A Practical Guide on Pharmacovigilance for Beginners

First Edition

A  PHARMACOVIGILANCE FOR 
PRACTICAL 
G
 
UIDE ON  BEGINNERS 

DR.S.GUNASAKARAN, MBBS, MD
R.SATHEESH KUMAR, M.PHARM
 A Practical Guide on Pharmacovigilance for Beginners

A Practical Guide on Pharmacovigilance for Beginners

First Edition, 2010

Copyright © Gunasakaran & Satheesh kumar, 2010.

All rights reserved. No part of this publication may be reproduced or
distributed in any form or by any means (electronic, mechanical,
photocopying, recording or otherwise), or stored in a database or retrieval
system, without the written permission from the authors.

The authors have made a conscientious effort to ensure that the

information contained in this book is accurate and in accordance with
the accepted standards at the time of publication. However, in this
rapidly changing world guidelines and practices are subject to change
without prior notification, therefore readers are advised to confirm these
as and when required.

Rs. 250 (INR)

Printed in India

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 A Practical Guide on Pharmacovigilance for Beginners

PREFACE

The Authors are pleased to present the First edition of “A Practical

Guide on Pharmacovigilance for Beginners”. This book is sketched to
provide a concise introduction along with practical applications of
pharmacovigilance that medical students, post graduates in
pharmacology, pharmacy students and life science graduates can
impart during their academics as well as during their industrial
exposures. This book is expected to provide basic knowledge about the
different aspects concerning adverse event reporting and will be an eye
opener for beginners who step into the field of pharmacovigilance.

This book details the global and domestic aspects of

pharmacovigilance, various drug regulatory bodies guidelines
governing the pharmacovigilance, and different reporting systems
prevailing among various regulatory agencies along with detailed
description of the standard terminologies used in the field of
pharmacovigilance. It also covers interesting case scenarios to ignite
the minds of bibliomaniacs – the future critiques of this book.

Each chapter is thoughtfully developed to help the reader understand

the fundamentals of pharmacovigilance. We are greatly honor-bound to
our colleagues who showed interests, encouragement & enthusiasm by
devoting their precious time in shape the dream into reality.

Further suggestions, criticisms and elucidation are always welcome

from the students and readers, which may be addressed to the
author’s desk at

Dr.S.Gunasakaran, MBBS, MD
Ph : + 91 98413 12609

Email : drgunasakaran@gmail.com

(Or)

Mr. Satheesh kumar, M.Pharm

Ph : + 91 94431 60516

Email : satheesh_r2001@yahoo.com
 A Practical Guide on Pharmacovigilance for Beginners

Contents Page no

1. Standard Terms & Definitions in

Pharmacovigilance………………………………………………………. 3

2. Global perspective of Pharmacovigilance…………………………... 21

3. Domestic perspective of Pharmacovigilance………………………. 29

4. Guidelines and laws governing Pharmacovigilance…………….. 41

5. Global Adverse Event Reporting systems and

Reporting forms………………………………………………………… 59

6. Individual Case Safety Reports…………………………………….. 115

7. Periodic Safety Update Reports……………………………………. 261

8. Answers for Case studies…………………………………………… 267

9. Answers for Exercise based Questions………………………….. 272

 A Practical Guide on Pharmacovigilance for Beginners

ABBREVIATIONS

ABPI Association of the British Pharmaceutical Industry

ADE Adverse Drug Event
ADE Adverse Drug Experience
ADHD Attention Deficit Hyperactivity Disorder
ADR Adverse Drug Reaction
ADRAC Adverse Drug Reaction Advisory Committee
AE Adverse Event
AEFI Adverse Events Following Immunization
AHFS American Hospital Formulary Service
ALT Alanine Transaminase
AML Acute Myeloid Leukemia
ANC Absolute Neutrophil Count
ANDA Abbreviated New Drug Application
AR Adverse Reaction
ASR Annual Safety Report
AST Aspartate Transaminase
BID Bis In Die
BLA Biologics License Application
BNF British National Formulary
BP Blood Pressure
CBC Complete Blood Count
CCDS Company Core Data Sheet
CCSI Company Core Safety Information
CDC Centre for Disease Control and prevention
CDSCO Central Drugs Standard Control
Organization
CFR Code of Federal Regulations
CHM Commission on Human Medicines
CIOMS Council of International Organization for
Medical sciences
CMS Centres for Medicare and medicaid Services
CNS Central Nervous System
CPS Compendium of Pharmaceuticals and Specalties
CRO Contract Research Organization
CSI Core Safety Information
CT Computerized Tomography
CTD Common Technical Document
DEG Diethylene glycol
DGHS Directorate General of Health Services
 A Practical Guide on Pharmacovigilance for Beginners

DILI Drug Induced Liver Injury

DM Diabetes Mellitus
DSEB Drug Safety and Evaluation Branch
DSUR Developmental Safety Update Report
EEA European Economic Area
EMEA/EMA European Medicines Agency
EU European Union
FDA Food and Drug Administration
FEI FDA Establishment Identifier
GI Gastro-Intestinal
HCTER Human Cells and Tissue Establishment Registration
HCV Hepatitis C Virus
HT Hypertension
IB Investigator’s Brochure
IBD International Birth Date
ICH International Council of Harmonization
ICH-GCP International Conference on Harmonization – Good Clinical
Practice
ICMR Indian Council of Medical Research
ICSR Individual Case Safety Reports
ICU Intensive Care Unit
ID Identification
IND Investigational New Drug
IND Investigational New Drug
INR International Normalized Ratio
IV Intravenous
kg Kilogram
lb Pound
LKM – 2 Liver Kidney Microsomal antibody type 2
MAH Marketing Authorization Holder
MAUDE Manufacturer and User Facility Device
Experience Database
MCHC Mean Corpuscular Hemoglobin Concentration
MCV Mean Corpuscular Volume
MDR Medical Device Reporting
MedDRA Medical Dictionary for Regulatory
Activities
Mfr Manufacturer
MHPD Marketed Health Products Directorate
MHRA Medicines and Health related products
Regulatory Agency
MHRA Medicines and Healthcare products Regulatory Agency
MIMS Monthly Index of Medical Specialties
 A Practical Guide on Pharmacovigilance for Beginners

MIS Management Information System

mmHg millimeter of mercury
MSSO MedDRA Maintenance and Support Service
Organization
NA Not Applicable
NCVIA National Childhood Vaccine Injury Act
NDA New Drug Application
NDC National Drug Code
NPAC National Pharmacovigilance Advisory
Committee
NPC National Pharmacovigilance Centre
NPP National Pharmacovigilance Programme
NPPI National Pharmacovigilance Programme of India
NYHA New York Heart Association
OD Once Daily
OEM Original Equipment Manufacturer
OMSM Office of Medicines Safety Monitoring
OTC Over The Counter
PC Personal Computer
Phv Pharmacovigilance
PI Product information
PMA Pre-Market Application
PPC Peripheral Pharmacovigilance Centre
PSUR Periodic Safety Update Reports
PSVT Paroxysmal Supra Ventricular Tachycardia
QA Quality Assurance
RPC Regional Pharmacovigilance Centre
SADRRF Suspected Adverse Drug Reaction Reporting Form
SGOT Serum Glutamic Oxaloacetic Transaminase
SGPT Serum Glutamic Pyruvic Transaminase
SmPC Summary of Product Characteristics
SMQs Standardized MedDRA Queries
SOP Standard Operating Procedure
STN Submission Tracking Number
TEN Toxic Epidermal Necrolysis
TGA Therapeutic Goods Administration
TID Ter In Die
UF User Facility
UK United Kingdom
ULN Upper Limit of Normal
UMC Uppsala Monitoring Centre
UNESCO United Nation Educational, Scientific and
Cultural Organization
 A Practical Guide on Pharmacovigilance for Beginners

UNK Unknown
US United States
USC United States Code
VAERS Vaccine Adverse Event Reporting System
WBC White Blood cells
WHO World Health Organization
WHO-ART World Health Organization Adverse Reaction Terminology
ZPC Zonal Pharmacovigilance Centre
 A Practical Guide on Pharmacovigilance for Beginners

CHAPTER 1

STANDARD TERMS AND DEFINITIONS IN

PHARMACOVIGILANCE

T
his chapter discuss in detail about the various standard
terminologies and definitions used in adverse event reporting
system and pharmacovigilance. The standard terms are
defined based on various drug regulatory guidelines and modified for
better ease of understanding to the readers. The glossary of terms
described here covers most of the terminologies which are in use in
the field of pharmacovigilance and risk management.

Pharmacovigilance
WHO defines Pharmacovigilance as “the science and activities
relating to the detection, assessment, understanding and prevention
of adverse effects or any other drug related problems.”

Pharmacovigilance is the process and science of monitoring the safety

of medicines and taking action to reduce risks and increase benefits
from medicines.

Drug
A drug includes any substance or mixture of substances
manufactured, sold or represented for use in:

• the diagnosis, treatment, mitigation or prevention of a

disease, disorder or

• abnormal physical state, or its symptoms, in human beings or

animals,

• restoring, correcting or modifying organic functions in human

beings or animals, or disinfection in premises in which food is
manufactured, prepared or kept.
 A Practical Guide on Pharmacovigilance for Beginners

Adverse Event (or Adverse Experience)

Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and
which does not necessarily have to have a causal relationship with
this treatment.

An adverse event (AE) can therefore be any unfavorable and

unintended sign (including an abnormal laboratory finding, for
example), symptom, or disease temporally associated with the use of
a medicinal product, whether or not considered related to the
medicinal product.

Adverse Drug Reaction (ADR)

In the pre-approval clinical experience with a new medicinal product
or its new usages, particularly as the therapeutic dose(s) may not be
established:
all noxious and unintended responses to a medicinal product related
to any dose should be considered adverse drug reactions.

The phrase "responses to a medicinal product" means that a causal

relationship between a medicinal product and an adverse event is at
least a reasonable possibility, i.e., the relationship cannot be ruled
out.

Regarding marketed medicinal products, a well-accepted definition of

an adverse drug reaction in the post-marketing setting is found in
WHO Technical Report 498 [1972] and reads as follows:

A response to a drug which is noxious and unintended and which

occurs at doses normally used in man for prophylaxis, diagnosis, or
therapy of disease or for modification of physiological function.

Unlisted / Unexpected Adverse Drug Reaction

An adverse reaction, the nature or severity of which is not consistent
with the applicable product information (e.g., Investigator's Brochure
for an unapproved investigational medicinal product and prescribing
information / Summary of Product Characteristics (SmPC) for
marketed products).

Listed / Expected Adverse Drug Reaction

An ADR whose nature, severity, specificity, and outcome are
consistent with the information in the CCSI.
 A Practical Guide on Pharmacovigilance for Beginners

Challenge
Administration of a suspect product by any route.

Dechallenge
Withdrawal of a suspect product from a patient's therapeutic
regimen.

Negative Dechallenge
Continued presence of an adverse experience after withdrawal of the
suspect product.

Positive Dechallenge
Partial or complete disappearance of an adverse experience after
withdrawal of the suspect product.

Rechallenge
Reintroduction of a suspect product suspected of having caused an
adverse experience following a positive dechallenge.

Negative Rechallenge
Failure of the product, when reintroduced, to produce signs or
symptoms similar to those observed when the suspect product was
previously introduced.

Positive Rechallenge
Reoccurrence of similar signs and symptoms upon reintroduction of
the suspect product.

Serious Adverse Event or Adverse Drug Reaction

A serious adverse event (experience) or reaction is any untoward
medical occurrence that at any dose:
* results in death,
* is life-threatening,
The term "life-threatening" in the definition of "serious"
refers to an event in which the patient was at risk of death
at the time of the event; it does not refer to an event which
hypothetically might have caused death if it were more
severe.

* requires inpatient hospitalisation or prolongation of existing

hospitalisation,
* results in persistent or significant disability/incapacity,
* is a congenital anomaly/birth defect.
 A Practical Guide on Pharmacovigilance for Beginners

CHAPTER 4

REGULATORY GUIDELINES AND LAWS

GOVERNING PHARMACOVIGILANCE

R
egulatory guidelines are adapted by different regulatory agencies
to suit to their national needs of reporting adverse events.
Assessment of safety will be done based on global detection of
safety signals and necessary steps needs to be taken to curtail the
unnecessary risks and hazards to public health and safety due to
medicinal products.
The various pharmacovigilance guidelines for different regulatory
markets such as United States, European Union, Canada, Australia, etc.,
are discussed below. Each regulatory agency drafted and implemented
their own set of guidelines to fulfill the regional requirements of updating
the safety of medicinal products both in the preapproval and post-
marketing phases.

ICH GUIDELINES

The International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human Use (ICH) is
a unique project that brings together the regulatory authorities of
Europe, Japan and the United States and experts from the
pharmaceutical industry in the three regions to discuss scientific and
technical aspects of product registration.

The purpose is to make recommendations on ways to achieve greater

harmonization in the interpretation and application of technical
guidelines and requirements for product registration in order to reduce
or obviate the need to duplicate the testing carried out during the
research and development of new medicines.
The objective of such harmonization is a more economical use of human,
animal and material resources, and the elimination of unnecessary delay
in the global development and availability of new medicines whilst
maintaining safeguards on quality, safety and efficacy, and
 A Practical Guide on Pharmacovigilance for Beginners

multidisciplinary (regulatory) obligations to protect public health. The

key concepts of ICH guidelines can be easily remembered as QSEM

Q - Quality
S - Safety
E - Efficacy
M – Multidisciplinary.

The ICH guidelines which deal with pharmacovigilance are E1, E2A,
E2B, E2C, E2D, E2E, E2F, M1 and M4.

S. No. ICH Name of the guidance

Guidance
01 E1 The extent of population exposure to
assess clinical safety for drugs intended
for long-term treatment of non-life-
threatening conditions
02 E2A Clinical Safety Data Management:
Definitions and Standards For Expedited
reporting
03 E2B Maintenance of the ICH guideline on
clinical safety data management : Data
elements for transmission of Individual
Case Safety Reports
04 E2BM Data Elements for Transmission Of
Individual Case Safety Reports
05 E2C Clinical Safety Data Management:
Periodic Safety Update Reports for
Marketed Drugs
06 E2D Post-approval safety data management:
Definitions and standards for expedited
reporting
07 E2E Pharmacovigilance Planning
08 E2F Development Safety Update Report
09 M1 Medical Dictionary for Regulatory
Activities
10 M4 The Common Technical Document

Table 2: ICH guidelines related to Pharmacovigilance

 A Practical Guide on Pharmacovigilance for Beginners

Assessment of case report as a Reportable one

or Not

There are minimum requirements need to be present in the case reports

for reportability such as
1. Identifiable patient
2. Identifiable source
3. Suspect medication(s)
4. An Event or Outcome

Identifiable patient and Identifiable Source:

The identifiablility of the patient and reporter is important to

avoid duplication of cases, detection of fraudulent ones, and facilitation
of follow-up of appropriate genuine cases.

A patient can be identified either by

• Initials/Name
• Age/Date of Birth (D.O.B)
• Age category
• Sex/gender
• Patient Identification number

The sources of information can be categorized into primary and

secondary source. The primary reporting source(s) of the information is a
person/source from which an adverse event report arises. Secondary
sources are the one who will transmit the information (e.g., industry to
regulatory authority).

The identifiable reporting source may be any one of the following

• Consumers
• Health care professionals
• Lawyers
• Care takers
• Literature reports
• Clinical study reports etc

Suspect Medicinal Product:

 A Practical Guide on Pharmacovigilance for Beginners

A Suspect medicinal product is the one which is suspected at first to be

the reason for the reported adverse event.

An Event or Outcome:
An event or outcome should be present for the case to be reportable to
the regulatory authorities.

All the above four criteria should be present to make the adverse event as
reportable one. In some cases, both the reporting source and identifiable
patient will be the same.

Exercise 5:

Dr. Dinesh called TH manufacturers and stated that 21 year old male
patient had rigor after administration of tablet diclofenac manufactured
by them, which is also marketed in US. As a Medical affairs executive,
• To which regulatory body will you report this case?

(a) DCGI

(b) FDA

(c) Both

Exercise 6:

Dr. Ramachandran, MD called LEL drug pharmaceuticals and stated

that 29 year old female patient had giddiness, vomiting and shortness of
breath after administration of codeine cough syrup manufactured by
them, which is also marketed in US.

• Which forms need to be filled in this case?

(a) MedWatch 3500

(b) MedWatch 3500 A

(c) SADRRF

(d) Both a and c

(e) Both b and c

 A Practical Guide on Pharmacovigilance for Beginners

Case scenarios:
Case 1

A Dermatologist called KA pharmaceuticals and reported that a 21

year old male patient named Johnson had urticaria after intake of
Terbinafine tablets.

Check the criteria of identifiable patient in this case.

Yes No
1. Name/Initials
2. Patient ID
3. Age /D.O.B
4. Age category
5. Sex

Whether this case report fulfills the criteria of an identifiable patient..?

Yes/No
Case 2

Dr. Johnson mailed PJ pharmaceuticals that a young man

complained of severe abdominal pain after the intake of amoxicillin
tablets.

Check the criteria of identifiable patient in this case.

Yes No
1. Name/Initials
2. Patient ID
3. Age /D.O.B
4. Age category
5. Sex

Whether this case report fulfills the criteria of an identifiable patient..?

Yes/No
 A Practical Guide on Pharmacovigilance for Beginners

Case 3

A nurse from Indiana Hosptials reported that a patient identification

number of IJN 3421 developed rash, itching and shortness of breath
after administration of theophylline injection intravenously.

Check the criteria of identifiable patient in this case.

Yes No
1. Name/Initials
2. Patient ID
3. Age /D.O.B
4. Age category
5. Sex

Whether this case report fulfills the criteria of an identifiable patient..?

Yes/No

Case 4

A pharmacist made a call to ABC Pharma and informed that a female

patient reported 3 episodes of vomiting after intake of azithromycin
tablets.

Check the criteria of identifiable patient in this case.

Yes No
1. Name/Initials
2. Patient ID
3. Age /D.O.B
4. Age category
5. Sex

Whether this case report fulfills the criteria of an identifiable patient..?

Yes / No
 A Practical Guide on Pharmacovigilance for Beginners

Answers for case studies

Case no Reportability Reportable criteria /

Remarks

1 Yes 1,3
2 Yes 4
3 Yes 2
4 Yes 5
5 Yes 3
6 No -
7 Yes 4
8 No -
9 No -
10 Yes 1
11 No No event or outcome
12 No No suspect medication

13 No No identifiable patient
14 Yes 1,2,3,4
15 Yes 1,2,3,4
16 Yes 1,2,3,4
17 No No suspect medication
18 Yes 1,2,3,4
19 Yes 1,2,3,4
20 No No identifiable patient
21 Yes 1,2,3,4
22 Yes 1,2,3,4
23 Yes 1,2,3,4
24 Yes 1,2,3,4
25 No No identifiable patient
A Practical Guide on Pharmacovigilance for Beginners