MBA Project - Importance of Post Marketing Survelliance in Clinical Research

8/8/2019 MBA Project - Importance of Post Marketing Survelliance in Clinical Research

1/103

Page 1 of102

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.


2/103

Page 2 of102

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 ExaminerInternal External

Date: 30th September 2010

Place: Mumbai University Seal


3/103

Page 3 of102

CE T CATE

This isto certify that Mr. Harshad K More MB Student of Til

i i has successfully completed their project

work for award of g B i Admi i i

He has done the project on mportance of Post Marketing Sur-

veillance in Clinical Research

Designation:-

Signature:-

Center For Advancementin Health Sciences

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

Tel: + 919820506932. Telefax: +912224140224

Email:[email protected]


4/103


5/103

Page 5 of102

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 methodolo y. 38

6. Data Analysis and Interpretation 46

7. Findin s 56

8 Sample Form 61

10. References 97


6/103


7/103


8/103

Page 8 of102

ters. An Approval Lettersignifies 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 Lettersignifies that the application substantially complies with the require-

ments 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 respondwithin 10 days of receipt. At this point, the sponsor may amend the application and address

the agencys concerns, request a hearing with the agency, or withdraw the application entire-

ly.

ORGANISATION OF THE COMMON TECHNICAL DOCUMENT FOR THE REGIS-

TRATION OF PHARMACEUTICALS FORHUMAN USE

Module 1. Administrative Information and Prescribin Information

This module should contain documents s pecific to each region; for example, application

forms or the proposed label foruse 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 Summaries2.3 : QUALITY OVERALL SUMMARY (QOS)

INTRODUCTION

2.3.S DRUGSUBSTANCE(NAME,MANUFACTURER)

2.3.S.1 General Information (name, manufacturer)

2.3.S.2 Manufacture (name, manufacturer)

2.3.S.3 Characterisation (name, manufacturer)

2.3.S.4 Control of Drug Substance (name, manufacturer)

2.3.S.5 Reference Standards orMaterials (name, manufacturer)

2.3.S.6 Container Closure System (name, manufacturer)

2.3.S.7 Stability (name, manufacturer)

2.3.P DRUGPRODUCT(NAME,DOSAGEFORM)

2.3.P.1 Description and Composition of the Drug Product (name, dosage form)


9/103

Page 9 of102

2.3.P.2 Pharmaceutical Development (name, dosage form)

2.3.P.3 Manufacture (name, dosage form)

2.3.P.4 Control of Excipients (name, dosage form)

2.3.P.5 Control of Drug Product (name, dosage form)

2.3.P.6 Reference Standards orMaterials (name, dosage form)

2.3.P.7 Container Closure System (name, dosage form)2.3.P.8 Stability (name, dosage form)

2.3.A APPENDICES

2.3.A.1 Facilities and Equipment (name, manufacturer)

2.3.A.2 Adventitious Agents Safety Evaluation (name, dosage form, manufacturer)

2.3.A.3 Excipients

2.3.R REGIONALINFORMATION

2.4 NONCLINICAL OVERVIEW

General Aspects

Content and Structural Format

2.5: CLINICAL OVERVIEW

Preamble

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

Introduction

General Presentation Issues


10/103

Page 10 of102

2.6.1 Introduction

2.6.2 Pharmacology Written Summary

2.6.2.1 Brief Summary

2.6.2.2 Primary Pharmacodynamics

2.6.2.3 Secondary Pharmacodynamics

2.6.2.4 Safety Pharmacology

2.6.2.5 Pharmacodynamic Drug Interactions

2.6.2.6 Discussion and Conclusions

2.6.2.7 Tables and Figures

2.6.3 Pharmacology Tabulated Summary (see Appendix B)

2.6.4 Pharmacokinetics Written Summary


2.6.4.2 Methods of Analysis

2.6.4.3 Absorption

2.6.4.4 Distribution

2.6.4.5 Metabolism (interspecies comparison)

2.6.4.6 Excretion

2.6.4.7 Pharmacokinetic Drug Interactions

2.6.4.8 Other Pharmacokinetic Studies



2.6.5 Pharmacokinetics Tabulated Summary (see Appendix B)

2.6.6 Toxicology Written Summary


2.6.6.2 Single-Dose Toxicity

2.6.6.3 Repeat-Dose Toxicity (including supportive toxico kinetics evaluation)

2.6.6.4 Genotoxicity


11/103

Page 11 of102

2.6.6.5 Carcinogenicity (including supportive toxico kinetics evaluations)

2.6.6.6 Reproductive and Developmental Toxicity

2.6.6.7 Local Tolerance

2.6.6.8 Other Toxicity Studies (if available)



2.6.7 Toxicology Tabulated Summary (see Appendix B)2.7: CLINICALSUMMARY

PreambleTable of ContentsDetailed Guidance on Sections of the Clinical Summary

2.7.1 Summary of Biopharmaceutic Studies and Associated AnalyticalMethods

2.7.1.1 Background and Overview

2.7.1.2 Summary of Results of Individual Studies

2.7.1.3 Comparison and Analyses of Results Across Studies

2.7.1.4 Appendix

2.7.2 Summary of Clinical Pharmacology Studies

2.7.2.1 Background and Overview



2.7.2.4 Special Studies

2.7.2.5 Appendix

2.7.3 Summary of Clinical Efficacy

2.7.3.1 Background and Overview of Clinical Efficacy



2.7.3.3.1 Study Populations

2.7.3.3.2 Comparison of Efficacy Results of all Studies


12/103

Page 12 of102

2.7.3.3.3 Comparison of Results in Sub-populations

2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations

2.7.3.5 Persistence of Efficacy and/or Tolerance Effects

2.7.3.6 Appendix

2.7.4 Summary of Clinical Safety

2.7.4.1 Exposure to the Drug

2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies

2.7.4.1.2 Overall Extent of Exposure

2.7.4.1.3 Demographic and Other Characteristics of Study Population

2.7.4.2 Adverse Events

2.7.4.2.1 Analysis of Adverse Events

2.7.4.2.2 Narratives

2.7.4.3 Clinical Laboratory Evaluations

2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety

2.7.4.5 Safety in Special Groups and Situations

2.7.4.5.1 Intrinsic Factors

2.7.4.5.2 Extrinsic Factors

2.7.4.5.3 Drug Interactions

2.7.4.5.4 Use in Pregnancy and Lactation

2.7.4.5.5 Overdose

2.7.4.5.6 Drug Abuse

2.7.4.5.7 Withdrawal and Rebound

2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of

Mental Ability

2.7.4.6 Post-marketing Data

2.7.4.7 Appendix

2.7.5 Literature References

2.7.6 Synopses of Individual Studies


13/103

Page 13 of102

Module 3 : Quality

3.1. TABLEOFCONTENTSOFMODULE3

3.2. BODYOFDATA

3.2.S DRUGSUBSTANCE(NAME,MANUFACTURER)

3.2.S.1 General Information (name, manufacturer)

3.2.S.1.1 Nomenclature (name, manufacturer)

3.2.S.1.2 Structure (name, manufacturer)

3.2.S.1.3 General Properties (name, manufacturer)

3.2.S.2 Manufacture (name, manufacturer)

3.2.S.2.1 Manufacturer(s) (name, manufacturer)

3.2.S.2.2 Description ofManufacturing Process and Process Controls

3.2.S.2.3 Control ofMaterials (name, manufacturer)

3.2.S.2.4 Controls of Critical Steps and Intermediates (name, manufacturer)

3.2.S.2.5 Process Validation and/or Evaluation (name, manufacturer)

3.2.S.2.6 Manufacturing Process Development (name, manufacturer)

3.2.S.3 Characterisation (name, manufacturer)

3.2.S.3.1 Elucidation of Structure and other Characteristics (name, manufacturer)

Error! Bookmark not defined.

3.2.S.3.2 Impurities (name, manufacturer)

3.2.S.4 Control of Drug Substance (name, manufacturer)

3.2.S.4.1 Specification (name, manufacturer) Error! Bookmark not defined.

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

3.2.S.4.3 Validation of Analytical Procedures (name, manufacturer) Error!

Bookmark not defined.

3.2.S.4.4 Batch Analyses (name, manufacturer)

3.2.S.4.5 Justification of Specification (name, manufacturer)

3.2.S.5 Reference Standards orMaterials (name, manufacturer)

3.2.S.6 Container Closure System (name, manufacturer)

3.2.S.7 Stability (name, manufacturer)


14/103

Page 14 of102

3.2.S.7.1 Stability Summary and Conclusions (name, manufacturer) Error!

Bookmark not defined.

3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment

3.2.S.7.3 Stability Data (name, manufacturer)

3.2.P DRUGPRODUCT(NAME,DOSAGEFORM)

3.2.P.1 Description and Composition of the Drug Product (name, dosage form)

3.2.P.2 Pharmaceutical Development (name, dosage form)

3.2.P.2.1 Components of the 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 Drug Product (name, dosage form)

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

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.2.3 Manufacturing Process Development (name, dosage form)

3.2.P.2.4 Container Closure System (name, dosage form)

3.2.P.2.5 Microbiological Attributes (name, dosage form)

3.2.P.2.6 Compatibility (name, dosage form)

3.2.P.3 Manufacture (name, dosage form)

3.2.P.3.1 Manufacturer(s) (name, dosage form)

3.2.P.3.2 Batch Formula (name, dosage form)

3.2.P.3.3 Description ofManufacturing Process and Process Controls

3.2.P.3.4 Controls of Critical Steps and Intermediates (name, dosage form)

3.2.P.3.5 Process Validation and/or Evaluation (name, dosage form)

3.2.P.4 Control of Excipients (name, dosage form)

3.2.P.4.1 Specifications (name, dosage form)

3.2.P.4.2 Analytical Procedures (name, dosage form)


15/103

Page 15 of102

3.2.P.4.3 Validation of Analytical Procedures (name, dosage form)

3.2.P.4.4 Justification of Specifications (name, dosage form)

3.2.P.4.5 Excipients of Human or Animal Origin (name, dosage form)

3.2.P.4.6 Novel Excipients (name, dosage form)

3.2.P.5 Control of Drug Product (name, dosage form)

3.2.P.5.1 Specification(s) (name, dosage form)Error! Bookmark not defined.

3.2.P.5.2 Analytical Procedures (name, dosage form)

3.2.P.5.3 Validation of Analytical Procedures (name, dosage form)

3.2.P.5.4 Batch Analyses (name, dosage form)

3.2.P.5.5 Characterisation of Impurities (name, dosage form)

3.2.P.5.6 Justification of Specification(s) (name, dosage form)

3.2.P.6 Reference Standards orMaterials (name, dosage form)

3.2.P.7 Container Closure System (name, dosage form)

3.2.P.8 Stability (name, dosage form)

3.2.P.8.1 Stability Summary and Conclusion (name, dosage form)

3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment

3.2.P.8.3 Stability Data (name, dosage form)

3.2.A APPENDICES

3.2.A.1 Facilities and Equipment (name, manufacturer)

3.2.A.2 Adventitious Agents Safety Evaluation (name, dosage form)

3.2.A.3 Excipient

3.2.R REGIONALINFORMATION

3.3 LITERATURE REFERENCES

Module 4: Nonclinical Study Reports

4.1 Table of Contents ofModule 44.2 Study Reports4.3 Literature ReferencesAppendix A

Examples of Tables and Figures for Written Summaries


16/103

Page 16 of102

Appendix B

The Nonclinical Tabulated Summaries - Templates

Appendix C

THE NONCLINICAL TABULATED SUMMARIES -EXAMPLES

MODULE5:CLINICALSTUDYREPORTS

Preamble

Detailed Organisation of Clinical Study Reports and Related Information

5.1 Table of Contents ofModule 5

5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports

5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports

5.3.1.3 In Vitro In Vivo Correlation Study Reports

5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies

5.3.2 ReportsofStudiesPertinenttoPharmacokineticsUsingHuman Biomaterials5.3.2.1 Plasma Protein Binding Study Reports

5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies

5.3.2.3 Reports of Studies Using Other Human Biomaterials

5.3.3 Reports of Human Pharmacokinetic (PK) Studies5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports

5.3.3.2 Patient PK and Initial Tolerability Study Reports

5.3.3.3 Intrinsic Factor PK Study Reports

5.3.3.4 Extrinsic Factor PK Study Reports

5.3.3.5 Population PK Study Reports

5.3.4 Reports of Human Pharmacodynamic (PD) Studies


17/103

Page 17 of102

5.3.4.1 Healthy Subject PD and PK/PD Study Reports

5.3.4.2 Patient PD and PK/PD Study Reports

5.3.5 Reports of Efficacy and Safety Studies

5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed

Indication

5.3.5.2 Study Reports of Uncontrolled Clinical Studies

5.3.5.3 Reports of Analyses of Data from More than One Study

5.3.5.4 Other Study Reports

5.3.6 Reports of Post-Marketing Experience

5.3.7 Case Report Forms and Individual Patient Listings

5.4 LITERATURE REFERENCES


18/103

Page 18 of102

Dru Approval Process (INDIA)

APPENDIX I

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

Massspectrum

NMRspectra

IRspectra

UV spectra

Polymorphic identification

2.4. Complete monograph specification including


19/103

Page 19 of102

Identification

Identity/quantification of impurities

Enantiomeric purity

Assay

2.5. ValidationsAssay method

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 FormulationDosage 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 sta-


20/103

Page 20 of102

bility 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 actions3.3. General pharmacological actions

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 Study4.4. 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 ofsites and Investigators.


21/103

Page 21 of102

8. Special studies

8.1. Summary

8.2. Bio-availability / Bio-equivalence.

8.3 Otherstudies e.g. geriatrics, paediatrics, pregnant or nursing women

9. Regulatory status in other countries

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 de-

velopment to the trial closure should be given here. Thissection will only summar-

ize the important conclusions derived from the study.


22/103

Page 22 of102

. a emen o comp ance w e u e nes or n ca r a s on armaceu ca

Products in India GCP Guidelines issued by the Central Drugs Standard Con-

trol Organization, Ministry of Health, Government of India.

4. List of Abbreviations and Definitions

5. Table of contents

6. Ethics Committee:

Thissection 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 sitesshould be provided. A declaration should state that EC notifica

tions as per Good Clinical Practice Guidelines issued by Central Drugs StandardControl Organization and Ethical

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

ofMedical 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 sec-

ondary objectives to be achieved should be mentioned here.

10. Investigational Plan:

Thissection should describe the overall trial design, the Subject selection criteria,

the treatment procedures, blinding / randomization techniques if any, allowed/ dis-

allowed concomitant treatment, the efficacy and safety criteria assessed, the data


23/103

Page 23 of102

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 devia-

tions. Enumerate the patientsscreened, randomised, and prematurely 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 thissec-

tion with appropriate tabular and graphical representation. A brief description of

the demographic characteristics of the trial patientsshould also be provided along-

with a listing of patients and observations excluded from efficacy analysis.

13. Safety Evaluation

Thissection should include the complete list

13.1 All serious adverse events, whether expected orunexpected and

13.2 unexpected advese events whetherserious or not (compiled from data received as

per Appendix XI).

The comparison of adverse events acrossstudy groups may be presented in a tabu

lar or graphical form. Thissection should also give a brief narrative of all impor

tant events consideredrelated 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


24/103

Page 24 of102

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

i. Publications from the trial

j. Important publications referenced in the study

k. Audit certificate, if available

l. Investigators 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 (includ-

ing dermal application)

Photo-allergy or dermal photo-toxicity:


25/103

Page 25 of102

ase , , - e rug or a me a o e s re a e o an agen caus ng p o o

sensitivity or the nature of action suggestssuch a potential.

Genotoxicity:

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 du-

ration 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 suggestssuch a po-

tential)

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 ref-

erences. In case of an application for directly starting a Phase II trial - complete


26/103

Page 26 of102

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.


ration 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


submitted while obtaining the permissions for Phase I and II trials, with appro-

priate references.

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

tails 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.


ration 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


submitted while obtaining the permissions for Phase I, II and III trials, with ap-

propriate references.


27/103

Page 27 of102

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.

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 institu-

tional affiliations and site locations

f. Name(s) of clinical laboratories and other departments and/or facilities partic-

ipating 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 de-

scription of how the current protocol extends existing data should be pro-

vided. If this is an entirely new indication, how this drug was considered for

this should be discussed. Relevant information regarding pharmacological,


28/103

Page 28 of102

toxicological and other biological properties of the drug/biologic/medical

device, and previous efficacy and safety experience should be described.

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 per-

forming thisstudy in the particular population included by the protocol should

be provided.

3. Study Objective(s) (primary as well assecondary) and their logical relation to

the study design.

Study Design

a. Overview of the Study Design: Including a description of the type ofstudy

(i.e., double-blind, multicentre, placebo controlled, etc.), a detail of the spe-

cific treatment groups and number of study Subjects in each group and in-

vestigative site, Subject number assignment, and the type, sequence and du-

ration ofstudy periods.

b. Flow chart of thestudy

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 thisstudy.

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.


29/103

Page 29 of102

6. Subject Eligibility

a. Inclusion Criteria

b. Exclusion Criteria

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

8. Study Conduct stating the types ofstudy activities that would be included in

thissection would be: medical history, type of physical examination, blood

orurine testing, electrocardiogram (ECG), diagnostic testing such as pul-

monary 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 withdraw-

al, 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 waiversshould be identified and the criteria used for

specific waiversshould 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 treat-

ment) 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 sta-

bility, storage requirements and dispensing requirements should be pro-

vided.


30/103

Page 30 of102

c. Dose modification forstudy 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

conditionsunder 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

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 forunblinding should be given

10. Adverse Events (See Appendix XI): Description of expected adverse

eventsshould be given.

Proceduresused 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 cod-

ing procedures

12. Study Monitoring and Supervision: A description ofstudy monitoring

policies and procedures should be provided along with the proposed fre-

quency ofsite monitoring visits, and who is expected to perform monitor-

ing.

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. Investigatorstudy


31/103

Page 31 of102

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)

b. The precise dosing required during the study

c. Method of packaging, labeling, and blinding ofstudy substances

d. Method of assigning treatments to Subjects and the Subject identification

code numbering systeme. Storage conditions forstudy substances

f. Investigational product accountability: Describe instructions for the re-

ceipt,storage, dispensation, and return of the investigational products to

ensure a complete accounting of all investigational products received, dis-

pensed, and returned/destroyed.

g. Describe policy and procedure for handling unused investigational prod-

ucts.

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 assecond-

ary) and safety endpoints.

Statistical analysis:

Give complete details of how the results will be analyzed and reporteda-

long with the description ofstatistical tests to be used to analyze the pri-

mary and secondary endpoints defined above. Describe the level ofsigni-

ficance, statistical tests to be used, and the methodsused for missing da-

ta; method of evaluation of the data for treatment failures, non-


32/103

Page 32 of102

comp ance, an u ec w rawa s; ra ona e an con ons or any n-

terim 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

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


33/103

Page 33 of102

ar ng a e an me o ay

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).

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 asserious. In addi-

tion 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 s pecific tests

and/or treatment that may have been conducted

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

tionship 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


34/103

Page 34 of102

ress

Telephone number

Profession (specialty)

Date of reporting the event to Licensing Authority:

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

Chapter 2

Objective of the study

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

effectsunder 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 orseverity

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 ofuse, or after long period of latency.

9. Postmarketing surveillance monitors increase in frequency orseverity of known ad

verse reaction.


35/103

Page 35 of102

10. Postmarketing surveillance identifies market response to drug and helps pharmaceut-

ical company to determine marketing strategies for medicinal product.

11.Through Postmarketing surveillance medical practitioner acts as bridge between pa-

tient and a pharmaceutical company. Any positive or negative outcome of Postmar-

keting surveillance gives a new approach or direction to Research and Development

team of company.

12.When any pharmaceutical company takes negative results of Postmarketing surveil-

lance in positive ways, it brings improvement in drug development and also streng-

thens concern for conducting clinical trial.

History of Post marketin surveillance

In the 1960s, 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 ef-

fects from the drug clioquinol, over which almost 4,000 civil suits were still pending in 1979

(68).

And in Great Britain in the early 1970s, more than 4 years after the drug had been introduced

there, the practolol syndrome wasuncovered.

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 ofMedical 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.


36/103

Page 36 of102

Many British drug companies now use the yellow card, and the yellow card system and re-

ports from drug companies together yield 90 percent of all reports ofsuspected adverse drug

reactions (ADRs).

The delayed discovery of practolols adverse effectsspurred 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 alladverse events occurring in a specified number of patients for an appropriate period of time;

endeavoring to avoid collecting masses ofunusable data and minimizing costs.

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 effectssuffi-

ciently 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 re-

lease.

More recently, the objectives of postmarketing surveillance in Great Britain have been ex-

panded, 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 adeno-

carcinoma in the adolescent female children of women who took diethylstilbestrol during

pregnancy.

PMS should also include assessment of efficacy, especially of long-term treatment.


37/103

Page 37 of102

Chapter 3

Profile of Company

1) Bristol-Myers Squibb PharmaBristol-Myers Squibb is a global BioPharma company firmly focused on itsMission to dis-

cover, develop and deliver innovative medicines that help patients prevail overserious 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 thisstrategy, 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 forshareholders, 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.


38/103

Page 38 of102

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

orsubmissions 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.

Pursuing ourMission 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 forsuccessfully 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. Weve also been recognized by the Human Rights Campaign Foundations 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 Newsweeks 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 ourshareholders and to our environment.


39/103

Page 39 of102

Cipla Pharma

The origins of Cipla can be traced back to 1935, when Dr Khwaja Abdul Hamied set up "TheChemical, Industrial and Pharmaceutical Laboratories Ltd", popularly known by the acronymCipla, 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 la-

boratory.

Cipla's product for hypertension Olmesartan, was exported to the American Roland Corpora-

tion.

In 1952, Cipla set up first research division for attaining self-sufficiency in technological de-

velopment.

In 1960, Cipla started operations at second plant at Vikhroli, Mumbai. In 1968, Cipla manu-

factured 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.


40/103

Page 40 of102

In 1997, Cipla launched transparent Rotahaler, the world's first such dry powder inhaler de-

vice.

In 2000, Cipla became the first company, outside the USA and Europe to launch CFC-free in-

halers.

Pradesh.

In 2002, Cipla set up fourstate-of-the-art manufacturing facilitiesset up in Goa.

In 2003, Cipla launched TIOVA (Tiotropium bromide), a novel inhaled, long-acting anticho-linergic bronchodilator.

In 2005, Cipla set up a state-of-the-art facility for manufacture of formulations at Baddi, Hi-

machal

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 & Fra rance: 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 applicationssuch as in personal care products, laundry detergents and room fre-

sheners.

Major Achievements of Cipla:

y Manufactured ampicillin for the first time in India

y Lauched etoposide, a breakthrough in cancer chemotherapy, in association with In-

dian Institute of Chemical Technologyy Launches transparent Rotahaler, the world's first such dry powder inhaler device

y Launches transparent Rotahaler, the world's first such dry powder inhaler device

y Became the first company, outside the USA and Europe to launch CFC-free inhalers


41/103

Page 41 of102

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 ren-

al system, it is also known that hypertension increases the risk of atherosclerotic cardiovascu-

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

lar 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 in-

crease 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 hyperten-

sive patients receiving antihypertensive medications, only 27.3% out of 3402 patients sur-


42/103

Page 42 of102

veyed had control of BP to recommended targets.6 This survey underlined the need to in-

crease 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 asset 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 antihyperten-

sive should be increased or patient should be shifted to low dose of different agent or move tocombination 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

the incidence ofstroke 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 nephropa-

thy and heart failure, but producesside 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 pos-

sess 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 ARBsused in the treatment of hypertension, heart failure and diabetic

nephropathy,


43/103

Page 43 of102

Chapter 5

Research methodolo y

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

under customary conditions of drug use. Controlled conditions allow forstudy of fewer

patients than in the other method

The four types ofstudies 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, minim-

ize 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 ei-

ther the control or treatment group. The control group receives placebo or an active compari-

son 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


44/103

Page 44 of102

an a ver se, are c ose y mon ore , so a ey are scovere as ey occur. e con ro e

clinical trial is considered the most definitive method for evaluating a drugs 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 forstudy 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, con-

trolled clinical trials might be impractical or too expensive.

Voluntary reportin 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 man-

ufacturers, who are required by law to report adverse reactions. In practice, most of the in-

formation obtained by the manufacturers originates from physicians and other health profes-

sionals. Such observationsserve as warnings of possible adverse drug effects, so that the infe-

rence of an association between a drug and an observed health condition may be furtherstu

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

thods. 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 stu-

dies 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 grou p 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 isused 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 back-

ground incidence of the condition). In this method, patients can be directly monitored to en-

sure they take the drug appropriately and to observe the drugs effects; or monitoring can be

less systematic. With less monitoring, a larger cohort can be followed, but bias is thus in-

creased.

Although uncommon, a Retrospective cohort study may also be conducted when purported

drug-induced effects have already been observed at the time the study isstarted. A retrospec-

tive cohort study must accurately ascertain patients past drug use. In principle, this could be


45/103

Page 45 of102

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 drugssuspected

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

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 ob-

tained. Among the advantages of retrospective case control studies compared with prospec-

tive cohort studies are the smaller number of patients required in retros pective 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 cohortand 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 pros pective cohort studies can be used to determine a drugs

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 particularsurveillance method to detect a drugs effect depends on two fac-

tors

1) The time that transpires between use of that drug and the occurrence of the drugs effect

2) How often the effect occurs (Some effects occur frequency).


46/103

Page 46 of102

ere are many o er e erm n ng ac ors, suc as accuracy o o serva on an accuracy an

completeness of medical records. But, these factors are more a problem in the design ofstudy

design. Latency ofsome drugs effects presentsserious 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

clinical trials, because of their relatively short duration, will detect only acute orsu b 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 isusually the way in which

long-term effects are first identified. Long-term effects are usually confirmed through retros-

pective case-control studies, but their reliance on historical data such as medical records can

limit the accuracy of these studies. The chance that a particularstudy will discover a drug ef

fect also depends on the studyssample size and the frequency of the drug effect. For exam-

ple, 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.


47/103

Page 47 of102

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.

Back round

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

Desi n of the investi ation

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 con-

tacted, 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,


48/103

Page 48 of102

enro men an n a on o rea men . s s , , an were sc e u e a en o wee , ,

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 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 wasused 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 antihyperten-

sive therapy at any time during the follow-u p based on their individual therapeutic goals

(usually


49/103

Page 49 of102

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 Desi n The surveillance was conducted as a multicentre (387 clinics all over India),

open label, post marketing real world surveillance. It consisted of an 8 weeksurveillance pe-

riod 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 re-

spectively. Subsequent visits 6 and 7 were scheduled alternatively at end of week 6 and 8 re-

spectively.


50/103

Page 50 of102

Assessments

There were a total ofseven 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 ofsphygmomanometer (patients resting for at least 5 minutes prior to recording), 3 read-

ings were taken at an interval of 10 minutes and the lowest of the 3 readings were recorded 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, eitherspontaneously 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 ofsurveillance. 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


51/103

Page 51 of102

tolerability and safety data was presented in form frequency, as recorded at the end of sur-

veillance. All analyses were pros pectively 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.

Chapter 6

Data Analysis and Interpretations

Case Study 1

Asshown 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 lattersample was tak-

en 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 sub-

jects (97.3% of the AE-Sample) are referred to as the Efficacy Sample. At the end of the

treatment observation period, after an average ofslightly 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 FormsMD (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 FormsMD (31.0%) and 853 cases with

both usable Compliance Form MD and Patient (22.2%).


52/103

Page 52 of102

Fi ure 1. Patient population and available data. Summary of the analysis patient popu-

lations of this investi ation and of the data available for analysis.

Table 1 summarizes the baseline demographic and clinical data for both the previously un-

treated 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 pre-

vious therapy (64.6%), cough (22.5%) and adverse events other than cough (16.6%). Themultivariate 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 nave patients (p =

0.0013). More pre-treated patients received a polytherapy regimen during the post-marketing

surveillance (p < 0.0001).

Baseline demo raphic and clinical data: Efficacy Sample.

Total 1785 (38.5%) 2854 (61.5%) 4639

Gender (f/m) 882/903 1605/1249 2487/2152

Mean age SD 57.9 12.7 63.6 12.3 61.4 12.8

Baseline SBP (Mean SD) 168.8 17.8 163.5 19.1 165.5 18.8

Baseline DBP (Mean SD) 101.2 8.6 96.3 10.4 98.2 10.0

Diabetes 165 (9.2%) 492 (17.2%) 657 (14.2%)

ISH 79 (4.4%) 408 (14.3%) 487 (10.5%)


53/103

Page 53 of102

WHO-risk and region categoriessee 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 ofsystolic 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 reduc-

tion was 11.7 11.3 mmHg (p < 0.001). Figure 2a shows the differences between nave 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. Nave 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 nave patients.

WHO-risk

Low (30%) 637 (35.7%) 1037 (36.3%) 1674 (36.1%)


54/103

Page 54 of102

Fi ure 2.a. Evolution of blood pressure durin observation period (~4 months): Effic a-

cy 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. Reachin of therapeutic tar ets: Efficacy Sample. Response to treatment is defined as

reaching DBP < 90 mmHg or a reduction of DBP = 10 mmHg. In real-life practice, a satisfac-

tory objective is also the normalization of DBP (< 90 mmHg). Target = 140/90 mmHg was

introduced because of digit preference ofstudy GPs (see results).


55/103

Page 55 of102

Since GPs did not receive specific instructions about therapeutic goals in thissurvey, 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 (65 years: 10.2%; 5565 years: 7.8%; = 55 years: 5.5%; p < 0.001) and by pre-

treated patients (9.6% vs. 5.5% nave; 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 subgroupsscoring above 90%.

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

prescribing guidance

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 ongo-

ing therapy were a reported good tolerance and reaching the a blood pressure 1

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%) 0.51%


56/103

Page 56 of102

Fi ure 3. On oin 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 u p and others. Multiple answers were

possible.

Fi ure 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 re-

gression model; Efficacy Sample. For detailed explanationssee results.


57/103

Page 57 of102

Perception of compliance

Patients with ongoing therapy at last visit were asked in the Compliance Form Patient to indi-

cate how many Irbesartan 150 mg tablets they took per week during the preceding 34 weeks.

Since after about one year only 853 patients returned the form, we have to assume a sampling

bias. Nevertheless, some within-grou p differences are worth mentioning. 777 patients

(91.1%) who returned the Compliance Form Patient reported an Irbesartan 150 mg intake of

67 times per week, i.e. more than 80% of the prescribed doses. All subgroupsscored 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 cardi-

ovascular eventsshowed a lower compliance (84%, n.s.). Compliance FormsMD 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)

Fi ure 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 =


58/103

Page 58 of102

WHO risk categories; ISH = isolated systolic hypertension; constant mono-and polytherapy;

treatment breaks; * = p < 0.05 comparedto the restofthe 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


59/103

Page 59 of102

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

Date post:	10-Apr-2018
Category:	Documents
Upload:	harshad-more
View:	271 times
Download:	0 times

MBA Project - Importance of Post Marketing Survelliance in Clinical Research

Documents