BEPACT Lung: Impact of Patient Characteristics on Pneumo-oncologists Non Small Cell Lung Cancer (NSCLC) Systemic Treatment Decision in Belgium: A Cross-sectional Study
Conditions: Stage IV Non-small Cell Lung Cancer
Sponsor: MSD Belgium BVBA

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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE 
STATION, NJ, U.S.A. 
SPONSOR: 
MSD Belgium BVBA/SPRL  
(hereafter referred to as the Sponsor) Clos du Lynx, 5, Lynx Binnenhof 
Bruxelles 1200 Brussel 
Belgium 
TITLE: 
BEPACT Lung: Impact of Patient Characteristics on pneumo-oncologists NSCLC 
systemic treatment decision in Belgium: A cross-sectional study. 
NCT03959137

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Table of Contents 
 
TABLE OF CONTENTS ............................................................................................................................. 2 
PROTOCOL SUMMARY ........................................................................................................................... 4 
1 
BACKGROUND AND RATIONALE ............................................................................................... 6 
1.1   BACKGROUND ..................................................................................................................................... 6 
1.2   RATIONALE ........................................................................................................................................11 
2   OBJECTIVES AND HYPOTHESES ...................................................................................................12 
2.1   PRIMARY OBJECTIVE(S) & HYPOTHESIS(ES) ......................................................................................12 
3   METHODOLOGY .................................................................................................................................13 
3.1   SUMMARY OF STUDY DESIGN ............................................................................................................13 
3.2   STUDY POPULATION...........................................................................................................................13 
3.3   INCLUSION CRITERIA .........................................................................................................................13 
3.4   EXCLUSION CRITERIA ........................................................................................................................14 
4   VARIABLES AND EPIDEMIOLOGICAL MEASUREMENTS ......................................................15 
4.1   OUTCOMES .........................................................................................................................................15 
4.2   COVARIATES ......................................................................................................................................15 
5   STUDY FLOW CHART ........................................................................................................................18 
6   STUDY PROCEDURES ........................................................................................................................19 
6.1   STUDY PROCEDURES ..........................................................................................................................19 
6.1.1   Administrative Procedures ........................................................................................................19 
6.1.1.1   General Informed Consent .....................................................................................................19 
6.1.1.2   Consent and Collection of Specimens for Future Biomedical Research (Required for Studies 
Collecting DNA)...................................................................................................................................19 
6.1.1.3   Medical History .....................................................................................................................19 
6.1.1.4   Prior and Concomitant Medications Review .........................................................................20 
6.1.1.4.1   Prior Medications ...............................................................................................................20 
6.1.1.4.2   Concomitant Medications ...................................................................................................20 
6.1.1.5   Assignment of Screening Number ..........................................................................................20 
6.1.1.6   Assignment of Randomization Number ..................................................................................20 
7   SAFETY REPORTING AND RELATED PROCEDURES ...............................................................21 
7.1   ADVERSE EVENT REPORTING .............................................................................................................21 
7.1.1   INVESTIGATOR RESPONSIBILITY: .......................................................................................21 
7.2   DEFINITIONS ..................................................................................................................................23 
7.2.1   Adverse Event (AE) ...................................................................................................................23 
7.2.2   Adverse Reaction (AR); also referred to as Adverse Drug Reaction (ADR) .............................23 
7.2.3   Serious Adverse Event (SAE)/Serious Adverse Reaction (SAR) ................................................23 
7.2.4   Non-serious Adverse Reaction (NSAR) .....................................................................................23 
7.2.5   Special Situations ......................................................................................................................23 
7.2.6    Health Outcome of Interest (HOI) ...........................................................................................24 
7.2.7   Sponsor's product ......................................................................................................................24 
7.2.8   Causality Assessment ................................................................................................................24 
8   PRODUCT QUALITY COMPLAINT REPORTING ........................................................................25 

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8.1 INVESTIGATOR RESPONSIBILITY:..............................................................................................25 
8.2 DEFINITIONS ....................................................................................................................................25 
8.2.1 Product Quality Complaint (PQC). ............................................................................................25 
8.2.2 Malfunction .................................................................................................................................25 
9   STATISTICAL ANALYSIS PLAN ......................................................................................................26 
9.1   STATISTICAL METHODS .....................................................................................................................26 
9.1.1   Primary Objective(s):  Calculation of Epidemiological Measure(s) of Interest (e.g. descriptive 
statistics, hazard ratios, incidence rates, test/retest reliability) ...........................................................26 
9.1.2   Secondary Objective(s):  Calculation of Epidemiological Measure(s) of Interest (e.g. hazard 
ratios, incidence rates, test/retest reliability).......................................................................................26 
9.1.3   Exploratory Objective(s):  Calculation of Epidemiological Measure(s) of Interest (e.g. hazard 
ratios, incidence rates, test/retest reliability).......................................................................................27 
9.2   BIAS ...................................................................................................................................................27 
9.2.1   Methods to Minimize Bias .........................................................................................................27 
9.2.2   Adjustment for Multiple Comparisons ......................................................................................27 
9.2.3   Limitations ................................................................................................................................27 
9.3   SAMPLE SIZE AND POWER CALCULATIONS ........................................................................................27 
10   ADMINISTRATIVE AND REGULATORY DETAILS ...................................................................28 
10.1   CONFIDENTIALITY ............................................................................................................................28 
10.1.1   Confidentiality of Data ............................................................................................................28 
10.1.2   Confidentiality of Subject Records ..........................................................................................28 
10.1.3   Confidentiality of Investigator Information ............................................................................28 
10.2   COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS .........................................................29 
10.3   COMPLIANCE WITH LAW, AUDIT AND DEBARMENT .........................................................................29 
10.4   COMPLIANCE WITH STUDY REGISTRATION AND RESULTS POSTING REQUIREMENTS .......................30 
10.5   QUALITY MANAGEMENT SYSTEM ....................................................................................................30 
10.6   DATA MANAGEMENT .......................................................................................................................31 
11  REFERENCES ......................................................................................................................................32 
12  APPENDICES .......................................................................................................................................33 
13   ATTACHMENTS .................................................................................................................................34 
14   SIGNATURES ......................................................................................................................................35 

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PROTOCOL SUMMARY 
 
 
Title 
BEPACT Lung: Impact of Patient Characteristics on pneumo-
oncologists NSCLC systemic treatment decision in Belgium: A cross-
sectional study. 
Vendor/Collaborator 
 
Rationale 
The treatment landscape of metastatic NSCLC is rapidly evolving. 
There are new diagnostic and treatment options available in the coming 
months and years.  
 
New combination treatments will give different solutions to pneumo-
oncologists who might be guided by certain patient and tumor 
characteristics.  
 
The link between  patient and tumor characteristics in untreated stage 
IV NSCLC patients and systemic treatment needs further investigation, 
allowing the identification of possible treatment issues, data gaps 
and/or areas of improvement. 
Primary Objective(s) 
Investigate the relation between patient, tumor and site characteristics 
and systemic treatment choices of stage IV untreated NSCLC. 
Study Design 
This is a multicenter, non-interventional, cross-sectional study. 
 
Consecutive patients with metastatic stage IV NSCLC selected for 
systemic treatment or best supportive care will be included in the trial at 
the time the patient signed the informed consent form (ICF). Patients that 
were selected for systemic treatment, should have received at least their 
first dose and a maximum of one cycle of the same treatment.  
 
The pneumo-oncologist that treats the patient will fill in the CRF, 
indicating the systemic treatment option and the link with the variable 
categories that impacted the choice for a systemic treatment option. 
Study Population 
210 patients with stage IV NSCLC starting first-line systemic treatment 
or best supportive care will be enrolled in line with inclusion and 
exclusion criteria.  
Study Duration 
Target estimated at 5 months, 210 eligible patients to be included. 
Exposure and Outcome 
The study outcome is defined as the systemic treatment choice. Systemic 
treatment choices are defined as :  
1) 
Chemotherapy (chemo)  
2) 
Immunotherapy (IO)  
3) 
immuno combined therapies (IO+IO) 
4) 
IO+chemo 
5) 
IO+bevacizumab+chemo (IO+bev+chemo)  
6) 
best supportive care (BSC). 
 
There is no exposure in this study. 
Statistical Methods 
- 
Descriptive statistics.  
- 
Hierarchical  logistic regression for discrete choices 
Sample Size and Power 
Calculations 
The study is descriptive and no sample size calculations will be 
performed.  
 

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In order to have a representative picture of the pneumo-oncologists’ 
NSCLC systemic treatment decision in Belgium, a minimum of 200 
patients need to be enrolled in the study.  
 
A maximum of 10% of the total study population can be enrolled in a 
site to avoid bias.  
 
A minimum of 30 patients need to be included in a subgroup for any 
given analysis. 
Limitations 
The experiment is not interventional and cross sectional. 

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1 
Background and Rationale 
1.1   Background 
Lung cancer remains one of the most frequent and most deadly tumor entities, with 1.6 
million tumor-related deaths annually worldwide. The World Health Organization (WHO) 
estimates that lung cancer is the cause of 1.37 million deaths globally per year. An 
estimated 71% of these deaths are caused by smoking, indicating that ∼400 000 deaths 
annually are attributed to lung cancer in lifetime never smokers. New epidemiological data 
have resulted in ‘non-smoking-associated lung cancer’ being considered a distinct disease 
entity, where specific molecular and genetic tumour characteristics have been identified 
(Novello S. Ann Oncol. 2016). 
In Belgium we had 8,196 new diagnoses of lung cancer in 2013, 70% males and 30% 
females. The 5-year relative survival proportion for the Belgian 2009-2013 cohort is about 
16% in males and 23% in females. Most patients with NSCLC are diagnosed in a very 
advanced stage; stage III or stage IV. The incidence rate in Belgium for stage IV non-small 
cell lung cancer (NSCLC) is ± 4000 per year (Belgian Cancer Register). 
Lung cancer comprises small-cell lung cancer (SCLC; approximately 15% of all lung 
cancers) and non–small-cell lung cancer (NSCLC; approximately 85%). The latter can be 
further subdivided into two major histological subtypes being adenocarcinoma and 
squamous cell carcinoma. When tissue samples or cytologic samples of lung cancer show 
clear morphologic features of adenocarcinoma or squamous-cell carcinoma, the diagnosis 
can be firmly established. If morphologic evaluation reveals neuroendocrine features, the 
tumor may be classified as SCLC or NSCLC (probably large-cell neuroendocrine 
carcinoma). If there is no clear morphologic evidence of adenocarcinoma or squamous-cell 
carcinoma, the tumor is classified as NSCLC not otherwise specified (NOS). The category 
of tumors classified as NSCLC NOS can be further subdivided according to 
immunocytochemical or immunohistochemical analysis, mucin staining, or molecular 
data. NSCLC that is positive for cytokeratin 7 and thyroid transcription factor 1, with 
negative markers for squamous-cell cancer, is classified as NSCLC favoring 
adenocarcinoma. A tumor that is positive for one or more markers of squamous-cell cancer, 
such as p63, cytokeratin 5, or cytokeratin 6, with negative adenocarcinoma markers, is 
classified as NSCLC favoring squamous-cell carcinoma. If all markers are negative, the 
tumor is classified as NSCLC NOS (Novello S. Ann Oncol. 2016). 
The discovery of treatable oncogenic alterations led to the recommendation to include 
molecular testing in the standard approach allowing further classification of nonsquamous 
NSCLC. This includes testing for mutations in the gene encoding for epidermal growth 
factor receptor (EGFR), for the BRAF V600E mutation, and for translocations in the genes 
encoding anaplastic lymphoma kinase (ALK) and rat osteosarcoma 1 (ROS1). 
Furthermore, EGFR and ALK molecular testing should be used to select patients for 
targeted tyrosin kinase inhibitor (TKI) therapy. However, the proportion of patients 
harboring these mutations in their tumor cells is low, and most tumours become resistant 
to targeted treatment (Pauwels P. Belg J Med Oncol. 2016). 

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Immunotherapy is a new paradigm for the treatment of NSCLC, and targeting the PD-1 
pathway is a promising therapeutic option. The PD-1 receptor is an immune checkpoint 
inhibitor expressed on activated B and T cells that normally downmodulates excessive 
immune responses. Binding of PD-1 to its ligands on tumour cells suppresses T cells 
through a negative feedback loop, leading to evasion of the immune response. 
Pembrolizumab (MK-3475) is a highly selective, humanised, IgG4 monoclonal antibody 
against PD-1. Nivolumab, atezolizumab and durvalumab block either PD1 or its ligand. 
Moreover, the proportion of tumor cells expressing PD-L1 has been shown to correlate 
with better responses and survival for anti-PD-(L)1 treated NSCLC patients. As a 
consequence, testing for PD-L1 expression has been added to standard diagnostic practice 
(Reck M. Immunotherapy. 2018). 
Current first-line treatment decisions for metastatic NSCLC patients are based on tumor 
histology, presence of genetic abberations and PD-L1 expression status. In patients with 
metastatic NSCLC who do not harbor genetic abberations, standard first-line treatment is 
platinum-doublet chemotherapy. Patients with high PD-L1 expression [PD-L1 Tumour 
Proportion Score (TPS) ≥ 50%] and no EGFR or ALK genomic tumor aberrations, 
Pembrolizumab monotherapy has become a standard of care. Pemetrexed maintenance 
therapy often follows first-line treatment with platinum-based chemotherapy in patients 
with non–squamous-cell NSCLC. With the introduction of novel therapies, however, 
accepted practices with respect to second and subsequent lines of therapy have changed 
substantially already during the last two years. Figure 1 gives an overview of the current 
treatment algorithm in metastatic NSCLC (Reck M. and Rabe K. F. N Engl J Med. 2017). 
Note that Bevacizumab is not reimbursed in Belgium for the treatment of NSCLC due to a 
suboptimal safety profile. 
 
Figure 1. Individualized Treatment Algorithm for NSCLC 
 
Reference: (Reck M. and Rabe K. F. N Engl J Med. 2017) 

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In October 2016, the FDA approved Pembrolizumab for the treatment of patients with 
previously untreated metastatic NSCLC that expresses PD-L1 with a TPS greater than or 
equal to 50% (TPS ≥ 50%). The results from the KEYNOTE-024 study demonstrated a 
significant improvement of both progression-free survival (PFS) and overall survival (OS) 
in favor of Pembrolizumab compared to platinum-based doublet chemotherapy. In 
December 2016, the Committee for Medicinal Products for Human Use (CHMP) also 
adopted a positive opinion for this new indication based on the KEYNOTE-024 study 
results and recommended a change to the terms of the marketing authorisation to be granted 
by the European Commission on January 31st 2017. Before that, the European Commission 
has adopted their Decision on 29 July 2016, approving KEYTRUDA monotherapy for the 
second-line treatment of NSCLC patients in the 28 EU member states, available in Belgium 
since May 2017. The treatment is available for patients in Belgium for first and second line 
since May 2017. Preliminary results of the KEYNOTE- 042, which is a randomized, open-
label, phase 3 study evaluating the efficacy and safety of Pembrolizumab monotherapy 
versus platinum-based chemotherapy in 1274  untreated, advanced and metastatic NSCLC 
patients with a PD-L1 TPS ≥ 1% in the first-line treatment setting, were presented at ASCO 
2018. The study met its primary endpoints of OS, demonstrating an improved survival 
benefit for patients with a PD-L1 TPS ≥ 1% treated with Pembrolizumab compared to 
platinum-based chemotherapy. 
In the nearby future, combination therapies of immunotherapy with chemotherapy or other 
molecules may become usual practice in first-line treatment. KEYNOTE-021, Cohort G, a 
rigorously conducted trial, which demonstrated both a clinical benefit as well as a 
manageable safety profile in favor of the combination regimen with pemetrexed and 
carboplatin. Specifically, significant improvements in overall response rate (ORR) and PFS 
were observed for the KEYTRUDA combination regimen compared to pemetrexed and 
carboplatin alone, and no new safety signals were observed for the combination regimen. 
In addition, based on data presented at ESMO 2017, a trend in improvement in the 
secondary endpoint of OS, continued to be seen for the KEYTRUDA combination regimen 
compared to pemetrexed and carboplatin alone despite its cross-over design. KEYNOTE-
189, which is a randomized, double-blind, phase 3 study evaluating the efficacy and safety 
of KEYTRUDA in combination with pemetrexed and either cisplatin or carboplatin versus 
pemetrexed and either cisplatin or carboplatin alone in 616  untreated, metastatic, 
nonsquamous, EGFR- and ALK-negative NSCLC patients in the first-line treatment 
setting, has demonstrated an impressive improvement of both OS and PFS regardless of 
PD-L1 expression (Gandhi L. N Engl J Med. 2018). According to the results, the 
estimated rate of survival at 12 months was 69.2% in the patients who received 
Pembrolizumab plus chemotherapy versus 49.4% in the chemotherapy only group. The 
improvement in OS for Pembrolizumab combination therapy was observed across the three 
PD-L1 TPS categories: 61.7% vs 52.2% TPS<1%, 71.5% vs 50.9% TPS 1-49%, and 73.0% 
vs 48.1% TPS≥50%, respectively. Furthermore, the median PFS was 8.8 months and 4.9 
months, respectively. Addition of Pembrolizumab did not appear to increase the frequency 
of adverse events of grade 3 or higher. Access for patients in Belgium might be possible 
by the end of 2018. Preliminary results of the KEYNOTE- 407, which is a randomized, 
double-blind, phase 3 study evaluating the efficacy and safety of Pembrolizumab in 
combination with carboplatin and either paclitaxel or nab- paclitaxel versus carboplatin 

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and either paclitaxel or nab- paclitaxel  in 560  untreated, metastatic, squamous NSCLC 
patients in the first-line treatment setting, were presented at ASCO 2018. The study met its 
dual primary endpoints of OS and PFS, demonstrating an improved survival benefit for 
patients treated with Pembrolizumab in combination with chemotherapy compared to 
chemotherapy alone. 
Nivolumab (Opdivo) was registered for squamous NSCLC by the end of May 2015, the 
registration for nonsquamous NSCLC followed one year later and acces was obtained for 
patients in Belgium since January 2017. The CHECKMATE-026 study, which is an 
international, randomized, open-label, phase 3 study evaluating the safety and efficacy of 
nivolumab versus platinum-based chemotherapy as first-line therapy in patients with 
(non)squamous stage IV or recurrent NSCLC with a PD-L1 expression level of 1% or 
more, did not meet its primary endpoint of PFS among patients with a PD-L1 expression 
level of ≥5%. Similar results regarding PFS were obtained for patients with a PD-L1 
expression level of ≥1% (Carbone D. P. N Engl J Med. 2017). On the other hand, the 
CHECKMATE-227 study met his co-primary endpoint, showing a significantly longer 
PFS with nivolumab plus ipilimumab compared with chemotherapy among patiens with 
advanced NSCLC and a tumor mutational burden of at least 10 mutations per megabase, 
irrespective of tumor PD-L1 expression level (Hellmann M.D., N Engl J Med.2018).  
Atezolizumab (Tecentriq) is registered for second line NSCLC since September 22nd  2017 
based on the OAK-trial and is on the market in Belgium since March 1st 2018. By the end 
of July 2017, AstraZeneca reported the initial results from the ongoing MYSTIC trial in 
Stage IV lung cancer. Imfinzi (durvalumab) plus tremelimumab combination did not meet 
its primary endpoint of PFS compared to chemotherapy, but the trial continued as planned 
to assess the additional primary endpoints of OS for both Imfinzi monotherapy and Imfinzi 
plus tremelimumab combination.  
December 2017, Roche announced detailed results from the Phase III IMpower150 study, 
which met its co-primary endpoint, showing that the combination of Tecentriq 
(atezolizumab) and Avastin (bevacizumab) plus chemotherapy provided a significant and 
clinically meaningful reduction in the risk of disease progression or death compared to 
Avastin plus chemotherapy in the first-line treatment of patients with stage IV or recurrent 
metastatic nonsquamous NSCLC. According to the results, patients who received 
Tecentriq and Avastin plus chemotherapy had a 38 percent risk reduction of their disease 
progression or death compared to those who received Avastin plus chemotherapy, with a 
respective median PFS of 8.3 months and 6.8 months. Furthermore, a doubling of the 1-
year PFS rate was observed in favor of the combination of Tecentriq and Avastin plus 
chemotherapy, compared to Avastin plus chemotherapy (37% versus 18%) (Reck M. 
ESMO IO Conference. 2017). Registration and reimbursement in Belgium can be 
expected during 2018. As mentioned before, Avastin is not reimbursed in Belgium for the 
treatment of NSCLC as the combination of bevacizumab, paclitaxel and carboplatin was 
observed to be more toxic compared to the combination of carboplatin and pemetrexed for 
an equal efficacy (Zinner R. G. J Thorac Oncol. 2015). Recently presented at ASCO 
2018, the IMpower-131 study, which is a randomized, double-blind, phase 3 study 
evaluating the efficacy and safety of Atezolizumab in combination with carboplatin and 
either paclitaxel (Arm 1) or nab- paclitaxel (Arm 2) versus carboplatin and nab- paclitaxel 

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(Arm 3)  in 196  untreated, metastatic, squamous NSCLC patients in the first-line treatment 
setting, met its co-primary endpoint PFS, showing a significant improved progression-free 
survival benefit for patients treated with atezolizumab in combination with carboplatin and 
nab-paclitaxel compared to patients treated with carboplatin and nab-paclitaxel alone. 
An overview of the current ongoing trials is shown in Figure 2. It includes an estimate of 
the new treatment modalities during 2018 and 2019. 
 
Figure 2: Ongoing trials - New treatment modalities during 2018-2019 
CHECKMATE-
227 
IO-chemo 
IO-IO 
3 
1 
Nivob 
Nivo + 
ipib 
Chemo
b  
Nivo + 
ipia  
Nivo + 
chemoa  
Chemoa 
✓ 
✓ 
CHECKMATE-
722 
IO-chemo 
IO-IO 
3 
2 
Nivo + ipi +  
platinum doublet 
chemo  
Nivo + ipi 
Platinum doublet 
chemo  
✓ 
✓ 
 
 
 
 
 
 
 
 
 
IMpower110 
IO-chemo 
3 
1 
Atezo 
Gemcitabine + cis/carb (PD) 
✓ 
✓ 
IMpower130 
IO-chemo 
3 
1 
Atezo + nab-P + carboplatin 
nab-P + carboplatin 
✓ 
IMpower131 
IO-chemo 
3 
1 
Atezo + nab-P + 
carboplatin 
Atezo + paclitaxel 
+ carboplatin 
nab-P + 
carboplatin 
✓ 
IMpower132 
IO-chemo 
3 
1 
Atezo + carboplatin/cisplatin 
+ pemetrexed 
Carboplatin/cisplatin + 
pemetrexed 
✓ 
 
 
 
 
 
 
 
 
NEPTUNE 
IO-IO 
3 
1 
Durva + tremelimumab  
Platinum doublet chemo 
✓ 
✓ 
MYSTIC 
IO-IO 
3 
1 
Durva 
Durva + treme 
Platinum doublet 
chemo 
✓ 
✓ 
ARCTIC 
IO-IO 
3 
3 
SOCa 
Durvaa 
SOCa 
Durvab 
Durva 
+ 
tremeb 
Tremeb 
✓ 
✓ 
POSEIDON 
IO-chemo 
3 
1 
Durva + treme + 
SOC 
Durva + SOC 
SOC 
✓ 
✓ 
 
 
 
 
Trial 
Type 
Phase 
Line 
Study arms 
SQ 
NSQ 
KEYNOTE-189 
IO-chemo 
3 
1 
Pembro + platinum doublet 
chemo + pemetrexed 
Platinum doublet chemo + 
pemetrexed 
then pembro (PD) 
✓ 
KEYNOTE-407 
IO-chemo 
3 
1 
 Pembro + platinum doublet 
chemo then pembro mono 
(PD) 
Platinum doublet chemo then 
saline then pembro (PD) 
✓ 
 
KEYNOTE-042 
IO-chemo 
3 
1 
Pembro 
Platinum-based Chemotherapy 
✓ 
✓ 
 
 
 
 
 
 
 
 
 

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1.2   Rationale 
The treatment landscape of metastatic NSCLC is rapidly evolving. There are new 
diagnostic and treatment options available in the coming months and years. New 
combination treatments will give different solutions to pneumo-oncologists who might be 
guided by certain patient and tumor characteristics. The link between  patient and tumor 
characteristics in untreated stage IV NSCLC patients and systemic treatment choices need 
to be investigated, allowing the identification of possible treatment issues, data gaps and/or 
areas of improvement.  
 
This cross-sectional study will document systemic treatment choice linked to patient, 
tumor and site characteristics. A better understanding of the current clinical practice in 
the Belgian sites should allow the medical community to have a better insight on which 
characteristics impact treatment choice in real life, helping to determine certain health 
care and scientific educational needs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2   Objectives and Hypotheses 
 
2.1   Primary Objective(s) & Hypothesis(es) 
The objective of this study is to investigate the relation between patient, tumor and site 
characterstics and systemic treatment choices of stage IV untreated NSCLC.  
 
Systemic treatment choices and best supportive care are defined as :  
1) Chemotherapy (chemo)  
2) Immunotherapy (IO)  
3) Immuno combined therapies (IO+IO) 
4) IO+chemo 
5) IO+bevacizumab+chemo (IO+bev+chemo)  
6) Best supportive care (BSC). 
 
It is hypothesized that there is a relation between the systemic treatment choice and the 
explanatory variable categories listed below. It is assumed that the variable categories have 
a different weight for the different systemic treatment options: 
• Patient demography characteristics 
• Medical history 
• Co-morbidities 
• Autoimmune disease 
• Current/recent medication  
• Prior cancer treatment in earlier stage  
• Site characteristics  
The details of the variables can be found in the section 4.2. 
For each of the variable categories, it will be queried whether the variable category had 
an impact on the systemic treatment choice. 
 

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3   METHODOLOGY 
3.1   Summary of Study Design 
This is a multicenter non-interventional cross-sectional study in stage IV NSCLC patients 
on first-line systemic treatment coming to the consultation. 
 
Consecutive patients with metastatic stage IV NSCLC selected for systemic treatment or 
best supportive care will be included in the trial at the time the patient signed the informed 
consent form (ICF). Patients that were selected for systemic treatment, should have 
received at least their first dose and a maximum of one cycle of the same treatment.  
 
The pneumo-oncologist that treats the patient will fill in the CRF, indicating the systemic 
treatment option and the link with the variable categories that impacted positively or 
negatively the systemic treatment option. The actual value of variables linked to a variable 
category will also be recorded in the CRF. 
 
A questionnaire has to be filled in characterizing the site and allowing the site to be 
assigned to a group based on the number of newly diagnosed patients per year with lung 
cancer and whether the site participates in interventional clinical trials. All sites will be 
retrospectively divided in four groups; high number of patients per year (more than median 
NSCLC patients per year) and participating in interventional clinical trials, high number of 
patients but not participating in interventional clinical trials, low number of patients (less 
than median NSCLC patients per year) and participating in interventional clinical trials or 
low number of patients and not participating in interventional clinical trials.  
 
 
3.2   Study Population 
210 eligible stage IV NSCLC subjects treated in approximately 21 Belgian hospitals 
starting first-line treatment or best supportive care will be enrolled in line with inclusion 
and exclusion criteria. The estimated recruitment period to reach the target of 210 eligible 
patients is 5 months. Upon inclusion of 210 eligible patients the recruitment will be closed. 
Only a maximum of 10% of subjects can be enrolled by one site. 
 
 
3.3   Inclusion Criteria  
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the study. 
 
In order to be eligible for participation in this trial, the subject must: 
• Have voluntarily agreed to participate by giving written informed consent/assent for 
the trial. 

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• Have a histologically or cytologically confirmed diagnosis of stage IV NSCLC on first-
line (1L) systemic treatment. 
• Have received at least their first dose of the selected systemic treatment and a maximum 
of 1 cycle of the same treatment. Patients that were selected to receive best supportive 
care will not have to comply to this inclusion criterion. 
• Be ≥ 18 years of age on day of signing informed consent. 
 
 
3.4   Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
• Has received prior systemic treatment for their metastatic NSCLC before the first dose 
of trial treatment. However, subjects who received adjuvant or neoadjuvant therapy 
during an earlier stage of their disease, but evolved to stage IV, are eligible. 
• TKI selected as first-line systemic treatment. 
• Is participating in an interventional trial or medical need program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4   Variables and Epidemiological Measurements 
4.1   Outcomes 
Systemic treatment choices and best supportive care are defined as :  
1) Chemotherapy (chemo)  
2) Immunotherapy (IO)  
3) immuno combined therapies (IO+IO) 
4) IO+chemo 
5) IO+bevacizumab+chemo (IO+bev+chemo)  
6) best supportive care (BSC). 
 
4.2   Covariates 
The actual values of the following covariates will be recorded within the eCRF, which 
can be discrete or continuous in nature. In addition to the actual values, the investigator 
will also have to indicate whether the covariates had an impact on the treatment choice in 
a binary fashion. 
 
✓ Patient demography characteristics at study entry:  
- 
Age 
- 
Gender: 
o  F  
o M 
- 
Weight loss  
o (%) 
- 
Smoking status:  
o Current  
o Former (≥ 1 year)  
o Never 
o Not known  
 
- 
ECOG status:  
o 0  
o 1 
o 2  
o 3-4 
- 
Patient’s preference 
o Yes  
o No 
 
✓ Medical history: 
- 
Metastatic disease stage:  
o M1a 
o M1b 

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o M1c 
- 
Tumor Burden: 
o Tumor size 
o Number of metastatic sites 
- 
Brainmets:  
o No  
o Symptomatic 
o Asympotomatic 
 
o Treated with SRT 
o Treated with WBRT 
- 
Livermets 
o Present 
o Not present 
- 
Concomitant malignancies 
o Present  
- 
Histology:  
o Squamous 
o Nonsquamous 
o NOS 
- 
IHC PD-L1:  
o PD-L1 TPS <1%,  
o PD-L1 TPS 1 - 49% 
o PD-L1 TPS ≥50% 
- 
High TMB (≥ 10 mutations/Mb (Cfr. CHECKMATE-227) 
o Present 
o Not present 
- 
Testing 
o Turn-around-time 
o Not tested 
o Biopsy availability 
o Type of NGS testing (e.g. whole exome, gene panel, platform, …) 
 
✓ Comorbidities 
- 
Myocardial infarction in the last year 
- 
Congestive heart failure 
- 
Peripheral vascular disease 
- 
Hypertension 
- 
Cerebrovascular event in the last year 
- 
Transient ischemic attack in the last year 
- 
Diabetes without complications 
- 
Renal disease 
- 
Liver disease 
- 
Hematological disease 
- 
Chronic obstructive pulmonary disease 
- 
Chronic infections 
- 
Mental disorders 

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✓ Autoimmune disease 
- 
Active inflammatory interstitial lung disease 
- 
Non-active inflammatory interstitial lung disease 
- 
Active inflammatory bowel disease (IBD) 
- 
Non-active IBD 
- 
Active inflammatory joint disease 
- 
Non-active inflammatory joint disease 
- 
Active psoriasis 
- 
Non-active psoriasis 
- 
Active connective tissue disease 
- 
Non-active connective tissue disease 
 
✓ Current/recent medication 
- 
Low dose corticosteroids 
- 
High dose (≥10 mg/day Prednisolone or eq) corticosteroids 
- 
Other immunosuppressants (i.e. Anti-TNF-α, MMF, …) 
- 
Antibiotics 
 
✓ Prior cancer treatment in earlier stage NSCLC 
- 
Single Modality treatment 
- 
Multi-Modality treatment 
- 
Surgery / radiotherapy 
- 
Previous IO treatment 
- 
Year of treatment 
 
For each variable category, the physician has to determine whether it had an impact on 
his/her treatment decision, yes or no. For all variable categories, for whom the answer was 
yes, the physician has to select the three most important variable categories that impacted 
his treatment decision. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5   Study Flow Chart  
 
V1 
V2* 
Informed consent 
X 
 
Inclusion 
X 
 
Exclusion 
X 
 
Systemic treatment option 
 
X 
Variable categories impacting treatment choice 
 
X 
Patient demography characteristics 
 
X 
Medical history 
 
X 
Co-morbidities 
 
X 
Autoimmune disease 
 
X 
Baseline medications 
 
X 
Prior cancer treatment in earlier stage 
 
X 
Site characteristics 
 
X 
 
 
*time of V2 and V1 can coincide. V2 will only be created if V1 is successfully passed. 
 
It is allowed that information is collected retrospectively. 
 

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6   STUDY PROCEDURES  
6.1   Study Procedures 
The Study Diagram in Section 5 summarizes the study procedures to be performed at each visit.  
Individual study procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for reasons 
related to subject safety.    
6.1.1   Administrative Procedures  
6.1.1.1   General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the study. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
study.  The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the subject’s 
dated signature or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a study and the study population will be added to the consent form template.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and 
regulations and Sponsor requirements. 
6.1.1.2   Consent and Collection of Specimens for Future Biomedical Research 
(Required for Studies Collecting DNA) 
Not applicable. 
 
6.1.1.3   Medical History 
 
Only relevant information based on the CRF will be collected. 
 

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6.1.1.4   Prior and Concomitant Medications Review 
Only relevant information based on the CRF will be collected. 
 
6.1.1.4.1   Prior Medications 
Only relevant information based on the CRF will be collected. 
 
6.1.1.4.2   Concomitant Medications 
Only relevant information based on the CRF will be collected. 
 
6.1.1.5   Assignment of Screening Number 
All consented patients will be given a unique depersonalized identification number. The 
patient number identifies the patient for all procedures occurring during observation. Data 
protection and other applicable regulatory requirements will be fulfilled. 
 
6.1.1.6   Assignment of Randomization Number 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7   Safety Reporting and Related Procedures 
Introduction 
 
This is a primary data collection non-interventional study being conducted within routine 
medical practice. All direction for medication usage is at the discretion of a physician in 
accordance with usual medical practice.  No administration of any therapeutic or 
prophylactic agent is required in this protocol, and there are no procedures required as 
part of this protocol.  
 
7.1   Adverse Event Reporting 
7.1.1   INVESTIGATOR RESPONSIBILITY: 
If the investigator becomes aware of any serious adverse event (SAE), including death 
due to any cause, or non-serious adverse reaction (NSAR) following the use of any 
Merck product, the event must be reported according to Table 1.  The investigator must 
evaluate each SAE for causality and record causality on the AE form for each event 
reported.   
 
Similarly, pre-specified Health Outcomes of Interest (HOIs) that meet criteria for 
SAE/NSAR, special situations, and any spontaneously reported AEs must be reported 
according to Table 1. 
 
 
 

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Table 1: AE Reporting Timeframes and Process for Investigators and Vendors 
EVENT TYPE  
INVESTIGATOR 
TIMEFRAME 
VENDOR 
TIMEFRAME 
Investigator to 
Vendor [1], [2] 
             OR 
Investigator to 
Merck  [3] 
Vendor to Merck 
[4] 
SAE, regardless of causality (primary data collection)  
Serious pre-specified HOI  
Serious Special Situation, regardless of causality 
24 hours from receipt 
2 BD/3 CD from time 
of receipt from 
investigator 
NSAR 
Non-Serious pre-specified HOI if NSAR 
Non-serious Special Situation, regardless of causality 
10 CD from receipt 
10 CD from time of 
receipt from 
investigator 
Spontaneously reported adverse events for Merck products-submit using above timeframes  
If the investigator elects to submit AEs for non-Merck products, they should be reported to the 
market authorization holder (MAH) for that product or to the health authority according to the 
institution’s policy or local laws and regulations.  Note: Per [2], below, AEs for comparators must 
be entered in study database. 
 
Follow-up to any event-submit using above timeframes 
BD-Business Day; CD-Calendar Day 
[1] AE reports from investigators must be transmitted via fax, secure email (if available), or entered directly into 
vendor’s electronic data collection (EDC) platform, if utilized. 
[2] Investigator to Vendor: Applies to events for Merck study product, non-Merck 
comparators, and other Merck products when a VENDOR is managing AE reporting from 
investigator to Merck.  Events for Merck study product and non-Merck comparators are 
entered in study database for tabulation in study report.  Events for other Merck products are not 
entered in study database but must be forwarded to Merck for regulatory reporting. 
[3] Investigator to Merck: Applies to studies that do not have a vendor managing AEs.  
[4] Vendor to Merck: Applies to events for Merck study product and other Merck products if 
the vendor is managing AE reporting between investigator and Merck.  Not applicable for studies 
not using a vendor for AE reporting. 
 
 
 
Submitting AE reports to Merck Global Safety: All AEs must be submitted to AER Mailbox 
FAX #215-661-6229    (US), or toll-free fax 1-800-547-5552 (ex-US and US availability), in 
English using an AE form (attached) for reporting to worldwide regulatory agencies as 
appropriate. 
 
 
 
 
 

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7.2   DEFINITIONS 
7.2.1   Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered sponsor’s product and which does not necessarily have to have a causal 
relationship with this product.   An adverse event can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of the product, whether or not considered 
related to the product.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with 
the use of the product, is also an adverse event. 
 
7.2.2   Adverse Reaction (AR); also referred to as Adverse Drug Reaction (ADR) 
An AE which has a causal relationship with the product, that is, a causal relationship 
between the product and the adverse event is at least a reasonable possibility. 
 
7.2.3   Serious Adverse Event (SAE)/Serious Adverse Reaction (SAR) 
An adverse event or adverse reaction that results in death, is life threatening, results in 
persistent or significant disability/incapacity, requires inpatient hospitalization, 
prolongation of existing inpatient hospitalization, is a congenital anomaly/birth defect, or 
is another important medical event.  Other important medical events that may not result 
in death, may not be life-threatening, or may not require hospitalization may be 
considered an SAE/SAR when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the other outcomes listed previously.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home and blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
 
7.2.4   Non-serious Adverse Reaction (NSAR) 
An adverse reaction that does not meet any of the serious criteria in 7.2.3. 
 
7.2.5   Special Situations 
The following special situations are considered important safety information and must be 
reported, regardless of seriousness or causality, if the investigator becomes aware of 
them: 
• Overdose  
• Exposure to product during pregnancy or lactation  
• Lack of therapeutic effect    
• Off-label use, medication error, misuse, abuse, or occupational exposure 
• Suspected transmission via a medicinal product of an infectious agent 
• Unexpected Therapeutic Benefit/Effect 

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7.2.6    Health Outcome of Interest (HOI) 
Health Outcomes of Interest (HOIs) are pre-specified clinical events or outcomes that are 
collected according to the protocol.  HOIs may be represented as diagnosis, treatment or 
procedures.  Examples of HOIs include syncope or hypoglycaemia collected as study 
endpoints.  HOIs must be assessed as part of AE collection and may meet criteria for AE 
reporting.  Specifically, the investigator must assess each HOI for serious criteria and 
causality.  If the HOI meets criteria specified in the protocol for AE reporting, then it 
must be reported as such. 
 
7.2.7   Sponsor's product  
Sponsor’s product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the Sponsor for human use. 
 
7.2.8   Causality Assessment 
A causality assessment is the determination of whether or not there is at least a 
reasonable possibility that a product caused the adverse event.    Causality must be 
recorded on the AE form by the investigator for each reported event in relationship to a 
Sponsor's product. 
 
Primary Data Collection 
The assessment of causality is to be determined by an investigator who is a qualified 
healthcare professional according to his/her best clinical judgment. Use the 
following criteria as guidance (not all criteria must be present to be indicative of 
causality to a Sponsor's product): There is evidence of exposure to the Sponsor's 
product; the temporal sequence of the AE onset relative to the administration of the 
Sponsor's product is reasonable; the AE is more likely explained by the Sponsor's 
product than by another cause.  
 
 
 
 
 
 
 
 
 
 
 
 

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8   Product Quality Complaint Reporting 
8.1 INVESTIGATOR RESPONSIBILITY: 
Any occurrence of a product quality complaint for a Merck product identified during the conduct 
of the study, must be reported by the study investigator or qualified designee using the Product 
Quality Complaint (PQC) Reporting Form following the directions in Table 2.  The PQC 
Reporting Form must be fully completed in English.  Once the PQC Reporting Form is submitted, 
the investigator or designee may be contacted for further information. 
 
If both an AE and a PQC occur, the AE should be reported according to the AE reporting 
requirements in the protocol and the PQC should be reported per Table 2. 
 
Table 2: PQC Reporting Timeframes and Process for Investigators  
EVENT TYPE  
INVESTIGATOR 
TIMEFRAME 
Investigator to Merck   
PQC 
24 hours from receipt 
PQC reports must be submitted via e-mail by the investigator to the local designated point 
of contact (DPOC) using a PQC form.   
 
Submitting PQC reports to Merck: All PQCs must be submitted to the local DPOC 
in English using a PQC form.  The following e-mail addresses should be used by 
country: 
dpoc_belux@merck.com 
 
8.2 DEFINITIONS 
8.2.1 Product Quality Complaint (PQC).  
Any communication that describes a potential defect related to the identity, strength, 
quality, purity or performance of a product identified by an external customer. This 
includes potential device or device component malfunctions. 
 
8.2.2 Malfunction 
The failure of a device (including the device component of a combination product) to 
meet its performance specifications or otherwise perform as intended. Performance 
specifications include all claims made in the labeling for the device. 
 
 
 
 
 

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9   Statistical Analysis Plan 
9.1   Statistical Methods 
The statistical analysis will be performed using SAS software 9.2. 
 
9.1.1   Primary Objective(s):  Calculation of Epidemiological Measure(s) of Interest 
(e.g. descriptive statistics, hazard ratios, incidence rates, test/retest 
reliability) 
Systemic treatment choices and best supportive care are defined as :  
1) Chemotherapy (chemo)  
2) Immunotherapy (IO)  
3) immuno combined therapies (IO+IO) 
4) IO+chemo 
5) IO+bevacizumab+chemo (IO+bev+chemo)  
6) best supportive care (BSC). 
 
Descriptive statistics of the relation between variable category and systemic treatment 
choice will be provided. The descriptive statistics will involve the number of times 
(frequency) a variable category is indicated as being linked to a systemic treatment option.  
 
For each of the variable categories that are linked to a systemic treatment choice, 
descriptive statistics of the underlying variables will be provided. These descriptive 
statistics will consist of: 
• For the quantitative variables, summary statistics including mean, standard 
deviation, 95% confidence interval on the mean, minimum, first quartile, median, 
third quartile, maximum, and number of available and number of missing 
observations.  
• For the categorical variables, frequencies and percentages. 
In an exploratory analysis, a penalized hierarchical logistic regression model for discrete 
choices will be used to evaluate the effect of the potential explanatory variables on the 1st 
line systemic treatment. 
 
 
9.1.2   Secondary Objective(s):  Calculation of Epidemiological Measure(s) of 
Interest (e.g. hazard ratios, incidence rates, test/retest reliability) 
No secondary objectives. 
 

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9.1.3   Exploratory Objective(s):  Calculation of Epidemiological Measure(s) of 
Interest (e.g. hazard ratios, incidence rates, test/retest reliability) 
Investigate if there are differences in the link between variable categories and systemic 
treatment choices for the 4 types of sites that are defined. 
 
9.2   Bias 
9.2.1   Methods to Minimize Bias 
It will be emphasized to the participating centres that consecutive patients need to be 
included in the study.  
 
210 eligible subjects will be included in approximately 21 participating sites with a 
maximum of 10% inclusion by each site. The risk of statistical bias is minimized by 
the fact that all sites start the inclusion period at the same time. However, toward the 
end of the inclusion period, the imposed maximum inclusion site limit may potentially 
lead to statistical bias, which will be described in detail in the study manuscript 
 
9.2.2   Adjustment for Multiple Comparisons 
Not applicable. 
9.2.3   Limitations 
The study is cross-sectional. 
 
9.3   Sample Size and Power Calculations 
The study is descriptive and no sample size calculations will be performed. In order to 
have a representative picture of the pneumo-oncologists’ NSCLC systemic treatment 
decision in Belgium, a minimum of 200 patients need to be enrolled in the study. 
 
A maximum of 10% of the total study population can be enrolled in a site to avoid bias.  
A minimum of 30 patients need to be included in a subgroup for any given analysis. 
 
 
 
 
 
 
 
 
 

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10   ADMINISTRATIVE AND REGULATORY DETAILS 
10.1   Confidentiality 
10.1.1   Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to the 
investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the Institutional Review Board, Ethics Review Committee or similar or expert 
committee; affiliated institution and employees, only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution and employees.  Data 
generated by this study will be considered confidential by the investigator, except to the extent 
that it is included in a publication as provided in the Publications section of this protocol. 
The study and its results will be registered on a publicly accessible database.  
10.1.2   Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative) or 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), may consult and/or copy 
study documents in order to verify worksheet/case report form data.  By signing the consent form, 
the subject agrees to this process.  If study documents will be photocopied during the process of 
verifying worksheet/case report form information, the subject will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor. 
 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this study in accordance with all applicable privacy laws, rules and regulations. 
 
10.1.3   Confidentiality of Investigator Information 
By signing this protocol, the investigator recognizes that certain personal identifying information 
with respect to the investigator, and all subinvestigators and study site personnel, may be used 
and disclosed for study management purposes, as part of a regulatory submissions, and as 
required by law.  This information may include: 
 
• 
name, address, telephone number and e-mail address; 
• 
hospital or clinic address and telephone number; 
• 
curriculum vitae or other summary of qualifications and credentials; and 
• 
other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  Additionally, 
the investigator’s name and business contact information may be included when reporting certain 
serious adverse events to regulatory agencies or to other investigators.  By signing this protocol, 
the investigator expressly consents to these uses and disclosures. 
 

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If this is a multicenter study, in order to facilitate contact between investigators, the Sponsor may 
share an investigator’s name and contact information with other participating investigators upon 
request. 
 
10.2   Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the Sponsor's 
responsibility to determine, based on these regulations, whether a request for Financial Disclosure 
information is required.  It is the investigator's/subinvestigator's responsibility to comply with any 
such request. 
 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 CFR 
Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to allow for 
the submission of complete and accurate certification and disclosure statements.  The 
investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by the 
Sponsor or through a secure password-protected electronic portal provided by the Sponsor.  The 
investigator/subinvestigator(s) also consent to the transmission of this information to the Sponsor 
in the United States for these purposes.  This may involve the transmission of information to 
countries that do not have laws protecting personal data.  
 
 
10.3   Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the study in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good 
Pharmacoepidemiology Practice; and all applicable local laws, rules and regulations relating to 
the conduct of the clinical study. 
 
The investigator also agrees to allow monitoring, audits, Institutional Review Board/Independent 
Ethics Committee review and regulatory agency inspection of study-related documents and 
procedures and provide for direct access to all study-related source data and documents. 
 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the study reimbursed to the 
investigator by the Sponsor. 
 
The Investigator shall prepare and maintain complete and accurate study documentation in 
compliance with Good Pharmacoepidemiology Practice, standards and applicable local laws, 
rules and regulations; and, for each subject participating in the study, provide all data, and, upon 
completion or termination of the study, submit any other reports to the Sponsor as required by 
this protocol or as otherwise required pursuant to any agreement with the Sponsor. 
 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator upon 
request and also shall be made available at the investigator’s site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any regulatory 
agencies.  The investigator agrees to promptly take any reasonable steps that are requested by the 
Sponsor as a result of an audit to cure deficiencies in the study documentation and 
worksheets/case report forms. 

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The investigator must maintain copies of all documentation and records relating to the conduct of 
the study in accordance with their institution’s records retention schedule which is compliant with 
all applicable regional and national laws and regulatory requirements.  If an institution does not 
have a records retention schedule to manage its records long-term, the investigator must maintain 
all documentation and records relating to the conduct of the study for 5 years after final report or 
first publication of study results, whichever comes later, per GPP guidelines. This documentation 
includes, but is not limited to, the protocol, worksheets/case report forms, advertising for subject 
participation, adverse event reports, subject source data, correspondence with regulatory 
authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, monitor visit logs, 
laboratory reference ranges, laboratory certification or quality control procedures and laboratory 
director curriculum vitae.  All study documents shall be made available if required by relevant 
regulatory authorities. The investigator must consult with the Sponsor prior to discarding study 
and/or subject files. 
 
The investigator will promptly inform the Sponsor of any regulatory agency inspection conducted 
for this study. 
 
Persons debarred from conducting or working on studies by any court or regulatory agency will 
not be allowed to conduct or work on this Sponsor’s studies.  The investigator will immediately 
disclose in writing to the Sponsor if any person who is involved in conducting the study is 
debarred or if any proceeding for debarment is pending or, to the best of the investigator’s 
knowledge, threatened. 
 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will promptly 
notify that site’s IRB/IEC. 
 
According to European legislation, a Sponsor must designate an overall coordinating investigator 
for a multi-center study (including multinational).  When more than one study site is open in an 
EU country, Merck, as the Sponsor, will designate, per country, a national principal coordinator 
(Protocol CI), responsible for coordinating the work of the principal investigators at the different 
sites in that Member State, according to national regulations.  For a single-center study, the 
Protocol CI is the principal investigator.  In addition, the Sponsor must designate a principal or 
coordinating investigator to review the study report that summarizes the study results and confirm 
that, to the best of his/her knowledge, the report accurately describes the conduct and results of 
the study in the study’s final report.  The Sponsor may consider one or more factors in the 
selection of the individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI 
during the anticipated review process, thorough understanding of study methods, appropriate 
enrollment of subject cohort, timely achievement of study milestones).  The Protocol CI must be 
a participating study investigator. 
 
10.4   Compliance with Study Registration and Results Posting Requirements 
Not applicable. 
 
10.5   Quality Management System  
By signing this protocol, the Sponsor agrees to be responsible for implementing and maintaining 
a quality management system with written development procedures and functional area standard 
operating procedures (SOPs) to ensure that studies are conducted and data are generated, 

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documented, and reported in compliance with the protocol, accepted standards of Good  
Pharmacoepidemiology Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the study. 
 
10.6   Data Management 
The investigator or qualified designee is responsible for recording and verifying the 
accuracy of subject data.  By signing this protocol, the investigator acknowledges that 
his/her electronic signature is the legally binding equivalent of a written signature.  By 
entering his/her electronic signature, the investigator confirms that all recorded data have 
been verified as accurate. 
 For an outsourced study the institutional policies of the vendor should be followed for 
development of data management plans.  However, the vendor should ensure compliance 
with  Good  Pharmacoepidemiology Practice, and all applicable federal, state, and local laws, 
rules and regulations relating to the conduct of the study.  
 
 

Product: MK-0000 
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11  References 
1. Guideline on good pharmacovigilance practices (GVP) – Annex I (Rev 3), 
EMA/876333/2011 Rev 3 
2. EU Directive 2001/20/EC on Clinical trials and detailed guidance on the collection, 
verification and presentation of adverse reaction reports arising from clinical trials on 
medicinal product for human use, ENTR/CT 3 Revision 2 dated April 2006. 
3. The Importance of Pharmacovigilance: Safety Monitoring of Medicinal Products. 
Geneva, WHO, 2002. 
4. Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiology 
Assessment.  Rockville, MD, Food and Drug Administration (FDA), March 2005. 
5. National Cancer Institute: 
http://www.cancer.gov/dictionary/?searchTxt=biomarker 
6. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, 
GENOMIC DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf. 
 
 
 

Product: MK-0000 
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12  Appendices 
 
Not applicable

Product: MK-0000 
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13   Attachments 
 

Product: MK-0000 
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14   SIGNATURES 
 
Sponsor's Representative 
 
TYPED NAME                                 SIGNATURE                                   DATE 
 
_________________________      ____________________________     __________ 
 
Investigator 
 
I agree to conduct this study in accordance with the design outlined in this protocol and to abide by 
all provisions of this protocol (including other manuals and documents referenced from this 
protocol); deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment.  I agree to conduct the study in accordance with generally accepted standards of Good 
Pharmacoepidemiology Practice.  I also agree to report all information or data in accordance with 
the protocol and, in particular, I agree to report any serious adverse experiences as defined in 
Section 7 – Safety Reporting and Related Procedures.  I understand that information that identifies 
me will be used and disclosed as described in the protocol, and that such information may be 
transferred to countries that do not have laws protecting such information.  Since the information 
in this protocol and the referenced Investigator’s brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct of the 
study is prohibited. I will ensure that the necessary precautions are taken to protect such information 
from loss, inadvertent disclosure, or access by third parties. 
 
          
 
TYPED NAME                                 SIGNATURE                                   DATE 
 
_________________________      ____________________________     __________