A

PROJECT REPORT ON
“IMPORTANCE OF POST MARKETING SURVEILLANCE
IN CLINICAL RESEARCH”
MASTER OF BUSINESS ADMINNISTRATION
(CLINICAL RESEARCH)

Submitted in partial fulfilment of

The requirements for award of

Master of Business Administration (clinical Research) of

Tilak Maharashtra University, Pune.

SUBMITTED BY:-
Harshad K More
PRN No.14209008929.

Of
Tilak Maharashtra University, Belapur.
Guided By
Prof. Vaidehi Limaye.

TILAK MAHARASHTRA UNIVERSITY,

GULTEKDI, PUNE -411037.

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 Tilak Maharashtra University, Pune
(Deemed Under Section 3 of UGC Act 1956 Vide Notification
No.F.9-19/85 – U3 dated 24 Th April 1987 By the Government of India.)
Vidyapeeth Bhavan, Gultekdi, Pune – 411 037.

CERTIFICATE

This is to Certify that the project entitled “Importance of Post

Marketing

Surveillance in Clinical Research’’ is a Bonafide work carried

out by Mr

Harshad K More, a student of Master of Business

Administration Third Semester,

Specialization in Clinical Research PRN. 14209008929 under

Tilak Maharashtra

Vidyapeeth, in the year 2010.

Head of the Department Examiner

Examiner

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 Internal
External
Date: 30th September 2010

Place: Mumbai University

Seal

Center For Advancement in Health Sciences

12/595, Srinivas (Kesar-villa), Dr. Ambedkar Road,
Matunga East, Mumbai,Maharashtra, PIN - 400019,
INDIA

Tel: + 919820506932. Telefax: +912224140224

CERTIFICATE

This is to certify that Mr. Harshad K More MBA Student of Tilak

Maharashtra University , Pune has successfully completed their project
work for award of Master Degree of Business Administration.

He has done the project on “ Importance of Post Marketing

Surveillance in Clinical Research”

Designation:-

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Signature:-

ACKNOWLEDGEMENT

I am very thankful to everyone who all supported me, for I have completed my
project effectively and moreover on time.

Successful completion of any project involves the support and guidance of

experience and learned people. I would like to extend my thanks to Tikal Maharashtra
University and Dr. Vaidehi Limaye (Faculty and Course Coordinator).

I am equally grateful to my madam Dr. Vaidehi Limaye she gave me moral

support and guided me in different matters regarding the topic. She had been very
kind and patient while suggesting me the outlines of this project and correcting my
doubts. I thank her for her overall supports.
Last but not the least, I would like to thank my parents who helped me a lot in
gathering different information, collecting data and guiding me from time to time in
making this project . Despite of my parent's busy schedule, they gave me different
ideas in making this project unique. I put an effort to complete and make it a great
project.

My thanks to GOD and also my family well wishers whose continuous

inspiration facilitated me for making this project into reality.

Thanking you

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 INDEX
SR. NO. CONTENTS PAGE NO.
1. Rationale of the study. 1

2. Objective of the study. 29

3. Profile of the company. 32

4. Review of literature. 36

5. Research methodology. 38

6. Data Analysis and Interpretation 46

7. Findings 56

8 Sample Form 61

10. References 97

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 Chapter – 1
Rationale of study -

The principal focus of postmarketing surveillance proposals has been on the safe use of pre-
scription drugs, even though the range of issues has encompassed both efficacy and safety
considerations, e.g., concern over refinements in use as well as better definition of drug risks.
However, must postmarketing surveillance deserves attention as a policy issue for both short-
and long-term objectives. Regarding short-term action, if current testing requirements for the
premarketing approval process are reduced, pharmaceutical manufacturers could be required
to maintain their drug evaluation responsibilities by increasing postmarketing surveillance.
Regarding long-term action, postmarketing surveillance remains a policy issue irrespective of
current interest in the premarketing approval process: it is only after marketing that a drug’s
full therapeutic and harmful potentials can be determined.
Postmarketing surveillance refers to a specific time in the life of a drug: the life span that
begins once the drug enters the general market. Postmarketing surveillance is important be-
cause at the time a drug is approved for marketing a number of clinically and epidemiologi-
cally important question are unanswered.
Postmarketing surveillance of drugs therefore plays an important role to discover undesirable
effects that might present a risk. Postmarketing surveillance studies provide additional infor-
mation on the benefits and risks of a drug resulting in possible drug safety hazards being
identified which impact on, or may influence the overall benefit /risk ratio of medicinal
product Postmarketing surveillance studies should compliment spontaneous adverse drug
reaction reporting system which are very important in the detection of background signals
which might indicate a problem .However spontaneous reporting system do not provide a
quantitative risk assessment i:e give the incidence of adverse reaction in a population there-
fore it is difficult to estimate relevance of a risk described in single case report without
knowing the number of exposed and treated within a given time period. Postmarketing sur-
veillance studies can provide a denominator and give the answer to specific questions which
have been generated by signals from the spontaneous reporting system.
Postmarketing surveillance studies are conducted for the purpose of confirming previously
unrecognized safety issues , investigating possible hazards or conforming the expected safety
profile of medicinal product under marketed conditions or to quantify established adverse
reaction and to identify risk factors

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Drug Approval Process (International)
An NDA is a regulatory mechanism that is designed to give the FDA sufficient information
to make a meaningful evaluation of a new drug. All NDAs must contain the following
information: preclinical laboratory and animal data, human pharmacokinetic and
bioavailability data, clinical data, methods of manufacturing, processing and packaging, a
description of the drug product and substance, a list of relevant patents for the drug, its
manufacture or claims, and any proposed labeling. In addition, an NDA must provide a
summary of the application’s contents and a presentation of the risks and benefits of the new
drug. Traditionally, NDAs consisted of hundreds of volumes of information, in triplicate, all
cross referenced. Since 1999, the FDA has issued final guidance documents that allow
sponsors to submit NDAs electronically in a standardized format. These electronic
submissions facilitate ease of review and possible approval.

The NDA must be submitted complete in the proper form and with all critical data. If the
FDA considers it “accepted,” it will then determine the application’s completeness. If
“complete,” the agency considers the application
“filed” and will begin the review process within 60 days.
The purpose of an NDA from the FDA’s perspective is to ensure that the new drug meets the
criteria to be “safe and effective.” Safety and effectiveness are determined through the Phase
III pivotal studies based on “substantial evidence” gained from a well-controlled clinical
study. Since the FDA realizes there are no absolutely safe drugs, FDA looks to the new
drug’s efficacy as a measure of its safety. It weighs the risks vs. benefits of approving the
drug for use in the U.S. market. Also, the NDA must be very clear about the manufacture and
marketing of the proposed drug product. The application must define and describe
manufacturing processes, validate Current Good Manufacturing Practices (CGMPs), provide
evidence of quality, purity, strength, identity, and bioavailability
(a pre inspection of the manufacturing facility will be conducted by the FDA). Finally, the
FDA will review all product packaging and labeling for content and clarity. Statements on a
product’s package label, package insert, media advertising, or professional literature must be
reviewed. Of note, “labeling” refers to all of the above and not just the label on the product
container.
The FDA is required to review an application within 180 d of filing. At the end of that time,
the agency is required to respond with an “action letter.”There are three kinds of action let

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ters. An Approval Letter signifies that all substantive requirements for approval are met with
and that the sponsor company can begin marketing the drug as of the date on the letter.
An Approvable Letter signifies that the application substantially complies with the
requirements but has some minor deficiencies that must be addressed before an approval
letter is sent. Generally, these deficiencies are minor in nature and the product sponsor must
respond within 10 days of receipt. At this point, the sponsor may amend the application and
address the agency’s concerns, request a hearing with the agency, or withdraw the application
entirely.

ORGANISATION OF THE COMMON TECHNICAL DOCUMENT FOR THE

REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

Module 1. Administrative Information and Prescribing Information

This module should contain documents specific to each region; for example, application
forms or the proposed label for use in the region. The content and format of this module cabe
specified by the relevant regulatory authorities.

Module 2 : Common Technical Document Summaries

General Principles of Nonclinical Overview and Summaries

2.3 : QUALITY OVERALL SUMMARY (QOS)

INTRODUCTION

2.3.S DRUG SUBSTANCE (NAME, MANUFACTURER)

2.3.A APPENDICES

2.3.R REGIONAL INFORMATION

2.4 NONCLINICAL OVERVIEW

General Aspects

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 Content and Structural Format

2.5: CLINICAL OVERVIEW

Table of Contents
Detailed Discussion of Content of the Clinical Overview Sections
2.5.1 Product Development Rationale
2.5.2 Overview of Biopharmaceutics
2.5.3 Overview of Clinical Pharmacology
2.5.4 Overview of Efficacy
2.5.5 Overview of Safety
2.5.6 Benefits and Risks Conclusions
2.5.7 Literature References

2.6 NONCLINICAL WRITTEN AND TABULATED SUMMARIES

Nonclinical Written Summaries

2.6.1 Introduction

2.6.2 Pharmacology Written Summary

2.6.2.2 Primary Pharmacodynamics

2.6.2.5 Pharmacodynamic Drug Interactions

2.6.2.6 Discussion and Conclusions

2.6.3 Pharmacology Tabulated Summary (see Appendix B)

2.6.4 Pharmacokinetics Written Summary

2.6.5 Pharmacokinetics Tabulated Summary (see Appendix B)

2.6.6 Toxicology Written Summary

2.6.6.4 Genotoxicity

2.6.6.6 Reproductive and Developmental Toxicity

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2.6.7 Toxicology Tabulated Summary (see Appendix B)

2.7 : CLINICAL SUMMARY

Preamble
Table of Contents
Detailed Guidance on Sections of the Clinical Summary
2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical
Methods

2.7.1.4 Appendix

2.7.2 Summary of Clinical Pharmacology Studies

2.7.3 Summary of Clinical Efficacy

2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations

2.7.4 Summary of Clinical Safety

2.7.5 Literature References

Module 3 : Quality

3.1. TABLE OF CONTENTS OF MODULE 3

3.2. BODY OF DATA

3.2.S DRUG SUBSTANCE (NAME, MANUFACTURER)

3.2.S.2.2 Description of Manufacturing Process and Process Controls

3.2.S.2.3 Control of Materials (name, manufacturer)

3.2.S.4.2 Analytical Procedures (name, manufacturer)

3.2.P DRUG PRODUCT (NAME, DOSAGE FORM)

3.2.P.2.1.1 Drug Substance (name, dosage form)

3.2.P.2.1.2 Excipients (name, dosage form)

3.2.P.2.2.1 Formulation Development (name, dosage form)

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3.2.P.2.2.2 Overages (name, dosage form)

3.2.P.2.2.3 Physicochemical and Biological Properties (name, dosage form)

3.2.P.3.3 Description of Manufacturing Process and Process Controls

3.2.A APPENDICES

3.2.R REGIONAL INFORMATION

Module 4: Nonclinical Study Reports

4.1 Table of Contents of Module 4

4.2 Study Reports
4.3 Literature References
Appendix A

Examples of Tables and Figures for Written Summaries

Appendix B

The Nonclinical Tabulated Summaries - Templates

Appendix C

THE NONCLINICAL TABULATED SUMMARIES - EXAMPLES

MODULE 5 : CLINICAL STUDY REPORTS

Preamble

Detailed Organisation of Clinical Study Reports and Related Information

5.1 Table of Contents of Module 5

5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutic Studies

5.3.2 ReportsofStudiesPertinenttoPharmacokineticsUsingHuman Biomaterials

5.3.3 Reports of Human Pharmacokinetic (PK) Studies

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5.3.4 Reports of Human Pharmacodynamic (PD) Studies

5.3.5 Reports of Efficacy and Safety Studies

5.3.6 Reports of Post-Marketing Experience

5.3.7 Case Report Forms and Individual Patient Listings

5.4 LITERATURE REFERENCES

Drug Approval Process (INDIA)

APPENDIX I

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DATA TO BE SUBMITTED ALONG WITH THE APPLICATION TO CONDUCT
CLINICAL TRIALS 

1. Introduction

A brief description of the drug and the therapeutic class to which it belongs.

2.    Chemical and pharmaceutical information

2.1. Information on active ingredients

Drug information (Generic Name, Chemical Name or  INN)

2.2. Physicochemical Data

a.   Chemical name and Structure
Empirical formula
Molecular weight
b.   Physical properties
Description
Solubility
  Rotation
Partition coefficient
Dissociation constant
2.3. Analytical Data
Elemental analysis
Mass spectrum
NMR spectra
IR spectra
UV spectra
Polymorphic identification
2.4. Complete monograph specification including
Identification
Identity/quantification of impurities

Enantiomeric purity
Assay
2.5. Validations
Assay method

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 Impurity estimation method
Residual solvent/other volatile impurities (OVI) estimation method
2.6. Stability Studies (for details refer Appendix IX)
Final release specification
Reference standard characterization
Material safety data sheet
2.7.   Data on Formulation
Dosage form
Composition
Master manufacturing formula
Details of the formulation (including inactive ingredients)
In process quality control check
Finished product specification
Excipient compatibility study
Validation of the analytical method
Comparative evaluation with international brand(s) or approved Indian brands,
Pack presentation
Dissolution
Assay
Impurities
Content uniformity
pH
Force degradation study
Stability evaluation in market intended pack at proposed storage conditions
Packing specifications
Process validation
When the application is for clinical trials only, the international non-proprietary
name (INN) or generic name, drug category, dosage form and data supporting
stability in the intended container-closure system for the duration of the clinical trial
(information covered in item nos. 2.1, 2.3, 2.6, 2.7) are required.
 

3.      Animal Pharmacology (for details refer Appendix IV)

3.1.   Summary
3.2.    Specific pharmacological actions
3.3.    General pharmacological actions

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3.4.    Follow-up and Supplemental Safety Pharmacology Studies
3.5.    Pharmacokinetics: absorption, distribution; metabolism; excretion

4.      Animal Toxicology (for details refer Appendix III)

4.1.   General Aspects
4.2.    Systemic Toxicity Studies
4.3.    Male Fertility Study
4.4.    Female Reproduction and Developmental Toxicity Studies
4.5.    Local toxicity
4.6.      Allergenicity/Hypersensitivity
4.7.      Genotoxicity
4.8.      Carcinogenicity

5.      Human / Clinical pharmacology (Phase I)

5.1. Summary
5.2. Specific Pharmacological effects
5.3. General Pharmacological effects
5.4. Pharmacokinetics, absorption, distribution, metabolism, excretion
5.5  Pharmacodynamics / early measurement of drug activity
 
6.      Therapeutic exploratory trials (Phase II)
6.1. Summary
6.2. Study report(s) as given in Appendix II

7.      Therapeutic confirmatory trials (Phase III)

7.1. Summary
7.2. Individual study reports with listing of sites  and Investigators.
 
8.      Special studies
8.1. Summary

8.2. Bio-availability / Bio-equivalence.
8.3 Other studies e.g. geriatrics, paediatrics, pregnant or nursing women
 
9.    Regulatory status in other countries

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9.1. Countries where the drug is
a. Marketed
b. Approved
c. Approved as IND
d. Withdrawn, if any, with reasons
9.2. Restrictions on use, if any, in countries where marketed /approved
9.3. Free sale certificate or certificate of analysis, as appropriate.

10.  Prescribing information

10.1. Proposed full prescribing information
10.2. Drafts of labels and cartons
11.  Samples and Testing Protocol/s
11.1. Samples of pure drug substance and finished product (an equivalent of 50 clinical
doses, or more number of clinical doses if prescribed by the Licensing Authority), with
testing protocol/s, full impurity profile and release specifications.

Appendix II

  STRUCTURE, CONTENTS AND FORMAT FOR CLINICAL STUDY REPORTS

1.      Title Page:-

This page should contain information about the title of the study, the protocol code,
name of the investigational product tested, development Phase, indication studied,
a brief description of the trial design,  the start and end date of patient accrual and
the names of the Sponsor and the participating Institutes (Investigators).

2.       Study Synopsis (1 to 2 pages): A brief overview of the study from the protocol
development to the trial closure should be given here. This section will only
summarize the important conclusions derived from the study.

3.  Statement of compliance with the ‘Guidelines for Clinical Trials on Pharmaceutcal

Products in India – GCP  Guidelines’ issued by the Central Drugs Standard
Control Organization, Ministry of Health, Government of India.

4.        List of Abbreviations and Definitions

5.        Table of contents

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6.        Ethics Committee:

This section should document that the study was conducted in accordance with the
ethical principles of Declaration of Helsinki. A detailed description of the Ethics
Committee constitution and date(s) of approvals of trial documents for each of the
participating sites should be provided.  A declaration should state that EC notifica
tions as per  Good Clinical Practice Guidelines issued by Central Drugs Standard
Control Organization and Ethical

Guidelines for Biomedical Research on Human Subjects, issued by Indian Council

of Medical Research have been followed.

7.    Study Team:

Briefly describe the administrative structure of the study (Investigators, site staff,
Sponsor/ designates, Central laboratory etc.).

8.         Introduction:

A brief description of the product development rationale should be given here.

 9.        Study Objective:

A statement describing the overall purpose of the study and the primary and
secondary objectives to be achieved should be mentioned here.

10.       Investigational Plan:

This section should describe the overall trial design, the Subject selection criteria,
the treatment procedures, blinding / randomization techniques if any, allowed/
disallowed concomitant treatment, the efficacy and safety criteria assessed, the data
quality assurance procedures and the statistical methods planned for the analysis of
the data obtained.
 

11. Trial Subjects

A clear accounting of all trial Subjects who entered the study will be given here.
Mention should also be made of all cases that were dropouts or protocol
deviations.  Enumerate the patients screened, randomised, and prematurely

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 discontinued. State reasons for premature discontinuation of therapy in each
applicable case.

12.      Efficacy evaluation

The results of evaluation of all the efficacy variables will be described in this
section with appropriate tabular and graphical representation. A brief description of
the demographic characteristics of the trial patients should also be provided
alongwith a listing of patients and observations excluded from efficacy analysis.

13.      Safety Evaluation

This section should include the complete list

13.1 All serious adverse events, whether expected or unexpected and
13.2 unexpected advese events whether serious or not (compiled from data received as
per Appendix XI).
The comparison of adverse events across study groups may be presented in a tabu
lar or graphical form. This section should also give a brief narrative of all impor
tant events considered related to the investigational product.

14.        Discussion and overall Conclusion

Discussion of the important conclusions derived from the trial and scope for further
development. 

15. List of References

16.      Appendices

List of Appendices to the Clinical Trial Report

a.        Protocol and amendments
b.       Specimen of Case Record Form
c.       Investigators’ name(s) with contact addresses, phone, email etc.
d.       Patient data listings
e.       List of trial participants treated with investigational product

f.       Discontinued participants

g.       Protocol deviations
h.       CRFs of cases involving death and life threatening adverse event cases

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 i.        Publications from the trial
j.        Important publications referenced in the study
k.       Audit certificate, if available
l.       Investigator’s certificate that he/she has read the report

Appendix III

  ANIMAL TOXICOLOGY (NON-CLINICAL TOXICITY STUDIES)

  Special Toxicity Studies

  Male Fertility Study:

  Phase I, II, III in male volunteers/patients

Female Reproduction and Developmental Toxicity Studies:

Segment II studies in 2 species; Phase II, III involving female patients of child-
bearing age.

Segment I study; Phase III involving female patients of child-bearing age.      

Segment III study; Phase III for drugs to be given to pregnant or nursing mothers
for long periods or where there are indications of possible adverse effects on
foetal development.

Allergenicity/Hypersensitivity: 

Phase I, II, III - when there is a cause of concern or for parenteral drugs
(including dermal application)

Photo-allergy or dermal photo-toxicity:

Phase I, II, III - if the drug or a metabolite is related to an agent causing photo
sensitivity or the nature of action suggests such a potential.

Genotoxicity:

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  In-vitro studies - Phase I
 Both in-vitro and in-vivo - Phase II, III

Arcinogenicity:

Phase III - when there is a cause for concern, or when the drug is to be used for
more than 6 months.

For Phase I Clinical Trials

Systemic Toxicity studies

. Single dose toxicity studies
Dose Ranging Studies
Repeat-dose systemic toxicity studies of appropriate duration to support the
duration to support the duration of proposed human exposure. 
Male fertility study
In-vitro genotoxicity tests
Relevant local toxicity studies with proposed route of clinical application (dura
tion depending on proposed length of clinical exposure)
Allergenicity/Hypersensitivity tests (when there is a cause for concern or for
parenteral drugs, including dermal application)
Photo-allergy or dermal photo-toxicity test (if the drug or a metabolite is related
to an agent causing photosensitivity or the nature of action suggests such a
potential)

For Phase II Clinical Trials

Provide a summary of all the non-clinical safety data (listed above) already
submitted while obtaining the permissions for Phase I trial, with appropriate
references. In case of an application for directly starting a Phase II trial -
complete details of the non-clinical safety data needed for obtaining the
permission for Phase I trial, as per the list provided above must be submitted.

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 Repeat-dose systemic toxicity studies of appropriate duration to support the
duration of proposed human exposure

In-vivo genotoxicity tests

Segment II reproductive/developmental toxicity study (if female patients of
child bearing age are going to be involved)
 
For Phase III Clinical Trials

Provide a summary of all the non-clinical safety data (listed above) already
submitted while obtaining the permissions for Phase I and II trials, with
appropriate references.

In case of an application for directly initiating a Phase III trial - complete

details of the non-clinical safety data needed for obtaining the permissions for
Phase I and II trials, as per the list provided above must be provided.
 
Repeat-dose systemic toxicity studies of appropriate duration to support the
duration of proposed human exposure
Reproductive/developmental toxicity studies
Segment I (if female patients of child bearing age are going to be involved),
and Segment III (for drugs to be given to pregnant or nursing mothers or where
there are indications of possible adverse effects on foetal development)
Carcinogenicity studies (when there is a cause for concern or when the drug is
to be used for more than 6 months)

For Phase IV Clinical Trials

Provide a summary of all the non-clinical safety data (listed above) already
submitted while obtaining the permissions for Phase I, II and III trials, with
appropriate references.

In case an application is made for initiating the Phase IV trial, complete details
of the non-clinical safety data needed for obtaining the permissions for Phase I,
II and III trials, as per the list provided above must be submitted.

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Appendix X

CONTENTS OF THE PROPOSED PROTOCOL FOR CONDUCTING

CLINICAL TRIALS

1.   Title Page

a. Full title of the clinical study,

b. Protocol / Study number, and protocol version number with date
c. The IND name/number of the investigational drug
d. Complete name and address of the Sponsor and contract research organization
if any
e. List of the Investigators who are conducting the study, their respective
institutional affiliations and site locations
f. Name(s) of clinical laboratories and other departments and/or facilities
participating in the study.

2.    Table of Contents

       A complete Table of Contents including a list of all Appendices.

1.        Background and Introduction

a.       Preclinical experience

b.      Clinical experience
   
Previous clinical work with the new drug should be reviewed here and a
description of how the current protocol extends existing data should be
provided. If this is an entirely new indication, how this drug was considered
for this should be discussed. Relevant information regarding
pharmacological, toxicological and other biological properties of the
drug/biologic/medical device, and previous efficacy and safety experience
should be described.

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2.   Study Rational

This section should describe a brief summary of the background information

relevant to the study design and protocol methodology.  The reasons for
performing this study in the particular population included by the protocol
should be provided.

 3.       Study Objective(s) (primary as well as secondary) and their logical relation to
the study design.

Study Design

a.       Overview of the Study Design: Including a description of the type of study
(i.e., double-blind, multicentre, placebo controlled, etc.), a detail of the
specific treatment groups and number of study Subjects in each group and
investigative site, Subject number assignment, and the type, sequence and
duration of study periods. 

b.      Flow chart of the study

c.   A brief description of the methods and procedures to be used during the study.

d.       Discussion of Study Design: This discussion details the rationale for the de
sign chosen for this study. 

5.   Study Population: the number of Subjects required to be enrolled in the

study at the investigative site and by all sites along with a brief description
of the nature of the Subject population required is also mentioned.

6.           Subject Eligibility

a.      Inclusion Criteria

b.      Exclusion Criteria

7.       Study Assessments – plan, procedures and methods to be described in detail

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8.       Study Conduct stating the types of study activities that would be included in
this section would be: medical history, type of physical examination, blood
or urine testing, electrocardiogram (ECG), diagnostic testing such as
pulmonary function tests, symptom measurement, dispensation and
retrieval of medication, Subject cohort assignment, adverse event review,
etc.   Each visit should be described separately as Visit 1, Visit 2, etc. 

Discontinued Subjects: Describes the circumstances for Subject

withdrawal, dropouts, or other reasons for discontinuation of Subjects . 
State how drop outs would be managed and if they would be replaced

Describe the method of handling of protocol waivers, if any.  The person(s)

who approves all such waivers should be identified and the criteria used for
specific waivers should be provided. Describes how protocol violations will
be treated, including conditions where the study will be terminated for non-
compliance with the protocol.

 9.            Study Treatment

a.       Dosing schedule ( dose, frequency, and duration of the experimental

treatment)  Describe the administration of placebos and/or dummy
medications if they are part of the treatment plan. If applicable,
concomitant drug(s), their doses, frequency, and duration of concomitant
treatment should be stated.
b.       Study drug supplies and administration: A statement about who is going to
provide the study medication and that the investigational drug formulation
has been manufactured following all regulations  Details of the product
stability, storage requirements and dispensing requirements should be
provided.
c.       Dose modification for study drug toxicity: Rules for changing the dose or
stopping the study drug should be provided.
d.    Possible drug interactions
e.      Concomitant therapy: The drugs that are permitted during the study andthe
conditions under which they may be used are detailed here. Describe the
drugs that a Subject is not allowed to use during parts of or the entire

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 study.  If any washout periods for prohibited medications are needed prior
to enrollment, these should be described here. 
f.       Blinding procedures: A detailed description of the blinding procedure if
the study employs a blind on the Investigator and/or the Subject
g.       If the study is blinded, the circumstances in which unblinding may be
done and the mechanism to be used for unblinding should be given
 
10. Adverse Events (See Appendix XI): Description of expected adverse
events should be given. 
      Procedures used to evaluate an adverse event should be described.  

11.            Ethical Considerations:  Give the summary of:

a.      Risk/benefit assessment:

b.      Ethics Committee review and communications
c.      Informed consent process
d.       Statement of Subject confidentiality including ownership of data and
coding procedures
12.       Study Monitoring and Supervision:  A description of study monitoring
policies and procedures should be provided along with the proposed
frequency of site monitoring visits, and who is expected to perform
monitoring.  
Case Record Form (CRF)  completion requirements, including who gets
which copies of the forms and any specifics required in filling out the
forms CRF correction requirements, including who i authorized to make
corrections on the CRF and how queries about study data are handled and
how errors, if any, are to be corrected should be stated. Investigator study
files, including what needs to be stored following study completion should
be described. 

13.            Investigational Product Management

a.   Give Investigational product description and packaging (stating all Ingre
dients and the formulation of the investigational drug and any placebos
used in the study)

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b.   The precise dosing required during the study 
c.      Method of packaging, labeling, and blinding of study substances
d.       Method of assigning treatments to Subjects and the Subject identification
code numbering system
e.      Storage conditions for study substances
f.       Investigational product accountability: Describe instructions for the
receipt,storage, dispensation, and return of the investigational products to
ensure a complete accounting of all investigational products received,
dispensed, and returned/destroyed. 
g.       Describe policy and procedure for handling unused investigational
products.

14.            Data Analysis:

Provide details of the statistical approach to be followed including sample

size, how the sample size was determined, including assumptions made in
making this determination, efficacy endpoints (primary as well as
secondary) and safety endpoints.

Statistical analysis:
Give complete details of how the results will be analyzed and
reportedalong with the description of statistical tests to be used to analyze
the primary and secondary endpoints defined above.  Describe the level
of significance, statistical tests to be used, and the methods used for
missing data; method of evaluation of the data for treatment failures, non-
compliance, and Subject withdrawals; rationale and conditions for any
interim analysis if planned. 
Describe statistical considerations for Pharmacokinetic (PK) analysis, if
applicable

15.            Undertaking by the Investigator (see Appendix VII)

16.       Appendices: Provide a study synopsis, copies of the informed consent

documents (patient information sheet, informed consent form etc.); CRF

Page 26 of 100
 and other data collection forms; a summary of relevant pre-clinical safety
information and any other documents referenced in the clinical protocol.

 Appendix XI

Data Elements for reporting serious adverse events occuring in a clinical

trial

Patient Details

Initials & other relevant identifier (hospital/OPD record number etc.)*

Gender

Age and/or date of birth

Weight

Height

Suspected Drug(s) 

Generic name of the drug*

Indication(s) for which suspect drug was prescribed or tested

Dosage form and strength

Daily dose and regimen (specify units - e.g., mg, ml, mg/kg)

Route of administration

Starting date and time of day

Stopping date and time, or duration of treatment

  Other Treatment(s)

Provide the same information for concomitant drugs (including non pre
scription/OTC drugs) and non-drug therapies, as for the suspected
drug(s).

Page 27 of 100
 Details of Suspected Adverse Drug Reaction(s)

 Full description of reaction(s) including body site and severity, as well

as the criterion (or criteria) for regarding the report as serious. In
addition to a description of the reported signs and symptoms, whenever
possible, describe a specific diagnosis for the reaction.*

Start date (and time) of onset of reaction

Stop date (and time) or duration of reaction

Dechallenge and rechallenge information

Setting (e.g., hospital, out-patient clinic, home, nursing home)

  Outcome

Information on recovery and any sequelae; results of specific tests

and/or treatment that may have been conducted

For a fatal outcome, cause of death and a comment on its possible

relationship to the suspected reaction; Any post-mortem findings.

Other information: anything relevant to facilitate assessment of the

case, such as medical history including allergy, drug or alcohol abuse;
family history; findings from special investigations etc.

Details about the Investigator*

Name

Address

Telephone number

Profession (specialty)

Date of reporting the event to Licensing Authority:

Date of reporting the event to Ethics Committee overseeing the site:

Page 28 of 100
  

Chapter – 2

Objective of the study

1. The primary objective of postmarketing studies is to develop information about drug

effects under customary conditions of drug use.

2. To compare the incidence of an adverse reaction treated and not treated with the drug\

3. To identify the risk factor associated with the development of an adverse reaction
treated with the suspected drug such as concurrent drugs, disease severity.

4. To identify risk factors responsible for an increased frequency or severity

5. To further clarify biological effects of adverse reactions due to a suspected drug

6. To measure the incidence of an adverse reaction treated with the suspected drug

7. Postmarketing surveillance of drug plays an important role to discover undesirable

effects that might present a risk

8. Postmarketing surveillance monitor long term effects that manifest themselves only
after long period of use, or after long period of latency.

9. Postmarketing surveillance monitors increase in frequency or severity of known ad

verse reaction.

10. Postmarketing surveillance identifies market response to drug and helps

pharmaceutical company to determine marketing strategies for medicinal product.

11. Through Postmarketing surveillance medical practitioner acts as bridge between

patient and a pharmaceutical company. Any positive or negative outcome of
Postmarketing surveillance gives a new approach or direction to Research and
Development team of company.

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 12. When any pharmaceutical company takes negative results of Postmarketing
surveillance in positive ways, it brings improvement in drug development and also
strengthens concern for conducting clinical trial.

History of Post marketing surveillance

In the 1960’s, at least two serious drug reactions were observed in many patients. The drug
thalidomide, taken worldwide, led to limb deformities (phocomelia) in the newborns of those
mothers who took the drug while pregnant. Less known, and almost exclusively observed in
Japan, was the optic nerve damage (subacute myelo-optic-neuropathy) and other adverse
effects from the drug clioquinol, over which almost 4,000 civil suits were still pending in
1979 (68).
And in Great Britain in the early 1970’s, more than 4 years after the drug had been introduced
there, the “practolol syndrome” was uncovered.
Practolol, a drug used to treat cardiovascular disease, was eventually found to cause skin
rashes, eye lesions, hearing impairment, and sclerosing peritonitis (56), with deaths occurring
in about 2 percent of reported cases (37).
Great Britain, with its national health system, already had a voluntary reporting system (37).
The national health system had instituted the use of “yellow cards” for reporting suspected
adverse drug reactions.
As a guide to reporting, certain drugs are marked the first 4 years after they are marketed
with an inverted black triangle in a booklet, the Monthly Index of Medical Specialties, which
is distributed to physicians and used as a source of information for prescribing drugs more
frequently than any other publication.
In 1976, a slip of yellow paper was inserted into prescription pads to remind physicians to
report reactions, leading to a large and consistent increase in the rate of reporting.
Many British drug companies now use the yellow card, and the yellow card system and
reports from drug companies together yield 90 percent of all reports of suspected adverse
drug reactions (ADRs).
The delayed discovery of practolol’s adverse effects spurred efforts to improve postmarketing
surveillance, and several international meetings quickly followed in Sestri Levante, Italy (20),
Honolulu, Hawaii (33), and London (53).
In Great Britain, efforts focused on “early detection of adverse drug reactions by recording all
adverse events occurring in a specified number of patients for an appropriate period of time;
endeavoring to avoid collecting masses of unusable data and minimizing costs”.

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Thus, the early impetus was toward monitoring new drugs for adverse effects through some
type of program that would help fill the gap between identifying those adverse effects
sufficiently common to be detected in the premarketing trials, and identifying those so rare
that voluntary reporting after marketing is their most feasible form of monitoring.

The proposed methods all centered around the prescribing practices of physicians, with the
experience of their patients on new drugs being examined periodically through questionnaires
to the prescribing physicians.
Such methods of monitoring include registered release, recorded release, and monitored
release.
More recently, the objectives of postmarketing surveillance in Great Britain have been
expanded, though not implemented:
The need for PMS [postmarketing surveillance] is not restricted to new drugs. Some of those
already marketed for many years may increase the risk of chronic disease or may have long-
delayed carcinogenic effects, as illustrated in the United States by the cases of vaginal
adenocarcinoma in the adolescent female children of women who took diethylstilbestrol
during pregnancy.
PMS should also include assessment of efficacy, especially of long-term treatment.

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 Chapter 3

Profile of Company

1) Bristol-Myers Squibb Pharma

Bristol-Myers Squibb is a global BioPharma company firmly focused on its Mission to dis-
cover, develop and deliver innovative medicines that help patients prevail over serious dis-
eases.

Around the world, our medicines help millions of people in their fight against cancer, cardi-
ovascular disease, diabetes, hepatitis B, HIV/AIDS, rheumatoid arthritis and psychiatric dis-
orders.

At Bristol-Myers Squibb, our BioPharma strategy uniquely combines the reach and resources
of a major pharma company with the entrepreneurial spirit and agility of a successful biotech
company. With this strategy, we focus on our customers’ needs, giving maximum priority to
accelerating pipeline development, delivering sales growth and continuing to manage costs.

The strategy is working. For the past three years, our total return for shareholders, including
dividends, has been among the best in the industry. We outperformed most mega pharma
companies, diversified companies and pure biotech companies. Reflecting our long-standing
commitment to deliver shareholder value, our company has paid dividends to stockholders
for more than 300 consecutive quarters.

In addition, we have delivered nine new products to patients in the past seven years. And
there are more medicines on the way. We anticipate up to six additional regulatory approvals
or submissions through 2012.

Our R&D organization is considered among the most productive in the industry. And the
String of Pearls strategy of innovative alliances, partnerships and acquisitions further en-
hances our internal capabilities. Our full array of 10 pearls encompasses many of our key dis-
ease areas, including cancer, cardiovascular disease, immunology, neuroscience and virology.

Page 32 of 100
Pursuing our Mission also means we are working to provide patient access to health care. We
are striving to that goal through public/private partnerships like SECURE THE FUTURE, our
groundbreaking $150 million program to help confront HIV/AIDS in Africa. In addition,

through our patient assistance programs, in 2009 we provided medicines worth more than
$290 million at estimated wholesale list price to qualifying patients in the U.S.

Innovation is critical for successfully executing our BioPharma strategy. That innovation is
enhanced by a diverse workforce and an inclusive culture. Bristol-Myers Squibb has been
recognized year after year as one of the best companies for female executives and working
mothers. We’ve also been recognized by the Human Rights Campaign Foundation’s Corpo-
rate Equality Index for achieving a perfect score for the past four consecutive years.

Preservation of our natural resources also represents one of our key commitments. At many
of our facilities worldwide, our company is integrating comprehensive energy management,
pollution controls and other practices to reduce environmental impacts. Bristol-Myers Squibb
was recognized as eighth among 500 of the largest U.S. corporations in Newsweek’s 2009
Green Ranking. And Bristol-Myers Squibb was included in the 2009 Dow Jones Sustainabil-
ity North America Index of leading sustainability-driven companies.

Bristol-Myers Squibb delivers on its commitments: to our patients and customers, to our em-
ployees, to our global communities, to our shareholders and to our environment.

Page 33 of 100
Cipla Pharma

The origins of Cipla can be traced back to 1935, when Dr Khwaja Abdul Hamied set up "The
Chemical, Industrial and Pharmaceutical Laboratories Ltd", popularly known by the acronym
Cipla, in a rented bungalow, at Bombay Central.

Cipla was registered as a public limited company on August 17, 1935.

Cipla's first product was launched into the market in 1937.
In 1940, during the Second World War when the drug supplies were cut off, Cipla started
producing fine chemicals.
In 1944, Cipla bought the premises at Bombay Central to build a modern pharmaceutical
laboratory.
Cipla's product for hypertension Olmesartan, was exported to the American Roland
Corporation.
In 1952, Cipla set up first research division for attaining self-sufficiency in technological
development.
In 1960, Cipla started operations at second plant at Vikhroli, Mumbai. In 1968, Cipla
manufactured ampicillin for the first time in India.
In 1976, Cipla launched medicinal aerosols for asthma.
In 1982, Cipla's fourth factory became operational at Patalganga, Maharashtra. In 1984, Cipla
developed anti-cancer drugs, vinblastine and vincristine in collaboration with the National
Chemical Laboratory, Pune.
In 1991, Cipla pioneered the manufacture of the antiretroviral drug, zidovudine.
In 1994, Cipla's fifth factory began commercial production at Kurkumbh, Maharashtra.
In 1997, Cipla launched transparent Rotahaler, the world's first such dry powder inhaler
device.
In 2000, Cipla became the first company, outside the USA and Europe to launch CFC-free in-
halers.
Pradesh.
In 2002, Cipla set up four state-of-the-art manufacturing facilities set up in Goa.
In 2003, Cipla launched TIOVA (Tiotropium bromide), a novel inhaled, long-acting
anticholinergic bronchodilator.
In 2005, Cipla set up a state-of-the-art facility for manufacture of formulations at Baddi,
Himachal

Page 34 of 100
Pharmaceuticals:
Cipla manufactures anabolic steroids, analgesics/antipyretics, antacids, anthelmintics, anti-
arthritis, anti-inflammatory drugs, anti-TB drugs, antiallergic drugs, anticancer drugs, anti

fungal, antimalarials, antispasmodics, antiulcerants, immunosuppressants etc,

OTC:
These include: child care products, eye care products, food supplements, health drinks, life
style products, nutraceuticals & tonics, skin care products, and oral hygiene products.

Flavour & Fragrance: Cipla manufactures a wide range of flavours, which are used in foods
and beverages, fruit juices, baked goods, and oral hygiene products. Cipla fragrances have
wide ranging applications such as in personal care products, laundry detergents and room
fresheners.

Major Achievements of Cipla:

 Manufactured ampicillin for the first time in India

 Lauched etoposide, a breakthrough in cancer chemotherapy, in association with In-
dian Institute of Chemical Technology
 Launches transparent Rotahaler, the world's first such dry powder inhaler device
 Launches transparent Rotahaler, the world's first such dry powder inhaler device
 Became the first company, outside the USA and Europe to launch CFC-free inhalers

Page 35 of 100
 Chapter 4
Review of literature

Hypertension is fast becoming a major public health problem in India, more in urban than in

rural population.1 Hypertension is associated with diseases involving cardiovascular and

renal system, it is also known that hypertension increases the risk of atherosclerotic

cardiovascular diseases by an average of 2- 3 fold. 2 World Health Report 2002, states that

cardiovascular diseases (CVDs) will be the largest cause of death and disability in India by

2020. In India prevalence of hypertension is reported to be in range of 20-40% and 12-17%,

among urban and rural adults respectively, with number of people with hypertension

expected to increase from 118.2 million in 2000 to 213.5 million in 2025.3 This increasing

trend among others has been attributed to increase in urbanization leading to change in life

style pattern, diet and increase in stress.4 2.3 million deaths were caused by CVDs in India in

the year 1990 and this is projected to double by the year 2020. Hypertension is directly

responsible for 57% of all stroke deaths and 24% of all coronary heart disease deaths in India.

In a survey (I-Target survey) carried out to find extent of BP control among Indian
hypertensive patients receiving antihypertensive medications, only 27.3% out of 3402
patients surveyed had control of BP to recommended targets.6 This survey underlined the
need to increase awareness among Indian hypertensive patients to achieve BP target of <
140/90 mmHg 7,8 or 130/80 mmHg in patient with diabetes mellitus7,8 as set by current
treatment guidelines. Treatment guidelines also suggest that depending on patients need,
treatment should be initiated with a low dose single agent or low dose combination of two
agents.8 In case low dose monotherapy fails to achieve desired BP control, dose of initial
antihypertensive should be increased or patient should be shifted to low dose of different
agent or move to combination therapy.8

The benefits of BP reduction in reducing morbidity and mortality in conditions associated

with hypertension have been clearly shown. In clinical trials, treating hypertension reduced

Page 36 of 100
the incidence of stroke by 35%–40%, myocardial infarction by 20%–25%, and heart failure
by >50%.7 However, many patients fail to respond adequately to treatment and thus are not

able to achieve the desired target BP. This is common with all antihypertensive agents. Drugs
acting on rennin-angiotensin-aldosterone system (RAAS) like angiotensin converting enzyme
inhibitors (ACEIs) and angiotensin II receptor (AT1) blockers (ARBs) provide effective
treatment of hypertension. Blockade of the RAAS by ACEIs has been shown to be effective
in treating cardiovascular and diabetic conditions, including hypertension, diabetic
nephropathy and heart failure, but produces side effects partly attributable to prevention of
bradykinin breakdown. These side effects, especially cough, may limit compliance and
occasionally can be life-threatening. Also, in the presence of ACE inhibition, angiotensin II
can be produced by non-ACE-related mechanisms, which can still act on the angiotensin
receptors. ARBs possess many positive features of ACEIs and fewer side effects, have
therefore emerged as an alternative way of blocking the RAAS and have been used in clinical
practice since 1995. Out of presently available ARBs used in the treatment of hypertension,
heart failure and diabetic nephropathy,

Page 37 of 100
 Chapter 5

Research methodology

The primary objective of postmarketing studies is to develop information about drug effects
under customary conditions of drug use. Controlled conditions allow for study of fewer
patients than in the other method
The four types of studies are generally used to identify drug effects:
1) Controlled clinical trials,
2) Spontaneous or voluntary reporting,
3) Cohort studies,
4) Case-control studies
Controlled clinical trials match treatment and control groups as closely as possible,
minimize bias through such methods as randomization and “double-blinding,” and directly
monitor patients for the duration of the study. For example, patients can be randomly
assigned to either the control or treatment group. The control group receives placebo or an
active comparison drug that looks exactly like the drug being tested, and both the
investigators and patients do not know who is receiving the real drug. (Personnel not directly
involved in the tests would of course know what substance each patient was receiving). In
this method, possible drug effects, both therapeutic
and adverse, are closely monitored, so that they are discovered as they occur. The controlled
clinical trial is considered the most definitive method for evaluating a drug’s efficacy and
safety, but the use of rigorous criteria for patient selection usually means that the patients
tested represent only a special class of the anticipated users of the drug(s), and the carefully
controlled conditions allow for study of fewer patients than in the other methods, Thus, for
example, to observe drug effects that are rare or that appear only after long-term use,
controlled clinical trials might be impractical or too expensive.
Voluntary reporting may be spontaneous, such as in a “letter to the editor” of a medical
journal about an unusual condition observed in a patient on a particular drug, or it may be
more organized, as with the “yellow card” system in Great Britain.
Most of the reporting to the Food and Drug Administration (FDA) is by pharmaceutical
manufacturers, who are required by law to report adverse reactions. In practice, most of the

Page 38 of 100
information obtained by the manufacturers originates from physicians and other health
professionals. Such observations serve as warnings of possible adverse drug effects, so that
the inference of an association between a drug and an observed health condition may be
further stu

died by cumulative, careful reporting, and confirmed or disconfirmed by more vigorous

methods. Underreporting is a serious deficiency of this voluntary method, and a drug may
also be wrongly associated with an adverse effect until the suspected association fails to show
up in repeated, statistically validated studies.

Cohort studies follow a defined group of patients (the cohort) for a period of time. In this
method, patients are not randomly assigned to groups, and there is no blinding. Cohort
studies are usually prospective, and observe the cohort from the beginning of drug use. A
group of patients taking the drug of interest is assembled and followed to see, for example, if
any adverse reactions occur. A second group of patients (the controls) with the same medical
condition, who are not taking the drug and who may be receiving alternative treatment, but
who are otherwise matched as closely as possible with the cohort, may be studied in parallel.
The control group is used to identify the frequency of occurrence of any condition observed
in the drug-exposed group, but which must be due to causes other than the drug (the
“background incidence” of the condition). In this method, patients can be directly monitored
to ensure they take the drug appropriately and to observe the drug’s effects; or monitoring
can be less systematic. With less monitoring, a larger cohort can be followed, but bias is thus
increased.
Although uncommon, a Retrospective cohort study may also be conducted when purported
drug-induced effects have already been observed at the time the study is started. A
retrospective cohort study must accurately ascertain patients’ past drug use. In principle, this
could be done by a “closed” pharmacy record system, in which users have been restricted to a
single supplier or payment source. In practice, the use data on individuals needs to be
connected to data on their outcome, as through computer files. Medicaid, Medicare, the
military, and some prepaid health maintenance organizations could be employed for this
purpose. Case-control studies identify patients with the adverse effects to be studied (the
cases), and compare them with a sample (the controls), drawn from the same cohort that gave
rise to the cases. Controls are matched as closely as possible with the cases, except with
regard to the drug’s suspected adverse effect, to examine whether exposure to the drug is the
cause. Patients with conditions suspected of being associated with a certain drug would have
their medical records reviewed

Page 39 of 100
or be interviewed concerning the use of that drug. The histories of the controls would also be
studied for information about drug use in the general population.
By comparing the proportion of drug users among the cases with the proportion of drug users
in the general population, it is possible to infer the relative frequency with which adverse
reactions occur in users of certain drugs as compared with nonusers. A sufficient number of

appropriate cases must be identified and accurate histories of exposure to drugs must be
obtained. Among the advantages of retrospective case control studies compared with
prospective cohort studies are the smaller number of patients required in retrospective case-
control studies, the relative ease of carrying out the study, the lower cost, and the shorter time
needed. A disadvantage of the retrospective case-control method is that a condition must have
been already identified and suspected as the effect of drug use. It is also harder to reduce bias
in a retrospective study than to do so in a prospective one. Bias is equally possible in cohort
and case-control studies, though each kind of study is liable to a different kind of bias. For
example, bias in the observations can arise with respect to identifying the effects of the drug
in cohort studies and with respect to identifying the exposure in case control studies.
Controlled clinical trials and prospective cohort studies can be used to determine a drug’s
beneficial as well as adverse effects. Case-control studies are usually used to trace adverse
effects back to prior drug use. Voluntary reporting can uncover additional uses of drugs as
well as their adverse effects, but reporting of adverse effects is much more common.

Detection and association

The ability of a particular surveillance method to detect a drug’s effect depends on two
factors
1) The time that transpires between use of that drug and the occurrence of the drug’s effect
2) How often the effect occurs (Some effects occur frequency).
There are many other determining factors, such as accuracy of observation and accuracy and
completeness of medical records. But, these factors are more a problem in the design of study
design. Latency of some drugs effects presents serious problems for the studies. Some effects
occur immediately, or within weeks or days after drug use, or with continued use of drug. But
the other effects may occur long after a drug has been discontinued or only when another
drug is taken simultaneously, or only in patients with certain predisposing conditions. Other
effects may not be manifest in the patients themselves, but rather in their children. The use of
DES (diethylstilbestrol), in pregnant women, for example, has been associated with vaginal
cancer in their daughters, but only after the daughters has reached adolescence. Controlled

Page 40 of 100
clinical trials, because of their relatively short duration, will detect only acute or sub acute
effects. Long term cohort studies can detect delayed effects, but the data bases necessary for
such long-term, large studies are still sparse. Voluntary reporting is usually the way in which
long-term effects are first identified. Long-term effects are usually confirmed through
retrospective case-control studies, but their reliance on historical data such as medical records
can limit the accuracy of these studies. The chance that a particular study will discover a drug
ef

fect also depends on the study’s sample size and the frequency of the drug effect. For
example, in a cohort study, if a drug causes blindness in 1 out of every 100 users (1/100),
how many users must be observed to find one case of blindness? If there were 1 million users
of the drug, there would be 10,000 users blinded. But in a small sample of only 100 users, the
probability of finding one or more cases of blindness in the sample would only be 63 percent.
If the sample were 200 users, the probability would increase to 86 percent. With a sample of
500, the probability would be 99 percent that at least one case of blindness would be found in
the observed users.

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Case Study – 1

Objective(s): To evaluate the tolerance and the blood pressure lowering effect of Irbesartan
150 mg as well as the factors affecting persistence in a large unselected population.

Background

Persistence is a key factor for long-term blood pressure control, which is of high prognostic
importance for patients at increased cardiovascular risk. Here we present the results of a post-
marketing survey including 4769 hypertensive patients treated with Irbesartan 150 mg in 886
general practices in Switzerland.

Methods

Design of the investigation

This prospective observational survey was conducted in general practices in all regions of
Switzerland from October 1997 to March 1999 i.e. shortly after the launch of Irbesartan 150
mg in the country. The general practitioners (GPs) were asked to document their daily routine
in the treatment of hypertensive patients with Irbesartan 150 mg; 1390 physicians were
contacted, 1045 included patients and 886 documented the treatment. It consisted of an 8
week surveillance period divided into six consecutive visits. Visit-1 (on day 1) included
screening, enrollment and initiation of treatment. Visits 2, 3, 4 and 5 were scheduled at end of
week 1, 2, 3 and 4 respectively. Subsequent visits 6 and 7 were scheduled alternatively at end
of week 6 and 8 respectively. They were asked to document blood pressure measurements at
every visit and to report concomitant antihypertensive medication and adverse events, as well
as changes or discontinuation of treatment. At the end of the observation period, GPs reported
if their patients were continuing the treatment with Irbesartan 150 mg, alone or in
combination with other antihypertensive drugs. Their GPs received a Compliance Form MD,
to report the last blood pressure measurement and if and when the patient had discontinued

Page 42 of 100
the treatment. The various forms were designed by external consultants. The data were
collected by mail using self-addressed envelopes and processed by the consultants.

Patient selection

All patients with newly diagnosed hypertension, or with treated hypertension requiring a
change in medication according to the GP, were considered for the survey. No standardized
definition was used but physicians considered a BP >140/90 mmHg as hypertension. There
were neither demographic nor clinical exclusion criteria. The only condition to participate
was that patients should not have been pre-treated with Irbesartan 150 mg. Treatment was
started with Irbesartan 150 mg. Thereafter, physicians were free to change the
antihypertensive therapy at any time during the follow-up based on their individual
therapeutic goals (usually <140/90 mmHg).

Statistical analysis

Values are presented as mean +/- sd. The statistical significance of between-group differences
was computed using the 2-sided Chi-square test, the Mann-Whitney-U test or ANOVA
methods as appropriate. For multivariate correlations, a logistic regression analysis with a
dichotomous dependent variable was used (e.g. therapy discontinuation: yes = 1; no = 0). To
support the results of the logistic regression models, Cox regression models with cumulative
survival functions were further computed.

Page 43 of 100
Case study -2

Objective(s): To assess the efficacy and safety of once daily olmesartan medoxomil 20 mg in
Indian patients with stage 1 essential hypertension.

Methods

Study Population

This was an open label, multicentre, real world observational postmarketing surveillance
conducted in male and female patients (N=825), in age group of 18 to 65 yrs who had clini-
cally diagnosed stage 1 hypertension (JNC-7 guidelines). Inclusion was restricted to patients
with sitting SBP in the range of 140-159 mm Hg, sitting DBP in the range of 90-99 mm Hg
and who were receiving olmesartan medoxomil 20 mg once daily as monotherapy.

Study Design The surveillance was conducted as a multicentre (387 clinics all over India),
open label, post marketing real world surveillance. It consisted of an 8 week surveillance
period divided into six consecutive visits. Visit-1 (on day 1) included screening, enrollment
and initiation of treatment. Visits 2, 3, 4 and 5 were scheduled at end of week 1, 2, 3 and 4
respectively. Subsequent visits 6 and 7 were scheduled alternatively at end of week 6 and 8
respectively.

Assessments

Page 44 of 100
There were a total of seven assessment visits planned for each patient (including the screen-
ing, enrolment cum initiation visit i.e. visit-1, see study design). At visit-1 medical history,
physical examination, vital signs, baseline BP and treatment history were recorded in the case
report form (CRF). BP was measured for each patient at all visits in sitting position with the
help of sphygmomanometer (patients resting for at least 5 minutes prior to recording), 3
readings were taken at an interval of 10 minutes and the lowest of the 3 readings were rec-
orded in the CRF at each visit.

At subsequent visits BP was recorded as above, and also each patient was assessed for any
adverse event/reaction, either spontaneously reported by the patient or noticed by the physi-
cian.

At the end of the surveillance i.e. visit-7, in addition to BP recording overall efficacy and to-
lerability of treatment was assessed by both doctor as well as physician and recorded in the
CRF.

Primary endpoint was achievement of target systolic blood pressure (SBP) of < 140 mm Hg,
diastolic blood pressure (DBP) of < 90 mm Hg and SBP < 130 mm Hg, DBP < 80 mm Hg in
patients with diabetes mellitus by the end of surveillance. Patients who achieved the primary
endpoint by visit-7 were considered as “responders” and rest as “nonresponders”.

Statistical Analysis

The data processing was performed by capturing data into e-Case Report Forms. Data entered
was checked by design for completeness and integrity. Demographic data was presented as
descriptive statistics and baseline and end of surveillance (EOS) characteristics were com-
pared by using the t-test for quantitative variables. Paired t-test was performed to assess the
statistical significance of the differences between baseline and surveillance visits, under each
group separately. A p value <0.05 was considered statistically significant. Overall efficacy,
tolerability and safety data was presented in form frequency, as recorded at the end of sur-
veillance. All analyses were prospectively planned and conducted on an intention-to-treat
(ITT) basis. Patient data loss was kept to a minimum by defining ITT eligibility as any pa-
tient with at least one baseline and one follow-up visit.

Page 45 of 100
 Chapter 6
Data Analysis and Interpretations
Case Study – 1

As shown in Figure 1, 5452 patients were enrolled by 1045 GPs, and 886 of those returned
the therapy documentation (End Form) of 4769 patients (87.5%). This latter sample was
taken to analyze the safety data and is referred to as AE-Sample (Tolerability Events). For the
evaluation of the effect on BP control, all cases with at least one follow-up value were taken
into account. 130 cases of the AE-Sample had no follow-up values; the remaining 4639
subjects (97.3% of the AE-Sample) are referred to as the Efficacy Sample. At the end of the
treatment observation period, after an average of slightly more than 4 months (133 ± 75 days,
mean ± SD), GPs reported that 3829 patients (82.5% of the Efficacy sample) continued the
treatment with Irbesartan 150 mg. This is referred to as the Sample with Ongoing Therapy. A
total of 1419 Compliance Forms MD (37.1% of the sample with ongoing therapy) and 928
Compliance Forms Patient (24.2%) were returned after on average more than 13 months from
baseline (402 ± 105 days). Due to lack of completeness, some forms had to be excluded from
the analysis, giving a total of 1186 valid Compliance Forms MD (31.0%) and 853 cases with
both usable Compliance Form MD and Patient (22.2%).

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Figure 1. Patient population and available data. Summary of the analysis patient
populations of this investigation and of the data available for analysis.

Table 1 summarizes the baseline demographic and clinical data for both the previously
untreated and the pre-treated patients. Almost two thirds of the patients (61,5%) entered the
study receiving another therapy for high blood pressure. The most frequent reasons why GPs
changed pre-treatment to introduce Irbesartan 150 mg were insufficient efficacy of the
previous therapy (64.6%), cough (22.5%) and adverse events other than cough (16.6%). The
multivariate analysis of factors correlated to pre-treatment shows that patients who switched
to Irbesartan 150 mg from other antihypertensive drugs were older, prevalently female and
from the German part of Switzerland (p < 0.001). They had significantly more risk factors,
associated clinical conditions (p < 0.0001) and target organ damages than naïve patients (p =
0.0013). More pre-treated patients received a polytherapy regimen during the post-marketing
surveillance (p < 0.0001).

Baseline demographic and clinical data: Efficacy Sample.

Total 1785 (38.5%) 2854 (61.5%) 4639
Gender (f/m) 882/903 1605/1249 2487/2152
WHO-risk
Mean age ± SD 57.9 ± 12.7 63.6 ± 12.3 61.4 ± 12.8
Low (<15%) 37 (2.1%) 101 (3.5%) 138 (3.0%)
Baseline SBP (Mean
Medium (15–20%) ± SD) 168.8 ± 17.8
837 (46.9%) 163.5 ± 19.1
1190 (41.7%) 165.5 ± 18.8
2027 (43.7%)
Baseline DBP (Mean ± SD) 101.2
High (20–30%) ± 8.6
274 (15.4%) 96.3 ± 10.4
526 (18.4%) 98.2 ± 10.0
800 (17.2%)
Diabetes
Very high (>30%) 165 (35.7%)
637 (9.2%) 492 (17.2%)
1037 (36.3%) 657 (14.2%)
1674 (36.1%)
ISH 79 (4.4%) 408 (14.3%) 487 (10.5%)

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WHO-risk and region categories see results. ISH = isolated systolic hypertension (defined as
≥ 140 mmHg systolic and < 90 mmHg diastolic blood pressure).

Effect on blood pressure

More that 90% of the Efficacy Sample patients received Irbesartan 150 mg 150 mg qd, as a
monotherapy or in combination with other antihypertensives. 69% of the Efficacy Sample
patients received a constant monotherapy and 5.6% a constant polytherapy. In the Efficacy
Sample, the mean reduction of systolic blood pressure (SBP) from baseline to the last visit

was 20.2 ± 19.5 mmHg (p < 0.001). For the diastolic blood pressure (DBP), the mean
reduction was 11.7± 11.3 mmHg (p < 0.001). Figure 2a shows the differences between naïve
and pre-treated patients. Despite previous treatment, the pre-treated group had clearly
inadequate mean baseline values of SBP and DBP (163.5 and 96.3 mmHg, respectively)
justifying a change in therapy. Naïve patients achieved a significantly greater reduction of
both SBP and DBP than pre-treated ones. At the last visit, the pre-treated group showed
higher SBP and similar DBP values in comparison to naïve patients.

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 Fi
gure 2. a. Evolution of blood pressure during observation period (~4 months): Efficacy
Sample. Baseline SBP (systolic blood pressure): previously untreated patients 168.8 mmHg,
pre-treated 163.5 mmHg (*p < 0.0001); SBP at last visit: previously untreated 142.8 mmHg,
pre-treated 146.9 mmHg (p < 0.0001). Baseline DBP (diastolic blood pressure): pre

viously untreated patients 101.2 mmHg, pre-treated 96.3 mmHg (*p < 0.0001); DBP at last
visit: previously untreated 85.9 mmHg, pre-treated 86.8 mmHg (p = 0.004).

b. Reaching of therapeutic targets: Efficacy Sample. Response to treatment is defined as

reaching DBP < 90 mmHg or a reduction of DBP = 10 mmHg. In real-life practice, a
satisfactory objective is also the normalization of DBP (< 90 mmHg). Target = 140/90 mmHg
was introduced because of digit preference of study GPs (see results).

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Since GPs did not receive specific instructions about therapeutic goals in this survey, various
therapeutic targets were used to evaluate the success in controlling blood pressure (Figure
2b). As shown in the figure, one third of the patients had normalized their BP (<140/90
mmHg) and two-thirds had a diastolic BP below 90 mmHg. The Sample with Ongoing
Therapy, as reasonably expected, appeared slightly more successful than the Efficacy Sample
in achieving the various targets (Figure 2b).

Tolerability profile

Adverse events were reported for 383 patients (8.0% of the AE-Sample), more often by older
patients (>65 years: 10.2%; 55–65 years: 7.8%; = 55 years: 5.5%; p < 0.001) and by pre-
treated patients (9.6% vs. 5.5% naïve; p < 0.001). Yet, in the majority of patients (90.7%),
Irbesartan 150 mg was well tolerated according to GPs. Tolerance was reported as poor only
for 131 patients (2.7%). Adverse events led to discontinuation of Irbesartan 150 mg in 343
cases (7.4%). The most frequent side effects are listed in Table 2, where they are compared
with their occurrence listed in the Swiss prescribing information [24]. Serious adverse events,
leading to death, disability, life-threatening conditions or hospitalization, were reported in 74
patients (1,3% of AE-sample), but GPs described a possible or probable connection with trial
medication only in 8 cases. Very good or good tolerance was reported by 824 patients in the
Compliance Form Patient (96.6% of the total), all subgroups scoring above 90%.

Table 2. Most reported adverse events in the AE-Sample (n = 4769) compared to the Swiss
prescribing guidance

AE - Sample Prescribing guidance

Total 383 (8.0%)
Dizziness 65 (1.4%) >1%
Nausea 53 (1.1%) >1%
Headache 43 (0.9%) >1%
Dyspepsia 24 (0.5%) 0.5–1%

Persistence

3829 patients out of 4639 continued the treatment with Irbesartan 150 mg after the last visit
(on average, more than 4 months from the start). The main reasons for discontinuation of the
remaining 810 patients were the occurrence of adverse events and an insufficient efficacy
(figure 3). In a logistic regression model, the factors that correlated more strongly with
ongoing therapy were a reported good tolerance and reaching the a blood pressure ≤ 1

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Figure 3. Ongoing treatment and discontinuation reasons: Efficacy Sample. (n =
4639)Other reasons included: patient moved, blood pressure normalized, break off attempt,
concurrent disease, effect too strong, lost to follow up and others. Multiple answers were
possible.

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Figure 4. Mean (line) and 95% confidence interval (box) for the odds ratio (OR) of the main
variables correlating significantly with ongoing treatment or discontinuation in a logistic
regression model; Efficacy Sample. For detailed explanations see results.

Perception of compliance

Patients with ongoing therapy at last visit were asked in the Compliance Form Patient to
indicate how many Irbesartan 150 mg tablets they took per week during the preceding 3–4
weeks. Since after about one year only 853 patients returned the form, we have to assume a
sampling bias. Nevertheless, some within-group differences are worth mentioning. 777
patients (91.1%) who returned the Compliance Form Patient reported an Irbesartan 150 mg
intake of 6–7 times per week, i.e. more than 80% of the prescribed doses. All subgroups
scored around 90% (Figure 5), but females reported a better compliance than males (92.9%
vs. 89.0%; p = 0.021). Patients with isolated systolic hypertension appear to adhere better to
therapy than other hypertensives (97.2% vs. 90.2%; p = 0.032), while patients with a low risk
for cardiovascular events showed a lower compliance (84%, n.s.). Compliance Forms MD
reported an overall ongoing treatment rate with Irbesartan 150 mg of 88.0% (1044 patients),
and a slightly higher rate for pre-treated patients (90.4%, n = 728)

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Figure 5. Self-reported compliance according to the patient for selected patient subgroups.
Good compliance with treatment after 1 year; Compliance Form Patient (n = 853). Good
compliance is defined as >80% adherence to the prescribed therapeutic regimen. In this case
it means Irbesartan 150 mg intake on 6 or 7 days a week, as reported by the patients. Risk =
WHO risk categories; ISH = isolated systolic hypertension; constant mono-and polytherapy;

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treatment breaks; * = p < 0.05 compared to the rest of the patients.

Case Study – 2

Data was received from a total of 825 patients (from 387 clinics) who participated and re-
ceived treatment with olmesartan 20 mg/day. Out of these 825 patients 139 (16.84%) patients

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were diabetic. Patients were further divided in two sub-groups: Stage 1 hypertensives with
diabetes mellitus. Demography and baseline characteristics are presented in Table 1.

There were significant changes in sitting systolic BP and sitting diastolic BP in overall study
population, from baseline to end of surveillance visit-7, with mean change of -18.7 (147.86 to
129.16; p<.0001; 95% cI) in sitting systolic BP levels and change of -14.47 (95.99 to 81.56;
p<.0001; 95% cI) in sitting diastolic BP, from visit-1 to end of surveillance visit-7. There was
also a significant mean reduction in heart rate of 4.82 (82.14 to 77.32; p<.0001; 95% CI),
from baseline to end of surveillance visit-7.

A similar significant change (p<.0001; 95% CI) of -14.4 and -11.63 in sitting SBP and DBP
respectively, in stage 1 hypertensive patients with diabetes was observed as compared to the
baseline (141.22 and 92.69 mm Hg, SBP & DBP respectively).
The overall “responder rate”, primary end point of study was evaluated for entire study
population and also the four sub-groups. The “responder rate” was defined as achievement of
SBP and DBP levels of < 140 mm Hg and < 90 mmHg respectively at EOS visit, essential
hyptensive (stage-1 or -2) patients and also SBP and DBP levels of < 130 mm Hg and < 80
mmHg respectively

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 Change in sitting SBP from baseline to EOS

Fig. 1: Change in sitting SBP observed in patients treated with olmesartan 20 mg given orally
once daily.

*Indicates a significant (p<0.0001) mean reduction in sitting SBP observed at EOS in

comparison to the baseline sitting SBP;

Page 56 of 100
Page 57 of 100
 Chapter -7

Findings

Case study - 1

Taken together, the data of this postmarketing survey confirm that Irbesartan 150 mg is a well
tolerated and effective antihypertensive agent when used in a real life setting at the dose of
150 mg. More interestingly, our data provide further insights on factors affecting either
positively or negatively the persistence with antihypertensive treatment. In particular, our
observations point out the importance of a good tolerability profile and of achieving a rapid
control of blood pressure in enhancing persistence whereas late changes in treatment and
addition of Irbesartan 150 mg in patients already treated with a fixed-dose combination
appears to be factors promoting a lower persistence.

Prospective observational surveys are not specifically designed to evaluate the

antihypertensive efficacy of a new agent since there is generally no control group and the
treatment schedule is not standardized. Moreover, there may be a selection bias since the
inclusion of patients was not randomised. Nevertheless, this type of survey may provide some
valid information on the antihypertensive effect that may be obtained in real life conditions
i.e. outside the rigorous context of a clinical trial and the rather large number of patients
included certainly limit the effect of a systematic selection bias. In the present case most
patients were treated with a Irbesartan 150 mg tablet per day because this was the dose
recommended at the time the survey was conducted, i.e. soon after the launch of Irbesartan
150 mg in Switzerland. All patient subgroups, but in particular naïve patients, responded
positively to the treatment. In fact, in the group of patients with follow-up values and after a
mean observation time of 4 months, the average reductions in blood pressure were of
comparable magnitude that those obtained in clinical trials and in other post-marketing
surveys. Such a substantial reduction could be achieved in spite of the fact that Irbesartan 150
mg represents the minimal recommended daily dosage nowadays.

Of note, no blood pressure target was pre-defined in our program. Moreover, one should
consider that the reported blood pressure values show a clear digit preference for figures
ending with a 0 or a 5. This reflects the tendency of the GPs to round blood pressure values,
explainable by the wide use of sphygmomanometers. Therefore, the effect on blood pressure
was

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assessed using different criteria. With the generally accepted targets of <140/90 mmHg or a
diastolic BP below 90 mmHg, respectively 26 % and 60% of patients were controlled with
Irbesartan 150 mg. In a more recent survey, in which physicians had the opportunity to use
the higher dose of 300 mg or the combinations of Irbesartan 150 mg or 300 mg with
hydrochlorothiazide 12.5 mg, the percentage of patients with a blood pressure below 140/90
mmHg increases to more than 60% .Looking at sub-populations, older patients and pre-
treated patients had more problems in reaching the therapeutic target chosen for analysis (≤
140/90 mmHg). The same was true for patients with more cardiovascular risk factors, but not
for people with associated clinical conditions – the highest risk factor according to the WHO
1999 guidelines, JNC-7 and ESH-ESC 2003 guidelines – who, on the contrary, reached the
target more easily This observation further emphasize the known difficulty to achieve a good
control of systolic blood pressure particularly in elderly patients with isolated systolic
hypertension. In post-marketing surveys in real life settings, the evaluation of safety is of
great importance. More than 90% of patients tolerated the treatment well or very well
according to their GPs and adverse events were reported by only 8% of them. Serious adverse
events possibly or probably related to Irbesartan 150 mg occurred in less than ten cases. The
patients with more risk factors tolerated Irbesartan 150 mg equally well, despite taking
significantly more drugs. The most frequent adverse events were dizziness, nausea, headache,
dyspepsia and diarrhea, and occurred at the rate described in the Swiss prescribing
information. These data therefore confirm the excellent tolerability profile of angiotensin II
receptor antagonists reported in clinical trials

The main observation of the present survey is the assessment of the factors determining long-
term persistence with the Irbesartan 150 mg treatment in our population. Out of the 4639
patients with complete follow-up data, 82.5% continued to take Irbesartan 150 mg for more
than 4 months. When evaluating factors affecting persistence some interesting observations
were made. The first and expected ones are that a good tolerability profile and the
achievement of a rapid blood pressure control are positively associated with the long-term
persistence with therapy. This finding would therefore encourage the use of well-tolerated
antihypertensive drugs such as angiotensin II receptor antagonists at high doses in order to
obtain a rapid control of blood pressure. It may also favor the use of fixed dose combinations
as first line treatment since these combinations are associated with a low side-effect profile
and an improved efficacy

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A consistent majority of the study population (61.5%) entered the trial after a failed
experience with other antihypertensive drugs. Irbesartan 150 mg proved to be the drug
inducing more persistence in a comparative study with newly-diagnosed patients therefore; it
was also interesting to appraise the persistence rate in pre-treated patients. To our surprise,
patients who switched from a fixed combination treatment tended to discontinue Irbesartan
150 mg more often. On the contrary, patients who abandoned the previous treatment because
of cough (a class side effect of ACE-Inhibitors), tended to stick more to Irbesartan 150 mg.
Moreover, late changes in treatment schedule had a negative impact on persistence whereas
early changes in treatment had a rather favorable impact on persistence. These negative
influences on persistence are probably linked to the increased complexity of the treatment
schedule which is known to impair compliance as well as persistence. Indeed, several
previous studies have demonstrated that drug adherence decreases in proportion with the
complexity of the drug regimen.

In this survey, an attempt was made to obtain information on drug adherence using simplified
questionnaires addressed to the patients and physicians. Unfortunately, only a small
proportion of these questionnaires were filled by the participants. There is therefore a high
probability of bias towards highly compliant patients. Moreover, questionnaires are known to
overestimate drug adherence. Hence it is not surprising that good compliance with the dosing
schedule was reported by more than 90% of the patients after about one year treatment,
meaning that this fraction of the patients reported to have taken Irbesartan 150 mg at least 6
times a week in the preceding 3–4 weeks. Yet, the results of more than 1000 questionnaires
confirm previous observations such as the lower compliance in men and the absence of effect
of age. Indeed, Degoulet at all have also reported thatmale sex is a variable significantly
associated with an increased dropout rate in hypertensive patients attending a hypertension
clinic. Of interest is the observation that patients with a low cardiovascular risk appear to
have a lower compliance whereas those presenting with an isolated systolic hypertension
have a higher compliance. These findings may be related to the patients' perception of their
disease and their degree of concern. Thus, patients with a low cardiovascular risk may be less
motivated to take their medications whereas patients with high systolic blood pressure may
be particularly concerned by their hypertension. In line with this finding, we have found
recently that epileptic patients well controlled under treatment are less compliant than those
experiencing repeated seizures despite treatment .In conclusion; this survey confirms that
Irbesartan 150 mg is a safe and effective antihypertensive drug in clinical practice. A high

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persistence with Irbesartan 150 mg was found in this program which is likely related to the
consistent reduc

tions in blood pressure and the good tolerability profile. This post-marketing survey has also
tend to confirm in a large population of patients that achieving an early control of blood
pressure may be a positive predictor of persistence.

Case study - 2

The analysis of this 8 weeks open-label, real world postmarketing surveillance confirmed the
efficacy and tolerability of olmesartan 20 mg, in the treatment of hypertension. The reduction
in levels of BP, both systolic (mean reduction of 18.71 mmHg) and diastolic (mean reduction
of 14.43 mmHg), achieved in this study are comparable to result previously reported in
randomized controlled clinical trials in hypertensive patients, with same dose of
olmesartan.11-16 The blood pressure lowering effect of olmesartan 20 mg given orally once
daily, were visible within first four weeks of therapy. This was in line with previously
observed early onset BP- lowering effect of olmesartan.

In sub-group analyses of stage 1 hypertensive patients SBP reduction of 18.7 mmHg and
DBP reduction of 14.43 mmHg respectively, were achieved at EOS visit-7 (end of week 8).
Significant results were achieved in stage 1 hypertensive, diabetic population in study. There
was a mean change of -14.4 mmHg and -11.63 in SBP and DBP respectively in diabetic stage
1 hypertensive patients at EOS visit-7 (end of week 8). The decline in level of SBP and DBP
in sub group analyses were significant (p<.0001; 95% CI). Our results confirm efficacy and
safe of olmesartan.

In this real world, postmarketing surveillance, the response rate at the end of study was
81.82% and 70.18% for SBP and DBP respectively, in stage 1 hypertensive patients without
diabetes mellitus. This response rate was approximately similar to previously reported with

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this dose of olmesartan.15, 21 In diabetic Stage 1 hypertensive population, 73.38% and
65.47% patients respectively, achieved primary end point (SBP < 130 mm Hg and DBP < 80
mmHg at EOS). It is known that diabetic patients are at increased risk of cardiovascular dis

ease and olmesartan can play a major role in treating such patients. Olmesartan has shown to
reduce renal vascular resistance and oxidative stress, and increase renal perfusion in addition
to significantly reducing BP, in type-2 diabetic patients. It is evident that intensive control of
BP reduces the mortality and morbidity associated with hypertension and guidelines
havebeen put in place to help physicians in treating patients with hypertension

Olmesartan is a selective AT1 receptor antagonist with proven BP-lowering effect. It has
rapid onset of action, with significant BP lowering effect from 2 weeks onwards.

Extensive clinical evidence from several large well designed trials and the clinical practice
setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olme-
sartan, as monotherapy or in combination with HCTZ, in patients with hypertension, includ-
ing elderly patients with isolated systolic hypertension. Olmesartan appear to be more ef-
fective than older ARBs (e.g. losartan and valsartan) in reducing DBP and/or SBP in some
trials.

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 Chapter 8

Sample Form

Clinical Trial Protocol

INTRODUCTION

Hypertension is a major health problem throughout the world because of its high prevalence
and its association with increased risk of cardiovascular disease. Advances in the diagnosis
and treatment of hypertension have played a major role in recent dramatic declines in
coronary heart disease and stroke mortality in industrialized countries. However, in many of
these countries, the control rates for high blood pressure have actually slowed in the last few
years. It is estimated that by 2010, 1.2 billion people will be suffering from hypertension
worldwide. In the Eastern Mediterranean Region, the prevalence of hypertension averages
26% and it affects approximately 125 million individuals. Of greater concern is that
cardiovascular complications of high blood pressure are on the increase, including the
incidence of stroke, end-stage renal disease and heart failure.
Recent data suggest that individuals who are normotensive at age 55 years have a 90%
lifetime risk for developing hypertension. The relationship between blood pressure and risk
of cerebrovascular disease events is continuous, consistent and independent of other risk
factors. Higher the blood pressure, greater the chance of myocardial infarction, heart failure,
stroke and kidney disease. For individuals aged 40–70 years, each increment of 20 mmHg in
systolic blood pressure (SBP) or 10 mmHg in diastolic blood pressure (DBP) doubles the risk
of cardiovascular disease. These alarming data support a need for greater emphasis on public
awareness of the problem of high blood pressure and for an aggressive approach to
antihypertensive treatment.
The Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure provides a classification of blood pressure for adults aged
≥18 year.
BP classification Systolic BP (mm Hg) Diastolic BP (mm Hg)
Normal <120 <80
Pre-hypertension 120-139 80-89

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 Stage-I hypertension 140-159 90-99
Stage-II hypertension ≥160 ≥100

A more elaborate classification of blood pressure is provided by the European Society of

Hypertension and the European Society of Cardiology (ESH/ESC)
BP classification Systolic BP (mm Hg) Diastolic BP (mm Hg)
Optimal <120 <80
Normal 120-129 80-84
High normal 130-139 85-89
Grade I hypertension (Mild) 140-159 90-99
Grade II hypertension (Moderate) 160-179 100-109
Grade III hypertension (Severe) ≥180 ≥110
Isolated systolic hypertension ≥140 <90

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Case study - 1
Objective(s): An Observational Study on the Efficacy, Safety and Tolerability of Irbesartan
150 mg patients with Hypertension

Irbesartan

Irbesartan is an angiotensin II receptor (AT1 subtype) antagonist. Irbesartan is a non-peptide

compound,

Chemically formula

2-butyl-3-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-1,3- diazaspiro[4.4]non-1-en-4-one.

Empirical formula: C25H28N6O,

Structural formula:

Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a

nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4.
Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in
water.Irbesartan is available for oral administration in unscored tablets containing 75 mg, 150
mg, or 300 mg. Inactive ingredients include: lactose, microcrystalline cellulose,
pregelatinized starch, croscarmellose sodium, poloxamer 188, silicon dioxide and
magnesiumstearate.

INDICATIONS

Hypertension

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AVAPRO is indicated for the treatment of hypertension. It may be used alone or in
combination with other antihypertensive agents.

CONTRAINDICATIONS

AVAPRO is contraindicated in patients who are hypersensitive to any component of this

product.

Mechanism of Action

Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed

by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor
agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and
secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the
sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the
vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to
the AT1 angiotensin II receptor. There is also an AT2 receptor in many tissues, but it is not
involved in cardiovascular homeostasis.

Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity
(more than 8500-fold) for the AT1 receptor than for the AT2 receptor and no agonist activity.

Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin
secretion, but the resulting increased plasma renin activity and circulating angiotensin II do
not overcome the effects of irbesartan on blood pressure.

Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels
known to be involved in the cardiovascular regulation of blood pressure and sodium
homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to
bradykinin; whether this has clinical relevance is not known.

Pharmacokinetics

Irbesartan is an orally active agent that does not require biotransformation into an active
form. The oral absorption of irbesartan is rapid and complete with an average absolute
bioavailability of 60% to 80%. Following oral administration of AVAPRO, peak plasma
concentrations of irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect
the bioavailability of AVAPRO.

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Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.The terminal
elimination half-life of irbesartan averaged 11 to 15 hours. Steadystate concentrations are
achieved within 3 days. Limited accumulation of irbesartan ( < 20%) is observed in plasma
upon repeated once-daily dosing.

Metabolism and Elimination

Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or

intravenous administration of 14C-labeled irbesartan, more than 80% of the circulating
plasma radioactivity is attributable to unchanged irbesartan. The primary circulating
metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The
remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic
activity.

Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either
oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is
recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.

In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan

was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither
metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated
with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition
of 3A4.

Distribution

Irbesartan is 90% bound to serum proteins (primarily albumin and α1-acid glycoprotein) with
negligible binding to cellular components of blood. The average volume of distribution is 53
liters to 93 liters. Total plasma and renal clearances are in the range of 157 mL/min to 176
mL/min and 3.0 mL/min to 3.5 mL/min, respectively. With repetitive dosing, irbesartan
accumulates to no clinically relevant extent.

Studies in animals indicate that radiolabeled irbesartan weakly crosses the bloodbrain barrier
and placenta. Irbesartan is excreted in the milk of lactating rats.

Dose and Dosage form: 150 mg, once daily tablet.

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Route of administration: Oral.

WARNINGS

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity
and death when administered to pregnant women. Several dozen cases have been reported in
the world literature in patients who were taking angiotensinconverting- enzyme inhibitors.
When pregnancy is detected, AVAPRO should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third
trimesters of pregnancy has been associated with fetal and neonatal injury, including
hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and
death. Oligohydramnios has also been reported, presumably resulting from decreased fetal
renal function; oligohydramnios in this setting has been associated with fetal limb
contractures, craniofacial deformation, and hypoplastic lung development. Prematurity,
intrauterine growth retardation, and patent ductus arteriosus have also been reported,
although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has
been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only
during the first trimester should be so informed. Nonetheless, when patients become
pregnant, physicians should have the patient discontinue the use of AVAPRO as soon as
possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug
acting on the renin-angiotensin system will be found. In these rare cases, the mothers should

be apprised of the potential hazards to their fetuses, and serial ultrasound examinations
should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, AVAPRO (irbesartan) should be discontinued unless it is

considered life-saving for the mother. Contraction stress testing (CST), a non-stress test
(NST), or biophysical profiling (BPP) may be appropriate depending upon the week of

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pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not
appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be

closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention
should be directed toward support of blood pressure and renal perfusion. Exchange
transfusion or dialysis may be required as means of reversing hypotension and/or substituting
for disordered renal function.

When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses
of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic
cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses ≥ 50
mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD],
300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at
doses ≥ 180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these
anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and
450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational
effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated
with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times
the MRHD on a body surface area basis) had a slight increase in early resorptions and a
corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in
rats and rabbits.Radioactivity was present in the rat and rabbit fetus during late gestation and
in rat milk following oral doses of radiolabeled irbesartan.

Hypotension in Volume- or Salt-Depleted Patients

Excessive reduction of blood pressure was rarely seen ( < 0.1%) in patients with
uncomplicated hypertension. Initiation of antihypertensive therapy may cause symptomatic
hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients
treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be
corrected prior to administration of AVAPRO, or a low starting dose should be used

If hypotension occurs, the patient should be placed in the supine position and, if necessary,
given an intravenous infusion of normal saline. A transient hypotensive response is not a

Page 69 of 100
contraindication to further treatment, which usually can be continued without difficulty once
the blood pressure has stabilized.

PRECAUTIONS

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal

function may be anticipated in susceptible individuals. In patients whose renal function may
depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe
congestive heart failure), treatment with angiotensinconverting- enzyme inhibitors has been
associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure
and/or death. AVAPRO would be expected to behave similarly.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis,
increases in serum creatinine or BUN have been reported. There has been no known use of
AVAPRO in patients with unilateral or bilateral renal artery stenosis, but a similar effect
should be anticipated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was observed when irbesartan was administered at doses of

up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice
for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic
exposure to irbesartan (AUC0-24 hour, bound plus unbound) about 3 and 11 times, respectively,
the average systemic exposure in humans receiving the maximum recommended dose (MRD)
of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided
an average systemic exposure about 21 times that reported for humans at the MRD. For male
and female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times,
respectively, the human exposure at 300 mg/day.

Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte
DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative
in several tests for induction of chromosomal aberrations (in vitro-human lymphocyte assay;
in vivo-mouse micronucleus study).

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Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses ≤
650 mg/kg/day, the highest dose providing a systemic exposure to irbesartan (AUC 0-24 hour,
bound plus unbound) about 5 times that found in humans receiving the maximum
recommended dose of 300 mg/day.

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters) See
WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Nursing Mothers

It is not known whether irbesartan is excreted in human milk, but irbesartan or some
metabolite of irbesartan is secreted at low concentration in the milk of lactating rats. Because
of the potential for adverse effects on the nursing infant, a decision should be made whether
to discontinue nursing or discontinue the drug, taking into account the importance of the drug
to the mother.

Pediatric Use

Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower
blood pressure effectively in pediatric patients ages 6 to 16 years. AVAPRO (irbesartan) has
not been studied in pediatric patients less than 6 years old.

Geriatric Use

Of 4925 subjects receiving AVAPRO in controlled clinical studies of hypertension, 911

(18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. No overall
differences in effectiveness or safety were observed between these subjects and younger
subjects, but greater sensitivity of some older individuals cannot be ruled out.

Laboratory Test Findings

Hypertension

In controlled clinical trials, clinically important differences in laboratory tests were rarely
associated with administration of AVAPRO.

Page 71 of 100
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum
creatinine were observed in less than 0.7% of patients with essential hypertension treated
with AVAPRO alone versus 0.9% on placebo. (Hematologic: Mean decreases in hemoglobin
of 0.2 g/dL were observed in 0.2% of patients receiving AVAPRO (irbesartan) compared to

0.3% of placebo-treated patients. Neutropenia (< 1000 cells/mm³) occurred at similar

frequencies among patients receiving AVAPRO (0.3%) and placebo-treated patients (0.5%)

DRUG INTERACTIONS

No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been

found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine.

In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites
with the known cytochrome CYP 2C9 substrates/inhibitors sulphenazole, tolbutamide and
nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the
pharmacodynamics of warfarin were negligible. Based on in vitro data, no interaction would
be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes
1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.

In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide,

or digoxin, irbesartan administration for 7 days had no effect on the pharmacodynamics of
warfarin (prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of
irbesartan were not affected by coadministration of nifedipine or hydrochlorothiazide.

SIDE EFFECTS

Hypertension

AVAPRO has been evaluated for safety in more than 4300 patients with hypertension and
about 5000 subjects overall. This experience includes 1303 patients treated for over 6 months
and 407 patients for 1 year or more. Treatment with AVAPRO was well tolerated, with an
incidence of adverse events similar to placebo. These events generally were mild and
transient with no relationship to the dose of AVAPRO.

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In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event
was required in 3.3% of patients treated with AVAPRO, versus 4.5% of patients given
placebo.

In placebo-controlled clinical trials, the following adverse event experiences reported in at

least 1% of patients treated with AVAPRO (n=1965) and at a higher incidence versus placebo
(n=641), excluding those too general to be informative and those not reasonably associated

with the use of drug because they were associated with the condition being treated or are very
common in the treated population, include: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs
1%), and fatigue (4% vs 3%).

The following adverse events occurred at an incidence of 1% or greater in patients treated

with irbesartan, but were at least as frequent or more frequent in patients receiving placebo:
abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza,
musculoskeletal pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality,
tachycardia, and urinary tract infection.

Irbesartan use was not associated with an increased incidence of dry cough, as is typically
associated with ACE inhibitor use. In placebo-controlled studies, the incidence of cough in
irbesartan-treated patients was 2.8% versus 2.7% in patients receiving placebo.

The incidence of hypotension or orthostatic hypotension was low in irbesartantreated patients

(0.4%), unrelated to dosage, and similar to the incidence among placebo-treated patients
(0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in
patients receiving irbesartan compared with placebo.

In addition, the following potentially important events occurred in less than 1% of the 1965
patients and at least 5 patients (0.3%) receiving irbesartan in clinical studies, and those less
frequent, clinically significant events (listed by body system). It cannot be determined
whether these events were causally related to irbesartan:

Body as a Whole: fever, chills, facial edema, upper extremity edema

Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina

pectoris, arrhythmic/conduction disorder, cardio-respiratory arrest, heart failure, hypertensive
crisis

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Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria

Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout

Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention

Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle

ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness

Nervous System: sleep disturbance, numbness, somnolence, emotional disturbance,

depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident

Renal/Genitourinary: abnormal urination, prostate disorder

Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea,

wheezing

Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain,
conjunctivitis, other eye disturbance, eyelid abnormality, ear abnorm

OVERDOSE

No data are available in regard to overdosage in humans. However, daily doses of 900 mg for
8 weeks were well-tolerated. The most likely manifestations of overdosage are expected to be
hypotension and tachycardia; bradycardia might also occur from overdose. Irbesartan is not
removed by hemodialysis.

To obtain up-to-date information about the treatment of overdosage, a good resource is a

certified regional Poison Control Center. Telephone numbers of certified Poison Control
Centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider
the possibilities of multiple-drug interactions, drug-drug interactions, and unusual drug
kinetics in the patient.

Laboratory determinations of serum levels of irbesartan are not widely available, and such
determinations have, in any event, no known established role in the management of irbesartan
overdose.

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Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were
in excess of 2000 mg/kg, about 25- and 50-fold the maximum recommended human dose
(300 mg) on a mg/m² basis, respectively.

STORAGE: Store at room temperature between 59 and 86 degrees F (15 to 30 degrees C)

away from light and moisture. Do not store in the bathroom. Keep all medicines away from
children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so.
Properly discard this product when it is expired or no longer needed. Consult your pharmacist
or local waste disposal company for more details about how to safely discard your product.

Design

The general practitioners (GPs) were asked to document their daily routine in the treatment of
hypertensive patients with Irbesartan 150 mg; 1390 physicians were contacted, 1045 included
patients and 886 documented the treatment. It consisted of an 8 week surveillance period
divided into six consecutive visits. Visit-1 (on day 1) included screening, enrollment and
initiation of treatment. Visits 2, 3, 4 and 5 were scheduled at end of week 1, 2, 3 and 4
respectively. Subsequent visits 6 and 7 were scheduled alternatively at end of week 6 and 8
respectively. They were asked to document two arterial blood pressure measurements at
every visit and to report concomitant antihypertensive medication and adverse events, as well
as changes or discontinuation of treatment.

Patient selection

All patients with newly diagnosed hypertension, or with treated hypertension requiring a
change in medication according to the GP, were considered for the survey. No standardized
definition was used but physicians considered a BP >140/90 mmHg as hypertension. There
were neither demographic nor clinical exclusion criteria. The only condition to participate
was that patients should not have been pre-treated with Irbesartan 150 mg. Treatment was
started with Irbesartan 150 mg. Thereafter, physicians were free to change the
antihypertensive therapy at any time during the follow-up based on their individual
therapeutic goals (usually <140/90 mmHg).

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Inclusion criteria:

1. Patients having age between 18-70 years.

2. Patients having a BP >140/90 mmHg as hypertension
3. The manual cuff value is calculated as a supine measurement, after the patient has
been seated quietly for 5 minutes.
4. Ability to provide written informed consent.
5. Ability to change the antihypertensive therapy at any time without risk to the patient
(investigators discretion).

Exclusion criteria:
1. Patients should not have been pre-treated with Irbesartan 150 mg.
2. History of chronic smoking, alcohol, barbiturate and narcotics.
3. Congestive heart failure within last six months.
4. Unstable angina within the past three months.
5. Stroke within the past six months.
6. Myocardial infarction or cardiac surgery within the past three monthsPatient
participated in another clinical trial within six months

Statistical analysis

Values are presented as mean +/- sd. The statistical significance of between-group differences
was computed using the 2-sided Chi-square test, the Mann-Whitney-U test or ANOVA
methods as appropriate. For multivariate correlations, a logistic regression analysis with a
dichotomous dependent variable was used (e.g. therapy discontinuation: yes = 1; no = 0). To
support the results of the logistic regression models, Cox regression models with cumulative
survival functions were further computed.

Page 76 of 100
Case study - 2

Objective(s): To assess the efficacy and safety of once daily olmesartan medoxomil 20 mg in
Indian patients with stage 1 essential hypertension.

Benicar (olmesartan medoxomil),

Benicar (olmesartan medoxomil), a prodrug, is hydrolyzed to olmesartan during absorption

from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor
antagonist.

Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-

methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic
2,3-carbonate.

Its empirical formula is C29H30N6O6 and its structural formula is:

Page 77 of 100
Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with
a molecular weight of 558.59. It is practically insoluble in water and sparingly soluble in
methanol. Benicar is available for oral use as film-coated tablets containing 5 mg, 20 mg, or
40 mg of olmesartan medoxomil and the following inactive ingredients:
hydroxypropylcellulose, lactose, low-substituted hydroxypropylcellulose, magnesium
stearate, microcrystalline cellulose, talc, titanium dioxide, and (5 mg only) yellow iron oxide.

INDICATIONS

Benicar is indicated for the treatment of hypertension. It may be used alone or in combination
with other antihypertensive agents.

CONTRAINDICATIONS

Benicar is contraindicated in patients who are hypersensitive to any component of this

product.

CLINICAL PHARMACOLOGY

Mechansim of action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting

enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-
angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and
release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan
blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of
angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore,
independent of the pathways for angiotensin II synthesis.

An AT2 receptor is found also in many tissues, but this receptor is not known to be associated
with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for
the AT1 receptor than for the AT2 receptor.

Page 78 of 100
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis
of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat
hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also
catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE (kininase II), it does
not affect the response to bradykinin. Whether this difference has clinical relevance is not yet
known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of

angiotensin II on renin secretion, but the resulting increased plasma renin activity and
circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

Pharmacokinetics

General

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to

olmesartan during absorption from the gastrointestinal tract. Olmesartan appears to be
eliminated in a biphasic manner with a terminal elimination half-life of approximately 13
hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg
and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within
3 to 5 days and no accumulation in plasma occurs with once-daily dosing.

The absolute bioavailability of olmesartan is approximately 26%. After oral administration,

the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does
not affect the bioavailability of olmesartan.

Metabolism and Excretion

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during
absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of
olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the
absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.

Distribution

Page 79 of 100
The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound
to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is
constant at plasma olmesartan concentrations well above the range achieved with
recommended doses.

In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across
the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to
milk at low levels in rats.

Dose and Dosage form: 20 mg, once daily tablet.

Route of administration: Oral.

WARNINGS

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity
and death when administered to pregnant women. Several dozen cases have been reported in
the world literature of patients who were taking angiotensin converting enzyme inhibitors.
When pregnancy is detected, Benicar should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third
trimesters of pregnancy has been associated with fetal and neonatal injury, including
hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and
death. Oligohydramnios has also been reported, presumably resulting from decreased fetal
function; oligohydramnios in this setting has been associated with fetal limb contractures,
craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth
retardation and patent ductus arteriosus have also been reported, although it is not clear
whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has
been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an
angiotensin II receptor antagonist only during the first trimester should be so informed.

Page 80 of 100
Nonetheless, when patients become pregnant, physicians should have the patient discontinue
the use of Benicar as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug
acting on the renin-angiotensin system will be found. In these rare cases, the mothers should
be apprised of the potential hazards to their fetuses and serial ultrasound examinations should
be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Benicar should be discontinued unless it is considered life-

saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the
fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be

closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention

should be directed toward support of blood pressure and renal perfusion. Exchange
transfusion or dialysis may be required as means of reversing hypotension and/or substituting
for disordered renal function.

There is no clinical experience with the use of Benicar in pregnant women. No teratogenic
effects were observed when olmesartan medoxomil was administered to pregnant rats at oral
doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [MRHD] of
olmesartan medoxomil on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day
(half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal
development as they were lethal to the does). In rats, significant decreases in pup birth weight
and weight gain were observed at doses ≥ 1.6 mg/kg/day, and delays in developmental
milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of
abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in
the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. The no
observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the
MRHD of 40 mg/day.

Hypotension in Volume- or Salt-Depleted Patients

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In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted
patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may
occur after initiation of treatment with Benicar. Treatment should start under close medical
supervision. If hypotension does occur, the patient should be placed in the supine position
and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive
response is not a contraindication to further treatment, which usually can be continued
without difficulty once the blood pressure has stabilized.

PRECAUTIONS

General

Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone

system, changes in renal function may be anticipated in susceptible individuals treated with
olmesartan medoxomil. In patients whose renal function may depend upon the activity of the
renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure),

treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists
has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal
failure and/or death. Similar results may be anticipated in patients treated with olmesartan
medoxomil. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery
stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported.
There has been no long-term use of olmesartan medoxomil in patients with unilateral or
bilateral renal artery stenosis, but similar results may be expected.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Olmesartan medoxomil was not carcinogenic when administered by dietary administration to

rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m 2 basis, about
480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two
carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout
mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of
up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic
effect of olmesartan medoxomil.

Page 82 of 100
Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster
embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames
(bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations
in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase
mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in
vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse
bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).

Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as

high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2
(female) or 9 (male) weeks prior to mating.

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters).

It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at
low concentration in the milk of lactating rats. Because of the potential for adverse effects on

the nursing infant, a decision should be made whether to discontinue nursing or discontinue
the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of hypertensive patients receiving Benicar in clinical studies, more than
20% were 65 years of age and over, while more than 5% were 75 years of age and older. No
overall differences in effectiveness or safety were observed between elderly patients and
younger patients. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.

Laboratory Test Findings: In controlled clinical trials, clinically important changes in

standard laboratory parameters were rarely associated with administration of olmesartan
medoxomil.Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit

Page 83 of 100
(mean decreases of approximately 0.3 g/dL and 0.3 volume percent, respectively) were
observed.
Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin were observed
infrequently. Five patients (0.1%) assigned to olmesartan medoxomil and one patient (0.2%)
assigned to placebo in clinical trials were withdrawn because of abnormal liver chemistries
(transaminases or total bilirubin). Of the five olmesartan medoxomil patients, three had
elevated transaminases, which were attributed to alcohol use, and one had a single elevated
bilirubin value, which normalized while treatment continue

DRUG INTERACTIONS

No significant drug interactions were reported in studies in which olmesartan medoxomil was
co-administered with digoxin or warfarin in healthy volunteers. The bioavailability of
olmesartan was not significantly altered by the co-administration of antacids
[Al(OH)3/Mg(OH)2]. Olmesartan medoxomil is not metabolized by the cytochrome P450
system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce
or are metabolized by those enzymes are not expected.

SIDE EFFECTS

Benicar has been evaluated for safety in more than 3825 patients/subjects, including more
than 3275 patients treated for hypertension in controlled trials. This experience included
about 900 patients treated for at least 6 months and more than 525 for at least 1 year.
Treatment with Benicar was well tolerated, with an incidence of adverse events similar to
placebo. Events generally were mild, transient and had no relationship to the dose of
olmesartan medoxomil.

The overall frequency of adverse events was not dose-related. Analysis of gender, age and
race groups demonstrated no differences between olmesartan medoxomil and placebo-treated
patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients
was 2.4% (i.e. 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e.
32/1179) of control patients. In placebo-controlled trials, the only adverse event that occurred
in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence
versus placebo was dizziness (3% vs. 1%).

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The following adverse events occurred in placebo-controlled clinical trials at an incidence of
more than 1% of patients treated with olmesartan medoxomil, but also occurred at about the
same or greater incidence in patients receiving placebo: back pain, bronchitis, creatine
phosphokinase increased, diarrhea, headache, hematuria, hyperglycemia,
hypertriglyceridemia, influenza-like symptoms, pharyngitis, rhinitis and sinusitis.

The incidence of cough was similar in placebo (0.7%) and Benicar (0.9%) patients.

Other (potentially important) adverse events that have been reported with an incidence of
greater than 0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive
patients treated with olmesartan medoxomil monotherapy in controlled or open-label trials
are listed below.

Facial edema was reported in 5 patients receiving olmesartan medoxomil. Angioedema has
been reported with angiotensin II antagonists.

OVERDOSE

Limited data are available related to overdosage in humans. The most likely manifestations of
overdosage would be hypotension and tachycardia; bradycardia could be encountered if para

sympathetic (vagal) stimulation occurs. If symptomatic hypotension should occur, supportive

treatment should be initiated. The dialyzability of olmesartan is unknown.

Study Design The surveillance was conducted as a multicentre (387 clinics all over India),
open label, post marketing real world surveillance. It consisted of an 8 week surveillance
period divided into six consecutive visits. Visit-1 (on day 1) included screening, enrollment
and initiation of treatment. Visits 2, 3, 4 and 5 were scheduled at end of week 1, 2, 3 and 4
respectively. Subsequent visits 6 and 7 were scheduled alternatively at end of week 6 and 8
respectively.

Inclusion criteria:

1. Age between 18 to 65 years old

2. Patients of either gender.

3. Ability to provide written informed consent.

Page 85 of 100
 4. Patients who had clinically diagnosed stage 1 hypertension (JNC-7 guidelines).

5. Patients with sitting SBP in the range of 140-159 mm Hg, sitting DBP in the range of
90- 99 mm Hg

Exclusion criteria:

1. History of chronic smoking, alcohol, barbiturate and narcotics.

2. Congestive heart failure within last six months.
3. Unstable angina within the past three months.
4. Stroke within the past six months.
5. Myocardial infarction or cardiac surgery within the past three months.
6. Patient participated in another clinical trial within six months

Statistical Analysis

The data processing was performed by capturing data into e-Case Report Forms. Data
entered was checked by design for completeness and integrity. Demographic data was
presented as descriptive statistics and baseline and end of surveillance (EOS)
characteristics were compared by using the t-test for quantitative variables. Paired t-test
was performed to assess the statistical significance of the differences between baseline
and surveillance visits, under each group separately. A p value <0.05 was considered
statistically signify

cant. Overall efficacy, tolerability and safety data was presented in form frequency, as
recorded at the end of surveillance. All analyses were prospectively planned and
conducted on an intention-to-treat (ITT) basis. Patient data loss was kept to a minimum
by defining ITT eligibility as any patient with at least one baseline and one follow-up
visit.

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 CASE REPORT FORM

Case study - 1

An Observational Study on the Efficacy, Safety and Tolerability

of Irbesartan 150 mg patients with Hypertension

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Investigator Name:

Address:

Patient's Initials:

Patient's No:

Visit 1 / Week 0

Date:

Personal Information:

Age: Years

Sex: Male Female

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Weight (kg):

Height (cm):

Hypertension History:

Newly diagnosed

Yes No

Date of diagnosis:

Prior treatment

YES NO
6 months
6-12 months
1-5 years
> 5 years

Severity of Hypertension:

Stage 1 Stage 2 Stage 3

Concomitant Disease Yes No

Coronary Artery Disease
Cerebrovascular Disease
Left Ventricular Hypertrophy
Congestive Heart Failure
Diabetes Mellitus
Peripheral Vascular Disease
Renal Impairment
Chronic Respiratory Disease
Dyslipidemia
Family History of Atherosclerosis or HTN
Smoking

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Current Medications:

Disease Medication

Current Antihypertensive Medications:

Yes No

* If yes:

Diuretic ______________________________________________

ACEI ________________________________________________

Beta Blocker __________________________________________

Calcium Channel Blocker _______________________________

Others ______________________________________________

Vital Signs:

Sitting Pulse Rate: / min

SBP DBP
Sitting Blood Pressure (mmHg)

Signature of Investigator Date

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 Visit 2 / Week 1

Date:

Vital Signs:

Sitting Pulse Rate / min

SBP DBP
Sitting Blood Pressure (mmHg)

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Premature Drug Discontinuation:

Yes No

* If yes please write below why:

________________________________________________________
________________________________________________________
________________________________________________________

Adverse Events

Yes No

* If yes please refer to the Adverse Events report form.

Blood Pressure Controlled (SBP < 140 & DBP < 90)

Yes No

* If no what measures are taken

____________________________________________________
____________________________________________________
____________________________________________________

Signature of Investigator Date

Visit 3 / Week 2

Date:

Vital Signs:

Sitting Pulse Rate: / min

Sitting Blood Pressure (mmHg) SBP DBP

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Premature Drug Discontinuation:

Yes No

* If yes please write below why:

________________________________________________________
________________________________________________________
________________________________________________________

Adverse Event

Yes No

* If yes please refer to the Adverse Events report form.

Blood Pressure Controlled (SBP < 140 & DBP < 90)

Yes No

* If no what measures are taken

______________________________________________________
______________________________________________________
______________________________________________________

Signature of Investigator Date

Visit 4 / Week 3

Date:

Vital Signs:

Sitting Pulse Rate: / min

Sitting Blood Pressure (mmHg) SBP DBP

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Premature Drug Discontinuation:

Yes No

* If yes please write below why:

________________________________________________________
________________________________________________________
________________________________________________________

Adverse Event

Yes No

* If yes please refer to the Adverse Events report form.

Blood Pressure Controlled (SBP < 140 & DBP < 90)

Yes No

* If no what measures are taken

______________________________________________________
______________________________________________________
______________________________________________________

Signature of Investigator Date

Visit 5 / Week 4

Date:

Vital Signs:

Sitting Pulse Rate: / min

Sitting Blood Pressure (mmHg) SBP DBP

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Premature Drug Discontinuation:

Yes No

* If yes please write below why:

________________________________________________________
________________________________________________________
________________________________________________________

Adverse Event

Yes No

* If yes please refer to the Adverse Events report form.

Blood Pressure Controlled (SBP < 140 & DBP < 90)

Yes No

* If no what measures are taken

______________________________________________________
______________________________________________________
______________________________________________________

Signature of Investigator Date

Visit 6 / Week 6

Date:

Vital Signs:

Sitting Pulse Rate: / min

Sitting Blood Pressure (mmHg) SBP DBP

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Premature Drug Discontinuation:

Yes No

* If yes please write below why:

________________________________________________________
________________________________________________________
________________________________________________________

Adverse Event

Yes No

* If yes please refer to the Adverse Events report form.

Blood Pressure Controlled (SBP < 140 & DBP < 90)

Yes No

* If no what measures are taken

______________________________________________________
______________________________________________________
______________________________________________________

Signature of Investigator Date

Visit 7 / Week 8

Date:

Vital Signs:

Sitting Pulse Rate: / min

Sitting Blood Pressure (mmHg) SBP DBP

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Premature Drug Discontinuation:

Yes No

* If yes please write below why:

________________________________________________________
________________________________________________________
________________________________________________________

Adverse Event

Yes No

* If yes please refer to the Adverse Events report form.

Blood Pressure Controlled (SBP < 140 & DBP < 90)

Yes No

* If no what measures are taken

______________________________________________________
______________________________________________________
______________________________________________________

Signature of Investigator Date

Off Study Form

Date: Last study drug consumed on:

Reason for Off Study

Completed study Treatment non-responder
AE/SAE Protocol non-compliance
Lost to follow-up Concomitant medication
Withdraw consent Death
Other
Comments:

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________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
____________________________________________

Investigator comment on outcome of trial

________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________
________________________________________________________________

Signature of Investigator: Date:

Global Overall Assessments

A. Tolerability and Safety

Excellent : No adverse even

Good : Mild adverse events

Fair : Moderate adverse events

Poor : Severe adverse events and drug discontinuation

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B. Efficacy {Response}

Excellent DBP < 85 mmHg

Good DBP 85-89 mmHg

Fair DBP 90-99 mmHg

Poor DBP > 99 mmHg

C. Controlled:

Yes (SBP < 140 and DBP < 90 mmHg)

No (SBP > 140 and/or DBP > 90 mmHg)

Signature of Investigator Date

References

1. Gupta R. Meta-analysis of prevalence of hypertension in India. Indian Heart J 1997;

49: 43-8
2. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and
treatment. J Am Med Assoc 1996; 275: 1571-6
3. Reddy S. Regional Case Studies – India. Nestle Nutr Workshop Ser Pediatr Program.
2009;63:15-24
4. Das SK, Sanyal K, Basu A. Study of urban community survey in India: growing
trend of high prevalence of hypertension in a developing country. Int J Med Sci
2005; 2: 70-78

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5. Gupta R; Trends in hypertension epidemiology in India. J Hum Hypertens 2004 Feb;
18(2): 73-8.
6. a-analysis of prevalence of hypertension in India. Indian Heart J 1997; 49: 43-8
7. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and
treatment. J Am Med Assoc 1996; 275: 1571-6
8. Reddy S. Regional Case Studies – India. Nestle Nutr Workshop Ser Pediatr Program.
2009;63:15-24
9. Das SK, Sanyal K, Basu A. Study of urban community survey in India: growing
trend of high prevalence of hypertension in a developing country. Int J Med Sci
2005; 2: 70-78
10. Gupta R; Trends in hypertension epidemiology in India. J Hum Hypertens 2004 Feb;
18(2): 73-8.
11. Hathial M. Blood pressure control among Indians with hypertension: the I-Target
survey. J Indian Med Assoc 2007 Jul; 105: 401-2
12. Cohn JN, Tognoni G: A randomized trial of the angiotensin-receptor blocker
valsartan in chronic heart failure.
13. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL,
Olofsson B, Ostergren J, Yusuf S, Pocock S: CHARM Investigators and Committees
14. http://www.rxlist.com/avalide-drug.htm

15. www.fas.org/ota/reports/8220.pdf

16. http://www.journalclub.org/2004/11/27/n26

17. http://203.90.70.117/PDS_DOCS/B0647.pdf

18. www.docstoc.com/docs/4504470/CIOMS-Form

19. www.fda.gov

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