Clinical trial NCT05258747
Conditions: Ovarian Cancer Breast Cancer
Keywords: cancer of the ovaries, female reproductive cancer, ovarian carcinoma, female breast cancer
Sponsor: Sandoz
Start date: 2022-04-07; Completion date: 2022-10-20
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a two-way crossover bioequivalence study between test and reference product in patients diagnosed with BRCA mutated ovarian cancer, recurrent ovarian cancer or metastatic breast cancer.

Detailed description:
This is a two-way crossover bioequivalence study between test and reference product in patients diagnosed with BRCA mutated ovarian cancer, recurrent ovarian cancer or metastatic breast cancer.

Patients will be enrolled after providing written informed consent and treatments will be allocated to patient by carrying out randomization using statistical techniques.

Patients that are already on a stable dose of Lynparza® (olaparib) tablets and have met the eligibility criteria will be directly randomized for participation in the study.

After randomization patients will receive either test or reference product in a crossover manner based on the randomization schedule. Patients will receive the dose of 300 mg twice daily for 16 days in a crossover design.

In period-I (Day 1 to Day 8), patients will receive either Test product or Reference product for 8 days based on the randomization schedule.

In period-II (Day 9 to Day 16), patients will be switched to the other product for a second period of 8 days.

Arms: arm 1: participants will receive 2 x 150 mg Olaparib tablets twice daily for 16 days in a crossover design arm 2: participants will receive 2 x 150 mg Olaparib tablets twice daily for 16 days in a crossover design
Interventions: intervention 1: Olaparib tablets, 150 mg intervention 2: Lynparza® (olaparib) tablets 150 mg
Intervention descriptions: intervention 1: Olaparib tablets, 150 mg of Lek Pharmaceuticals d.d., Slovenia intervention 2: Lynparza® (olaparib) tablets 150 mg Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware (DE).

Protocol documents:
Prot_000.pdf: 
 
Study Protocol 
  
Sandoz Global Clinical Development 
 
Protocol Number: 21-VIN-0166 
 
Protocol Title: A Randomized, Open Label, Multi-centre, Two-treatment, Two-period, 
Two-sequence, Two-stage, Multiple Dose, Steady-state, Crossover, Bioequivalence 
Study of Olaparib Tablets, 150 mg (Lek Pharmaceuticals d.d.) and Lynparza® 
(Olaparib) Tablets 150 mg (AstraZeneca Pharmaceuticals LP), in Patients With BRCA 
Mutated Ovarian Cancer, Recurrent Ovarian Cancer or Metastatic Breast Cancer 
Under Fasting Condition 
 
 
 
NCT Number:  
 
NCT05258747 
Document date: 
 
20 Sep 2021  
Document version:  
1.0  
 
 


Protocol Number 
Study Sites 
Protocol Title 
Version Number 
Protocol Date 
Sponsor 
Contract 
Research 
Organization 
(CRO) 
Confidential 
PROJECT NO. 
Investigator sites 
A randomized, open label, multi-centre, two-treatment, two-period, two-sequence, 
two-stage, multiple dose, steady-state, crossover, bioequivalence study of Olaparib 
tablets, 150 mg 
and Lynparza® (olaparib) tablets 150 mg 
ts with BRCA mutated ovarian cancer, 
breast cancer under fasting condition. 
Confidentiality Statement 
The information contained in this document is trade secrets and commercial information that are privileged 
or confidential, especially unpublished data, and is the property of the 
(or under its control), and therefore provided to you in confidence as an 
vesttgator or consu tant, or 
review by you, your staff and an applicable Institutional Ethics Committee. By accepting this document 
ou a ee that this information will not be disclosed to others without written authorization from 
unless such disclosure is required by applicable law or regulations or to the 
extent necessary to o tam mformed consent from those persons (including their legally acceptable 
representatives as applicable) to whom the drug may be administered. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information 
supplied to you that is indicated as privileged or confidential. 


1.0 
AUTHORIZATION OF PROTOCOL 
1.1 
Protocol Preparation and Authoriz,ation 
I, the undersigned, have read and understood this pr9t<>col and hereby agree to conduct the study in 
accordance with this protocol and to comply with al~ the pertinent requirements of the Ethical guidelines for 
biomedical research on human participants (ICMR.) 2017, New Drugs and Clinical Trials Rules (2019) of 
India, US FDA regulations, rules and guidelines, cGCP guideline(s), ICH (Step 5) 'Guidance on Good 
Clinical Practice' ICH Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013), Code of Federal 
Regulations on the Protection of Human Subjects (45 CPR Part 46) and with procedures oriented to Good 
Laboratory Practice and. applicable regulatory guidelines. 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree. to ensure that 
all associates assisting in the conduct of this study are informed regardin_g their obligations. 
Confiden.tial 
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1.2 
Quality Assurance Statement 
The contents of the protocol were reviewed for compliance with the applicable VIN SOPs, pertinent 
requirements of the Ethical guidelines for biomedical research on human participants (ICMR) 2017, New 
Drugs and Clini.cal Trials Rules (2019) of India, USFDA regulations, rules and guidelines, cGCP 
guideline(s), ICH (Step 5) 'Guidance on Good Clinical Practice' ICR Guidance E6 (R2), Declaration of 
Helsinki (Brazil, 2013) ). Code of Federal Regulations on the Protection of Human Subjects (45 CFR Part 
46) and with procedures oriented to Good Laboratory Practice and applicable regulatory guidelines. 
Confidential 
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1.3 
Sponsor's Review and Approval 
I, the undersigned, have read, understood and approve this protocol. We agree to comply with all 
requirements of the Ethical guidelines for biomedical research on human participants (ICMR) 2017, New 
Drugs and Clinical Trials Rules (2019) of India, USFDA regulations, rules and gu.idelines, cGCP 
guideline(s), !CH (Step 5) 'Guidance on Good Clinical Practice' ICH Guidance E6 (R2), Decla.ration of 
Helsinki (Brazil, 2013), Code of.Federal Regulations ort the Protection of Human Subjects (45 C.FR Part 46) 
and with procedures oriented to Good Laboratory Practice and applicable regulatory guidelines. 
Confidential 
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TABLE OF CONTENTS 
1.0 AUTHORIZATION OF PROTOCOL .................................................................................................. 2 
1.1 
Protocol Preparation and Authorization ............................................................................................... 2 
1.2 
Quality Assurance Statement ............................................................................................................... 3 
1.3 
Sponsor's Review and Approval .......................................................................................................... 4 
2.0 LIST OF ABBREVIATIONS ....................................... - ....................................................................... 8 
3.0 SYNOPSIS .............................................................................................................................................. 10 
4.0 INVESTIGATORS AND STUDY ADMINISTR.ATNE STRUCTURE ......................................... 26 
4.1 
Clinical Facilities ................................................................................................................................ 26 
4.2 
Bio-analytical, Phannacokinetics and Biostatistics Services and Quality Assurance ........................ 26 
4.3 
M.edical Experts .................................................................................................................................. 26 
5.0 BACKGROUND INFORMATION ..................................................................................................... 27 
5.1 
lntroduction2 .. ................................... ............................ ... .... .................................................... ........... 27 
5.2 
Phannacology2 ................................................................................................................................... 27 
5 .3 
Adverse Reactions2 ...................•... ....•...............•... ..... .•.•...... ......•...•...•.•...•...••••. ••••............•.•..•••.•... .•.. 29 
5.4 
Warnings andprecautions2 .......................................................................... ....................................... 39 
5.5 
Indications and usage2.l ...................................................................................................................... 40 
5.6 
Therapeutic Dosage2 ... .......................................................................... ................................. ..... ... .... 41 
5.7 
Contraindication3 .. ............. ........................................................................................................ ......... 42 
5.8 
Drug lnteraction2 ••..•.••.•.••......•.•...........•....•.•.....•••.••••.... .•... ...........•..•..•.•.•.•.•..•..•....•.•...••..•...•..•.•.•.•....• 42 
5.9 
Use in specific populations2 ..................... ................... ...... ..... ............................... ......... ... . ......... ....... 42 
6.0 OBJECTIVE .......................................................................................................................................... 43 
7.0 STUDY DESIGN .................................................................................................................................... 43 
7.1 
Number ofPatients ............................................................................................................................. 44 
7.2 
Randomization Method ...................................................................................................................... 44 
7.3 
Blinding .............................................................................................................................................. 46 
7.4 
Duration of Study ............................................................................................................................... 46 
7.5 
Washout .............................................................................................................................................. 46 
7.6 
Premature Termination of the Study .................................................................................................. 46 
8.0 INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................... 47 
8.1 
Procurement, Storage and Accountability Procedures for Investigational Medicinal Products ....... .47 
8.1.1 
Receipt and storage of lnvestigational Medicinal Products ...................................................... .4 7 
8.1.2 Accountability of Investigational Medicinal Products ............................................................... 47 
8.2 
Dispensing ........................................................................................................................................... 48 
8.3 
Handling ofUnused Investigational Medicinal Products ................................................................. .48 
8.4 
Maintenance of Randomization Code and Dispensing Record .......................................................... 48 
8.5 
Retention samples .............................................................................................................................. 49 
8.6 
Th1P Non-Conformances .................................................................................................................... 49 
Confidential 
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9 .0 SELECTION AND WITHDRAW AL OF PATIENTS _ ......................................... -......................... 50 
9 .1 
Inclusion Criteria ................................................................................................................................ 50 
9 .2 
Exclusion Criteria ............................................................................................................................... 52 
9.3 
Withdrawal Criteria ............................................................................................................................ 53 
10.0 TREATMENT OF PATIENTS ............................................................................................................ 54 
10.1 Housing .............................................................................................................................................. 54 
10.2 Dosing ................................................................................................................................................ 55 
10.3 Dosing Compliance ............................................................................................................................ 57 
10.4 Sanipling Schedule ............................................................................................................................. 57 
10.5 Sample Collection Procedure ............................................................................................................. 58 
10.6 Blood Volume .................................................................................................................................... 58 
11.0 RESTRICTIONS ................................................................................................................................... S9 
11.1 Posture restriction ............................................................................................................................... 59 
11.2 Dietary and water restriction .............................................................................................................. 59 
11.3 Concomitant Medications .................................................................................................................. 59 
11.4 Others ................................................................................................................................................. 60 
12.0 CLINICAL AND SAFETY ASSESSMENT ............................................... - ....................................... 60 
12.1 Clinical Exrunination .......................................................................................................................... 62 
12.2 Safety monitoring and reporting ........................................................................................................ 63 
12.2.l Adverse Events ........................................................................................................................... 63 
12.2.1.1 Definition of adverse events and reporting requirements ........................................ 63 
12.2.1.2 The Most Common Adverse Events Associated with Study Medication ................ 66 
12.2.2 Serious Adverse Events (SAE) ................................................................................................... 66 
12.2.2.1 
SAE reporting ........................................................................................................... 67 
12.2.3 Investigator Notification and 6 monthly line listings ................................................................. 69 
12.2.4 Health authority reporting .......................................................................................................... 70 
12.2.5 Pregnancy Reporting .................................................................................................................. 70 
12.2.6 Special case scenarios ................................................................................................................ 70 
12.2.7 IMP related complaints .............................................................................................................. 71 
12.2.8 Reconciliation ............................................................................................................................. 71 
12.2.9 Investigator Training .................................................................................................................. 71 
13.0 SAMPLE PROCESSING AND TRANSFER PROCEDURES ......................................................... 71 
14.0 BIOANALYTICAL PROCEDURES ................................................................................................... 72 
14.l Method Validation .............................................................................................................................. 72 
14.2 Assayof Samples ............................................................................................................................... 73 
1S.0 PBARMACOKINETICS AND STATISTICAL ANALYSIS ........................................................ ,_ 73 
15 .1 Phannacokinetic Parameters .............................................................................................................. 7 4 
15.2 Statistical Analysis ............................................................................................................................. 75 
15.2.1 Analysis of variance ................................................................................................................... 76 
Confidential 
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15.2.2 Intra- patient Variability ............................................................................................................. 77 
15 .2.3 Two one-sided tests for bioequivalence ..................................................................................... 78 
15.2.4 Ratio analysis ............................................................................................................................. 78 
15.2.5 Power .......................................................................................................................................... 78 
15.2.6 Bioequivalence criteria ............................................................................................................... 78 
15.2. 7 Safety data .................................................................................................................................. 79 
16.0 AMENDMENT AND PROTOCOL DEVIATION IN REGARDS TO THE PROTOCOL ........... 79 
16.1 Amendment to protocol. ..................................................................................................................... 79 
16.2 Protocol deviation definition and reporting ....................................................................................... 79 
17.0 SOURCE DATA ACCESSIBILITY .................................................................................................... 80 
18.0 QUALITY CONTROL AND QUALITY ASSURANCE ..................... ._ ........................................... 80 
19.0 ETHICS ....................................................................................... ._ ........................................................ 80 
19.1 Ethics Committee ............................................................................................................................... 80 
19.2 Written Informed Consent. ................................................................................................................. 81 
19.2.1 Patient Participation Fee ............................................................................................................. 81 
19.2.2 Post-trial access .......................................................................................................................... 82 
20.0 DATA HANDLING AND RECORD KEEPING ................................................................................ 82 
21.0 STUDY REPORTS AND SUPPLEMENT ARY DOCUMENTS . .-.................................................. 82 
22.0 ARCHIVING .......................................................................................................................................... 82 
23.0 INSURANCE POLICY ......................................................................................................................... 83 
24.0 CONFIDENTIALITY OF DATA ........................................................................................................ 83 
25.0 PUBLICATION POLICY ..................................................................................................................... 83 
26.0 REFERENCES ....................................................................................................................................... 84 
27.0 LIST OF ANNEXURES ........................................................................................................................ 85 
27.1 ANNEXURE I: SCHEDULE OF EVENTS ...................................................................................... 86 
27.2 ANNEXURE JI: LABORATORY PARAMETERS ......................................................................... 88 
27.3 ANNEXURE III: ECOG Performance Status13 ............................ .............................................. ... .... 89 
27.4 ANNEXURE IV: List of Prohibited drugs during the study
14 
•••••.••••••••••.••.••••• •.••••.••••••••••••••••••.••• ••••. 90 
27.5 ANNEXURE V: SIGNATURE(S) OF INVESTIGATOR(S) ........................................................... 91 
Confidential 
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2.0 
LIST OF ABBR.EVIA TIO NS 
BHCG 
Human chorionic gonadotropin 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BE 
Bioequivalence 
BP 
Blood Pressure 
BSA 
Body surface area 
Cmax 
Maximum Measured Plasma Concentration 
CBC 
Complete Blood Count 
COA 
Certificates of Analysis 
CRF 
Case Record Form 
CRO 
Contract/Clinical Research Organization 
CTC 
Common toxicity criteria 
CTCAE 
Common Terminology Criteria for Adverse Event 
CV 
Coefficient of Variation 
DCGI 
Drugs Controller General of India 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCTD 
Electronic Common Technical Document 
FCBP 
Female of child bearing potential 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized As Safe 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ICMR 
Indian Council of Medical Research 
IEC 
Institutional Ethics Committee 
IMP 
lnvestigational medicinal product 
Confidential 
Page 8 of91 


IRB 
Institutional Review Board 
K3EDTA 
Tripotassium etbylenediarninetetraacetic acid 
LC-
Liquid Chromatography-Tandem Mass Spectrometry 
MS/MS 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
ml/mL 
Millilitre 
mmHg 
Millimetre of Mercury 
NA 
Not Applicable 
NCI 
National Cancer Institute 
NCS 
Not Clinically Significant 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetic 
RBC 
Red Blood Cell 
REMS 
Risk Evaluation and Mitigation Strategy 
Rpm 
Revolutions per minute 
RS 
Respiratory System 
SAS 
Statistical Analysis System 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOP 
Standard Operating Procedure 
Tmaxss 
Time of the Maximum Measured Plasma Concentration over the steady state dosing 
interval 
ULN 
Upper Limit of Normal 
USFDA 
United States Food and Drug Administration 
Confidential 
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3.0 
SYNOPSIS 
Name of Sponsor 
Name of 
Investigation al 
Medicinal 
Product 
Title of Study 
Clinical Study 
Centre(s) 
Central 
Laboratory study 
centre(s) 
BRCA Test 
Laboratory study 
centre(s) 
Bio-analytical 
Study Centre(s) 
Statistical Centre 
Confidential 
Reference Product: L ynparza 
Manufactured for: 
A randomized, open label, multi-centre, two-treatment, two-period, two-sequence, 
two-stage, multiple dose, steady-state, crossover, bioequivalence study of Olaparib 
tablets, 150 mg 
and Lynparza® (olaparib) tablets 150 mg 
in patients with BRCA mutated ovarian cancer, 
recurrent ovarian cancer or metastatic breast cancer under fasting condition. 
at different investigators' sites in India 
Page 10of91 


Objectives 
Methodology 
Confidential 
• Primary Objective: To assess the pharmacokinetics and establish bioequivalence 
of the Test Product (Olaparib tablets, 150 mg) relative to that of Reference Product 
(Lynparza® (olaparib) tablets 150 mg) in patients with BRCA mutated ovarian 
cancer, recurrent ovarian cancer or metastatic breast cancer. 
• Secondary Objective: To monitor the adverse events of patients and to assess 
safety of each of the two formulations. 
This is a two-way crossover bioequivalence study between test and reference product 
in patients diagnosed with BRCA mutated ovarian cancer, recurrent ovarian cancer or 
metastatic breast cancer that are receiving Lynparza® (olaparib) tablets (2*150 mg 
twice daily) or are eligible to receive Lynparza® (olaparib) tablets (2*150 mg twice 
daily). 
The study will be conducted in 2 stages, in the Stage 1 sufficient number of patients 
will be enrolled to achieve 56 evaluable patients and Stage 2 (if needed) sample size 
will be decided on the basis of data obtained after the completion of Stage I. 
Patients will be enrolled after providing written infonned consent and treatments will 
be allocated to patient by carrying out randomization using statistical techniques. 
The patients will undergo screening for a maximum period of 40 days (up to 30 days 
for patients that are already receiving a stable dose of Lynparza® (olaparib) tablets), 
which will include a Dose Stabilization period of IO days ( only applicable for patients 
not yet on a stable dose ofLynparza® (olaparib) tablets). 
The patients found eligible for participation in the study, but not yet on a stable dose 
of Lynparza® (olaparib) tablets, will be enrolled in the Dose Stabilization period. 
Dose Stabilization period will be applicable for patients that are not on a stable dose 
of Lynparza® (olaparib) tablets 2*150 mg (for at least IO days). Following this, 
patients will be randomized to participate in the study. Patients that do not tolerate the 
mentioned dose or require dose modifications for any reason will be considered as 
screen failure. Patients who miss 2 or more consecutive doses or more than 3 non-
consecutive doses in the Dose Stabilization period will be considered screen failure. 
Patients that are already on a stable dose of Lynparza® (olaparib) tablets (2*150 mg 
twice daily) for at least 10 days and have met the eligibility criteria wilJ be directly 
Page 11 of 91 


Number of 
Patients 
Inclusion 
Criteria 
Confidential 
randomized for participation in the study. 
After randomization patients will receive either test or reference product in a 
crossover manner based on the randomization schedule. Patients will receive the dose 
of300 mg twice daily for 16 days in a crossover design. 
In period-I (Day I to Day 8), patients will receive either Test product or Reference 
product for 8 days based on the randomization schedule. 
In period-II (Day 9 to Day 16), patients will be switched to the other product for a 
second period of 8 days. 
Blood samples for pharmacokinetic assessment will be collected on Days 1, 6, 7 and 
8 and on Days 14, 15 and 16. 
After the study is completed (after last Pharmacokinetic (PK) sample collection on 
Day 16), patients may be continued on their established dose of Olaparib using an 
approved Olaparib product as prescribed by their clinicians. 
Plasma concentration of Olapanb will be quantified using a validated analytical 
method. 
Statistical Analysis of pharmacokinetic parameters of test and reference formulations 
will be performed to assess bioequivalence. 
A sufficient number of patients will be enrolled to have 56 evaluable patients in Stage 
1 (about, but not limited to, 70 enrolled patients). Stage 2 sample size (if needed) will 
be decided on the basis of data ( observed CV) obtained after the completion of Stage 
1. Maximwn sample size (Stage 1 + Stage 2) is expected, but not limited to, 
approximately 120 enrolled patients. This is a 2-stage design according to Potvin C 
method1• 
Enrollment will be continued until at least 56 evaluable patients will complete Stage 
1. If additional patients are recruited, those patients will continue the study until 
completion/withdrawal and be included in the pbarmacokinetic and statistical 
analyses as applicable. 
To be eligible for the study, patients must meet all the following inclusion criteria: 
1. 
First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian 
Cancer maintenance treatment of adult patients with deleterious or suspected 
deleterious gennline or somatic BRCA-mutated advanced epithelial ovarian, 
Page 12of91 


Confidential 
fallopian tube or primary peritoneal cancer who are in complete or partial 
response to first-line platinum-based chemotherapy. Select patients based on a 
diagnostic test for BRCA mutation by NOS - Next Generation Sequencing 
method. 
OR 
Maintenance Treatment of Recurrent Ovarian Cancer maintenance 
treatment of adult patients with recurrent epithelial ovarian, fallopian tube or 
primary peritoneal cancer, who are in complete or partial response to platinum-
based chemotherapy. 
OR 
Advanced Germline BRCA-mutated Ovarian Cancer After 3 or More 
Lines of Chemotherapy treatment of adult patients with deleterious or 
suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian 
cancer who have been treated with three OJ' more prior lines of chemotherapy. 
Select patients based on a diagnostic test for BRCA mutation by NOS - Next 
Generation Sequencing method 
OR 
Germline BRCA-mutated HER2-negative Metastatic Breast Cancer 
treatment of adult patients with deleterious or suspected deleterious gBRCAm, 
HER2-negative metastatic breast cancer, who have been treated with 
chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with 
hormone receptor (HR.)-positive breast cancer should have been treated with a 
prior endocrine therapy or be considered inappropriate for endocrine therapy. 
Select patients based on a diagnostic test for BRCA mutation by NOS - Next 
Generation Sequencing method 
2. 
Non-smoking, non-pregnant, non-lactating female patient :::18 years of age with 
a body mass index (BMI) in the range of 18.50 to 30.00 kg/m2 (both inclusive). 
3. 
Able to give written informed consent for participation in the trial and willing to 
adhere to protocol requirements. 
4. 
Patients that are already receiving a stable dose of Lynparza® (olaparib) tablets 
(2*150 mg tablets) 300 mg twice daily for at least 10 days. 
OR 
Patients requiring Olaparib in the dose of300 mg (2*150 mg tablets) twice daily 
as per the discretion of the Investigators; these patients will be stabilized on 
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Confidential 
Olaparib as a part of study and those patients that tolerate Olaparib in the dose 
of300 mg twice daily for 10 days will be randomized in the study. Patients that 
do not tolerate the mentioned dose or require dose modifications for any reason 
will be considered as screen failure. Patients who miss 2 or more consecutive 
doses or more than 3 non-consecutive doses in the Dose Stabilization period will 
be considered screen failure. 
5. 
Patient having an estimated survival of at least 3 months. 
6. 
Adequate organ and bone marrow function based upon the following laboratory 
criteria at the time of eligibility assessment prior to dosing in period I: 
Body system 
Parameters 
Bone marrow function a) Hemoglobin 2::9.0 g/dL 
enal function 
b) Absolute neutrophil count 2: 1500/uL 
c) Platelet count 2:100,000/uL 
d) WBC count > 3000/mm3 
Creatinine Clearance > 50 mUmin (calculated 
based on Cockcroft-Gault formula) 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status of0-2. 
8. 
Absence of blood transfusion in the 28 days prior to randomization. 
9. 
Women of non child bearing potential with documented evidence of 
hysterectomy / bilateral salpingectomy / bilateral oophorectomy at least 6 
months prior to IMP administration) or postmenopausal for at least 12 
consecutive months. 
OR 
Women of child bearing potential must have negative pregnancy test at 
screening visit and before randomization and must agree to use an effective 
method of avoiding pregnancy (including oral, transdermal or implanted 
contraceptives [any hormonal method in conjunction with a secondary method], 
intrauterine device, female condom with spermicide, diaphragm with 
spermicide, absolute sexual abstinence, use of condom with spermicide by 
sexual partner or sterile [ at least 6 months prior to IMP administration] sexual 
partner) for at least 4 weeks prior to IMP administration, during the study and 
up to 6 months after the last dose of IMP. Cessation of birth control after this 
point should be discussed with a responsible physician. 
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Exclusion 
Criteria 
Confidential 
Patients who meet any of the following criteria at screening will not be enrolled in the 
study: 
I. History of known hypersensitivity to olapanl, or its components which, in the 
opinion of the Investigator, would compromise the safety of the patient or the 
results of the study. 
2. Patients found positive for HN, Syphilis, Hepatitis B surface antigen or Hepatitis 
C antibody at screening. 
3. Have ongoing clinically significant adverse event(s) due to prior treatments 
administered, as detennined by the investigator. 
4. Patients with Pneumonitis 
5. Patients with severe hepatic impairment (Child Pugh classification category C) 
6. Patients who received any chemotherapy, radiotherapy, or any other anti-cancer 
therapy within 4 weeks from the last dose prior to first dosing in period 01 (or a 
longer period depending on the defined characteristics of the agents used). 
7. History or presence of any active infection or uncontrolled systemic disease (e.g. 
cardiovascular disease, hypertension, diabetes meilitus etc.) or any clinically 
significant disease, condition, disorder or abnormal laboratory finding that, in the 
opinion of the Investigator, may either put the patient at risk because of 
participation in the study, or influence the study results or the patient's ability to 
participate in the study. 
8. Patient had major surgery within 4 weeks prior to first dosing in Period 01, or 
who have not recovered from prior major surgery. 
9. In the opinion of the Investigator, the patient will not be compliant with the 
requirements of the study procedures. 
10. Blood loss (1 unit or 350 ml} within 90 days prior to first dosing in Period 01 for 
the current study. 
11. Receipt of an investigational medicinal product or participation in another drug 
research study involving IMP admimstration within 30 days (or 5 half-lives, 
whichever is longer) prior to first dosing in Period 01 for the current study. 
Note: Elimination half-life of the study drug should be taken into consideration 
for inclusion of the patient in the study. 
12. Usage of strong and moderate CYP3A4 inhibitors (e.g., cimetidine, ciprofloxacin, 
Page 15 of91 


Mode of 
Administration 
for Test and 
Reference 
product 
Confidential 
grapefruit juice) or strong and moderate CYP3A4 inducers (e.g., carbamazepine, 
phenytoin, St. John's Wort, rifampicin) within 30 days prior to first dosing in 
Period 01 (refer annexure IV for a full list of prohibited medications). 
13. History of difficulty in accessibility of veins or intolerance to direct venipuncture. 
14. Pregnant or lactating females. 
15. Patient positive 
on Breath alcohol 
analyzer 
test 
at 
the 
time 
of 
baseline/randomization visit. 
16. Positive on urine test for drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, marijuana, cocaine, and morphine) prior to receiving the first 
dose of investigational medicinal product in the study. 
17. History or presence of alcoholism or drug abuse. 
18. Patients with psychiatric illness/social situations that would limit compliance with 
study requirements. 
19. Difficulty in swallowing tablets. 
20. Problems with fasting. 
21. History or presence of clinically significant lactose, galactose, or fructose 
intolerance. 
Patients will be dosed or advised to take the investigational medicinal product (2*150 
mg twice daily) (allocated as per randomization schedule) orally in sitting posture 
with approximately 240 (±5 mL) of drinking water at ambient temperature which 
must be completely consumed. Patients will be instructed not to chew, crush, touch or 
divide the tablet but to swallow as a whole. On days of housing, dosing will be 
followed by thorough hand and mouth check for assessing compliance. 
Dosing time on Day 1 morning will be considered as reference time for dosing in the 
entire study. Evening dose will be administered 12 hours after the morning dose. All 
the patients will be required to consume the investigational medicinal product 
preferably at the same time each day. 
Window period of within I hour will be allowed if the patient misses the scheduled 
time of dosing. If a patient misses a dose, the dose should be taken as soon as 
possible, if this can be done within I hour of the scheduled time. The next dose 
should be taken at its scheduled time. If a patient misses a dose for more than 1 hour, 
they should take the next dose at its scheduled time. 
Page 16of9l 


In period I: 
On Day 0, patient will be asked to reach the site at least 12 how;s prior to scheduled 
dosing on Day 1 and will be housed for 12 hours after morning dose of Day 1. Patient 
will be administered two tablets (2*150 mg tablets) of investigational medicinal 
product in morning and evening as per randomization schedule under supervision of 
trained study personnel at clinical facility. 
Dosing on Day l (morning as well as evening) would be done at site. Patients will be 
discharged after administration of evening dose of Day 1 at site. Dosing from Day 2 
to Day 5 morning can be done at home by patients. The patient will be provided with 
sufficient investigational medicinal product for dosing at their home from Day 2 to 
Day 4 (for morning and evening daily dosing at 12-hours interval) and Day 5 
morning dosing. Day 5 evening dose will be done at site. 
Patient will also be provided with a patient diary card to enter the details of study 
drug consumption and details of AE (if any) at their home. Patient and their attendant 
will be provided with adequate instructions to complete the patient diary card at their 
home. 
Patient will be requested to come to the clinical facility for evening dose on Day 5 (at 
least 12 hours prior to scheduled morning dosing on Day 6) for housing in the clinical 
facility. 
During the patients stay in the clinical facility on Day 6, Day 7 and Day 8 patients 
will be administered the investigational medicinal product at the scheduled time of 
dosing in morning and evening daily at 12-hours interval under supervision of trained 
study personnel. 
In period II: 
Patient will be crossed over to the other investigational medicinal product (allocated 
as per randomization schedule) on Day 9 morning dose. Dosing on Day 9 (morning as 
well as evening) would be done at site. Patient will be discharged after administration 
of evening dose of Day 9 at site. Dosing from Day 10 to Day 13 morning can be done 
at home by patients. The patient will be provided with sufficient investigational 
medicinal product for dosing at their home from Day 10 to Day 12 (for morning and 
evening daily dosing at 12-hours interval) and Day 13 morning dosing. Day 13 
evening dose will be done at site. 
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Page 17 of91 


Posture 
restrictions 
Dietary and 
Water 
restrictions 
Confidential 
Patient will also be provided with a patient diary card to enter the details of study 
drug consumption and details of AE (if any) at their home. Patient and their attendant 
will be provided with adequate instructions to complete the patient diary card at their 
home. 
Patient will be requested to come to the clinical facility for evening dose on Day 13 
(at least 12 hours prior to scheduled morning dosing on Day 14) for housing in the 
clinical facility. 
During the patients stay in the clinical facility on Day 14, Day 15 and Day 16 patients 
will be administered the investigational medicinal product at the scheduled time of 
dosing in morning and evening daily at 12-hours interval under supervision of trained 
study personnel. 
Note: 
• 
In the Dose Stabilization period, patients will receive approved marketed 
version of Olaparib, details of the same will be included in IMP plan. 
• 
After the study is completed (after last PK sample collection on Day 16), 
patients may be continued on their current dose of Olaparib using an approved 
Olaparib product as prescribed by their clinicians. 
Patients will be advised to remain awake and in semi-reclined position for the first 4 
hours after morning dosing on Day 1, Day 8 and Day 16. They will be asked to rise 
only with assistance during this period of time and at the first rising when this period 
is over. 
After 4 hours after dosing, the patients will be allowed to engage in normal activities 
while avoiding strenuous physical exertion. 
On housing days, patients will be required to do an overnight fast. of at least 8 hours 
before their scheduled time for dosing and for 4 hours after dosing for the morning 
dose, and 2 hours before their scheduled time for dosing and 2 hours after dosing for 
the evening dose. 
For dosing at home, all patients will be required to remain in fasting condition of at 
least 2 hours before their scheduled time for dosing and 2 hours after dosing for 
morning and evening dose. 
On housing days, patients will receive standard meals (lunch, snacks and dinner) with 
Page 18 of91 


Housing 
Duration of 
Study 
the same quantity and same menu will be used (on housing days) for both periods. 
There will not be any pre-dose and post-dose water restriction during dosing at home. 
On housing days, water will not be allowed for I hour before and 1 hour after 
morning dose and evening dose drug administration, when no liquid should be 
permitted other than that 240 mL (:1:5 m.L) for drug dosing. 
Patients will be housed in the clinical facility at least 12 hours prior to morning dose 
on Day I and will be confined for at least 12 hours after morning dose on Day 1. 
The patients will also be housed in the clinic at least 12 hours before morning dose on 
Day 6 until 12 hours post morning dose on Day 9. The patients will also be housed in 
the clinic at least 12 hours before morning dose on Day 14 until 12 hours post 
morning dose on Day 16. 
Note: In addition to above requirements, the patients may be housed in the clinical 
facility (hospital) for the entire duration of the study or a definite duration in the 
study, if in the opinion of the Investigator, it facilitates the study procedures or for 
social reasons (like difficulty in travelling etc.). The Investigator will be required to 
document this decision in the patient source document (like patient hospital records). 
Hospitalizations peifonned for these reasons will not be considered as SAE. 
However, if the patient is hospitalised for reasons related to safety or adverse events, 
the hospitalization will be considered as SAE. 
Total expected study duration will be approximately 64 days consisting of: 
• 
Screening period including 10-day Dose Stabi)ization period: 40 days 
• 
Treatment Period: 16 days 
• 
End of Study: on Day 16 
• 
Safety follow-up visit: On Day 24 ± 2 days; 8 ± 2 days after End of Study 
For patients who are already receiving a stable dose of Lynparza® (olaparib) tablets 
(2*150 mg twice daily) for at least 10 days before screening visit, the duration of 
screening period will be 30 days. Expected study duration will be approximately 54 
days. 
Blood Collection 
A total of 43 blood samples each of 03 mL will be collected from each patient for PK 
Times 
assessment during the study. 
The venous blood samples will be withdrawn from each patient in each period at the 
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Page 19of 91 


minutes. In all instances, however, the exact time of dosing and of each sample 
collection must be recorded. Samples collected outside the scheduled time will be 
considered as protocol deviations. 
Note: 
• -b]ood sample must be collected prior to next drug administration. 
• 
Blood sample collection (PK samples) will be collected first if other activities 
are coinciding. 
Clinical and 
It is the responsibility of the PI to ensure that adequate medical supervision and care 
safety assessment 
is available for the study patients during housing and during the study duration to 
ensure the utmost safety and well-being of the study patients. At study sites, medical 
personnel will be available 24 hours a day and physician in charge will remain at the 
clinical site for at least the first 4 hours following drug administration. On PK 
sampling days (Day 8 and 16), investigator will remain at the clinical site for at least 
the first 4 hours following morning drug administration. In addition, if necessary, 
investigators will be available on-call at all times. 
Confidential 
Medical and Medication history and Review of Inclusion and Exclusion Criteria: 
Screening and at the time of randomization. 
IIER2 Testing (Only applicable for breast cancer patients): Screening (If the 
report is not available with the patients at the time of screening). 
Germline or Somatic BRCAl and BRCA2 diagnostic test for olaparib by NGS -
Next Generation Sequencine method: Screening (the details for applicable patients 
and type of sample as per the section 5.6) 
Note: The Gcrmline or Somatic BRCAl and BRCA2 test need not be repeated in 
those patients who have been started on olaparib post BRCA testing done by NGS -
Next Generation Sequencing method. 
Page20of91 


Confidential 
Physical examination: Screening, Day 0, Day 5, Day 13 and end of study (Day 16), 
Safety follow up (on day 24±2). 
Demographics: Age, gender, ethnicity and race will be noted at screening visit. 
Vital signs and body measurements: 
Body height: Screening visit 
Body weight Screening, End of Study 
Body temperature, Blood pressure, Heart rate and Respiratory rate: 
o Screening 
o Day 0, Day 5 and Day 13 
o Before morning dose on Day 1, Day 6 to Day 9 and on Day 14 to Day 16 
o At 3 hour after morning dose on Day 6 to Day 9 and on Day 14 to Day 16 
o End of study (Day 16) 
o Safety follow up (On day 24±2) 
o Note: Blood pressure, pulse rate, respiratory rate and body temperature 
prior to IMP administration will be measured within 60 minutes prior to 
dosing and after administration of the IMP will be measured within ± 30 
minutes of the scheduled time. 
Additional vital examinations may be performed at any time during the study as per 
Investigator's judgment; all results must be documented appropriately. 
HIV, HCV, HbSAg, and VDRL or RPR (for syphilis): Screening 
12-Lead ECG: Screening, Day 5, Day 13 and End of Study (Day 16) 
2D-ECHO: Screening 
Orine drug Screen (benzodiazepines, opioids, amphetamines, cannabinoids, 
cocaine and barbiturates) and Alcohol Breath Test: Day 0, Day 5 and Day I 3. 
Note: Separate mouthpiece will be used in breath test for every patient in the study. 
Pregnancy test: Screening visit (Serum), Day 0, Day 5, Day 13 (Urine), and at End 
of Study Visit (Serum) for FCBP only. 
X-ray (chest): To be performed based on Investigator's discretion. 
Page21 of 91 


Concomitant 
Medications 
Confidential 
Hematology, Blood chemistry and Urinalysis: Screening, and at the end of the 
study (Day 16) 
CBC, Creatinine Clearance, S Bilirubin, SGPT and SGOT: Prior to dosing in 
period 1 (Day -2 to 0) and period 2 (can be performed after evening dose on Day 8) 
(can be done at local laboratory) 
In addition to protocol-specific laboratory tests and/or clinical examinations at 
scheduled time points, additional tests/clinical examination may be conducted to 
evaluate patient safety at any time during the study, at the discretion of the 
Investigator ( can be done in local laboratory or nearby clinic/hospital/institution). 
Note: It is recommended that general precautions should be taken by the staff with 
respect to ongoing COVID-19 pandemic situation during the trial. 
Prohibited Medications: Moderate or strong CYP 3A4 inhibitors or inducers (refer 
annexure IV) 
Patients should be instructed to avoid grapefruit, grapefruit juice, Seville oranges, 
Seville orange juice, starfruit and pomelo. 
Any drug therapy taken by a patient should be the same for both periods. If a change 
in concomitant medications is necessary or if drug therapy (prescription or over-the-
counter) other than that specified in the protocol is required prior to or during the 
study, decisions shall be taken by the Investigator and sponsor to continue or 
discontinue the patient based on the following: 
• 
The phannacology and pharmacokinetics of the non-study medication. 
• 
The likelihood of a drug-drug interaction, thereby affecting the pharmacokinetic 
comparison of study medicine. 
• 
The likelihood of a drug-drug LC-MS/MS cross-interaction, thereby affecting the 
determination of olaparib concentration in patient plasma. 
• 
The time and duration of administration of the non-study medicine. 
If it is necessary for the patient's safety to add any medication that interferes or 
changes the PK of olaparib, the patient should be withdrawn from the study. 
Before prescribing any drug it is mandatory to refer Prescribing Information of 
Lynparza® including but not limited to interaction with other medicinal products and 
Page22of9l 


Drug Analysis 
Pharmacokinetic 
and Statistical 
Methods 
Confidential 
other forms of interaction, contraindications, special warnings and precautions for 
use, undesirable side effects, etc. 
The Investigator should ask the patient to notify the study site of any new 
medications they take after the start of the study. 
All instances of concomitant drug administration will be recorded and reported in the 
CRF and final report. 
Medication taken prior to first dosing: All prescription medications and over-the-
counter drugs (including vitamins and herbal remedies) taken within 30 days prior to 
screening must be recorded in the CRF. 
Concomitant medications: All the medications ongoing at the time of consent and 
medications conswned until the end of the study safety assessments will be recorded 
in prior/concomitant medications section of the CRF. 
The concentration of Olaparib in plasma samples will be quantified at 
using a validated LC-MS/MS method. 
test version o Bio-analytical plan for details. 
tic and statistical analysis will be performed a 
Using the concentration time profile of Olaparib, the following pharmacokinetic 
parameters will be computed and reported: 
Primary variables: Cmo.xss and AUCco.,,)Ss 
Secondary variables: Cmmss, T maxSS, CavSs, swing and percentage of fluctuation. 
ANOV A, least squares means for test .and reference formulations, difference between 
test and reference formulations, intra-subject variability and power will be calculated 
for In-transformed pharmacokinetic parameters Cma>cSs and AUC<o-,)ss. Geometric least 
squares means of test and reference formulations, T/R ratio, 90% confidence interval 
for geometric least squares means ratio and Two One-Sided Tests for 90% confidence 
interval limits will be calculated for phannacokinetic parameters Cmax.5s and AUC<o-
•>Ss. 
By considering the three day's morning pre-dose concentrations in a given period, 
Page 23 of91 


Bioequivalence 
criteria 
Confidential 
steady state analysis will be performed for each subject in each period by using the 
linear regression analysis to obtain the p-values. The above analyses will be done 
using procedure PROC REG in SAS, version 9 .4 or higher. 
For achieving the steady state following procedure shouJd be assessed: 
Step 1: For each subject in each period the P-values should be statistically 
insignificant at 5% level of significance. 
If, P-values are found statistically insignificant, those patients are considered to 
achieve steady state. If, P-values are found significant for particular subject then go 
for the second step. Go for second step for patients who have missing pre-dose 
sample for Day 6 or Day 14. 
Step 2: Ratio of the pre-dose concentrations of last two pre-dose should be 2: 80.00% 
or should be :S 120.00%. 
Jn case ratio of last two pre-dose concentrations is found to be 2: 80.00% or :s 
120.00% patients will be considered to achieve steady state. If two pre-dose 
concentrations is found to be less than 80.00% or greater than 120.00%, patients will 
not be considered to achieve steady state and will be removed from bioequivalence 
evaluation. 
Two stage design according to Potvin C: 
Evaluate the power at stage I using the variance estimate from stage 1 and an a level 
of0.05. If the power is greater than or equal to 80%, evaluate BE at stage 1 using an 
a level of 0.05 and stop whether BE is met or not. If the power is less than 80%, 
evaluate BE using an a of 0.0294. If the BE criterion is met, stop. If the BE criterion 
is not met, calculate the sample size based on the variance estimated at stage I and an 
a level of0.0294 and continue to stage 2. If the ratio is outside 80.00%-125.00% then 
study will not proceed for stage 2. Evaluate BE at stage 2 using data from both stages 
and an a level of 0.0294. Stop here whether BE is met or not and regardless of the 
power achieved. 
For Stage 1 with Power 2: 80%: 
Based on the statistical results of 90% confidence intervals for the geometric least 
squares means ratio for the log-transformed pharmacokinetic parameters Cmaxss and 
AUC<o-,)Ss for Olaparib the conclusions will be drawn whether test formulation is 
bioequivalent to reference formulation under Fasting condition. Acceptance range for 
bioequivalence is 80.00%-125.00% for 90% confidence intervals of the geometric 
Page 24of91 


least square means ratio of Cmaxss and AUC(o-,Jss. 
For Stage 1 with Power< 80% and for Stage 2, ifrequired: 
Based on the statistical results of94.12% confidence intervals for the geometric least 
squares means ratio for the log-transformed pharmacokinetic parameters Cmaxss and 
AUC(o-tJss for Olaparib the conclusions will be drawn whether test fonnulation is 
bioequivalent to reference formulation under Fasting condition. Acceptance range for 
bioequivalence is 80.00%-125.00% for 94.12% confidence intervals of the geometric 
least square means ratio of Cmaxss and AUC(1MJss. 
Ethical Issue 
The study will commence only after a written approval is obtained from the 
Institutional Ethics Committee and applicable regulatory authorities. The study will 
be conducted as per the biomedical research on human participants (ICMR) 2017 
guidelines, New Drugs and Clinical Trial Rules (2019) of India, USFDA regulations, 
rules and guidelines, ICH (Step 5) 'Guidance on Good Clinical Practice' JCH 
Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013) and with procedures 
oriented to Good Laboratory Practice and applicable regulatory guidelines. 
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Page 25of91 


4.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
4.1 
Clinical Facilities 
Investigator's Sites 
4.2 
Bio-analytical, Pbarmacokinetics and Biostatistics Services and Quality Assurance 
4.3 
Medical Experts 
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Page26of91 


5.0 
BACKGROUND INFORMATION 
5.1 
Introduction
2 
Olapanl> is a poly (ADP-ribose) polymerase (PARP) inhibitor. It has the following chemical structure: 
0 
Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility across the 
physiological pH range. 
Olaparib tablets for oral use contain 100 mg or 150 mg of olaparib, however only the 150 mg tablet strength 
will be used in this study. 
5.2 
Pharmacology2 
Mechanism of Action 
Olapanl> is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARPI, PARP2, and 
PARP3. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA 
repair. 
Pharmacodynamics 
Cardiac Electrophysiology 
The effect of olaparib on cardiac repolarization was assessed in 119 patients following a single dose of 300 
mg and in 109 patients following multiple dosing of 300 mg twice daily. No clinically relevant effect of 
olaparib on QT interval was observed. 
Pharmacokinetics 
The area under the curve (AUC) of olaparib increases approximately proportionally following administration 
of single doses of25 mg to 450 mg (0.08 to 1.5 times the recommended dose) and maximal concentrations 
(Cmax) increased slightly less than proportionally for the same dose range. Olaparib showed time-dependent 
pharmacokinetics and an AUC mean accumulation ratio of 1.8 is observed at steady state following a dose of 
300 mg twice daily. 
The mean (CV%) olaparib Cmax is 5.4 µg/mL (32%) and AUC is 39.2 µg*h/mL (44%) following a single 
300 mg dose. The mean steady state olaparib Cmax and AUC is 7.6 µg/mL (35%) and 49.2 µg*b/mL (44%), 
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Page 27of91 


following a dose of 300 mg twice daily. 
Absorption 
Following oral administration of olaparib, the median time to peak plasma concentration is 1.5 hours. 
Effect of Food 
Co-administration of a high fat and high calorie meal (800-1000 kcal, 50% of the calorie content made up 
from fat) with olaparib slowed the rate (tmax delayed by 2.5 hours) of absorption, but did not significantly 
alter the extent of olaparib absorption (mean AUC increased by approximately 8%). 
Distribution 
The mean (± standard deviation) apparent volume of distribution of olaparib is 158 :1: 136 L following a 
single 300 mg dose of Olaparib. The protein binding of olaparib is approximately 82% in vitro. 
Elimination 
The mean (± standard deviation) terminal plasma half-life of olaparib is 14.9 ± 8.2 hours and the apparent 
plasma clearance is 7.4 ± 3.9 L/h following a single 300 mg dose of Olaparib. 
Metabolism 
Olaparib is metabolized by cytochrome P450 (CYP) 3A in vitro. 
Following an oral dose ofradiolabeled olaparib to female patients, unchanged olaparib accounted for 70% of 
the circulating radioactivity in plasma. It was extensively metabolized with unchanged drug accounting for 
15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable 
to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or 
sulfate conjugation. 
Excretion 
Following a single dose ofradiolabeled olaparib, 86% of the dosed radioactivity was recovered within a 7-
day collection period, 44% via the urine and 42% via the feces. The majority of the material was excreted as 
metabolites. 
Specific Populations 
Patients with Renal Impairment 
In a renal impairment trial, the mean AUC increased by 24% and Cmax by 15%, when olaparib was dosed in 
patients with mild renal impairment (CLcr-51 -80 milmin defined by the Cockcroft-Gault equation; n= 13) 
and by 44% and 26%, respective]y, when olaparib was dosed in patients with moderate renal impairment 
(CLcr=31-50 mUmin; n=13), compared to those with normal renal function (CLcr ~81 mUmin; n=l2). 
There was no evidence of a relationship between the extent of plasma protein binding of olaparib and 
creatinine clearance. There are no data in patients with severe renal impairment or end-stage renal disease 
(CLcr $30 mL/min). 
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Page 28 of91 


Patients with Hepatic Impairment 
Tn a hepatic impairment trial, the mean AUC increased by 15% and the mean Cmax increased by 13% when 
olaparib was dosed in patients with mild hepatic impairment (Child-Pugh classification A; n=lO) and the 
mean AUC increased by 8% and the mean Cmax decreased by 13% when olaparib was dosed in patients with 
moderate hepatic impairment (Child-Pugh classification B; n=8), compared to patients with normal hepatic 
function (n=13). Hepatic impairment has no effect on the protein binding of olaparib and, therefore, total 
plasma exposure was representative of free drug. There are no data in patients with severe hepatic 
impairment (Child-Pugh classification C). 
Drug Interaction Studies 
Clinical Studies 
CYP3A Inhibitors: Concomitant use ofitraconazole (strong CYP3A inhibitor) increased olaparib Cmax by 
42% and AUC by 170%. Concomitant use of fluconazole (moderate CYP3A inhibitor) is predicted to 
increase olaparib Cmax by 14% and AUC by 121%. 
CYP3A Inducers: Concomitant use of rifampicin (strong CYP3A inducer) decreased olaparib Cmax by 71 ¾ 
and AUC by 87%. Concomitant use of efavirenz (moderate CYP3A inducer) is predicted to decrease olaparib 
Cmax by 31 % and AUC by 60%. 
In vitro Studies 
CYP Enzymes: Olaparib is both an inhibitor and inducer ofCYP3A and an inducer ofCYP2B6. Olaparib is 
predicted to be a weak CYP3A inhibitor in hwnans. 
UGT Enzymes: Olaparib is an inhibitor ofUGTIA 1. 
Transporters: Olaparib is an inhibitor ofBCRP, OATPlBl, OCTl, 0Cf2, OAT3, MATE!, andMATE2K. 
Olaparib is a substrate and inhibitor of the efflux transporter P-gp. The potential for olaparib to induce P-gp 
has not been evaluated. 
5.3 
Adverse Reactions2 
Adverse Reactions from Clinical Studies 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not 
reflect the rates observed in practice. 
The data described in the "Warnings and precautions" section of Prescribing information2 reflect exposure 
to olaparib as a single agent in 2901 patients; 2135 patients with exposure to 300 mg twice daily tablet dose 
including five controlled, randomized, trials (SOLO-I, SOL0-2, OlympiAD, POLO, and PROfound) and to 
400 mg twice daily capsule dose in 766 patients in other trials that were pooled to conduct safety analyses. In 
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Page 29 of 91 


these trials, 56% of patients were exposed for 6 months or longer and 28% were exposed for greater than one 
year in the Olaparib group. 
In this pooled safety population, the most common adverse reactions in 10% of patients were nausea ( 60% ), 
fatigue (55%), anemia (36%), vomiting (32%), diarrhea (24%), decreased appetite (22%), headache (16%), 
dysgeusia (15%), cough (15%), neutropenia (14%), dyspnea (14%), dizziness (12%), dyspepsia (12%), 
leukopenia (II%), and thrombocytopenia (10%). 
First-Line Maintenance Treatment ofBRCA-mutated Advanced Ovarian Cancer 
SOLO-1 
The safety of Olaparib for the maintenance treatment of patients with BRCA-mutated advanced ovarian 
cancer following first-line treatment with platinum-based chemotherapy was investigated in SOLO-1. 
Patients received Olaparib tablets 300 mg orally twice daily (n=260) or placebo (n=l30) until disease 
progression or unacceptable toxicity. The median duration of study treatment was 25 months for patients who 
received Olaparib and 14 months for patients who received placebo. Among patients who received Olaparib, 
dose i.ntenuptions due to an adverse reaction of any grade occurred in 52% and dose reductions due to an 
adverse reaction occurred in 28%. The most frequent adverse reactions leading to dose interruption or 
reduction of Olaparib were anemia (23%), nausea (14%), and vomiting (10%). Discontinuation due to 
adverse reactions occurred in 12% of patients receiving Olaparib. The most frequent adverse reactions that 
led to discontinuation of Olaparib were fatigue (3.1 %), anemia (2.3%), and nausea (2.3%). 
Table: Adverse Reactions Occurring in SOLO-I (2:10% of Patients Who Received Olaparib) 
Adverse Reaction 
Gastrointestinal Disorders 
Nausea 
Abdominal paint 
Vomiting 
Diarrhea' 
Constipation 
Dyspepsia 
Stoma ti tis§ 
Olaparib tablets 
n=260 
All Grades 
(%) 
77 
45 
40 
37 
28 
17 
ll 
Grades 
3-4(%) 
I 
2 
0 
3 
0 
0 
0 
General Disorders and Administration Site Conditions 
Fatigue1 
67 
4 
Confidential 
Placebo 
n=130 
AU Grade.~ 
(%) 
38 
35 
15 
26 
19 
12 
2 
42 
Grades 
3-4(%) 
0 
0 
0 
0 
0 
2 
Page 30of91 


Blood and Lymphatic System Disorders 
Anemia 
38 
21 
9 
2 
Neutropenia" 
17 
6 
7 
3 
Leukopenia" 
13 
3 
8 
0 
Thrombocytopenia
0 
11 
l 
4 
2 
Infections and Infestations 
Upper respiratory tract infection/ 
28 
0 
23 
0 
influenza/nasopharyngitis/bronchitis 
UTP 
13 
1 
7 
0 
Nervous System Disorders 
Dysgeusia 
26 
0 
4 
0 
Dizziness 
20 
0 
15 
l 
Metaboli'lm and Nutrition Disorders 
Decreased appetite 
20 
0 
10 
0 
Respiratory, Thoracic and Mediastinal Disorders 
Dyspoea• 
15 
0 
6 
0 
• Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.0. 
t Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal distension, abdominal discomfort, 
and abdominal tenderness. 
tlncludes colitis, diarrhea, and gastroenteritis. 
§Includes siomatitis, aphthous ulcer; and mouth ulceration. 
1 Includes asthenia, fatigue, lethargy, and malaise. 
# Includes neutropenia, and febrile neutropenia. 
I> Includes leukopenia. and white blood cell count decreased. 
6 lncludes platelet count decreased, and thrombocytopenJa. 
a Includes urosepsis, urinary tract infection, urinary tract pain, and pyuria 
e Includes dyspnea, and dyspnea exertional. 
In addition, the adverse reactions observed in SOL0-1 that occurred in <10% of patients receiving Olaparib 
were increased blood creatinine (8%), lymphopenia (6%), hypersensitivity (2%), MDS/AML (1%), 
dermatitis (1%), and increased mean cell voh.uhe (0.4%). 
Table 3 Laboratory Abnormalities Reported in ~25% of Patients in SOL0 -1 
Laboratory Parameter . 
Olaparib tablets 
Placebo 
nt=260 
nt=130 
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Page 31 of91 


Grades 1-4 
Grades3-4 
Grades 1-4 
(%) 
(%) 
(¾) 
Decrease in hemoglobin 
87 
19 
63 
Jncrease in mean corpuscular volume 
87 
43 
Decrease in leukocytes 
70 
7 
52 
Decrease in lymphocytes 
67 
14 
29 
Decrease in absolute neutrophil count 
51 
9 
38 
Decrease in platelets 
35 
20 
Jncrease in serum creatinine 
34 
0 
18 
• Patients were allowed to enter clinfoal studies with laboratory values ofCTCAE Grade I. 
Grades 3-4 
(%) 
2 
5 
6 
2 
0 
t This number represents the safety population. The derived values in the .table are based on the total number of 
evaluablepatients for each laboratory parameter. 
Maintenance Treatment of Recurrent Ovarian Cancer 
SOL0-2 
The safety of Olaparib for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian 
cancer was investigated in SOL0-2. Patients received Olaparib tablets 300 mg orally twice daily (n=195) or 
placebo (n=99) until disease progression or unaccep~ ble toxicity. The median duration of study treatment 
was 19.4 months for patients who received Olaparib and 5.6 months for patients who received placebo. 
Among patients who received Olaparib, dose interruptions due to an adverse reaction of any grade occurred 
in 45% and dose reductions due to an adverse reaction occurred in 27%. The most frequent adverse reactions 
leading to dose interruption or reduction of Olaparib were anemia (22%), neutropenia (9%), and 
fatigue/asthenia (8%). Discontinuation due to an adverse reaction occurred in 11% of patients receiving 
Olaparib. 
Below tables summarize adverse reactions and laboratory abnormalities in SOL0-2. 
Table: Adverse Reactions* in SOL0-2 ('?:lOo/o of Patients Who Received Olaparib) 
Adverse Reaction 
Olaparib tablets 
Placebo 
n=195 
n=99 
Grades 1-4 
Grades3-4 
Grades 1-4 
Grades 3-4 
(%) 
(%) 
(%) 
(%) 
Gastrointestinal Disorders 
Nausea 
76 
3 
33 
0 
Vomiting 
37 
3 
19 
I 
Diarrhea 
33 
2 
22 
0 
Stomatitis1 
20 
I 
16 
0 
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General Disorders and Administration Site Conditions 
Fatigue including asthenia 
66 
4 
39 
2 
Blood and Lymphatic Disorders 
Anemia• 
44 
20 
9 
2 
Infections and Infestations 
Nasopharyngitis/URl/sinusitis/ 
36 
0 
29 
0 
rhinitis/influenza 
Museuloskeletal and Connective Tissue Disorders 
Artbralgia/myalgia 
30 
0 
28 
0 
Nervous System Disorders 
Dysgeusia 
27 
0 
7 
0 
Headache 
26 
I 
14 
0 
Metabolism and Nutrition Disorders 
Decreased appetite 
22 
0 
11 
0 
* Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
vcrsion4.0. 
t Represents grouped term consisting of abscess oral, aphlbous ulcer, gingival abscess, gingival disorder, gingival 
pain, gingivitis, mouth ulceration, mucosa! infection, mucosal inflammation, oral candidiasis, oral discomfort, 
oral herpes, oral infection, oral mucosal erytherna, oral pain, orophaxyngeal di.<;comfort, and oropharyngeal pain. 
f Represents grouped term consisting of anemia, hematocrit decreased, hemoglobin decreased, iron deficiency, mean cell 
vohune increased and red blood cell count decreased. 
In addition, the adverse reactions observed in SOL0-2 that occurred in <20% of patients receiving Olaparib 
were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%), thrombocytopeuia 
(14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), MDS/AML (8%), edema (8%), rash 
(6%), and lymphopenia (1%). 
Table: Laboratory Abnormalities Reported in 2::25% of Patients in SOL0 -2 
Laboratory Parameter 
Olaparib tablets 
Placebo 
nt=195 
nt=99 
Grades 1-4 
Grades 3-4 
Grades 1-4 
Grades3-4 
(%) 
(%) 
(%) 
(%) 
Increase in mean corpuscular volume• 
89 
-
52 
-
Decrease in hemoglobin 
83 
17 
69 
0 
Decrease in leukocytes 
69 
5 
48 
l 
Decrease in lymphocytes 
67 
11 
37 
I 
Decrease in absolute neutrophil count 
51 
7 
34 
3 
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Increase in serum creatinine 
44 
0 
29 
0 
Decrease in platelets 
42 
2 
22 
I 
• Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1. 
t This number represents the safety population. The derived values in the table are ba.~ed on 1hc total number of 
evaluablepatients for each laboratory parameter. 
t Represents the proportion of subjects whose mean c01p uscular volume was> upper limit ofnormal (ULN). 
Study 19 
The safety of Olaparib as maintenance monotherapy was evaluated in patients with platinum sensitive 
ovarian cancer who had received 2 or more previous platinum containing regimens in Study 19. Patients 
received Olaparib capsules 400 mg orally twice daily (n=136) or placebo (n= 128). At the time of final 
analysis, the median duration of exposure was 8.7 months in patients who received Olapanb and 4.6 months 
in patients who received placebo. 
Adverse reactions led to dose interruptions in 35% of patients receiving Olaparib; dose reductions in 26% 
and discontinuation in 6% of patients receiving Olaparib. 
Below tables swnmarize adverse reactions and laboratory abnormalities in Study 19. 
Table: Adverse Reactions* in Study 19 ~0% of Patients Who Received Olaparib) 
Adverse Reaction 
Olaparib capsules 
Placebo 
o=l36 
n=l28 
Grades 1-4 
Grades3-4 
Grades 1-4 
Grades 3-4 
(%) 
(%) 
(%) 
(%) 
Gastrointestinal Disorders 
Nausea 
71 
2 
36 
0 
Vomiting 
35 
2 
14 
I 
Diarrhea 
28 
2 
25 
2 
Constipation 
22 
l 
12 
0 
Dyspepsia 
20 
0 
9 
0 
General Disorders and Administration Site Conditions 
Fatigue (including asthenia) 
63 
9 
46 
3 
Blood and Lymphatic Disorders 
Anemiar 
23 
7 
7 
I 
Cnfections and Infestations 
Respiratory tract infection 
22 
2 
11 
0 
Metabolism and Nutrition Disorders 
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Decreased appetite 
21 
0 
13 
0 
Nervous System Disorders 
Headache 
21 
0 
13 
I 
• Graded according to NCI CTCAE v4.0. 
t Represents grouped tenns of related terms that reflect the medical concept of the adverse reaction. 
In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Olaparib were 
dysgeusia (16%), dizziness (15%), dyspnea (13%), pyrexia (10%), stomatitis (9%), edema (9%), increase in 
creatinine (7%), neutropenia (5%), thrombocytopenia (4%), leukopenia (2%), MDS/ AML (1 %) and 
lymphopenia (1%). 
Table: Laboratory Abnormalities Reported in ~5% of Patients in Study 19 
Laboratory Parameter· 
Olaparib capsules 
Placebo 
nt==136 
nt==129 
Grades 1-4 
Grades3-4 
Grades 1-4 
Grades3-4 
(%) 
(%) 
(%) 
(%) 
Decrease in hemoglobin 
82 
8 
58 
1 
Increase in mean corpuscular volume~ 
82 
-
51 
-
Decrease in leukocytes 
58 
4 
37 
2 
Decrease in lymphocytes 
52 
10 
32 
3 
Decrease in absolute neutrophil count 
47 
7 
40 
2 
Increase in serum creatinine 
45 
0 
14 
0 
Decrease in platelets 
36 
4 
18 
0 
* Patients were allowed to enter clinical studies with laboratory values ofCTCAE Grade I . 
t This number represents the safety population. The derived values in the table are based on the total number of 
evaluablepatients for each labor.itory parameter. 
t Represent~ the proportion of subjocts whose mean corpuscular volume was> ULN. 
Advanced Germline BRCA-mutated Ovarian Cancer After 3 Q[ Mote Lines ofChemothem12::x: 
Pooled Data 
The safety of Olaparib was investigated in 223 patients (pooled from 6 studies) with gBRCAm advanced 
ovarian cancer who had received 3 or more prior lines of chemotherapy. Patients received Olaparib capsules 
400 mg orally twice daily until disease progression or unacceptable tolerability. The median exposure to 
Olaparib in these patients was 5.2 months. 
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There were 8 (4%) patients with adverse reactions leading to death, two were attnbuted to acute leukemia, 
and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, 
sepsis, and suture rupture. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 
4%, and discontinuation in 7%. 
Below tables swnmarize the adverse reactions and laboratory abnormalities from the pooled studies. 
Table: Adverse Reactions Reported in Pooled Data (~0% of Patients Who Received Olaparib) 
Adverse Reaction 
Olaparib capsules 
w:223 
Grades 1-4 
Grades3-4 
(%) 
(%) 
General Disorders 
Fatigue/asthenia 
66 
8 
Gastrointestinal Disorders 
Nausea 
64 
3 
Vomiting 
43 
4 
Diarrhea 
31 
I 
Dyspepsia 
25 
0 
Decreased appetite 
22 
1 
Blood and Lymphatic Disorders 
Anemia 
34 
18 
Infections and Infestations 
Nasopharyngi tis/URI 
26 
0 
Musculoskeletal and Connective Tissue Disorders 
Artbralgia/musculoskeletal pain 
21 
0 
Myalgia 
22 
0 
Table: Laboratory Abnormalities Reported in ~5% of Patients in Pooled Data 
Laboratory Parameter· 
Olaparib capsules 
nt=223 
Grades 1-4 
Grades3--4 
(%) 
(%) 
Decrease in hemoglobin 
90 
15 
Mean corpuscular volume elevation 
57 
-
Decrease in lymphocytes 
56 
17 
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Decrease in platelets 
30 
3 
Increase in creatinine 
30 
2 
Decrease in absolute neutrophil count 
25 
7 
• Patients were allowed to enter clinical studies with laboratory values of CTCAE Gr.ide I. 
t This number represents the safety population. The derived values in the table are based on the total number of evaluablepatients for 
each laboratory parameter 
The following adverse reactions and laboratory abnormalities have been identified in :::.IO to <20% of the 223 
patients receiving Olaparib and not included in the table: cough (16%), constipation (16%), dysgeusia (16%), 
headache (15%), peripheral edema (14%), back pain (14%), urinary tract infection (14%), dyspnea (13%), 
and dizziness (11 %). 
The following adverse reactions and laboratory abnormalities have been identified in <10% of the 223 
patients receiving Olaparib and not included in the table: leukopenia (9%), pyrexia (8%), peripheral 
ncuropatby (5%), hypomagnesemia (5%), rash (5%), stomatitis (4%), MDS/AML (1.8%), and venous 
thrombosis (including pulmonary embolism) (1%). 
Qermline BR CA-mutated HER2-neS!!tive Metastatic Breast Cancer 
OlvmpiAD 
The safety of Olaparib was evaluated in gBRCAm patients with HER2-negative metastatic breast cancer who 
had previously received up to two lines of chemotherapy for the treatment of metastatic disease in 
OlympiAD. Patients received either Olaparib tablets 300 mg orally twice daily (n=205) or a chemotherapy 
(capecitabine, eribulin, or vinorelbine) of the healthcare provider's choice (n=9I) until disease progression or 
unacceptable toxicity. The median duration of study treatment was 8.2 months in patients who received 
Olaparib and 3.4 months in patients who received chemotherapy. 
Among patients who received Olaparib, dose interruptions due to an adverse reaction of any grade occurred 
in 35¾ and dose reductions due to an adverse reaction occurred in 25%. Discontinuation due to an adverse 
reaction occurred in 5% of patients receiving Olaparib. 
Below tables summarize the adverse reactions and laboratory abnormalities in OlympiAD. 
Table: Adverse Reactions* in OlympiAD (~20% of Patients Who Received Olaparib) 
Adverse Reaction 
Olaparib tablets 
Chemotherapy 
n=205 
n=91 
Grades 1-4 1 Grades 3-4 
Grades 1-4 
I 
Grades3-4 
(o/o) 
(0/4) 
(%) 
(%) 
Gastrointestinal Disorders 
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Nausea 
58 
0 
35 
l 
Vomiting 
30 
0 
15 
l 
Diarrhea 
21 
I 
22 
0 
Blood and Lymphatic Disorders 
AnemiaT 
40 
16 
26 
4 
Neutropeoia• 
27 
9 
50 
26 
Leukopenia9 
25 
5 
31 
13 
General Disorders and Administration Site Conditions 
Fatigue (including asthenia) 
37 
4 
36 
1 
Infedions and Infestations 
Respiratory tract infectionT 
27 
I 
22 
0 
Nervous System Disorders 
Headache 
20 
I 
15 
2 
* Graded according to NCI CTCAE v4.0. 
t Represents grouped terms consisting of anemia (anemia erythropenia, heroatocrit decreased, hemoglobin decreased 
and redblood cell cowl decreased). 
tRepresents grouped terms consisting ofneutropenia (febrile neutropenia, granulocyte count decreased, 
granulocytopenia,neutropenia, neutropenic iufcc1ion, ncutropcnic sepsis, and neutrophil counl decreased). 
§ Represents grouped tenns consisting ofleukopenia (leukopenia and white blood cell count decreased). 
I Represents grouped terms consisting of bronchitis, inf111enza, lower respiratory tract infection. nasopharyngitis, 
pharyngitis,respiratory tract infection, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract 
infection bacterial 
In addition, adverse reactions in OlympiAD that occurred in <20% of patients receiving Olaparib were cough 
(18%), decreased appetite (16%), thrombocytopenia (11%), dysgeusia (9%), lymphopenia (8%), dyspepsia 
(8%), dizziness (7%), stomatitis (7%), upper abdominal pain (7%), rash (5%), increase in serum creatinine 
(3%), and dermatitis (1%). 
Table: Laboratory Abnormalities Reported in 2::25% of Patients in OlympiAD 
Olaparib tablets 
nt=205 
Chemotherapy 
nt= 91 
. 
Laboratory Parameter 
Grades 1-4 
Grades 3-4 
Grades 1-4 
Grades3-4 
(%) 
(%) 
(%) 
(%) 
Decrease in hemoglobin 
82 
17 
66 
3 
Decrease in lymphocytes 
73 
21 
63 
3 
Decrease in leukocytes 
71 
8 
70 
23 
Increase in mean corpuscular vohunei: 
71 
-
33 
-
Decrease in absolute neutrophil count 
46 
11 
65 
38 
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I Decrease in platelets 
I 
33 
I 
3 
I 
28 
I 
* Patients were allowed to enter clinical studies wi1h laboratory values ofCTCAE Grade I. 
t This number represents the safety population. The derived values in lhe table are based on the total number of 
evaluablepatients for each laboratory parameter. 
t Represents the proportion of subjects whose mean corpuscular volume was> ULN. 
Postmarketing Experience
2 
0 
l 
The following adverse reactions have been identified during post approval use of Olaparib. Because these 
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure. 
• 
Immune System Disorders: Hypersensitivity including angioedema. 
• 
Skin and subcutaneous tissue disorders: Erythema nodosum, rash, dennatitis. 
5.4 
Warnings and precautions2 
Myelodysplastic Syndrome/Acute Myeloid Leukemia 
Myelodysplastic syndrome (MDS)/Acute Mycloid Leukemia (AML) has occurred in patients treated with 
Olaparib and some cases were fatal. 
In clinical studies emolling 2901 patients with various cancers who received Olaparib as a single agent, the 
cumulative incidence of MDS/AML was approximately 1.5% (43/2901). Of these, 51% (22/43) had a fatal 
outcome. The median duration of therapy with Olaparib in patients who developed MDS/AML was 2 years 
(range: < 6 months to> 10 years). All of these patients had received previous chemotherapy with platinum 
agents and/or other DNA damaging agents including radiotherapy. 
Do not start Olaparib until patients have recovered from hematological tox1c1ty caused by previous 
chemotherapy (:S Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter 
for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt Olaparib 
and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 
weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and 
blood sample for cytogenetics. IfMDS/AML is confirmed, discontinue Olaparib. 
Pneumonitis 
In clinical studies enrolling 2901 patients with various cancers who received Olaparib as a single agent, the 
incidence of pneumonitis, including fatal cases, was 0.8% (24/2901). If patients present with new or 
worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, 
interrupt Olaparib treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, 
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discontinue Olaparib treatment and treat the patient appropriately. 
Embryo-Fetal Toxicity 
Olaparib can cause fetal harm when administered to a pregnant woman based on its mechanism of action and 
findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the 
period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients 
receiving the recommended human dose of 300 mg twice daily. Apprise pregnant women of the potential 
hazard to a fetus and the potential risk for loss of the pregnancy. Advise females of reproductive potential to 
use effective contraception during treatment and for 6 months following the last dose ofOlaparib. 
Venous Thrombocmbolic Events 
Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with metastatic 
castration resistant prostate cancer who received Olaparib plus androgen deprivation therapy (ADT) 
compared to 3.1 % of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. 
Patients receiving Olaparib and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of 
patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms 
of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-
term anticoagulation as clinically indicated. 
5.5 
Indications and usage2,3 
First-Line Maintenance Treatment of BRCA-motated Advanced Ovarian Cancer 
Olapanb is indicated for the maintenance treatment of adult patients with deleterious or suspected deleterious 
germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer 
who are in complete or partial response to first-line platinwn-based chemotherapy. Patients must have 
confirmation of deleterious or suspected deleterious germline and/or somatic mutations in the BRCA I or 2 
using a validated test. 
Maintenance Treatment of Recurrent Ovarian Cancer 
Olaparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, 
fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based 
chemotherapy. There is no requirement for BRCAI/2 testing. 
Advanced Germline BRCA-mutated Ovarian Cancer After 3 or More Lines of Chemotherapy 
Olaparib is indicated for the treatment of adult patients with deleterious or suspected deleterious germline 
BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy. Patients must have confumation of a deleterious or suspected deleterious gBRCA 1/2 mutation 
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before treatment. gBRCAI/2 mutation status should be determined by a validated test. 
Germline BRCA-mutated HER2-negative Metastatic Breast Cancer 
Olaparib is indicated for the treatment of adult patients with deleterious or suspected deleterious gBRCAm, 
HER2-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, 
adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been 
treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Patients must 
have confirmation of a deleterious or suspected deleterious gBRCAI/2 mutation before treatment. 
gBRCAl/2 mutation status should be determined by a validated test method. 
5.6 
Therapeutic Dosage2 
DOSAGE AND ADMINISTRATION 
Patient Selection 
Patients for treatment with Olaparib should be selected based on the presence of deleterious or suspected 
deleterious BRCA mutations, or genomic instability based on the indication, biomarker, and sample type as 
indicated in the table below. 
Table: Biomarker Testing for Patient Selection for indications included in the study 
Indication 
Biomarker 
Sample Type 
Tumor 
Blood 
First-line maintenance 
BRCAlm, BRCA2m 
treatment-of germline 
or somatic BRCAm 
X 
X 
advanced ovarian 
cancer 
Maintenance treatment 
No requirement for 
of recurrent ovarian 
biomarker testing 
cancer 
Advanced gBRCAm 
gBRCAlm, gBRCA2m 
X 
ovarian cancer 
gBRCAm HER2-
gBRC'Alm, gBRCA2m 
negative metastatic 
X 
breast cancer 
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5.7 
Contraindication3 
Hypersensitivity to the active substance or to any of the excipients of olaparib. Breast-feeding during 
treatment and for 1 month after the last dose. 
5.8 
Drug Interaction2 
Use with Anticancer Agents 
Clinical studies of Olaparib with other myelosuppressive anticancer agents, including DNA damaging agents, 
indicate a potentiation and prolongation of myelosuppressive toxicity. 
Effect of Other Drugs on Olaparib 
Strong and Moderate CYP3A Inhibitors 
Coadministration of CYP3A inhibitors can increase olaparib concentrations, which may increase the risk for 
adverse reactions. Strong and Moderate CYP3A Inhibitors are prohibited during the study (refer annexure 
IV). 
Strong and Moderate CYP3A Inducers 
Concomitant use with a strong or moderate CYP3A inducer decreased olapanb exposure, which may reduce 
Olaparib efficacy. Strong and Moderate CYP3A Inducers are prohibited during the study (refer annexure N). 
5.9 
Use in specific populations2 
Pregnancy 
Risk Summary 
Based on findings in animals and its mechanism of action, Olaparib can cause fetal harm when administered 
to a pregnant woman. There are no available data on Olaparib use in pregnant women to inform the drug-
associated risk. In an animal reproduction study, the administration of olaparib to pregnant rats during the 
period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients 
receiving the recommended bum.an dose of 300 mg twice daily. Apprise pregnant women of the potential 
hazard to the fetus and the potential risk for loss of the pregnancy. 
The estimated background risk of major birth defects and miscarriage for the indicated population is 
unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and 
the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies. 
Females and Males of Reproductive Potential 
Pregnancy Testing 
C-Onfidential 
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Pregnancy testing for females of reproductive potential is required prior to initiating treatment with Olaparib. 
Contraception 
Olaparib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive 
potential to use effective contraception during treatment with Olaparib and for at least 6 months following 
the last dose. 
Renal Impairment 
No dosage modification is recommended in patients with mild renal impairment (Cl.er 51 to 80 mUmin 
estimated by Cockcroft-Gault). Patients with moderate (Cl.er 31 to 50 mUmin) and severe (CLcr S30 
ml.lmin) renal impairment are not eligible for the study. Olaparib dosage should be reduced to 200 mg twice 
daily in patients with moderate renal impairment (CLcr 31 to 50 mL/min). There are no data in patients with 
severe renal impairment or end~stage disease (CLcr S30 mL/min) If dose reduction is needed, the patient 
should be withdrawn from the study. 
Hepatic Impairment 
No adjustment to the starting dose is required in patients with mild or moderate hepatic impainnent (Child-
Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh 
classification C). 
6.0 
OBJECTIVE 
• 
Primary Objective: To assess the pharmacokinetics and establish bioequivalence of the Test Product 
(Olaparib tablets, 150 mg) relative to that of Reference Product (Lynparza® (olaparib) tablets 150 mg) in 
patients with BRCA mutated ovarian cancer, recurrent ovarian cancer or metastatic breast cancer. 
• 
Secondary Objective: To monitor the adverse events of patients and to assess safety of each of the two 
formulations. 
7.0 
STUDY DESIGN 
A randomized, open label, multi-centre, two-treatment, two-period, two-sequence, two-stage, multiple dose, 
steady-state, crossover, bioequivalcnce study of Olaparib tablets, 150 mg 
and 
Lynparza® (olaparib) tablets 150 mg 
in patients with BRCA mutated 
ovarian cancer, recurrent ovarian cancer or metastatic breast cancer under fasting condition. 
Rationale: 
The sponsor has developed a generic alternative to the reference-listed brand of olaparib 150 mg tablets. 
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Therefore, this study is being conducted to evaluate the bioequivalence of the test product Olaparib tablets, 
150 mg 
with Lynparza® (olapanb) tablets 150 mg 
• 
in p 
ed ovarian cancer, recurrent ovarian cancer or metastatic breast cancer 
under fasting condition. Current study is randomized, open label, multi-center, two-treatment, two-period, 
two-sequence, two-stage, multiple dose, steady-state, bioequivalence study. The study design and endpoints 
arc based on the FDA product specific guidance ofOlaparib tablet 150 mg4. 
Rationale for selection of two-stage design: 
Bioequivalence studies are generally conducted in healthy subjects and therefore organized in a way that all 
study subjects are dosed at the same time. Consequently, all the superseding procedures (blood draws, meals, 
safety checks, bioanalytics) are done for all subjects in parallel. In contrast, if a bioequivalence study is done 
in patients, these are being recruited for the study as they come to the doctor's office, meaning that they are 
included in the study one by one. In such instances it therefore makes sense to have an interim check to 
assess whether adequate study power was already achieved, and recruitment can be stopped. When the CV is 
relatively high and not enough data are known, a two-stage adaptive design is ideal since it allows to measure 
the observed variability from the actual patients participating in the trial and make adjustments as required 
and as planned in the methodology (approved by the regulators). In addition, adaptive designs are encouraged 
also due to COVID-19 Pandemic, as indicated by the FDA public note5• For these reasons, two-stage design 
is proposed for this bioequivalence study. 
7.1 
Number of Patients 
Considering a maximum expected intra-patient variability of 35% based on available literature estimates, a 
true ratio (T/R) of 0.95, 56 evaluable patients are adequate to achieve at least 81 % power at 5% level of 
significance to meet the bioequivalence limit of 80.00% to 125.00% at Stage 1. 
Sufficient nwnber of patients will be enrolled to have 56 evaluable patients in the Stage I (about, but not 
limited to, 70 enrolled patients) and Stage 2 sample size (if needed) will be decided on the basis of data 
(observed CV) obtained after the completion of Stage 1. Maximum sample size (Stage I + Stage 2) is 
expected, but not limited to, approximately 120 enrolled patients. This is a 2-stage design according to Potvin 
C method 1• Overall expected power is 86%. 
Enrollment will be continued until at least 56 evaluable patients will complete the Stage 1. In case additional 
patients are recruited, those patients will continue the study until completion/withdrawal and be included in 
the phannacokinetic and statistical analyses as applicable. 
Note: Patients enrolled in Stage 1 will not be eligible for Stage 2. 
7 .2 
Randomization Method 
Randomization will be carried out using SAS® (SAS Institute Inc., USA) version 9.4 or higher. 
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Randomization will be done in blocks using PROC PLAN such that the design is balanced. The order of 
receiving reference and test formulations for each patient dwing two-periods of study will be determined 
according to the randomization schedule for Stage 1 and Stage 2 (as applicable). Randomization will be 
generated separately for each stage. 
Period 1 
Period2 
Sequence I 
Test (T) 
Reference (R) 
Sequence2 
Reference (R) 
Test(T) 
Screening and Randomization Numbering 
Each patient will be assigned a unique number that will serve to identify laboratory specimens and all 
documents and will be used throughout the study. If a patient fails to qualify for allocation to the study i.e. is 
a screen failure, bis/her number must not be reused for another patient. 
The screening number will be a combination of the center number, the project number and the patient 
number. The center number will be assigned by- to the investigative site (e.g., A, B, C, D) and 
subsequent sites are assigned consecutive alphabet numbers. Upon signing the informed consent form, the 
patient will be assigned a screening number by the Investigator. At each site, the first patient consented is 
assigned screening number e.g., 
, and sµbsequent patients are assigned consecutive numbers 
(e.g., the second patient consented is assigned screening number 
, the third patient is assigned 
screening nwnber 
). Once a screening number assigned to a patient, that number will not be 
reused for any other patient. 
If the patient is deemed eligible for enrollment into the study and will commence dosing with IMP in Period 
1, then a randomization number will be assigned. The randomization number will be assigned by a 
combination of Site ID and Dosing sequence (e.g., A-01 where A is Site ID and 01 is number of first patient 
dosed, A-02 where A is site ID and 02 is nwnber of second patient dosed). Patient will be randomized on 
first come first serve basis and will be given a randomization nwnber accordingly irrespective of their 
screening number. 
There should be a source document maintained at the site which links the screening number to the 
randomization assignment number (once assigned) and this information wiU also be reflected in screening 
and enrollment log of site investigator file. 
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7.3 
Blinding 
This is an open label study. However, the bio-analyst at- will be blinded to the randomization sequence 
of study drug administration to each of the patient Samples that are shipped to the analytical laboratory will 
not contain treatment information on the sample label. 
7.4 
Duration of Study 
Total expected study duration will be approximately 64 days consisting of: 
• 
Screening period including l 0-day Dose Stabilization period: 40 days 
• 
Treatment Period: 16 days 
• 
End of Study: on Day 16 
• 
Safety follow-up visit: On Day 24 ± 2 days; 8 ±: 2 days after End of Study 
For patients who are already receiving a stable dose ofLynparza® (olaparib) tablets (2*150 mg twice daily) 
for at least 10 days before screening visit, the duration of screening period will be 30 days. Expected study 
duration will be approximately 54 days. 
7.5 
Washout 
There will be no Washout period between study periods. 
7.6 
Premature Termination of the Study 
The sponsor reserves the right to discontinue the participation of either an individual site or the whole study 
at any time, for any reason, including, but not limited to the following: 
• 
Determination of unexpected, significant, or unacceptable risk to participants; 
• 
Patient enrolment is unsatisfactory; 
• 
The Investigator has received from the sponsor all investigational medicinal products, means and 
information necessary to perform the clinical study and has not included any patient after a reasonable 
period of time mutually agreed upon; 
• 
Non-compliance of the investigator, delegated staff with any provision of the clinical study protocol, 
and/or breach of the applicable laws and regulations or breach of the ICH GCP. 
The investigator or the CRO reserves the right to discontinue the study for safety reasons at any time. Toe 
Ethics Committee (EC) or Regulatory Authority may ask to terminate the study, if there are major violations 
of ethical considerations or due to any serious adverse event(s). In all cases sponsor needs to be notified prior 
to study termination. Reasons for termination of study will be provided to patients. In case sponsor/PI 
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decides to terminate the study, the reason(s) for the termination will be notified to the EC and/or Regulatory 
Authority as applicable within 30 working days. 
In the case that the study is discontinued prematurely for any reason including lack of commercial interest in 
pursuing the new drug application, a summary report will be submitted within 3 months. The summary report 
should provide a brief description of the study, the number of patients exposed to the drug, dose and duration 
of exposure, details of adverse drug reactions, if any, and the reason(s) for discontinuation of the study. 
8.0 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Test Product (1) 
Reference Product (R) 
Manufactured for: 
8.1 
Procurement, Storage and Accountability Procedures for Investigational Medicinal Products 
8.1.1 
Receipt and storage oflnvestigational Medicinal Products 
Adequate supplies ofinvestigational medicinal products (IMPs) for dose administration and sample retention 
purpose will be received by Pharmacy custodian at clinical facility o 
from 
sponsor. Test and reference products will be received in their respective pack as supplied by sponsor or as per 
the storage container / label information provided. After receipt of IMPs, they will be transferred to the 
pharmacy. IMPs will be stored in a secure area with restricted access, under controlled storage conditions 
described in the product package labelling, unless otherwise instructed per protocol or ™P management 
plan. Certificates of analysis (COA) with the details of the product will be received from sponsor. 
IMPs sufficient for dosing and retention shall be distributed to sites b 
These 
IMPs shall be distributed to sites in conta.iners labeled with the details of Product name, Product Type 
(Test/Reference), Strength, No. of dosage units, Manufacturer, Batch or Lot No., Expiry date and Storage 
conditions. IMP management plan will be prepared to describe the WP handling, storage, 
distribution/dispensing in detail. 
The Investigator has overall responsibility for ensuring that !MPs are stored in a safe, limited access location, 
according to the conditions noted on the label. All IMPs are to be stored at 20°C to 25°C (68°F to 77°F), 
excursions permitted to 15°C to 30°C (59°F to 86°F), unless otherwise specified in the label. In case of 
temperature excursion (storage outside the labeled storage conditions) of IMP, the monitor must be contacted 
without delay. And in such case the investigator will be instructed by-in consultation with sponsor) to 
either go ahead with the use of WP or quarantine the IMP. 
8.1.2 
Accountability of Investigational Medicinal Products 
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Accountability for each unit of the IMPs will be documented in the respective logs at 
individual investigator sites. The inventory log of IMP shipments will be maintained at 
8.2 
Dispensing 
Dispensing will be done by the delegated site personnel for the IMPs received from 
Only the Investigator and his/ her team will be responsible for the dispensing/administration/dosing of 
IMPs at the sites. Only patients randomized in the study will receive IMPs. The IMPs will be issued to the 
patient(s) according to the randomization schedule. Treatments for individual patients will be dispensed at 
the study sites. Patient will be given adequate IMPs for dosing at home for Days 2 to 4 (morning and 
evening), Day 5 (morning), Days 10 to 12 (for morning and evening) and Day 13 (morning). Patients will be 
reminded to store the IMPs in the original package at 20°C to 25°C (68°F to 77°F) and to return all unused 
IMPs to the study staff. 
The Investigator team will be responsible for the accountability of admimstered/dosed IMPs at the study site. 
The drug accountability log for recording the receipt, issuance to the patients, and return of the IMPs will be 
maintained by the Investigator or authorized personnel. Limited responsibility may be delegated to a 
pharmacy representative if the investigator chooses to use a hospital or clinical pharmacy for the dispensing 
of the IMPs. However, this delegation must be documented. 
Reconciliation between the amounts ofIMPs supplied, dispensed and unused must be performed by the CRA 
/ monitor / designee and any discrepancies in the reconciliation of the IMPs should have necessary 
clarification. 
8.3 
Handling of Unused Investigational Medicinal Products 
IMPs that have not been dispensed to the patient will be retained in their original containers by the 
Investigator under controlled temperature unless otherwise advise by the 
IMPs that are 
dispensed but un-dosed (e.g., due to the patient being unwell or withdrawal from study etc.) including unused 
IMPs returned by the patients will be labeled as "Not For Use,,, and should be retained at site along with the 
unused samples. This product will be maintained, under controlled temperature conditions, on site until 
further instruction is obtained from the 
ost study completion. 
8.4 
Maintenance of Randomization Code and Dispensing Record 
Randomization code and IMP dispensing record will be kept under controlled access. Personnel involved in 
dispensing of I.MPs (dispensing phannacist), and the Investigator will be accountable for ensuring the 
compliance to randomization schedule and the monitor will confirm compliance during the monitoring visit 
Note: Details of IMP handling, dispensing, preparation and administration will be as per the latest version of 
IMP Plan. 
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8.5 
Retention samples 
Investigator site shall retain the reserve samples as provided b-
These samples must be stored in 
sealed original container under conditions described in section 8.1.l to preserve the original characteristics of 
the products for at least 5 years after obtaining the marketing approval or for 5 years after completion of the 
trial, if not approved for marketing. 
Respective clinical site should be responsible for the use of IMPs for conduct of the study and for retention of 
reserve samples. Site will randomly select the samples from the supplied lMPs for retention as reserve 
samples in a sealed original container and use the remaining IMPs for study purpose. Each clinical site will 
be responsible for the appropriate storage of IMPs and to maintain temperature records for the entire 
duration, until the retention quantities are handed-over to the regulatory agency or until expiration of the 5 
year retention period and sponsor's confirmation. 
If the investigator is unable to retain the reserve samples at site, a third party may be used for retention of 
reserve samples after completion of the study. 
Retention of !MPs will be as per the applicable regulatory requirements, details of which will be provided in 
the IMP plan. 
Note: Separate study-specific IMP plan will be prepared. The storage, receipt, handling, dispensing 
and retention of IMPs will be handled as per latest version of the IMP plan. 
8.6 IMP Non-Conformances 
I. Definitions 
Non-conformances to the investigational medicinal product (test and reference product) or medical 
device can include: 
I) Complaints connected to the quality of the product such as 
o 
any fault of quality and/or effectiveness e.g. change of visual appearance, change of amount, 
damaged tablets/capsules, presence of foreign matter. 
o 
any fault of the containers and outer packages e.g. surface imperfection, container leakage, 
broken syringe/plunger, missing contents, device malfunction. 
o 
any fault of the labeling e.g. missing or illegible label. 
o 
any falsification of the medicinal product or medical device e.g. suspected product mix-up, 
tampering or counterfeiting. 
2) Deviations connected to the transport of the product, such as damaged transport carton and/or 
damaged secondary package upon receipt of the shipment, missing drugs from the shipment 
package, unsuitable transport conditions. 
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2. Process 
In case any of the non-conformances listed above are detected or information about these 
nonconformaoces has been received, the completed Non-conformance Report must be sent to the 
sponsor study manager within 24 hours. In parallel local monitor or CRA of the respective study must 
be informed about the non-conformance. If possible, a photo of affected material should be attached 
to the report. Affected material should be retained and stored according to the storage conditions label 
and/or returned to sponsor if requested by the sponsor. 
9.0 
SELECTION AND WITHDRAWAL OF PATIENTS 
All patients will undergo screening procedure up to 40 days prior to Day I ( up to 30 days prior to Day 1 for 
patients that are already receiving a stable dose of Lynparza® (olaparib) tablets). The patients will be selected 
based on the following inclusion and exclusion criteria. 
9.1 
Inclusion Criteria 
To be eligible for the study, patients must meet all the following inclusion criteria: 
l. First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer maintenance 
treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-
mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete 
or partial response to first-line platinum-based chemotherapy. Select patients based on a diagnostic 
test for BRCA mutation by NGS - Next Generation Sequencing method. 
OR 
Maintenance Treatment of Recurrent Ovarian Cancer maintenance treatment of adult patients 
with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or 
partial response to platinum-based chemotherapy. 
OR 
Advanced Germline BRCA-mutated Ovarian Cancer After 3 or More Lines of Chemotherapy 
treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated 
(gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy. Select patients based on a diagnostic test for BRCA mutation by NGS - Next 
Generation Sequencing method. 
OR 
Germline BRCA-mutated HER2-negative Metastatic Breast Cancer treatment of adult patients 
with deleterious or suspected deleterious gBRCA.m, HER2-negative metastatic breast cancer, who 
have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with 
hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy 
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or be considered inappropriate for endocrine therapy. Select patients based on a diagnostic test for 
BRCA mutation by NGS - Next Generation Sequencing method. 
2. Non-smoking, non-pregnant, non-lactating female patient ?:18 years of age with a body mass index 
(BMI) in the range of 18.50 to 30.00 kg/m2 (both inclusive). 
3. Able to give written informed consent for participation in the trial and willing to adhere to protocol 
requirements. 
4. Patients that are already receiving a stable dose of Lynparza® (olaparib) tablets (2*150 mg tablets) 
300 mg twice daily for at least 10 days. 
OR 
Patients requiring Olaparib in the dose of300 mg (2*150 mg tablets) twice daily as per the discretion 
of the Investigators; these patients will be stabilized on Olaparib as a part of study and those patients 
that tolerate Olapanb in the dose of 300mg twice daily wilJ be randomized in the study. Patients that 
do not tolerate the mentioned dose or require dose modifications for any reason will be considered as 
screen failure. Patients who miss 2 or more consecutive doses or more than 3 non-consecutive doses 
in the Dose Stabilization period will be considered screen failure. 
5. Patient having an estimated survival of at least 3 months. 
6. Adequate organ and bone marrow function based upon the following laboratory criteria at the time of 
eligibility assessment prior to dosing in period 1: 
Body system 
Parameters 
Bone marrow function a) Hemoglobin ::!9.0 g/dL 
b) Absolute neutrophil count::!1500/uL 
c) Platelet count ::!100,000/uL 
d) WBC count> 3000/mm3 
Renal function 
Creatinine Clearance > 50 mLJmin (calculated 
based on Cockcroft-Gault formula) 
7. :Eastern Cooperative Oncology Group (ECOG) performance status of0-2. 
8. Absence of blood transfusion in the 28 days prior to randomization. 
9. Women of non child bearing potential with docwnented evidence of hysterectomy / bilateral 
salpingectomy / bilateral oophorectomy at least 6 months prior to IMP administration) or 
postmenopausal for at least 12 consecutive months. 
OR 
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Women of child bearing potential must have negative pregnancy test at screening visit and before 
randomization and must agree to use an effective tnethod of avoiding pregnancy (including oral, 
transdermal or implanted contraceptives [any hormonal method in conjunction with a secondary 
method], intrauterine device, female condom with spennicide, diaphragm with spermicide, absolute 
sexual abstinence, use of condom with spermicide by sexual partner or sterile [ at least 6 months prior 
to IMP administration] sexual partner) for at least 4 weeks prior to IMP administration, during the 
study and up to 6 months after the last dose of IMP. Cessation of birth control after this point should 
be discussed with a responsible physician. 
9.2 
Exclusion Criteria 
Patients who meet any of the following criteria at screening will not be enrolled in the study: 
l . History of known hypersensitivity to olaparib or its components which, in the opinion of the Investigator, 
would compromise the safety of the patient or the results of the study. 
2. Patients found positive for HIV, Syphilis, Hepatitis B surface antigen or Hepatitis C antibody at 
screening. 
3. Have ongoing clinically significant adverse event(s) due to prior treatments administered, as determined 
by the investigator. 
4. Patients with Pneumonitis. 
5. Patients with severe hepatic impairment (Child Pugh classification category C) 
6. Patients who received any chemotherapy, radiotherapy, or any other anti-cancer therapy within 4 weeks 
from the last dose prior to first dosing in Period O I ( or a longer period depending on the defined 
characteristics of the agents used). 
7. History or presence of any active infection or uncontrolled systemic disease ( e.g. cardiovascular disease, 
hypertension, diabetes mellitus etc.) or any clinically significant disea.c;e, condition, disorder or abnormal 
laboratory finding that, in the opinion of the Investigator, may either put the patient at risk because of 
participation in the study, or influence the study results or the patient's ability to participate in the study. 
8. Patient had major surgery within 4 weeks prior to first dosing in Period 01, or who have not recovered 
from prior major surgery. 
9. In the opinion of the Investigator, the patient will not be compliant with the requirements of the study 
procedures. 
10. Blood loss (1 unit or 3 50 ml) within 90 days prior to first dosing in Period O l for the current study. 
l l. Receipt of an investigational medicinal product or participation in another drug research study involving 
IMP administration within 30 days (or 5 half-lives, whichever is longer) prior to first dosing in Period 01 
for the current study. 
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Note: Elimination half-life of the study drug should be. taken in consideration for inclusion of the patient 
in the study. 
12. Usage of strong and moderate CYP3A4 inhibitors (e.g., cimetidine, ciprofloxacin, grapefruit juice) or 
strong and moderate CYP3A4 inducers (e.g., carbamazepine, phenytoin, St. John's Wort, rifampicin) 
within 30 days prior to first dosing in Period 01 (refer annexure IV for full list of prohibited medications). 
13. History of difficulty in accessibility of veins or intolerance to direct venipuncturc. 
14. Pregnant or lactating females. 
15. Patient positive on Breath alcohol analyzer test at the time of baseline/randomization visit. 
16. Positive on urine test for drugs of abuse (including amphetamines, barbiturates, benzodiazepines, 
marijuana, cocaine, and morphine) prior to receiving the first dose of investigational medicinal product in 
the study. 
17. History or presence of alcoholism or drug abuse. 
18. Patients with psychiatric illness/social situations that would limit compliance with study requirements. 
I 9. Difficulty in swallowing tablets. 
20. Problems with fasting. 
21. History or presence of clinically significant lactose, galactose, or fructose intolerance. 
9 .3 
Withdrawal Criteria 
An investigator may withdraw a patient from the study for any of the following: 
1. The patient may be withdrawn from the trial at the discretion of the investigator and/or the sponsor if 
judged to be non-compliant with protocol/trial procedures. 
2. Any major/significant deviation from the protocol that in the opinion of the investigator/sponsor may 
impact the patient's safety and/or the scientific integrity of the trial. 
3. Any major safety concern such as (but not limited to) serious, life-threatening, or intolerable AEs that, in 
the opinion of the investigator and/or sponsor requires withdrawal from the study. 
4. Patients who experience emesis within two times of Tmax value (i.e. 3 hours) on Day 8 or Day 16. 
Patients who experience emesis at any other time during the study will be evaluated for their continued 
participation in the study based on the investigator's and sponsor's assessment. 
5. Patients who experience diarrhea (defmed as three or more episodes of loose stools during a 24 hour 
interval) at any time during the study will be evaluated by the investigator and sponsor and a decision for 
continued participation in the study will be made based on the potential impact of the event on the 
integrity of the study results and patient's safety. 
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6. Ifa patient found positive for Coronavirus infection (COVID-19) during the study. 
7. If patient requires dose modification (i.e. change from 300 mg twice daily) or dose interruption during 
study participation. 
8. Any patient who requires the use of unacceptable concomitant medicines. 
9. If a patient becomes pregnant or develops hypersensitivity to Olapanb or to any of the excipients during 
the course of the trial. 
I 0. Significant inter-current illness and/or surgery that in the opinion of the investigator and/or sponsor 
requires withdrawal from the study. 
11. Disease exacerbation/progression that in the opinion of the investigator requires interruption and/or 
change in therapeutic modality. 
12. If the patient requires any concomitant medication, which as per judgment of the investigator may 
significantly interfere with the phannacokinetic property of the study IMP. 
13. Ifit is felt in the investigator's opinion that it is not in the patient's best interest to continue. 
14. If the patient on their own, wishes to withdraw consent. 
15. Missing sample(s) or incidence of AEs that affect the pharmacokinetics of the analyte, thus preventing a 
planned statistical comparison. 
16. Patients who miss 2 or more consecutive IMP doses or more than 3 non-consecutive doses in a given 
period. 
Any patient withdrawal during the study along with the reason thereof shall be documented in the CRF and 
reported to sponsor. 
The planned sample size accounts for withdrawal among the randomized patients, so withdrawn patients will 
not be replaced. 
Irrespective of the reason of withdrawal, 
the patient 
will be requested to complete all 
procedures/activities required for End of Study safety assessment as far as possible. 
10.0 TREATMENT OF PATIENTS 
10.1 Housing 
Patients will be housed in the clinical facility at least 12 hours prior to morning dose on Day I and will be 
confined for at lea<;t 12 hours after morning dose on Day l . 
The patients will also be housed in the clinic at least 12 hours before morning dose on Day 6 until 12 hours 
post morning dose on Day 9. The patients will also be housed in the clinic at least 12 hours before morning 
dose on Day 14 until 12 hours post morning dose on Day 16. 
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Note: In addition to above requirements, the patients may be housed in the clinical facility (hospital) for the 
entire duration of the study or a definite duration in the study, if in the opinion of the Investigator, it 
facilitates the study procedures or for social reasons (like difficulty in travelling etc.). The lnvestigaJor will 
be required to document this decision in the patient source document (like patient hospital records). 
Hospitalizations performed for these reasons will not be considered as SAE. However, if the patient is 
hospitalised for reasons related to safety or adverse events, the hospitalization will be considered as SAE. 
10.2 Dosing 
Stabilization Phase: 
The patients found eligible for participation in the study, but not yet on a stable dose ofLynparza® (olaparib) 
tablets, will be emolled in the Dose Stabilization period. Dose Stabilization period will be applicable for 
patients that are not on a stable dose of Lynparza® (olaparib) tablets 2*150 mg (for at least 10 days). 
Following this, patients will be randomized to participate in the study. Patients that do not tolerate the 
mentioned dose or require dose modifications for any reason will be considered as screen failure. Patients 
who miss 2 or more consecutive doses or more than 3 non-consecutive doses in the Dose Stabilization period 
will be considered screen failure. 
Patients that are already on a stable dose of Lynparza® (olaparib) tablets (2*150 mg twice daily) for at least 
l O days and have met the eligibility criteria will be directly randomized for participation in the study. 
Periods I and II: 
Patients will be dosed or advised to take the investigational medicinal product (2*150 mg twice daily) 
(allocated as per randomization schedule) orally in sitting posture with approximately 240 (±5 mL) of 
drinking water at ambient temperature which must be completely consumed. Patients will be instructed not to 
chew, crush, touch or divide the tablet but to swallow as a whole. On days of housing, dosing will be 
followed by thorough hand and mouth check for assessing compliance. 
Dosing time on Day 1 morning will be considered as reference time for dosing in the entire study. Evening 
dose will be administered 12 hours after the morning dose. All the patients will be required to conswne the 
investigational medicinal product preferably at the same time each day. 
Window period of within I hour will be allowed if the patient misses the scheduled time of dosing. If a 
patient misses a dose, the dose should be taken as soon as possible, if this can be done within 1 hour of the 
scheduled time. The next dose should be taken at its scheduled time. If a patient misses a dose for more than 
1 hour, they should take the next dose at its scheduled time. 
In period I: 
On day 0, patient will be asked to reach the site at least 12 hours prior to scheduled dosing on Day I and will 
be housed for 12 hours after morning dose of Day l. Patient will be administered two tablets (2* 150 mg 
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tablets) of investigational medicinal product in morning and evening as per randomization schedule under 
supervision of trained study personnel at clinical facility. 
Dosing on Day l (morning as well as evening) would be done at site. Patients will be discharged after 
administration of evening dose of Day l at site. Dosing from Day 2 to Day 5 can be done at home by 
patients. The patient will be provided with sufficient Investigational medicinal product for dosing at their 
home for Day 2 and Day 4 (for morning and evening daily dosing at 12-hours interval) and Day 5 morning 
dosing). Day 5 evening dose will be done at site. 
Patient will also be provided with a patient diary card to enter the details of study drug consumption and 
details of AE (if any) at their home. Patient and their attendant will be provided ·with adequate instructions to 
complete the patient diary card at their home. 
Patient will be requested to come to the clinical facility for evening dose on Day 5 (at least 12 hours prior to 
scheduled morning dosing on Day 6) for housing in the clinical facility. 
During the patients stay in the clinical facility on Day 6, Day 7 and Day 8, patients will be administered the 
investigational medicinal product at the scheduled time of dosing in morning and evening daily at 12-hours 
interval under supervision of trained study personnel. 
In period II: 
Patient will be crossed over to the other investigational medicinal product (allocated as per randomization 
schedule) on Day 9 morning dose. Dosing on Day 9 (morning as well as evening) would be done at site. 
Patient will be discharged after administration of evening dose of Day 9 at site. Dosing from Day l O to Day 
13 morning can be done at home by patients. The patient will be provided with sufficient investigational 
medicinal product for dosing at their home from Day 10 to Day 12 (for morning and evening daily dosing at 
12-hours interval) and Day 13 morning dosing. Day 13 evening dose will be done at site. 
Patient will also be provided with a patient diary card to enter the details of study drug consumption and 
details of AE (if any) at their home. Patient and their attendant will be provided with adequate instructions to 
complete the patient diary card at their home. 
Patient will be requested to come to the clinical facility for evening dose on Day 13 (at least 12 hours prior to 
scheduled morning dosing on Day 14) for housing in the clinical facility. 
During the patients stay in the clinical facility on Day 14, Day 15 and Day 16 patients will be administered 
the investigational medicinal product at the scheduled time of dosing in morning and evening daily at 12-
hours interval under supervision of trained study personnel. 
Note: 
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• 
In the Dose Stabilization period, patients will receive approved marketed version of Olaparib, details 
of the same will be included in IMP plan. 
• 
After the study is completed (after last PK sample collection on Day 16), patients may be continued 
on their current dose of O1.aparib using an approved Olaparib product as prescribed by their clinicians. 
10.3 Dosing Compliance 
Compliance for dosing will be assessed by checking the patient's diary for IMP consumption at home, 
pasting the duplicate label of dispensed container on the 'Dosing' section of individual source data fonn and 
a thorough check of the oral cavity using torch immediately after dosing when the dosing will be done in 
clinical facility. In addition to this the study coordinator will remind the patient on daily basis for 
conswnption of IMP and a telephone log will be generated for the same. 
Missing dose 
Window period of within l hour will be allowed if the patient misses the scheduled time of dosing. If a 
patient misses a dose, the dose should be taken as soon as possible, if this can be done within 1 hour of the 
scheduled time. The next dose should be taken at its scheduled time. If a patient misses a dose for more than 
I hour, they should take the next dose at its scheduled time. Patients who miss 2 or more consecutive doses 
or more than 3 non-consecutive IMP doses in a given period will be discontinued from the study. 
10.4 Sampling Schedule 
A total of 43 blood samples each of 03 mL will be collected from each patient for PK assessment during the 
study. 
The venous blood samples will be withdrawn from each patient in each period at the following timepoints: 
The post dose blood samples will be collected with an allowable deviation of ± 2 minutes. In all instances, 
however, the exact time of dosing and of each sample collection must be recorded. Samples collected outside 
the scheduled time will be considered as protocol deviations. 
Note: 
1. 12.00 hours blood sample must be collected prior to next drug administration. 
2. Blood sample collection (PK samples) will be collected first if other activities are coinciding. 
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10.S Sample Collection Procedure 
Blood samples will be collected through an indwelling intravenous cannula placed preferably in the foreann 
vein of the patients. Heparin-lock technique, injecting 0.5 mL of 5 IU/mL of heparin in normal saline 
solution, will be used to prevent clotting of blood in the indwelling cannula. While sampling through the 
cannula, blood samples will be collected after discarding the first 0.5 mL of heparinized blood from the 
cannula. If insertion of cannula is not possible, alternatively blood samples may be drawn by a fresh vein 
puncture or in case of blockade in an existing cannula, extra saline will be injected to stimulate the cannula 
and later blood samples will be collected after discarding the first 0.5 mL ofblood. If required, blood samples 
may also be collected through a fresh vein puncture. 
Blood samples will be withdrawn using syringe / adaptor and transferred into pre-labeled (Project No., 
Patient No., Period, Sampling time point and Sample code) vacutainer containing K3EDTA as anticoagulant. 
10.6 Blood Volume 
Total blood loss will not exceed 187 mL for each patient. 
For each patient, a total of 43 PK samples each of 03 mL will be collected during the study and the total 
volume of blood drawn including 0.5 mL of discarded blood prior to each sample collected through cannula, 
up to 10 mL of blood drawn for screening prior to the study, up to 10 mL of blood drawn for CBC, 
Creatinine Clearance, S Bilirubin, SGPT and SGOT prior to dosing in periods I and 2 and up to 10 mL of 
blood drawn for post-study safety assessment will not exceed 177 + 10.0 mL (if required in case of sample 
hemolyzed, sample clotted, spillage or lost or any other reason) for each Patient. 
PK assessment ( 43 PK samples x 03 mL each) 
= 
l29mL 
+ 
36 x 0.5 mL discarded blood 
= 
l8mL 
+ For Screening prior to the study 
= 
l0mL 
+ For CBC, Creatinine Clearance, S Bilirubin, SGPT and SGOT prior to = 
I0mL 
dosing in period 1 and 2 
+ 
Blood withdrawn for post study safety assessment 
= 
l0mL 
177mL+10mL 
!Blood Loss including 10 mL in case if blood recollection is required 
= 
= 187mL 
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11.0 RESTRICTIONS 
11.l Posture restriction 
Patients will be advised to remain awake and in semi-reclined position for the first 4 hours after morning 
dosing on Day I, Day 8 and Day 16. They will be asked to rise only with assistance during this period of 
time and at the first rising when this period is over. 
After 4 hours after dosing, the patients will be allowed to engage in normal activities while avoiding 
strenuous physical exertion. 
11.2 Dietary and water restriction 
On housing days, patients will be required to do an overnight fast of at least 8 hours before their scheduled 
time for dosing and for 4 hours after dosing for the morning dose, and 2 hours before their scheduled time for 
dosing and 2 hours after dosing for the evening dose. 
For dosing at home, all patients will be required to remain in fasting condition of at least 2 hours before their 
scheduled time for dosing and 2 hours after dosing for morning and evening dose. 
On housing days patients will receive standard meals (lunch, snacks and dinner) with the same quantity and 
same menu will be used ( on housing day) for both periods. 
There will not be any pre-dose and post-dose water restriction during dosing at home. 
On housing days, water will not be allowed for 1 hour before and l hour after morning dose and evening 
dose drug administration, when no liquid should be permitted other than that 240 mL (±5 mL) for drug 
dosing. 
11.3 Concomitant Medications 
Prohibited Medications: Moderate or strong CYP 3A4 inhibitors and inducers (refer annexure IV). Patients 
should be instructed to avoid grapefruit, grapefruit juice, Seville oranges, Seville orange juice, starfruit and 
pomelo. 
Any drug therapy taken by a patient should be the same for both periods. If a change in concomitant 
medications is necessary or if drug therapy (prescription or over-the-counter) other than that specified in the 
protocol is required prior to or during the study, decision shall be taken by the Investigator and sponsor to 
continue or discontinue the patient based on the following: 
• 
The phannacology and pharmacokinetics of the non-study medication. 
• 
The likelihood of a drug-drug interaction, thereby affecting the pharmacokinetic comparison of study 
medicine. 
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• 
The likelihood of a drug-drug LC-MS/MS cross-interaction, thereby affecting the determination of 
olaparib concentration in patient plasma. 
• 
The time and duration of administration of the non-study medicine. 
If it is necessary for the patient's safety to add any medication that interferes or changes the PK of olaparib, 
the patient should be withdrawn from the study. 
Before prescribing any drug it is mandatory to refer Prescribing Information of Lynparza® including but not 
limited to interaction with other medicinal products and other forms of interaction, contraindications, special 
warnings and precautions for use, undesirable side effects, etc. 
The Investigator should ask the patient to notify to the study site about any new medications they take after 
the start of the study. All instances of concomitant drug administration will be recorded and reported in the 
CRF and final report. 
Medication taken prior to first dosing: All prescription medications and over-the-counter drugs (including 
vitamins and herbal remedies) taken within 30 days prior to screening must be recorded in the CRF. 
Concomitant medications: All the medications ongoing at the time of consent and mediations consumed 
until the end of the study safety assessments will be recorded in prior/ concomitant medications section of the 
CRF. 
11.4 Others 
Patients will be instructed during screening to refrain from smoking, chewing tobacco, pan or pan masala, 
gutkha, masala (containing betel nut and tobacco) and from consuming any alcoholic products, Xanthine-
containing items (i.e., tea, coffee, cola drinks, or chocolate/coca etc.) from 48 hours prior to IMP 
administration on Day I until the last PK blood sample collection of study. All patients will also be instructed 
to abstain from grapefruit, pomelo, starfruit or Seville orange containing food/juice, recreational drugs 
(cocaine, amphetamines, barbiturates, benzodiazepines, cannabinoids and morphine) 28 days prior to 
randomization until the last PK blood sample collection of study. Patients should refrain from strenuous 
exercise for 24 hours before each check-in day. 
12.0 CLINICAL AND SAFETY ASSESSMENT 
It is the responsibility of the PI to ensure that adequate medical supervision and care is available for the study 
patients during housing and during the study duration to ensure the utmost safety and well-being of the study 
patients. At study sites, medical personnel will be available 24 hours a day and physician in charge will 
remain at the clinical site for at least the first 4 hours following drug administration. On PK sampling days 
(Day 8 and 16), Investigator will remain at the clinical site for at least the first 4 hours following morning 
drug administration. In addition, if necessary, Investigators will be available on-call at all times. 
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Medical and Medication history and Review of Inclusion and Exclusion Criteria: Screening and at the 
time of randomization. 
HER2 Testing (Only applicable for breast cancer patients): Screening (If the report is not available with 
the patients at the time of screening). 
Germline or Somatic BRCAl and BRCA2 diagnostic test for olaparib by NGS - Next Generation 
Sequencing method: Screening (the details for applicable patients and type of sample as per the section 5.6). 
Note: The Gennline or Somatic BRCAl and BRCA2 test need not be repeated in those patients who have 
been started on olaparib post BRCA testing done by NGS - Next Generation Sequencing method. 
Physical examination: Screening, Day 0, Day 5 and Day 13 and End of Study (Day 16), Safety follow up 
(on day 24±2). 
Additional vital examinations may be performed at any time during the study as per Investigator's 
judgement; all results must be documented appropriately. 
HlV, HCV, HbSAg, and VDRL or RPR (for syphilis): Screening 
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12-Lead ECG: Screening, Day 5, Day 13 and End of Study (Day 16) 
2D-ECHO: Screening 
Urine drug Screen (benzodiazepines, opioids, amphetamines, cannabinoids, cocaine and barbiturates) 
and Alcohol Breath Test: Day 0, Day 5 and Day 13 
Note: Separate mouthpiece will be used in breath test for every patient in the study 
Pregnancv test: Screening visit (Serum), Day 0, Day 5, Day 13 (Urine), and at End of Study visit (Serum) 
for FCBP only. 
X-ray (chest): To be performed based on Investigator's discretion. 
Hematology, Blood chemistry and Urinalysis: Screening, and at the end of the study (Day 16). 
CBC. Creatinine Clearance, S Billirubin. SGPT and SGOT: Prior to dosing in period I (Day -2 to 0) and 
period 2 (can be performed after evening dose on Day 8) (can be done at local laboratory). 
In addition to protocol-specific laboratory tests and/or clinical examinations at scheduled time points, 
additional tests/clinical examination may be conducted to evaluate patient safety at any time during the study, 
at the discretion of the Investigator (can be done in local laboratory or nearby clinic/hospital/institution). 
Note: It is recommended that general precautions are taken by the staff with respect to ongoing COVID-19 
pandemic situation during the trial. 
12.1 Clinical Examination 
Relevant medical history/ Current medical conditions 
Relevant medical history and current medical conditions occurring until provision of ~ritten informed 
consent will be reported in the Relevant Medical History and current medical conditions section of the CRF. 
Physical examination 
This evaluation will include an examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and nervous system evaluation. 
Information about the physical examination must be present in the somce documentation at the study site. 
Clinically significant findings that are present at the time of screening will be included in the relevant 
medical history and Current medical conditions section of the CRF. Clinically significant findings or 
worsening of any pre-existing conditions/diseases after providing written informed consent (after screening) 
must be recorded in the Adverse Event section of CRF. 
ECG evaluations 
Standard 12-lead ECGs will be performed. The patient identifiers, the date and actual time of the tracing 
must appear on each page of the tracing. Tracings will be dated and signed by the person who makes the 
interpretation. 
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Chest X-ray 
Chest X-ray will be performed based on Investigator's discretion. 
Standard clinical laboratory evaluations 
The Investigator will evaluate the clinical significance of each laboratory value outside of the reference 
rmge. This decision shalJ be based upon the nature and degree of the observed abnormality. Values which 
are considered clinically significant will be noted in the Notes field of the CRF. The investigator may choose 
to repeat any abnormal result ONCE, in order to rule out laboratory error. ''NCS" will be entered on the 
original laboratory sheet which are outside the reference range but are judged "not clinically significant" and 
archived with the source documents. The physician making these assessments shall date and sign or initial 
each laboratory report. Clinically relevant deviations of laboratory test results (see section 12.2.1) occurring 
during or at completion of the study must be reported as adverse events. 
12.2 Safety monitoring and reporting 
12.2.1 Adverse Events 
12.2.1.1 Definition of adverse events and reporting requirements 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
(including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject 
after providing written study-specific informed consent for participation in the study. Therefore, an AE may 
or may not be temporally or causally associated with the use of a medicinal (invesrigational) product. The 
investigator has the responsibility for managing the safety of individual subject and identifying adverse 
events. The occurrence of adverse events must be sought by non-directive questioning of the subject at each 
visit during the study. Adverse events also may be detected when they are volunteered by the subject during 
or between visits or through physical examination findings, laboratory test findings, or other assessments. 
Any AE (non-serious and serious) occurring after the subject has provided study-specific informed consent 
and until the last study visit of the subject, has to be recorded on the AE pages of the Case Report Form 
(CRF). 
Medical conditions/diseases present before providing written informed consent arc only considered AEs if 
they worsen after enrolment 
Adverse events (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. Abnormal laboratory values or test 
results constitute adverse events only if they fulfill at least one of the following criteria: 
• 
they induce clinical signs or symptoms; 
• 
they are considered clinically significant; 
they require therapy. 
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Once an adverse event is detected, it must be followed until its resolution or until it is judged to be permanent 
(e.g. continuing at the end of the study), and assessment must be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the interventions required to treat it, and 
the outcome. 
Information about already known adverse drug reactions for the Investigational Medicinal Product drug can 
be found in the Reference Safety Jnfonnation ( e.g. Prescribing information). 
Each adverse event should be evaluated to determine the following: 
A. Severity of AEs 
Adverse events should be assess.ed and graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0. Grade refers to the severity of the AE. The CTCAE version 5.0 displays 
Grades I through 5 with unique clinical descriptions of severity for each AE based on this general guideline. 
Grade 1 
Grade2 
Grade 3 
Grade4 
Grade 5 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*. 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care AOL**. 
Life-threatening consequences; urgent intervention indicated. 
Death related to AE. 
*Instrumental ADL (Activities of Daily Living) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
B. Relationship to IMP 
Adverse event's relationship to the study treatment should be determined (suspected/not suspected). 
Causality assessments are critical and must be provided for each unique AE in relation to each IMP, non-
investigational medicinal product (NIMP) or other concomitant medication, if applicable. Missing causality 
assessments will be handled as suspected to IMP by the sponsor. The causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. 
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If the event is due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be 'Not suspected.' The rationale for this guidance is that 
the symptoms of a lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of underlying disease can 
only be evaluated meaningfuJly by an analysis of cohorts, not on a single subject. 
C. Evaluation of AEs ( duration, action taken, outcome) 
The duration (start and end dates) of adverse event should be recorded. Determine whether AB constitutes a 
serious adverse event (see Section 12.2.2 for definition of SAE) and which seriousness criteria have been 
met. 
Actions taken with respect to investigation medicinal product should be documented as per the below given 
tabulation using CDISC STDM terminology. 
Adverse Event Variable Label 
CDISC STDM Terms 
• Dose increased; 
• Dose not changed; 
• Dose rate reduced; 
Action Taken with the WP 
• Dose reduced; 
• Drug interrupted; 
• Drug withdrawn; 
• Not applicable; 
• Not known 
The outcome ofthc adverse should be documented and assigned to one of the following categories: 
Adverse Event Variable Label 
CDISC STDM Terms 
• Not recovered/not resolved; 
• Recovered/resolved; 
Outcome of event 
• Recovered/resolved with sequelae; 
• Recovering/resolving; 
• Fatal; or 
• Unknown. 
All AEs must be treated appropriately. The treatment of the AE should be documented in the CRF. 
Concomitant medication, other non-IMP treatments or changes in the administration of the IMP should be 
specified and documented. Treatment may include one or more of the following: 
• 
No action taken (i.e. further observation only); 
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• 
IMP dosage adjusted/temporarily interrupted; 
• 
IMP permanently discontinued due to this AE; 
• 
Concomitant medication given; 
• 
Non-drug therapy given, patient hospitalized/ patient's hospitalization prolonged. 
Adverse events should be recorded in the CRF under the signs, symptoms or diagnosis associated with them. 
All AEs including both volunteered and the ones considered clinically relevant and reportable as AE by 
investigator will be recorded in the CRF and in the patient's medical records, irrespective of its association 
with study medications. Independent /Institutional Ethics Committee (IEC) will be informed regarding AEs 
as necessary. 
12.2.1.2 The Most Common Adverse Events Associated with Study Medication 
• 
Patients should be carefully monitored for adverse events/toxicity. To manage adverse events such 
as Myelodysplastic syndrome/Acute myeloid leukemia, Haematological toxicity, Pneumonitis, or 
Venous Thromboembolic Events, the dose may be reduced or interrupt the treatment. 
• 
To manage adverse reactions, consider interruption of treatment or dose reduction. The 
recommended dose reduction is 250 mg taken twice daily. If a further dose reduction is required, 
then reduce to 200 mg taken twice daily. 
• 
Dose adjustment is to be done by the Investigator as per the approved Summary of Product 
Characteristics, Prescnbing Infonnation ofLynparz.a® and the protocol. 
• 
Refer Summary of Product Characteristics and Prescribing Information of Lynparza® for further 
information on management of AEs. 
NOTE: If patient requires dose modification (i.e., change from 300 mg twice daily) or dose interruption 
during study participation, the patient should be withdrawn from the study. 
12.2.2 Serious Adverse Events (SAE) 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s) or medical conditions(s)] which meets any one of the following criteria: 
• 
results in death 
• 
is life-threatening: Life-threatening in the context of a SAE refers to a reaction in which the subject 
was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if it were more severe. 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is 
for: 
-
Routine treannent or monitoring of the studied indication, not associated with any deterioration in 
condition 
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-
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since signing the study specific infonned consent 
-
General care, not associated with any deterioration in condition 
-
Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a 
SAE given above and not resulting in hospital admission 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
is medically significant Medical and scientific judgment should be exercised in deciding whether 
other situations should be considered serious reactions, such as important medical events that might 
not be immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. Such events 
should be considered as "medically significant". Examples of such events. are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICHE2D 
Guidelines). All malignant neoplasms will be assessed as serious under "medically significant", if 
other seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction. All reports of intentional misuse and abuse of the product are 
also considered serious adverse events irrespective if a clinical event has occurred. 
A (Serious) Adverse Drug Reaction ((S)ADR) is any (S)AE for which the investigator or sponsor assess a 
reasonable possibility for a causal relationship to a medicinal product. 
A (Serious) Unexpected Adverse Reactions is defined as a (serious) adverse drug reaction, which is not 
consistent with the Reference Safety Information ( e.g. Summary of Product Characteristics (SmPC), Product 
Monograph, Investigator's Brochure). Reports which add significant information on the specificity, increase 
of occurrence, or severity of a known, already documented serious adverse reaction constitute unexpected 
events. The term 'severity' is used here to describe the intensity of a specific event. This has to be 
distinguished from the term 'serious'. 
12.2.2.1 SAE reporting 
It is vitally important that the investigator reports immediately, i.e., no later than 24 hours after 
awareness, any SA Es, or updates to previously reported SAEs, even if the investigator does not consider the 
AE to be drug-related. 
The investigator should send SAE reports on the "Serious Adverse Event Report Form" (Novartis fonn), as 
initial or follow-up reports, via fax or email to the Country Organization Patient Safety Team, and in copy to 
the responsible Study Manager (Sponsor / CRO) as well as to the Indian Health Authority DCGI, to the 
addresses provided in the table below. 
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The investigator should also send all updates / new information on a new SAE Report Form as a follow-up to 
the previously reported SAE. The follow-up information should describe whether the event has resolved or 
continues, if a diagnosis is available, if and how it was treated, and whether the subject continued or 
withdrew from study participation. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the 
original episode, regardless of when the event occurs. 
An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously 
reported one must be reported separately as a new event. 
Any queries from the Country Organization Patient Safely Team, to Contract Research Organization (CRO) 
or sponsor regarding SAE reports should be answered by the investigator within 24 hours. 
For more detailed information refer to the "Quick Reference Guide for Completing the SAE Form" and the 
Manual for Completing the Novartis SAE Form for Clinical Trials" (Novartis documents). 
The investigator should retain a delivery confirmation of the SAE reports for all recipients in the investigator 
study file. 
If a patient dies during participation in the study and an autopsy is performed, a copy of the report must be 
submitted. 
The investigator will send a full/detailed report of SAE, after due analysis within 14 days of SAE to the 
Sponsor/Sponsor's representative, Central Licensing Authority, chairman of Ethics Committee, and the Head 
of the institution where the trial is being conducted. 
Note: the initial SAE report must be sent within 24 hours of awareness. 
In case investigator fails to report any SAE within stipulated period, the investigator shall have to furnish the 
reason for the delay to the satisfaction of licensing authority along with the report of SAE. 
Ongoing serious adverse events at the time oflast visit 
For any SAEs still ongoing at the time of last visit, the investigator should continue to follow-up until the 
SAE has resolved or has stabilized or is judged permanent for SAEs considered to be related to IMP 
(SAD Rs), and for up to 30 days after the last dosing of subject for non-related SAEs. The investigator should 
send SAE follow-up reports to recipients as described in the preceding paragraphs. Where appropriate, 
medical tests and examinations will be performed to document resolution of event(s). The investigator should 
send SAE follow-up reports including all relevant new or reassessed infonnation (e.g., concomitant 
treatment, medical history) obtained on the SAE /pregnancy as described in the preceding paragraphs. 
Serious adverse events occurring after the last visit 
Any SAEs experienced within the 30 day period following the last administration of study treatment has to 
be reported to sponsor. In case a compound with a long half-life is investigated, the 30-day period will be 
extended accordingly. 
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to sponsor if 
rt the SADR 
12.2.3 Investigator Notification and 6 monthly line listings 
If a SADR is not listed in the Reference Safety Information (e.g. Prescribing information), the sponsor may 
urgently require further information from the investigator for Health Authority reporting. 
The sponsor may, if applicable, issue Investigator Notifications and 6 monthly line listings of Suspect.ed 
Unexpected Serious Adverse Reactions (SUSARs) to all investigators concerned with any study with the 
same IMP. 
The submission of these Investigator Notifications and 6-monthly !foe listings, if applicable, to local IRBs / 
Ethics Committees is the responsibility of the investigator or the CRO as stipulated in the study contract. The 
submission of Investigator Notifications and 6-monthly line listings to national Ethics Committee is the 
responsibility of the CRO, if applicable. 
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12.2.4 Health authority reporting 
The sponsor will submit all reportable cases within the requested timelines to all concerned health 
authorities. 
12.2.5 Pregnancy Reporting 
The investigator must report any cases of pregnancy of subjects in the course of a study immediately (within 
24 hours) of awareness to the Country Organization Patient Safety Team and in copy to the Study Manager 
(Sponsor/ CRO). Pregnancies are only reported from the time of first IMP dose. 
The investigator should immediately withdraw the subject from the study, and should follow-up each case of 
pregnancy, and report the outcome, including spontaneous or voluntary termination, details of the birth, and 
any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Cases of pregnancy are reported on a "Drug Exposure in Pregnancy Fonn" (Novartis fonn). Pregnancy 
follow-up are reported on the same form and should include an assessment of the relatedness of any 
untoward pregnancy outcome to the IMP. 
Any SAE during pregnancy of a subject must be reported on the SAE Report Form and reported as described 
The investigator should retain a delivery confirmation of the "Drug Exposure in Pregnancy Form" for all 
recipients in the investigator study file. 
For more detailed information refer to the "Quick Reference Guide for Completing the Drug Exposure in 
Pregnancy Form" (Novartis document). 
12.2.6 Special case scenarios 
Special case scenarios can be serious or non-serious (see table below), and they should be reported like AE 
cases as described in section 12.2.2 and 12.2.3, even ifno (other) AEs are associated with their occurrence. 
Drug exposure during breastfeeding 
Intentional Overdose by patient (including suicide 
attempts, suicide attempt is always serious) 
Drug I drug interactions 
Withdrawal syndrome/ reaction 
Drug dependence, misuse, abuse or addiction (always 
serious) 
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X 
Only if associated with SAE 
Only if associated with SAE 
Only if associated with SAE 
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Suspected Transmission of infectious agents (always 
serious) 
Death (incl. without other event, always serious) 
12.2.7 IMP related complaints 
X 
X 
In case of quality complaints related to the IMP, the investigator within 24 hours of learning of its occurrence 
informs the sponsor as described in section 8.6. Any AE associated with a quality complaint needs to be 
documented and reported in addition by the investigator as described in sections 12.2.1, 12.2.2 and 12.2.3. 
12.2.8 Reconciliation 
Reconciliation between the safety database of the sponsor and the clinical database at the CRO will be done 
periodically as described in Safety Management Plan by comparing line listings from the safety database 
with the data in the clinical database. 
The Monitor will review the CRFs / the clinical database for potentially unreported cases. For any reportable 
case, the following parameters need to match exactly between the clinical and the safety database: trial 
number, site number, subject/patient number, nmdomization number, investigational drug, seriousness, date 
of death (if applicable) and investigator causality. All other parameters only need to be plausibly and 
medically consistent. 
For any reportable case assessed as suspected or for other events of special interest (if applicable), a more 
detailed reconciliation should be conducted, including also treatment dates, outcome, medical history and 
concomitant therapy. 
12.2.9 Investigator Training 
By his/her signature of the study protocol, the principal investigator certifies that he/she has been trained in 
the Sponsor AE/SAE and pregnancy reporting obligations by the CRO as defined in the study protocol. 
Note: All the activities will be performed as per the latest version of Safety Management Plan. 
13.0 SAMPLE PROCESSING AND TRANSFER PROCEDURES 
Clinical Laboratory Samples: 
All clinical laboratory blood and urine samples will be transferred to the central laboratory/local laboratory in 
controlled temperature and in pre validated laboratory kits which will be supplied to all the sites by the 
central laboratory. In case of emergency, samples can be sent to local laboratory for safety assessment at the 
discretion of the Investigator. 
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Phannacokinetic samples: 
After collection of blood samples from patients at each time point, they will be centrifuged at 4000 
revolutions per minute (RPM) for IO minutes under ambient conditions or at 2-8°C temperature as per 
method requirement to separate plasma. After centrifugation, the plasma will be aspirated and transferred 
into 2 clear polypropylene aliquots. A minimum of 0.5 mL plasma will be transferred to the first aliquot and 
remaining mL of plasma will be transfer in to aliquot 2. Aliquots will be pre-labeled with at least the 
following information: Blood sampling time point, Protocol Nwnber, Study Period, Aliquot Number and 
Subject/patient (terms may be used interchangeably) Nwnber. The plasma samples will be stored at -20±5°C 
in a freezer until shipment to the Bioanalytical facility o 
India and then stored 
at -78±8°C until analysis. 
After completion of analysis aliquot 1 will be discarded after confirmation with sponsor and aliquot 2 will be 
stored at -78:l:8°C. 
Throughout sample collection and following centrifugation, the samples will be kept in wet ice-bath until 
stored in the freezer. Entire sample processing should be completed within 2 hours of sample collection. 
Sample Shipment 
After completion of clinical phase/each period of the stud , the 
clinical site to the bioanalytical research facility of 
All plasma samples will be 
transported to 
in at least two shipments, with each set of aliquots in separate 
shipments. Once the analytical site confinns the receipt of the first shipment the second set of aliquots will be 
sent based on the request from the analytical site. During transfer, all samples will be packed with sufficient 
dry ice for maintaining the integrity of samples and to prevent thermal degradation. Data Jogger(s) will be 
placed in each shipment to monitor the temperature during shipment. 
Note: Please refer latest version of Laboratory Manual and Bio-analytical plan for details. 
14.0 BIOANALYTICAL PROCEDURES 
The concentration of Olaparib in plasma samples will be quantified at 
-using validated LC-MS/MS method. 
14.1 Method Validation 
Bioanalytical method will be validated at 
which is in accordance with the 
current regulatory guidelines on validation ofbioanalytical methods. 
Method validation of 01 
arib in human plasma will be carried out by using analytical method developed at 
This analytical method will be validated for the sensitivity, specificity, matrix 
effect, linearity, ruggedness, accuracy and precision (repeatability and reproducibility), percent recovery and 
stability of samples (freeze-thaw stability, bench-top stability, autosampler stability, short-term and long-
term stability of stock solution and internal standard). 
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14.2 Assay of Samples 
The plasma sample will be quantified for Olaparib using a validated method. Plasma samples of patients 
included in the PK dataset (defined in section 15) will be analyzed. 
Pharmacokinetic repeats will not be performed for this study. 
The analysis of patient's samples will be done using calibration curve with quality control samples, 
distributed throughout each batch. The details for the preparation of the calibration curve and quality control 
samples and the analytical batch acceptance criteria will be discussed in the respective in-house procedure. 
The analyst will not have access to the randomization schedule until analysis is completed. 
Incurred Study Sample Re-analysis 
Incurred Study sample analysis will be performed to ensure method reproducibility as per 
-
Note: All the activities will be performed as per the latest /updated version of bioanalytical plan for the 
study. 
15.0 PHARMACOKINETICS AND STATISTICAL ANALYSIS 
Phannacokinetic and statistical analyses for plasma concentration versus time profile of Olaparib will be 
performed on the data obtained from patients included in the PK dataset. 
PK dataset 
Data from the following patients will be included in the PK dataset: 
• 
Patients who have completed both periods and have missed samples in any period that may not affect 
the estimation of the Cmax,ss and/or AUC parameters and have been predetermined prior to the 
bioanalytical analysis to not significantly impact the overall outcome of the study; 
• 
Patients who complied with all protocol requirements, or encountered protocol deviations that do not 
impact the estimation of the PK parameters. 
Patients withdrawn prior to sample analysis for phannacokinetic reasons (i.e., an event that could result in an 
inadequately characterized pharmacokinetic profile for olaparib) will not be included in the PK and statistical 
analysis. 
Any decision for excluding data from the final data set will be provided with a detailed explanation and will 
be properly recorded and dated. 
PK dataset will be defined in consultation with the sponsor at different study stages for different sets of 
patients, prior to initiation of sample analysis for each set of patients. This dataset will be reassessed, if 
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required (e.g., missing concentration value due to analytical reason), upon completion of the sample analysis. 
The PK dataset will be finally confumed by the sponsor prior to database lock. 
Safety Dataset 
The safety dataset will include randomized patients who receive at least one dose of IMP. Data from subjects 
in this dataset will be used for the assessment of safety. 
IS.I Pharmacokinetic Parameters 
Phannacokinetic parameters Cmaxss, Cminss, AUC(o-.)SS, CavSS, T maxSS, Swing, percentage of fluctuation will be 
calculated using plasma concentration vs time profile (Actual time of sample collection) data of both 
investigational medicinal products in individual patients using Phoenix®winNonlin® Software Version 8.2 or 
higher (Pharsight Corporation, USA). 
Primary parameters: 
CmaxSS 
Maximum plasma concentration during the dosing interval at steady state 
AUC(o-1:>ss 
Area under the plasma concentration versus time curve for one dosing interval at steady state 
Secondary Parameters: 
CminSS 
Concentration at the end of a dosing interval 
CavSS 
Average plasma concentration over the steady state dosing interval 
Tmaxss 
Time of maximwn measured plasma concentration over the steady state dosing 
interval 
Swing 
(Cmax55---Cininssf Cmmss]*IOO 
Percentage of 
[Cmaxss-Cmu,ss/Cavss]* l 00 
fluctuation 
Pharrnacokinctic parameters will be calculated by non-compartmental analysis using Phoenix®winNonlin® 
software Version 8.2 or higher (Pharsight Corporation, USA). All pbarmacokinetic parameters will be 
estimated from the Plasma concentration time profile data. 
All concentration values below the Limit of Quantification (LOQ) will be set to "zero" for all 
pharmacokinetic and statistical calculations. Any missing sample will be reported as "Missing" and will not 
be included for pharmacokinetic and statistical analysis. 
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Data from patients with missing concentration values (missed blood draws, lost samples, samples unable to 
be quantified) may be used if pharmacokinetic parameters can be estimated using the remaining data points. 
Otherwise, concentration data from these subjects will be excluded from the final analysis. 
In case of sample collection deviations, the actual time point of sample collection will be used for the 
computation of pharrnacokinctic parameters. 
Missing plasma samples will be handled as pe~ 
15.2 Statistical Analysis 
SAS® Software, Version 9.4 or higher will be used for statistical analysis of pharmacokinetic parameters 
Cmaxss and AUC(o--t)ss. 
By considering the three day's morning pre-dose concentrations in a given period, steady state analysis will 
be perfonned for each subject in each period by using the linear regression analysis to obtain the p-values. 
The above analyses will be done using procedure PROC REG in SAS, version 9.4 or higher. 
For achieving the steady state following procedure should be assessed: 
Step 1: For each subject in each period the P-values should be statistically insignificant at 5% level of 
significance. 
If, P-values are found statistically insignificant, those patients are considered to achieve steady state. If, P-
values are found significant for particular subject then go for the second step. Go for second step for patients 
who have missing pre-dose sample for Day 6 or Day 14. 
Step 2: Ratio of the pre-dose concentrations of last two pre-dose should be?: 80% or should be :5120.00%. 
In case ratio of last two pre-dose concentrations is found to be ?: 80% or ::: 120.00% patients will be 
considered to achieve steady state. If two pre-dose concentrations is found to be less than 80% or greater than 
120%, patients will not be considered to achieve steady state and will be removed from bioequivalence 
evaluation. 
Two stage design according to Potvin C: Evaluate the power at stage l using the variance estimate from stage 
I and an ex. level of0.05. If the power is greater than or equal to 80% (calculated by observed variability and 
GMR=0.95), evaluate BE at stage I using an a level of 0.05 and stop whether BE is met or not. If the power 
is less than 80%, evaluate BE using an a of0.0294. If the BE criterion is met, stop. If the BE criterion is not 
met, calculate the sample size based on the variance estimated at stage 1, GMR.=0.95 and an a level of 
0.0294 and continue to stage 2. If the ratio is outside 80.00%-125.00% then study will not proceed for stage 
2. Evaluate BE at stage 2 using data from both stages and an a level of 0.0294. Stop here whether BE is met 
or not and regardless of the power achieved. 
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Evaluate power at stage 1 usi11g o:::.:ievel o·f O.OS 
------------
If power~ so~1 ..... evaluate 
If power< 80%, evaluate BE at 
BE at stage 1 (a=- 0.05) 
stage 1 (a:= 0.0294) 
and stop 
1 
If BE met, s op 
l 
Pass or fail 
PEJSS 
ff BE not met, calcu1ate sample 
size based on stage 1 and a = 
0.0294. continue to stage 2 
-i 
Evaluate BE at stage 2 usi;ng 
data from both stages 
(a= 0 . 0294) and: stop 
l 
P~ss or fail 
For outlier identification, appropriate statistical tests could be performed. Outliers are defined as subjects 
having discordant values of one or more pharmacokinetic parameters when compared with other values, e.g., 
a subject differs notably from the rest of the subjects for the test product response versus the reference 
product response. Outlier test will be performed using appropriate statistical method as per -for 
"Detection of Outliers". Subject data will not be removed from the statistical analysis solely based on the 
results of statistical outlier tests. Outlier data may only be removed from the statistical analysis if there is a 
real-time documentation demonstrating a protocol violation during the clinical and/or analytical phase of the 
BE study. 
15.2.1 Analysis of variance 
For Stage 1: 
The ln-transformed phannacokinetic parameters (Cmaxss and AUCco.,Jss) will be analyzed using ANOVA 
model with the main effects of Center, Treatment, Period (Center), Sequence, Sequence*Ccnter as fixed 
effects and Patient (Within Sequence *Center) as random effect. 
The sequence effect will be tested at the 0.10 level of significance using the Patient (within 
Sequence*Center) mean square from the ANOV A as the error tenn. All other main effects will be tested at 
the 0.05 level of significance against the residual error (mean square error/MSE) from the ANOVA as the 
error tenn. 
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Each analysis of variance will include calculation ofleast-squares means, the difference between the adjusted 
formulation means and the standard error associated with the difference. The above analyses will be done 
using procedure PROC GLM in SAS, version 9.4 or higher. 
For Stage 2: 
The In-transformed pharmacokinetic parameters (Croaxss and AUC(o.,,)ss) will be analyzed using ANOVA 
model with the main effects of Center, Stage, Treatment, Period (Center*Stage), Sequence, 
Sequence*Center, Center*Stage, Sequence*Center*Stage, as 
fixed 
effects 
and Patient (Within 
Sequence*Center*Stage) as random effect. 
The Sequence, Stage and Center effects will be tested using the Patient (within Sequence*Center*Stage) 
effect as the error term. 
The sequence effect will be tested at the 0. l O level of significance using the Patient (within 
Sequence*Center*Stage) mean square from the ANOV A as the error term. All other main effects will be 
tested at the 0. 05 level of significance against the residual error (mean square error/MSE) from the ANOV A 
as the error term. 
Each analysis of variance will include calculation ofleast-squares means, the difference between the adjusted 
formulation means and the standard error associated with the difference. The above analyses will be done 
using procedure PROC GLM in SAS, version 9.4 or higher 
Note: Prior to ANO VA analysis for assessment of center effect, data from all the centers will be arranged in 
ascending order based on the number of evaluable patients available per center. This shall lead to center 
with /east number of evaluable patients followed by cenler which has more number of evaluable patients in 
increasing order. This will lead to center with maximum number of evaluable patients as last center and 
center with least number of patients as first center. In case any center has less than jive evaluable patients, 
data from this center will be pooled with subsequent center as per the center arrangement done as mentioned 
above. if there are more than one center with less than five patients in each center, the data of all this centers 
will be combined until five or more than five patients are available and this will be treated as separate center 
for further data analysis. After combining centers as mentioned above, further assessment will be done for 
treatment sequence available for combined center data. After combining two or more centers, at least one 
patient should be having TR and RT sequence each. in case same is true, centers combined will be used 
further for data analysis. Jncase same is not observed, data combining will be continued for subsequent 
center as per the center arrangement done as mentioned above. This shall be continued until at least one 
patient for each treatment sequence TR and RT is available. 
Note: Analysis of study will be peiformed as per latest/updated Statistical Analysis Plan (SAP). 
15.2.2 Intra- patient Variability 
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Intra-subject variability will be calculated using mean square error of ANOV A for In-transformed analysis of 
Cmaxss and AUC<o-<).SS for Olaparib. 
15.2.3 Two one-sided tests for bioequivalence 
90% (if power is more than 80% at stage 1) & 94.12% (as applicable, if the power is less than 80% at stage 1 
and stage 2) confidence intervals for the difference between least squares means of test and reference 
formulations will be calculated using mean square error, obtained in ANOV A, for In-transformed Cmax5s and 
AUC<o.,,)ss. 90% (if power is more than 80% at stage 1) & 94.12% (as applicable, if the power is less than 80% 
at stage 1 and stage 2) confidence interval for the geometric least squares means ratio will be obtained by 
taking the exponent of lower and upper limits of 90% (if power is more than 80¾ at stage 1) & 94.12% (as 
applicable, if the power is less than 80% at stage 1 and stage 2) confidence interval, obtained for the least 
squares means difference. 
Two one-sided test, namely Schuirmann's test, will be employed at 5% level of significance for the lower 
and upper limits of 90% (if power is more than 80% at stage 1) & 94.12% (as applicable, if the power is less 
than 80% at stage I and stage 2) confidence interval to check whether the 90% (if power is more than 80% at 
stage I) & 94.12 (as applicable, if the power is less than 80% at stage 1 and stage 2) confidence interval for 
Cmaxss and AUCco-<)ss will be entirely within the bioequivalence limits of80.00% to 125.00%. 
15.2.4 Ratio analysis 
Geometric least squares means for test and reference formulations will be obtained by taking the exponent of 
least squares means oftest and reference formulations for In-transformed Cmaxss and AUC<o .. Jss. Ratio will be 
obtained by taking the exponent of difference of least squares means of test to reference formulations for ln-
transfonned Cmaxss and AUC<o-,Jss. The comparisons of interest are T vs. R, so the ratios determined will be of 
the form T/R, where T = Test formulation and R = Reference formulation. 
15.2.5 Power 
Power of test to detect at least 20% mean difference between formulations will be reported for Cmax,ss and 
AUCco-,)Ss. 
15.2.6 Bioequivalence criteria 
For Stage 1 with Power 2: 80%: 
Based on the statistical results of 90% confidence intervals for the geometric least squares means ratio for the 
ln-phannacokinetic parameters CmaxSS and AUCco-,)Ss for Olaparib the conclusions will be drawn whether test 
formulation is bioequivalent to reference formulation under Fasting condition. Acceptance range for 
bioequivalence is 80.00%-125.00% for 90% confidence intervals of the geometric least squares means ratio 
of Cmaxss and AUC<o-<)SS. 
For Stage 1 with Power< 80% and for Stage 2, if required: 
Based on the statistical results of94.12% confidence. intervals for the geometric least squares means ratio for 
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the log-transformed pharmacokinctic parameters CmaxSs and AUC<o-t)Ss for Olaparib the conclusions will be 
drawn whether test formulation is bioequivalent to reference formulation under Fasting condition. 
Acceptance range for bioequivalence is 80.00%-125.00% for 94.12% confidence intervals of the geometric 
least square means ratio of Cmaxss and AUCco-,)Ss. 
15.2.7 Safety data 
All randomized patients who have received a dose of IMP will be included in safety evaluation. Results 
obtained when evaluating safety and tolerability (adverse events, vital signs, and clinical laboratory tests) 
will be listed in the report. AEs occurring prior to first IMP administration will be presented in a separate 
listing within study report. All AEs will be classified by System Organ Class, Preferred Tenn (using the 
Medical Dictionary for Regulatory Activities (MedDRA), version 20.0 or higher), and Severity with respect 
to treatment received. 
16.0 AMENDMENT AND PROTOCOL DEVIATION IN REGARDS TO THE PROTOCOL 
16.1 Amendment to protocol 
Any significant change in study procedure or study design will only be in effect upon mutual agreement with 
Sponsor, and after obtaining approval or a favorable opinion from Ethics Committee (EC). All such changes 
will be documented in amended version of protocol and a list of changes with reference to previous version 
will be generated. The Investigator will not implement any changes to the protocol and/or ICF without 
consent of sponsor and without issuing an amendment except when necessary to eliminate an immediate 
hazard to subject. 
16.2 Protocol deviation definition and reporting 
A protocol deviation is an unintended excursion from the approved protocol. 
A major protocol deviation is a protocol deviation that may, as evaluated by the investigator, or person 
designated by the investigator, lead to withdrawal of a subject from the study or to exclusion from the 
bioanalytical and/or statistical part. Deviations not classified as major are considered as minor protocol 
deviations. 
Major protocol deviations should be reported to the sponsor by the CRO and monitor (if present on site) at 
the earliest possible time. The sponsor can propose to re-classify a protocol deviation (minor to major or vice 
versa) upon evaluation. In such case, the classification made by the sponsor prevails and will be 
communicated to the CRO together with a written justification. 
The sponsor must be informed of minor protocol deviations within 10 working days, but before start of the 
following clinical study period or before start of the bio-analytic phase/ statistical phase. 
The exceptions are minor protocol deviation which can be reported with the draft study report: 
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• 
logistic deviations (time deviations from scheduled time for blood sampling; follow up visits that 
occurred outside the protocol required time frame because of the participant's schedule etc.) 
• 
administrative deviations (e.g. change of names) 
Protocol deviation notification and reports are submitted to HA and/or relevant IRB according to applicable 
requirements/guidelines/law. 
Procedure for documenting protocol deviations 
The investigator, or person designated by the investigator, should docwnent and explain any deviation from 
the approved protocol. The notification of protocol deviation to sponsor can be in exceptional cases 
communicated by verbal means (if immediate action/notification is needed) and must be followed-up with 
written documentation (e.g. by e-mail; period update). All protocol deviations must be described in the final 
study report. 
17.0 SOURCE DATA ACCESSIBILITY 
Quality Assurance (QA) auditors and Quality Monitors o 
as well as sponsor's 
monitors and auditors, IEC and Regulatory agency(ies) will have access to all documents related to the study, 
including the subject's medical records, source documents, drug accountability records and study drugs 
during study monitoring, inspection and audits. 
18.0 QUALITY CONTROL AND QUALITY ASSURANCE 
The raw data generated during the course of the study as well as reports will undergo a thorough quality 
control check and random quality assurance process for conformance to this protocol and all the governing 
SOPs by the Monitors and the auditors from Quality Assurance department o 
respectively. The final report will contain a statement of quality assurance duly s1gne 
Assurance department. 
19.0 ETIDCS 
19.1 Ethics Committee 
This protocol, corresponding Informed Consent Document (ICD) (containing information about the study to 
be given to patients) to be used to obtain written informed consent of study patients and other relevant 
essential documents will be reviewed by IEC and patients will not be emolled into the study until IEC 
approves the protocol and ICD. 
Study will be conducted as per the ICMR Guidelines for Biomedical Research on Human Subjects, New drug 
and clinical trials rules (2019) of India, ICH-GCP Guidelines and in accordance with the Declaration of 
Helsinki (Ethical Principles for Medical Research Involving Hwnan Subjects, revised by the WMA General 
Assembly, Brazil 2013). 
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19.2 Written Informed Consent 
The Investigator or designated study personnel before initiation of any study related procedure will inform 
the patient (in English or in a language best understood by the patient) through an oral presentation regarding 
the purpose, procedures to be carried out, information on the investigational medicinal products, potential 
hazards, benefits and rights of the study patients. Patients will be encouraged to ask questions and clarify 
their doubts regarding any aspect of the study and the same would be documented in the source notes with 
sign and date. Ample time will be given to the patients after completion ofICD discussion to think and take 
an informed and voluntary decision. The Investigator will ensure that the entire process of informed consent 
is followed as per local regulatory requirement for each patient at the respective site maintaining the 
confidentiality of patient's personal information and all relevant records will be maintained in the source file. 
The responsibility for taking informed consent must remain with a medically qualified person and cannot be 
delegated to a non-medically qualified person. The Investigator/designee will also ensure that the entire 
informed consent process is documented in the source notes of the patient. 
If the patient is unable to give informed consent, then the patient's legally acceptable representative (LAR) 
should be present during the entire informed consent process and will also append his/her signature on the 
ICD to confirm that the study infonnation was presented to and understood by the patient. If the patient's 
legally acceptable representative is unable to read/write, an impartial witness should be present during the 
entire informed consent process, and will append his/her signature on the ICD with sign/thumb impression of 
LAR. In both cases, the patient will be required to sign the ICD, or, if unable to do so, give a thumb 
impression on the ICD. Only those patients who are able to understand the ICD and to adequately 
communicate with the study personnel will be enrolled in the study. 
In case a patient cannot read/write, then the patient will be required to give a thumb impression and an 
impartial witness should be present during the entire informed consent process, and will append his/her 
signature on the ICD to confirm that the study information was presented to and understood by the patient. 
The ICD will also be signed by the Investigator or his/her designate. 
If any new information becomes available during the course of the study that may be relevant to the patient's 
willingness to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written ICD must be obtained. 
The Investigator will ensure that all the patients are given a copy of the signed and dated ICD immediately 
after the informed consent process is completed. 
19.2.1 Patient Participation Fee 
Patients will be paid an adequate participation fee, approved by Institutional / Independent Ethics Committee 
(IEC), on account of their participation in the study. In case of withdrawal of a patient before completion of 
the study, patients will be paid a pro-rated participation depending upon the extent of participation and any 
controversy pertaining to this will be forwarded to Institutional Ethics Committee (IEC) and the decision of 
Institutional / Independent Ethics Committee (IEC) will be final as well as binding on both the patients and 
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19.2.2 Post-trial access 
Based on the Investigator discretion, patients who complete the study in its entirety may receive Olaparib 
tablet 150 mg on compassionate basis. If patient who completed the study does not have access to Olaparib 
treatment (e.g., Olapanb reimbursement is not possible), Olaparib 150 mg 41-blets may be offered for a period 
of up to 9 months, provided that the patient is deriving benefit (no disease progression as assessed by the 
physician), and the benefit outweighs the risk for the patient. 
20.0 DATA HANDLING AND RECORD KEEPING 
All clinical data generated during the conduct of the study will be entered in the source notes and will be 
transcribed in the respective CRF. The computer-generated randomization schedule will also be treated as 
raw data. All raw data and transcribed data forms compiled by the study personnel assisting in the study will 
be checked for completeness. All data related to the project will be in the custody of the Investigator or 
Project Manager until transferred to archives. 
All bioanalytical raw data generated during the conduct of the project compiled by the study personnel 
assisting in the study will be checked for completeness. All analytical data generated through analytical 
system will be exported and transferred electronically through intranet to Pharmacokinetic Biostatistics (PB) 
department for further evaluation. The PB department, after receipt of the raw data, will perform a statistical 
analysis and the statistical data will be generated which will be further sent for compilation of the final 
clinical study report. 
21.0 STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS 
The fmal report will be compiled and sent as per eCTD (Module 5) format. All copies of supplementary 
documents such as approved final version of Protocol along with all appendices, .IEC approval letter, List of 
IEC members, CVs of investigators, all patient CRFs, adverse event form (if any), IMP Accountability 
records, Randomization list, Summary report of pharmacokinetic and statistical Analysis, Protocol 
deviations, Demographics and Baseline Characteristics, Sampling deviations and Safety data will be 
submitted to sponsor with the final study report. 
22.0 ARCHIVING 
All raw data generated in connection with this study, together with a copy of this protocol, signed !CDs and 
the final report will be archived at least 25 years as per sponsor requirements, according to the ICH guideline 
for good clinical practice and as per applicable regulatory requirements. 
The investigator must notify the Sponsor prior to destroying any study essential documents following the 
clinical study completion or discontinuation. 
If the investigator's situation is such that archiving can no longer be ensured by him/her, the investigator shall 
inform the sponsor and the relevant records shall be transferred to a mutually agreed upon designee. 
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Sponsor should be contacted for further instructions, when agreed storage period of study samples expires. 
In case of sample destruction, Certificate of Destruction is provided to Sponsor. 
23.0 INSURANCE POLICY 
on behalf of sponsor has a clinical trial insurance policy to cover the risks to 
patients and/or any other eventualities pertaining to study. 
24.0 CONFIDENTIALITY OF DATA 
The data identifying each patient by name will be kept confidential and will be accessible to the study 
personnel (involved in check-in procedure and Monitors) and if necessary, to the QA auditors, IEC, Sponsor 
representative and Regulatory agency(ies). 
25.0 PUBLICATION POLICY 
The results of the study including all data obtained will be the property of sponsor of this study. 
encourages the scientific publication of data from clinical research trials. However, Investigators must not 
present or publish partial or complete study results individually. 
The Investigators and -
may propose appropriate scientific manuscripts or abstracts from the study 
data. All proposed publications must be reviewed b, _  
before submission for publication. 
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26.0 REFERENCES 
I. Potvin D, Diliberti CE, Hauck WW, Parr AF, Schuirmann DJ, Smith RA. Sequential design approaches 
for bioequivalence studies with crossover designs. Phann Stat. 2008 Oct-Dec;7(4):245-62. 
2. LYNPARZA® (Olaparib) tablets 150 mg US Prescribing Information. 03/2021 
3. Lynparza 150 mg Film-Coated Tablets, Summary of Product Characteristics, 07 June 2021 
4. Guidance on Olaparib published by Office of Generic Drugs Published Sep 2018 
https://www.accessdata.fda.gov/drugsatfda docs/psg/Olaparib%20Oral%20Tablet%20NDA%20208558 
%20RC%2009-20 J 8.pdf 
5. https:/ /www.fda.gov/dmgs/coronavirus-covid-19-drugs/bioeguivalence-studies-submission-andas-during-
covid-19-pandemic?utm medium=email&utm source=govdelivery 
6. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, Published: November 27, 
2017: U.S. Department of Health and Human Services. 
7. Bioanalytical Method Validation Guidance for Industry, U.S. Department of Health and Human Services, 
May 2018. 
8. Declaration of Helsinki, Fortaleza, Brazil, October 2013. 
9. International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use- Good Clinical Practice (ICH-GCP) E6 (R2). 
10. Guidelines for Bioavailability and Bioequivalence studies, Central Drugs Standard Control Organization, 
Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, 
March 2005. 
11. Ethical Guidelines for Biomedical Research on Human Participants, Indian Council of Medical Research, 
October 2017 
12. New Drugs and Clinical Trial Rules (2019) of Central Drugs Standard Control organization, Ministry of 
Health and Family Welfare, Government of India 
13. ECOG performance status published in Arn. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T .E., McFadden, E.T., Carbone, P.P.: Toxicity and Response Criteria of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
14. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers 
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27.0 LIST OF ANNEXURES 
• 
I 
• 
II 
• 
III 
• IV 
• 
V 
Confidential 
Schedule of Events 
Laboratory parameters 
ECOG Performance Status 
List of Prohibited drugs during the study 
Signature(s) oflnvestigator(s) 
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27.2 ANNEXURE II: LABORATORY PARAMETERS 
Haemoglobin 
Neutrophils 
WBCCount 
Lymphocytes 
Platelet Count 
Eosinophils 
Absolute Neutrophil Count 
Basophils 
Monocytes 
SGOT(AST) 
Blood Sugar 
SGPT(ALT) 
Total Protein 
Gamma GT (GGT) 
Serum Albumin 
Alkaline Phosphatase (ALP) 
Serum Cholesterol 
Total Bilirubin 
Serum Triglyceride 
Direct Bilirubin 
Serum Creatinine 
Indirect Bilirubin 
eGFR evaluation (MDRD) 
Serum Uric acid 
Blood Urea Nitrogen/Urea 
SEROit1:}Qi~flij,;t~.-llr: 
. · · ~k ''~~t,:;M;;,;'.lf..;,~~~if1lll!!fi,'\l~t~<I~~ · ;,., 
, .; W'J! 
. 
. ., , ,..,~· .i~!!'.'!l!Jlil':••'~~"'J-"''~·'~"'" ._ rt .. w•fili!:iii-..~!ili:r,ii!.l"t?}•,f:f/J!~-1!i~f,~'ii•.lf~~~ffel~~~-· '!?,? .,,;.~ \ls~ 
HIV (I & 2) 
HbsAg (Hepatitis B surface 
HCV antibodies 
Syphilis (VDRL or RPR) 
antibodies 
antigen) 
Odor 
Bilirubin 
Epithelial Cells Protein 
Leucocyte 
Clarity 
Blood 
RBC 
Bacteria 
Crystals 
Volume 
Ketones 
Casts 
Specific gravity Urobilinogen 
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27.3 ANNEXURE ID: ECOG Performance Status13 
Grade Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to cany out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to cany out any work activities. 
Up and about more than 50% of waking hrs 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hrs. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
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27.4 ANNEX.URE IV: List of Prohibited drugs during the study14 
CYP3A4 inhibitors 
Aprepitant, Amiodarone, Amprenavir, Atazanavir, Atomoxetine, Boceprivir, 
Cimetidine, 
Ciprofloxacin, 
Cilostazol, 
Clarithromycin, 
Chloramphenicol, 
Chlorzoxazone, Claritbromycin, Clotrimazole, Cobicistat, Conivaptan,Crizotinib, 
Cyclosporine, Danoprevir , Darunavir, Dasabuvir Diltiazem, Delaviridine, Diethyl 
dithiocarbamate, 
Dronedarone, 
Erythromycin, 
Elvitegravir 
,Esomeprazole, 
Fluconazole, Fluoxamine, Fosaprepitant, Fosumprenavir, Grapefruit, Gestodene, 
Idelalisib, Jmatinib, Indinavir, Itraconazole, Ivacaftor, Ketoconazole, Lesinurad, 
Lopinavir , Lomitapide, 
Mibefradil, Mifepristone, Nefazodone, Nelfinavir, 
Norfluoxetine, Diltiazem, Netupitant/Palonosetron, Norfloxacin, Ombitasvir , 
Omeprazole, Paritaprevir Posaconazole, Pantoprazole, Ranitidine, Ranolazine, 
Ritonavir, Regorafenib, Ribociclib, Starfruit, Pomelo, Seville orange, Saquinavir, 
Starfruit, 
Telaprevir, 
Telitbromycin, 
Tipranavir, 
Ticagrelor, 
Tofisopam, 
Troleandomycin , Verapamil, Voriconazole 
CYP3A4 inducers 
Apalutamide, Armodafmil, Barbiturates, Brigatinib, Boscntan, Carbamazepine, 
Efavirenz, Enzalutamide, Etravirine, Glucocorticoids, Mitotane, Modafinil, 
Nafcillin, Nevirapine, Oxcarbazepine, Phenytoin, Pioglitazone, Phenobarbital, 
Primidone, Rifampin, Rifabutin, Rufinamide, St. John's wort, Troglitazone 
Note: This list of drugs iS not exhaustive. However, any drug which is not mentioned above and having a 
possible effect on 0/aparib pharmacokinetics, should be confirmed with Medical Monitor/Medical Expert. 
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I . 
27.5
1 jANNEXUREV: SIGNATURE($}' · F!_ 
, · TIGATO~S). i,• ·"-~,,,,.;•fl;tr;f J\f 
I, th~ imciersigned, _o/'ve read and ~ersto4 .~ protocol, entitl~ 
. 
. . J. ·t, .. . 
"A ;~domiud, open labeI,.multi~enfte; two-treatm~nt. two,:.p_erlod, two-seq_uence,-tw9;;s~ge, multipie. 
dose. 1steady-state, crossover, bioequivalence st 
-
and Lynpana• (olaparib) bblets 150 mg 
,in patients w 
BRCA muta.ted ~varian· cancer, recu.r_r~nt ova 
, 
. •~iunder fasting 
condition." 
· -
. 
·· 
· 
• ' ~- · 
and · hereby agree to conduct the -study ,in accordance with, this protocol and to comply with all the 
requirements regarding the obligations of investigators and alI other pertinent requirements of the Ethical 
guidelines for biomedical research on human participants (IGMR) 2017, New Drugs and Clinical Trials 
Rules (2019).ofindia, USFDA regulations, roles and guidelines, cGCP guideline(s), !CH (Step S) 'Guidance 
on Good Clinical Practice' JCH Ouidan.ce 'p6 (R2); Declaratioii of-Helsinki (Brazil, 2013) , Code of Federal 
Regulations on the Prote(:tion of Human:.Subjects (45 CPR Plirt 46) and with "procedures oriented to Good 
Lab~~tory Practice and appUcablereguJ~~ guidelines: 
;,1 
• 
"' 
I a~ to comply with all relevant SO~s.required for the conduct of this study. I further agree to ensure that 
. the .. -'. nduct of this study are informed.regarding their 9bligations. . 
. 
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27,5 ANNEXURE V: SIGNATURE(S) OF INVESTidATOR(S) 
I, the undersigned, have read and understood th.is protocol, ~ntitled 
! 
1 
. 
I 
: 
-
'' A i-andomiz~, open .label; multi-centre, two-tre3tment, tw0:period, iwo-~~n'e~ce, two:st4ge, multiple · 
dose, .steady~state, crossover,· bioeqnivalenee study _of Olaparib ta.hie , 150 mg 
-an4 Lynparza® (olaparib) tablets 150 mg 
1n I?1 en 
Wl 
BRCA Djutated ovarian ~ncer, rec~rtent ovarian cancer or met.as atic breast cancer under ·fasting 
d·t· " 
· I 
' 
con 1 10~. 
. 
. 
. 
, 
. 
· 
1 • · 
/ 
1 
· · 
I 
• 
. 
; 
. 
. ' 
and hereby agree to conduct the study in accordance . with this protpQOl and to eomply !with ~u · the 
requirements regarding the obligations of investigators and all other pe.fti,pent requirements of the Ethical 
guidelines for biomedical research on human participants. (ICMR) 201r., Ne~ Dru~s -and C1inical Trials 
Rules (2019) of India; USFDA regulations, rules and guidelines, cGCP gipdeline(s), ICH (Step?) 'Guidance 
on Good· Clinical Practice' ICH Guidance E6 (R2), Declaration of Helsr· (Brazil, 2013) • Co1e of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46) and with· procedures oriei;,ted to Good 
Laboratory Practice and al?plicable regulatory guidelines. 
. ' 
: 
. 
. 
I 
. 
; 
I agree to comply with ajl relevant SOPs required for: the conduct of this ptudy. I further agtee Ip ensure that 
.aU associates assisting in the conduct of this study are informed regarding ~heir obligatiohs. 
' · 
• 
• 
I 
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· Piige 91 of9l 


27.5 .Al."'fflEXURE V; SIGNATURE(S) OF INVESTIGATOR(S) 
I. the undersigned, hav.e read and understOQd this protocol, entitled 
"A randomized, open label, multi-centre, two-treatment, two-period, two-sequence,_ two-stage, -Jn~tfple 
dose, steady-state, crossover, bioequivalence stud of Olaparib tablets, 150 mg 
-
and Lynparza® (olaparib) tablets 150 mg 
m_ p2 _ents WI 
8RCA mutated ovarJan cancer, recurrent ovarian cancer or metastatic b.rea:s:t c:attcef ·ti.iidet' (a.$'ting 
condition." 
and hereby agree to conduct the study in accordance with this protocol and to comply with all the 
requirements regarding the obligations of investigators and all other pertinent tequirements of the Ethical 
guidelines for biomedical research on bUllia:n participants (ICMR) 2017, New Drugs and Clinical Trials 
Rules (2019) of India, USFDA regulations, rules and guide.lines, cGCP guideline(s); ICH (StepS) 'Guidance 
on Good Clinical Practice' ICH Guidance E6 {R2J, Declaration -of Helsinki (Br~l, 2013) , Code of Federal 
Regulations on.the Protection of Human Subjects (45 CFR Part 46) and with procedures orient~ to Good 
Laboratory Practice and applicable regulatory guidelines. 
I agree to comply with all relevantBOPs required for the conduct of this study. I further agree to ensure that 
all associates assisting in the conduct of this study are mfonned regarding their ob'ligati6ns. 
Confidential 
i'age 9'1 of9 I 


27.5 ANNEXURE V: 
OF INVESTIGATOR(S) 
I, the undersigned, have read and understood this protocol, entitled 
"A randomized, open label, multi-centre, two-treatment, two-period, two-sequence, two-st 
dose, steady-state, crossover, bioeq:nivalence study of Olaparib tablets, 150 mg 
.. 
and Lynparza~ (obparlb) tablets 150 mg 
BRCA mutated ovarian cancer, recurrent. ovarian cancer or metastatic breast cancer under fasting 
condition." 
and hereby agree to conduct the study in accordance with this protocol and to comply with all the 
requirements regarding the obligations of investigators and all other pertinent requirements of the Ethical 
guidelines for biomedical research on human participants (ICMR) 2017, New Drugs and Clinical Trials 
Rules (2019) of India, USFDA regulations, rules and guidelines, cGCP guideline(s), ICH (Step 5) 'Guidance 
on Good Clinical Practice' ICH Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013), Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46) and with procedures oriented to Good 
Laboratory Practice and applicable regulatory guidelines. 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to ensure that 
all associates assisting in the conduct of this study are infonned regarding their obligations. 


27.5 Ai.'mEX~ V: SIGNATURE{S)"OF INVESTIGATOR(SJ 
I, ili.e .un~ersi~~ ~aye rea(land' unde~toi;i.~ thls ~col., entirIC4 
"A ranaomized,.op,en Iabe( multJ-centr-e, two-treatment, two-perlod, tw'o~equence,..:tW'o.stegc,_rnVltiplc' 
do.se,. study--sta'fe, ·CT0$SO,;;er, bioeqn1vatence stud . of Olaparil>. tablets, 1$0 mg 
and Lynpi(rz~* (ob.P,;trib) tab.let.t tS0 mg· 
·In pa~~(s w t 
BRCA mutat~ci'.xovarian eance·r, recurrent ov.arian:·cancer; or metastatic breasr cailc~r under:;t~sti~g 
condition." 
and hereby :agree tQ conduct: th~ $!Qt in accor~ce wi.lh thi$ protocol an~ to (l()f!1P1Y with all the 
requirements ~egarding tb~:·ool,ig~pnsh{f investjgatdrs and -~IJ .oilier p~rti'nint; requirements, of' the Ethical 
guidelines for biomedical ·research on bwnan participants (ICMR) 2017. New Drugs'·-·nnd Clinict!l Trials 
Rules (2019) oflndia, USFDA regulations, ,rules and-guidelines-; cGCf> guidelfoe(s), lQT-(S~ep 5) '9uidancc 
on, G.Qod, Clinical P'ractice: TGH· dui~nl!e E61(R2), _Q;etliration of ;Helsinki ·(~J!, 29 fa).,. CQdr.rnf.f.c:~er~I 
Regulations on,the' Protection' of Human Subje<:ts: (4S CFR 'Part:'4:C>) a~d ·W'iffi procedilref 'oricn'ted. (~ Good 
Laboratory Practice and applicable regu1atory guidelfues. 
' 
1 agree to comply Wtth all relevant SOPs required for.·the conduct,ofthis··.stu'dy. l furtliet~agree to C.tl~~re t~at 
all-associ:ites ~isting in Uit,co.nducfof thls study ai_-e '.informed reg.atding. thei1•:obligatfons: 
Coclidcnlial 


27.5 ANNEXU.RE V: SIGNATURE(S) OF INVESTIGATOR(S) 
• 
• 
' 
• 
• 
• 
• 
+ 
' 
' 
: 
I, the undersigned, have r~ad and understood th.is pr~tocol'. entitled 
"A randomized, open JabeJ, multi-centre_, ~".o~treatment, two-period, hy()-Sequence 
dose, steady-state, c_rossover, bioequivalcnce stu 
a a · ta l 
5 m 
• 
and Lynparza® (o]aparib) tablets 150 mg 
BRCA mutated ovari~n cancer, recurrent ovar~an ca.ncer o~ metastatic ~reast ~anc~r under fa~ting 
condition." . · · · 
· . · 
· . 
• .. 
· · 
. 
· · ·. 
, · . · 
· 
·. · · 
· 
and hereby agree to conduct the study in accordance with this protocol and to comply with all the 
requirements rt?garding the obligations of investigat9rs and all other pertinent requirements of the Ethical 
guid~lines for biomedical resea.rch on huma_n parti.cipants (ICMR) 2017, New, b 'rugs and Clinical Trials 
Rules (2019) of:India, USFDA regulations, rules and gt1idelines, cGCP guideline(s), ICH (Step 5) 'Guidance 
on Qo9d Clinical Practice' ICH Guidance .E6 (R2), Declaraticm of Helsinki (BrazU, 2013), Code of Federal: 
Regulations on the Protection of Human :subjbcts ( 45 CFR Part 46) and wi.th · procedures o,riented . to Gooq 
Laboratory .Practice and appli<;able regulatory guidelines. 
· · 
·. 
· · · · 
' · · · 
· · · 
· · , . 
. I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to ensure th,~t. 
all associates assisfing in the conduct of this study are infonnec:l regarding their obligations. 
.· 
; ' ·. 
'I
. 
i 
,: 
., ' · 
I 
• ' 
. : '. . 
:.-,', · 'P11gc 91 pf91 
. : ·. 
·. ·. 
; 
. ··-:· : .'-\ ·:.·: . 
... _ ·.: .-.-. . 
.-. / . .' _.: 
-~: .< \.:·.-r·• . , 
. 
!. ' ·:_ .- : I , ·1 • 
• 
, 
• : 
t, 
, 
. '
; 
, , 


___ 
.. ..--,-~-- ·----
_,. . .,:;...,,...,. ,.... ... ---~· ~-........ ,,.-
27.5 ANNEXURE V: SIGNATURE(S) OF INVESTIGATOR(S) 
l, the undersigned, have read and understood this protocol, entitled 
j 
"A randomized, open label, multi-centre, two-treatment, two-periocl, two-seq11ence, tw.o-stage, multiple 
dose, sttady-state, crossover, bioequivalence stu , of OJa · arib tablets, 150 m 
and L~nparza• (olapar.ib) tablets 150 mg 
BRCA mutated ovarian cancer, recurrent ovarian cancer or metastatic breast cancer under fasting 
condition." 
and hereby agree to conduct the study in accordance with this protocol and to comply with all the 
requirerilen~ regarding the obligations of investigators and all other pertinent requirements 'bf the Ethical , 
guidelines for biomedical research on human participants (ICMR) 2017, New Drugs and Clinical Trials 
Rules (2019) of India, USFDA regulations, rules and guidelines, cGCP guideline(s), ICH (Step 5) 'Guidance 
on Good Clinical Practice' ICH Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013) , Code of Federal 
Regulations on the Protection of Human Subjects ( 45 CPR Part 46) and with procedures oriented to Good 
Laboratory Practice and applicable regulatory guidelines. 
• 
l 
\ 
f 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to enst re that 
all associates assisting in the conduct of this study are informed regarding their obligations. 
Confidential 
Page 91 of91 
,) 


27,5 ANNEXURE V:. SIGNATURE(S).O:FINVESTlGA'tO.R{S) 
r. the undersigned, have read~ undemoodthis pr:otocot, entided 
"A randomized; opq label, multk:cntrc;, tw.o~treatmeut; two-period, two--seq11ence, tw~~. multiple 
dose, s~dy~te, crOS$o'Ve.i-, biocq,uivaletJce study of O .. · lb .tablets, 150 BJ 
and Lyiq')•r~• (olaparib) tablets 150 mg 
BRCA mutated ov•riaa cancer, n:currut .o'\"arian .~ 
or metastatic br.eas& m~et uder fastlag 
coadition..,, 
and hereby agree to conduct the study in aceordance . .with this _pr-Otocol -.anct to comply with ·all the 
requirements regarding tbe obligati~ns of investigators and all oilier pertinent requiremerits of the-Ethical 
guidelines for biomedical re~h on human participants {[CMRf2017, New Drugs and Clinical Trials 
Rules (2019) of Jndia, USFDA regµlations, rules and guidelines.,. cGCP miitfeline'(s). ICH (St~ S) 'Guidan~ 
on Good Cl~ical P@ctice' ICH Guidance Ef(R,2},Deelaration of.Helsinkl (Brazil; 20i3) t Code of Federal 
.Regulations on the Protection of Human Subj'ects (4S CPR .Part 46) and with procedures oriented to Good 
Laboratory Practice and 11PPlicable regulatory gm<leliries. 
I agree to comply with all relevant SOPs required for the conduct of this.study. ] further aa,ee to ensure that . 
Confidential 
. re91-ot9J 


ff 
,, 
1 
' ·p~ 
, 
,· . . r .. ,,, . 
: 
, 
i 
';1 
I, the undersigned, ha:ve n:aa!ancfi uaderstO® this 
,. A randomized, opeJJ l?tbl"~ mtiltl--cdltre. two-: 
dose. 
erossove;r, b,ioequjvalence s 
-and Lynpara® {ol~patJb) tablets 150 
.. 
BRCA mutated ovaria:n canl:(\J', recurr-enf' ov 
, 
under fststbrg . 
condition." 
' 
l 
and .hereby agree •l~ conduc~ .tbe_ sJudy 
ac~or1oce with this jrrot0.~l- and t~ c~mp~ with ·all .. the 
r.equuements regarding tile obhgauons of mvesttgatqrs and all other pettu~entreqwrenrents of the Bihical 
guidelines for bio~edicaJ r~h o~ human part~cfJ>~nts. (IClvfR) 20 ( 7:, .N_ew Drugs ~
.Clinical. Trials 
Rule-s (2019} of.Jndia, USFOA; rt:gulattons., :mies -and gwdehnes, cGCP gtudehne(s), lCH (Step 5},'Gutdance 
ou Good Clinical Practice• rCE'i Guidanc.e .56: (R2). l).ecl.aration ofHelsinki {Bni.zil, 20 I 1) , Code.of Fcdeml 
Regulations on the Protection :pfHuman Subjects t4$ CTR Part 46) and \Vltlt procedures ociented to Good 
Laboratory :Practice and appli.cabl~ regolatory-guidclules. 
! 
i 
I agree to comply with all tefe:vant SOP.s required forJ,the conduct of.lhis.,study. J further agree to ensure that 
all associatesass,sti:ng in the c.6.nduct of this study are '·ntormedregatdingth.eirobtigations. 
Conftdeofi.al 
I 
! 


27.5 ANNEA'URE V: SlGNATURE(S) OF INVESTIGATOR(S) 
I, the undersjgncd. have read ond understood this protocol, enlitle:d 
"A randomized. open label; .multi-centre, hvo-frcalm.cnf, hvo-pcriod, fwcHteq1Jence, two,;sfe 
dose, steady-state. crosso,·cr, biocquh•nlcncc stud or OJa arib tablets, 150 m 
and Lynpnrza41 (ofoparib) fnbicts ISO mg 
,m pol en "'. 
DRCA mutnccd o,11rian cancer, recurrent ovarian cancer or mct,nsJatie r~st caiu:cr under fllSfing 
condition.'' 
and hereby agree to conduct the study ip acco(:dam:.e with this protocol and lo comply with all the 
requirements· regarding thi:: obligations of investigators :ind all other pertinent requite-m~nts of the Ethkal 
guidelin~s for .biomedical rese~rch on human participants (lCMR) 2017~ New Drugs and ClihicaI Trials 
Rules (20 l 9) of India, USFDA regulations, rules and guidelines, cOCP-guidel~ne(s), JCH (step S) 'Guidance 
on Good Clinical Practice• ICH GuiclJlnce E6 (RZ), Declaration of Helsinki (Brazil, 2013} • Code of Federal. 
Regulations on the Protection of Human Subjecrs (45 CFR Part 46) and with procedures oriented lo Good 
Laboratory Practice and applicable regc,ilatory guidelines. 
I agree 10 comply with all relevant SOP.s required for the conduct of this. study. I fµrtber a&'e~ lo ensure ,that 
aU .associates-assisting in the conduct of this study are infoi:med tegarding their obligations. 
Confidc'11ial 
P,1ge9J of91 




27.S ANNEXURE V: SIGNATURE(S) OF TNVESTIGATOR(S) 
I, the undersigned, have read and understood this protocol, entitled 
"A randomized, open label, multi-centre, two-treatment, two-period, two-sequenc 
dose, steady-state, cros~ver, bioequivalence study of Olaparib tablets, 150 mg 
and Lynparza® (olal;)arib) tablets 150 mg 
in patients with 
A mutated ovarian cancer, recurrent ovarian cancer or m.etastatic breast cancer under fasting 
condition." 
and hereby agree to conduct the study in accordance with this protocol and to comply with all the 
requirements regarding the obligatjons of investigators and aJI. other pertinent requirements of the Ethical 
guidelines for biomedical research on human p~cjpants (ICMR) 2017, New Drugs, and Clinical Trials 
Rules (2019) of India, USFDA regulations, rules and guidelines, cGCP guidelinc(s), lCH (Step 5) 'Guidanc-c 
on Good Clinical Practice' ICH Guidance E6 (R2), Declaration ofHelsinki (Brazil, 2013), Code of Federal 
Re1:,,ulations on the Protection of Human Subjects (45 CFR Part 46) and with procedures oriented to Good 
Labo,dtory Practice and applicable regulatory guidelines. 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to ensure that 
all associates assisting in the conduct of this study are informed regarding their obligations, 
Confidcmial 
Pifge91 of91 


27.5 ANNEXURE V: SIGNA TORE(S) OF INVESTIGA TOR(S) 
1, the undersigned, have read and understood this protocol, entitled 
"A randomized, open label, multi-centre, two-treatment, two-period, two-seqo 
steady-state, crossover, bioequivalence stu 
and Lyoparza® (olaparib) tablets 150 mg 
m patients With 
CA mutated ovarian cancer, recurrent ovarian cancer or metasta c bre2st cancer under fasting 
condition."' 
and hereby agree lo conduct U1e study in accordance with this protocol and to comply with all the 
requirements regarding the obligations of investigators and all other pertinent requirements of the Ethical 
guidelines for biomedical research on human participants (ICMR) 2017, New Drugs and Clinical Trials 
Rules (2019) of India, USFDA regulations, rules and guidelines, cGCP guideJine(s), ICH (Step 5) 'Guidance 
on Good Clinical Practice' ICH Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013) , Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46) and with procedures oriented to Good 
Laboratory Practice and applicable regulatory guidelines. 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to ensure that 
all associates assisting in the conduct of this study are inforn:ied regarding their obligations. 
Confidential 
Pai:c91 of9I 


.. 
27.S ANNEXURE V: SIGNATURE(S) OF INVESTIGATOR{S) 
I; the undersi~ued1 hl\ve read.and understood this ,protocol, entitled 
"A randomized, openlabel, multi-centre, two-treatment two-period, tw9-seq · 
steady-state, crossover, bioequivalence st 
and Lynparza® {olaparib) tablets 1S0 mg 
BRCA mutated ovarian cancer, recurrent ovarian cancer or me as 
condition." 
and hereby agree to conduct the study in accordance with this protocol and to comply with all the 
requirements regarding the obligations of investigators and all other pertinent requirements of the Ethical 
guidelines for biomedical research on human participants (IGMR) 2017, New Drugs and Clinical Trials 
Rules (2019) of India, USFDA regulations, rules and guidelines, cGCP guideline(s), ICH (Step 5) 'Guidance 
on Good Clinical Practice' ICH Guidance Eo (R2), .Oeclaration of Helsinki (Brazil, 2013), Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR P.~ 46) and with procedures oriented to Good 
Laboratory Practice and applicable regulatory guidelines. 
1 agree to comply with all relevant SOPs required for the conduct ofthis study. I further agree to ensure that 
. . 
. . . 
. 
. 
. 
. 
.. 
. . 
. 
Confidential 
Page91 of91 


27.S ANNEXURE V: SIGNATURE(S) OF INVESTIGATOR(S) 
I, the undersigned, have read and understood this protocol, entitled 
"A randomized, ope11 label, multi-centre, two-treatment, two-period, two-sequence two-sta. 
dose, steady-state, crossover, bloequivaleoce stud of Ola arib tablet,, 150 m 
and Lynparza® (olaparib) tablets 150 mg 
in pat{ents with 
BRCA mutated ovarian cancer, recurrent ovarian l:1lncer or metastatic breast cancer under fasting 
condition." 
and hereby agree to conduct the study in accordance with this protocol and to comply with all· the 
requirements regarding the obligations of investigators and all other pertinent requirements of the Ethical 
guidelines for biomedical research on human participants (ICMR) 2017, New Drugs and Clinical Trials 
Rules (2019) of India, USFDA regulations, rules and guidelines, cGCP guideline(s), ICH (Step 5) 'Guidance 
on Good Clinical Practice' ICH Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013), Code of Federal 
Regulations on the Protection •of Human Subjects (45 CFR Part 46) and with procedures oriented to Good 
Laboratory Practice and applicable regulatory guidelines. 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to ensure that 
all associates assisting in the conduct of this study are informed regarding their obligations. 
Confidential 
Page 91 of91 


Protocol-Number: 
Errata No. 02 in Protocol Version 01 
A randomized, open label, multi-centre, two-treatment, two-period, two-sequence, two-stage, 
If I d 
t d state, crossover, bio.equivalence srudy of Ola arib tablets, 150 mg 
and Lynparza® (olaparib) tablets 150 mg 
), 
p 
BRCA mutated -ovarian cancer, recurren ovanan 
ce 
. 
breast cancer under fasting conctition. 
Sr. 
No. 
2 
Section 
Typed as 
It should be read as 
Section 
3.0 6. Adequate or!,>an and 6. Adequate organ and bone 
Synopsis and bone marrow function marrow function based upon 
Section 
9.1 based upon the following ·the 
following 
laboratory 
Inclusion 
laboratory criteria at the criteria · at 
the 
time 
of 
criteria. 
time 
of 
eligibility eligi.bility 
assessment 
at 
assessment 
p~ior 
to screening and prior to dosing 
Annexure I: dosing in period l: 
in period l : 
Schedule of Ena! function 
Renal function 
Events (And 
Wherever 
applicable 
throughout 
· the protocol) 
Section 
3.0 CBC, 
Creatioine 
Synopsis and Clearance, S Bilirubin, 
Section 
12 SGPT and SOOT: Prior 
Clinical and to dosing in period I 
Safety 
(Day -2 to 0) and period 
assessment. 
2 ( can be performed after 
Annexure I: 
Schedule of 
Events (And 
Wherever 
applicable 
throughout 
the protocol) 
evening dose on Day 8) 
( can be done at local 
labor-dtory) 
CBC, Creatinine Clearance, S 
Bilirubin, SGPT and SGOT: 
Screening, Prior to dosing in 
period l · (Day -2 to 0) and 
period 2 ( can be performed 
after Morning dose on Day 
8) ( can be done at local 
laboratory) 
Reason for 
cha.nge 
o rectify the 
error and 
provide 
better clarity 
with respect 
to c.linical 
test 
To rectify the 
error and 
provide 
betler clarity 
with respect 
to clinical 
test 
Page 1 of3 


Sr. 
No. 
3 
4 
Section 
Typed as 
Section 
sample 
13 The plasma samples will 
be stored at -2.()±5°C in a 
processing 
and ttansfer 
procedures 
freezer until shipment to 
the Bioanalytical facility 
of 
-
-
It should be read as 
Reason for 
The pfo:sma samples wi.Il be To x:ectify.the 
stored at -15° C or colder in 
e.rror an<l 
a freezer until .shipment to the 
provide 
Bioanalyt1cal 
focftity 
of better clarlty · 
with respect 
and -
and then stored at -
then stored at -78±8°C 78±8°C until analysis. 
to storage 
condition of 
PK.samples 
at site. 
Section 
19.2.2 
Post 
trial access 
until analysis. 
Based on the Investigator 
discretion, patients who 
complete the study in its 
entirety 
may 
receive 
Olaparib tablet 150 mg 
on compassionate basis. 
Based on the Investigator 
discretion, 
patients 
who 
complete the study in its 
enfjrety may receive Olaparih 
tablet 
150 
mg 
and/()r 
Olaparib tablet 100 mg on 
compassionate basis. 
Dose modification/reduction 
of olaparib can be done 
based 
on 
discretion 
of 
investigator 
i;tft.er 
· completion of study. 
As per the 
suggestion of 
pdncipal 
invesfigator 
. 
... 


.... 
Page 3 of3 
.... 


Page 3 of3 




~goJof3 




Page3 of3 




Page3 of3 


Page 3 of3 


Page3 of3 


Page3of3 


Page3 of3 


:// 
.. 
( 
I 
I 
J j 
l 
\ 
Page3 of3 
1 l 
. I 
: i 
t 


'f.age~ of3 


Protocol Number: 
Errata No. 01 in Protocol Version 01 Date 
A randomized, open label, multi-centre, two-treatment, two-peri 
o-sequence, n 
· 
state, crossover, bioequivalence study of 
and Lynparza® (olaparib) tablets 150 mg 
BRCA mutated ovarian cancer, recurrent ovanan cancer or me s atic 
reast cancer un er asting condition. 
Sr. 
Section 
No. 
TYJled as 
It should be read as 
1 
Annexure I; · Procedure 
Check in 
Procedure 
Check in 
Reason 
for 
change 
•. ·,-.-·•~,'!' "'Schedule..,~fst:--: 
·'t"-+';~ 
~-~~-, .. -,<,..~ ':1a¥~ i:-~ 
1>- ,~ -.-,iu,.u-~-· 
.. ·-• ·-~¥:·,.-mi~e-:: 11!~:~-w~:---- ,.,.,.._.,, ......... h,_v 
Events ... (And 
Day 
0, 
Day 
O, 
2 
Wherever 
day 
5 
day 5 and 
applicable 
and day 
day 13 
throughout 
13 
the protocol) 
Study 
drug 
X 
administration 
Procedure 
PK 
sampling 
Day 1, day 
6,day 7,day 
8,day 
14,day 
15 
and day 16 
X 
Study 
drug 
X(on 
DayS 
administration 
Procedure 
PK 
sampling 
and Day 
13) 
Day I, Day 
9, 
day 
6,day 7,day 
8,day 
14,day 15 
and day 16 
X (except 
on day 9) 
To rectify 
the error 
and provide 
better 
clarity. 
Section 
Synopsis, 
3.0 Urine 
drug 
Screen Urine 
(benzodiazepines, opioids, 
amphetamines, 
cannabinoids, cocaine and 
barbiturates) : Day 0, Day 5 
drug 
Screen 
( To rectify 
and 
Section 
12 
Clinical 
and 
Safety 
barbiturates, 
the error 
amphetamines, 
benzodiazepines, 
marijuana(THC), 
cocaine, 
and morphine): Day 0, Day 
and provide 
better 
clarity with 
respect to 
clinical test 


Sr. 
Section 
No. 
assessment. 
Typed llS 
It shouJd be read as 
and Day 13 
5 and Day l3 
Note: Above mentioned changes are applicable to all the relevant section of protocol. 
Reason 
for 
change 


Sr. 
Section 
Typed as 
It sb.ould be read as 
Reason 
No. 
for 
change 
assessment. 
and Day 13 
5 and Day 13 
Note: Above mentioned changes are applicable to all the relevant section of protocol. 




change 
assessment. 
and Day 13 
5 and Day 13 
Note: Above mentioned changes are·applicable to all the relevant section ofprotocoL 
' 
t j 
l 


-:r.of · 
:tl(~)lg~: 
• 
• 
~! ~-•~ 
• 
1 
• 
'., 
(' 
, 
oJ.';f.,;t'~;;l'C' <N 
• 
• 
;_ 
" 
/ 
-~k 
, 
_,., 
::,_.. !~.:• 
Note: .A:bove:m:,~ti.0.9'¢d:c,hange:s.~ ;~pR.1J~b.Ie to. ~lJ, thetf~Jgvant s~ction gtsJ).rotocoJ.,,, 
·-


Sr. 
Section 
Typed as 
It should be read as 
Rea.son 
No. 
for 
change 
assessment. 
and Day 13 
5 and Day 13 
Note: Above mentioned changes are applicable to all the relevant section of protocol. 


.. 
Sr. 
Sectien 
Typed as 
It should be rcead as 
Reason 
J 
Na. 
for 
d1.ange 
a.o;sessment. 
-andDay t3 
S·.andDay 13 
Not~: Above meptioned cbmtgc:s are aF.plicabl~ to all theulevant. s~~ion of protocol. 


S.r.:' 
.. 
No .. 


1 
It should be tead as 
assessment. 
and Day 13 
5 and Day 13 
change 


;• · •·.; ~:r.~ 
..... 
I, 
; .. : 
··l}· 
1:·:\:t~~,~t}f},~~~'!~:· 
~...,..----,-----------~------..... --_ .... _____ --~-~------.... ~-,...;.--"" 
·. • .r. 
I· 


Sr. 
Section 
Typed as 
lt s.hou.ld be te-ad u 
Reason 
No. 
for 
ehaQge 
assessment. 
and Day 13 
5andDay l3 
Note: Above mentioned changes are applicable to all the relevant section of protocol 


Sr. 
Section 
No. 
assessment. 
Typed as 
It should be read as 
and Day 13 
5 and Day 13 
Note: Above mentioned changes are applicable to all the relevant section of protocol. 
Reason 
for 
change 


Sr. 
Section~ . 
No. 
assessment. 
Typed as. 
and Day 13 
It should be read as 
5. and Day 13 
Reason 
for 
change 
Note: Above mentioned changes are applicable to all the relevant section of protocol. 


assessment. 
and Day 13 
5 andl>ay_ lJ 
' 
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SAP_001.pdf: 
 
Statistical Analysis Plan 
  
Sandoz Global Clinical Development 
 
Protocol Number: 21-VIN-0166 
 
Protocol Title: A Randomized, Open Label, Multi-centre, Two-treatment, Two-period, 
Two-sequence, Two-stage, Multiple Dose, Steady-state, Crossover, Bioequivalence 
Study of Olaparib Tablets, 150 mg (Lek Pharmaceuticals d.d.) and Lynparza® 
(Olaparib) Tablets 150 mg (AstraZeneca Pharmaceuticals LP), in Patients With BRCA 
Mutated Ovarian Cancer, Recurrent Ovarian Cancer or Metastatic Breast Cancer 
Under Fasting Condition 
 
 
 
NCT Number:  
 
NCT05258747 
Document date: 
 
03 Dec 2022  
Document version:  
1.0  
 
 


Protocol No. 
Statistical Analysis Plan 
STATISTICAL ANALYSIS PLAN (SAP) 
Version 01: 
PROTOCOL No: 
A randomized, open labe~ multi-centre, two-treatment, two-period, two-se{!Uence, two-stage, multiple 
dose, steady-state, crossover, bioequivalence stud of Ola arib tablets 150 m 
-
and Lynparza® (olaparib) tablets 150 mg 
BRCA mutated ovarian cancer, recurrent ovarian cancer or metastatic breast cancer under fasting 
condition 
Page I of30 


Protocol No. 
Statistical Analysis Plan 
Statistical Analysis Plan Signature Page 
We, the undersigned, declare that we have thoroughly reviewed this guideline for completeness and 
accuracy with the Protocol Requirements, CRF details, Database, SOPs and lCH-GCP. 
Pagc2 of30 


Page 3 of30 


Table of Contents 
1. Administrative Structure ................................................................................................................................ 8 
1.1 Study Sponsor ........................................................................................................................................... 8 
1.2 Introduction and Scope ............................................................................................................................. 8 
1.3 Responsibility of data management ........................................................................................................... 8 
1.4 Responsibility of Statistical Analysis ................................ ......................................................................... 8 
2. Study Objectives ............................................................................................................................................. 8 
3. Study design ................................................................................................................................................... 9 
3.1 General Aspects ........................................................................................................................................ 9 
3.2 Randomization ..................................................................................................................... : .................... 9 
3.3 Blinding .................................................................................................................................................. 10 
3.4 StudyEndpoints ...................................................................................................................................... 10 
4. Analysis Populations ................................................................................................................................... 11 
4.1 Randomized Population .......................................................................................................................... 11 
4.2 Safety p·opulation ................................................................................................................................... l l 
4.3 PK population ......................................................................................................................................... 11 
S. General Aspects of Statistical Analysis ......................................................................................................... 12 
5.1 Presentation of Summaries and Analyses ................................................................................................ 12 
5 .2 Precision of Display ................ ................................................................................................................ 12 
5 .3 Analysis Time Points .............................................................................................................................. 12 
5.4 Methods for Handling Missing Data ........................................................................................................ 13 
6. Patient Eligibility and Protocol compliancc ................................................................................................... 13 
6.1 Inclusion Criteria .................................................................................................................................... 13 
6.2 Exclusion Criteria ................................................................................................................................... 15 
6.3 Withdrawal Criteria ................................................................................................................................ 17 
6.4 Protocol Deviations ................................................................................................................................. 18 
7. Statistical analysis ....................................................................................................................................... 18 
7 .1. Dataset Definitions ................................................................................................................................ 18 
7.1.1. Safety Datasct ..................................................................................................................................... 18 
7. L.2. Concentration Set (CS) ........................................................................................................................ 18 
7.1.3. Pharmacokinctic Concentration Set (PKCS) ........................................................................................ 18 
7.1.4. PK Paramerer Set (PK.PS) ................................................................................................................... 18 
8. General Aspects of Phannacokinetic and Statistical Analysis ........................................................................ l 9 
Page 4 of30 


8.1 Pharmacokinetics analysis ....................................................................................................................... 19 
9. Statistical Analysis ....................................................................................................................................... 20 
9.1 Steady-state assessment .......................................................................................................................... 20 
9.2 BE assessment ........................................................................................................................................ 20 
9.2.2 Analysis ofVariance ............................................................................................................................ 21 
9.2.3 Intra-Subject Variability ....................................................................................................................... 23 
9.2.4 Power .................................................................................................................................................. 23 
9.2.5 Two one-sided tests for bioequivalence ................................................................................................ 23 
9.2.6 Ratio Analysis ...................................................................................................................................... 24 
9.2. 7 Bioequivalcncc criteria ......................................................................................................................... 24 
9.2.8 Clinical Data - CDISC Study Data Tabulation Model .......................................................................... 24 
9.2.9 Analysis Data - CDISC Analysis Data Model ...................................................................................... 25 
l O. Outliers ....................................................................................................................................................... 25 
11. Evaluation of Safety Parameters (Safety Population) ................................................................................... 25 
1 l . l Adverse Events ..................................................................................................................................... 25 
11.2 Serious Adverse Events (SAEs) ............................................................................................................ 29 
12. Software and Programming Considerations ................................................................................................. 30 
12.1 Software used for Analysis .................................................................................................................... 30 
12.2 Validation for Analysis Programs .......................................................................................................... 30 
13 List of Artnexure .......................................................................................................................................... 30 
I 3. I Statistical report for Justification of using Two-Stage Potvin C Design, v2 ............................................ 30 
Page 5 of30 


LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
% 
Percent 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC(O•l)SS 
Area under the plasma concentration versus time curve for one dosing interval at steady state 
BA 
Bio availability 
BE 
B ioequ ivalence 
COSCO 
Central Drug Standard Control Organization 
CruaxSS 
Maximum plasma concentration during the dosing interval at steady state 
CRO 
Contract Research Organization 
CV 
Coefficient ofV ariation 
DCGI 
Drug Controller General oflndia 
EC 
Ethics Committee 
Hrs 
Hours 
ICD 
Informed Consent Document 
ICH 
International Council for Haononisation of Technical Requjrcments for Pharmaceuticals 
for Human Use 
lCMR 
Indian Counc.il of Medical Research 
IMP 
Invcsrigational Medicinal Product 
K,EDTA 
Tri Potassium Ethylene Diamine Tetra Acetic Acid 
Kc1 
The elimination rate constant associated with the terminal (log-linear) portion of the 
curve. Estimated by linear regression of log concentration. vs. time 
LAR 
Legally Acceptable Representative 
LOQ 
Limit of Quantification 
Ltd. 
Limited 
PK 
Pharmacokinetic 
PKCS 
Pbarmacokioetics Concentration Set 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
Page 6 of30 


SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
ss 
Study State 
USA 
United States of America 
USFDA 
United States Food and Drug Administration 
Vd 
Volume of distribution 
Page? of30 


1. Administrative Structure 
1.1 Study Sponsor 
1.2-Introduction and Scope 
This Statistical •
. 
(SAP) is based on the final Clinical Study Protocol 
Version 01 dated 
fhe SAP provides details on the planned statistical met o o ogy or 
the analysis of the stu y ata. This SAP outlines in detail all aspects pertaining to the planned 
analyses and presentations for this study. The Mock she11s details like Table, listing and figure 
sbaU be generated in separate document. 
The statistical analyses will be made in accordance with the ICH-E9 guidelines "Statistical Principles 
for Clinical Trials" and guidelines from CDSCO, US FDA regulations and applicable regulatory 
guidelines. 
1.3 Responsibility of data management 
Responsibility of providing clean data for the statistical analysis lies with data managemen-
has captured the data in software where data cleaning and query 
management process are described in detail in the data management plan and the related SOPs. 
1.4 Responsibility of Statistical Analysis 
Statistics team will be responsible for programming statistical analysis as per 
approved SAP. Statistician fro 
will be responsible for Pharmacokinetic 
analysis. The Mock shells details like Table, listing and figure shall be generated as per approved 
Statistical Analysis Plan (SAP). 
2. Study Objectives 
Primary Objective: 
• 
To assess the pharmacokinetics and establish bioequivalence of the Test Product (Olaparib 
tablets, 150 mg) relative to that of Reference Product (Lynparza® (olaparib) tablets 150 mg) in 
patients with BRCA mutated ovarian cancer, recurrent ovarian cancer or metastatic breast 
cancer. 
Page 8 of30 


Secondary Objective: 
• 
To monitor the adverse events of patients and to assess safety of each of the two fonnulations. 
3. Study design 
A randomized, open labe~ multi-centre, two-treatment, two-period, two-sequence, two-stage, multiple 
dose, steady-state, crossover, bioequivalence study 
3.1 General Aspects 
Sample Size 
Considering a maximum expected intra-patient variability of 35% based on available literature 
estimates, a true ratio (T/R) of 0.95, 56 evaluable patients are adequate to achieve at least 81% power at 
5% level of signjficance to meet the bioeguivalence limit of 80.00% to 125.00% at Stage l. 
....... ..... " . 
e enrolled to have 
in the Stage 1 -
and Stage 2 sample size (jf .needed) will be decided on the basis of 
data ( observed CV) obtained after the completion of Stage 1. Maximum sample size (Stage 1 + Stage 2) 
is expected, bot not limited to, 
This is a 2-stage design according 
to Potvin C method1• Overall expected power is 86%. 
Enrollment will be continued until at least 
n case 
additional patients are recruited. those patients will continue the study until completion/withdrawal and 
be included in the pharmacoldnetic and statistical analyses as applicable. 
Note: Patients enrolled in Stage I will not be eligible for Stage 2. 
lnvestigational Products 
Test 
: Olaparib tablets, 150 mg o 
Product 
(T) 
Reference 
Lynparza® (olaparib) tablets 150 mg. Manufactured for: 
Product 
(R) 
3.2 Randomization 
Randomization wiJI be carried out using SAS® (SAS Institute Inc., USA) version 9.4 or higher. 
Randomization will be done in blocks using PROC PLAN such that the design is balanced. The order 
of receiving reference and test formulations fur each patient during two-periods of study will be 
determined according to the randomization schedule for Stage I and Stage 2 (as appHcable). 
Page9of30 


Randomization will be generated separately for each stage. 
Period 1 
Period 2 
Sequence 1 
Test (T) 
Reference (R) 
Sequence 2 
Reference (R) 
Test (T) 
Screening and Randomization Numbering 
Each patient will be assigned a unique number that will serve to identify laboratory specimens and a11 
documents and will be used throughout the study. If a patient fails to qualify for allocation to the study 
ie. is a screen failure, his/her number must not be reused for another patient. 
The screening number will be a combination of the center number, the project number and the patient 
number. The center number will be assigned by -
to the investigative site (e.g., A, B, C, D) and 
subsequent sites are assigned consecutive alphabet numbers. Upon signing the informed consent form, 
the patient will be assigned a screening number by the Investigator. At each site, the first patient 
consented is assigned screening number e.g., 
nd subsequent patients are assigned 
consecutive numbers (e.g., the second patient consented is assigned screening number 
the third patient is assigned screening number 
Once a screening number assigned to a 
patient, that number will not be reused for any other patient. 
If the patient is deemed eligible for enrollment into the study and will commence dosing with IMP in 
Period 1, then a randomization number will be assigned. The randomization number will be assigned 
by a combination of Site ID and Dosing sequence (e.g., A-01 where A is Site ID and 0 1 is number of 
first patient dosed, A-02 where A is site ID and 02 is number of second patient dosed). Patient will be 
randomized on first come first serve basis and will be given a randomization number accordingly 
irrespective of their screening number. 
There should be a source document maintained at the site which links the screening number to the 
randomization assignment number (once assigned) and this information will also be reflected in 
screening and enrollment log of site investigator file. 
3.3 Blinding 
This is an open label study. However, the bio-analyst at - wil be blinded to the randomization 
sequence of study drug administration to each of the patient. Samples that are shipped to the analytical 
laboratory will not contain treatment information on the sample label. 
3.4 Study Endpoints 
Page 10 of30 


This study does not have efficacy endpoints. Pharmacokinetic Assessments will be carried out for 
assessment of Bioeq uivalence. 
Primary Parameters: - C.noxSS, AU~o-T))ss 
Secondary Parameters: - Cmmss, T m11~ss, Cavss, swing and percentage of fluctuation. 
The key safety variables of the study are as follows: 
• 
Relev~t Medical and Medication History 
• 
HER2 Testing 
• 
Germline or Somatic BRCAl and BRCA2 diagnostic test 
• 
Physical examination 
• 
Demography 
• 
Vital signs (Height, weight, Blood pressure, pulse rate, respiratory rate and body temperature) 
• 
X-ray(chest) 
• 
ECG 
• 
Hematology, Blood chemistry & Urinalysis 
• 
lmmunological/Serology tests (HIV, HBsAg, HCV antibody, VDRL) 
• 
Urine Screen for drugs of abuse 
• 
Pregnancy test for Female patients 
• 
Adverse events/ Serious Adverse Events 
• 
Concomitant medications 
4. Analysis Populations 
4.1 Randomized Population 
Randomized population will include a1l patients who are randomized. A patient will be considered to 
have been randomized if patient has a randomization number assigned. 
4.2 Safety Population 
The safety dataset will include randomized patients wbo receive at least one dose of IMP. Data from 
subjects in this dataset will be used for the assessment of safety. 
4.3 PK population 
Pharmacokinetic and statistical analyses for plasma. concentration versus time profile of Olaparib will 
be performed on the data obtained from patients -included in the PK dataset. 
PK dataset 
Page ll of30 


Data from the following patients will be included in the PK dataset: 
• 
Patients who have completed both periods and have missed samples in any period that may not 
affect the estimation of the Cmax,ss and/or AUC parameters and have been predetermined prior to 
the bioanalytical analysis to not significantly impact the overall outcome of the study; 
• 
Patients who complied with all protocol requirements, or encountered protocol deviations that 
do not impact the estimation of the PK parameters. 
Patients withdrawn prior to sample analysis for pharmacokinetic reasons (i.e., an event that could result 
in an inadequately characterized pharmacokinetic profile for o laparib) will not be included in the PK 
and statistical analysis. 
Any decision for excluding data from the fmal data set will be provided with a detailed explanation and 
will be properly recorded and dated. 
PK dataset will be defined in consultation with the sponsor at different study stages for different sets of 
patients, prior to initiation of sample analysis for each set of patients. This dataset will be reassessed, if 
required ( e.g., missing concentration value due to analytical reason), upon completion of the sample 
analysis. The PK dataset will be finally confirmed by the sponsor prior to database lock. 
5. Genera) Aspects of Statistical Analysis 
5.1 Presentation of Summaries and Analyses 
Descriptive statistics of primary and secondary pharmacokinetic parameters will be computed and 
reported for Olaparib tablets, 150 mg. 
5.2 Precision of Display 
Descriptive statistics such as Mean, Median and Geometric mean will be rounded up to three digits 
after decimal; SD with rounded up to four digits after decimal, minimum, maximum and %CV with 
rounded up to two digits after decimal. 
5.3 Analysis Time Points 
All the assessments will be performed as mentioned in the Sampling Schedule as per Protocol. 
A total of 43 blood samples each of 03 mL will be collected from each patient for PK assessment 
during the study. 
The venous blood samples will be withdrawn from each patient in each period at the following time 
points: 
Page 12 of 30 


The post dose blood samples will be collected with an allowable deviation of ± 2 minutes. In all 
instances, however, the exact time of dosing and of each sample collection must be recorded. Samples 
collected outside the scheduled time will be considered as protocol deviations. 
Note: 
1. 12.00 -hour blood sample must be collected prior to next drug administration. 
2. Blood sample collection (PK samples) will be collected first if other. activities are coinciding. 
5.4 Methods for Handling Missing Data 
All concentration value below the limit of Quantification (LOQ) will be set to "zero" for all 
pharmacokinetic and statistical calculation. Any missing sample will be reported as "Missing" and will 
not be included for pbannacokinetic and statistical analysis. 
Data from patients with missing concentration values (missed blood draws, lost samples, samples 
unable to be quantified) may be used if pharmacokinetic parameters can be estimated using the 
remaining data points. Otherwise, concentration data from these subjects will be excluded from the 
final analysis. 
In case of sample collection deviations, the actual time point of sample collection will be used for the 
computation of pbarrnacokinetic parameters. 
Missing plasma samples will be handled as per 
6. Patient Eligibility and Protocol compliance 
6.1 Inclusion Criteria 
To be eligible for the study, patients must meet all the following inclusion criteria: 
1. First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer 
maintenance treatment of adult patients with deleterious or suspected deleterious germline or 
somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer 
who are in complete or partial response to first-line platinum-based chemotherapy. Select 
patients based on a diagnostic test for BRCA mutation by NGS - Next Generation Sequencing 
method. 
Page 13 of30 


OR 
Maintenance Treatment of Recurrent Ovarian Cancer maintenance treatment of adult 
patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in 
complete or partial response to platinum-based chemotherapy. 
OR 
Advanced Germline BRCA-mutated Ovarian Cancer After 3 or More Lines of 
Chemotherapy treatment of adult patients with deleterious or suspected deleterious gennline 
£RCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more 
prior lines of chemotherapy. Select patients based on a diagnostic test for BRCA mutation by 
NGS - Next Generation Sequencing method. 
OR 
Germline BRCA-mutated HER2-negative Metastatic Breast Cancer treatment of adult 
patients with deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast 
cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic 
setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated 
with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select 
patients based on a diagnostic test for BRCA mutation by NGS - Next Generation Sequencing 
method. 
2. Non-smoking, non-pregnant, non-lactating female patient ~18 years of age with a body mass 
index (BMI) in the range of 18.50 to 30.00 kg/m2 (both inclusive). 
3. Able to give written informed consent for participation in the trial and willing to adhere .to 
protocol requirements. 
4. Patients that are already receiving a stable dose of Lynparza® (olaparib) tablets (2*150 mg 
tablets) 300 mg twice daily for at least 10 days. 
OR 
Patients requiring Olaparib in the dose of 300 mg (2*150 mg tablets) twice daily as per the 
discretion of the Investigators; these patients will be stabilized on Olaparib as a part of study 
and those patients that tolerate Olaparib in tbe dose of300mg twice daily will be randomized in 
the study. Patients that do not tolerate the mentioned dose or require dose modifications for any 
reason will be considered as screen failure. Patients who miss 2 or more consecutive doses or 
more than 3 non-consecutive doses in the Dose Stabilization period will be considered screen 
failure. 
5. Patient having an estimated survival o f at least 3 months. 
Page 14 of30 


6. Adequate organ and bone marrow function based upon the following laboratory criteria at the 
time of eligibility asse~ment prior to dosing in period 1: 
Body system 
Parameters 
Bone marrow function a) Hemoglobin ?:;9.0 g/d.L 
b) Absolute neutropbil count ~1500/uL 
c) Platelet count ~l 00,000/uL 
d) WBC count > 3.000/mm3 
Renal function 
Creatinine Clearance > 50 mL/min (calculated 
based on Cockcroft-GauJt formula) 
7. Eastern Cooperative Oncology Group (ECOG) perfonnance status of0-2. 
8. Absence of blood transfusion in the 28 days prior to randomization.. 
9. Women of non child bearing potential with documented evidence of hysterectomy / bilateral 
sa lpingectomy / bilateral oophorectomy a1 least 6 months prior to IMP administration) or 
postmenopausal for at least 12 consecutive months. 
OR 
\Vomen of child bearing potential must have negative pregnancy test at screening visit and 
before randomization and must agree to use an effective method of avoiding pregnancy 
(in.eluding oral, transdermal or implanted contraceptives [any hormonal method in conjunction 
with a secondary method], intrauierine device, female condom with spermicide, diaphragm with 
spermicide, absolute sexual abstinence, use of condom with spermicide by sexual partner or 
sterile [at least 6 months prior to IMP administration] sexual partner) for at least 4 weeks prior 
to IMP administration, during the study and up to 6 months after the last dose of IMP. Cessation 
of birth control after this point should be discussed with a responsible physician. 
6.2 Exclusion Criteria 
Patients who meet any of the following criteria at screening will not be enrolled in the study: 
I. History of known hypersensitivity to olaparib or its components which, in the opinion of the 
Investigator, would compromise the safety of the patient or the results of the study. 
2. Patients found positive for HlV, Syphilis, Hepatitis B surface antigen or Hepatitis C antibody at 
screening. 
3. Have ongoing clinically significant adverse event(s) due to prior treatments administered, as 
determined by the investigator. 
Page 15 of 30 


4. Patients with Pneumonitis. 
5. Patients with severe hepatic impairment (Child Pugh classification category C) 
6. Patients who received any chemotherapy, radiotherapy, or any other anti~cancer therapy within 
4 weeks from the last dose prior to first dosing in Period O 1 ( or a longer period depending on 
the defined characteristics of the agents used). 
7. History or presence of any active infection or uncontrolled systemic disease ( e.g. cardiovascular 
disease, hypertension, diabetes mellitus etc.) or any clinically significant disease, condition, 
disorder or abnormal laboratory finding that, in the opinion of the Investigator, may either put 
the patient at risk because of participation in the study, or influence the study results or the 
patient's ability to participate in the study. 
8. Patient had major surgery within 4 weeks prior to first dosing in Period 01, or who have not 
recovered from prior major surgery. 
9. In the opinion of the Investigator, the patient will not be compliant with the requirements of tbe 
study procedures. 
10. Blood loss (1 unit or 350 ml) within 90 days prior to first dosing in Period 01 for the current 
study. 
11. Receipt of an investigational medicinal product or participation in another drug research study 
involving IMP administration w ithin 30 days (or 5 half-lives, whichever is longer) prior to first 
dosing in Period O 1 for the current study. 
Note: Elimination half-life of the study drug should be taken in consideration for inclusion of 
the patient in the study. 
12. Usage of strong and moderate CYP3A4 inhibitors (e.g., cimetidine, ciprofloxacin, grapefruit 
juice) or strong and moderate CYP3A4 inducers (e.g., carbamazepine, phenytoin, St. John's 
Wort, rifampicin) within 30 days prior to first dosing in Period 01 (refer annexure IV for full list 
of prohibited medications). 
13. History of difficulty in accessibility of veins or intolerance to direct venipuncture. 
14. Pregnant or lactating females. 
15. Patient positive on Breath alcohol analyzer test at the time of baseline/randomization visit. 
16. Positive on l1rine test for drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, marijuana, cocaine, and morphine) prior to receiving the first dose of 
investigational medicinal product in the study. 
17. History or presence of alcoholism or drug abuse. 
18. Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
Page 16 of 30 


19. Difficulty in swallowing tablets. 
20. Problems with fasting. 
21. History or presence of clinically significant lactose, galactose, or fructose intolerance. 
6.3 Withdrawal Criteria 
An investigator may withdraw a patient from the study for any of the following: 
1. The patient may be withdrawn from the trial at the discretion of the investigator and/or the 
sponsor if judged to be non-compliant with protocol/trial procedures. 
2. Any major/significant deviation from the protocol that in the opinion of the investigator/sponsor 
may impact the patient's safety and/or the scientific integrity of the trial. 
3. Any major safety concern such as (but not limited to) serious, life-threatening, or intolerable 
AEs that, in the opinion of the investigator and/or sponsor requires withdrawal from the study. 
4. Patients who experience emesis within two times ofTmax. value (i.e. 3 hours) on Day 8 or Day 
16. Patients who experience emesis at any other time during the study will be evaluated for their 
continued participation in the study based on the investigator's and sponsor's assessment. 
5. Patients who experience diarrhea (defined as three or more episodes ofloose stools during a 24 
hour interval) at any time during the study will be evaluated by the investigator and sponsor and 
a decision for continued participation in the study will be made based on the potential impact of 
the event on the integrity of the study results and patient's safety. 
6. If a patient found positive for Coronavirus infection (COVID-19) during the study. 
7. If patient requires dose modification (i.e. change from 300 mg twice daily) or dose interruption 
during study participation. 
8. Any patient who requires the use of unacceptable concomitant medicines. 
9. If a patient becomes pregnant or develops hypersensitivity to Olaparib or to any of the 
excipients during the course of the trial. 
10. Significant inter-current illness and/or surgery that in the opinion of the investigator and/or 
sponsor requires withdrawal from the study. 
11. Disease exacerbation/progression that in the opinion of the investigator requires interruption 
and/or change in therapeutic modality. 
12. lf the patient requires any concomitant medication, which as per judgment of the investigator 
may significantly interfere with the pbarrnacokinetic property of the study IMP. 
13. If it is felt in the investigator's opinion that it is not in the patient's best interest to continue. 
14. If the patient on their own, wishes to withdraw consent. 
15. Missing sample{s) or incidence of AEs that affect the pharmacokinetics of the analyte, thus 
Page 17 of30 


preventing a planned statistical comparison. 
16. Patients who miss 2 or more consecutive IMP doses or more than 3 non-consecutive doses in a 
given period. 
Any patient withdrawal during the study along with the reason thereof shall be documented in the CRF 
and reported to sponsor. 
The planned sample size accounts for withdrawal among the randomized patients, so withdrawn 
patients will not be replaced. 
Irrespective of the reason of withdrawal, the patient will be requested to complete all 
procedures/activities required for End of Study safety assessment as far as possible. 
6.4 Protocol Deviations 
All protocol deviations will be listed, including those on timing window for PK sample collection. This 
listing will be generated for all randomized patients. 
7. Statistical analysis 
7 .1. Dataset Definitions 
7.1.1. Safety Dataset 
The safety dataset will include randomized patients who receive at least one dose of IMP. Data from 
subjects in this dataset wi11 be used for the assessment of safety. 
7.1.2. Concentration Set (CS) 
All available concentration data of analyzed PK population will be reported in a separate table as CS. 
7.1.3. Pharmacokinetic Concentration Set (PKCS) 
PKCS will be defined prior to start of sample analysis and will be reassessed, if required (e.g., missing 
concentration value due to analytical reason) upon completion of sample analysis and prior to data 
analysis. PKCS dataset will be used to perform assessment of steady-state. 
Subjects included in PKCS needs to be approved by sponsor. 
7 .1.4. PK Parameter Set (PK.PS) 
PKPS is dataset of PK parameters for subject from PKCS dataset excluding subjects that: 
- do not achieve steady-state. 
Page 18 of30 


- have other per protocol reason for exclusion from BE assessment. 
PKPS will be used for Pharmacokinetic analysis and BE assessment. 
8. General Aspects or Pbarmacokinetic and Statistical Analysis 
Pharmacokinetic for plasma concentration versus time profile ofOlaparib will be performed on the data 
obtained from patients included in the PKPS dataset. 
8.1 Pbarmacokinetics analysis 
Pharmacokinetic parameters Cmaxss, Cminss, AUCc0-t)ss, Cavss, T rnaxss, Swing, percentage of fluctuation 
will be calculated using plasma concentration vs time profile (Actual time of sample collection) data of 
both investigational medicinal products in individual patients using Phoenix®WinNonlin® Software 
Version 8.2 or higher (Pharsigbt Corporation, USA). 
Primary Parameters: 
CmaxSS 
Maximum plasma concentration during the dosing interval at steady state 
AUCco-~iss 
Area under the plasma concentration versus time curve for one dosing interval 
at steady state 
Secondary Parameters: 
CminSS 
Concentration at the end of a dosing interval 
CavSS 
Average plasma concentration over the steady state dosing interval 
TmaxSS 
Time of maximum measured plasma concentration over the steady state dosing 
interval 
Swing 
[ Cmaxss-Cminssl CminSS ]* 100 
Percentage 
of 
[Cmaxss-Cminss/Cavss]* 100 
fluctuation 
Pharmacokinetic 
parameters 
will 
be 
calculated 
by 
non-compartmental 
analysis 
using 
Phoenix®WinNonlin® software Version 8.2 
or higher (Pharsight Corporation, USA). All 
pharmacokinetic parameters will be estimated from the Plasma concentration time profile data. 
All concentration values below the Limit of Quantification (LOQ) will be set to "zero" for all 
pharmacokinetic and statistical calculations. Any missing sample will be reported as ''Missing" and will 
not be included for pharmacokinetic and statistical analysis. 
Page 19 of30 


Data from patients with missing concentration values (missed blood draws, lost samples, samples 
unable to be quantified) may be used if phannacokinetic parameters can be estimated using the 
remaining data points. Otherwise, concentration data from these subjects will be excluded from the 
final analysis. 
In case of sample collection deviations, the actual time point of sample collection will be used for the 
computation of pharmacokinetic parameters. 
Missing plasma samples will be bandied as pee 
9. Statistical Analysis 
SAS® Software, Version 9.4 or higher will be used for statistical analysis of phatmacokinetic 
parameters Cmaxss and AUC(o-'t)SS. 
9.1 Steady-state assessment 
PKCS dataset wil1 be used for steady-state assessment. 
By considering the three day's morning pre-dose concentrations in a given period, steady state analysis 
will be performed for each subject in each period by using the linear regression analysis to obtain the p-
values. The above analyses will be done using procedure PROC REG in SAS, version 9 .4 or higher. 
For achieving the steady state following procedure should be assessed: 
Step 1: For each subject in each period the P-values should be statistically insignificant at 5% level of 
significance. 
If, P-values are found statistically insignificant, those patients are considered to achieve steady state. If, 
P-values are found significant for particular subject then go for the second step. Go for second step for 
patients who have missing pre-dose sample for Day 6 or Day 14. 
Step 2: Ratio of the pre-dose concentrations of last two pre-dose should be 
80% or should be 
120.00%. 
In case ratio of last two pre-dose concentrations is found to be 2: 80% or S 120.00% patients will be 
considered to achieve steady state. If two pre-dose concentrations is found to be less than 80% or 
greater than 120%, patients will not be considered to achieve steady state and will be removed from 
bioequivalence evaluation. 
9.2 BE assessment 
PK.PS dataset will be used for BE assessment. 
9.2.1 Steps of a two stage design according to Potvin C 
Page 20 of30 


Stage 1: 
Siepl: 
Evaluate the power at stage 1 using the variance estimate from stage 1, GMR of 0.95 and an CL 
level of 0.05 for each of Cmaxss and AUCco-'t)SS parameters. 
Before proceeding to Step 2, notify the sponsor (via email) regarding stage 1 power and CV 
values. However, the other BE assessment results (e.g. GMR point estimates or confidence 
intervals) should not be calculated at Step 1 nor shared with the sponsor. After a 
confirmatory email is received from the sponsor, proceed to Step 2. 
Step 2: 
Step 2.1: If power (calculated using the observed variability and GMR of0.95) is greater than or 
equal to 80% for both of the parameters (Cmaxss and AUCco-t)Ss), evaluate BE at stage 1 using an 
a level of 0.05 and stop regardless of whether BE is met or not. 
OR 
Step 2.2: If the power for either of the two parameters (Cmaxss or AUC<O-'t)ss) is less than 80%, 
evaluate BE using an a level of0.0294. 
Stage 2 
Step 2.2.1: if the BE criterion is met, stop. 
OR 
Step 2.2.2: ff the BE criterion is not met, calculate the sample size for stage 2 based on 
the variance estimated at stage 1, GMR of 0.95 and an a level of 0.0294, round up to 
nearest even number, add 20% subjects for dropouts and continue to stage 2. If the 
calculated sample size for stage 2 is less than 12, include at least 12 subjects in stage 2. 
If the GMR point estimate for any parameter (Cmaxss or AUCco-~)ss) is outside 80.00%-
125.00% then study will not proceed for stage 2. 
Evaluate BE at stage 2 using data pooled from both stages and an a level of 0.0294. Stop here whether 
BE is met or not and regardless of the power achieved. 
9.2.2 Analysis of Variance 
For Stage 1: 
The In-transformed pharmacokinetic parameters (Cmaxss and AUCco-t1ss) will be analyzed using an 
ANOV A model with Center, Treatment, Period (Center), Sequence, Sequence*Center as fixed effects 
and Patient (Within Sequence*Center) as a random effect. 
Sequence and Center main effects and Sequence*Center interaction effect will be tested using Patient 
(within Sequence*Center) mean square from the ANOVA model as the error term. All other main 
Page 21 of30 


effects will be tested against residual error (mean square error) from the ANOVA model as the error 
tenn. 
Main effects will be tested at the 0.05 level of significance, whereas the interaction effect will be tested 
at the 0.10 level of significance. 
Results from each analysis of variance will include formulation least-squares means, the difference 
between the adjusted formulation means, the standard error associated with. the difference and the 
associated confidence interval. The above analyses will be done using procedure PROC MIXED in 
SAS, ve.rsion 9.4 or higher. Kenwart-Roger method for the denominator degrees of freedom will be 
applied. 
For combined Stage 1 and Stage 2 data: 
The selection of final statistical model after stage 2 will be based on the centers selected for stage 2: 
• 
If all stage 1 centers will be used in stage 2, then the In-transformed pharmacokinetic 
parameters (Cmaxss and AUC(o-,)SS) will be analyzed using an ANO VA model with the effects of 
Center, Stage, Treatment, Period (Center*Stage), Sequence, Sequence*Center, Center*Stage, 
Sequence*Center*Stage as fixed, and Patient (Within Sequence*Center*Stage) as a random 
effect. 
• 
Alternatively, if all stage 1 centers will not be used in stage 2, then the In-transformed 
pbarmacokinetic parameters (Cmaxss and AUC<o-iiss) wil1 be analyzed using an ANOVA model 
with the effects of Center, Stage, Treatment, Period (Center), Sequence, Sequence*Center as 
fixed, and Patient (Within Sequence*Center*Stage) as a random effect. 
The Sequence, Stage, Center and all included interaction effects wi11 be tested using the Patient (within 
Sequence*Center*Stage) effect as the error term. All other main effects will be tested against the 
residual error (mean square error) from the ANOVA model, as the error term. 
Main effects will be tested at the 0.05 level of significance, whereas the interaction effects will be 
tested at the 0.10 level of significance. 
If Center*Stage effect is included in the model and is found to be significant, visual exploration of data 
will be performed to explain the potential reasons for this interaction. 
Results from each analysis of variance will include formulation least-squares means, the difference between 
the adjusted formulation means, the standard error associated with the difference and the associated 
confidence interval. The above analyses will be done using procedure PROC MIXED in SAS, version 9.4 or 
higher. Kenwart-Roger method for the denominator degrees of freedom will be applied. 
Page 22 of30 


Note: Prior to Stage 1 ANO VA analyses and the assessment of center effect, combining of the small 
centers will be performed so as to assure that in each of the new, combined centers there will be a 
minimum of .five evaluable patients and that each combined center includes at least one evaluable 
subject from each of the two sequences. 
The small centers will be combined using the following three step procedure: 
J. Centers will be first arranged in ascending order bqsed on the number of evaluable patients per 
center (i.e., from smallest to largest center) and then in ascending order of site label (e.g. A to Z). 
2. Starting with the smallest center, a center with Jess than five evaluable patients will be combined 
with a subsequent center. If there will be more than one center with less than five patients all these 
centers will be combined until at least frve evaluable subjects will be available in the new, combined 
center. The procedure will continue with the next center in the arranged order, until all combined 
centers include at least five evaluable subjects. 
3. Starting with the first combined center, a combined center with all subjects from either TR or RT 
sequence will be joined with the subsequent center until all combined centers include at least one 
evaluable subject from each of the two sequences. 
The combined centers (instead of the original centers) will be used in both stage I and stage 2 
analyses. 
Note: Analysis of study will be performed as per latest/updated Statistical Analysis Plan (SAP). 
9.2.3 Intra-Subject Variability 
Intra-subject variability will be calculated using mean square error of ANOV A for ln-transfom1ed 
analysis of Cmaxss and AUCco-T)SS for Olaparib. 
9.2.4 Power 
Power will be calculated as per section 9.2.1 and will be reported for Cmaxss and AUCto-'t)SS. 
9.2.5 Two one-sided tests for bioequivaJence 
90% (if power is more than 80% at stage 1) & 94.12% (as applicable, if the power is less than 80% at 
stage 1 and stage 2) confidence intervals for the difference between least squares means of test and 
reference formulations will be calculated using mean square error, obtained in ANOVA, for In-
transformed Cmaxss and AUC{o-~iss. 90% (if power is more than 80% at stage 1) & 94.12% (as 
applicable, if the power is less than 80% at stage 1 and stage 2) confidence interval for the geometric 
least squares means ratio will be obtained by taking the exponent of lower and upper limits of 90% (if 
power is more than 80% at stage I) & 94.12% (as applicable, if the power is less than 80% at stage 1 
and stage 2) confidence interval, obtained for the least squares means difference. 
Two one-sided test, namely Schuirmann's test, will be employed at 5% level of significance for the 
Page 23 of30 


lower and upper limits of90% (if power is more than 80% at stage 1) & 94.12% (as applicable, if the 
power is less than 80% at stage 1 and stage 2) confidence interval to check whether the 90% (if power 
is more than 80% at stage 1) & 94.12 ( as applicable, if the power is less than 80% at stage 1 and stage 
2) confidence interval for Cmaxss and AUCcO-t)SS will be entirely within the bioequivalence limits of 
80.00¾to 125.00%. 
9.2.6 Ratio Analysis 
Geometric least squares means for test and reference formulations will be obtained by taking the 
exponent of least squares means of test and reference formulations for In-transformed Cmaxss and 
AUQo-~>ss. Ratio will be obtained by taking the exponent of difference of least squares means of test to 
reference fonnulations for 111-transformcd Cmaxss and AUCco-t)SS- The comparisons of interest are T vs. 
R, so the ratios determined will be of the form T/R, where T = Test fonnulation and R = Reference 
formulation. 
9.2.7 Bioequivalence criteria 
For Stage 1 with Power 2:. 80%: 
Based on the statistical results of 90% confidence intervals for the geometric least squares means ratio 
for the ln-pharmacokinetic parameters Cmaxss and AUCco-i)SS for Olaparib the conclusions will be drawn 
whether test formulation_ is bioequivalent to reference formulation under Fasting condition. Acceptance 
range for bioequivalence is 80.00%-125.00% for 90% confidence intervals of the geometric least 
squares means ratio of Cmaxss and AUC(O-'t)SS-
For Stage l with Power< 80% and for Stage 2, if required: 
Based on the statistical results of 94.12% confidence intervals for the geometric least squares means 
ratio for the log-transformed pharmacokinetic parameters Cmaxss and AUC(O-'t)SS for Olaparib the 
conclusions will be drawn whether test formulation is bioequivalent to reference formulation under 
Fasting condition. Acceptance range for bioequivalence is 80.00%-125.00% for 94.12% confidence 
intervals of the geometric least square means ratio ofCmaxSs and AUCco..,.)ss. 
9.2.8 Clinical Data - CDISC Study Data Tabulation Model 
Domains will be mapped to CDISC (Clinical Data Interchange Standards Consortium) SDTM, SDTM 
IG (Implementation Guide). AU versions valid as per FDA Data Standards Catalog will be used for 
SDTM. No derived data required for analysis will be included in the SDTM domains. The SAP will not 
be amended to provide information on additional SDTM domains, although this will be allowed if 
necessary. All SDTM domains will be fully documented with define documents (DEFINE.XML) and a 
clinical study data reviewer's guide after database lock and final analyses are completed. Validation of 
CDISC SDTM domains will be done using Pinnacle 21 Community (version 3.1.2 or higher). 
Page 24 of30 


9.2.9 Analysis Data - CDISC Analysis Data Model 
All planned and exploratory analyses will be completed using the ADaM (Analysis Data Model) data 
sets (ADaM, ADaM IG) derived from the SDTM domains for this study. All versions valid as per FDA 
Data Standards Catalog will be used for ADaM. Analysis data sets will contain all derived study 
endpoints required for analysis. All analysis data sets will be fully documented with define documents 
(DEFINEJCML) and an analysis data reviewer's guide (ADRG) after database lock and final analyses 
are completed. Validation of CDISC ADaM domains will be done using Pinnacle 21 Community 
(version 3.1.2 or higher) 
10. Outliers 
For outlier identification, appropriate statistical tests could be performed. Outliers are defined as 
subjects having discordant values of one or more pbarmacokinetic parameters when compared with 
other values, e.g., a subject differs notably from the rest of the subjects for the test product response 
versus the reference product response. Outlier test will be performed using appropriate statistical 
method as per-- for "Detection of Outliers". Subject data will not be removed from the 
statistical analysis solely based on the results of statistical outlier tests. Outlier data may only be 
removed from the statistical analysis if there is a real-time documentation demonstrating a protocol 
violation during the clinical and/or analytical phase of the BE study. 
11. Evaluation of Safety Parameters (Safety Population) 
All randomized patients who have received a dose cifIMP will be included in safety evaluation. Results 
obtained when evaluating safety and tolerability (adverse events, vital signs, and clinical laboratory 
tests) will be listed in the report. AEs occurring prior to first IMP administration will be p resented in a 
separate listing within study report. All AEs will be classified by System Organ Class, Preferred Term 
(using the Medical Dictionary for Regulatory Activities (MedDRA), version 20.0 or higher), and 
Severity with respect to treatment received. 
11.1. Adverse Events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation 
subject after providing written study-specific informed consent for participation in the study. Therefore, 
an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. The investigator has the responsibility for managing the safety of individual 
subject and identifying adverse events. The o.ccurrence of adverse events must be sought by non-
directive questioning of the subject at each visit during the study. Adverse events also may be detected 
when they are volunteered by the subject during or between visits or through physical examination 
findings, laboratory test findings, or other assessments. 
Page 25 of30 


Any AE (non-serious and serious) occurring after the subject has provided study-specific infonned 
consent and until the last study visit of the subject, has to be recorded on the AE pages of the Case 
Report Form (CRF). 
Medical conditions/diseases present before providing written informed consent are only considered 
AEs if they worsen after enrolment. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. Abnormal laboratory values 
or test results constitute adverse events only if they fulfill at least one of the following criteria: 
• 
they induce clinical signs or symptoms; 
• 
they are considered clinically significant; 
• 
they require therapy. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the interventions 
required to treat it, and the outcome. 
Information about already known adverse dtug reactions for the lnvestigational Medicinal Product dmg 
can be found in the Reference Safety Information (e.g. Prescribing information). 
Each adverse event should be evaluated to determine the following: 
A. Severity of AEs 
Adverse events should be assessed and graded according to the Common Temunology Criteria for 
Adverse Events (CTCAE) version 5.0. Grade refers to the severity of the AE. The CTCAE version 5.0 
displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guideline. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL *. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL *-"'. 
Page 26 of30 


Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL (Activities of Daily Living) refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
**Self-care AOL refer to bathing, dressing and undressing, feeding self, using the toilet, talcing 
medications, and not bedridden. 
B. Relationship to IMP 
Adverse event's relationship to the. study treatment should be determined (suspected/not suspected). 
Causality assessments are critical and must be provided for each unique AE in relation to each IMP, 
non-investigational medicinal product (NIMP) or other concomitant medication, if applicable. Missing 
causality assessments will be handled as suspected to IMP by the sponsor. The causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the 
relationship cannot be ruled out. 
If the event is due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be 'Not suspected.' The rationale for this guidance 
is that the symptoms of a lack of efficacy or progression of underlying illness are not caused by the trial 
drug, they happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a single 
subject. 
C. Evaluation of AEs (duration, action taken, outcome) 
The duration (start and end dates) of adverse event should be recorded. Determine whether AE 
constitutes a serious adverse event (see Section 12.2.2 for definition of SAE) and which seriousness 
criteria have been met. 
Actions taken with respect to investigation medicinal product should be documented as per the below 
given tabulation using CDISC STDM terminology. 
Page 27 of30 


Adverse Event Variable Label 
CDISC STDM Terms 
Action Taken with the IMP 
• Dose increased; 
• Dose not changed; 
• Dose rate, reduced; 
• Dose reduced: 
• Drug interrupted; 
• Drug withdrawn; 
• Not applicable; 
•Not known 
The outcome of the adverse should be documented and assigned to one of the following categories: 
Adverse Event Variable Label 
CDISC STDM Terms 
Outcome of event 
• Not recovered/not resolved; 
• Recovered/resolved; 
• Recovered/resolved with sequelae; 
• Recovering/resolving; 
• Fatal; or 
• Unknown. 
All AEs must be treated appropriately. The treatment of the AE shou ld be documented in the CRF. 
Concomitant medication, other non-IMP treatments or changes in the administration of the IMP should 
be specified and documented. Treatment may include one or more of the following: 
• 
No action taken (i.e. further observation only); 
• 
lMP dosage adjusted/temporarily interrupted; 
• 
IMP permanently discontinued due to this AE; 
• 
Concomitant medication given; 
• 
Non-drug therapy given, patient hospitalized/ patient's hospitalization prolonged. 
Adverse events should be recorded in the CRF under the signs, symptoms or diagnosis associated with 
them. 
All AEs including both volunteered and the ones considered clinically relevant and reportable as AE by 
investigator will be recorded in the CRF and in the patient's medical records, irrespective of its 
association with study medications. Independent /Institutional Ethics Committee (IEC) will be 
informed regarding AEs as necessary. 
Page 28 of30 


The Most Common Adverse Events Associated with Study Medication 
• 
Patients should be carefully monitored for adverse events/toxicity. To manage adverse events 
such as Myelodysplastic syndrome/ Acute myeloid leukemia, Haematological toxicity, 
Pneumonitis> or Venous Thromboembolic Events, the dose may be reduced or interrupt the 
treatment. 
• 
To manage adverse reactions, consider interruption of treatment or dose reduction. The 
recommended dose reduction is 250 mg taken twice daily. If a further dose reduction is 
required, then reduce to 200 mg taken twice daily. 
• 
Dose adjustment is to be done by the Investigator as per the approved Summary of Product 
Characteristics, Prescribing Information of Lynparza® and the protocol. 
• 
Refer Summary of Product Characteristics and Prescribing Information of Lynparza® for further 
information on management of AEs. 
NOTE: If patient requires dose modification (i.e., change from 300 mg twice daily) or dose 
interruption during study participation, the patient should be withdrawn from the study. 
11.2 Serious Adverse Events (SAEs) 
An SAE is def med as any adverse event [ appearance of ( or worsening of any pre-existing)] undesirable 
sign(s), symptom(s) or medical conditions(s)] which meets any one of the following criteria: 
• 
results in death 
• 
is life-threatening: Life-threatening in the context of a SAE refers to a reaction in which the 
subject was at risk of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if it were more severe. 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
-
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
-
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and bas not worsened since signing the study specific informed 
consent 
General care, not associated with any deterioration in condition 
-
Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions 
of a SAE given above and not resulting in hospital admission 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
is medically significant: Medical and scientific judgment should be exercised in deciding 
whether other situations should be considered serious reactions, such as important medical 
events that might not be immediately life threatening or result in death or hospitaLiza,tion but 
Page 29 of30 


might jeopardize the subject or might require intervention to prevent one of the other outcomes 
listed above. Such events should be considered as "medically significant". Examples of such 
events are intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization or development of 
dependency or abuse (please refer to the ICHE2D Guidelines). AU malignant neoplasms will be 
assessed as serious under "medically significant", if other seriousness criteria are not met and 
the malignant neoplasm is not a disease progression of the study indication. Any suspected 
transmission via a medicinal product of an infectious agent is also considered a serious adverse 
reaction. All reports of intentional misuse and abuse of the product are also considered serious 
adverse events irrespective if a clinical event has occurred. 
A (Serious) Adverse Drug Reaction ((S)ADR) is any (S)AE for which the investigator or sponsor 
assess a reasonable possibility for a causal relationship to a medicinal product. 
A (Serious) Unexpected Adverse Reactions is defined as a (serious) adverse drug reaction, which is 
not consistent with the Reference Safety Information ( e.g. Summary of Product Characteristics 
(SmPC), Product Monograph, Investigator's Brochure). Reports which add significant information on 
the specificity, increase of occurrence, or severity of a known, already documented serious adverse 
reaction constitute unexpected events. The term 'severity' is used here to describe the intensity of a 
specific event. This bas to be distinguished from the term 'serious'. 
12. Software and Programming·Considerations 
12.1 Software used for Analysis 
SAS® Software, Version 9.4 or higher (SAS Institute Inc., Cary, NC, USA) will be used for 
randomization and statistical analysis. Phoenix WinNonlin® software Version 8.2 or higher (Pharsight 
Corporation, USA) will be used for carrying out the pharmacokinetic analysis. 
12.2 Validation for Analysis Programs 
Validated programs will be used for Randomization and Analysis of variance (ANOVA) application by 
pharmacokinetic and biostatistics department 
, respectively. 
13 List of Annexure 
13.1 Statistical report for Justification of using Two.Stage Potvin C Design, v2 
Page 30 of30 


Statistical Report 
Regarding the Justification for using the FDF Modified Two-Stage Potvin 
Method C Design for a Two-Period, Two Sequence, Two-Stage, Multiple-Dose 
Crossover Study To Assess Bioequivaleoce Between the Test and Reference 
Olaparib Products 
Ver. 2 


1 TABLE OF CONTENTS 
1 TABLE OF CONTENTS .............................................................................................................. 2 
LJST OF TABLES ......................................................................................................... -.............. 4 
LIST OF FIGURES ............. , ......................................................................................................... s 
l 
Strl\fMARY ................................. ·-···-···-···· .................................................................................. 6 
1 INTRODUCTION .......................................................................................................................... 7 
PURPOSE OF TilE ll'f:PORT ....................... ... -...................................................................................... 7 
L'f'l-RODUCllON ........................................ ...................... •••••••••••·••••••••••••••••••••"•"'"••••••••••••••• .. •••••••••••••• 7 
STATISTICAL MEIBODOLOGY ............................................................................................ 8 
STATISTICAL MODELS FOR ASSESSING BIOEQUJVALJc;NCE ............................................................... 9 
FDF MODJFIED POTVIN METITOD C DESIGN ................................. "' ................................................ LO 
SAMPLE SIZE DET.Elli'\UNA'.llON FOR A SINGLE-STAGE DESIGN ...................................................... 11 
RESULTS .......................................... -.. .-.......................................... 
c ...... 
-
......
. ........................... 12 
Ev Al .I IA TION or: THE OPERATING CHARACTERISTICS OF THE FOP MODl'FTED POTVIN METHOD 
C DESIGN .................................................. ......................................................................................... 12 
EFFICIENCY/ COST EVALUATION OF rm: FDF MODJFJED POTVJN MEraOD C DESJGN'" ............ 19 
VALIDATIONOFTDE ~C.'TION FOR THE FDFMODIFIID POTVIN METHOD C DESIGN 
SIMULATION ........................................................................................................................................ 21 
COMPARISON OF TIE RA TE AND POWER Of IBE FDF MODIFllilJ POTVIN C DESIGN TO THOSE OF 
POTVINC DESIGN ................................................................................................................................ 21 
STEP DY STEP EFl'~CTS 01' M ODiflCA TIONS TO POTVIN C McfHOD ................................................... 24 
R.EPRODUCIBILlTY Of 'Ilill RESULTS .................................................................................................... 26 
2 REFERENCES ............................................................................................................................. 27 
1 APPEN.DIX A: R CODE .. -......................................................................................................... 29 
FUNCTION POWJ.:R.TSD.2 (FOR CALCULA.11NG nu: ' F.MPfillC' POWJ'.R OF TWO-STAGE BE STUDTF,S 
ACCORDING TO FDF l\'10D CFIED POTI'IN C DESIGN VIA SIMULATIONS) .......................................... 29 
R PROGRAM l•OR CALCULATING TYPE 1 ERROR RA TE OVER TllE GRID OF CV% AND Nl ......... 36 
R PROGRAM FOR CALCUl,AT~G POWER OVER 'flIE GR.ID OF CV% AND Nl ................................ 3 7 


APPENDIX B: THE EVALUATION OF OPERA TING CHARACTERJSTICS OF THE 
FDF MODIFIED POTVIN METHOD C DESLGN FOR THE MAXIMAL TOTAL SAMPLE 
SIZE OF EITHER 150 OR 200 ........... ,. ............................................................................................ 39 


2 LIST OF TABLES 
1'ablc J. l'crms in the ANO VA models/or In-transformed PK parameten (CmoxSS and A UC(O-T)SS) applied in the first and 
final stage of the rwo-stage Potvin Method C {left) and the FDFmodified Potvin Method C design (riglu) .......................... JO 
Table 1. Estimated Type I Hrrar (fJF.) Rare nf the FDF modified Porvin C Two.Stage Design (at ThetaO of J.25) ............... J J 
Table J. Estimated Power of the FDF modified l'otvirr C Two-Sta~ Dc.rign (al 11,eta() o/0.95) .......................................... J ,I 
Table 4. Estimated Power of the FDF modified Potvin C Two-Stage Design (at 17teta0 o/0. 90) .......................................... 14 
Table 5. Estimated Mean Total Sample Size of the FDF modified Potvin C Two-Stage Design (at ThetoO oj"0.95) .............. I 5 
Table 6. Details of tlte FDF modified Potvin Method C Design Simula lion Results/or CV% of35% ................................... 19 
Table 7. Derails of the Potvin Me1had C Design Simulation Results/or CJl"A of 35% ................................................. ·-······ 20 
Table 3. J:,"stimated Type I l:irror (TIE) Rnteofthe Potvin C Two.Stage Design (al ThetoO of / .15) ...................................... 21 
Table 9. Estimat,:c/ Power of the Potvin C Two-Stage Design (at ThclaO of 0.95) .................................................................. 21 
Table 10. Effect of FDF Modifications to the Potvtn C Met/1od on the Estimated Type I Error Rare ..................................... 25 
Table 11. p;/fect of FDF Modifications to /he Potvin C Method on &timated Power ............................................................ 26 
Table I 2. Descrip1ive Statislics of the 20 Repealed TIE Estimates ......................................................................................... 26 
Table /3. Descripttve S1atls1ics of the 2() Repllca1ed Power Es1ima1es ................................................................................. 27 
Tabfc B /. Estimated Typo I Error (TIE) Rate of t/1e FDF modified Potvin C Two-Stage Design (at 771etaO of /.25 and Nmax 
of 150) ..................................................................................................................................................................................... 39 
Table 1J2. Esfimoted Power of the FDF modified Potvin C Two-Stage Design (01 rheraO of0.95 and Nmax of JJOJ ............ 39 
Table JJ3. & timatt:d Type J Error (TIE} Rote of the FDF modified Potvin C Two.Stage Design (at 71,eta0 of 1.25 and Nmax 
o/100) ..................................................................................................................................................................................... 40 
Table B4. Estimated Power of the FDF modljled Potvin C Two-Stage Design (al ThettrO of 0.95 and Nmax of 100) ............ 40 


3 LIST OF FIGURES 
Fl~ure 1. Potvin MeJhod C (left) and FDF modified Potvin Method C (right) Design Schema ................................................ 9 
Figure 2. Estimated Power oft he FDF Modified Potvin C Two-Stage Method (at nl-56 and ThetaOfrom O.PO to 0.95) .... 16 
Figure 3. &iimared Power oftheFDF Modified Potvin C Two-Stage Med1od {at nJ- 52, 56, 58 andThetaOfrom 0.90 to 
0.95).............................. ....................................................................................................................................... .. . .... 17 
Figure 4. &ffm<Ited Power aft he PDF Modified Potvin C Mc1hod (at The1aO of0.95). ........................................................ 18 
Ftg,1re5. F..~tima1ed Toto/ Sample Size of the FDF Mod(fieti Potvin C Method (al ThetaO o/0.95) ....................................... 18 
Figure 6. £ $ti mated Type I Error rate/or 1/10 FDF modified Potvin C design (left) and Potvin C design (right) .................. 23 
Figure 7. Esrlmated p-0wer for 1he FDF modified Poivfn C design (left) and Potvln C deslg11 (right) ................................... 24 


2 SUMMARY 
The "FDP" modified two-stage Potvin Method C design is described and evaluated within. 
The modifications to the original Potvin Method C [l] include Lwo futility criteria and an 
adjustment to the error degrees of freedom for studies performed at multiple sites. In other 
words, the PDF modified two-stage Potvin Method design assumes that the site/center is 
included in the statistical models for assessing bioequivalence. 
The evaluations are performed by calculating the estimated Type I Error rate and power of the 
FOF modified Potvin Method C design via simulations. The simulations are performed over 
the relevant grid defined by stage I sample size (nl) ranging fro4 
and the coefficient 
of variation (CV%) in a range from 20% lo 40%. 
The results demons1rate that, al least over lhe grid defined by the ul and CV% values, lhe 
estimated Type I Error Rate and Power are relatively close to those reported for Potvin Method 
C in [l), with a slight decrease in both the power and the Type I error (TlE) rate for the FDF 
modified method. The TIE and power of the FDF modified method is decreasing (as compared 
Lo the original Potvin Method C) with increasing CV% and decreasing stage 1 sample size 
(nl). 
No inflation of the Type I Error rate was observed over the grid of relevant nl and CV% values. 
The estimated power does not fall below the 0.80 for any combination of relevant n I and CV% 
values. 
The efficiency/ cost evaluation of the FDF modified two-stage Potvin Method design indicates 
that using a stage 1 sample size of -
determined for a single stage design under the 
assumption of CV% of35%, geometric mean ratio of 0.95, power of 80%, and alpha level of 
5%) the expected power for the FDF design is increased to 0.86 (from a power of 0.80 of a 
single stage design) while increasing the expected mean total sample size by 4%. 


3 INTRODUCTION 
PURPOSE OF THE REPORT 
As per email communications be 'nnin I October 2021 and under the terms and conditions 
agreed to with 
CAIR Center has agreed to supply an operating 
characteristics evaluation of the FDF modified two-stage Potvin Method C Design W, uswg 
simulation. The report is to be submitted along with the protocol in Bio-Tt-U) package material 
for FDA review and will later be an appendix of Statistical analysis plan. 
INTRODUCTION 
A Lwo-period, two sequence, two-stage, multiple-dose crossover study to assess 
bioequivalence of the test and reference olaparib formulation is to be performed. The study 
will be conducted at multiple sites (approximately 20). Primary PK endpoints are Cmax,ss and 
AUCtau,ss, and a bioequivalence criteria for lbe geometric means ratio (GMR) 90% Cl being 
contained within a 80%-125% range wm be applied to these endpoints. 
This reports describes steps taken and the simulations performed lo assure rhat the selected 
two-stnge design (i.e., the FDF modified Potvin Method C) controls for the Type I F.rror (TIE) 
and has sat1sfactory power to make the planned bioequjvalence study ethical. 
In Section 4 on Statistical Methodology we first define the models that will be applied in 
assessing bioequivalence at the first and final stage of the two-stage procedure. Next, the FDF 
modified two-stage Potvin Method C design will be defined, and the sample size under a single 
stage design (and for the stage l of the two-stage design) will be determined. 
Results in Section 5 are split inlo lhree major components so as to include the evaluation of 
the operating characteristics, efficiency/ cost evaluation and the results regarding validation of 
the function for the FDF modified two-stage Potvin Method C design (simulations and 
calculations). 
Appendix A provides R codes for calculating the "empiric,, {estimated) power of BE studies 
using the FDF modjfied two-stage Potvin Method C via simulations (function "power.tsd.2"), 
and for calculating the "empiric" (estimated) power and a Type I Error (TIE) rate over a grid 
of relevant n I and CV% values. 
Appendix B oontains tables of the estimated Type I error rate and power when the maximal 
total sample size is set to either 150 or 200. 


4 STATISTICAL METHODOLOGY 
Since 2008, a number of adaptive two-sLage sequential designs for biocquivalence two-
sequence, nvo-period, two-treatment crossover studies have been suggested and evaluated with 
respect to TIE rate and power (Potvin et nl. U], Montague el al. W, Karalis ct al. fl], Kieser 
et al. [il, Schuetz f.21, Maurer ct al. [fil. Fuglsang [1], [[), etc.). 
The Potvin Method C, introduced by Potvin el al. W (although critici7.ed l~I. with several 
adaptations/ alternatives having been suggested) still appears to be the method of choice. 
For the current study we developed a modification to the original Potvin Method C, which is 
described in detail below, and the evaluation of the FDF modified met.hod with regard to the 
Type I Error (TIE) rate and power is presented in the Results Section below. 
Toe validity of simulation results regarding estimates of the TIE rate and Power depends 
primarily on the match between the actual/ planned BE evaluation procedure and tl1e procedure 
for lhe simulation and evaluation of studies used in estimating TIE and Power. 
In the case of a two-stage design, this means that every step in the actual evaluation procedure 
must be adequately reflected in the program for simulating studies and estimating the TIE rate 
and power. 
For the planned BE study it was decided to apply a two-stage Potvin Method C, but with the 
following three modifications (see Figure I below): 
1. To mclude the fotili ty criterion of Point Estimate (PE) at stage l (i.e., to stop the study 
if PE falls outside lherauge of 0.80-1.25), 
2. To include the ful.ility criterioa of the maximal total sample si7,e, i.e., to stop the study 
if the totaJ required sample size is greater than the pre-specified maximum (e.g., either 
120, 150 or 200), and 
3. To adjusUdecrease the error degrees of freedom (df) for the number of sites in lhe BE 
evaluation at the firs1 and final stage of the two stage procedure (ie., in the estimation 
of the Type I Error (TIE) rate and power, using simulation). 
A Potvin method C design that includes the above three modifications will in this report be 
referred to as the "FDF modified Potvin Method C design". 


PwO<f.il:l 
...... taJ 
Oldl•.....-O~ 
a...t• O.O?N 
,-..... ,..... 
7l.D.Fuuytulll 
"' ..... Gl4 
• ..a.o....,,.J, 
Figure 1. Potvin Method C (left) and FDF modified Potvin Method C (rie:ht) Design Schema 
With the open-s01uce R package "Power2stage", version 0.5-3. [ilj, several functions are 
provided for calcolating, via simulations, the "empiric" (estimated) power of BE studies using 
many two-stage designs, including the Potvin Method C design. However, the modification of 
the Potvin Method C design by using futility criterion of PE (point l above) is available wilh 
the function "power.tsd.fC", whereas the modification using fulility criterion of maximal total 
sample size (point 2 above) is available wilh the function "power.tsd". [n other words, there is 
not a single function that allows for both of the futility criteria to be applied simultaneously 
(i.e., in the same design). 
With regard to modification 3 above, no function in Power2stage allows for the adjustment of 
the degrees of frce<lom. Modification 3 must be implemented because Lhe statistical models 
applied for assessing bioequivalence in lhe planne<l BE study are different than those applied 
in studies designed according to the standard Potvin Method C design. Functions for estimating 
TIE and Power in the Power2stage version 0.5-3. package can only be used for simu.lnting data 
for single-site 2x2 crossover two-stage studies, and not for simulating data for more complex 
models. 
STATISTICAL MODELS FOR ASSESSING BIOEQUN ALENCE 
As displayed iu Table 1 below, the models for assessing bioequivalence for studies conducted 
at multiple sites (i.e., under the FDF modified Potvin Method C design) are more complex than 
those to be conducted at a single site (i.e., under the Potvin Method C design). 


Thus, the appropriate adjustments must be made to the function for calculating, via 
simulations, the "empiric" (estimated) power of BE studies using the FDF modified Potvin 
Method C design. 
Table 1. Terms in the ANO VA models for In-transformed PK parameters (CmaxSS and 
AUC(O--c)SS) applied in the first and final stage of the two-stage Potvin Method C (left) 
and the FDF modified Potvin Method C desi!!ll (ril!ht) 
Stae:e 
Potvin Method C <fesi1>'1l 
FDF modified Potvin Method C desi!!n 
1 
Fixed effects: 
Fixed effects: 
Treatment, Sequence, Period, 
Treatment, Sequence, Site, Period (Site), 
Random effect: 
Patient (Sequence) 
Sequence*Site 
Random effect: 
Patient (Seoueoce"'SiLc) 
Final 
Fixed effects: 
Fixed effects: 
Treatment, Sequence, Stage, 
Sequence, Treatment, Site, Stage, 
Period (Stage), Sequence*Stage 
Period (Site*Stage), Sequence•Site, 
Random effect: 
Stage*Site, Sequence"'Site•Stage 
Patient (Sequence*Stage) 
Random effect: 
Patient (SeQuenc-e* Site"'Stage) 
It should be noted lhat a term for Treatment*Site interaction is not included in the ANOVA 
models for data from the FDF modified Potvin Method C design. The justification includes 
the following: 
• Implementation of the standardized procedures and careful monitoring across all sites 
will be defined in the protocol, which should minimi:lC a chance for the heterogeneity 
of the treatment effect across sites. 
• 
According to the protocol, excessive variation in the number of subjects per site will 
be avoided. Small sites will be combined using a predefined procedure (to assure a 
minimum of five subjects per center). 
• 
Since stage I sample size is determined so as to detect bioequivalence with power of 
at least 80%, the test for site-by-treatment interaction is potentially underpowered. 
• As stated in [!11 "If the treatment effect is homogeneous across centers, the routine 
inclusion of interaction terms in the model reduces lhe efficiency of the test (or the 
main effects." 
FDF MODIFIED POTVIN METHOD C DESIGN 
The aforementioned three modifications were applied to the R function power.tsd (from the R 
package "Power2slage", version 0.5-3), where the modified function was named 
"power.tsd.2". 
The modifications were implemented in lhe following three steps: 


1. With regard to modification 1 above, a new argument ("fCrit") was included, and the 
corre,.c;ponding code was transferred from the function "power.tsd.fC" (fTom the R 
package "Power2stage", version 0.5-3) to the function named "power.tsd.l". 
2. Futility criterion of the maximal total sample size criterion was already included in the 
original function power.tsd (as the "Nmax'' argument), and thus was available in lhe 
"powcr.tsd. l" function by setting the Nmax argument to either 120, 150 or 200. 
3. With regard to modification 3, three new arguments were added to the function 
"power.tsd.1": "gr.ave", "gr.min" and "gr.tot", specifying the average, minimum 
group/site/center size, and the total available nwnber of sites, respectively. The new 
function is named "power. tsd.2". (Note: "size" corresponds to the number of evaluable 
patients per center). The current default values of gr.ave, gr.min, and gr.tot are set to 5, 
5, and 20, respectively. These values were developed from an anlicjpated/assumed 1ocal 
number of (approximately 20) sites/centers being available, and under the assumption 
tbat the smaller sites (of size less than 5) will be combined (as per the procedure 
described in the Srudy Protocol, and later i.n the Statistical Analysis Plan). 
Technical note: The expected number of sites u.sed at each of the two stages depends on n (the 
number of patients being evaluated), and e-0nsequenUy, the error degrees of freedom adjusted 
for sites depends on n and on the number of sites where t.bese n patients were eyaluated. In 
other words, nwnber of sites is not a constant. 
For example, using a stage 1 sample size (n I) of 60. the expected number of sites would be 
(60/5=) 12 (hence df=60-2-(12-1)=41), whereas for a final total sample size (ntol) of 120, the 
expected number of sites would be equal to the total available number of sites, e.g., 20 (hence 
df= l20-3-(20- l) = 9&). The second argument to the modified function (gr.min) is used for 
improved/ more accurate calculation of the adjusted degrees of freedom. A relatively accurate 
adjustment to the error degrees of freedom would not be possible using the single additional 
argument (i.e., from total available number of sites). 
SAMPLE SIZE DETERMINATION FOR A SINGLE-STAGE DESIGN 
As demonstrated in the Study Protocol, under the assumption of a maximum expected intra-
patient variability of 35%, a true ratio (T/R) of 0.95, 56 evaluable patients are adequate to 
achieve at least 81 % power at 5% level of significance to meet the bioequivalence limit of 
80.00% lo 125.00%. Thus, 56 evaluable patients are planned to be included in stage 1 of the 
two-stage FDF modified Potvin Method C design. 
Simulations presemed in the Results Section below indicate that the e7'J)ected final stage power 
is 0.86 (i.e., 86%) of the two-stageFDF modified Potvin Method C when using stage 1 sample 
si1.e of 56, assuming a CV% of 35%, and limiting the ma:dmum total samp)e si7.c to 120. Tl1e 
same expected power is achieved wilh the standard Potvin method C (for the given 
combination ofnl and CV%, as is demons1ratcd in the Results Sectfon below). 


5 RESULTS 
ResuJts are split into three major components and are presented as follows: 
• Evaluation of the operating characteristics of the FDF modified Potvin Method C 
design, 
• Efficiency/ cost evaluation of the FDF modified Potvin method C design, and 
• 
Validation of the function for the FDF modified Potvin Method C desjgn simulation. 
EVALUATION OF THE OPERATlNG CHARACTERISTlCS OF THE FDF MODIFIED 
POTVIN METHOD C DESIGN 
The tables and graphs below portray (in tabular and graphical form) the estimated Type I Error 
(TIE) rate, power and mean total sample size for !he case when the maximum total sample size 
is set to 120. Toe estimated TIE rate and power for a maximum total sample size 
llllllare provided in Appendix 13. 
Estimates of the TIE rate are based on 1 million simulations, whereas the estimates of power 
and mean total sample size are based on one-hundred thousand simulations. This means I.bat 
the standard error for TIE rate and power were set to approximately 0.0002 and 0.001, 
respectively. 
All results are presented for stage 1 sample size (n I) ranging fronalil. and a coefficient 
of variation (CV%) of20% lo 40%. 
It may be observed that (at least over the grid defined by thenl and CV% vaJues) the estimated 
Type I Error Rate and Power are relatively close to those reported for Potvin Method C in fl], 
with a slight decrease in both the power and the Type I error rate for the FDF modified method. 
Moreover, by comparing the power reported in Table 3 below with lhat in Table I of W, it 
may be seen I.bat the power of the FDF modified method is decreasing (as compared to Potvin 
Method C) with increasing CV% and decreasing nl. Thus, the highest drop (of0.023, from 
0.831 to 0.808) occurs for a CV% of 40% and a stage 1 sample size o-
(Note that I.be 
decrease in power was to be expected because a reduction in error degrees of freedom yields a 
subsequent increase in con.fidence interval width.) Nonetheless, the estimated power is still 
above 0.80 for alJ relevant combinations of n 1 and CV%, as long as the expected true T/R ratio 
is set to 0.95 (please see Table 3 and Figures 2, J. and!). 
1 The range for nl is slightly extended from the initially planned range o~
, so as to include rwo 
nl values-
for the validation using previously published results [or the original Potvin C 
mctb.od (1 ]. 


Likewise, by comparing the Type l Error rate of the FDF modified method with that of the 
original Potvin method C, it can be observed tha 
e (of 0.0012, from 0.0469 
to 0.0457) occurs for a CV% of40% and stage I 
shown in Table 2below. 
No inflation of the Type I Error rate was observed over the grid ofrelevanl n l and CV% values. 
Table 2. Estimated Type I Error (TIE) Rate of the FDF mod.ified Potvin C Two-Stage 
Desi n at ThetaO ofl.25 
CV 
20% 0.0499 0.0500 0.0499 0.050-0 0.0499 0.0498 0.0499 0.0500 
22% 0.0499 0.0500 0.0499 0.0500 0.0499 0.0498 O.o499 0.0500 
24% 0.0499 0.0500 0.0499 0.0500 0.0499 0.0498 0.0499 0.0500 
26% 0.0499 0.0500 0.0499 0.0500 0.0499 0.0498 0.0499 0.0500 
28% 0.0498 0.0499 0.0499 0.0499 0.0499 0.0498 0.0499 0.0500 
3 0¾ 
0.0492 0.0497 0.0497 0.0497 0.0497 0.0497 0.0499 0.0500 
32% 0.0483 0.0489 0.0490 0.0492 0.0494 0.0495 0.0498 0.0499 
34% 0.0473 0.0479 0.0479 0.0483 0.0487 0.0490 0.0493 0.0496 
36% 0.0464 0.0472 0.0-i?.3 0.0473 0.0476 0.0480 0.0486 0.0487 
38o/o 0.0461 0.0466 0.0466 0.0464 0.0469 0.0471 0.0475 0.0480 
40% 0.0457 0.0464 0.0458 0.0458 0.0463 0.0463 0.0467 0.0464 


Table 3. Estimated Power of the FDF modified Potvin C Two-Stage Design (at TbetaO 
of 0.95 
CV 
20% 0.9939 0.9954 09963 0.9973 0.9979 0.9984 0.9987 0.9990 
2"2% 0.9843 0.9S71 0.9895 0.9915 0.9929 0.9943 0.9954 0.9964 
24% 0.9673 0.9726 0.9771 0.9802 0.9837 0.9862 0.9883 0.9899 
26% 0.9438 0.9511 0.9577 0.9632 0.9682 0.9727 0.975.8 0.9793 
28% 0.9157 0.9241 0.9327 0.9400 0.9462 0.9524 0.9577 0.9628 
30% 0.8877 0.8958 0.9045 0.9133 0.9203 0.9273 0.9348 0.9410 
31% 0.8635 0.8715 087&1 0.8849 0.8936 0.9012 0.9096 0.9168 
34% 0.8440 0.8530 0.8567 0.8623 0.8706 0.8764- 0.8845 0.8916 
36% 0.8355 0.8423 0.8402 0.8452 0.8518 0.8554 0.8624 0.8666 
38% 0.82G3 0.8315 0.833 1 0.8347 0.8374 0.8418 0.8459 0.849'1 
40% 0.8083 0.8149 08203 0.8229 0.8261 0.8306 0.8309 0.8337 
Table 4. Estimalcd Power of the FDF modified Potvin C Two-Stage Design (at ThetaO 
of 0.90 
CV 
20% 0.8887 0.8986 0.9094 0.9192 0.9264 0.9335 0.9403 0.9469 
-- -
-
22% 0.8320 0.8456 0.8S85 0.8697 0.8803 0.8899 0.9004 0.9092 
24% 0.7738 0.7894 0.8036 0.8153 0.8294 0.8400 0.8526 0.8619 
26% 0.7165 0.7334 0.7485 0.7623 0.7755 0.7888 0.8009 0.8112 
28¾ 0.6644 0.6808 0.6950 0.710-0 0.7228 0.7362 0.74&5 0.7624 
30% 0.6217 0.6356 0.6476 0.661 I 0.6741 0.6874 0.6996 0.7141 
32'¼ 0.5885 0.6007 0.6 102 0.6197 0.6325 0.6441 0.6557 0.6679 
34°/4 0.5683 0.5773 0.5846 0.5888 0.5988 0.6074 0.6169 0.6271 
36'¼ 0.5571 0.5641 0.5<i60 0.5685 0.5754 0.5826 0.5898 0.5955 
38¾ 0.5495 0.5532 0.5580 0.5565 0.5611 0.5661 0.5720 0.5726 
40o/• 0.5371 0.5428 0.5450 0.5438 0.5481 0.5531 0.5571 0.5554 


Table 5, Estimated Mean Total Sample Size of the FDF modified Potvin C Two-Stage 
Des· n (at ThetaO of0.95 
CV 
20% 48.0 50.0 52.0 54.0 56.0 58.0 60.0 62.0 
22% 48.0 50.0 52.0 54.0 56.0 58.0 60.0 62.0 
24% 48.0 50.0 52.0 54.0 56.0 58.0 60.0 62.0 
26% 48.0 50.0 52.0 54.0 56.0 58.0 60.0 62.0 
28% 48.2 50.1 52.1 54.0 56.0 58.0 6-0.0 62.0 
30% 48.7 50.5 523 54.2 56. 1 58.l 60.0 62.0 
32% 49.9 51.5 530 54.7 56.5 58.3 60.2 62.1 
34% 52.0 53.2 54,5 55.9 57.4 59.0 60.7 62.5 
36% 55.2 56.1 56.8 58.0 59.2 60.6 62.0 63.5 
38% 59.0 59.6 60.2 61.0 6Ul 62.9 64.0 165.2 
40% 62.8 63. 1 63.8 64.4 65.l 65.9 66.8 67.7 


Estimated Power of the Modified Potvin C Two-Stage Method (at n1. and Theti10 
from 0.90 to 0.95) 
0,9 
-
0.8 _,,.,,,, 
.,,, 
..,.. 
.,.. 
,.. 
,,,-
.,,. ,,- · 
.,,,,-
.,,, 
0.7 .,-
.,.,.,. 
--
,.,. 
..,. 
.,. 
.,, 
0.90 
0.91 
0.92 
0.93 
0.94 
0.95 
thetaO 
CV 
20% 
22% -- -
24% --26% -- ·-· 28% -
-
30% 
32,0 
34,E, - ~- . -. 30~ -
··- 38'MI .. . ... -. - 40~ 
Figure 2. Estimated Power of the FDF Modified Potvin C Two-Stage Metbod (at oI=56 and 
Thetao from 0.90 to 0.95) 


Estimated Power of the Modified Potvin C Two-Stage Method (at n1=- and 
ThetaO from 0.90 to 0.95) 
nl = 
n1 = 
n1 = 
0.90 0,91 0.92 0.93 0.94 0.95 0.90 0.91 0.92 0.93 0.94 0.95 0.90 0.91 0.92 0.93 
0.95 
CV 
--- 20% -- -
22% -
• -
24% -
-
26% --·-· 28% -
-
30% 
32'lb 
34'6 -·-·- -
30')6 -·· -
38'6 ----- • 40'MI 
Figure 3. Estimated Power of the FDF Modified Potvin C Two-Stage Method (at nl=52, 56, 58 
and Theta0 from 0.90 to 0.95) 


Estimated Power or the Modlf1ed Potvin c 1WO.Stage Method (et Thetao or 0.95) 
0/ --r----------- ------------------------------, 
381( 
,. .. 
Ot1't 
oallO 
-
o,m -
0"12> 
-
o,oos 
-
011"6 
Figure 4. Estimated Power of t.be FDF Modified Potvin C M rethod (at ThetaO of 0.95) 
E&tlmated Total Sampi. SlU ortt,e Mod ff•d PoMn C Twt>-$1119,. M•tt>od (at ThttaO of 0.1)5) 
..... , 
51.1» 
sua·t -
sruo -
ao.m -
nn• -
s,.r,, 
Figure s. Estimated Total Sample Size of the FDF Modified Potvin C Method (at 
ThetaO of0.95) 


EFFICIENCY/ COST EVALUATION OF Tiffi FDF MODIFIED POTVIN METHOD C 
DESIGN 
For an assumed maximum CV%of35%, a detailed evaluation of the expected outcomes of the 
PDF modified Potvin method C (based on simulated studies) is exhibited in Table 6 below for 
a stage 1 sample size ranging fro~
~cted mean total sample size is compared 
to the sample size of a single-stage design, i.e.,lllllldetermined under lbe assumption of CV¼ 
of35%, geometric mean ratio of0.95, power of 80%~ and alpha level of5%). 
It can be observed that by using a two-stage FDF modified Potvin Method C design, total/final 
power is increased to 86% at a cost of an expected two additional patients (i.e., an expected 
increase in the number of patients/cost of 4%). Only 9.8% of the studies are expected to 
proceed to stage 2. Of the 90.2% studies that are expected to be stopped in stage J . 80.4% are 
expected to pass, whereas 9.8% are expected to fail. 
By increasing stage 1 sample size to, say .• 
the expected power is increased to 87 .2%, but 
at Lhe price of an expected 9.4% increase in the number of patients/cost as compared with tl1e 
single-stage design. 
On the other hand, if the stage 1 sample size were decreased to, say ... there would be a 
slight decrease in expected cost/number of subject (as compared with a single-stage design), 
but the expected power at the final stage, and stage 1 would be decreased (from 86% to 85% 
and from 80.4% to 76%, respectively). 
For comparison pmposes, the same evaluation is performed using Polvin Method C design, as 
is shown in Table 7 below. 
Table 6. Details of the :FDF modified Potvin Method C Design Simulation R esults for 
CV% of35% 
Studic.~ 
Studies 
failed Power Studies 
Single 
Expected 11toppcd 
in 
in 
io 
Final stage Increase in # 
mea:n in stage stage 1 
stage stage 2 power 
total 
of 
nl 
total N 
l (¾) 
(¾) l (%) 
(%) 
(%) 
N patients/cost 
7.6% 
70.5% 
21.8% 
83.8% 
( 4.6%) 
8.2% 
73.4% 
18.4% 84.5% 
( 2.8%) 
9.0% 
75.9% 
15.1% 
84.8% 
( 0.8%) 
9 .6% 
78.1% 
12.3% 85.2% 
1.4% 
9.8% 
80.4% 
9.8% 86.0% 
3.9% 
10.2% 
82. 1% 
7.7% 86.6% 
6.6% 
10.3% 
84.0% 
5.7% 87.2% 
9.4% 
10.3% 
85.5% 
4.2% 87.9% 
12.3% 


Table 7. Details of the Potvin Method C Desi 
Simulation Results for CV% of35% 
Stu<lies 
Stadies 
failed Power Studies 
Single 
Expected stop1m l 
in 
in 
in Final stage lncreasein # 
mean in '9tagc stage 1 
stage stage 2 power 
total 
of 
n1 
total N 
l (%) 
(%) l (%) 
(%) 
(¾) 
IS patients/cost 
78.2% 
7.1% 71.2% 
21.8% 84.0% 
( 5.1%) 
81.9% 
8.0% 
73.8% 
18. 1% 
84.4% 
( 3.3¾) 
85.4% 
9.0% 
76.Jo/o 
14.6% 
84.8% 
( 1.3¾) 
88.5% 
9.8% 
78.6% 
I 1.6% 
85.3% 
0.9% 
91.0% 
10.3% 80.7% 
9.0% 
85.8% 
3.4 % 
93.3% 
L0.6% 
82.7% 
6.7% 
86.4% 
6.0% 
95.2% 
10.8% 84.4% 
4.8% 
87.1% 
8.9% 
96.6% 
10.7% 86.0% 
3.4% 87.8% 
11.9% 


VALIDATION OF THE FUNCTION FOR THE FDF MODIFIED POTVIN METHOD C 
DESIGN SIMULATION 
Comparison ofTlE Rate and Power offhe FDF modified Potvin C Design to 
those of Potvin C Desig:n 
For validation purposes, estimates of TIE rate and power (for the relevant combinations of nl 
and CV%) were calculated using power.tsd function (i.e., Potvin C design) using 10
6 and 105 
simulated studies, respectively. The resuhs, presented in Tables 8 and 2. below were fust 
compared to those published by Potvin et al. in Table I, and then to results for the FDF modified 
Potvin C design (Tables 2 and 1). 
The published TIE estimates and those generated using power.tsd function agree to the third 
decimal place (the combinations for wtlich the comparison was possible are shown in bold 
italic). Likewise, the publisbed power estimates and those generated using power.tsd function 
agree to the second decimal place. 
With regard to the comparison between estimated TIE rate for the FDF modified Potvin C and 
for the (standard) Potvin C design, the curves in figme 6 illustrate that the difference between 
TIE estimates nre most pronounced for small nl ~
d CV¾ greater than, say, 35%. 
Estimates of the TIE rote for the PDF modified Potvin C design appear to be decreasing much 
faster with increasing variability (CV%) and decreasing sample size at stage I (nl) than that 
for Potvio C design. 
Likewise. Figure 7 reveal that the estimated power for the FDF modified Potvin C design 
appear to be decreasing much faster with increasing CV% than Lhat for the~esign. 
Th.is decline in power is most pronounced for stage 1 sample sizes between --
Table 8. Estimated Type I Error (TIE) Rate of the Potvin C Two-Stage Design (at 
ThetaO of 1.25) 
CV 
20% 0.0498 0.0498 0.0499 0.0497 0.0498 0.0499 0.0497 0.0500 
22-% 0.0498 0.0498 0.0499 0.0497 0.0498 0.0499 0.0497 0.0500 
'24% 0.0498 0.0498 0.0499 0.0497 0.0498 0.0499 0.0497 0.0500 
26% 0.0498 0.0498 0.0499 0.0497 0.0498 0.0499 0.0497 0.-0500 
28% 0.0497 0.0498 0.0499 0.0497 0.0498 0.0499 0.0497 0.0500 
30% 0.0493 0.0495 0.0497 0.()496 0.04-97 0.0499 0.0496 0.0500 
32% 0.0484 0.0488 0.0492 0.0492 0.0494 0.0497 0.0495 0.0499 


34% 0.0476 0.0478 0.0482 0.0484 0.0487 0.0493 0.0491 0.0497 
36o/o 0.0467 0.0470 0.0475 0.0474 0.0479 0.0484 0.0484 0.0490 
38% 0.0464 0.0467 0.0468 0.0467 0.0468 0.0473 0.0475 0.0479 
40% 0.0470 0.0467 0.0464 0.0464 0.0464 0.0466 0.0465 0.0471 
Table 9. Estimated Power of the Potvin C Two-Sta 
CV 
20% 0.994Z 0.9952 0.9967 0.9914 0.9979 0.9984 ().9988 0.9990 
22% 0.9850 0.9873 0.9897 0.9916 0.9932 0.9948 0.9958 0.9963 
24% 0.96S6 0.9728 0.9772 0.9814 0.9842 0.9863 0.9887 0.9902 
26% 0.9445 0.9519 0.9.582 0.964 2 0.9692 0.9729 0.9 770 0.9797 
28% 0.9160 0.9251 0.9333 0.9404 0.9475 0.9527 0.9588 0.9636 
30¾ 0.8865 0.8961 09044 0.9134 0.9218 0 9290 Q.9157 0.9425 
32% 0.8632 0.8693 0.8773 0.8855 0.8936 0.9020 0.9092 0.9170 
34% 0.8466 0.8507 0.8562 0.8621 0.8685 0.8757 0.8831 0.8907 
36¾ 
0.8382 0.8384 0.8428 0.8458 0.8499 0.8550 0.8603 0.8663 
38% 0.8324 0.8348 0.8353 0.8364 0.8388 0.8410 0.8453 0.8482 
40% 0.8284 0.8293 0.8309 0.8321 0.8333 0_8345 0.8164 0.8383 


Estimated Type I Error of the Modified Potvin C Two-Stage Method (.:1t True Ratio 
(ThetaO) of 1.25, and targeted power of0.80) 
0.049 
i 
0. 
0.048 
ii 
.5 
ui 
w 
0.047 
0.046 
Method"' Modified Potvin C 
Method"' Potvin C 
..... 
..... 
------
..... 
" \ 
\ 
. \ 
\ 
·.\ \ 
\\ \ 
\ 
I 
I \:. \ 
. \\ ' 
\ 
\ i- \ 
,. 
CV 
Figure 6. Estimated Type I Error rate for the FDF modified Potvin C design (left) and Potvin C 
design (right) 


a; 
0 a. 
-0 
CJ> 
.e 
(4 
w 
Estimated Power of the Modified Potvin C Two-Stage Method (at ThetaO of0.96, and 
targeted power of0.80) 
Method= Modified Polvfn C 
Method= Potvin C 
1.00 
0.95 
0.90 
085 
0.80 -+--------------lf----------------1 
:t % 
% % % {' 
,t ~-:r.g, 
% 
:.g, 
,t :t' :t 
;g, 
:.t 
CV 
Fi!!ure 7. Estimated po·wer for the FDF modified Potvin C design Ocft) and Potvin C design 
(right) 
Step by Step Effects of Modiflcations to Potvin C Method 
In Tables 10 and ll are presented effects of eacb of the three aforementioned modification to 
Potvin C design regarding step by step changes in estimated TIE/ power, proportion BE in 
Stage 1, % Studies in Stage 2, and estimated mean total sample size (n total) 
Two combinations of n l and CV% ( 48, 40% and 60, 40%) were selected for step by step 
comparisons (i.e., from Potvin et al. [ll results to the power.tsd.2 function results), because for 
a lower CV% the effect of FDF modification on the power and TIE rate is almost negligible. 
In other words, for CV% lower than, say, 30% (and nl in a range from -
the absolute 
difference between the estimated power and TIE rate for the FDF modified method and those 
for the estimated power and TIE rate for the original Potvin C method, respectjvely, are less 
than a standard error of the simulation estimate. 
Both the estimated TIE and power appear to be decreasing somewhat at each step, i.e., for each 
of the three FDF modifications. The same can be observed for the percentage of studies in 
stage 2, which decreases e.g., from 43. 7% to 42.9% (by including the Futility Nmax criterion), 


to 41.5% (by including the Futility PE criterion), and to 41.1 % (by adjus1ing the degrees of 
freedom), as is shown in column 5 of Table 11. 
The large drop in % of studies in stage 2 by including the Futility PE criterion when estimating 
T1E (Table 10) is to be anticipated, and can be observed/verified by applying the power.tsd.fc 
function from the Power2Stage package. 
Table 10. Effect ofFDF Modifications to the Potvin C Method on the Estimated Type I 
Error Rate 
Potvin G'Method Modifications 
Estimated TIE,BE in Stage 1~ 
% Studies in Stage :z" mean n total 
Source/ 
Futility 
Futjlity 
Adjustment 
n1 
nl 
function 
PE 
Nmax 
ofD.F 
cv•/o=4Oo/o 
CV%=40% 
PotvinC W 
-
-
-
0.04(59, na, 
0.0470, na, 
89.3%, 78.l 
64.4%, 77 .. 3 
-power.tsd 
-
-
-
0.0470, 0.0317, 
0.0465, 0.0379, 
88.8%, 77.9 
63.5%, 77.1 
power.~d 
-
120 
-
0.0469. 0.0317, 
0.0465. 0.0379, 
87.9%,, 77.2 
63.0%, 76.8 
powct·.tsd.1 
PE 
120 
-
0.0467, 0.03 l 7, 
0.0464, 0.0379, 
42.7¾,62.2 
30.7%, 68.3 
power.tsd.2 
PE 
120 
5,5,20 
0.0457, 0.0323, 
0.0467, 0.0384 
41.4%, 62. l 
30.0%, 68.4 


Table 11. Effect of FDF Modifications to the Potvin C Method oo Estimated Power 
Potvin C Method Modifications 
Estimated Power, BE in Stage 1, 
% Studies ~n Stage 2, mean n total 
Source/ 
¥utility 
Futility, 
Adjustment nl= 
nl 
fu11ction 
PE 
Mnax 
ofDF 
CV%=40% 
CV%=40% 
Potvin C[!] 
. 
-
. 
0.831, na, 
0.836, aa, 
43.8, 63.9 
24.3%, 66.9 
powcr.tsd 
. 
-
. 
0.828, 0.544, 
0.836, 0.697, 
43.7%, 63.8 
23.9"/4, 66.8 
power.tsd 
. 
120 
-
0.821, 0.544, 
0.834, 0.697, 
42.9%, 63.2 
23.6%,66.6 
power.tsd.1 
PE 
120 
. 
0.8 I 8, 0.544, 
0.834, 0.697. 
4] .5%, 62.6 
23.1%, 66.5 
power.tsd.2 
PE 
120 
5,5,20 
0.808, 0.539, 
0.831, 0.694, 
41.1%, 62.8 
22.9%, 66.8 
Reproducibility of the Results 
Toe reproducibility of TIE rate and power results were checked using four pairs of nl and 
CV% values. For power simulations, tbe 110 
parameter (True geometric mean ratio) was 
set to 0.95, the maximal rotal sample size to 
and the number of simulations to 105, whereas 
for TIB rate simulations, lhe lbetaO parameter was set to 1.25, lhe maximal total sample size to 
120, and lhe number of simulations 10 106. The estimation of each of the TIE rate and power 
were repeated 20 Limes, using 20 randomly selected random number seeds. 
As expected from the central limit theorem, standard deviation of TIE rate estimates is 
approximately equal to 0. 0002, which is the estimated standard error for a proportion of 0.05 
using 106 replications (as shown in Table 12). Likewise, the standard deviation of power 
estimates is approximately equal to 0.001, which is lhe estimated standard error [or a 
proportion of 0.80 using 105 replications (as is presented in Table 13). 
Table 12. Descri tive Statistics of the 20 Re eated TIE Estimates 
CV¾ m.ean_TIE 
s.tddev 
min 
max 
35% 
0.048289 .000234102 0.047950 0.048714 
35% 
0.049058 .000240110 0.048616 0.049505 
40% 
0.046328 .000184795 0.045884 0.046622 
40% 
0.046657 .000229704 0.046161 0.047012 


Table 13. Descri tive Statistics oftbe 20 Re licated Power Estimates 
CV% meao_POWER 
stddev 
min 
max 
JS% 
0.85957 .OO0n4762 0.85807 0.86063 
35¾ 
0.87180 .001132665 0.86967 0.87389 
40% 
0.82530 .001503721 0.82233 0.82797 
40¾ 
0.83162 .001441604 0.8295 1 0.83416 
6 REFERENCES 
[I l Potvin D. DiLibcrti CE, Hauck WW, Parr AF, Schuinnann DJ, S.mitb RA. Sequential design ap-
proaches for bioequivalcnce studies with crossover designs.Phann. Stat. 2008; 7(4):245-62. doi: 
10.JOOVpst.294 
[2] Montague TH, Potvin D, DiLibeni CE, Hauck WW, Parr AF, Schuinnann DJ. Additional results 
for 'Sequential design approaches for bioequivalence smdieswicbcrossovcr designs'. 
Pharmaceutical Statistics 2012; 1 1:8-13. 
L3] Karalis V, M.acberas P. An insight into the properties of n two-stage design in biocquiv11lence 
studies. Pharmaceutical Research 2013; 30:1824- 1835. 
l4] Kieser M, Rauch G. Two-stage designs for crossover bioequivalence trials. Stat Med. 
2015;34(16):2403- 16. 
[5] Schuetz H. Two-stage designs in bioeguivalencc trials. Eur J Clin Pbarmacol. 2015;7 I (3):271-81. 
f61 Maurer W. Jones B. Chen Y. Controlling the type I error rate in two-stage sequential adaptive 
designs when testing for average bioequivalcncc. Stat Med. 2018 May 10;37(10): 1587-1607. 
[71 Fuglsang A (2013) Sequential bioequivalcnce trial designs with increased power and controlled 
type I error rates. AAPS J 15:65~61. 
[8J f uglsang A. Futility rules in bioequivalence trials with sequential designs. AAPS J. 
2014;16(1):79-62 
[9] Jones B, Kcoward MG (2014) Chapters 12- 14. In: Jones B, Kcnward MG (eds) Design and 
analysis of cross-over trials, 3rd cdn. Chapman & HalUCRC, Boca Ralon, pp 365-380 
[IO]Joncs B, Patterson, SD (2017) Biocq11ivalence and Statistics in Clinical Pharmacology, 2nd 
Ectition, Chapman and Hall/CRC, CRC Press. Boca Raton. 
fl !lLabes D, Schutz H, LangB. PowcrTOST: Power and Sample size based on Two One-Sided t-Tests 
(TOST) for (Bio)Equivalence Studies. R package version 1.4~2. 2016. https://cran.r-
project.org/package=PowcrTOST 
[ l 21 Labes D, Schulz H. Powcr2Stagc: Power and Sample-Size Distribution of2-Stagc Bio•cquivalenoc 
Studies. R package version 0.5-3. 2021. https://cran.r-project.orglpackage=Power2Stagc 
[ 131 FDA, CDER, CBER: Guidance for Industry E9 Statistical Principles for Clinical Trials. Sep 1998. 


REVISION HISTORY 
Version# 
Description 
Date 
1 <Draft) 
OrilrinaVinitial document 
08 Nov 2021 
1 (Final) 
Final Document with Hyperliuks 
11 Nov 2021 
2 
Table l adjusted, a paragraph added below Table 1, 
10Nov2022 
Reference 13 added 
First page adjusted 


7 Appendix A: R Code 
FUNCTION POWER.TSD.2 (FOR CALCULATING THE 'EMPIRJC' POWER OF TWO-
STAGE BE STUDIES ACCORDING TO FDF MODIFIED POTVIN C DESIGN VIA 
SIMULATIONS) 








• 












8 Appendjx B: The Evaluation of Operating Characteristics of the 
PDF modified Potvin Method C Des 
aximal Total 
Sample Size of either 
Table Bl. Estimated Type I Error (TIE) Rate of the FDF modified Potvin C Two-Stage 
Desi n (at ThetaO of 1.25 and Nmax of 150) 
CV 
20% 0.0499 0.0500 0.0499 0.0500 0.0499 0.(),198 0.0499 0.0500 
22% 0.0499 0.0500 0.0499 0.0500 0.0499 0.0498 0.0499 0.0500 
24% 0.0499 0.0500 0.0499 0.0S00 0.0499 0.0498 0.0499 0.0500 
26¾ 
0.0499 0.0500 0.0499 0.0500 0.0499 0.0198 0.049'> 0.0500 
28% 0.0498 0.0499 0.0499 0.0499 0.0499 0.0498 0.0499 0.0500 
30% 0.0492 0.0497 0.0497 0.0497 0.0497 0.0497 0.0499 0.0500 
32¾ 
0.0483 0.0489 0.0491 0.0492 0.0494 0.0495 0.04?8 0.0499 
34% 0.0473 0.0480 0.0480 0.0482 0.0487 0.0489 0.0494 0.0496 
36¾ 0.0465 0.0471 0.047•~ 0.0472 0.0477 0.0481 0.0485 0.0487 
38°/4 0.04-59 0.0465 0.0467 0.0463 0.0469 0.0470 0.0476 0.0480 
40°/4 0.0462 0.0466 0.0460 0.0458 0.0464 0.0464 0.0468 0.0466 
Table .82. Estimated Power of the FDF modified Potvin C Two-Stage Design (at ThetaO 
of 0.95 and Nmax ofl50 
CV 
20% 0.9939 0.9954 0.9963 0.9973 0.9979 0.9984 0.9987 0.9990 
22% 0.9843 0.9871 0.9895 0.9915 0.9929 0.9943 0.9954 0.9964 
24% 0.9673 0.9726 0.9771 0.9802 0.9837 0.9862 0.9883 0.9899 
26% 0.943& 0.951 1 0.9577 0.9632 0.9682 0.9727 0.9758 0.9793 
2R0/4 0.9157 0.9241 0.9327 0.9400 0.9462 0.9524 0.9577 0.9628 
30% 0.8877 0.8958 0.9045 0.9 l33 0.9203 0.9273 0.9348 0.9410 
3.2°/. 0.8635 0.&715 0.8781 0.8849 0.&936 0.9012 0.9096 0.9168 


0.8449 0.8523 0.8569 0.8623 0.8709 0.8764 0.8845 0.8916 
36% 0.&359 0.&422 0.841 1 0.8455 0.8522 0.8558 0.8625 0.8663 
38% 0.8294 0.8348 0.8358 0.8370 0.8387 0.8421 0.8458 0.8500 
40% 0.8210 0.8253 0.8294 0.8318 0.8335 0.8371 0.8369 0.8379 
Table B3. Estimated Type I Error (TIE) Rate of the FDF modified Potvin C Two-Stage 
Desi n at ThetaO of 1.25 and Nmax of200 
CV 
20% 0.0499 0.0500 0.0499 0.0500 0.0499 0.0498 0.0499 0.0500 
22% 0.0499 0.0500 0.0499 0.0500 0.0499 0.0498 0.0499 0.0500 
24% 0.0499 0.0500 0.0499 0.0500 0.0499 0.0498 0.0499 0.0500 
26% 0.0499 o.osoo 0.0499 0.0500 0.0499 0.0498 0,0499 o.osoo 
28% 0.0498 0.0499 0.0499 0.0499 0.0499 0.0498 0.0499 0.0500 
30% 0.0492 0.0497 0.0497 0.0497 0.0497 0.0497 0.0499 0.0500 
J2% 0.0483 0.0489 0.0491 0.0492 0.0494 0.0495 0.0498 0.0499 
34% 0.0473 0.0480 0.0480 0.0482 0.0487 0.0489 0.0494 0.04% 
36% 0.0464 0.0470 0.0474 0.0473 0.0477 0.0482 0.0'185 0.0487 
38% 0.0460 0.0467 0.0466 0.0463 0.0468 0.0471 0.0474 0.0478 
40% 0.0461 0.0467 0.0460 0.0458 0.0464 0.0465 0.0467 0.04(xi 
Table B4. Estimated Power of the FDF modified Potvin C Two-Stage Design (at Theta0 
of 0.95 and Nma~ of 200) 
CV 
20% 0.9939 0.9954 0.9963 0.9973 0.9979 0.9984 0.9987 0.9990 
22% 0.9843 0.9871 0.9895 0.9915 0.9929 0.9943 0.9954 0.9964 
24% 0.9673 0.9726 0.9771 0.9802 0.9837 0.9862 0.9883 0.9899 
26% 0.9438 0.95 11 0.9577 0.9632 0.9682 0.9727 0.9758 0.9793 
28% 0.9157 0.9241 0.9327 0.9400 0.9462 0.9524 0.9577 0.9628 


30•/o 0.8877 0.8958 0.9045 0.9133 0.9203 0.9273 0.9348 0.9410 
32¾ 0.8635 0.8715 0.8781 0.8849 0.8936 0.9012 0.9096 0.9168 
34% 0.8449 0.8523 0.8569 0.8623 0.8709 0.8764 0.8845 0.8916 
36•/o 0.8359 0.8422 0.841 1 0.8455 0.8522 0.8558 0.8625 0.8663 
38¾ 0.8292 0.8339 0.8358 0.8371 0.8382 0.8421 0.8458 0.8500 
40% 0.8222 0.8259 0.8298 0.8314 0.8337 0.8361 0.8369 0.8378 






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