ASSIGNMENT NO: 01

TO GIVE AN OVER VIEW AND PROTOCOL FOR

THE CONDUCT OF CLINICAL TRIAL FOR AN ANTI BACTERIAL DRUG

(MODEL DRUG)

SUBMITTED TO
Prof. Gautam Singhvi
Instructor-in-charge

SUBMITTED BY:

Sr. NAME ID NO.

NO.

1. Gunja Chaturvedi 2008H146101

2. R.Vidya 2008H146102

Submitted for the partial fulfillment of the requirements of the

course

CLINICAL RESEARCH (PHA G543)

BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE

PILANI (RAJASTHAN)
AUGUST, 2009

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 INDEX
A. Study details

B. Introduction & Objectives

1. Background

2. Introduction

3. Preclinical data for the Model drug

4. Mechanism of action

5. Bioequivalence requirement

6. Pharmacology

6.1.1 Absorption

6.1.2 Distribution

6.1.3 Metabolism

6.1.4 Excretion

6.1.5 Adverse drug events

6.1.6 Dosage

7. Study design

7.1.1 Summary

7.1.2 No. of subjects planned

7.1.3 No. of subjects enrolled

7.1.4 No. of subjects included in primary analysis & safety datasheet

7.1.5 Gender

7.1.6 Mean (SD) of age

7.1.7 Diagnosis and main criteria for eligibility

7.1.8 Investigational product, dose and mode of administration

7.1.9 Washout periods

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 7.1.10 Duration of treatment

8. Restrictions

8.1.1 Medications

8.1.2 Diet

8.1.3 Activity

9. Study population

9.1.1 Screening assessments (lab tests and general examinations)

9.1.2 Inclusion criteria

9.1.3 Exclusion criteria

10. Study endpoints

10.1.1 Primary endpoints

10.1.2 Secondary endpoints

11. Schedule of assessment

12. Study medication

12.1.1 Handling, storage & accountability procedure

12.1.2 Return or Destruction of Study Drug

13. Analytical procedures , Pharmacokinetic studies and assessment of patient compliance

13.1.1 Microbiological assessment

13.1.2 Pharmacokinetic Characteristics

13.1.3 Assessment of compliance

14. Safety:

14.1.1 Clinical safety measurement

15. Handling of safety parameters

15.1.1 Adverse drug events management

15.1.2 Reporting of Serious Adverse Events

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16. Statistical considerations

17. Deviations

18. Ethical Considerations

19. Subject Compensation for Participating in the study

20. Termination of the Study

21. Study Documentation

22. Quality Assurance Audits

23. Confidentiality of Data

24. Archives

25. Publication Policy

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 STUDY DETAILS
 Protocol title: A multicenter, Randomized, Double-Blind, Active Control, Parallel Assignment,
Safety/Efficacy Study for the Model drug monotherapy versus comparator treatment
(vancomycin & vancomycin + ceftazidime)

 Investigational product: Model drug

 Category: Antibacterial

 Indication: skin & complicated skin structure infections and Nosocomial pneumonia

 Brief description: This study is a multicenter, randomized, Double-Blind, Active Control, Parallel
Assignment, Safety/Efficacy Study and the purpose of this study is to (1) compare the clinical
cure rate of Model drug monotherapy versus a comparator (vancomycin & vancomycin +
ceftazidime) in the treatment of patients with complicated skin and skin structure infections and
(2) in the treatment of patients with nosocomial pneumonia.

 Study sponsor: ………………………..

 Protocol no: 2009011OFB

 IND no: The study is not conducted under an IND.

 Study phase: Phase III

 Study initiation date: October 2009(the first subject enrolled)

 Study completion date: February 2011(last subject off the study)

 Clinical study manager: ……………………………..

 Good Clinical practice: This study is carried out in accordance with (US FDA) regulations &
international conference or harmonization (ICH) Good Clinical Practice (GCP) guidelines.
Essentials documents will be retained in accordance with ICH GCP.

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 INTRODUCTION AND OBJECTIVES
1. Background: Skin and skin-structure infections are common, and range from minor pyodermas
to severe necrotizing infections. Complicated infections are defined as involving abnormal skin
or wounds, occurring in compromised hosts, or requiring surgical intervention. Classification
schemes for these infections are varied and confusing. Distinguishing characteristics include the
etiological agent(s), clinical context and findings, depth of tissue involvement and rate of
progression. The most common pathogens are aerobic Gram-positive cocci, but complicated
infections frequently involve Gram-negative bacilli and anaerobic bacteria. Initial antibiotic
therapy is usually empirical, and later modified by the results of stains and cultures of wound
specimens. Broad-spectrum coverage is frequently needed for complicated infections. This study
is basically a randomized, double‐blind, multicenter trial involving patients with a broad range of
complicated skin and skin‐structure infections due to either gram‐positive or gram‐negative
bacteria is conducted to compare Model drug monotherapy with treatment with vancomycin
plus ceftazidime.

2. Introduction: Model drug is a prodrug, a prototypical cephalosporin with bactericidal activity

against a broad spectrum of gram-positive bacteria, including methicillin-resistant
staphylococcus species. It is also active against many gram-negative bacteria, including many
Enterobacteriaceae.

3. Preclinical data for the Model drug:

Pharmacokinetic and Pharmacodynamic characteristics of the Model drug

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4. Mechanism of action: Model drug has a bactericidal mode of action that involves tight binding
to many common essential penicillin-binding proteins (PBPs) in both gram-positive & gram-
negative bacteria. It has distinctive bactericidal activity against methicillin-resistant
staphylococci primarily due to its novel strong binding to the staphylococcal PBP2a, the PBP that
is chiefly responsible for β-lactum resistance in methicillin-resistant staphylococci including
methicillin-resistant S.aureus (MRSA).

5. Bioequivalence requirement: The requirement of the following study is to compare the efficacy
of the Model drug to that of Vancomycin & vancomycin +ceftazidime combination in patients
with primarily complicated skin and skin structure infections(cSSSIs) caused by gram- positive
bacteria and secondly for nosocomial pneumonia. The primary objective is to assess
noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in
patients.

6. Pharmacology:

6.1.1 Absorption: Model drug is administered intravenously and therefore has 100%
bioavailability.

6.1.2 Distribution: Model drug binds minimally (16%) to plasma proteins & binding is
independent of the concentration. Its steady-state volume of distribution (18L)
approximates extracellular fluid volume in humans.

6.1.3 Metabolism: Conversion from the prodrug (Model drug) to the active moiety occurs
rapidly and is mediated by plasma esterase.Prodrug concentrations are negligible and
measurable in plasma and urine only during infusion. The active Model drug undergoes
minimal metabolism to the open-ring metabolite, which is microbiologically inactive.
Systemic exposure of the open-ring metabolite was considerably lower than for Model
drug, accounting for approximately 45 of the parent exposure.

6.1.4 Excretion: Model drug is eliminated primarily unchanged by renal excretion and the
predominant mechanism responsible for the elimination is glomerular filtration, with
some active reabsorption .In preclinical studies probenecid did not affect the
pharmacokinetics of the Model drug, thereby indicating no involvement of active tubular
secretion mechanisms. Elimination half life of the open-ring metabolite was slightly
longer, approximately 5 hours compared with Model drug, which was approximately 3
hours. Following single dose administration, approximately 89% of the administered dose
is recovered in the urine as active Model drug (83%), the open-ring metabolite (5%) and
prodrug (Model drug) (<1%).

6.1.5 Adverse drug events: Although there is no such specific adverse reactions of the model
drug but since it belongs to the cephalosporin class, the precautions that are inherent to
this class would still apply. This drug should be given cautiously to patients with a

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 hypersensitivity to penicillin, to pregnant and breast-feeding women, to patients younger
than 18 years of age and to the patients with renal impairment or severe hepatic
impairment. As with all antibiotics that affect normal gastrointestinal flora, Model drug
may increase the risk for C. difficile infection.

6.1.6 Dosage:

 500mg i.v. (equivalent to q12h over 60 min) of the Model drug or 1g Vancomycin q12h
for 7 – 14 days.

 500mg equivalents of the Model drug given as i.v. infusion q8hr over 120 min plus
placebo q12hr over 60 min or 1g Vancomycin q12hr over 60min plus 1g ceftazidime
q8hr over 120 min for 7 -14 days.

7. Study design:

7.1.1 Summary:In this study the patients are randomized (2:1) to receive intravenous infusions
of the Model drug 500mg over 120 minutes every 8 hours and placebo over 60 minutes
every 12 hours, or Vancomycin 1g over 60 minutes every 12 hours plus ceftazidime 1g
over 120 minutes every 8 hours for 7 – 14 days.Vancomycin dose is adjusted based on
the serum concentrations according to local practices.

7.1.2 No. of subjects planned: 1000

7.1.3 No. of subjects enrolled: ……….

7.1.4 No. of subjects included in primary analysis & safety datasheet: ……….

7.1.5 Gender : Male =…….. & Female = ……… (No. of males and females)

7.1.6 Mean (SD) of age: The age of the enrolled subjects should be mentioned in terms of
mean (standard deviation) of the age.

Note: Subjects withdrawn or dropped out subsequent to dosing will not be replaced.
Data will be presented on all the subjects who completed the study. If necessary, an
unequal number of subjects per sequence will be used, and data will be presented on all
the subjects who completed the study.

7.1.7 Diagnosis and main criteria for eligibility: Complicated skin and skin structure
infections(cSSSI),including non-limb threatening diabetic foot infections without
concomitant osteomylitis caused by Enterobacter cloacae, Escherichia coli,Klebsiella
pneumonia,Proteus mirabilis, Staphylococcus aureus (including methicillin-resistant
isolates) and Streptococcus pyogenes.

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 7.1.8 Investigational product, dose and mode of administration: Model drug, 500 mg and
intravenous.

7.1.9 Washout periods: 2 weeks

7.1.10 Duration of treatment: 7 – 14 days

8. Restrictions:
8.1.1 Medications - Subjects should not have received any medication (except vitamins
preparations) including over the counter medications (OTC) during the 3 weeks period
prior to the onset of the study. They will be instructed during screening not to take any
prescription and OTC medications until the completion of the study. If drug therapy
other than that specified in the protocol is required during the study or in the washout
period, decisions to continue or discontinue the subject will be based on the following:
 The pharmacology and pharmacokinetics of the non-study medication.
 The likelihood of a drug-drug interaction, thereby affecting pharmacokinetic
comparison of the study medication.
 The time of administration of the non-study medication.

8.1.2 Diet – No special dietary restrictions are there as such.

8.1.3 Activity – If any special activity has to be restricted of performed will be instructed to
the subjects on the spot while administering the drug.

9. Study population:

9.1.1 Screening assessments (lab tests and general examinations):

HEMATOLOGY URINALYSIS ADDITIONAL TESTS

 Haemoglobin PHYSICAL  HIV I & II
 Total leukocyte count EXAMINATION  HBsAg
 Differential leukocyte  Colour  HCV
count  Appearance  VDRL
 Platelet count  pH
 Specific gravity
BIO-CHEMISTRY  Protein
 Blood Urea Nitrogen  Glucose
 Creatinine  Glomerular filtration
 Total bilirubin rate
 Alkaline phosphatase  Renal Clearance
 AST
 ALT MICROSCOPIC
 Glucose EXAMINATION
 Sodium  RBC
 Potassium  WBC
 Epithelial Cells
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  Chloride  Crystals
 Calcium  Casts
 Magnesium  Others
 Uric acid

 Note: The underlined tests are important test from the study point of view.
 All the samples during screening will be collected and analyzed at Clinical laboratory
situated at BITS Clinical Pharmacology Unit.
9.1.2 Inclusion criteria :

1. Diagnosis of an infection consistent with complicated skin and skin structure infections
caused by gram-positive bacteria.
2. Age range should be in 18 – 92 years.
3. Any kind of surgical site infection within 30 days of surgery or trauma with purulent
drainage or 3 or more signs of infection.
4. Abscess for less than 7 days with purulent drainage or aspirate and evidence of loculated
fluid.
5. Erythema and/or induration of 20 mm or more in diameter.
6. Cellulitis for less than 7 days with advancing edema, erythema or induration and one other
sign of infection.

9.1.3 Exclusion criteria :

1. Known or suspected hypersensitivity to any study medication (especially cephalosporin or

vancomycin allergy)
2. If the renal clearance is less than 30ml/min or Oliguria less than 20ml/hr in response to fluid
challenge.
3. Alanine aminotransferase /aspartate aminotransferase levels 3 times the upper limit of the
normal.
4. Patient who is pregnant or lactating, neutropenic or HIV –infected with CD4+ count less than
0.2 X 109 /L.
5. Any known or suspected condition or concurrent treatment contraindicated by the
prescribing information
6. Previous enrollment in this study
7. Treatment with any investigational drug within 30 days before enrollment.

10. Study endpoints:

10.1.1 Primary endpoints: Noninferiority of the Model drug group when compared with the
Vancomycin-Ceftazidime group on clinical cure rates at the test-of-cure visit of clinically
evaluable and intent-to-treat populations.

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 10.1.2 Secondary endpoints: Microbiological eradication rate at 7-14 days after the end of
therapy; Clinical cure rate and microbiological relapse at late follow-up visit; All deaths
due to pneumonia within 30 days after randomization.

11. Schedule of assessment:The clinical evaluations (at the baseline, during treatment, and after
treatment) will include a microbiological assessment of the site of infection, evaluation of the
signs and symptoms of infection, and at the Test-of-cure(TOC) and Late-follow-up(LFU) visits, an
evaluation of the clinical outcome. The clinical outcome at the TOC visit, 7 to 14 days following
the End-of –therapy(EOT) visit, will be categorized as cure, failure, or not evaluable. Cure is
defined as a resolution of all signs and symptoms of the infection or improvement to such an
extent that no further antimicrobial therapy will be necessary. Failure is defined as a need for
further treatment with a nonstudy antibiotic and discontinuation of the study drug due to a
treatment-related Adverse Event (AE) or due to a lack of efficacy of the study drug after at least
3 days of study therapy. Patients assessed for failing therapy at the EOT visit will be considered
failures at the TOC visit. Patients who will deviate from the protocol-defined treatment or
evaluation procedures will be considered not evaluable.

12. Study medication:

12.1.1 Handling, storage & accountability procedure:Upon receipt of the of the study
treatment supplies, an inventory must be performed and a drug receipt log filled out and
signed by the person accepting the shipment. It is important that the designated study
staff counts and verifies that the shipment contains all the items noted in the shipment
inventory. Any damaged or unusable study drug in a given shipment (active drug or
comparator) will be documented in the study files. The investigator must notify study
sponsor of any damaged or unusable study treatments that were supplied to the
investigator’s site.
12.1.2 Return or Destruction of Study Drug:At the completion of the study, there will be a final
reconciliation of drug shipped, drug consumed, and drug remaining. This reconciliation
will be logged on the drug reconciliation form, signed and dated. Any discrepancies
noted will be investigated, resolved, and documented prior to return or destruction of
unused study drug. Drug destroyed on site will be documented in the study files.

13. Analytical procedures , Pharmacokinetic studies and assessment of patient complaince:

13.1.1 Microbiological assessment: The microbiological assessments will include pathogen
identification and susceptibility testing of all specimens, in addition to genotypic
characterization of staphylococci (by testing for Panton-Valentine leukocidin [PVL] and
mecA genes). Patients will be assessed for microbiological outcome at the TOC visit, and
this outcome will be determined by Gram stain and culture of any discharge or infected
tissues. The microbiological outcome for the patients will be categorized as eradication,
presumed eradication, colonization, persistence, presumed persistence, super infection,
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 or not evaluable. Patients will be considered to have an eradicated microbiological
outcome if no pathogen is isolated from any culture (fluid or tissue) taken at the original
site of infection and to have a presumed eradicated microbiological outcome if no
material suitable for culture is obtained from the primary site of infection in the absence
of clinical signs or symptoms of infection. Patients will be considered not evaluable with
regard to microbiological outcome if no pathogen is isolated at the time of entry into the
trial, no clinical evaluation is done at the TOC visit, no data related to microbiological
outcome is collected at the TOC visit, or protocol-defined procedures is not conducted.
Only patients with a microbiological outcome of eradication or presumed eradication at
the TOC assessment will be evaluated for relapse at the LFU assessment.
13.1.2 Pharmacokinetic Characteristics: The following pharmacokinetic parameters will be
calculated for the Model drug by using suitable software like Win Nonlin .
Parameters Description

AUC0t The area under the plasma concentration versus time

curve, from time zero to the last measurable
concentration, as calculated by the linear trapezoidal
method.

AUC0 The area under the plasma concentration versus time

curve, from time zero to infinity. AUC0is
calculated as the sum of AUC0t plus the ratio of the
last measurable plasma concentration to the
elimination rate constant.

AUC0t/ AUC0 The ratio of AUC0t/ AUC0

C max Maximum plasma concentration over the time span

specified.

Tmax Time of the maximum measured plasma

concentration. If the maximum value occurs at more
than 1 time point, T is defined as the first time
max
point with this value.

Kel Apparent first order terminal elimination rate constant

calculated from a semi-log plot of the plasma
concentration versus time curve. The parameter will
be calculated by linear least-square regression analysis
using the maximum number of time points in the
terminal lig- linear phase(e.g three or more non-zero
plasma concentrations)

T1/2 The apparent first-order terminal elimination half life

will be calculated as 0.693/ K .
el

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 13.1.3 Assessment of compliance: Patient compliance will assessed by checking for any
hypersensitivity reactions occurring after the administration of the drug. Events involving
exacerbations or the worsening of preexisting illnesses will be recorded.

14. Safety:

14.1.1 Clinical safety measurement: It is the responsibility of the Principal Investigator to

oversee the safety of the study at his/her site. This safety monitoring will include careful
assessment and appropriate reporting of adverse events as noted above, as well as the
construction and implementation of a site data and safety-monitoring plan (see section 9
Auditing, Monitoring and Inspecting). Medical monitoring will include a regular
assessment of the number and type of serious adverse events.

15. Handling of safety parameters:

15.1.1 Adverse drug events management:

 At each contact with the subject, the investigator must seek information on adverse
events by specific questioning and, as appropriate, by examination. Information on all
adverse events will be recorded immediately in the source document, and also in the
appropriate adverse event module of the case report form (CRF). All clearly related
signs, symptoms, and abnormal diagnostic procedures results will be recorded in the
source document, though grouped under one diagnosis.

 All adverse events occurring during the study period must be recorded. The clinical
course of each event will be followed until resolution, stabilization, or until it is
determined that the study treatment or participation is not the cause. Serious adverse
events continuing throughout the study period will be followed up to determine the
final outcome. Any serious adverse event that occurs after the study period and is
considered to be possibly related to the study treatment or study participation will also
be recorded and reported immediately.

15.1.2 Reporting of Serious Adverse Events:

Study Sponsor Notification by Investigator: A serious adverse event will be reported to

the study sponsor by telephone within 24 hours of the event. A Serious Adverse Event
(SAE) form will be completed by the investigator and faxed to the study sponsor within
24 hours. The investigator will keep a copy of this SAE form on file at the study site.

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 At the time of the initial report, the following information should be provided:

 Study identifier  Whether study treatment was

 Study Center discontinued
 Subject number  The reason why the event is classified
 A description of the event as serious
 Date of onset  Investigator assessment of the
association between the event and
 Current status study treatment

Within the following 48 hours, the investigator will provide further information on the serious adverse
event in the form of a written narrative. This will include a copy of the completed Serious Adverse Event
form, and any other diagnostic information that will assist the understanding of the event. Significant
new information on ongoing serious adverse events will be provided promptly to the study sponsor.

16. Statistical considerations:

 This trial is designed to test the noninferiority of Model drug monotherapy compared to the
effectiveness of vancomycin plus ceftazidime treatment. The primary end point is the clinical
cure rate at the TOC visit. The null hypothesis is that the clinical cure rate for Model drug -
treated patients would be more than 10% inferior to the clinical cure rate for vancomycin plus
ceftazidime -treated patients, and the alternative hypothesis will be that the clinical cure rate
for Model drug -treated patients would not be more than 10% inferior to the clinical cure rate
for vancomycin plus ceftazidime -treated patients. Similar hypotheses will be applied to the
analysis of the microbiological outcome.
 The final sample size calculation will be based on the confidence interval (CI) approach for a
normal approximation of binomial probability. Clinical and microbiological outcomes will be
analyzed by the use of two-sided 95% CIs for the between-treatment difference (Model drug
minus vancomycin plus cetazidime) in the clinical cure rates and microbiological eradication
rates at the TOC visit. The microbiological eradication rate and its CIs will be summarized by
infection type and initial pathogen.

17. Deviations:
All protocol deviations will be appropriately reviewed and documented in the raw data and
those which will affect the integrity of the study will be reported in the final report. In addition,
deviations from the original pharmacokinetic and statistical evaluation plan will be justified in
the final report.

18. Ethical Considerations:

 This study is to be conducted according to US and international standards of Good Clinical

Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines),
applicable government regulations and Institutional research policies and procedures.
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  This protocol and any amendments will be submitted to a properly constituted independent
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal
prescriptions, for formal approval of the study conduct. The decision of the EC/IRB concerning
the conduct of the study will be made in writing to the investigator and a copy of this decision
will be provided to the sponsor before commencement of this study. The investigator should
provide a list of EC/IRB members and their affiliate to the sponsor.

 All subjects for this study will be provided a consent form describing this study and providing
sufficient information for subjects to make an informed decision about their participation in
this study. The consent form will be submitted with the protocol for review and approval by
the EC/IRB for the study. The formal consent of a subject, using the EC/IRB-approved consent
form, must be obtained before that subject is submitted to any study procedure. This consent
form must be signed by the subject or legally acceptable surrogate, and the investigator-
designated research professional obtaining the consent.

- Drop-out/Withdrawal of Subjects from Study: Subjects will be informed that they are free to
dropout from the study at any time without stating any reason. The investigator may withdraw
a subject from the study for any of the following reasons:
a) The subject suffers from significant intercurrent illness or undergoes surgery during the
course of the study.

b) The subject experiences adverse event, when withdrawal would be in the best interest of
the subjects.

c) The subject fails to comply with the requirements of the protocol or if the subject is
uncooperative during the study.

Details of reasons for withdrawal of subjects will be recorded and reported. Every effort will be
made to obtain a complete follow-up for any withdrawn subject.

19. Subject Compensation for Participating in the study:

The subjects will be adequately compensated on account of their participation in the study. In
case of drop-out/withdrawal of a subject before completion of the study, the guidelines issued
by the Institutional Review Board of the concerned hospital will be final and binding on both
BITS Research Laboratories and the study subjects. The compensation in this study will be Rs.
10,000/- per completed subject.

20. Termination of the Study:

BITS Research Laboratories reserves the right to discontinue the trial at any time. Reasons for
this termination will be provided to the subjects. The Principal Investigator reserves the right to
discontinue the study for safety reasons at any time.

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21. Study Documentation:

All data generated during the conduct of the study will be directly entered in the raw data
recording forms as governed by the SOPs of Department of Clinical Pharmacology and
Development and/or Clinical Pharmacology & Pharmacokinetics, BITS Research Laboratories
except the analytical data of clinical laboratory of the Clinical Pharmacology Unit, which will be
transcribed into the study related forms and the raw data retained by the laboratory for
records. The computer-generated chromatograms will also be treated as raw data. All raw data
and transcribed data forms will be completed by the study personnel assisting in the study and
will be checked wherever applicable for completeness and logistics by the Clinical Investigator
or his designate Research Scientist for clinical data and the Laboratory Supervisor for the bio-
analytical data. The Clinical Investigator and the Laboratory Supervisor will supervise
compilation of data until ready for archiving.

22. Quality Assurance Audits:

The raw data generated during the course of the study, including the clinical and analytical
operations and the final reports will be liable for inspection and quality audit for conformance to
this protocol and all the governing SOPs by an auditor from the Corporate Quality Assurance
Department of BITS Research Laboratories.

23. Confidentiality of Data:

The data identifying each study subject by name will be kept confidential and will be accessible
to the study personnel, Quality Assurance Auditor during audits and if necessary, to the
Institutional Review Board of the concerned hospital and various regulatory agencies.

24. Archives:

A representative sample of the drug supplies used in the study will be retained at the BITS
Clinical Pharmacology Unit.

All data generated in connection with this study, together with the original copy of this protocol
and the final report will be archived.

25. Publication Policy:

Neither the complete nor any part of the results of the study carried out under this protocol, nor
any of the information provided by the sponsor for the purposes of performing the study, will be
published or passed on to any third party without the consent of the study sponsor. Any
investigator involved with this study is obligated to provide the sponsor with complete test
results and all data derived from the study.

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