A Long-term Follow-up Study for Cardiac Safety in the Patients With HER2 Positive Early or Locally Advanced Breast Cancer Who Have Completed the SB3-G31-BC
Conditions: Breast Neoplasms
Sponsor: Samsung Bioepis Co., Ltd.

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Clinical Study Protocol 
A Long-term Follow-up Study for Cardiac Safety in the Patients with 
HER2 Positive Early or Locally Advanced Breast Cancer Who Have 
Completed the SB3-G31-BC  
 
 
 
Product 
SB3 (proposed trastuzumab biosimilar) 
EudraCT Number 
2015-005663-17 
US IND Number (if applicable) 
N/A 
Protocol Number 
SB3-G31-BC-E 
 
 
Version and Effective Date 
2.0/Amendment 1 
Nov 26, 2018 
 
1.0 
Dec 17, 2015 
 
 
 
 
 
 
Sponsor 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
 
 
 
 
This document contains confidential information belonging to Samsung Bioepis Co., Ltd. Your 
acceptance or review of this document constitutes agreement that you will not copy or disclose the 
information contained herein to others or use it for unauthorised purposes without written 
authorisation from the Sponsor. 
 
 

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SYNOPSIS 
Name of 
Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished 
Product: 
SB3 (proposed trastuzumab biosimilar) 
Name of Active 
Ingredient: 
Trastuzumab 
Title of Study: 
A long-term follow-up study for cardiac safety in the patients with human epidermal growth factor 
receptor 2 (HER2) positive early or locally advanced breast cancer who have completed the SB3-G31-
BC 
Protocol No: 
SB3-G31-BC-E 
Indication: 
HER2 positive early or locally advanced breast cancer 
Objectives: 
Primary Objective: 
The primary objective is to observe the incidence of symptomatic congestive heart failure (CHF) New 
York Heart Association (NYHA) class II, III, and IV and asymptomatic significant left ventricular 
ejection fraction (LVEF) decrease in subjects who participated in the SB3-G31-BC trial and treated 
with SB3 (proposed trastuzumab biosimilar) or Herceptin® as neoadjuvant and adjuvant treatment. 
Secondary Objectives: 
The secondary objectives are: 
• 
To observe the incidence of cardiac death and other significant cardiac conditions 
• 
To observe the long term efficacy of SB3 compared to Herceptin® by 
- 
Event-free survival (EFS) and disease-free survival (DFS) 
- 
Overall survival (OS) 
Study Design: 
This is an observational cohort study. 
[Cardiac Safety and Survival Cohort]: The group consists of subjects who completed the SB3-G31-
BC trial and provide informed consent for the long-term follow-up of cardiac safety and survival. 
Subjects who have completed the clinical trial SB3-G31-BC will be asked to consent to participate in 
this study. Consenting subjects will be enrolled sequentially into the study in accordance with SB3-
G31-BC-E trial protocol version 1.0 and will be monitored according to the local clinical practices 
which are based on the Herceptin® Summary of Product Characteristics (SmPC) or local label. No 
additional procedures/subject visits in comparison with the usual clinical practice are planned for the 
study. 
Data will be collected from medical records for up to 5 years or death, unless they are lost for the 
follow-up or withdraw the informed consent. 

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Name of 
Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished 
Product: 
SB3 (proposed trastuzumab biosimilar) 
Name of Active 
Ingredient: 
Trastuzumab 
[Survival Only Cohort]: The group consists of subjects who participate in this trial among subjects 
who received the SB3 or Herceptin® in the SB3-G31-BC trial and were not sequentially enrolled into 
this SB3-G31-BC-E trial as a Cardiac Safety and Survival Cohort. 
Subjects who received SB3 or Herceptin® in accordance with the clinical trial SB3-G31-BC and were 
not sequentially enrolled to SB3-G31-BC-E trial as a Cardiac Safety and Survival Cohort will be asked 
to consent to participate in this study as a Survival Only Cohort. If prospective data collection is not 
possible (e.g. when the subject is deceased or lost to follow-up), a waiver of informed 
consent/authorization will be requested for the retrospective data collection from medical records, 
where applicable and in accordance with national regulations and local ethics. If informed consent from 
(ICF) waiver for the deceased subject is not allowed, their next-of-kin (if applicable) will be informed 
accordingly, and will be asked to give their consent where applicable and approved by institutional 
review board (IRB)/independent ethics committee (IEC) and in accordance with national regulations. 
Data will be collected from medical records for up to 5 years from their last investigational product (IP; 
SB3 or Herceptin®) administration or death, unless they are lost for the follow-up or withdraw the 
informed consent. Data for the study will be collected prospectively from the date of the study informed 
consent signed and data before informed consent will be obtained from medical records retrospectively. 
If prospective data collection is not possible, data could be collected retrospectively from medical 
records. 
Number of Subjects:  
It is planned that approximately 612 subjects will be enrolled. 
Target Population:  
Patients with HER2 positive early or locally advanced breast cancer who received SB3 or Herceptin® 
according to clinical trial SB3-G31-BC. 
Eligibility Criteria: 
[Cardiac Safety and Survival Cohort] 
Inclusion criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1.  Subjects who have completed the study treatment of SB3-G31-BC trial according to the 
protocol. 
2.  Subjects must provide informed consent. 
Exclusion criteria 
Subjects unwilling to follow the study requirements are not eligible for the study. 

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Name of 
Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished 
Product: 
SB3 (proposed trastuzumab biosimilar) 
Name of Active 
Ingredient: 
Trastuzumab 
[Survival Only Cohort] 
Inclusion criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1.  Subjects who received SB3 or Herceptin® according to the clinical trial SB3-G31-BC. 
2.  Subjects who provide informed consent. If prospective data collection is not possible (e.g. 
when the subject is deceased or lost to follow-up), a waiver of informed consent/authorization 
will be requested for the retrospective data collection from medical records, where applicable 
and in accordance with national regulations and local ethics. If ICF waiver for the deceased 
subject is not allowed, their next-of-kin (if applicable) will be informed accordingly, and will 
be asked to give their consent where applicable and approved by IRB/IEC and in accordance 
with national regulations. 
Exclusion criteria 
There is no exclusion criteria for the Survival Only Cohort. 
Planned Study Period: 
The study will close at 5 years after the last subject has received the last IP (SB3 or Herceptin®) in the 
setting of clinical trial SB3-G31-BC. 
Investigational Products:  
SB3 (proposed trastuzumab biosimilar) or European Union sourced Herceptin® 
Criteria for Evaluation 
Primary endpoint 
• 
The incidence of symptomatic CHF and asymptomatic significant LVEF decrease 
- 
CHF, defined as NYHA II, III, IV, confirmed by a cardiologist, accompanied by a 
significant LVEF decrease 
- 
Significant LVEF decrease, defined as an absolute decline of at least 10% points from 
baseline LVEF (LVEF at screening of the SB3-G31-BC trial) and resulting LVEF less 
than 50% 
Secondary endpoints 
• 
The incidence of cardiac death and other significant cardiac conditions 
- 
Cardiac death, defined as death definitely as a result of heart failure, myocardial 
infarction, or documented arrhythmia, or as probable cardiac death within 24 hours of a 

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Name of 
Sponsor/Company: 
Samsung Bioepis Co., Ltd. 
Name of Finished 
Product: 
SB3 (proposed trastuzumab biosimilar) 
Name of Active 
Ingredient: 
Trastuzumab 
cardiac event 
• 
EFS, defined as the time from the date of randomisation for the SB3-G31-BC trial to the date 
where an event occurs. An event is breast cancer recurrence, or progression (local, regional, 
distant, or contralateral), or death due to any cause. 
• 
DFS, defined as the time from the date of surgery for the SB3-G31-BC trial to the date where 
an event occurs. An event is breast cancer recurrence (local, regional, distant, or contralateral) 
or death due to any cause. 
• 
OS, defined as the time from the date of randomisation for the SB3-G31-BC trial to the date 
of death, regardless of the cause of death. Subjects who were alive at the time of analysis will 
be censored at the date of the last follow-up assessment. 
Statistical Methods 
The subject demographics and baseline characteristics from SB3-G31-BC trial will be summarised by 
treatment group for the Long-term Follow-up Set and Survival Follow-up Set. 
The incidence of CHF, asymptomatic LVEF decrease, cardiac death, and other significant cardiac 
conditions and all other safety data will be summarised descriptively by treatment group in the SB3-
G31-BC trial and also listed for the Long-term Follow-up Set. 
For time to event data, survival analysis for EFS, DFS, and OS will be performed for the Long-term 
Follow-up Set and Survival Follow-up Set, respectively. Kaplan-Meier curves will be calculated and 
displayed by treatment group in the SB3-G31-BC trial. Additionally, the stratified Cox proportional 
hazard regression model will be applied to estimate hazard ratio (SB3/Herceptin®). The stratification 
factors are hormone receptor status, breast cancer type, and region. The hazard ratio will be presented 
along with its p-value and corresponding 95% confidence interval (CI). 
Exploratory analyses will be conducted to detect any patterns or systemic data issues. 
All analyses will be performed periodically and at the end of the study. 

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Figure 1. Graphical Study Design 
D = day, EBC = early breast cancer, EOS = end of study; FEC = 5-fluorouracil, epirubicin, cyclophosphamide; HER2 = human epidermal growth factor receptor 2; LABC = locally advanced 
breast cancer, n = number of subjects; LABC = locally advanced breast cancer; pCR = pathological complete response, ® = randomisation 
1. Loading dose of 8 mg/kg, and then a maintenance dose of 6 mg/kg every 3 weeks 
2. Docetaxel 75 mg/m2 
3. 5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 
4. Primary endpoint: Pathologic complete response (pCR) in breast tumour 
5. EOS (end of study) means that end of core study (SB3-G31-BC trial) is scheduled 30 days after the last dose of investigational product. 
6. After the last SB3 or Herceptin® administration in the SB3-G31-BC trial, subjects will have safety follow-up visits every 6 months for 24 months, then yearly for additional 3 years. For 
Cardiac Safety and Survival Cohort, subjects will be enrolled sequentially into the study in accordance with SB3-G31-BC-E trial protocol version 1.0 and all data for the study will be 
collected prospectively. For the Survival Only Cohort, data for the study will be collected prospectively from the date of the study informed consent signed and data before informed consent 
will be obtained from medical records retrospectively in accordance with recommended schedule of activities. If prospective data collection is not possible, data could be collected 
retrospectively from medical records.

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Table 1. Recommended Schedule of Activities for the Cardiac Safety and Survival Cohort 
Assessments 
Follow-up 
Visit 
ICF 
1 
2 
3 
4 
5 
6 
7 
Study Month  
- 
6 
12 
18 
24 
36 
48 
60 
Informed consent1 
 
 
 
 
 
 
 
 
Physical exam2 
 
 
 
 
 
 
 
 
Mammography  
 
 
 
 
 
 
 
 
LVEF (ECHO or MUGA scan)3 
 
 
 
 
 
 
 
 
Cardiac events4, 6 
Continuously 
Breast cancer 
recurrence/progression6 
Continuously 
Survival5, 6 
Continuously 
ECHO = echocardiogram; ICF = informed consent form; MUGA = multiple gated acquisition; LVEF = left ventricular ejection fraction 
 
1. The acceptable time lag from end of study of the SB3-G31-BC trial to obtain the informed consent is one year. 
2. Physical exam includes clinical breast exam. 
3. LVEF will be measured by 2D ECHO or MUGA scan. The same method should be used for each subject during the SB3-G31-BC trial and this study. 
4. Cardiac events will be recorded in case of SB3 or Herceptin® related cardiac toxicities during follow-up. 
5. Survival can be followed up by telephone contacts. 
6. For the investigation of cardiac events, breast cancer recurrence/progression, and survival, at least scheduled visits, and activities are recommended. 
 
 

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Table 2. Recommended Schedule of Activities for the Survival Only Cohort 
Assessments 
Follow-up 
Visit2 
ICF 
1 
2 
3 
4 
5 
6 
7 
Study Month from Last IP 
Administration 
- 
6 
12 
18 
24 
36 
48 
60 
Informed consent1 
 
 
 
 
 
 
 
 
Breast cancer 
recurrence/progression2,3 
Continuously 
Survival2, 3, 4 
Continuously 
ICF = informed consent form; IP = investigational product 
1. Subjects will provide informed consent. If prospective data collection is not possible (e.g. when the subject is deceased or lost to follow-up), a waiver of informed consent/authorization will 
be requested for the retrospective data collection from medical records, where applicable and in accordance with national regulations and local ethics. If ICF waiver for the deceased subject 
is not allowed, their next-of-kin (if applicable) will be informed accordingly, and will be asked to give their consent where applicable and approved by institutional review board 
(IRB)/independent ethics committee (IEC) and in accordance with national regulations. 
2. For the investigation of breast cancer recurrence/progression and survival, at least scheduled visits, and activities are recommended. 
3. Data will be collected prospectively from the date of the study informed consent signed and data before informed consent will be obtained from medical records retrospectively. If 
prospective data collection is not possible, data could be collected retrospectively from medical records. 
4. Survival can be followed up by telephone contacts. 

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LIST OF ABBREVIATIONS 
ADCC 
Antibody dependent cell-mediated cytotoxicity 
AE 
Adverse event  
ASCO 
American society of clinical oncology 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CRO 
Contract research organisation 
CRF 
Case report form 
DFS 
Disease-free survival 
DNA 
Deoxyribonucleic acid 
EBC 
Early breast cancer 
EC 
Epirubicin/cyclophosphamide 
ECHO 
Echocardiography 
EFS 
Event-free survival 
EMA 
European medicines agency 
EOS 
End of study 
ESMO 
European Society for Medical Oncology 
FEC 
5-fluorouracil, epirubicin, and cyclophosphamide 
GCP 
Good Clinical Practice 
HER2 
Human epidermal growth factor receptor 2 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 

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ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IP 
Investigational product 
IRB 
Institutional review board 
IV 
Intravenous 
LABC 
Locally advanced breast cancer 
LVEF 
Left ventricular ejection fraction 
MUGA 
Multiple gated acquisition 
NCI-CTCAE v4.0 National Cancer Institute-Common Terminology Criteria for Adverse Events 
version 4.0 
MBC 
Metastatic breast cancer 
NCCN 
National comprehensive cancer network 
NYHA 
New York Heart Association 
OS 
Overall survival 
pCR 
Pathologic complete response 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SOP 
Standard operating procedure 
SmPC 
Summary of Product Characteristics 
tpCR 
Total pathologic complete response 
TTP 
Time to Progression 
 
 

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TABLE OF CONTENTS 
SYNOPSIS ........................................................................................................................................ 2 
LIST OF ABBREVIATIONS ......................................................................................................... 9 
TABLE OF CONTENTS .............................................................................................................. 11 
LIST OF TABLES ......................................................................................................................... 14 
LIST OF FIGURES ....................................................................................................................... 14 
LIST OF STUDY STAFF .............................................................................................................. 15 
1. INTRODUCTION ...................................................................................................................... 16 
1.1. Breast Cancer ...................................................................................................................... 16 
1.1.1. HER2 Positive Breast Cancer .................................................................................... 16 
1.1.2. Current Standard of Neoadjuvant Therapy in HER2 Positive Breast Cancer ............ 16 
1.2. SB3-G31-BC Clinical Trial ................................................................................................. 16 
1.2.1. Overview of SB3 ........................................................................................................ 16 
1.2.2. Overview of SB3-G31-BC Trial ................................................................................ 17 
1.3. Clinical Data of Herceptin® ................................................................................................ 18 
1.3.1. Herceptin® in Metastatic Breast Cancer ..................................................................... 18 
1.3.2. Herceptin® in Early Breast Cancer (Adjuvant)-Efficacy Results ............................... 18 
1.3.3. Herceptin® in Early Breast Cancer (Adjuvant)-Cardiac Safety Results ..................... 19 
1.3.4. Herceptin® in Early Breast Cancer (Neoadjuvant)-Efficacy Results ......................... 19 
1.3.5. Herceptin® in Early Breast Cancer (Neoadjuvant)-Cardiac Safety Results ............... 20 
1.3.6. Safety Concern in Co-administration of Anthracyclines with Herceptin® ................. 21 
1.4. Rationale for the Study ....................................................................................................... 21 
2. STUDY OBJECTIVES .............................................................................................................. 22 
2.1. Primary Objectives .............................................................................................................. 22 
2.2. Secondary Objectives .......................................................................................................... 22 
3. STUDY DESIGN ........................................................................................................................ 22 
3.1. Overview of Study Design .................................................................................................. 22 
3.1.1. End of Trial ................................................................................................................ 23 
3.2. Number of Subjects ............................................................................................................. 23 
4. STUDY POPULATION ............................................................................................................ 24 
4.1. Overview ............................................................................................................................. 24 
4.2. Eligibility Criteria ............................................................................................................... 24 
5. STUDY PROCEDURES AND ASSESSMENTS .................................................................... 25 
5.1. Recommended Schedule of Activities for the Cardiac Safety and Survival Cohort (Table 1)
 ................................................................................................................................................... 25 
5.1.1. Screening Period and Subjects Numbering (ICF Visit).............................................. 25 
5.1.2. Follow-up (Visit 1-7) ................................................................................................. 25 

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5.2. Collection of Data for the Cardiac Safety and Survival Cohort .......................................... 25 
5.2.1. Follow-up Information ............................................................................................... 25 
5.2.2. Cardiac Assessments .................................................................................................. 26 
5.2.3. Recurrence/Progression and Survival Assessments ................................................... 27 
5.3. Recommended Schedule of Activities for the Survival Only Cohort (Table 2) .................. 27 
5.3.1. Subjects Numbering (ICF Visit) ................................................................................. 27 
5.3.2. Follow-up (Visit 1-7) ................................................................................................. 28 
5.4. Collection of Data for the Survival Only Cohort ................................................................ 28 
5.4.1. Follow-up Information ............................................................................................... 28 
5.4.2. Recurrence/Progression and Survival Assessments ................................................... 28 
5.5. Study Treatment .................................................................................................................. 28 
5.6. Unblinding .......................................................................................................................... 29 
5.7. Subject Withdrawal ............................................................................................................. 29 
5.8. Premature Discontinuation of the Study ............................................................................. 29 
6. SAFETY MONITORING AND REPORTING....................................................................... 29 
6.1. Safety Reporting Requirements for SB3-G31-BC-E .......................................................... 29 
6.2. Serious Adverse Events ....................................................................................................... 30 
6.2.1. Serious Adverse Event Reporting .............................................................................. 30 
7. STATISTICAL CONSIDERATION AND ANALYTICAL PLAN ...................................... 31 
7.1. Analysis Sets ....................................................................................................................... 31 
7.2. Statistical Methods and Analytical Plan .............................................................................. 31 
7.2.1. Demographics and Baseline Characteristics .............................................................. 31 
7.2.2. Analysis for Primary and Secondary Objective ......................................................... 32 
7.3. Sample Size ......................................................................................................................... 32 
8. DATA COLLECTION AND MANAGEMENT ..................................................................... 32 
8.1. Data Confidentiality ............................................................................................................ 32 
8.2. Monitoring .......................................................................................................................... 33 
8.3. Data Handling and Record Keeping ................................................................................... 33 
8.4. Database Management ........................................................................................................ 33 
8.5. Quality Control and Quality Assurance .............................................................................. 34 
9. ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES ................... 34 
9.1. Institutional Review Board or Independent Ethics Committee ........................................... 34 
9.2. Ethical Conduct of the Study .............................................................................................. 34 
9.3. Informed Consent ................................................................................................................ 34 
9.4. Financing and Insurance ..................................................................................................... 35 
10. PUBLICATION POLICY ....................................................................................................... 35 
11. REFERENCES ......................................................................................................................... 37 
APPENDICES ................................................................................................................................ 39 
Appendix 1: Criteria for New York Heart Association Functional Classification ..................... 39 

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Appendix 2: Framingham Criteria for Congestive Heart Failure .............................................. 40 
CHANGE HISTORY OF PROTOCOL AMENDMENT .......................................................... 41 
Amendment 1: Version 2.0, Nov 26, 2018 ................................................................................. 41 
 
 
 

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LIST OF TABLES 
Table 1. Recommended Schedule of Activities for the Cardiac Safety and Survival Cohort ............ 7 
Table 2. Recommended Schedule of Activities for the Survival Only Cohort................................... 8 
Table 3. Efficacy of Adjuvant Herceptin® in Breast Cancer ............................................................ 18 
Table 4. Efficacy of Adjuvant Herceptin® in Breast Cancer ............................................................ 20 
Table 5. Reporting Guideline for Left Ventricular Ejection Fraction Decrease ............................... 27 
 
LIST OF FIGURES 
Figure 1. Graphical Study Design ...................................................................................................... 6 
 
 
 

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LIST OF STUDY STAFF 
SPONSOR: 
Samsung Bioepis Co., Ltd. 
107, Cheomdan-daero, Yeonsu-gu, 
Incheon, 21987 
Republic of Korea 
 
Clinical Project Manager  
 
 
 
 
Clinical Research 
Physician  
  
 
 
 
Clinical Development 
Associate 
 
 
 
 
Statistician  
 
 
 
 
Project Safety Lead 
 
 
 
 
Safety Physician 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD

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1. INTRODUCTION 
1.1. Breast Cancer 
1.1.1. HER2 Positive Breast Cancer 
Breast cancer is the most common cancer in women worldwide. It is also the principle cause of 
death from cancer among women globally [Siegel, 2013]. Of the total number of patients 
diagnosed with breast cancer, 20% to 25% have tumours that exhibit human epidermal growth 
factor receptor 2 (HER2) protein overexpression or gene amplification. HER2 belongs to a family 
of four transmembrane receptor tyrosine kinases that mediate the growth, differentiation, and 
survival of cells [Slamon, 1987; Slamon, 1989]. HER2 overexpression is associated with 
aggressive tumour biology and with poor clinical outcomes compared with tumours that do not 
have HER2 overexpression [Cooke, 2001]. 
Trastuzumab (Herceptin®, Roche Registration Limited), a humanised monoclonal antibody that 
blocks the activity of HER2, improved clinical outcomes in patients with both early and metastatic 
HER2 positive breast cancer. Lapatinib (Tykerb®, GlaxoSmithKline), HER2 directed tyrosine 
kinase inhibitor, given in combination with capecitabine, also improved progression-free survival 
(PFS) in patients who had disease progression on Herceptin®. So far, Herceptin® is the most widely 
used drug in breast cancer and also the only drug approved for the treatment of early-stage breast 
cancer. 
1.1.2. Current Standard of Neoadjuvant Therapy in HER2 Positive Breast Cancer 
While many studies demonstrate high pathologic complete response (pCR) rates and good 
tolerability with a variety of chemotherapy/Herceptin® combinations, there is no clear consensus 
on the duration of therapy or whether to include anthracycline, and if anthracycline is included, on 
whether it should be given concurrently or sequentially with Herceptin®. 
The current recommendation of the National Comprehensive Cancer Network (NCCN) guideline is 
to use paclitaxel plus Herceptin® followed by 5-fluorouracil, epirubicin, and cyclophosphamide 
(FEC) plus Herceptin®, based on the initial small MD Anderson study [Buzdar, 2005]. European 
Medicines Agency (EMA) provided the possibility of using neoadjuvant Herceptin® together with 
anthracyclines when EMA approved Herceptin® to be used as neoadjuvant therapy based on the 
NOAH study [Gianni, 2010]. 
Although optimal neoadjuvant regimen cannot be established, it appears that a combination of 
taxanes and anthracyclines can produce higher pCR rates compared to the taxane only regimen. 
1.2. SB3-G31-BC Clinical Trial 
1.2.1. Overview of SB3 
SB3 has been developed as a similar biological medicinal product to Herceptin® (trastuzumab, 

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Roche Registration Limited). SB3 and Herceptin® have identical primary structure and the active 
substance for both products is trastuzumab produced in Chinese Hamster Ovary cell line 
transformed by recombinant deoxyribonucleic acid (DNA) technology. Trastuzumab (anti-185, 
rhuMab HER2) is a humanised monoclonal antibody that binds to HER2 protein and inhibits the 
proliferation of HER2 overexpressing human tumour cells. 
SB3 was extensively characterised and compared to Herceptin® using ‘state-of-the-art’ methods. 
These studies were in accordance with the principles laid out in the comparability guidelines 
including the ‘Guideline on similar biological medicinal products containing biotechnology-
derived proteins as active substance: Quality issues (revision 1)’ 
[EMEA/CHMP/BWP/247713/2012]. It was demonstrated that SB3 has similar structural and 
physicochemical characteristics with Herceptin®. In regards to the mechanism of action, SB3 
inhibits HER2 expressing human tumour cell proliferation and mediates antibody dependent cell-
mediated cytotoxicity (ADCC) against such tumour cells in vitro equivalently to Herceptin®. 
Biosimilarity between SB3 and Herceptin® was demonstrated through extensive quality and non-
clinical similarity exercises, and a Phase I study was conducted in healthy subjects to compare the 
pharmacokinetics (PK), safety, tolerability, and immunogenicity and a Phase III study has been 
conducted in subjects with HER2 positive breast cancer to compare the efficacy, safety, PK, and 
immunogenicity of SB3 to Herceptin®. Information on the safety of SB3 based on the reference 
product information and non-clinical exercises is presented in the Investigator’s Brochure (IB). 
1.2.2. Overview of SB3-G31-BC Trial 
The SB3-G31-BC clinical trial is a randomised Phase III, double-blind, parallel group, multicentre 
study to compare the efficacy, safety, PK, and immunogenicity between SB3 and Herceptin® in 
women with HER2 positive early breast cancer (EBC) or locally advanced breast cancer (LABC) 
in neoadjuvant setting (EudraCT Number 2013-004172-35). Subjects were randomised in a 1:1 
ratio to either receive SB3 or Herceptin® in neoadjuvant setting for 8 cycles concurrently with 8 
cycles of chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-FEC). Then subjects 
underwent surgery. After surgery, subjects received further 10 cycles of adjuvant SB3 or 
Herceptin® as per randomisation to complete one year of therapy (Figure 1).  
The primary objective was to demonstrate comparable clinical efficacy of SB3 and Herceptin®, in 
terms of pCR rate of the primary breast tumour in women with HER2 positive EBC or LABC in 
neoadjuvant setting. 
The secondary objectives were to evaluate the efficacy of SB3 compared to Herceptin® by total 
pCR (tpCR) rate, overall clinical response rate, event-free survival (EFS), overall survival (OS), 
the safety, and tolerability of SB3 compared to Herceptin®, the PK of SB3 compared to Herceptin®, 
the immunogenicity of SB3 compared to Herceptin® 
A total of 875 subjects were randomised; 437 subjects to the SB3 treatment group and 438 subjects 
to the Herceptin® treatment group. Among them, 380 subjects in the SB3 treatment group and 384 

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subjects in the Herceptin® treatment group completed the trial. 
1.3. Clinical Data of Herceptin® 
1.3.1. Herceptin® in Metastatic Breast Cancer 
Herceptin® has clinical activity in patients with HER2 positive metastatic breast cancer (MBC), 
both as single-agent therapy in first-line and salvage settings and in combination with 
chemotherapy. A pivotal Phase III study demonstrated that the combination of trastuzumab and 
chemotherapy significantly prolonged time to progression (TTP) and OS compared with 
chemotherapy alone in patients with HER2 positive MBC [Slamon, 2001]. Similarly, in a 
randomised Phase II trial, the addition of trastuzumab to docetaxel improved response rate, TTP, 
and OS compared with docetaxel alone in women with HER2 positive MBC [Marty, 2005]. 
Therefore, Herceptin® is currently approved for use as monotherapy in patients with HER2 positive 
MBC who have received one or more chemotherapy regimens and for use in combination with 
taxane for their metastatic disease. 
1.3.2. Herceptin® in Early Breast Cancer (Adjuvant)-Efficacy Results 
Herceptin® was investigated in 4 large multicentre, randomised studies in the adjuvant setting. A 
summary of the results is showed in Table 3. All studies demonstrated that adjuvant Herceptin® 
treatment for up to 1 year reduced by nearly half the risk of relapse. Also the risk of death was 
significantly reduced. Based on the results of the HERA trial, Herceptin® was approved for the 
treatment of patients with HER2-positive EBC following surgery, chemotherapy (neoadjuvant or 
adjuvant), and radiotherapy (if applicable). 
Table 3. Efficacy of Adjuvant Herceptin® in Breast Cancer 
Adjuvant Study 
DFS 
Hazard Ratio (95% CI),  
p-value 
OS 
Hazard Ratio (95% CI),  
p-value 
Median 
Follow-Up 
NCCTG N9831 and NSABP B-31 
23 months 
AC → TH (n = 1872) 
0.48 (0.39, 0.59) p ≤ 0.0001 
0.67 (0.48, 0.92) 
p = 0.014 
AC → T (n = 1880) 
HERA [Piccart-Gebhart, 2005] 
12 months 
Chemo → H (n = 1694) 
0.54 (0.43, 0.67) p < 0.0001 
0.76 
p = 0.26 
Chemo → Observation 
 (n = 1693) 
BCIRG 006 [Slamon, 2011] 
65 months 
TCH (n = 1075) 
0.75 
p = 0.04 
0.77 
p = 0.04 
AC → TH (n = 1074) 
0.64 
p < 0.001 
0.63 
p < 0.001 
AC → T (n = 1073) 
 
 
A = anthracycline; C = cyclophosphamide; CI = confidence interval; DFS = disease-free survival; H = Herceptin®; n = 
number of subjects; OS = overall survival; T = docetaxel 

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1.3.3. Herceptin® in Early Breast Cancer (Adjuvant)-Cardiac Safety Results 
Cardiac dysfunction, including congestive heart failure (CHF) is a relevant safety issue related to 
Herceptin® treatment. The main findings from the HERA trial were: 
 
The incidence of New York Heart Association (NYHA) class III or IV CHF in patients 
receiving Herceptin® was low (0.6%) and compares with 0.1% of patients in the 
observation arm. None of these events was fatal, with the exception of one observation 
patient who developed CHF class IV leading to death. 
 
Three percent of the Herceptin® patients had CHF NYHA class I and II during the study 
compared with 0.5% in the observation arm patients. In the majority of cases, following 
cessation of Herceptin® treatment with or without standard cardiac medication, 
stabilization of left ventricular ejection fraction (LVEF) or return towards the baseline 
value was observed. 
 
The incidence of cardiac dysfunction (defined as at least one drop in LVEF < 50% and of 
≥ 10% points from baseline) was 7.4% in the one-year Herceptin® arm compared with 2.3% 
in the observation arm. 
 
The longer-term assessment of trastuzumab-related cardiac adverse events (AEs) for up to 
48 months reported that the cumulative incidence of any type of cardiac events increases 
during the scheduled treatment period of one year but it remains relatively constant 
thereafter [Procter, 2010]. 
In the NSABP B-31 trial, the incidence of symptomatic CHF in patients receiving Herceptin® was 
4.1% compared to 0.1% in the observation arm. There was one patient who developed CHF class 
IV leading to death. 
In the NCCTG N9831 trial, the incidence of symptomatic CHF in patients receiving 
Herceptin® was 2.9% compared with 0% of patients in the observation arm. Only one patient in the 
investigational arm developed CHF class IV leading to death. 
Based on results from the BCIRG 006 trial, concomitant administration of Herceptin® with a non-
anthracycline based regimen such as docetaxel and carboplatin carries a very low risk of severe 
CHF (0.3%). 
1.3.4. Herceptin® in Early Breast Cancer (Neoadjuvant)-Efficacy Results 
Many clinical studies have been conducted or are being conducted to investigate the role of 
Herceptin® in neoadjuvant setting. The major studies which investigated the efficacy of 
neoadjuvant Herceptin® are described below. A summary of the study design and efficacy results is 
showed in Table 4. 

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Table 4. Neoadjuvant Herceptin® Studies in Breast Cancer 
Study 
HER2 Positive 
Patients 
Clinical Stage 
Chemotherapy 
Definition of 
pCR 
pCR 
Rate 
Buzdar 
(2005) 
23 
T1-4, N0-2 
PH → FECH 
ypT0 ypN0 
65% 
NOAH 
(2010) 
117 
LABC, incl. 
inflammatory 
APH → PH → 
CMFH 
ypT0 
43% 
GeparQuattro 
(2010) 
445 
> 1 cm, T1-4, N+if 
T2, inflammatory 
ECH → TH ± X 
ypT0/is 
32% 
TECHNO 
(2011) 
217 
> 2 cm or 
inflammatory 
EC → PH 
ypT0 ypN0 
39% 
HannaH 
(2012) 
299 
I-IIIc, 
inflammatory 
TH → FECH 
ypT0/is 
41% 
A = anthracycline; C = cyclophosphamide; E = epirubicin; F = 5-floururacil; H = Herceptin®; LABC = locally advanced 
breast cancer M = methotrexate; P = paclitaxel; pCR = pathologic complete response; T = docetaxel; X = Xeloda® 
1.3.5. Herceptin® in Early Breast Cancer (Neoadjuvant)-Cardiac Safety Results 
Buzdar AU et al. [Buzdar, 2005] 
Herceptin® was given concurrently with preoperative chemotherapy (paclitaxel 225 mg/m2 every 3 
weeks for 4 cycles) followed by FEC (5-fluouracil 500 mg/m2, epirubicin 75 mg/m2, and 
cyclophosphamide 500 mg/m2 every 3 weeks for 4 cycles). There was no clinical cardiac 
dysfunction observed and there were no cardiac deaths. 
NOAH Study [Gianni, 2010] 
Herceptin® was administered concurrently with 10 cycles of neoadjuvant chemotherapy. 
Chemotherapy regimen consisted of 3 cycles of doxorubicin 60 mg/m2 and paclitaxel 150 mg/m2 
for followed by and 4 cycles of paclitaxel 175 mg/m2 followed by an additional 3 cycles of CMF. 
National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0 (NCI-
CTCAE v4.0) grade 2 and 3 LVEF changes were infrequent in both study arms. The safety data 
suggest that the neoadjuvant regimen used in the NOAH study is tolerated well and has an 
acceptable cardiac safety profile. 
GeparQuattro Study [Untch, 2010] 
HER2 positive patients were randomised to receive pre-operative intravenous (IV) Herceptin® 
concurrently with either epirubicin/cyclophosphamide (EC) followed by docetaxel, or EC followed 
by docetaxel plus concomitant capecitabine or EC followed by docetaxel followed by capecitabine. 
There were no cardiac safety concerns in this study. LVEF decreases beyond 45% were not 
observed, neither was CHF grade 4. 
TECHNO Study [Untch, 2011] 
Patients were treated with neoadjuvant epirubicin plus cyclophosphamide for 4 cycles, followed by 

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paclitaxel plus Herceptin® for 4 cycles. Herceptin® was then continued after surgery for a total of 1 
year. Cardiac toxicity was reported in eight patients (3.7%) of who six presented with an 
asymptomatic LVEF decrease and two with symptomatic chronic heart failure. 
HannaH Study [Ismael, 2012] 
The HannaH study compared PK, efficacy, and safety between subcutaneous (SC) trastuzumab and 
IV trastuzumab. The incidence of grade 3 to5 AEs was similar between groups. No cases of 
symptomatic CHF were reported. Six (2.1%) of 298 patients in the IV group and seven (2.4%) of 
297 in the SC group had a significant LVEF drop. 
1.3.6. Safety Concern in Co-administration of Anthracyclines with Herceptin® 
In contrast to the early experiences in MBC, simultaneous neoadjuvant therapy with anthracyclines 
and Herceptin® appears to have an acceptable cardiac toxicity profile [Slamon, 2011]. Buzdar 
study did not observe any chronic heart failure (total cumulative dose of epirubicin 300 mg/m2), 
[Buzdar, 2007] and only 1 of the 455 patients of the GeparQuattro study (total cumulative dose of 
epirubicin 360 mg/m2) developed a persistent decrease in LVEF below 50% during the neoadjuvant 
therapy [Untch, 2010]. In the NOAH study, only 2 patients (2%) developed symptomatic cardiac 
failure during 2 year follow-up and both patients responded to cardiac drugs. However, definite 
requirements before combining Herceptin® and anthracyclines in this setting include careful 
selection of patients according to pre-existing cardiac diseases and risk factors (such as a higher 
than normal LVEF before start of treatment), and restriction. 
Epirubicin is investigated for concurrent use with Herceptin®; because epirubicin is considered to 
have cumulative risk of cardiotoxicity up to a 1000 mg/m2, while doxorubicin has potential 
cardiotoxic cumulative doses at ≥ 450 mg/m2. The Hercules study evaluated the cardiac safety of 
Herceptin® in combination with EC in patients with HER2 positive MBC [Untch, 2010]. Two 
different doses of epirubicin for 6 cycles were tested (60 mg/m2 and 90 mg/m2). The increase in 
epirubicin dose from 60 mg/m2 to 90 mg/m2 was associated with an increase in cardiac events from 
15.0% to 23.3%. More specifically, the incidence of CHF NYHA class III/IV increased from 1.7% 
to 5.0%. However, the dose of epirubicin did not affect the efficacy variables. This result strongly 
suggests that Herceptin® in combination with low-dose epirubicin is a feasible and may be active 
regimen for patients with HER2 positive EBC. 
1.4. Rationale for the Study 
According to the Summary of Product Characteristics (SmPC) of Herceptin®, for patients with 
EBC, cardiac assessments, as performed at baseline, should be repeated every 3 months during 
treatment and every 6 months following discontinuation of treatment until 24 months from the last 
administration of Herceptin®. In patients who receive anthracycline containing chemotherapy 
further monitoring is recommended yearly up to 5 years from the last administration of Herceptin®, 
or longer if a continuous decrease of LVEF is observed. 
The incidence of symptomatic CHF and asymptomatic significant LVEF decrease was not yet 

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investigated in the SB3 treated subjectts in neoadjuvant and adjuvant setting. This study will 
observe the incidence of cardiac event regarding LVEF of SB3 (proposed trastuzumab biosimilar) 
and Herceptin® in subjects with HER2 positive breast cancer who had completed SB3-G31-BC 
trial. 
This study will evaluate long-term efficacy outcomes to all subjects enrolled in this extension study 
between treatment groups (SB3 and Herceptin®). EFS, disease-free survival (DFS), and OS will be 
presented based on the events including breast cancer recurrence/progression and death. 
2. STUDY OBJECTIVES 
2.1. Primary Objectives 
The primary objective is to observe the incidence of symptomatic CHF and significant 
asymptomatic LVEF decrease in HER2 positive EBC or LABC subjects treated with SB3 or 
Herceptin® as neoadjuvant and adjuvant treatment. 
 
CHF is defined as NYHA II, III, and IV confirmed by a cardiologist, accompanied by a 
significant LVEF decrease. 
 
Significant LVEF decrease is defined as an absolute decline of at least 10% points from 
baseline LVEF (LVEF at screening of the SB3-G31-BC trial) and resulting LVEF less 
than 50%. 
2.2. Secondary Objectives 
The secondary objectives are: 
 
To observe the incidence of cardiac death and other significant cardiac conditions 
 
To observe the long term efficacy of SB3 compared to Herceptin® by 
- 
EFS and DFS 
- 
OS 
3. STUDY DESIGN 
3.1. Overview of Study Design 
This is an observational cohort study.  
[Cardiac Safety and Survival Cohort]: The group consists of subjects who completed the SB3-
G31-BC trial and provide informed consent for the long-term follow-up of cardiac safety and 
survival. 
Subjects who have completed the clinical trial SB3-G31-BC will be asked to consent to participate 

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in this study. Consenting subjects will be enrolled sequentially into the study in accordance with 
protocol version 1.0 and will be monitored according to the local clinical practices which are based 
on the Herceptin® SmPC or local label. No additional procedures/subject visits in comparison with 
the usual clinical practice are planned for the study. 
Baseline data (such as demographics, breast cancer type, TNM stage, medical history, surgical 
history, pre-treatment LVEF, neoadjuvant and adjuvant treatment, and postoperative radiation 
therapy) will be transferred from the SB3-G31-BC trial. Follow-up data will be collected from 
medical records for up to 5 years or death, unless subjects are lost for the follow-up or have 
withdrew the informed consent. 
[Survival Only Cohort]: The group consists of subjects who participate in this trial among 
subjects who received the SB3 or Herceptin® in the SB3-G31-BC trial and were not sequentially 
enrolled into this SB3-G31-BC-E trial as a Cardiac Safety and Survival Cohort. 
Subjects who received SB3 or Herceptin® in accordance with the clinical trial SB3-G31-BC and 
were not sequentially enrolled to SB3-G31-BC-E trial as a Cardiac Safety and Survival Cohort will 
be asked to consent to participate in this study as a Survival Only Cohort. If prospective data 
collection is not possible (e.g. when the subject is deceased or lost to follow-up), a waiver of 
informed consent/authorization will be requested for the retrospective data collection from medical 
records, where applicable and in accordance with national regulations and local ethics. If informed 
consent form (ICF) waiver for the deceased subject is not allowed, their next-of-kin (if applicable) 
will be informed accordingly, and will be asked to give their consent where applicable and 
approved by institutional review board (IRB)/independent ethics committees (IEC) and in 
accordance with national regulations. 
Data will be collected from medical records for up to 5 years from their last investigational product 
(IP; SB3 or Herceptin®) administration or death, unless they are lost for the follow-up or withdraw 
the informed consent. Data for the study will be collected prospectively from the date of the study 
informed consent signed and data before informed consent will be obtained from medical records 
retrospectively. If prospective data collection is not possible, data could be collected 
retrospectively from medical records. 
3.1.1. End of Trial 
The study will close at 5 years after the last subject has received the last IP (SB3 or Herceptin®) in 
the setting of clinical trial SB3-G31-BC. 
3.2. Number of Subjects 
A total of 875 subjects received the study IP in the SB3-G31-BC trial. Incorporating 20% of refusal 
rate for consent to this observational study and 10% of lost to follow-up, approximately 612 
subjects are expected to be enrolled to this study. 

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4. STUDY POPULATION 
4.1. Overview 
[Cardiac Safety and Survival Cohort] 
The study population for the Cardiac Safety and Survival Cohort is women who completed in the 
clinical trial SB3-G31-BC (A Phase III randomised, double-Blind, parallel group, multicentre study 
to compare the efficacy, safety, PK, and immunogenicity between SB3 [proposed trastuzumab 
biosimilar] and Herceptin® in women with newly diagnosed HER2 positive EBC or LABC in 
neoadjuvant setting). 
[Survival Only Cohort] 
The study population for the Survival Only Cohort is women who received SB3 or Herceptin® in 
accordance with the clinical trial SB3-G31-BC and were not sequentially enrolled into this SB3-
G31-BC-E trial as a Cardiac Safety and Survival Cohort. 
4.2. Eligibility Criteria 
[Cardiac Safety and Survival Cohort] 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1.  Subjects have completed the study treatment of the SB3-G31-BC trial according to the 
protocol. 
2.  Subjects must provide informed consent. 
Exclusion Criteria 
Subjects unwilling to follow the study requirements are not eligible for the study for the Cardiac 
Safety and Survival Cohort. 
[Survival Only Cohort] 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1.  Subjects who received SB3 or Herceptin® according to the clinical trial SB3-G31-BC 
2.  Subjects who provide informed consent. If prospective data collection is not possible (e.g. 
when the subject is deceased or lost to follow-up), a waiver of informed consent/authorization 
will be requested for the retrospective data collection from medical records, where applicable 

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and in accordance with national regulations and local ethics. If ICF waiver for the deceased 
subject is not allowed, their next-of-kin (if applicable) will be informed accordingly, and will 
be asked to give their consent where applicable and approved by IRB/IEC and in accordance 
with national regulations. 
Exclusion Criteria 
There is no exclusion criteria for the Survival Only Cohort. 
5. STUDY PROCEDURES AND ASSESSMENTS 
5.1. Recommended Schedule of Activities for the Cardiac Safety and Survival Cohort (Table 
1) 
5.1.1. Screening Period and Subjects Numbering (ICF Visit) 
All subjects who completed the clinical trial SB3-G31-BC until end of study (EOS) will be asked 
to consent to participate in this study. The acceptable time lag from EOS of the SB3-G31-BC trial 
to obtain the informed consent is one year. The subject identification number of the SB3-G31-BC 
trial will be also used for this study. 
5.1.2. Follow-up (Visit 1-7) 
Subjects will be followed for 5 years after the EOS of the SB3-G31-BC trial. Each visit is 
recommended to occur every 6 month in the first 24 months, then yearly (i.e. every 12 months) 
according to local practice which is based on the SmPC or local label of Herceptin® . The 
recommended schedule for Visit 1 is 6 months after the last SB3 or Herceptin® administration. 
There is no pre-defined visit window. The following procedure will be performed during follow-up 
visits in the routine care setting. 
 
Physical examination including clinical breast exam 
 
Mammography 
 
LVEF measurement (2D echocardiography [ECHO] or multiple gated acquisition [MUGA] 
scan) 
 
Monitoring of cardiac events 
5.2. Collection of Data for the Cardiac Safety and Survival Cohort 
5.2.1. Follow-up Information 
Following data will be collected: 
 
Physical examination including clinical breast exam 

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 
Mammography 
 
LVEF measurement (2D ECHO or MUGA scan) 
 
Cardiac disorders: Onset, outcome, and medical intervention indicated or not 
- 
Symptomatic CHF 
- 
Asymptomatic LVEF decrease 
- 
Cardiac death 
- 
Other significant cardiac conditions (acute myocardial infarction, severe arrhythmia, 
ischemic heart disease, valvular dysfunction, etc.) 
 
Recurrence/progression of the breast cancer 
 
Death (in case scheduled visit is not available, it is allowed to collect survival information 
by telephone contacts) 
For the investigation of cardiac events, breast cancer recurrence/progression, and survival, at least 
scheduled visits and activities are recommended. 
In case of start of any new treatment for recurrent disease, only survival data will be collected. 
5.2.2. Cardiac Assessments 
This study plans to observe the incidence of symptomatic CHF, asymptomatic significant LVEF 
decrease, and cardiac death. CHF should be classified according to the NYHA classification 
(Appendix 1). Symptomatic CHF is defined as NYHA class II, III, IV, confirmed by a cardiologist, 
accompanied by a significant LVEF decrease. For reference, symptoms that can be associated with 
CHF are provided in (Appendix 2). Significant LVEF decrease is defined as an absolute decline of 
at least 10% points from baseline LVEF (LVEF at screening of the SB3-G31-BC trial) and to less 
than 50%. Cardiac death is defined as death definitely as a result of heart failure, myocardial 
infarction, or documented arrhythmia or as probable cardiac death within 24 hours of a cardiac 
event. 
LVEF may be measured by 2D ECHO or MUGA scan as specified in the recommended schedule 
of activities (Table 1) and as medically indicated. The same method should be used for each subject 
during the SB3-G31-BC trial and this study. Also the assessment by same assessor from the SB3-
G31-BC trial is recommended. It is advised that LVEF assessment is performed as per the SmPC or 
local label of Herceptin® SmPC. 
The information about onset, outcome, and medical intervention indicated or not of cardiac events 
will be collected. 

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Table 5. Reporting Guideline for Left Ventricular Ejection Fraction Decrease 
Observation 
Term to be Reported 
Grading 
Asymptomatic decline in LVEF 
N/A 
N/A 
Asymptomatic significant LVEF decrease (LVEF 
decline ≥ 10% points from baseline and resulting LVEF 
< 50%) 
Asymptomatic significant LVEF 
decrease 
N/A 
Symptomatic significant LVEF decrease 
CHF 
NYHA 
CHF = congestive heart failure; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association 
  
5.2.3. Recurrence/Progression and Survival Assessments 
This study also plans to observe breast cancer recurrence/progression and death. Follow-up plans 
after cancer surgery and adjuvant treatment for breast cancer are described in several oncology 
guidelines including the NCCN guidelines version 1.2015, American Society of Clinical Oncology 
(ASCO) clinical practice guideline 2012, and European Society for Medical Oncology (ESMO) 
guidelines. Physical examinations are recommended every 3 to 12 months for the first 5 years, and 
annually thereafter. Mammography is recommended every 12 months. Diagnosis of breast cancer 
recurrence/progression will be made by clinical, radiological, or pathological findings. 
In this study, EFS is defined as the time from the date of randomisation for the SB3-G31-BC trial 
to the date where an event occurs and DFS is defined as the time from the date of surgery for the 
SB3-G31-BC trial to the date where an event occurs. An event is defined as breast cancer 
recurrence or progression (local, regional, distant, or contralateral), or death due to any cause. OS 
is defined as the time from the date of randomisation for the SB3-G31-BC trial to the date of death, 
regardless of the cause of death. Subjects who were alive at the time of analysis will be censored at 
the date of the last follow-up assessment. 
5.3. Recommended Schedule of Activities for the Survival Only Cohort (Table 2) 
5.3.1. Subjects Numbering (ICF Visit) 
Subjects who received SB3 or Herceptin® in accordance with the clinical trial SB3-G31-BC and 
were not sequentially enrolled to SB3-G31-BC-E trial as a Cardiac Safety and Survival Cohort will 
be asked to consent to participate in this study as a Survival Only Cohort. If prospective data 
collection is not possible (e.g. when the subject is deceased or lost to follow-up), a waiver of 
informed consent/authorization will be requested for the retrospective data collection from medical 
records, where applicable and in accordance with national regulations and local ethics. If ICF 
waiver for the deceased subject is not allowed, their next-of-kin (if applicable) will be informed 
accordingly, and will be asked to give their consent where applicable and approved by IRB/IEC 
and in accordance with national regulations. The subject identification number of the SB3-G31-BC 
trial will be also used for this study. 

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5.3.2. Follow-up (Visit 1-7) 
Subjects will be followed for 5 years after the last administration of IP (SB3 or Herceptin®) in the 
SB3-G31-BC trial. After enrolment into this trial, each visit is recommended to occur every 6 
month in the first 24 months, then yearly (i.e. every 12 months) from the last administration of IP 
(SB3 or Herceptin®) in the SB3-G31-BC trial according to local practice which is based on the 
SmPC or local label of Herceptin®. If the recommended visit is already passed at the timing of 
enrolment, data will be retrospectively collected according to Section 5.4. 
5.4. Collection of Data for the Survival Only Cohort 
5.4.1. Follow-up Information 
Following data will be collected: 
 
Recurrence/progression of the breast cancer 
 
Death (in case scheduled visit is not available, it is allowed to collect survival information 
by telephone contacts) 
For the investigation of breast cancer recurrence/progression and survival, at least scheduled visits 
and activities are recommended. 
In case of start of any new treatment for recurrent disease, only survival data will be collected. 
5.4.2. Recurrence/Progression and Survival Assessments 
Based on the time point of informed consent (or a waiver of informed consent, if applicable) for 
the study, retrospective and prospective data will be collected as follows. 
 
Retrospective data collection: Most recent breast cancer recurrence/progression and 
survival assessment data (whether recurrence/progression occurs or not) between the end 
of SB3-G31-BC trial and informed consent (or a waiver of informed consent, if applicable) 
for this extension study will be obtained from medical records retrospectively. 
 
Prospective data collection: Breast cancer recurrence/progression assessment and survival 
data after informed consent will be collected prospectively in the same manner as Cardiac 
Safety and Survival Cohort. 
Subjects who were alive at the time of analysis will be censored at the date of the last follow-up 
assessment. 
5.5. Study Treatment 
There is no IP or a treatment prescribed by this protocol. Decision about any treatment will be 
made according to the local practice and at the discretion of the Investigator. 

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5.6. Unblinding 
While this study is ongoing, blindness of SB3 or Herceptin® administered during the SB3-G31-BC 
trial will be maintained until the data base lock of the SB3-G31-BC trial. 
During blinding period, unblinding should be considered when knowledge of the treatment 
assignment is deemed essential for the subject’s care by their Investigator or a regulatory body. If 
the blind is broken, it may be broken only for the subject in question. If time permits, before 
requesting that the blind be broken for an individual subject, the Investigator should discuss the 
situation with the Sponsor via phone or e-mail. The Sponsor must be notified immediately if a 
subject and/or Investigator is unblinded during the course of the study along with the reason for 
breaking the blind. Pertinent information regarding the circumstances of unblinding of a subject’s 
treatment code must be documented in the subject’s source documents. This includes who 
performed the unblinding, the subject(s) affected, the reason for the unblinding, the date of the 
unblinding and the relevant IP information. 
5.7. Subject Withdrawal 
Subjects are free to discontinue the study at any time without giving their reasons. Already 
collected data will be analysed for this study unless subjects refuse. 
A subject must be withdrawn in the event of any of the following: 
 
Withdrawal of the subject’s consent 
 
Newly diagnosed malignant neoplasm other than breast cancer to be treated during 
prospective data collection 
 
Administrative or other reasons 
5.8. Premature Discontinuation of the Study 
The whole study may be discontinued prematurely in case of the Sponsor’s decision that 
discontinuation of the study is justifiable for medical reasons. Health authorities and IRBs/IECs 
will be informed about the discontinuation of the study in accordance with applicable regulations. 
6. SAFETY MONITORING AND REPORTING 
Subjects registered in this study can be waived from the reporting requirement of IP-related serious 
AEs (SAEs) after EOS described in Section 7 of the protocol for the SB3-G31-BC trial. 
6.1. Safety Reporting Requirements for SB3-G31-BC-E 
Since SB3-G31-BC-E is to assess the long-term cardiac safety for SB3 or Herceptin®, which is 
mainly about post-dose cardiac toxicities captured through cardiac assessments described in 
Section 5.2.2 and not by AE reporting, other non-serious AEs are not intended to be collected 

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through this study. However, for any type of SAE (cardiac or non-cardiac) that may be determined 
by the Investigator to be related to the IP then that SAE should be reported through a separate 
paper SAE report form to the Sponsor and not via the case report form (CRF). (note: AEs should 
be classified as ‘related’ if there is a reasonable possibility that the IP caused the AE. This means 
that there are facts (evidence) or arguments to suggest a causal relationship.) Such IP-related SAEs 
that occur from the subject’s sign of the ICF to the EOS should be reported for the purpose of this 
study. However, even after the EOS, IP-related SAEs can be reported to the Sponsor separate from 
this study in the same way. 
For more details of AEs including the definition of seriousness, severity, causality and 
expectedness, please refer to Section 7 of the protocol for the SB3-G31-BC trial. 
6.2. Serious Adverse Events  
An SAE is any untoward medical occurrence at any dose that: 
 
Results in death 
 
Is life-threatening 
 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability/incapacity 
 
Results in congenital anomaly/birth defects 
 
Is medically important 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation. However, if it is determined that the event 
may jeopardise the subject and may require intervention to prevent one of the other outcomes 
listed in the definition above, the important medical event should be reported as SAE. 
6.2.1. Serious Adverse Event Reporting 
SAEs that are determined to be related to the IP by the Investigator (either cardiac or non-cardiac) 
must be immediately reported at least within 24 hours of the Investigator becoming aware of the 
event to the Sponsor or its designated representative using the SAE form provided by the Sponsor. 
Contact information for SAE reporting will be provided in SAE Report Completion Instruction. In 
particular, if the reported SAE is fatal or life-threatening, the Sponsor must be notified immediately, 
irrespective of the extent of available AE information. This timeframe also applies to additional 
(follow-up) information that becomes available on previously forwarded SAE reports. The sponsor 
will then follow expedited reporting procedures according to local and international regulations as 
appropriate. 
The Investigator is obligated to pursue and provide information to the Sponsor on such reported 

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SAEs in accordance with the timeframes for reporting specified above. In addition, the Investigator 
may be requested by the Sponsor to obtain specific additional follow-up information in an 
expedited fashion. In general, this will include a description of the reported SAE, which should be 
provided in sufficient detail so as to allow for a complete medical assessment of the case and 
independent determination of causality (as mentioned above, for the scope of this study only IP-
related SAEs are expected to be reported). Information on other possible causes of the event, such 
as concomitant medications and illnesses must be provided. If the reported SAE resulted into the 
subject’s death, a summary of available autopsy findings must be submitted as soon as possible to 
the Sponsor or its designated representative. 
All reported SAEs will be followed until event resolution or stabilisation (for chronic events), if 
possible. For chronic events that does not fully resolve until years later, the outcome should be 
reported as ‘resolved with sequelae’ as soon as the event has stabilised or returned to baseline. 
Follow-up information for the reported SAE should be actively sought and submitted as the 
information becomes available. 
7. STATISTICAL CONSIDERATION AND ANALYTICAL PLAN 
This is primarily designed to observe the incidence of symptomatic CHF, asymptomatic significant 
LVEF decrease, and other cardiac events in breast cancer subjects treated with SB3 or 
Herceptin® according to the protocol SB3-G31-BC trial. There is no pre-defined hypothesis testing, 
therefore all analyses will be performed for the observational or exploratory purpose. 
All analyses will be performed periodically and at the end of the study. 
7.1. Analysis Sets 
The following set will be used for the analyses performed in the study: 
 
Long-term Follow-up Set: This set consists of all subjects who provide informed consent 
for the long-term follow-up of cardiac safety and survival. This set includes Cardiac 
Safety and Survival Cohort defined in Section 3.1  
 
Survival Follow-up Set: This set consists of all subjects who enrolled for this study. This 
set includes Cardiac Safety and Survival Cohort and Survival Only Cohort defined in 
Section 3.1. 
Subjects will be analysed according to the treatment (SB3 or Herceptin®) received in the SB3-G31-
BC trial. 
7.2. Statistical Methods and Analytical Plan 
7.2.1. Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics from the SB3-G31-BC trial will be summarised 
by treatment group for the Long-term Follow-up Set and Survival Follow-up Set. Continuous 

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variables will be summarised with descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum). Categorical variables will be summarised with counts and percentage. 
Relevant medical history from the SB3-G31-BC trial will be summarised by treatment group for 
the Long-term Follow-up Set and Survival Follow-up Set. 
7.2.2. Analysis for Primary and Secondary Objective 
The incidence of symptomatic CHF and asymptomatic significant LVEF decrease will be 
summarized by treatment group for the Long-term Follow-up Set. The incidence of cardiac death 
and other significant cardiac conditions will be analysed similarly. 
For time to event data, survival analysis for EFS, DFS, and OS will be performed for the Long-
term Follow-up Set and Survival Follow-up Set respectively. Kaplan-Meier curves will be 
calculated and displayed by treatment group in the SB3-G31-BC trial. Additionally, the stratified 
Cox proportional hazard regression model will be applied to estimate hazard ratio 
(SB3/Herceptin®). The stratification factors are hormone receptor status and breast cancer type, and 
region. The hazard ratio will be presented along with its p-value and corresponding 95% 
confidence interval (CI). 
Exploratory analyses will be conducted to detect any patterns or systemic data issues. 
7.3. Sample Size  
No formal sample size calculation was done as there is no hypothesis to be tested. A total of 875 
subjects received the study IP in the SB3-G31-BC trial. Incorporating 20% of refusal rate for 
consent to this observational study and 10% of lost to follow-up, approximately 612 subjects are 
expected to be enrolled to this study. 
8. DATA COLLECTION AND MANAGEMENT 
8.1. Data Confidentiality 
Information about study subjects will be kept confidential. Subject identification information will 
be labelled with a code number, and will not include the subject’s name or other information that 
could identify them. A list linking the code and the subject’s name will be kept in the site files as 
required by Good Clinical Practice (GCP) to protect the subject’s confidentiality. 
The coded information will be sent to the Sponsor (or designee) who will analyse it and report the 
study results both to regulatory and ethical authorities. The Sponsor may also place data on public 
websites or publish journal articles based upon these results. Subject names or other directly 
identifiable information will not appear on any reports, publications, or other disclosures of clinical 
study outcomes. Care will be taken to prevent subjects being identified through these publications. 
In addition, data may be shared with other companies or researchers to aid further research into 
breast cancer. Such data sharing practices will be covered by confidentiality agreements. No-one 
outside the Investigator site will have access to subject-identifiable information. 

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8.2. Monitoring 
The Sponsor has engaged the services of a contract research organisation (CRO) to perform all 
monitoring functions within this clinical study. The monitors will work in accordance with the 
CRO standard operating procedures (SOPs) and have the same rights and responsibilities as 
monitors from the Sponsor organisation. 
During the study, monitors will check that written informed consent has been obtained correctly 
from subjects and that data are recorded correctly and completely. Monitors will also conduct 
proper source data verification and verify protocol adherence. Further details on the monitoring 
processes and the level of source data verification to be performed will be described in the 
monitoring plan. The monitor will provide written reports to the Sponsor on each occasion they 
make contact with the Investigator regardless of whether it is by phone or in person. 
8.3. Data Handling and Record Keeping 
The Investigator must maintain essential study documents (protocol and protocol amendments, 
completed CRFs, signed ICFs, relevant correspondence, and all other supporting documentation) 
until at least 2 years after the last approval of a marketing application in an International 
Conference on Harmonisation (ICH) region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years after the formal discontinuation of 
clinical development of the IP or 15 years after completion of the study. These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the 
Investigator site, institution or private practice in which the study is being conducted. Subject 
identification codes (subject names and corresponding study numbers) will be retained for the 
same period of time. These documents may be transferred to another responsible party, deemed 
acceptable by the Sponsor, and who agrees to abide by the retention policies. Written notification 
of transfer must be submitted to the Sponsor. The Investigator must contact the Sponsor prior to 
disposing of any study records and obtain written permission to do so. 
8.4. Database Management 
Data generated within this clinical study will be handled according to the relevant SOPs of the data 
management of the Sponsor (or an appropriate company designated by the Sponsor to perform 
these activities). The study CRF is the primary data collection instrument for the study. Subject 
data will be captured in a CRF and reviewed by the monitor in order to check adherence to the 
protocol and to detect any data inconsistency or discrepancy as per study monitoring plan. 
The Investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the CRF. He/she must also check that the data reported in the CRF correspond to those 
in the medical records. 
Forms should be available during periodic visits by study monitors to enable review for 
completeness and acceptability. Any correction to the data entered into the CRF must be carried out 
by the Investigator or a designated member of staff. These changes may be made either on the 

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initiative of the site staff or in response to monitoring or data queries. Any changes to written and 
electronic data should be made in a system which can provide an audit trail. The audit trail records 
the old information, the new information, and identification of the person making the changes, date 
of correction made and reason for change. The Investigator must sign and date the CRF pages as 
indicated. 
Cardiac events will be coded using the Medical Dictionary for Regulatory Activities. The versions 
of coding dictionaries used will be stated in the clinical study report. 
8.5. Quality Control and Quality Assurance 
The Investigator and institution will allow the monitors from the Sponsor or its agents and 
appropriate regulatory authorities direct access to source documents to perform verification. The 
study site may be subject to review by the IRB/IEC, and/or to quality assurance audits performed 
by the Sponsor, and/or to inspection by appropriate regulatory authorities. 
9. ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
9.1. Institutional Review Board or Independent Ethics Committee 
The Investigator and the Sponsor will follow all local laws and regulations relating to contact with 
and approvals from the IRB/IEC. 
The Investigator must provide the Sponsor with documentation of IRB/IEC approval of the 
protocol and informed consent before the study may begin at the Investigator site. The Investigator 
will supply documentation to the Sponsor relating to the annual renewal of the protocol from the 
IRB/IEC and any approvals of revisions to the ICF or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC any new information that may adversely 
affect the safety of subjects or the conduct of the study. Similarly, the Investigator will submit 
written summaries of the study status to the IRB/IEC on a regular basis and in accordance with the 
timelines required locally. Upon completion of the study, the Investigator will provide the ethics 
committee with a report on the outcome of the study if required by local regulations. 
9.2. Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, the ICH guidelines, GCP, the 
Declaration of Helsinki (2013) and all applicable and current regulatory requirements. 
9.3. Informed Consent 
The ICF will be used to explain the risks and benefits of study participation to the subject in simple 
terms before the subject enters into the study. The ICF contains a statement that the consent is 
freely given, that the subject is aware of the risks and benefits of entering the study, and that the 

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subject is free to withdraw from the study at any time. Written consent will be given by the subject 
after the receipt of detailed information on the study. The Investigator is responsible for ensuring 
that informed consent is obtained from each subject and for obtaining the appropriate signatures. 
The Investigator will provide each subject with a copy of the signed and dated ICF and this will be 
documented in the subject’s source notes. When prospective data collection is not possible (e.g. 
when the subject is deceased or lost to follow-up), waiver of informed consent/authorization will 
be requested for the retrospective collection where applicable and approved by IRB/IEC and in 
accordance with national regulations. If ICF waiver for the deceased subject is not allowed, their 
next-of-kin (if applicable) will be informed accordingly, and will be asked to give their consent on 
data-handling procedures where applicable and approved by IRB/IEC and in accordance with 
national regulations.  
If it is not possible for the subject or next of kin (if applicable) to physically come to site for an in-
person informed consent discussion, informed consent process will be performed remotely where 
applicable and approved by IRB/IEC and in accordance with national regulations. In such cases, 
the Investigator will discuss the study information and consent by a means other than face to face 
communication. If the subject or next of kin (if applicable) are interested to participate in study, the 
investigator or designee will send two copy of ICFs for subject. The subject or next of kin (if 
applicable) can request additional phone call with investigator in case of question and discuss. The 
subject or next of kin (if applicable) will send the two written consent to the site. Upon receipt of 
two signed ICFs, the investigator will sign the ICF and place 1 copy in the Investigator Study File 
and send 1 copy back to the subject or next of kin (if applicable). 
9.4. Financing and Insurance 
Samsung Bioepis is the Sponsor of this study and will be providing the finances to cover the 
operation of the study. Details of financial agreements are provided in the Clinical Study 
Agreements with the Investigator sites and in contracts with other companies involved in the 
running of the study. 
The Sponsor has obtained suitable insurance for this study. A copy of the insurance details will be 
provided to each Investigator who will be responsible for providing the IRB/IEC with these details 
according to local requirements. 
10. PUBLICATION POLICY 
The Sponsor supports the efforts of health authorities to increase the transparency of medical 
research conducted in human subjects. The Sponsor will comply with the guidelines of regulatory 
authorities with regards to public registration and disclosure of clinical study data. 
The clinical study data collected during the study are confidential and proprietary to the Sponsor. 
The Sponsor shall have the right to delete any confidential or proprietary information contained in 
any proposed abstract or presentation. 

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Any publications from this study should be approved by the Sponsor prior to publication or 
presentation. The rights of the Investigator with regard to publication of this study are described in 
the Clinical Study Agreement. 
 
 

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11. REFERENCES 
 
Buzdar A U, Ibrahim N K, Francis D, et al. Significantly higher pathologic complete remission rate 
after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a 
randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J 
Clin Oncol. 2005; 23 (16): 3676-3685. 
Buzdar A U, Valero V, Ibrahim N K, et al. Neoadjuvant therapy with paclitaxel followed by 5-
fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in 
human epidermal growth factor receptor 2-positive operable breast cancer: An update of the initial 
randomized study population and data of additional patients treated with the same regimen. Clin 
Cancer Res. 2007; 13 (1): 228-233. 
Cooke T, Reeves J, Lanigan A, et al. Her2 as a prognostic and predictive marker for breast cancer. 
Ann Oncol. 2001; 12 Suppl 1: S23-28. 
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab followed 
by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with her2-positive 
locally advanced breast cancer (the noah trial): A randomised controlled superiority trial with a 
parallel her2-negative cohort. Lancet. 2010; 375 (9712): 377-384. 
Guideline on similar biological medicinal products containing biotechnology-derived proteinsas 
active substance: Quality issues (revision 1). EMA. (Dec 2014). EMEA/CHMP/BWP/247713/2012. 
Retrieved Jan 25, 2018  
from http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/WC5
00167838.pdf 
Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of 
(neo)adjuvant trastuzumab in patients with her2-positive, clinical stage i-iii breast cancer (hannah 
study): A phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012; 13 (9): 869-878. 
Marty M, Cognetti F, Maraninchi D, et al. Randomized phase ii trial of the efficacy and safety of 
trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-
positive metastatic breast cancer administered as first-line treatment: The m77001 study group. J 
Clin Oncol. 2005; 23 (19): 4265-4274. 
Piccart-Gebhart M J, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy 
in her2-positive breast cancer. N Engl J Med. 2005; 353 (16): 1659-1672. 
Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac 
adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol. 2010; 28(21):3422-8. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63 (1): 11-30. 
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in her2-positive breast cancer. N 
Engl J Med. 2011; 365 (14): 1273-1283. 
Slamon D J, Clark G M, Wong S G, et al. Human breast cancer: Correlation of relapse and survival 
with amplification of the her-2/neu oncogene. Science. 1987; 235 (4785): 177-182. 

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Slamon D J, Godolphin W, Jones L A, et al. Studies of the her-2/neu proto-oncogene in human 
breast and ovarian cancer. Science. 1989; 244 (4905): 707-712. 
Slamon D J, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody 
against her2 for metastatic breast cancer that overexpresses her2. N Engl J Med. 2001; 344 (11): 
783-792. 
Untch M, Fasching P A, Konecny G E, et al. Pathologic complete response after neoadjuvant 
chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor 
receptor 2-overexpressing breast cancer: Results from the techno trial of the ago and gbg study 
groups. J Clin Oncol. 2011; 29 (25): 3351-3357. 
Untch M, Muscholl M, Tjulandin S, et al. First-line trastuzumab plus epirubicin and 
cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive 
metastatic breast cancer: Cardiac safety and efficacy data from the herceptin, cyclophosphamide, 
and epirubicin (hercules) trial. J Clin Oncol. 2010; 28 (9): 1473-1480. 
Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with trastuzumab in her2-positive breast 
cancer: Results from the geparquattro study. J Clin Oncol. 2010; 28 (12): 2024-2031. 
 
 
 

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APPENDICES 
Appendix 1: Criteria for New York Heart Association Functional Classification 
Class 
Patient Symptoms 
Class I 
No limitation of physical activity. 
No symptoms (fatigue, palpitation, or dyspnoea) with ordinary physical activity 
Class II 
Slight limitation of physical activity 
Comfortable at rest, but symptomatic (fatigue, palpitation, or dyspnoea) at 
ordinary physical activity 
Class III 
Marked limitation of physical activity 
Comfortable at rest, but symptomatic (fatigue, palpitation, or dyspnoea) at less 
than ordinary activity 
Class IV 
Unable to perform any physical activity 
Symptomatic (fatigue, palpitation, or dyspnoea) at rest, and discomfort with any 
ordinary physical activity 
If any physical activity is undertaken, discomfort is increased. 
 
Reference: 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 
1994:253-256. 
 
 

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Appendix 2: Framingham Criteria for Congestive Heart Failure 
A definite diagnosis of CHF requires that a minimum of two major or one major and two minor 
criteria be present concurrently. The presence of other conditions capable of producing the 
symptoms and signs (such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or 
nephrotic syndrome) are considered in evaluating the findings. 
This criteria is provided as a checklist. However, participating clinicians make decision on 
diagnosis of symptomatic CHF. 
Major Criteria: 
 
Paroxysmal nocturnal dyspnea or orthopnea 
 
Distended neck veins (in other than the supine position) 
 
Rales 
 
Increasing heart size by X-ray 
 
Acute pulmonary edema 
 
Ventricular S (3) gallop 
 
Increased central venous pressure (> 16 cm water at right atrium) 
 
Hepatojugular reflux 
 
Weight loss > 4.5 kg in 5 days in response to CHF treatment 
 
Minor criteria: 
 
Bilateral ankle edema 
 
Night cough 
 
Dyspnea on ordinary exertion 
 
Hepatomegaly 
 
Pleural effusion 
 
Decrease in vital capacity by one-third from maximum record 
 
Tachycardia (120 beats per minute or more) 
 
Reference: 
Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. 
J Am Coll Cardiol. 1993; Oct. 22(4 Suppl A):6A-13A. 
 

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CHANGE HISTORY OF PROTOCOL AMENDMENT 
Amendment 1: Version 2.0, Nov 26, 2018 
Section Affected 
Original Content 
Amended/New Content 
Rationale 
SYNOPSIS – 
Objectives and 2.2. 
Secondary Objectives 
• To observe the long term efficacy of SB3 compared to 
Herceptin® by 
- event-free survival 
• To observe the long term efficacy of SB3 compared to 
Herceptin® by 
- Event-free survival (EFS) and disease-free survival 
(DFS) 
To add DFS in 
secondary endpoint 
SYNOPSIS – Study 
Design and 3.1. 
Overview of Study 
Design 
N/A 
[Cardiac Safety and Survival Cohort]: The group 
consists of subjects who completed the SB3-G31-BC 
trial and provide informed consent for the long-term 
follow-up of cardiac safety and survival. 
To add cohort 
definition in 
accordance with 
updated study design 
SYNOPSIS – Study 
Design and 3.1. 
Overview of Study 
Design 
Consenting subjects will be enrolled sequentially into 
the study and will be monitored according to the local 
clinical practices which are based on the Herceptin® 
SmPC or local label. 
Consenting subjects will be enrolled sequentially into 
the study in accordance with protocol version 1.0 
and will be monitored according to the local clinical 
practices which are based on the Herceptin® SmPC or 
local label. 
To add description for 
clarification of each 
cohort 
SYNOPSIS – Study 
Design and 3.1. 
Overview of Study 
Design 
N/A 
[Survival Only Cohort]: The group consists of subjects 
who participate in this trial among subjects who 
received the SB3 or Herceptin® in the SB3-G31-BC 
trial, were not sequentially enrolled into this SB3-G31-
BC-E trial as a Cardiac Safety and Survival Cohort. 
Subjects who received SB3 or Herceptin® in 
accordance with the clinical trial SB3-G31-BC and 
were not sequentially enrolled to SB3-G31-BC-E trial 
To add cohort 
definition and detailed 
explanation in 
accordance with 
updated study design 

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Section Affected 
Original Content 
Amended/New Content 
Rationale 
as a Cardiac Safety and Survival Cohort will be asked 
to consent to participate in this study as a Survival 
Only Cohort. If prospective data collection is not 
possible (e.g. when the subject is deceased or lost to 
follow-up), a waiver of informed consent/authorization 
will be requested for the retrospective data collection 
from medical records, where applicable and in 
accordance with national regulations and local ethics. 
If ICF waiver for the deceased subject is not allowed, 
their next-of-kin (if applicable) will be informed 
accordingly, and will be asked to give their consent 
where applicable and approved by institutional review 
board (IRB)/independent ethics committee (IEC) and 
in accordance with national regulations. 
Data will be collected from medical records for up to 5 
years from their last investigational product (IP; SB3 
or Herceptin®) administration or death, unless they are 
lost for the follow-up or withdraw the informed 
consent. Data for the study will be collected 
prospectively from the date of the study informed 
consent signed and data before informed consent will 
be obtained from medical records retrospectively. If 
prospective data collection is not possible, data could be 
collected retrospectively from medical records. 
SYNOPSIS – Number 
It is planned that approximately 579 subjects will be 
enrolled. 
It is planned that approximately 579 612 subjects will be 
enrolled. 
To reflect updated 
study design 

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of Subjects 
SYNOPSIS – 
Eligibility Criteria and 
4.2. Eligibility Criteria 
N/A 
[Survival Only Cohort] 
Inclusion criteria 
Subjects must meet all of the following criteria to be 
eligible for the study: 
1. Subjects who received SB3 or Herceptin® according 
to the clinical trial SB3-G31-BC. 
2. Subjects (or legal representative, if applicable) who 
provide informed consent. If subjects were lost to 
follow-up or died after the end of SB3-G31-BC trial 
and prospective data collection is not possible, a waiver 
of informed consent/authorization will be requested for 
the retrospective data collection from medical records, 
where applicable and in accordance with national 
regulations and local ethics. If ICF waiver for the 
deceased subject is not allowed, their next-of-kin (if 
applicable) will be informed accordingly, and will be 
asked to give their consent where applicable and 
approved by IRB/IEC and in accordance with national 
regulations. 
Exclusion criteria 
There is no exclusion criteria for the Survival Only 
Cohort. 
To add eligibility 
criteria for Survival 
Only Cohort in 
accordance with 
updated study design 
SYNOPSIS – Planned 
Study Period 
Enrolment is expected to last approximately 10 months. 
The study will close at 5 years after the last patient has 
Enrolment is expected to last approximately 10 months. 
The study will close at 5 years after the 
To reflect updated 
study design 

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been enrolled (Figure 1). 
last patient subject has been enrolled (Figure 
1).received the last IP (SB3 or Herceptin®) in the 
setting of clinical trial SB3-G31-BC. 
SYNOPSIS – Criteria 
for Evaluation 
N/A 
• DFS, defined as the time from the date of surgery for 
the SB3-G31-BC trial to the date where an event 
occurs. An event is breast cancer recurrence (local, 
regional, distant, or contralateral) or death due to any 
cause. 
To add definition of 
DFS 
SYNOPSIS – Statistical 
Methods and 7.2.2. 
Analysis for Primary 
and Secondary 
Objective  
The incidence of CHF, asymptomatic LVEF decrease, 
cardiac death, and other significant cardiac conditions and 
all other variables will be summarised descriptively by 
SB3-G31-BC treatment group and also listed. 
For time to event data, Kaplan-Meier curves will be 
calculated and displayed by SB3-G31-BC treatment group. 
Median survival times and the corresponding 95% CI will 
be also provided. 
The subject demographics and baseline characteristics 
from SB3-G31-BC trial will be summarised by 
treatment group for the Long-term Follow-up Set and 
Survival Follow-up Set. 
The incidence of CHF, asymptomatic LVEF decrease, 
cardiac death, and other significant cardiac conditions and 
all other variables safety data will be summarised 
descriptively by SB3-G31-BC treatment group in the SB3-
G31-BC trial and also listed for the Long-term Follow-
up Set. 
For time to event data, survival analysis for EFS, DFS, 
and OS will be performed for the Long-term Follow-up 
Set and Survival Follow-up Set, respectively. Kaplan-
Meier curves will be calculated and displayed by treatment 
group in the SB3-G31-BC trial. Additionally, the 
stratified Cox proportional hazard regression model 
will be applied to estimate Hazard ratio 
To reflect updated 
study design 

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(SB3/Herceptin®). The stratification factors are 
hormone receptor status and breast cancer type, and 
region. The hazard ratio will be presented along with 
its p-value and corresponding 95% confidence interval 
(CI). Kaplan-Meier curves will be calculated and 
displayed by SB3-G31-BC treatment group. Median 
survival times and the corresponding 95% CI will be 
also provided. 
Exploratory analyses will be conducted to detect any 
patterns or systemic data issues. 
Figure 1 
 
 
To reflect updated 
study design 
Figure 1 
6. After the last SB3 or Herceptin® administration, subjects 
will have safety follow-up visits every 6 months for 24 
months, then yearly for additional 3 years. 
6. After the last SB3 or Herceptin® administration in the 
SB3-G31-BC trial, subjects will have safety follow-up 
visits every 6 months for 24 months, then yearly for 
additional 3 years. For Cardiac Safety and Survival 
Cohort, subjects will be enrolled sequentially into the 
study in accordance with SB3-G31-BC-E trial protocol 
version 1.0 and all data for the study will be collected 
prospectively. For the Survival Only Cohort, data for 
the study will be collected prospectively from the date 
of the study informed consent signed and data before 
To reflect updated 
study design 

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informed consent will be obtained from medical 
records retrospectively in accordance with 
recommended schedule of activities. If prospective data 
collection is not possible, data could be collected 
retrospectively from medical records. 
Table 1 
Table 1. Recommended Schedule of Activities 
Table 1. Recommended Schedule of Activities for the 
Cardiac Safety and Survival Cohort 
To reflect updated 
study design 
Table 1 
6. For the investigation of cardiac events, breast cancer 
recurrence/progression, and survival, at least scheduled 
visits and activities are recommended. And also there will 
be additional unscheduled visits IF there is suspicion of 
such events. 
6. For the investigation of cardiac events, breast cancer 
recurrence/progression, and survival, at least scheduled 
visits and activities are recommended. And also there will 
be additional unscheduled visits IF there is suspicion of 
such events. 
To reflect updated 
study design 
Table 2 
N/A 
Added 
To reflect updated 
study design 
LIST OF STUDY 
STAFF 
Previous study staffs 
Current study staffs at the time of protocol amendment 
To update study staffs 
1.2.2. Overview of 
SB3-G31-BC Trial 
A total of 806 subjects (403 per treatment arm) were 
randomised in the study. Each subject will be on clinical 
study for approximately 12 months, corresponding to 8 
cycles of neoadjuvant therapy before surgery followed by 
10 cycles of adjuvant therapy after surgery. Post therapy, 
subjects will be followed at 30 days after last dose of IP. 
As clinical study has not been completed up to date, 
clinical data is currently not available. 
A total of 806 subjects (403 per treatment arm) were 
randomised in the study. Each subject will be on 
clinical study for approximately 12 months, 
corresponding to 8 cycles of neoadjuvant therapy 
before surgery followed by 10 cycles of adjuvant 
therapy after surgery. Post therapy, subjects will be 
followed at 30 days after last dose of IP. As clinical 
study has not been completed up to date, clinical data is 
currently not available. 
A total of 875 subjects were randomised; 437 subjects 
To update information 
in accordance with 
SB3-G31-BC trial 

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to the SB3 treatment group and 438 subjects to the 
Herceptin® treatment group. Among them, 380 subjects 
in the SB3 treatment group and 384 subjects in the 
Herceptin® treatment group completed the trial. 
Table 3 
 
 
To update data in 
accordance with the 
reference 
Table 4 
 
 
To update data in 
accordance with the 
reference 
1.4. Rationale for the 
Study 
N/A 
This study will evaluate long-term efficacy outcomes to 
all subjects enrolled in this extension study between 
treatment groups (SB3 and Herceptin®). EFS, disease-
free survival (DFS), and OS will be presented based on 
the events including breast cancer 
recurrence/progression and death. 
To reflect updated 
study design 
3.1.1. End of Trial 
N/A 
The study will close at 5 years after the last subject has 
received the last IP (SB3 or Herceptin®) in the setting 
of clinical trial SB3-G31-BC. 
To add definition of 
end of trial 
3.2. Number of 
Subjects and 7.3. 
Sample Size 
More than 716 out of 806 subjects are expected to 
complete study treatment in SB3-G31-BC trial. 
Incorporating 20% of refusal rate for consent to this 
More than 716 out of 806 subjects are expected to 
complete study treatment in SB3-G31-BC trial. A total 
of 875 subjects received the study IP in the SB3-G31-
To reflect updated 
study design 

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observation study, approximately 573 subjects over 10 
months are expected to be enrolled to this study. 
BC trial. Incorporating 20% of refusal rate for consent to 
this observational study and 10% of lost to follow-up, 
approximately 573 612 subjects over 10 months are 
expected to be enrolled to this study. 
4.1. Overview 
N/A 
[Survival Only Cohort] 
The study population for the Survival Only Cohort is 
women who received SB3 or Herceptin® in accordance 
with the clinical trial SB3-G31-BC and were not 
sequentially enrolled into this SB3-G31-BC-E trial as a 
Cardiac Safety and Survival Cohort. 
To reflect updated 
study design 
5.2.1. Follow-up 
Information 
For the investigation of cardiac events, breast cancer 
recurrence/progression, and survival, at least scheduled 
visits and activities are recommended. And also there will 
be additional unscheduled visits IF there is suspicion of 
such events. 
For the investigation of cardiac events, breast cancer 
recurrence/progression, and survival, at least scheduled 
visits and activities are recommended. And also there will 
be additional unscheduled visits IF there is suspicion of 
such events. 
To reflect updated 
study design 
5.2.3. 
Recurrence/Progression 
and Survival 
Assessments 
In this study, EFS is defined as the time from the date of 
randomisation for SB3-G31-BC to the date where an event 
occurs. 
In this study, EFS is defined as the time from the date of 
randomisation for the SB3-G31-BC trial to the date where 
an event occurs and DFS is defined as the time from the 
date of surgery for the SB3-G31-BC trial to the date 
where an event occurs 
To add definition of 
DFS 
5.3. Recommended 
Schedule of Activities 
for the Survival Only 
Cohort (Table 2) 
N/A 
Section 5.3 including 5.3.1 and 5.3.2 was added. 
To reflect updated 
study design 
5.4. Collection of Data 
for the Survival Only 
N/A 
Section 5.4 including 5.4.1 and 5.4.2 was added. 
To reflect updated 
study design 

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Cohort 
5.7. Subject Withdrawal 
• Newly diagnosed malignant neoplasm other than breast 
cancer to be treated. 
• Newly diagnosed malignant neoplasm other than breast 
cancer to be treated during prospective data collection. 
To reflect updated 
study design 
6. SAFETY 
MONITORING AND 
REPORTING 
N/A 
Subjects registered in this study can be waived from 
the reporting requirement of IP-related serious AEs 
(SAEs) after EOS described in Section 7 of the protocol 
for the SB3-G31-BC trial. 
To clarify safety 
reporting 
7.1. Analysis Sets 
Long-term Follow-up set: this set consists of all subjects 
who provide informed consent for this study. Subjects will 
be analysed according to the treatment received in SB3-
G31-BC. 
• Long-term Follow-up Set: This set consists of all 
subjects who provide informed consent for the long-term 
follow-up of cardiac safety and survival. This set 
includes Cardiac Safety and Survival Cohort defined in 
Section 3.1  
• Survival Follow-up Set: This set consists of all 
subjects who enrolled for this study. This set includes 
Cardiac Safety and Survival Cohort and Survival Only 
Cohort defined in Section 3.1. 
Subjects will be analysed according to the treatment 
(SB3 or Herceptin®) received in the SB3-G31-BC trial. 
To reflect updated 
study design 
7.2.1. Demographics 
and Baseline 
Characteristics 
Subject demographics and baseline characteristics from 
SB3-G31-BC will be summarised by treatment group. 
… 
Relevant medical history from SB3-G31-BC will be 
summarised by treatment group. 
Subject demographics and baseline characteristics from the 
SB3-G31-BC trial will be summarised by treatment group 
for the Long-term Follow-up Set and Survival Follow-up 
Set. 
… 
Relevant medical history from the SB3-G31-BC trial will 
To reflect updated 
study design 

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be summarised by treatment group for the Long-term 
Follow-up Set and Survival Follow-up Set. 
7.2.2. Analysis for 
Primary and Secondary 
Objective 
The incidence of symptomatic CHF and asymptomatic 
significant LVEF decrease will be summarized by 
treatment group. 
The incidence of symptomatic CHF and asymptomatic 
significant LVEF decrease will be summarized by 
treatment group for the Long-term Follow-up Set. 
To reflect updated 
study design 
9.3. Informed Consent 
Written consent must be given by the subject and/or legal 
representative, after the receipt of detailed information on 
the study. 
Written consent must will be given by the subject and/or 
legal representative, after the receipt of detailed 
information on the study. The Investigator is responsible 
for ensuring that informed consent is obtained from 
each subject and for obtaining the appropriate 
signatures. The Investigator will provide each subject 
with a copy of the signed and dated ICF and this will be 
documented in the subject’s source notes. When 
prospective data collection is not possible (e.g. when the 
subject is deceased or lost to follow-up), waiver of 
informed consent/authorization will be requested for 
the retrospective collection where applicable and 
approved by IRB/IEC and in accordance with national 
regulations. If ICF waiver for the deceased subject is 
not allowed, their next-of-kin (if applicable) will be 
informed accordingly, and will be asked to give their 
consent on data-handling procedures where applicable 
and approved by IRB/IEC and in accordance with 
national regulations.  
If it is not possible for the subject or next of kin (if 
applicable) to physically come to site for an in-person 
To reflect updated 
study design 

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informed consent discussion, informed consent process 
will be performed remotely where applicable and 
approved by IRB/IEC and in accordance with national 
regulations. In such cases, the Investigator will discuss 
the study information and consent by a means other 
than face to face communication. If the subject or next 
of kin (if applicable) are interested to participate in 
study, the investigator or designee will send two copy of 
ICFs for subject. The subject or next of kin (if 
applicable) can request additional phone call with 
investigator in case of question and discuss. The subject 
or next of kin (if applicable) will send the two written 
consent to the site. Upon receipt of two signed ICFs, the 
investigator will sign the ICF and place 1 copy in the 
Investigator Study File and send 1 copy back to the 
subject or next of kin (if applicable). 
All sections 
The latest Manual of Style (version 3.0) of Samsung 
Bioepis was not fully applied. 
Updated in accordance with Manual of Style version 3.0 
by Samsung Bioepis 
Administrative update 
irrelevant to study 
design and/or 
procedures 
 

PPD
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Samsung Bioepis – Confidential and Proprietary Information 
 
SIGNATURE PAGE 
Declaration of the Principal/Coordinating Investigator 
Protocol Title: A Long-term Follow-up Study for Cardiac Safety in the Patients with HER2 
Positive Early or Locally Advanced Breast Cancer Who Have Completed the SB3-G31-BC 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal 
product, as well as with the moral, ethical and scientific principles governing clinical research as 
set out in the Declaration of Helsinki, 2013 and the guidelines on Good Clinical Practice applicable 
to this clinical study. 
Principal/Coordinating Investigator 
Name: 
 
Institution: 
 
Signature: 
 
Date: 
 
 
 
 
(Month, Day, Year) 
 

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Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26 
Effective Date: 2017-04-10                  Confidential                             Page 1 of 23 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Protocol No.: SB3-G31-BC-E 
 
 
 
 
 
A Long-term Follow-up Study for Cardiac Safety in the Patients 
with HER2 Positive Early or Locally Advanced Breast Cancer 
Who Have Completed the SB3-G31-BC 
 
 
  
 
 
 
 
 
 
 
Sponsor: Samsung Bioepis Co., Ltd. 
Author: 
 
Protocol Version: SB3-G31-BC-E_Version 2.0/Amendment 1, Nov 26, 2018 
SAP Version: SAP_SB3-G31-BC-E_Addendum 2_2021-01-26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Final
Form DA-05-03 Statistical Analysis Plan 
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Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26 
Effective Date: 2017-04-10                  Confidential                             Page 3 of 23 
 
History of Revision 
 
 
Protocol No. 
SB3-G31-BC-E 
Sponsor 
Samsung Bioepis Co., Ltd. 
CRO 
LSK Global PS 
Approval 
Date 
Amended Version 
Reason 
2018-01-16 
Addendum 1 
1. Wording 
change 
for 
“Significant 
LVEF 
decrease”  
2. ‘Asymptomatic significant LVEF decrease’ is 
redefined. 
3. Description of summary of significant LVEF 
decrease is included in section 10.1. 
4. Explanation on interim analysis is modified 
since the frequency of analyses can be 
adjusted by the sponsor’s decision. 
 
 
5. Table 14.3-2.2 is combined with Table 14.3-2.1. 
2021-01-26 
Addendum 2 
1. To reflect the amendment of protocol (version 
2.0) 
- 
Updating study design 
- 
Adding survival follow-up set 
- 
DFS is defined as secondary endpoint 
2. Adding 
contents 
about 
premature 
discontinuation of the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26 
Effective Date: 2017-04-10                  Confidential                             Page 4 of 23 
List of Contents 
 
 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 6 
2. 
STUDY OBJECTIVES ........................................................................................................... 7 
2.1 
Primary Objective ........................................................................................................ 7 
2.2 
Secondary Objective ................................................................................................... 7 
3. 
INVESTIGATIONAL PLAN ................................................................................................... 7 
3.1 
Overall Study Design and Plan ................................................................................... 7 
3.2 
Study Duration ........................................................................................................... 10 
3.3 
Dosage, Administration and Schedule ...................................................................... 10 
3.4 
Randomisation and Unblinding ................................................................................. 10 
3.5 
Schedule of Study ..................................................................................................... 10 
3.6 
Determination of the Sample Size .............................................................................. 11 
4. 
ANALYSIS SETS.................................................................................................................. 11 
4.1 
Long-term Follow-up set ........................................................................................... 12 
4.2 
Survival Follow-up set ............................................................................................... 12 
5. 
DOCUMENTATION OF VARIABLES .................................................................................. 12 
5.1 
Analysis Variables ..................................................................................................... 12 
5.1.1 
Primary Objective Endpoint .......................................................................... 12 
5.1.2 
Secondary Objective Endpoints ................................................................... 13 
6. 
SUBJECT DISPOSITION .................................................................................................... 16 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .................................................. 16 
8. 
MEDICAL HISTORY ............................................................................................................ 17 
9. 
EFFICACY EVALUATION ................................................................................................... 17 
9.1 
Event-Free Survival, Disease-Free Survival and Overall Survival ............................ 17 
10. SAFETY EVALUATION ....................................................................................................... 18 
10.1 Symptomatic CHF and Asymptomatic significant LVEF decrease ............................ 18 
10.2 Cardiac Death and Other Cardiac Event................................................................... 19 
10.3 Other Safety Measures ............................................................................................. 19 
10.3.1 Left Ventricular Ejection Fraction.................................................................. 19 
10.3.2 Others ........................................................................................................... 19 
11. ADDITIONAL EVALUATION ............................................................................................... 20 
11.1 Subgroup Analysis ..................................................................................................... 20 
12. GENERAL PRESENTATION OF SUMMARIES AND ANALYSES .................................... 20 
12.1 Significance Level ..................................................................................................... 20 
12.2 Summary Statistics .................................................................................................... 20 
12.3 Decimals .................................................................................................................... 20 
12.4 Statistical Analysis Methods ...................................................................................... 20 
12.5 Relative Study Day .................................................................................................... 20 
12.6 Baseline ..................................................................................................................... 20 
12.7 Study Period and Visit Window Definitions ............................................................... 21 
12.8 Software for Statistical Analysis ................................................................................ 21 
13. DATA HANDLING COVENTIONS....................................................................................... 21 
13.1 Handling of Missing Data .......................................................................................... 21 
13.2 Repeated or Unscheduled Assessments .................................................................. 21 
13.3 Handling of Incomplete Date ..................................................................................... 21 
13.4 Character Values of Clinical Laboratory Evaluation .................................................. 22 
14. INTERIM ANALYSIS ........................................................................................................... 22 
15. CHANGE FROM PROTOCOL ............................................................................................ 22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26 
Effective Date: 2017-04-10                  Confidential                             Page 5 of 23 
16. SAS PROCEDURE FOR TESTING .................................................................................... 23 
16.1 Test of Survival Time ................................................................................................. 23 
17. REFERENCES .................................................................................................................... 23 
Appendix. Mock-up TFL ............................................................................................................ 23 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26 
Effective Date: 2017-04-10                  Confidential                             Page 6 of 23 
1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
BMI  
Body Mass Index   
BSA 
Body Surface Area 
CHF 
Congestive heart failure 
CI 
Confidence interval 
DFS 
Disease-free survival 
EBC 
Early breast cancer 
ECHO 
Echocardiography 
EFS 
Event-free survival 
EOS 
End of study 
HER2 
Human epidermal growth factor receptor 2 
ICF 
Informed consent form 
IP 
Investigational product 
LABC 
Locally advanced breast cancer 
LVEF 
Left ventricular ejection fraction 
MedDRA  
Medical Dictionary for Regulatory Activities   
MUGA 
Multiple gated acquisition 
NYHA 
New York Heart Association 
PT 
Preferred Term 
OS 
Overall survival 
pCR 
Pathologic complete response 
SAS  
Statistical Analysis System   
SOC  
System Organ Class  
SmPC 
Summary of product characteristics 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26 
Effective Date: 2017-04-10                  Confidential                             Page 7 of 23 
2. STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to observe the incidence of symptomatic congestive heart failure (CHF) 
New York Heart Association (NYHA) class II, III, and IV and asymptomatic significant Left 
Ventricular Ejection Fraction (LVEF) decrease in subjects who participated in the SB3-G31-BC 
trial and treated with SB3 (proposed trastuzumab biosimilar) or Herceptin® as neoadjuvant and 
adjuvant treatment. 
 
Symptomatic CHF is defined as NYHA II, III, and IV, confirmed by a cardiologist, 
accompanied by a significant LVEF decrease. 
 
Significant LVEF decrease is defined as an absolute decline of at least 10 % points 
from baseline LVEF (LVEF at screening of SB3-G31-BC trial) and resulting LVEF less 
than 50% 
 
2.2 
Secondary Objective 
The secondary objectives are: 
 
To observe the incidence of cardiac death and other significant cardiac conditions 
 
To observe the long term efficacy of SB3 compared to Herceptin® by   
- 
Event-free survival and disease-free survival 
- 
Overall survival 
 
3. INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is an observational cohort study.  
[Cardiac Safety and Survival Cohort]: The group consists of subjects who completed the 
SB3-G31-BC trial and provide informed consent for the long-term follow-up of cardiac safety 
and survival.  
Subjects who have completed the clinical trial SB3-G31-BC will be asked to consent to 
participate in this study. Consenting subjects will be enrolled sequentially into the study in 
accordance with SB3-G31-BC-E trial protocol version 1.0 and will be monitored according to the 
local clinical practices which are based on the Herceptin® SmPC or local label. No additional 
procedures/subject visits in comparison with the usual clinical practice are planned for the study. 
Baseline data (such as demographics, breast cancer type, TNM stage, medical history, surgical 
history, pre-treatment LVEF, neoadjuvant and adjuvant treatment, postoperative radiation 
therapy) will be transferred from the SB3-G31-BC study. Follow-up data will be collected from 
medical records for up to 5 years or death, unless subjects are lost for the follow-up or have 
withdrew the informed consent. 
[Survival Only Cohort]: The group consists of subjects who participate in this trial among 
subjects who received the SB3 or Herceptin® in the SB3-G31-BC trial and were not sequentially 
enrolled into this SB3-G31-BC-E trial as a Cardiac Safety and Survival Cohort. All subjects in 
Bosnia & Herzegovina and APAC countries including India are solely applicable for the Survival 
Only Cohort. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Form DA-05-03 Statistical Analysis Plan 
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Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26 
Effective Date: 2017-04-10                  Confidential                             Page 8 of 23 
Subjects who received SB3 or Herceptin® in accordance with the clinical trial SB3-G31-BC and 
were not sequentially enrolled to SB3-G31-BC-E trial as a Cardiac Safety and Survival Cohort 
will be asked to consent to participate in this study as a Survival Only Cohort. Cardiac and other 
safety assessment will be performed in subjects who provide informed consent for follow-up of 
cardiac safety and all data will be collected prospectively. If prospective data collection 
regarding breast cancer recurrence and survival status is not possible (e.g. when the subject is 
deceased or lost to follow-up), a waiver of informed consent/authorization will be requested for 
the retrospective data collection from medical records, where applicable and in accordance with 
national regulations and local ethics. If informed consent form (ICF) waiver for the deceased 
subject is not allowed, their next-of-kin (if applicable) will be informed accordingly, and will be 
asked to give their consent where applicable and approved by institutional review board 
(IRB)/independent ethics committees (IEC) and in accordance with national regulations. 
Data will be collected from medical records for up to 5 years from their last investigational 
product (IP; SB3 or Herceptin®) administration or death, unless they are lost for the follow-up or 
withdraw the informed consent. Data for the study will be collected prospectively from the date 
of the study informed consent signed and data before informed consent will be obtained from 
medical records retrospectively. If prospective data collection regarding breast cancer 
recurrence and survival status is not possible, data could be collected retrospectively from 
medical records. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Form DA-05-03 Statistical Analysis Plan 
Sponsor : Samsung Bioepis Co., Ltd. 
Protocol No.: SB3-G31-BC-E 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                                               Confidential                                                          Page 9 of 23 
 
 
Figure 1. Graphical Study Design 
D = day, EBC = Early breast cancer, EOS = end of study; FEC = 5-fluorouracil, epirubicin, cyclophosphamide; HER2 = human epidermal growth factor receptor 2; LABC = 
Locally advanced breast cancer, n = number of subjects; LABC = locally advanced breast cancer; pCR = pathological complete response, ® = randomisation 
1. Loading dose of 8 mg/kg and then a maintenance dose of 6 mg/kg every 3 weeks 
2. Docetaxel 75 mg/m2 
3. 5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 
4. Primary endpoint: pathologic complete response (pCR) in breast tumour 
5. EOS (End of Study) that means end of core study (SB3-G31-BC) is scheduled 30 days after the last dose of Investigational product (IP). 
6. After the last SB3 or Herceptin® administration, subjects will have safety follow-up visits every 6 months for 24 months, then yearly for additional 3 years. For Cardiac 
Safety and Survival Cohort, subjects will be enrolled sequentially into the study in accordance with SB3-G31-BC-E trial protocol version 1.0 and all data for the study will 
be collected prospectively. For the Survival Only Cohort, data for the study will be collected prospectively from the date of the study informed consent signed and data 
before informed consent will be obtained from medical records retrospectively in accordance with recommended schedule of activities. If prospective data collection is 
not possible, data could be collected retrospectively from medical records. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Form DA-05-03 Statistical Analysis Plan 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 10 of 23 
 
3.2 
Study Duration 
The study will close at 5 years after the last subject has received the last IP (SB3 or Herceptin®) 
in the setting of clinical trial SB3-G31-BC 
The whole study may be discontinued prematurely in case of the Sponsor’s decision that 
discontinuation of the study is justifiable for medical reasons. Health authorities and IRBs/IECs 
will be informed about the discontinuation of the study in accordance with applicable regulations. 
 
3.3 
Dosage, Administration and Schedule 
There is no investigational product or a treatment in this trial. Decision about any treatment will 
be made according to the local practice and at the discretion of investigator. 
  
3.4 
Randomisation and Unblinding 
All subjects in SB3-G31-BC-E were unblinded after data base lock for SB3-G31-BC trial. 
 
3.5 
Schedule of Study 
Recommended Schedule of Activities for the Cardiac and Survival Cohort 
Assessments 
Follow-up 
Visit 
ICF  
1 
2 
3 
4 
5 
6 
7 
Study Month  
- 
6 
12 
18 
24 
36 
48 
60 
Informed consent1 
 
 
 
 
 
 
 
 
Physical exam2 
 
 
 
 
 
 
 
 
Mammography  
 
 
 
 
 
 
 
 
LVEF (ECHO or MUGA 
scan) 3 
 
 
 
 
 
 
 
 
Cardiac events4, 6 
Continuously 
Breast cancer 
recurrence/progression6 
Continuously 
Survival5, 6 
Continuously 
  ECHO = echocardiogram; ICF = informed consent form; MUGA = multiple gated acquisition; LVEF = left 
ventricular ejection fraction 
1. The acceptable time lag from EOS of SB3-G31-BC to obtain the informed consent is one year. 
2. Physical exam includes clinical breast exam. 
3. LVEF will be measured by 2D echocardiography or MUGA scan. The same method should be used for 
each subject during SB3-G31-BC & this study.   
4. Cardiac events will be recorded in case of SB3 or Herceptin® related cardiac toxicities during follow-up. 
5. Survival can be followed up by telephone contacts. 
6. For the investigation of cardiac events, breast cancer recurrence/progression, and survival, at least 
scheduled visits and activities are recommended. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 11 of 23 
 
Recommended Schedule of Activities for the Survival Only Cohort 
Assessments 
Follow-up 
Visit2 
ICF 
1 
2 
3 
4 
5 
6 
7 
Study Month from Last 
IP Administration 
- 
6 
12 
18 
24 
36 
48 
60 
Informed consent1 
 
 
 
 
 
 
 
 
Physical exam*, 2, 3 
 
 
 
 
 
 
 
 
Mammography*, 2 
 
 
 
 
 
 
 
 
LVEF (ECHO or MUGA 
scan) *, 2, 4 
 
 
 
 
 
 
 
 
Cardiac events*, 2, 5, 6 
Continuously 
Breast cancer 
recurrence/progression6, 7 
Continuously 
Survival6, 7, 8 
Continuously 
ECHO = echocardiogram; ICF = informed consent form; IP = investigational product; MUGA = multiple 
gated acquisition; LVEF = left ventricular ejection fraction 
Note: All subjects in Bosnia & Herzegovina and APAC countries including India are solely applicable for the 
Survival Only Cohort. 
*: Physical exam, mammography, LVEF (ECHO or MUGA scan), and cardiac events are collected in India 
only. 
1. Subjects will provide informed consent. If prospective data collection is not possible (e.g. when the 
subject is deceased or lost to follow-up), a waiver of informed consent/authorization will be requested 
for the retrospective data collection from medical records, where applicable and in accordance with 
national regulations and local ethics. If ICF waiver for the deceased subject is not allowed, their next-
of-kin (if applicable) will be informed accordingly, and will be asked to give their consent where 
applicable and approved by institutional review board (IRB)/independent ethics committee (IEC) and in 
accordance with national regulations. 
2. Cardiac and other safety assessment will be performed in subjects who provide informed consent for 
follow-up of cardiac safety and all data will be collected prospectively. 
3. Physical exam includes clinical breast exam. 
4. LVEF will be measured by 2D ECHO or MUGA scan. The same method should be used for each 
subject during the SB3-G31-BC trial and this study. 
5. Cardiac events will be recorded in case of SB3 or Herceptin® related cardiac toxicities during follow-up. 
6. For the investigation of cardiac events, breast cancer recurrence/progression and survival, at least 
scheduled visits, and activities are recommended. 
7. Data will be collected prospectively from the date of the study informed consent signed and data before 
informed consent will be obtained from medical records retrospectively. If prospective data collection is 
not possible, data could be collected retrospectively from medical records. 
8. Survival can be followed up by telephone contacts. 
 
 
3.6 
Determination of the Sample Size 
No formal sample size calculation was done as there is no hypothesis to be tested. A total of 
875 subjects received the study IP in the SB3-G31-BC trial. Incorporating 20% of refusal rate for 
consent to this observation study and 10 % of lost to follow-up, approximately 612 subjects are 
expected to be enrolled to this study. 
 
4. ANALYSIS SETS 
The following sets will be used for the analyses performed in the study. Subjects will be 
analysed according to the treatment received in SB3-G31-BC trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 12 of 23 
 
4.1 
Long-term Follow-up set 
Long-term follow-up set: This set consists of all subjects who provide informed consent for the 
long-term follow-up of cardiac safety and survival. This set includes Cardiac Safety and Survival 
Cohort defined in the Section 3.1. 
4.2 
Survival Follow-up set 
Survival Follow-up Set: This set consists of all subjects who enrolled for this study. This set 
includes Cardiac Safety and Survival Cohort and Survival Only Cohort defined in Section 3.1. 
 
5. DOCUMENTATION OF VARIABLES 
5.1 
Analysis Variables  
5.1.1 
Primary Objective Endpoint 
The primary objective is to observe the incidence of symptomatic CHF and asymptomatic 
significant LVEF decrease in HER2 positive EBC or LABC subjects treated with SB3 or 
Herceptin® as neoadjuvant and adjuvant treatment. 
(1) Symptomatic CHF  
Symptomatic CHF is defined as the following criteria:  
 
An absolute decline of at least 10 % points from baseline LVEF and resulting 
LVEF less than 50% on the “LVEF (echo or MUGA scan)” page on the eCRF, and 
 
Selected as cardiac events of “Symptomatic CHF (NYHA class II, III, IV)” on the 
page of ‘Cardiac events’ in eCRF 
Incidence rate will be calculated using following formula. 
 
Incidence 
rate 
of 
symptomatic CHF 
= 
Number of subjects with symptomatic CHF 
× 100 
 
Number of subjects in the Long-term follow-
up set 
 
(2) Asymptomatic significant LVEF decrease 
Asymptomatic significant LVEF decrease is defined as the following criteria: 
 
An absolute decline of at least 10 % points from baseline LVEF and resulting 
LVEF less than 50% on the “LVEF (echo or MUGA scan)” page on the eCRF, and 
 
Not selected as cardiac events of “Symptomatic CHF (NYHA class II, III, IV)” on 
the ‘Cardiac events’ page on the eCRF. 
Incidence rate will be calculated using following formula. 
 
Incidence rate of 
asymptomatic significant 
LVEF decrease  
= 
Number of subjects with asymptomatic 
significant LVEF decrease 
× 100 
 
Number of subjects in the Long-term follow-
up set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 13 of 23 
 
 
5.1.2 
Secondary Objective Endpoints 
The secondary objectives are to observe the incidence of cardiac death and other significant 
cardiac conditions and to observe the long term efficacy of SB3 compared to Herceptin® by 
event-free survival, disease-free survival and overall survival. 
(1) Cardiac Death  
Cardiac death is defined as death definitely as a result of heart failure, myocardial 
infarction, or documented arrhythmia or as probable cardiac death within 24 hours of a 
cardiac event, which is “Cardiac death” of “Primary cause of death” item on the End of 
Follow-up page in eCRF. Incidence rate will be calculated using following formula. 
 
Incidence rate of cardiac 
death 
= 
Number of subjects with cardiac death 
× 100 
 
Number of subjects in the Long-term follow-
up set 
  
(2) Other Cardiac Event  
Other cardiac event is defined as acute myocardial infarction, severe arrhythmia, 
ischemic heart disease, valvular dysfunction and other significant cardiac conditions. 
on the “Cardiac events” page in eCRF.  
If cardiac events of significant LVEF decrease are recorded as “other significant 
cardiac conditions” to the “Cardiac events” of cardiac events page in eCRF, they will be 
excluded from the analysis.  
Incidence rate will be calculated using following formula. 
 
Incidence rate of other 
cardiac event 
= 
Number of subjects with other cardiac event 
× 100 
 
Number of subjects in the Long-term follow-
up set 
 
(3) Event-Free Survival (EFS) 
EFS is defined as the time from the date of randomisation for SB3-G31-BC trial to the 
date where an event occurs. An event is breast cancer recurrence or progression (local, 
regional, distant or contralateral) or death due to any cause. Breast cancer recurrence 
is identified as the record with “Yes” to the item “Was the breast cancer recurred?” on 
the “Breast Cancer recurrence” page or “Yes” to the item “Was the breast cancer 
recurrence/progression confirmed between the end of SB3-G31-BC trial and the 
informed consent for this SB3-G31-BC-E study?” on the “Retrospective data collection” 
in the eCRF. 
Subjects who did not have recurrence or progression or who were alive at the time of 
analysis will be censored at the date of the last follow-up assessment (breast cancer 
recurrence, physical examination, or mammography assessment). 
 
EFS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 14 of 23 
 
- 
Status = 0, if recurrence or progression or died due to any cause 
     
  = 1 (censored), if alive at the last follow-up assessment, and no recurrence 
or progression until the last follow-up assessment 
Duration (months) = [date of recurrence confirmed, progression, death or the last 
follow-up assessment (censored), whichever occurs first – the date of randomisation 
for SB3-G31-BC + 1] / [365.24/12] 
Refer to Table 5.1 for detailed censoring and event date options and outcomes for EFS. 
Table 5.1. Outcome and event/censored dates for EFS analysis 
Situation 
Date 
Outcome 
Progression occurred during SB3-G31-
BC trial 
Date of progression 
Event (Progression) 
Recurrence occurred during SB3-G31-
BC trial 
Date of recurrence 
Event (Recurrence) 
No breast cancer assessment after the 
end of SB3-G31-BC trial. 
Date 
of the last 
evaluable 
clinical 
response in SB3-
G31-BC trial 
Censored 
Subject had breast cancer assessment 
after the end of SB3-G31-BC trial and 
breast cancer not recurred. 
Date of the most 
recent 
breast 
cancer assessment 
with normal result 
Censored 
Recurrence or progression occurred 
between the end of SB3-G31-BC trial 
and the informed consent for SB3-G31-
BC-E trial. 
Date of recurrence/ 
progression 
confirmed 
Event 
(Recurrence/progression) 
Recurrence occurred during the SB3-
G31-BC-E trial and progression not 
occurred. 
Date of recurrence 
Event (Recurrence) 
Subject early terminated by death and 
progression or recurrence were not 
occurred. 
Date of death 
Event (Death) 
- Breast cancer assessment includes physical examination and mammography assessment with normal 
results 
- For subjects without post-baseline clinical response assessment, randomisation date will be used as the 
censoring date. 
 
(4) Disease-Free Survival (DFS) 
DFS is defined as the time from the date of surgery for the SB3-G31-BC trial to the 
date where an event occurs. An event is breast cancer recurrence or death due to any 
cause. Breast cancer recurrence is identified as the record with “Yes” to the item “Was 
the breast cancer recurred?” on the “Breast Cancer recurrence” page or “Yes” to the 
item “Was the breast cancer recurrence/progression confirmed between the end of 
SB3-G31-BC trial and the informed consent for this SB3-G31-BC-E study?” on the 
“Retrospective data collection” in the eCRF. 
Subjects who did not have recurrence or who were alive at the time of analysis will be 
censored at the date of the last follow-up assessment (breast cancer recurrence, 
physical examination, mammography assessment).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 15 of 23 
 
 
DFS  
- 
Status = 0, if recurrence or died due to any cause 
     
  = 1 (censored), if alive at the last follow-up assessment, and no recurrence 
until the last follow-up assessment 
Duration (months) = [date of recurrence confirmed, death or the last follow-up 
assessment (censored), whichever occurs first – the date of surgery for SB3-G31-BC + 
1] / [365.24/12] 
Refer to Table 5.2 for detailed censoring and event date options and outcomes for 
DFS. 
Table 5.2. Outcome and event/censored dates for DFS analysis 
Situation 
Date 
Outcome 
Recurrence occurred during SB3-G31-BC trial 
Date of recurrence 
Event 
(Recurrence) 
No breast cancer assessment after the end of 
SB3-G31-BC trial. 
Date of the last evaluable 
clinical response in SB3-
G31-BC trial 
Censored 
Subject had breast cancer assessment after 
the end of SB3-G31-BC trial and breast cancer 
not recurred. 
Date of the most recent 
breast 
cancer 
assessment with normal 
result 
Censored 
Breast cancer recurred after the end of SB3-
G31-BC trial and progression not occurred. 
Date of recurrence 
Event 
(Recurrence) 
Subject early terminated by death and 
progression or recurrence were not occurred. 
Date of death 
Event (Death) 
- Breast cancer assessment includes physical examination and mammography assessment with normal 
results 
- For subjects without post-baseline clinical response assessment, randomisation date will be used as the 
censoring date. 
(5) Overall Survival (OS) 
OS is defined as the time from the date of randomisation for SB3-G31-BC trial to the 
date of death which is identified as the record with a response of “Death” to the item 
"Main reason for early termination” on the End of Follow-up page of the eCRF, “Dead” 
to the time “Subject survival status” on the Survival page, or with a response of “Fatal” 
to the item “Outcome” on the Cardiac events page, regardless of the cause of death.  
Subjects who were alive at the time of analysis will be censored at the date of the last 
follow-up visit (including the date of study completion if a subject completes the study) 
or the last phone contact successfully completed. 
 
OS  
- 
Status = 0, if died from any cause 
     
  = 1 (censored), if alive until the last follow-up 
- 
Duration (months) = [date of death or the last follow-up visit (censored), whichever 
occurs first – the date of randomisation for SB3-G31-BC + 1] / [365.24/12] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 16 of 23 
 
6. SUBJECT DISPOSITION  
The number of subjects who consent to participate in this follow-up study, completed or early 
terminated from the study will be summarised by treatment group for the Long-term Follow-up 
Set and Survival Follow-up Set. The reasons for early termination will be summarised and the 
listing will be provided. The number of subjects who died and the reason for death will be 
summarised and the listing will be provided. Also, the number of subjects included in the 
analysis set will be summarised and the listing of study disposition will be provided. 
Subject disposition in the study will be presented in the following tables, figure and listing.  
- T. Subject Disposition by Treatment Group – Long-term Follow-up Set 
- T. Subject Disposition by Treatment Group – Survival Follow-up Set 
- T. Number (%) of Subjects in the Analysis Sets by Treatment Group – Survival Follow-up Set 
- T. Summary of Safety Observation Duration – Long-term Follow-up Set 
- T. Summary of Safety Observation Duration – Survival Follow-up Set 
- F. Subject Disposition by Treatment Group – Long-term Follow-up Set 
- F. Subject Disposition by Treatment Group – Survival Follow-up Set 
- L. Subject Disposition 
 
 
7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Subject demographics and baseline disease characteristics from SB3-G31-BC will be 
summarised by treatment group for the Long-term Follow-up Set and Survival Follow-up Set. 
Continuous variables will be summarised with descriptive statistics (n, mean, standard deviation, 
median, minimum, maximum). Categorical variables will be summarised with counts and 
percentage.  
Demographics 
 
Continuous variables: Age(years), Height(cm), Weight(kg), Body Surface Area (BSA) 
(m²), Body Mass Index (BMI) (kg/m2), LVEF(%) at screening of SB3-G31-BC study 
 
Categorical variables: Age group(<20,<30,.. ,<60,≥60years) Gender(Male, Female), 
Race(White, American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or other Pacific Islander, Other), Ethnicity(Hispanic or Latino, Chinese, 
Indian (Indian subcontinent), Japanese, Mixed Ethnicity, Other), Region(Region 1 
(Korea),Region 2 (Malaysia, Mexico, Philippines, Vietnam), Region 3 (Bosnia and 
Herzegovina, Ukraina), Region 4 (Bulgaria, Czech Republic, France, Romania), 
Region 5 (Poland), Region 6 (India), Region 7 (Russian Federation)), Child bearing 
potential(Yes, No), Menopausal status(Yes, No), ECOG performance status(0, 1, >1), 
ECG result(Normal, Abnormal NCS, Abnormal CS) 
 
Baseline disease characteristics 
 
Categorical variables: Name of diagnosis(Invasive carcinoma of breast, Carcinoma in 
situ (non-invasive) of breast), Number of breast tumour lesions(One, More than one), 
Histopathological tumour classification(Invasive ductal carcinoma NOS, Invasive 
lobular carcinoma, Other), Clinical T stage(cT0, cTis, cT1, cT2, cT3, cT4), Clinical N 
stage(cN0, cN1, cN2, cN3), Clinical M stage(cM0, cM1), Clinical TNM staging(Stage 0, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Form DA-05-03 Statistical Analysis Plan 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 17 of 23 
 
Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, Stage IV), Breast 
cancer 
type(Operable, 
Locally 
advanced, 
Inflammatory), 
Hormone 
receptor 
status(ER+/PR+, ER+/PR-, ER-/PR+, ER-/PR-), Sentinel lymph node biopsy performed 
prior to treatment(Positive, Negative, Not determined) 
Data will be summarised in the following tables. 
- T. Demographic Characteristics by Treatment Group – Long-term Follow-up Set 
- T. Demographic Characteristics by Treatment Group – Survival Follow-up Set 
- T. Baseline Disease Characteristics by Treatment Group – Long-term Follow-up Set 
- T. Baseline Disease Characteristics by Treatment Group – Survival Follow-up Set 
- L. Demographics Characteristics of SB3-G31-BC 
- L. Disease Stage at Screening of SB3-G31-BC 
 
 
8. MEDICAL HISTORY 
All collected continuing medical conditions and medical/surgical history data from SB3-G31-BC 
will be summarised by treatment group for the Long-term Follow-up Set and Survival Follow-up 
Set. Continuing medical condition was identified the items with ‘Ongoing’ status. They will be 
summarised according to the System Organ Class(SOC) and Preferred Term(PT) using Medical 
Dictionary for Regulatory Activities (MedDRA)version 16.1, and the number and percentage(%) 
of subjects will be presented for SOC and PT. 
Data will be summarised in the following tables. 
- T. Medical and Surgical History by Primary System Organ Class, Preferred Terms and 
Treatment Group – Long-term Follow-up Set 
- T. Medical and Surgical History by Primary System Organ Class, Preferred Terms and 
Treatment Group – Survival Follow-up Set 
- T. Continuing Medical Conditions by Primary System Organ Class, Preferred Terms and 
Treatment Group – Long-term Follow-up Set 
- T. Continuing Medical Conditions by Primary System Organ Class, Preferred Terms and 
Treatment Group – Survival Follow-up Set 
- L. Medical History and Continuing Disease  
- L. Surgical History 
 
 
9. EFFICACY EVALUATION 
9.1 
Event-Free Survival, Disease-Free Survival and Overall Survival  
(1) 
Event-Free Survival  
(2) 
Disease-Free Survival 
(3) 
Overall Survival 
For time to event data, survival analysis for EFS, DFS, and OS will be performed for the Long-
term Follow-up Set and Survival Follow-up Set respectively. Kaplan-Meier curves will be 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 18 of 23 
 
calculated and displayed by treatment group in the SB3-G31-BC trial. Median survival times and 
the corresponding 95% CI will also be provided. EFS, DFS, OS rates will be estimated using the 
Kaplan-Meier method and the corresponding 95% CI will be calculated. Additionally, the 
stratified Cox proportional hazard regression model will be applied to estimate Hazard ratio 
(SB3/Herceptin). The stratification factors are hormone receptor status and breast cancer type, 
and region. The hazard ratio will be presented along with its p-value and corresponding 95% CI.  
For DFS analysis, only subjects who have had surgery after completion of 8 cycles in SB3-G31-
BC trial will be included in the analysis. 
The analysis results will be summarised in the following tables, figures and listing. 
- T. Analysis of Event-Free Survival – Long-term Follow-up Set 
- T. Analysis of Event-Free Survival – Survival Follow-up Set 
- T. Analysis of Disease-Free Survival – Long-term Follow-up Set 
- T. Analysis of Disease-Free Survival – Survival Follow-up Set 
- T. Analysis of Overall Survival – Long-term Follow-up Set 
- T. Analysis of Overall Survival – Survival Follow-up Set 
- F. Analysis of Event-Free Survival – Long-term Follow-up Set 
- F. Analysis of Event-Free Survival – Survival Follow-up Set 
- F. Analysis of Disease-Free Survival – Long-term Follow-up Set 
- F. Analysis of Disease-Free Survival – Survival Follow-up Set 
- F. Analysis of Overall Survival – Long-term Follow-up Set 
- F. Analysis of Overall Survival – Survival Follow-up Set 
- L. Subjects with Breast Cancer Recurrence 
- L. Time to Event Parameters by Subjects 
 
 
10. SAFETY EVALUATION 
10.1 Symptomatic CHF and Asymptomatic significant LVEF decrease 
 
(1) 
Symptomatic CHF  
(2) 
Asymptomatic significant LVEF decrease 
The incidence of symptomatic CHF and asymptomatic significant LVEF decrease will be 
summarised by treatment group for the Long-term follow-up Set. The number and percentage of 
subjects and the number of events (for symptomatic CHF) will be presented.  
As the upper level of those two cardiac events, incidence of significant LVEF decrease, which is 
defined as an absolute decline of at least 10 % points from baseline LVEF and resulting LVEF 
less than 50% on the “LVEF (echo or MUGA scan)” page on the eCRF, will also be summarised 
by treatment group. 
The analysis results will be summarised in the following tables. 
- T. Incidence of Symptomatic Congestive Heart Failure (CHF) and Asymptomatic Significant 
Left Ventricular Ejection Fraction (LVEF) Decrease – Long-term Follow-up Set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Form DA-05-03 Statistical Analysis Plan 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 19 of 23 
 
10.2 Cardiac Death and Other Cardiac Event 
 
(1) 
Cardiac Death  
(2) 
Other Cardiac Event  
The incidence of cardiac death and other cardiac events will be analysed similarly with primary 
objective analyses. The number and percentage of subjects and the number of events (for other 
cardiac event) will be presented. Acute myocardial infarction, severe arrhythmia, ischemic heart 
disease, valvular dysfunction and other significant cardiac conditions will be summarised as 
number of subjects. 
The analysis results will be summarised in the following tables and listing. 
- T. Incidence of Cardiac Death – Long-term Follow-up Set 
- T. Incidence of Other Cardiac Event – Long-term Follow-up Set 
- L. Subjects with Cardiac Events 
 
10.3 Other Safety Measures 
10.3.1 Left Ventricular Ejection Fraction   
For LVEF, descriptive statistics (number of subjects, mean, standard deviation, median, 
minimum, maximum) will be presented by each visit as well as for change from baseline (LVEF 
at screening of SB3-G31-BC).  
Moreover, the worst value during overall study period where ‘worst’ indicates the lowest value 
during overall study period, including SB3-G31-BC and SB3-G31-BC-E, will be summarised by 
treatment group. The worst value of LVEF will be categorised in ‘≥ 50’, ‘≥ 45 and < 50’, ‘< 45’. 
The ‘≥ 45 and < 50’ will be broken down into ‘Decrease of < 10 points from baseline’ and 
‘Decrease of ≥ 10 points from baseline’. 
The LVEF will be summarised in the following table and listed. 
- T. Summary of Left Ventricular Ejection Fraction (LVEF) (%) by Visit and Treatment– Long-
term Follow-up Set 
- T. Summary of Worst Value for Left Ventricular Ejection Fraction (LVEF) (%) during Overall 
Study Period from Screening of SB3-G31-BC by Treatment Group – Long-term Follow-up Set 
- T. Incidence of Significant Change in Worst Value of LVEF during Overall Study Period from 
Screening of SB3-G31-BC – Long-term Follow-up Set 
- L. Echocardiogram/MUGA Scan (LVEF)  
 
 
10.3.2 Others 
The following safety measures will be provided:  
Physical examination (Listing only)  
Mammography (Listing only)  
- L. Physical examination  
- L. Mammography  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 20 of 23 
 
11. ADDITIONAL EVALUATION 
11.1 Subgroup Analysis 
No subgroup analysis is planned in this study. 
 
12. GENERAL PRESENTATION OF SUMMARIES AND ANALYSES 
12.1 Significance Level 
Statistical test will be conducted at a two-sided 5% significance level, if necessary. 
 
12.2 Summary Statistics 
Continuous data will be summarised with descriptive statistics (number of subjects, mean, 
standard deviation, median, minimum, maximum) and categorical data will be presented with 
frequency (N) and percentage (%).  
 
12.3 Decimals 
Mean, standard deviation, median, minimum, maximum for descriptive statistics of continuous 
data, and percentage for categorical data, will be presented down to 2 decimal places. 
  
12.4 Statistical Analysis Methods 
Not applicable 
 
12.5 Relative Study Day 
Study Day in days will be calculated from Day 1 of Cycle 1 date in SB3-G31-BC study and it will 
be used to show start/stop day of assessments or event.  
- If the date of the event is on or after the Day 1 of Cycle 1 date in SB3-G31-BC study, day = 
event date – first study drug date + 1. 
- If the date of the event is prior to the Day 1 of Cycle 1 date in SB3-G31-BC study, day = event 
date – first study drug date. 
If the event date was partially missing, the date will appear partial or missing in the listings and 
study day will be calculated after partial date imputation as described in section 13.3 Handling 
of Incomplete Date. 
 
12.6 Baseline 
For analysis of LVEF, the last measurement prior to the time of the first IP administration of SB3-
G31-BC will be used as baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 21 of 23 
 
12.7 Study Period and Visit Window Definitions 
Unless specifically mentioned, each endpoint by time point will be summarised for regular visits. 
 Visit Name 
Actual Point 
 Visit Label 
Screening of SB3-G31-BC  
Date of Screening for SB3-
G31-BC 
Screening of SB3-G31-BC 
(BL) 
ICF Visit 
Date of Informed Consent for 
SB3-G31-BC-E 
 
Visit 1 
6 months 
Visit 1 (6 months) 
Visit 2 
12 months 
Visit 2 (12 months) 
Visit 3 
18 months 
Visit 3 (18 months) 
Visit 4 
24 months 
Visit 4 (24 months) 
Visit 5 
36 months 
Visit 5 (36 months) 
Visit 6 
48 months 
Visit 6 (48 months) 
Visit 7 
60 months 
Visit 7 (60 months) 
 
12.8 Software for Statistical Analysis 
SAS® Version 9.4 or higher, SAS institute, Cary, NC, USA 
 
13. DATA HANDLING COVENTIONS 
13.1 Handling of Missing Data 
For all endpoints, observed data will be used for analysis without imputation of missing values, 
and data that was censored without occurrence of the event will be handled as censoring. 
 
13.2 Repeated or Unscheduled Assessments 
Generally, data recorded at the nominal visit will be presented for by-visit summary. Repeated or 
unscheduled assessment will not be included in the by-visit summaries. 
Repeated or unscheduled assessment will be included when defining the asymptomatic 
significant LVEF decrease and the worst value of LVEF. 
Listings will include scheduled, unscheduled, repeated and early termination data in 
chronological order along with scheduled visits.  
 
13.3 Handling of Incomplete Date 
For survival analysis, if the date of death is partially missing, such as day or month, date 
comparison will be made by imputing the missing date. If the day of the date is unknown (i.e., 
date is “YYYY/MM/UK”), it will be imputed as ‘01’.If the month of the date is unknown (i.e., date 
is “YYYY/UK/UK”), it will be imputed as ‘01/01’. If the date of death is completely missing, it will 
be imputed as the last date to confirmed survival. 
For cardiac events, if start date of an event is partially missing, such as day or month, date 
comparison will be made by imputing the missing date. If the day of the start date is unknown 
(i.e., date is “YYYY/MM/UK”), it will be imputed as ‘01’.If the month of the start date is unknown 
(i.e., date is “YYYY/UK/UK”), it will be imputed as ‘01/01’. If start date of an event is completely 
missing, it will be censored at the date of the last follow-up visit. If stop date is partially missing, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 22 of 23 
 
it will be imputed as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown). 
For recurrence date, if the date is partially missing, such as day or month, date comparison will 
be made by imputing the missing date. If the day of the date is unknown (i.e., date is 
“YYYY/MM/UK”), it will be imputed as ‘01’.If the month of the date is unknown (i.e., date is 
“YYYY/UK/UK”), it will be imputed as ‘01/01’. If the recurrence date is completely missing, it will 
be the last follow-up date prior to the date of visit confirmed the recurrence. 
For the date of end of participation, if the subject was early terminated due to death, the date of 
end of participation will be the date of death which is completed imputation. 
 
13.4 Character Values of Clinical Laboratory Evaluation 
No clinical laboratory evaluation is planned in this study. 
 
14. INTERIM ANALYSIS 
Analyses will be conducted once a year from 2017 to 2021. However, the frequency of the 
analyses can be adjusted by the sponsor’s decision. 
 
15. CHANGE FROM PROTOCOL 
Unlike the analysis plan of the protocol section 7.2.2, the exploratory analyses will not be 
conducted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No.: SB3-G31-BC-E 
 
 
SAP Addendum 2_2021-01-26  
Effective Date: 2017-04-10                  Confidential                             Page 23 of 23 
 
16. SAS PROCEDURE FOR TESTING 
16.1 Test of Survival Time 
Cox Proportional Hazard Regression Model 
PROC PHREG DATA=dataset;  
CLASS treatment hormone_receptor_status breast_cancer_type region/REF=first; 
MODEL Time*event(1)= treatment / TIES=EFRON ALPHA=0.05 RL;  
STRATA hormone_receptor_status breast_cancer_type region; 
RUN; 
 
Kaplan-Meier Estimation for Median Survival or Survival Rate at Certain Timepoints 
PROC LIFETEST DATA=dataset conftype=linear METHOD=KM PLOTS = SURVIVAL 
ALPHA=0.05; 
TIME Time*event(1); 
STRATA treatment; 
RUN; 
 
 
 
17. REFERENCES 
Not applicable 
 
 
Appendix. Mock-up TFL  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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