical chart review include patient demographics, clinical characteristics at the time of 
diagnosis/initiation of a line of therapy, treatment-related data points (dates of initiation, 
discontinuation, dosing), AEs occurring during therapy, disease response, date of progression 
and/or death.  
 
Given the small number of patients targeted for study inclusion and anticipated differences in 
baseline characteristics between afatinib-treated and patients treated with other systemic 
therapies, statistical comparisons are not planned. In lieu of statistical comparisons between 
cohorts, the non-afatinib arm will provide context for interpreting results among those treated 
with afatinib. Specifically, this context includes what patients with NRG1 gene fusions not 
treated with afatinib look like, how they are managed and treated, and what their clinical 
outcomes look like. The non-afatinib arm will provide a broader understanding of NRG1 gene 
fusions among patients with solid tumors 
 
Data collection is anticipated to begin in the third/fourth quarter of 2020, allowing for a 
minimum follow-up period of 3 months. All patients are required to have initiated index 
therapy (i.e., afatinib in any line; other systemic therapy among those without any history of 
afatinib) between 01/01/2017 and 03/31/2020. As such, the maximum follow-up period is 
approximately 39 months. The index date is the date of initiation of afatinib or other systemic 
therapy between 01/01/2017 and 03/31/2020 for the other systemic therapy cohort.   
 
9.2 SETTING 
Approximately 20 or more unique providers will participate in this research study. To minimize 
potential bias, the maximum number of patients each provider may select and complete data 
abstraction for is capped at 30; for any provider who submits >10 patients, their data will be 
reviewed in detail by a clinician and analyst to identify any data quality issues (see Section 
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will be collected through an electronic case report form (eCRF) completed by the patients’ 
providers who volunteer to participate in the study. Providers will be compensated at fair 
market value for the time to complete data abstraction and quality control procedures, which 
are estimated to take up to 1 hour per patient.  
 
Recruitment of providers will be conducted electronically. Providers who responded to an 
initial feasibility request and reported treating potentially eligible patients will be contacted and 
invited to participate. Recruitment to fill the up-to-120-patient quota will run for 4 weeks from 
the date of recruitment launch. During that time, the per-cohort quotas will be electronically 
monitored to ensure that the final number of patients achieves up to 70 patients with NRG1 
gene fusion-positive solid tumors treated with afatinib and up to 50 with an NRG1 gene fusion-
positive solid tumor not treated with afatinib at the time of data collection. As recruitment for 
a cohort is completed, no further patient data entry will be allowed for that cohort; however, 
providers actively completing an eCRF at the time of quota close for a cohort will be allowed 
to complete that eCRF, and the total number of patients per cohort may exceed the quotas.  
 
Providers will be asked to identify all eligible patients, and starting with the earliest index date, 
chronologically select consecutive patients meeting the eligibility criteria and complete the data 
abstraction. The eCRF is structured to allow data collection regarding patient clinical history 
at the time of initial diagnosis of their solid tumor, initiation of index therapy (including dates 
of dose starts, stops, and interruptions), response to therapy, dates of disease progression, AEs, 
(including dates of onset, recovery, and reported deaths). 
9.2.1 Provider/Site/Patient Selection 
Provider Eligibility 
 
Providers who meet the following criteria will be eligible to participate: 
1) Are board-certified oncologist/hematologist. 
2) Have treated/are treating at least one eligible patient with an NRG1 fusion-positive solid 
tumor. 
3) Are able to participate in research approved by an external institutional review board 
(IRB). 
4) Agree to participate in data quality assurance/control processes. 
 
Providers will select patients meeting the study eligibility criteria as described below. Providers 
will be asked to select eligible patients chronologically, starting with the first patient who first 
initiated any line of afatinib or chemotherapy, on or after 01/01/2017 through 03/31/2020. 
 
 
Patient Eligibility 
 
Inclusion Criteria: 
 Adults, 18 years of age or older, at the time of diagnosis with any solid tumor. 
 Confirmed NRG1 gene fusion in any solid tumor.  
 Initiated afatinib or other systemic therapy (in any line of therapy) for treatment of a 
solid tumor with NRG1 gene fusion on or after 01/01/2017 through 03/31/2020. 

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 Followed up for ≥3 months after initiation of afatinib or other systemic therapy (unless 
deceased prior to 3 months of follow-up). 
 
 
Exclusion Criteria: 
 Treatment with any TKI/ErbB-directed therapy other than afatinib 
9.3 VARIABLES 
9.3.1 Exposures 
The primary exposure of interest is treatment with afatinib. Two cohorts of patients will be 
created: the afatinib-treated cohort includes patients with an NRG1 gene fusion-positive solid 
tumor who had received afatinib in any line of therapy; the second cohort includes patients 
with an NRG1 gene fusion-positive solid tumor who had not received afatinib prior to the date 
of data collection. Patients treated with afatinib monotherapy and their outcomes will be 
described in addition to the two main aforementioned treatment groups.  
9.3.2 Outcomes 
Demographic and clinical characteristics of patients with NRG1 gene fusion-positive solid 
tumors treated with afatinib and of patients with NRG1 gene fusion-positive solid tumors 
treated with other systemic therapy will be summarized for each cohort. These variables serve 
as outcomes in terms of fulfilling study objectives. These variables also serve as covariates to 
contextualize other study outcomes (e.g., ORR, DOR, DOCB, PFS, TOT, TTP, OS, AEs).  
 
Table 1. Patient demographics and clinical characteristics. 
 
Characteristic 
Definition 
Sex 
Patient sex, as charted 
Age(s) 
Age at diagnosis of solid tumor and age at initiation of afatinib or other 
systemic therapy 
Region 
US census region of patient: Northeast, South, Midwest, West 
Race/ethnicity Race and ethnicity of patient, as charted 
Tumor type 
Description/classification of primary tumor of patient (e.g., NSCLC, 
cholangiocarcinoma, pancreatic cancer) 
ECOG PS 
ECOG PS of patient at initiation of afatinib or other systemic therapy 
Comorbidities Comorbidities present at initiation of afatinib or other systemic therapy, 
following Charlson comorbidity index  
Stage 
Stage of tumor at initiation of afatinib or other systemic therapy 
NRG1 results 
Date of NRG1 gene fusion test; laboratory performing test (e.g., academic, 
reference, in-house lab; name of lab); NRG1 gene fusion partner 
Other 
biomarkers 
Tumor-specific biomarkers tested and their results (e.g., MSI/MMR, EGFR, 
HER2) 
 

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The ORR among patients with NRG1 gene fusion-positive solid tumors treated with afatinib 
and among patients with NRG1 gene fusion-positive solid tumors treated with other systemic 
therapy will be calculated as the proportion of patients with a complete response (CR) or partial 
response (PR) out of all patients (CR+PR/all patients) (see Table 2 below). Disease response 
for determining the ORR will be reported as recorded in the patient’s EHR, including the date 
of radiographic imaging used to substantiate the patient’s initial and best response to therapy. 
Providers will indicate whether the patient experienced a CR, PR, stable disease (SD), or 
progressive disease (PD). No independent blinded review of radiology studies will be 
conducted. Lesion measurements at baseline (initiation of afatinib; initiation of other systemic 
therapy for non-afatinib treated patients), initial response, and best response will be abstracted 
as available. Changes in the number, locations, and sizes of lesions at initial and best response 
to therapy will be evaluated by 
 using RECIST v1.1 guidelines. The sum of lesion 
measurements will be assessed at baseline and at follow-up scans to calculate the percent 
change in sum of target lesions, as well as account for new lesions on follow-up scan in order 
to classify response by RECIST v1.1 criteria. Actual scan images will not be reviewed; the 
calculation of real-world disease response will be based on the lesion measurements provided. 
Other outcomes include PFS, TOT, TTP, OS, DOR, DOCB, AEs. Definitions of these 
outcomes are shown in Table 2.  
 
Table 2. Study outcomes and definitions. 
 
Outcome 
Definition 
ORR 
Proportion of patients with a complete response (CR) or partial response 
(PR) out of all patients (CR+PR/all patients) at initial response assessment 
and best response  
DOCB 
Duration of clinical benefit (DOCB) will be calculated as the time from 
initial response (for any patient with a complete, partial, or stable disease 
response initially) until the earliest of either disease progression or death. 
Patients who discontinue therapy due to a reason other than progression 
will be censored on the date of discontinuation. Patients still on therapy at 
the time of data cut-off will be censored on their last visit date.  
DOR 
Duration of response will be calculated as the time from initial response 
(for any patient with a complete or partial response initially) until the 
earliest of either disease progression or death. Patients who discontinue 
therapy due to a reason other than progression will be censored on the date 
of discontinuation. Patients still on therapy at the time of data cut-off will 
be censored on their last visit date.  
TOT 
Time from initiation of a line of therapy until discontinuation for any 
reason; patients on therapy at the time of data cut-off will be censored on 
the last date of treatment. 
TTP 
Time from initiation of a line of therapy until discontinuation due to disease 
progression; patients on therapy or those who discontinued due to a reason 
other than disease progression will be censored on the last date of 
treatment. 

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PFS 
Time from initiation of a line of therapy until disease progression or death; 
patients on therapy at the time of data cut-off will be censored on the last 
date of treatment. Patients who discontinue a line of therapy for a reason 
other than disease progression but who subsequently die prior to the receipt 
of any other therapy will be considered an event on the date of death. 
OS 
Time from initiation of any therapy in the metastatic setting until death; 
patients alive at the time of data cut-off will be censored on the last date 
the patient was seen by the provider/clinic.  
AE 
An adverse event is defined as any untoward medical occurrence in a 
patient administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. AEs from a prepopulated list 
(including “other, please specify”) during each line of therapy will be 
indicated by providers. The number and proportion of patients 
experiencing each AE reported during afatinib or other systemic therapy 
will be reported. See Section 11.1 and Table 3 for further details. 
 
 
In addition to TOT, to further characterize treatment patterns for those treated with afatinib and 
those treated with other systemic therapy, the following will be collected (and calculated based 
on the collected data): 
 Treatment history (i.e., regimens, duration, number of cycles, sequence)  
 Starting dose of afatinib or other systemic therapy 
 Dose modifications of afatinib or other systemic therapy (i.e., dose reductions and 
their timing, dose increases and their timing, dose delays and their duration and 
timing) 
 Rationale for afatinib or other systemic therapy discontinuation 
 
AEs will be collected and analyzed in the Clinical Study Report. Providers will be shown 
information describing what constitutes an AE/ADR/SAE/FAE per BI policies. The processes 
for safety reporting and analysis of the safety data will be implemented and conducted as per 
the BI non-interventional study (NIS) standard operating procedures. 
 
will complete any reporting of events to BI per event reporting protocols.  
 
The diagnosis, time, attribution (treatment-related or not per provider interpretation) and 
severity of the reported AEs during index therapy will be collected. If death is cited as rationale 
for discontinuation then provider will abstract data related to date of death, cause of death.  
 
Table 3. Adverse events data collection. 
 
Variable 
Definition / response options 
AEs during a given line of 
therapy 
During each line of therapy, providers will indicate the 
AE that occurred including severity.  
Start date of AE 
Date each AE occurred 

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Severity (see section 11.1) 
Severity of each AE, as assessed by the provider, 
provided the following guidance: 
 Mild (mild symptoms; clinical or diagnostic 
observations only [e.g. lab work]; intervention 
not performed) 
 Moderate (minimal, local or noninvasive 
intervention performed [e.g., administration of 
fluids] 
 Severe (medically significant ranging from not 
immediately life-threatening, life-threatening 
consequences, to death related to AE; [e.g., 
extensive 
monitoring, 
hospitalization 
or 
prolongation of hospitalization]) 
Resolution 
Outcome of each AE will be collected as: 
 Recovered/Resolved 
 Recovered/Resolved with sequelae 
 Not yet recovered/Not yet resolved 
 Fatal 
 Unknown  
Outcome 
For all AEs, the outcome of the AE, regardless of 
severity indicated, will be assessed by participating 
providers. These outcomes will allow for the 
classification of serious and fatal AEs as defined in 
Section 11 
 Dose reduction 
 Dose hold/dose delay/schedule change 
 Discontinuation of treatment 
 Unscheduled office visit/treatment  
 Resulting in death 
 Life-threatening  
 Required inpatient hospitalization 
 Resulted in persistent or significant disability 
 Prolonged existing hospitalization 
End date of AE 
Date 
AE 
resolved/patient 
recovered 
(if 
resolved/recovered) 
Causal relationship of AE to 
treatment 
See section 11.2 for guidance on assessing causal 
relationship (i.e., afatinib  or other systemic therapy) 
 
9.3.3 Covariates  
Patient demographics clinical characteristics will be described in each cohort of patients. As 
described above, these variables will be summarized descriptively as study outcomes and also 

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considered as covariates to contextualize the clinical outcomes of the study (e.g., ORR, DOR, 
PFS, TOT, OS, AEs). These variables are described in Section 9.3.2 Outcomes, above. 
 
9.4 DATA SOURCES 
All study data will be entered by the investigators into the eCRF. The eCRF captures data for 
each of the study variables described in Section 9.3 - Variables. The eCRF is designed to allow 
providers to efficiently move through the patient chart or EMR based on the journey of the 
patient through the course of disease. The eCRF conforms to the rules and regulations of the 
Health Insurance Portability and Accountability Act (HIPAA) of 1996 governing the 
abstraction and storage of protected health information (PHI).  
 
De-identified, patient-level data will be obtained from providers in the 
 
 who will complete an electronic case report 
form (eCRF) for eligible patients.
will recruit providers from 
 to participate. 
 is a community of over 
7,000 oncologists, hematologists and urologists from across the U.S., with varying levels of 
time in practice, from practices both within and outside of group purchasing organizations. A 
subset of this group (~800) participates in retrospective observational research studies. All 
provider participation in the study is voluntary.  
 
To be eligible to participate, providers must have treated at least one patient meeting the study 
eligibility criteria, be able to participate in research approved by an external institutional review 
board (IRB), and agree to participate in data quality control processes. No provider at practices 
that require local IRB approval at the practice will be eligible to participate. A waiver of 
obtaining patient consent will be sought for the study. No protected health information (PHI) 
beyond dates of diagnosis, treatments, and outcomes will be collected.   
 
Providers will abstract demographic-, clinical-, and treatment- related data as available from 
the patient’s electronic health record (EHR), starting from the time of primary malignancy 
diagnosis through the last date of follow-up with the patient or death. Providers will complete 
an eCRF for all eligible patients and will begin data abstraction beginning with the first eligible 
patients and select consecutive patients moving forward in time. Data elements that are 
required are specified in the study inclusion/exclusion criteria; non-required data elements may 
be missing/unknown. Providers may abstract data into the eCRF for both patients they 
personally managed/treated or those managed/treated by other providers within their practice.  
9.4.1 Source Documents 
Providers are compensated for their time completing data abstraction into the eCRF and 
subsequent data verification as necessary. No source documents will be provided to 
 for 
verification; however, 
 will require duplicate data entry for a sample of patients (see 
Section 9.8.2 Data Validation) after initial data collection to verify data point accuracy. 

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9.4.2 Dataset and Records 
9.5 STUDY SIZE 
The total target number of patients is up to 120 patients, including up to 70 patients with an 
NRG1 gene fusion-positive solid tumor treated with afatinib and up to 50 patients with an 
NRG1 gene fusion-positive solid tumor who had not received afatinib at the time of data 
collection. The target number of patients was based on the results of a pilot feasibility study 
conducted by 
 with BI.  
 
In December 2019, 
 conducted outreach to approximately 800 providers in 
 to 
inquire as to the number of patients with NRG1 gene fusion-positive solid tumors treated with 
afatinib they had personally managed or who were cared for at their practice. Providers were 
presented with similar inclusion criteria as those described herein. In total, 12 oncologists 
completed short eCRFs describing a total of 108 patients. Of the 108, 67 patients were treated 
with afatinib and 41 had not received afatinib therapy.  
 
Based on the feasibility study, 
 will target number of patients of up to 70 afatinib-treated 
patients with NRG1 gene fusion-positive solid tumors and up to 50 patients with NRG1 gene 
fusion-positive solid tumors who have not received afatinib. Although the feasibility study did 
not identify this number of patients, further recruitment to non-responders to the survey 
invitation will be used to achieve the target number of patients planned for this study. Given 
the small number of patients targeted for study inclusion and anticipated differences in baseline 
characteristics between afatinib-treated and patients treated with other systemic therapies, 
statistical comparisons are not planned. In lieu of a comparative analysis between the afatinib-
treated and non-afatinib treated patients are exploratory, the number of patients in each cohort 
and the precision of estimates are presented (Table 4). With up to 70 patients in the afatinib-
treated cohort, the standard error (SE) of any bivariate response variable is expected to be 
between  5.5% and 11.7%. 
 
 
Table 4. Precision of point estimates around number of patients. 
Point Estimate 
of Proportion 
Total Number of eCRFs 
n=30  
(SE) 
n=50 
(SE) 
n=70 
(SE) 
n=100 
(SE) 
n=150 
(SE) 
5% 
± 7.8% 
± 6.0% 
± 5.5% 
± 4.3% 
± 3.6% 
20% 
± 14.3% 
± 11.1% 
± 9.4% 
± 7.8% 
± 6.4% 
30% 
± 16.4% 
± 12.7% 
± 10.7% 
± 9.0% 
± 7.3% 
40% 
± 17.5% 
± 13.6% 
± 11.5% 
± 9.6% 
± 7.8% 
50% 
± 17.9% 
± 13.9% 
± 11.7% 
± 9.8% 
± 8.0% 
9.6 DATA MANAGEMENT 
The research team will be responsible for the programming, testing, and hosting of data from 
submitted eCRFs. Providers will access the eCRF through a secure web-based portal with all 
data stored on encrypted, password protected, and HIPAA-compliant servers housed within the 
 electronic data storage infrastructure. These processes and systems are vetted during the 

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field-testing procedures. The software used to program the eCRF is the Qualtrics Survey 
Software. A log of any modifications made to the underlying data as a result of quality 
control/quality assessment procedures will be maintained. An original copy of the submitted 
data will always also be maintained. The log will describe any changes made to the database 
by 
  
9.7 DATA ANALYSIS 
Demographic and clinical characteristics will be reported by descriptive analyses including 
counts and frequencies for dichotomous and categorical variables, while measures of centrality 
(mean, median) and spread (min, max, standard deviation, interquartile range, as appropriate) 
will be used for continuous variables. These characteristics will be described at the time of 
initial diagnosis of advanced/metastatic disease and at the time of initiation of each line of 
therapy received, for the afatinib cohort and separately for the other systemic therapy cohort. 
No statistical comparisons will be made across these two cohorts in terms of demographic, 
clinical characteristics, and clinical outcomes.  
 
The calculations for all outcomes (e.g., ORR, DOR, DOCB, TOT, TTP, PFS, OS) are defined 
in Table 2 in Section 9.3.2 Outcomes. For disease response, the point estimate for ORR and 
associated 95% confidence interval (CI) will be calculated for initial response to index therapy 
(i.e., afatinib or other systemic therapy) and best response to index therapy, for each cohort. 
ORR will be reported among subgroups within each of the treatment cohorts, by tumor type 
and line of therapy. The Kaplan-Meier method will be used to estimate time-to-event outcomes 
(DOR, DOCB, TOT, TTP, PFS, and OS) to account for any right-censoring (e.g., patient had 
not discontinued therapy, patient had not progressed, or died). Time-to-event outcomes will be 
described for each of the two treatment cohorts and in subgroups within the two treatment 
cohorts, according to solid tumor and line of therapy. All study outcomes will be reported 
separately for those treated with afatinib monotherapy. In the event an outcome cannot be 
assessed for a given patient, that patient would be omitted from assessment of that outcome; 
reason for omission in a given outcome assessment will be reported.   
 
Cumulative incidence, severity, and timing of AEs during the index therapy will be 
summarized and displayed in number/percentage form for each of the treatment cohorts, 
separately. All safety endpoints will be analyzed descriptively. AE reporting is summarized in 
Section 11 Management and Reporting of Adverse Events/Adverse Reactions. 
 
9.8 QUALITY CONTROL 
 will conduct all data quality assurance and control activities. The following sections 
outline the data quality assurance and control measures implemented throughout data 
collection, management, and inspection, prior to constructing a final analytic data file. These 
procedures are conducted from a programming standpoint (e.g., logic checks built into the data 
collection tool) via statistical analysis to identify patterns and outliers, and by clinical review 
to identify implausible data or incongruent data points on a given patient.  

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9.8.1 eCRF Functionality Testing 
Prior to data collection and during the field test, 
 will test the eCRF. This quality control 
process begins with extensive testing of the eCRF to ensure functionality across web-based 
user environments, looping logic to ensure proper alignment of data-related fields (required 
responses to certain fields prior to entering data into subsequent field), and other programmatic 
checks to ensure the reduction of the input of erroneous data (such as specifying maximums 
for year of birth or initiation of treatment within the dates of the enrollment period). Only data 
ranges consistent with known clinical parameters will be allowed to be entered into the eCRF.  
In addition, the eCRF will be field-tested among four providers to ensure its functionality, the 
correct interpretation of the questions in relation to the data points of interest, and the length of 
time required for completion for a single patient. Field-testing includes a 
 researcher 
viewing the screen of the provider completing the eCRF with actual patient data and asking 
probing questions regarding the functionality, interpretability (variables are aligned with 
clinical definitions or clinical interpretations), and availability of the variables requested. No 
data from the pre-testing phase will be used in the analysis for this research. Pre-testing of the 
eCRF will not commence until receiving IRB approval for the conduct of the study. The pre-
test results will be reviewed by BI with 
 however, BI will not have access to the 
individual data collected. Any changes made to the eCRF document as a result of the pre-test 
will require the resubmission of the eCRF and study protocol to the IRB.   
9.8.2 Data Validation 
Multiple levels of quality control and quality assessment occur during the study. First, the 
eCRF includes programmed internal validity checks, including date validation (e.g., date of 
initiation of index therapy cannot occur before date of initial diagnosis of cancer) and logic that 
forces providers to respond to required questions. Next, the eCRF will be pre-tested with four 
clinicians prior to data collection. During this pre-test, 
 staff will hold a web-based 
conference with a selected provider during which the provider will abstract data into the eCRF 
while 
 research staff members monitor and probe the provider regarding the clarity of 
eCRF data fields. After conducting this pre-test, 
 will present 
findings to BI and suggest revisions to the eCRF as needed. The revised eCRF will be filed 
with the study IRB.  
 
During data collection, 
 clinical research staff review all submitted eCRFs inspecting 
each for implausible patient clinical profiles based on treatment sequencing, lab and radiology 
results, or outcomes that are inconsistent with known clinical parameters, or other clinical data 
that are inconsistent with known standards and outcomes. In addition to review of the submitted 
data by the clinical research team, the study statistician will conduct an analysis of submitted 
data to identify any data points inconsistent (outliers) with the study population average. This 
analysis will include a descriptive analysis of the provider characteristics, demographics, 
baseline clinical and disease characteristics, and characteristics of treatment patterns (e.g., 
TOT). Data points flagged as outliers will be delivered to the clinical research team for further 
assessment. 
 
Should outliers be discovered, 
 clinical research would contact the provider submitting 
the eCRF for data validation. All providers are informed in their contractual agreement that 

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follow-up with clinical staff at 
 may be required. Participating providers are asked to 
create a 4-digit unique identifier code per patient that is provided to
through the eCRF 
and used for identifying the patient record for validation between 
and the provider. 
Individual eCRFs will be removed from providers unable to validate a data point, and re-
sampling will not occur. All other data will be considered valid provided additional patients 
from that provider are not selected for random validation.  
 
Random data validation occurs by selecting a random eCRF from each provider submitting a 
patient. Providers who have been previously verified by 
 will not be subject to 
completion of the random validation. A verified provider is any physician abstractor who has 
completed at least two of the following: (1) completed and acknowledged our web-based chart 
data abstraction training in the past 2 years, (2) participated in a chart review pre-test with 
screen sharing, (3) participated in 2 previous chart review studies in the past 2 years and 
accurately validated data, and (4) have completed a phone interview with the 
 team for 
data validation. A provider may be verified but still required to answer questions regarding 
patients with data flagged by 
or 
groups. 
Providers subject to random validation are asked to complete a 3-data point validation exercise 
for the patient whereby the provider is given the unique patient identifier but no other 
information. The provider is asked to re-enter the respective data elements. The three data 
points may include elements such as the month/year of index treatment initiation, stage at 
diagnosis, and date of index treatment discontinuation (or date of last treatment/prescription if 
patient is still on therapy). A provider who fails to validate all data points for a selected patient 
will be required to submit to further clinical data review. Patients for whom the data are deemed 
questionable by the research team staff will be excluded; providers will not be compensated 
for excluded data. No resampling to replace the excluded eCRF will occur. Provider who are 
nonresponsive to any validation request will have all data submitted excluded from the study.   
 
For all data validation processes, a log of records that undergo statistical and clinical review 
will be kept, recording the reason a given record was flagged for further follow-up. Should data 
quality checks and confirmation with providers reveal discrepancies, corrections will be made 
to the database. These corrections (including whether a record was dropped entirely) will be 
documented in an audit trail. The number of records undergoing each step of data validation 
and the number of records corrected or excluded from the final data set will be reported.  
9.9 LIMITATIONS OF THE RESEARCH METHODS 
The limitations of this approach include provider selection bias, patient selection bias, and the 
lack of source document verification. Regarding bias, only providers who meet the study 
eligibility requirements and who volunteer to participate in the research study are known; 
therefore, the representativeness of the providers to all oncologists in the U.S. cannot be 
verified directly. Additionally, providers will select the patients meeting study eligibility 
criteria, so they may not include all potentially eligible patients. As such, the representativeness 
of the patient sample to all patients in the U.S. or in the population of patients within the 
 
 also cannot be verified. Source document verification cannot be performed by 
 
however, quality assessment/control procedures to minimize misclassification errors are 
described in Section 9.8 – Quality Control.  
 

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1) As an exploratory, retrospective, non-randomized study with up to 70 and up to 50 
patients per cohort (respectively), post-hoc propensity score matching cannot be 
conducted and unadjusted/crude comparisons between the two cohorts cannot be made 
as underlying demographic/clinical characteristics may exist between the cohort. 
Therefore, statistical comparisons of outcomes between the two cohorts cannot be 
made.  
2) Not all patient characteristics will be included in the data collection (e.g., income and 
other variables that may influence provider-prescribing behavior or treatment 
decisions) and cannot be accounted for in the descriptive analyses. 
3) Loss to follow-up during the study period may occur if patients transfer care to other 
providers and centers. As such, treatments, visits, and outcomes occurring after the 
date of last visit may be missing. 
4) Treatment patterns reflected in the study represent only the practices of providers who 
have agreed to participate, and may vary from non-responding providers, i.e., those 
who refused study participation or who were unresponsive to the screening invitation. 
No data is available to describe non-responders. 
5) This study employs purposive sampling that selects providers and patients based on 
pre-specified selection criteria and hence this may not be representative of all patients 
diagnosed with NRG1 gene fusion-positive solid tumors treated with the drugs of 
interest or representative of all providers treating these types of patients.   
6) AEs may be underreported/under-documented in a routine clinical setting as they may 
occur outside of the office setting and often go unreported compared to what would be 
expected from a controlled trial or prospective observational study setting. Moreover, 
providers may not be able to verify that the AEs evaluated in this study meet the criteria 
as established by CTCAE or other guidelines. Therefore, the frequency of occurrence 
of AEs cannot be confirmed by this dataset. 
7) Although providers will be required to record all patient experiences in the medical 
charts, there may be some undercounting of events that are unknown to providers due 
to having occurred outside the office. Thus, the accuracy and completeness of data 
collected in this study is limited by the quality of data in the patient’s medical chart. 
9.10 OTHER ASPECTS 
N/A 
9.11 SUBJECTS 
See Section 9.2 – Provider/Site/Patient Selection for a description of the patients included 
in this study.  
9.11.1 Cases 
N/A 

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9.11.2 Controls 
N/A 
9.12 BIAS 
Provider and patient selection bias may exist in this study. Provider selection bias will be 
minimized by only allowing providers to contribute up to 30 patients each. It is expected, 
however, given the rarity of the patient profile included in this study, that the mean number of 
patients each provider will contribute is approximately 5 and the total number of providers 
participating will be greater than 20. Patient selection bias will be minimized to the extent 
possible by requesting providers complete eCRFs for eligible patients starting chronologically 
with the earliest patient meeting the criteria and selecting patients consecutively thereafter. To 
assess the degree of selection made by the participating provider, the total number of patients 
meeting the study selection criteria will be collected (e.g., 5 patients meet study 
inclusion/exclusion criteria) will be compared to the number of patients contributed to the study 
(e.g., 3 patients submitted as CRFs).  
 
In addition, the extent of both provider and patient selection bias is likely minimized by the 
stringent study selection criteria. Because of the relative rarity of NRG1 fusion-positive 
histology, the total prevalence of this patient population is likely small, minimizing potential 
selection biases. 

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10 PROTECTION OF HUMAN SUBJECTS  
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. All study materials including the 
research protocol and paper-version of the eCRF will be reviewed by a central IRB prior to any 
data abstraction including field-testing of the eCRF. A wavier of HIPAA authorization for use 
of PHI will be requested from the IRB since the following three requirements will be met: 
 
1. The use or disclosure of the PHI involves no more than minimal risk to the individuals, 
based on the following elements: 
a. An adequate plan to protect identifiers from improper use and disclosure; 
b. An adequate plan to destroy the identifiers at the earliest opportunity consistent with 
conduct of the research (unless there is a health or research justification for retaining 
the identifiers, or such retention is otherwise required by law); and 
c. Adequate written assurances that the PHI will not be reused or redisclosed to any 
other person or entity, except as required by law, for authorized oversight of the 
research project, or for other research for which the use or disclosure of PHI would 
be permitted by HIPAA. 
2. The research could not be practicably conducted without access to and use of the PHI; 
and 
3. The research could not practicably be conducted without the waiver. 
 
Providers are required to be able to participate in research covered by a central IRB. At all 
times, patients’ PHI will be kept confidential in accordance with HIPAA. The eCRF will not 
capture any data related to the patient’s name, full date of birth, social security number, health 
insurance plan number, medical record number, or other such PHI. However, date of disease 
diagnosis, date(s) of treatment(s) administered (including dates of dose changes), date of the 
development of health states of interest (i.e., SAEs/FAEs, disease progression), and date of 
death (if available) will be collected in the eCRF. These items are  considered PHI under 
HIPAA. All study results will be reported in aggregate; however, an anonymized patient-level 
dataset will be delivered to BI at the completion of the analytic cohort build. 
 
This study was designed and shall be implemented and reported in accordance with the 
Guidelines for Good Pharmacoepidemiology Practices of the International Society for 
Pharmacoepidemiology (ISPE 2008), the STROBE (Strengthening the Reporting of 
Observational Studies in Epidemiology) guidelines, and with the ethical principles laid down 
in the Declaration of Helsinki.  
 

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11 MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This is a retrospective, non-interventional, non-randomized study using data contained in 
structured and unstructured areas of the patients EHR previously collected as part of routine 
clinical care. We are asking chart abstractors (i.e., the patients’ treating providers) to abstract 
information on AEs during afatinib or other systemic therapy. Reporting of these events will 
be conducted in the manner described in section 11.2.  
 
In addition, reporting requirements and procedures for other AEs identified during the chart 
review are described in 11.2. 
 
11.1 DEFINITIONS OF ADVERSE EVENTS 
Adverse event (AE) 
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 AE can therefore be any unfavourable and unintended sign (e.g., abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product.  
Adverse drug reaction (ADR) 
An ADR 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 
AE is at least a reasonable possibility. Adverse reactions may arise from the use of the product 
within or outside the terms of the marketing authorization or from occupational exposure. 
Conditions of use outside the marketing authorization include off-label use, overdose, misuse, 
abuse, and medication errors. 
Serious adverse event (SAE) 
SAE is defined as any AE that: 
 results in death 
 is life-threatening  
 requires in-patient hospitalization, or  
 prolongation of existing hospitalization  
 results in persistent or significant disability or incapacity, or 
 is a congenital anomaly/birth defect 
 
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe. 

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Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious events, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 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 hospitalization or 
development of drug dependency or drug abuse. Any suspected transmission via a medicinal 
product of an infectious agent is also considered a serious adverse reaction. 
No AESIs have been defined for this study. 
 
11.2 ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING  
11.2.1 
Collection of AEs 
The study design is of non-interventional nature.  
The following will be collected and documented on the CRF by the abstracting provider: 
 All adverse events (AEs) (serious and non-serious) 
 
All AEs, 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 AE 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in contrast 
to an AE, 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 the 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. 
 No medically sound alternative etiologies could explain the event (e.g., pre-existing 
or concomitant diseases, or co-medications). 

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 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 the 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, considering the 
pharmacological properties of the compound (e.g., after five half-lives).  
Of note, this criterion may not apply 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 AE 
Providers will be asked to classify AEs as mild, moderate, or severe based on the medical 
intervention associated with the AE (see below). 
 Mild: mild symptoms; clinical or diagnostic observations only (e.g., lab work); 
intervention not performed 
 Moderate: minimal, local, or noninvasive intervention performed (e.g., administration 
of fluids) 
 Severe: medically significant, ranging from not immediately life-threatening, life-
threatening consequences, to death related to AE; (e.g., extensive monitoring, 
hospitalization or prolongation of hospitalization) 
Regardless of the severity of the AE indicated by the provider, the following outcomes will 
be collected for all AEs, in order to further classify them as serious and/or fatal. 
 Resulting in death 
 Life-threatening  
 Required inpatient hospitalization 
 Resulted in persistent or significant disability 
 Prolonged existing hospitalization 
 
Pregnancy 

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In rare cases, pregnancy might have occurred during the study period. Patients who were 
identified as pregnant while on afatinib will be reviewed. Any drug exposure during pregnancy, 
which occurred in a female patient or a partner to a male patient will be reported by means of 
Part A of the Pregnancy Monitoring Form. The outcome of the pregnancy associated with 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 and/or Pregnancy 
Monitoring Form from start of data extraction once informed consent is signed (if required) 
onwards until the end of data extraction and provide to BI unique entry point: 
Type of Report 
Timeline 
All serious ADRs associated with afatinib  
immediately within 24 hours 
All AEs with fatal outcome in patients 
exposed to afatinib  
*Exemption applies 
immediately within 24 hours 
All non-serious ADRs associated with 
afatinib  
7 calendar days 
Drug exposure during pregnancy 
7 calendar days 
 
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 fax and/or email the NIS AE Form. 
*Exemption 
Death due to disease progression of the underlying malignancy is a study endpoint and the 
natural course of the disease. As such, it is exempted from reporting as an SAE. Progression of 
the subject's underlying malignancy will be recorded on the appropriate pages of the eCRF 
only and will not be reported on the NIS AE Form. However, when there is evidence suggesting 
a causal relationship between afatinib and the progression of the underlying malignancy, the 
event must be reported as an SAE on the NIS AE Form and on the eCRF. 
Information required 
For each reportable AE, the investigator should provide the information requested on the 
appropriate CRF pages and the NIS AE form. 
Reporting of AEs assessed as related to any other BI drug 

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The investigator is encouraged to report all AEs related to any BI drug other than afatinib 
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 unexpected benefit. 
11.3 REPORTING TO HEALTH AUTHORITIES  
AE reporting to regulatory agencies will be done by the Marketing Authorization Holder 
(MAH) according to local and international regulatory requirements.  
 

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12 PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The study sponsor (BI) will disseminate the results internally as appropriate and will not release 
final results until finalization of the study report.  
 
The study sponsor will submit data from this study to appropriate conferences and journals 
after readout of the study data. Publication planning will involve dissemination of results (both 
effectiveness and safety/tolerability) from this study in peer-reviewed publications such as 
abstracts, posters, podium presentations, and manuscripts. 
 

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13 REFERENCES 
13.1 PUBLISHED REFERENCES 
 
1. 
Fernandez-Cuesta, L., et al., CD74-NRG1 fusions in lung adenocarcinoma. Cancer 
Discov, 2014. 4(4): p. 415-22. 
2. 
Fernandez-Cuesta, L. and R.K. Thomas, Molecular Pathways: Targeting NRG1 
Fusions in Lung Cancer. Clin Cancer Res, 2015. 21(9): p. 1989-94. 
3. 
Shin, D.H., J.Y. Jo, and J.Y. Han, Dual Targeting of ERBB2/ERBB3 for the 
Treatment of SLC3A2-NRG1-Mediated Lung Cancer. Mol Cancer Ther, 2018. 17(9): 
p. 2024-2033. 
4. 
Cheema, P.K., M. Doherty, and M.S. Tsao, A Case of Invasive Mucinous Pulmonary 
Adenocarcinoma with a CD74-NRG1 Fusion Protein Targeted with Afatinib. J Thorac 
Oncol, 2017. 12(12): p. e200-e202. 
5. 
Gay, N.D., et al., Durable Response to Afatinib in Lung Adenocarcinoma Harboring 
NRG1 Gene Fusions. J Thorac Oncol, 2017. 12(8): p. e107-e110. 
6. 
Jones, M.R., et al., Successful targeting of the NRG1 pathway indicates novel 
treatment strategy for metastatic cancer. Ann Oncol, 2017. 28(12): p. 3092-3097. 
7. 
Jonna, S., et al., Detection of NRG1 Gene Fusions in Solid Tumors. Clin Cancer Res, 
2019. 25(16): p. 4966-4972. 
8. 
Trombetta, D., et al., Frequent NRG1 fusions in Caucasian pulmonary mucinous 
adenocarcinoma predicted by Phospho-ErbB3 expression. Oncotarget, 2018. 9(11): p. 
9661-9671. 
9. 
Liu, S.F.R.B.H.e.a., Incidence of neuregulin1 (NRG1) gene fusions across tumor 
types. Journal of Clinical Oncology, 2018. 36(15_suppl): p. 12084. 
10. 
Drilon, A., et al., Response to ERBB3-Directed Targeted Therapy in NRG1-
Rearranged Cancers. Cancer Discov, 2018. 8(6): p. 686-695. 
 
 
13.2 UNPUBLISHED REFERENCES 
Not applicable 

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS  
None 
 

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS  
Doc.Ref. EMA/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). 
 
Study title: Assessment of Real-World Outcomes Associated with Afatinib (Gilotrif) 
Use in Patients with Solid Tumors Harboring NRG1 Gene Fusions 
 
 
EU PAS Register® number: N/A 
Study reference number (if applicable): CTMS 1200.335 
 
Section 1: Milestones 
Yes 
No 
N/A 
Section 
Number 
1.1 
Does the protocol specify timelines for  
 
 
 
 
1.1.1 Start of data collection1 
 
 
 
 
1.1.2 End of data collection2 
 
 
 
6 
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. 
 
 
 
 
                                                 
1 Date 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. 
2 Date from which the analytical dataset is completely available. 

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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? 
 
 
 
 
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised) 
 
 
 
 
2.1.4 Which hypothesis(-es) is (are) to be 
tested? 
 
 
 
 
2.1.5 If applicable, that there is no a priori 
hypothesis? 
 
 
 
 
Comments: 
 
 
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)  
 
 
 
9.1 
3.2 
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection? 
 
 
 
9.1, 9.2, 
9.4 
3.3 
Does the protocol specify measures of 
occurrence? (e.g., rate, risk, prevalence) 
 
 
 
9.3.2 
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)) 
 
 
 
 
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) 
 
 
 
9.3.2, 11 
Comments: 
 
 
Section 4: Source and study populations 
Yes 
No 
N/
A 
Section 
Number 
4.1 
Is the source population described? 
 
 
 
9.1, 9.2, 
9.2.1  
4.2 
Is the planned study population defined in 
terms of: 
 
 
 
 

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Section 4: Source and study populations 
Yes 
No 
N/
A 
Section 
Number 
4.2.1 Study time period 
 
 
 
 
4.2.2 Age and sex 
 
 
 
9.1 
4.2.3 Country of origin 
 
 
 
9.2.1 
4.2.4 Disease/indication 
 
 
 
 
4.2.5 Duration of follow-up 
 
 
 
 
4.3 
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria) 
 
 
 
9.2, 9.2.1 
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) 
 
 
 
9.3.1 
5.2 
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, 
use of validation sub-study) 
 
 
 
9.9* 
5.3 
Is exposure categorised according to time 
windows?  
 
 
 
9.2.1 
5.4 
Is intensity of exposure addressed?  
(e.g. dose, duration) 
 
 
 
9.2.1 
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? 
 
 
 
9.2.1** 
Comments: 
*General limitation described in Section 9.9 on accuracy of physician-abstracted data. 
**While not a comparator, the “other systemic therapy” cohort will provide context in 
which to assess results among afatinib-treated patients  
 
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? 
 
 
 
9.3.2 
6.2 
Does the protocol describe how the outcomes 
are defined and measured?  
 
 
 
9.3.2 

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001-MCS-90-124_RD-01 (4.0) 
Section 6: Outcome definition and 
measurement 
Yes 
No 
N/
A 
Section 
Number 
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) 
 
 
 
9.3.2, 9.9 
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) 
 
 
 
 
7.2 
Does the protocol address selection bias? (e.g. 
healthy user/adherer bias) 
 
 
 
9.12 
7.3 
Does the protocol address information bias? 
(e.g. misclassification of exposure and outcomes, time-
related bias) 
 
 
 
9.9 
Comments: 
 
 
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)  
 
 
 
 
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) 
 
 
 
9.4 
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics) 
 
 
 
9.4 
9.1.3 Covariates and other characteristics? 
 
 
 
9.4 
9.2 
Does the protocol describe the information 
available from the data source(s) on: 
 
 
 
 

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001-MCS-90-124_RD-01 (4.0) 
Section 9: Data sources 
Yes 
No 
N/
A 
Section 
Number 
9.2.1 Exposure? (e.g. date of dispensing, drug 
quantity, dose, number of days of supply prescription, 
daily dosage,  prescriber) 
 
 
 
9.3.2 
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event) 
 
 
 
9.3.2 
9.2.3 Covariates and other characteristics? 
(e.g. age, sex, clinical and drug use history, co-
morbidity, co-medications, lifestyle) 
 
 
 
9.3.2 
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)) 
 
 
 
9.3.2* 
9.3.3 Covariates and other characteristics? 
 
 
 
9.3.2* 
9.4 
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)  
 
 
 
 
Comments: 
*Where applicable  
 
Section 10: Analysis plan 
Yes 
No 
N/
A 
Section 
Number 
10.1 Are the statistical methods and the reason for 
their choice described?  
 
 
 
9.7 
10.2 Is study size and/or statistical precision 
estimated? 
 
 
 
9.5 
10.3 Are descriptive analyses included? 
 
 
 
9.7 
10.4 Are stratified analyses included? 
 
 
 
9.7 
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? 
 
 
 
9.7 
10.8 Are relevant sensitivity analyses described? 
 
 
 
9.7 
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) 
 
 
 
9.6 

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001-MCS-90-124_RD-01 (4.0) 
Section 11: Data management and quality 
control 
Yes 
No 
N/
A 
Section 
Number 
11.2 Are methods of quality assurance described? 
 
 
 
9.8 
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? 
 
 
 
 
12.1.2 Information bias? 
 
 
 
9.9 
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). 
 
 
 
 
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) 
 
 
 
9.5 
Comments: 
 
 
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 
13.2 Has any outcome of an ethical review 
procedure been addressed? 
 
 
 
 
13.3 Have data protection requirements been 
described? 
 
 
 
10 
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?  
 
 
 
5 
Comments: 
 
 

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001-MCS-90-124_RD-01 (4.0) 
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)?  
 
 
 
12 
15.2 Are plans described for disseminating study 
results externally, including publication? 
 
 
 
12 
Comments: 
 
 
Name of the main author of the 
protocol: 
Date: 11/May/2020 
Signature:   
 
 

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001-MCS-90-124_RD-01 (4.0) 
ANNEX 3. ADDITIONAL INFORMATION  
None