Pharmacovigilance Guide

PHARMACOVIGIL ANCE
GUIDE
PHARMACOVIGIL ANCE 1
FOREWORD
All medicines have potential to cause harm during their usage. Adverse events associated
with the use of medicines have considerable social and economic consequences. The de-
tection and evaluation of adverse e ects associated with medicines involves specialists
from a range of scienti c disciplines who are attracted by the challenges of adding new
knowledge that supports safe use of medicines. But pharmacovigilance can only be e ec-
tive if it is relevant to the daily lives and embedded in the professional practice of all
those who use medicines -the prescriber, the patient and their carer. There is clear evi-
dence that reports from patients provide invaluable information on the impact of an ad-
verse e ect on life and work, and are of an equivalent level of seriousness to those from
healthcare professionals. This all adds up to the value of a broad appreciation and an up-
to-date understanding of the principles and practice of pharmacovigilance. In order for
such a pharmacovigilance system to be successful, there is need to train all health care
professionals in a well-structured programme.
This is a detailed manual giving a step by step approach to understand the pharmacovigi-
lance. This manual is intended for those who are looking for training in pharmacovigi-
lance. This manual of a clear and succinct yet comprehensive guide to the eld provides
exactly the right introduction for those new to the challenges and the excitement of
pharmacovigilance. It conveys the importance to public health protection of an e ective
safety net to pick up new information, and the need for well planned strategies to gener-
ate new evidence as an enabler of innovation.
The aim of this training manual is to guide students in drug safety regulations around the
globe and requirements of adverse drug event reporting. Understanding the principles,
rules, requirement and regulations helps industry specialists avoid or overcome drug-re-
lated challenges. What is more, being 100% quali ed allows them to complete their tasks
in a more cost- and time-e cient manner. The ultimate goal is to ensure rational and safe
use of e ective medicines.
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TABLE OF CONTENTS
Pharmacovigilance - Introduction ............................5
History and evolution of Pharmacovigilance ..........8
Major Drug recalls ................................................14
Drug development and Role of Pharmacovigilance19
Drug Discovery: ...........................................................19

Drug Development: ......................................................19
Clinical Trials: ..............................................................20
Phases of clinical trials:.................................................21
Types of Clinical trials: .................................................22
Regulatory Review and Approval .................................23
Terms and De nitions in Pharmacovigilance .........26
Sources of Individual Case Reports .......................33
Spontaneous reports: ...................................................33

Literature reports: ........................................................33
Reports from other sources ...........................................34
Reports originating from solicited sources: .....................35
License partner reports: ...............................................35
Regulatory authority reports:........................................35
Legal Reports: .............................................................35
Pharmacovigilance Process ...................................37
Individual case safety report (ICSR): .............................37

Aggregate Reporting: ..................................................38
Signal Management: ...................................................38
ICSR - Case processing ...........................................41
Validation of reports: ...................................................41
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Follow-up of reports .....................................................43
Duplicate search ..........................................................44
Coding in drug dictionaries: .........................................45
Event coding and MedDRA: .........................................47
Seriousness assessment ................................................50
Listedness/expectedness assessment ..............................51
Causality Assessment ...................................................54
Narrative writing .........................................................58
Regulatory reporting Requirements for ICSR ........61
Reports of special situations .................................63
Use of a medicinal product during pregnancy or breastfeeding: 63

Use of a medicinal product in the pediatric or elderly population 64
Reports of overdose, abuse, off-label use, misuse, medical error or occupation expo-
sure ............................................................................64
Lack of therapeutic ef cacy ..........................................65
Reports related to quality defects or counterfeit medicinal products 65
Reports of Suspected transmission of an infectious agent via a medicinal product 66
Vaccine Pharmacovigilance ...................................67
Adverse events following immunization (AEFI): ..............67

Reportable AEFIs: ........................................................68
Materiovigilance ...................................................68
Pharmacovigilance Inspection and audits .............70
Pharmacovigilance Inspections: ....................................70

Pharmacovigilance Audits: ...........................................70
Case Scenario........................................................71
Case Scenario : Spontaneous Adverse Report received from a consumer: 71

Pharmacovigilance interview questions..........................73
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PHARMACOVIGIL ANCE - INTRODUC-
TION
Pharmaceutical drugs are a valuable part of patient care throughout the world. They have
brought enormous bene ts, but no medicine is 100% safe for all people in all situations.
These medicines are a powerful, usually chemical or biological invasion of the body; that is
why they can cure the disease but also why they sometimes cause damage. While some
medicines can cause severe or even fatal adverse drug reactions, most have predominantly
bene cial e ects for most people even while they may cause occasional minor harm (such as
a headache, rash or tiredness).
For doctors to adequately care for their patients, drug safety must be monitored and report-
ed from initial testing to everyday use. This is the world of pharmacovigilance. Pharmacovig-
ilance is all about the safer and more e ective use of medicines for everyone, young and old.
It covers everything to do with noticing, assessing, understanding, managing and preventing
adverse e ects of medicines for individuals and populations.
Pharmacovigilance is an arm of patient care. It aims at making the best use of medicines for
the treatment or prevention of disease. No one wants to harm patients, but unfortunately
any medicine will sometimes do just this. Good pharmacovigilance will identify the risks
and the risk factors in the shortest possible time so that harm can be avoided or minimized.
When communicated e ectively, this information allows for the intelligent, evidence-based
use of medicines and has the potential for preventing many adverse reactions..
What is pharmacovigilance?
!
The World Health Organization de nes pharmacovigilance (PV) as “the science and activi-
ties relating to the detection, assessment, understanding and prevention of adverse e ects
or any other drug-related problem.”
PV is de ned by the European Commission (EU) as the “Process and science of monitoring
the safety of medicines and taking action to reduce the risks and increase the bene ts of
medicines”. !
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The goals of PV are to bolster patient safety concerning medicine use by providing a system
to collect, assess, and distribute drug safety data. PV activities involve monitoring approved
drugs and investigational medicinal products (IMPs) to:
• Identify previously unknown adverse e ects
• Recognize changes in the frequency or severity of known adverse e ects
• Assess a drugs risk/bene t to determine if action is required to improve safety
• Ensure the accuracy of information communicated to healthcare professionals and pa-

tients, and to ensure information contained in patient information lea ets (PILs) is up
to date
Why is pharmacovigilance important?
!
The information collected during the pre-marketing phase is incomplete with regard to ad-
verse drug reactions and this is mainly because:
• Patients used in clinical trials are limited in number and are not representative to the pub-
lic at large. In addition, the conditions of use of medicines di er from those in clinical
practice and the duration is limited.
• Information about rare but serious adverse reactions, chronic toxicity, use in special
groups (such as children, the elderly or pregnant women) or drug interactions is often in-
complete.
• Therefore, post-marketing surveillance is important to permit detection of less common

but sometimes very serious ADRs.
• Thus, post-marketing surveillance is important to permit detection of less common, but

sometimes very serious ADRs.
• Therefore health professionals worldwide should report on ADRs as it can save lives of
their patients and others.
The aims of pharmacovigilance are to:
• Improve patient care and safety in relation to the use of medicines and all medical and
paramedical interventions;
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• Improve public health and safety in relation to the use of medicines;
• Detect problems related to the use of medicines and communicate the ndings in a timely
manner;
• Contribute to the assessment of bene t, harm, e ectiveness and risk of medicines, leading
to the prevention of harm and maximization of bene t;
• Encourage the safe, rational and more e ective (including cost-e ective) use of medicines;
and
• Promote understanding, education and clinical training in pharmacovigilance and its e ec-
tive communication to the public. !
Products Covered by Pharmacovigilance:
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HISTORY AND EVOLUTION OF
PHARMACOVIGIL ANCE
Where and when did Pharmacovigilance begin? Medical remedies have been recognized by
mankind for thousands of years, and so have their potential dangers, side e ects, and bene-
ts. During the 20th century there were some serious adverse events associated with med-
ical products and drugs that resulted in pressure on governments, businesses to produce le-
galization and guidance, as well as the evolution of regulatory bodies to protect the safety of
patients.
The history of Pharmacovigilance started 172 years ago, on Jan 29, 1848, when a young girl
from the north of England died after receiving chloroform anesthetic before removal of an
infected toenail. The cause of death was investigated and concluded as either lethal ar-
rhythmia or pulmonary aspiration. As a result of other deaths and alerts raised by the clini-
cians and the public about the safety of anesthesia, The Lancet Journal established a com-
mission to take on this problem. The commission exhorted English doctors, including the
doctor in colonies, to report deaths caused by the anesthesia. The results were published in
The Lancet in 1893.
In USA, Biologics control act passed in 1902, following the death of children caused by con-
taminated vaccines. Vaccines were produced from horses and one of the horse had produced
over 30 quarts of diphtheria antitoxin, had contracted tetanus which led to child deaths. The
US Federal Food and Drug Act was formed on June 30, 1906, and it established that drugs
must be pure and free of any contamination. Furthermore, in 1911, this organization for-
bade false therapeutic indications of drugs.
In 1937, there were 107 deaths in the USA, because of the use of sulfanilamide elixir, con-
taining diethyl glycol as the solvent. This solvent was considered the cause of deaths, but
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the manufactory companies were not aware about its toxicity at that time. Consequently,
the Federal Food, Drug and Cosmetic Act was established in 1938; its aim was to renovate
the public health system. Indeed, the new system foresaw that the safety of drugs should be
demonstrated before their market approval, and introduced the possibility of conducting fac-
tory inspections.
In 1949, Council for International Organizations of Medical Sciences (CIOMS) established

jointly WHO and UNESCO.
In 1961, a big change of Pharmacovigilance happened following the tragedy of Thalidomide.

Dr. McBride, an Australian doctor, wrote a letter to the editor of the Lancet Journal, in
which he suggested a connection between congenital malformation of babies and thalido-
mide. In fact, he observed that the incidence of congenital malformations of babies (1.5%)
had increased up to 20% in women who had taken thalidomide during pregnancy.
Pharmacovigilance and drug safety were developed to prevent another Thalidomide disaster.
The present day approach to drug safety and adverse event reporting started with the
Thalidomide disaster. The tragedy of thalidomide brought to light many problems and criti-
cal issues, in particular, the reliability of animal tests, the behavior of the industrial compa-
ny, and the importance of monitoring the drugs after their marketing. In particular, this
tragedy changes the system of Pharmacovigilance, because the spontaneous reporting of ad-
verse drug reactions became systematic, organized, and regulated.
In 1962, USA Kefauver-Harris amendment to the law (requirement to prove safety and e -
cacy before issuing MA) was established.
In 1964, the “Yellow card” (YC) was structured in the UK. YC is a speci c form to compile a
spontaneous report of drug toxicity. In Europe (1965), European legislation with the EC Di-
rective 65/65 developed. In 1966, a pilot study of Boston Collaborative Drug Surveillance
Program started. It was the rst group to conduct epidemiologic researches to quantify the
potential adverse e ects of drugs utilizing in-hospital monitoring and had an essential role
in the development and application of methods in drug epidemiology.
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In 1968, the WHO Programme for International Drug Monitoring was instituted and ten
members participated in this program (Australia, UK, USA, Germany, Canada, Ireland, Swe-
den, Denmark, New Zealand, and Netherlands). The network has since expanded signi -
cantly as more countries worldwide developed national Pharmacovigilance centers for the
recording of ADRs. Currently, many countries participate in the programme, which is coor-
dinated by WHO together with its collaborating centre in Uppsala, Sweden (UMC). The
UMC is responsible for maintaining the global ADR database, Vigibase.
The WHO Collaborating Centre analyses the reports in the database to:
• Identify early warning signals of serious adverse reactions to medicines;
• Evaluate the hazard;
• Undertake research into the mechanisms of action to aid the development of safer and
more e ective medicines.
In 1990, CIOMS I: International reporting of adverse drug reaction released.
In 1991, European Rapid alert system signed into forces to facilitate early exchange of in-
formation concerning possible safety hazards relating to marketing medicinal products.
In 1992, the European Society of Pharmacovigilance (ESoP) was funded, turned into the In-
ternational Society of Pharmacovigilance (IsoP). The aims of this society were to promote
Pharmacovigilance, and enhance all aspects of the safe and proper use of medicines.
In 1995, the European Medicines Agency (EMA) was set up. In 2001, EudraVigilance was
founded. It is the o cial European database for managing and analyzing information on
suspected adverse reactions to medicines which have been authorized for the market or be-
ing studied in European clinical trials.
In 1999, Revised MedWatch 3500A, draft MedDRA. MedWatch is the form used by compa-
nies to report adverse events to FDA. MedDRA - the Medical Dictionary for Regulatory Ac-
tivities - is a medical terminology used to classify adverse event information associated with
the use of biopharmaceuticals and other medical products
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In 1999: Institute of Medicine (IoM) was formed to report on errors and risk issues. Around
the start of the 21st century, there were several high pro le drug withdrawals due to safety
reasons, and the IoM issued its report on errors and risk issues. This was a groundbreaking
report analyzing the impact of medication errors and the risks to patients due to side e ects
from drugs. This report was a major factor that lead to the introduction of “Risk Manage-
ment”. Prior to 2000, it was the job of regulators to assess the risks due to drugs, based on
adverse event reports received. Following the IoM report, regulators started to ask drug
companies to get involved in risk assessment and risk mitigation.
In 2001, Post-marketing Safety Reporting Guidelines (Guidance from FDA on how to report
adverse events) started.
In 2002, PDUFA III - The multiple Prescription Drug User Fees Acts allowed FDA to charge
companies for the drug approval process. This third act allowed FDA to use some of the
money to monitor risks for up to two years post-approval. It required companies to prepare
a “risk management plan” to address this two-year period, if their drug had signi cant risks
associated
In 2003, The “Tome” - Nicknamed because of its length: 94 pages of proposed rule on ad-
verse event reporting. The pre-marketing section was nalized in 2010. Most of the rule has
not yet been nalized.
In 2005, Final Risk Management Guidances were developed. The FDA risk management
guidances, nalized in 2005, speci ed how to perform signal detection, risk assessment and
risk mitigation.
In 2007, FDA Amendment Act and in 2010, New IND Reporting Rules were released.
In 2009, MHRA released black triangle scheme to report all suspected adverse reactions to
designated black triangle drugs.
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A major change in European Pharmacovigilance was observed with the new legislation (Di-
rective 2010/84/EU), in 2012. The main changes in the new legislation were:
• Modi cation of the de nition of adverse drug reactions (ADR);
• Greater involvement of patients and citizens in Pharmacovigilance activities;
• Strengthening of the Eudravigilance database containing reports of suspected reactions

reported by all EU Member States;
• Increasing transparency and timeliness of important information on Pharmacovigilance

problems;
• Obligation of “additional monitoring” for the products contained in the speci c list
kept by the EMA;
• Possibility to impose further safety and/or e cacy studies on the certi cates of market-
ing authorization at the time of granting the trust;
• Establishment within the EMA of the Pharmacovigilance Risk Assessment Committee

(PRAC).
Furthermore, the new legislation set-up measures to facilitate the performance of PV, called
the Good Pharmacovigilance Practices (GVP). The guideline on GVP is divided into two cat-
egories: modules covering major Pharmacovigilance processes and product- or population-
speci c considerations.
In November 2017, the new EudraVigilance format was launched; in particular, the market-
ing authorizations will have extended access to the EudraVigilance database to support the
ful llment of their Pharmacovigilance obligations. These obligations include the continuous
monitoring of EudraVigilance data and the communication of validated signals to the
Agency and national regulatory authorities, as outlined in Commission Implementing Regu-
lation (EU) N. 520/20121.
The origin of pharmacovigilance in India goes back to 1986, when a formal adverse drug re-
action (ADR) monitoring system consisting of 12 regional centers, each covering a popula-
tion of 50 million, was proposed for India. However, nothing much happened until a decade
later when in 1997, India joined the WHO Adverse Drug Reaction Monitoring Programme
based in Uppsala, Sweden. This attempt was unsuccessful and hence, from 1 January 2005,
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the WHO- sponsored and World Bank-funded National Pharmacovigilance Program for In-
dia was made operational. The National Pharmacovigilance Program established in January
2005, was to be overseen by the National Pharmacovigilance Advisory Committee based in
the Central Drugs Standard Control Organization (CDSCO).
MAJOR DRUG RECALLS
A drug recall is a request from a manufacturer to return a product after the discovery of
safety issues or product defects that might endanger the consumer or put the maker/seller
at risk of legal action. A recall is a serious process. It highlights a dangerous situation that
requires fast and e ective action to protect the public from harm. Product recalls are becom-
ing extensive and have increased radically. Below are few major recalls in the history;
1. Benaxoprofen:
Manufacturer: Eli Lilly
Recalled: 1982
Benaxoprofen (Ora ex) was removed from market in the UK and USA after being linked to
3500 side e ects and 61 deaths. Benaxoprofen was used for the pain and in ammation of
arthritis that has been associated with 61 deaths in Britain and 11 deaths in USA. The drug
has been associated with fatal kidney and liver damage, as well as an unexpectedly frequent
side e ects, including sensitivity to sunlight and the separation of ngernails.
2. Diethylstilbestrol (DES)
Manufacturer: Multiple manufacturers (DES was never patented as it was created with
British public funds).
Recalled: 1975 (after 37 years on the market)
DES was prescribed for more than 30 years to prevent miscarriages and other complications
during pregnancy. It was not until 1971 before it was connected to a rare tumor that kept
appearing in the daughters of women who had taken it. The FDA only banned DES pre-
scriptions to women because no such problems have been found in men. In fact, it can still
be prescribed to men to treat estrogen de ciency. Litigation over DES led to a landmark
products liability award that heavily in uenced how both courts and the FDA approach
oversight of drugs with multiple manufacturers.
3. Fen uramine/phentermine (Fen-Phen)
Manufacturer: Wyeth-Ayerst Laboratories
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Fen-Phen’s was a hugely popular weight loss drug, its popularity peaking in the 1990s. It is
estimated that as many as 6.5 million people took it to help ght obesity. After consumers
began experiencing heart disease and other pulmonary problems, the FDA recalled the med-
icine.
4. Terfenadine (Seldane)
Manufacturer: Hoechst Marion Roussel (now Aventis)
Seldane was a popular antihistamine brought to market in 1985 to treat allergies without
causing drowsiness. The FDA sought a recall from the manufacturer after cases of cardiac
arrhythmia (abnormal electrical activity in the heart) appeared in patients taking Seldane
with other drugs.
5. Mibefradil (Posicor)
Manufacturer: Roche
Recalled: 1998 (after one year on the market)
In only one year on the market, Posicor was linked to 123 deaths. Considered relatively safe
when taken alone, Posicor became potentially deadly when combined with any of 25 di er-
ent drugs. The large number of deaths is troublesome considering that the drug was pre-
scribed to no more than 200,000 people worldwide in the space of one year, a relatively
small number. It is often cited as a strong example of what can go wrong when drugs are
rushed to market.
6. Troglitazone (Rezulin)
Manufacturer: Warner-Lambert
Recalled: 2000 (after one year on the market)
Rezulin, an anti-diabetic and anti-in ammatory drug, was eventually found to be causally
connected with hepatitis.
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7. Phenylpropanolamine (PPA)
Manufacturer: No principal manufacturer, widely manufactured across the industry
Recalled: In 2000 (at least 60 years on the market)
PPA, a psychoactive drug that saw many uses over its long history, is unique because the
FDA never formally approved it. For decades it was used for everything from dieting to cold
medication to treatment of psychological disorders, existing in a kind of limbo where it was
neither banned nor fully endorsed. That is, until an analysis by Yale University in 2000 rec-
ognized its connection with cardiac events and stroke, particularly in women. The study es-
timated that 1 woman might have a stroke due to phenylpropanolamine for every 107,000 to
3,268,000 women who use products containing phenylpropanolamine as an appetite sup-
pressant within a three-day window. The FDA estimates that between 200 to 500 strokes
per year would have been prevented if PPA was replaced with something that presented less
risks. More than 25,000 lawsuits have been led against a variety of drug companies.
8. Cerivastatin (Baycol)
Manufacturer: Bayer
Recalled: 2001 (after four years on the market)
Baycol, prescribed to patients as a treatment for high cholesterol, is reportedly responsible

for more than 100,000 deaths and about as many lawsuits. It was connected to a severe
muscle disorder known as rhabdomyolysis, which clogs the kidneys with protein from dying
muscle tissue.
9. Rofecoxib (Vioxx)
Manufacturer: Merck
Recalled: 2004 (after ve years on the market)
Vioxx is considered to be the largest drug recall in history. Vioxx, prescribed to more than
20 million people as a pain reliever for arthritis, was found to be responsible for increased
risk of heart attack and stroke. The Lancet reported that as many as 140,000 people could
have su ered from serious coronary heart disease from taking the drug in the US alone.
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10. Valdecoxib (Bextra)
Manufacturer: P zer
Recalled: In 2005 (after just one year on the market)
Bextra, like Vioxx, is a non-steroidal anti-in ammatory drug that was prescribed to treat
arthritis and pain from other in ammatory disorders. It was removed from the market not
long after Vioxx over similar concerns – increased risk of heart attack and stroke. In some
cases, it was also found to cause a fatal skin condition.
11. Able Laboratories Generic Prescription Drugs
Manufacturer: Able Laboratories
Recalled: 2005
On May 23, 2005, all of Able Laboratories’ products were removed from the market due to
questions surrounding the quality of the manufacturing process. Some drugs were found to
be too potent; others not potent enough. Moreover, four of its managers were found to have
fraudulently distributed misbranded and adulterated drugs.
Recent Recalls:
In January 2020, European Medicines Agency (EMA) suspended Picato gel which is used for
treating the skin condition actinic keratosis, a rough, scaly patch on your skin that can de-
velop from exposure to the sun. The drug was initially marketed in 2012, In September
2019, after data suggested the occurrence of a higher number of skin cancer cases, the EMA
requested a safety review of the drug, using its PRAC. Hundreds of patients experienced
malignant tumors (squamous cell carcinoma) and benign tumours (keratoacanthoma), basal
cell carcinoma and Bowen’s disease.
On Feb. 13, 2020, the FDA requested that Eisai Inc. voluntarily withdraw the drug over the
potential cancer link. The agency based its decision on results from a ve-year study of
Belviq users that the company had conducted to make sure there were no serious cardiovas-
cular risks associated with the drug. Belviq, or lorcaserin, was a weight loss drug approved
by the FDA in 2012 to treat obesity. It was also prescribed to overweight people who had se-
rious weight-related health conditions such as diabetes and high blood pressure. When the
FDA approved Belviq, it required Eisai to conduct a long-term study into the drug’s cardio-
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vascular e ects. The study involved 12,000 people, some taking Belviq and others taking a
placebo. Data from the trial showed that 7.7 percent of the people taking Belviq developed
cancer, compared to 7.1 percent taking the placebo.
In September 2020, The Therapeutic Goods Administration (TGA - Australia) withdrawn

Befexamac in Australia Market due to serious skin reactions (allergic contact dermatitis).
Befexamac is an over the counter (OTC) non steroidal anti in ammatory drug (NSAID),
used in combination with lignocaine in rst aid creams that are applied on skin.
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DRUG DEVELOPMENT AND ROLE OF
PHARMACOVIGIL ANCE
For patients, new medicines o er fewer side e ects, fewer hospitalizations, improved quality
of life, increased productivity, and importantly, extended lives. But developing medicines is a
long, complex process. On average, it takes at least ten years for a new medicine to complete
the journey from initial discovery to the marketplace, with clinical trials alone taking six to
seven years on average.
Drug development is the process of bringing a new drug molecule into clinical practice. In
its broadest de nition this encompasses all steps from the basic research process of nding
a suitable molecular target to supporting the commercial launch of the drug. In a narrower
sense, development refers only to the clinical parts of this process, with discovery used to
describe the nonclinical research components
DRUG DISCOVERY:
In the process of drug discovery, the rst step is to identify an appropriate ‘drug’ target
which can be a biomolecule or a protein receptor that is explicitly associated with a disease
condition or pathology. After the target has been identi ed, the next step involves target val-
idation and the con rmation of its role in the disease progression. This is followed by test-
ing of the target against di erent small molecule compounds to identify lead compounds
which can interact with the target biomolecule and display the potential therapeutic activity
either by nullify or slow the disease development. The lead compounds can be identi ed by
screening a library of compounds through various methods, such as high-throughput
screening de novo synthesis and isolation from the natural products.
DRUG DEVELOPMENT:
The drug development phase involves stringent testing and optimization of the selected
compounds to identify the ‘drug candidate’ which might be most e ective in terms of safety,
toxicity dosage, and e cacy. For this purpose, the selected lead compounds are tested in
cells (in vitro) and in animals (in vivo) to study their pharmacodynamic and pharmacokinet-
ic properties, which include Absorption, Distribution, Metabolism, Excretion and Toxicity
(ADME/Tox) properties. The successful lead candidate must be non-toxic and should have
good bioavailability, can be distributed to the drug target in the body, and can be metabo-
lized e ciently and e ectively as well as successfully excreted from the body.
This part of the development process is referred to as the ‘preclinical phase’ in which the
drug candidate is meticulously examined, optimized, and prepared for testing in humans.
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This phase is followed by the ‘clinical phase’ of development, in which the e cacy and safe-
ty of a drug candidate is scrutinized in patients.
CLINICAL TRIALS:
Clinical trials are medical research studies involving people. They aim to test whether di er-
ent treatments are safe and how well they work. Some trials involve healthy members of the
public. Others involve patients who may be o ered the option of taking part in a trial during
their care and treatment. Clinical trials are carried out to try to answer speci c questions
about health and illness.
They aim to nd the best ways to:
• Prevent disease and reduce the number of people who become ill
• Treat illness to improve survival or increase the number of people cured
• Improve the quality of life for people living with illness, including reducing symptoms of
disease or the side e ects of other treatments, such as cancer chemotherapy
• Diagnose diseases and health problems.
Why are clinical trials important?
Clinical trials are the best way to compare di erent approaches to preventing and treating
illness and health problems. Health professionals and patients need the evidence from trials
to know which treatments work best. Without trials, there is a risk that people could be giv-
en treatments which have no advantage, waste resources and might even be harmful. Many
treatments that are now in common use in health care were tested in clinical trials.
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Some types of clinical trial are designed to look at a treatment at an early stage of its devel-
opment. Researchers and regulators will look at the information they have gathered and de-
cide whether it is safe and appropriate to continue the development of that treatment. If the
treatment has no bene t or has serious side e ects, it may not be developed further. During
the later stages of development of a treatment researchers will report on the bene ts and
risks so that doctors can decide whether or how best to use it. It is important that the re-
sults of clinical trials are published so that others can use the information to help them
make decisions about treatment and health care.
PHASES OF CLINICAL TRIALS:
Clinical trials are carried out in a number of stages. For trials of medicines and other treat-
ments, early stage studies are carried out in a small group of people to assess safety by look-
ing for unwanted side e ects. Later stage clinical trials usually involve larger numbers of
participants.
Phase 1 clinical trial:
Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.
Length of Study: Several months
Purpose: Safety and dosage, absorption and metabolism, e ects of organs and tissues.
Approximately 70% of drugs move to the next phase
In this phase it is important to enroll a relatively healthy patient population with as few
complications and concomitant diseases as possible.
Food e ect studies are often conducted to investigate the potential impact of food intake on
the absorption of the drug. These studies are usually run as a crossover study, with volun-
teers being given two identical doses of the drug, one after fasting and one after a meal.
Study Participants: Up to several hundred people with the disease/condition.
Length of Study: Several months to 2 years
Purpose: E cacy, short term side e ects and dose range
Approximately 33% of drugs move to the next phase
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Study Participants: 300 to 3,000 volunteers who have the disease or condition
Length of Study: 1 to 4 years
Purpose: E cacy and monitoring of adverse reactions
Phase 3 trials aim to:
• compare the e ects of newer drugs with the standard treatment,
• if there is one nd out how well the drug works and how long the e ects last
• nd out more about how common and serious any side e ects or risks are and about any
possible longer term problems that could develop.
Approximately 25-30% of drugs move to the next phase
TYPES OF CLINICAL TRIALS:
1. Controlled trials: Controlled trials are designed to compare di erent treatments. Most con-
trolled trials compare a new treatment with the standard or usual treatment by setting up
two groups of people. One group, known as the trial group or intervention group, are given
the new treatment. The other group is given the standard treatment and is known as the
control group. In situations where there is no standard treatment the control group may not
be given any treatment at all or may be given a placebo.
A placebo treatment is designed to appear very similar to the treatment being tested. For
example, in a drug trial the placebo looks exactly like the real drug, but in fact it is inactive.
By comparing people’s responses to the placebo and to the treatment being tested, re-
searchers can tell whether the treatment is having any real bene t. The control group is very
important. Comparing the results of the control group with those of the treatment group is
the only way researchers can reliably nd out whether any improvement seen with the new
treatment is really due to that treatment and not just due to chance.
2. Blind trials: In a blind trial, the participants are not told which group they are in. This is
because if they knew which treatment they were getting, it might in uence how they felt or
how they reported their symptoms. To prevent people from guessing which treatment they
are getting, all the treatments are made to look as similar as possible. For example, in a drug
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trial all the tablets will look the same whether they are the new treatment or the standard
treatment.
Types of blinded trials:
• Single-blinded study: The treating physician is aware of which treatment the partici-
pant is receiving, but the participant is not, or vice versa
• Double-blinded study: The participant, treating physician, site sta , and study team are
unaware of the treatment assignment
• Partial-blinded study: Within a study arm, some of the study drugs are blinded and
others are open- label (e.g., ZDV + 3TC [open] plus nel navir or nel navir-placebo
[blinded])
• Open-label or Unblinded Study: Both the participant and the treating clinician respon-
sible for the participant (including site sta ) are aware of the participant’s treatment
assignment.
3. Randomisation: Many trials are randomised. This means that people are allocated at ran-
dom to the treatment groups in the trial, usually by using a computer programme. This is
done so that each group has a similar mix of people of di erent ages, sex and state of health.
If it were left to the doctor or patient to decide who should get which treatment they might
be in uenced by what they know about their illness. Patients who are more or less likely to
respond to a new treatment might all go into one particular group. In that situation, if one
group did better that the other it would not be clear whether the di erence was due to the
treatment or because the groups were di erent. If the people are allocated to the treatment
groups at random, like will be compared with like. If one group does better than the other, it
is likely to be because of the treatment, as the two groups are very similar in every other
way.
R E G U L AT O RY R E V I E W A N D A P P R OVA L
The outcome of the ‘clinical trial’ decides whether the drug candidate is safer and e ective
enough in treating the disease. At this point, new drug applications (NDA) with all the es-
sential evidence, including quality, preclinical and clinical data collected during development
of the drug candidate, are submitted to the relevant regulatory authorities, e.g., the United
States Food and Drug Administration (USFDA), which oversees the development, approval,
and marketing of drugs They need to approve the drug applications so that the company can
commercialize the drug in their jurisdictions (e.g., a New Drug Application (NDA) in USA,
and Marketing Authorization Application (MAA) in Europe).
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Marketing (Commercialization):
This is the last phase of drug development process. Once the drug has been approved, it is
marketed or commercialized. The drug manufacturers need to submit marketing authoriza-
tion applications in every country in which they want to sell the drug.
Following this, post-marketing surveillance is conducted by the manufacturer to continue

evaluating the safety and e cacy of the marketed drug, and to better design its further de-
velopment. These studies are considered as phase 4 clinical trials and are compulsory in
some countries, e.g, Japan and Philippines. As the drug is typically targeted to a very large
number of patients, the manufacturer is expected to monitor this stage cautiously and sub-
mit reports to the FDA. The reports include evidence for medicine-related problems, e.g.,
treatment failure, adverse reaction, counterfeit/poor quality medicines, drug interactions, or
incorrect use. These reports are signi cant in terms of generating proof of e cacy that will
inspire public con dence and trust.
Study Participants: Several thousand volunteers who have the disease/condition
Purpose: Bene t/risk relationship of drug, Less common and longer term side e ects and
Labeling information.
Phase 4 trials aim to nd out:
• how well the drug works when it is used more widely
• the long-term risks and bene ts
• more about the possible rare side e ects
Not all Phase IV studies are post-marketing surveillance studies. There are multiple obser-
vational designs and evaluation schemes that can be used in Phase IV studies to assess the
e ectiveness, cost-e ectiveness, and safety of an intervention in real-world settings.
Introducing a new medicine to the patients is not only a highly time-consuming and expen-
sive process but also requires an extremely essential and strict vigilance on the safety and ef-
cacy of the drug. Therefore pharmacovigilance plays a pivotal role in drug discovery and de-
velopment. The drugs may appear to be safe and well-tolerated in preclinical and clinical
testing, but their safety in the ‘real world’ may not be distinct, after-e ects of the drug when
used frequently or in combination with other drugs are generally unknown, safety in vulner-
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able groups with di erent metabolic pro les (e.g, pregnant women and breastfeeding moth-
er, elderly person, young children) can be uncertain, and rumors and myths can destroy the
integrity, adherence to, and success of a treatment.
Pharmacovigilance plays a critical role at various stages of drug discovery and development
process; for example, in clinical research, pharmacovigilance requires submission of the re-
ports on adverse events during clinical trials to regulatory authorities within a speci ed time
frame, noti cation of such events to all investigators and ethics committees, and a safety re-
view by independent Drug Safety Monitoring Boards (DSMB). Annual reports, a summary
and analysis of all the serious adverse events, new safety ndings from animal studies, and
evaluations of bene t and risk are also required. "
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TERMS AND DEFINITIONS IN
PHARMACOVIGIL ANCE
Pharmacovigilance has its own unique terminology that is important to understand. Most of
the following terms are speci c to drug safety, although some are used by other disciplines
within the pharmaceutical sciences as well.
Adverse event (AE): is de ned as "An adverse event is any untoward medical occurrence in a
patient or clinical-trial subject administered a medicinal product and which does not neces-
sarily have to have a causal relationship with this treatment”.
An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal
laboratory nding), 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), Suspected adverse (drug) reaction: is de ned as“A response to a
medicinal product which is noxious and unintended and which occurs at doses normally
used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, cor-
rection or modi cation of physiological function”.
Response in this context means that a causal relationship between a medicinal product and
an adverse event is at least a reasonable possibility.
Examples:
1. Abortion, miscarriage or uterine hemorrhage associated with misoprostol (Cytotec), a

Labor-inducing drug (this is a case where the adverse e ect has been used legally and ille-
gally for performing abortions).
2. Addiction with many sedatives and analgesics such as diazepam, morphine,etc.
3. Birth defects associated with Thalidomide and Accutane.
4. Bleeding of the intestine associated with aspirin therapy.
Serious Adverse Events (SAEs): are de ned as any untoward medical occurrence(s) that at any
dose results in death, hospitalisation or prolongation of existing hospitalisation, persistent
or signi cant disability/incapacity or a congenital anomaly or birth defect. Serious Adverse
Events (SARs) are serious adverse events but causally related to investigational medicinal
products.
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Suspected Serious Adverse reactions (SSARs): are any adverse reactions considered consistent
with information available about an Investigational medicinal Product (IMP). They must be
reviewed at regular intervals to see if the pro le of any IMP has changed and a record made
of this.
Suspected Unexpected Serious Adverse Reactions (SUSARs): are any serious events suspected to be
caused by a medicinal product, but which are not consistent with information about the
medicinal product (these are the most serious of events and are subject to expedited report-
ing procedures)
Dechallenge: Withdrawal of a product from the patient's therapeutic regimen is called dechal-
lenge.
• Positive dechallenge is improvement of reaction when dechallenge occurs. Resolution of

suspected ADR when the drug is withdrawn.
• Negative dechallenge is continued presence of an adverse experience after withdrawal of

the drug.
Rechallenge: Reintroduction of a product suspected of having caused an adverse event follow-

ing a positive dechallenge is called Rechallenge.
• Negative rechallenge is failed to produce signs or symptoms similar to those observed

when the product was previously introduced.
• Positive rechallenge is reoccurrence of similar signs and symptoms upon reintroduction

of product.
• Rechallenge is only justi able when the bene t of re-introducing the drug to the patient
outweighs the risk of recurrence of the reaction. This is rare. In some cases the reaction
may be more severe on repeated exposure.
Side e ects: Unwanted but often unavoidable, pharmacodynamic e ects that occur at thera-
peutic doses. Predicted from the pharmacological pro le of a drug and known to occur in a
given percentage of drug recipients
Examples:
• Side e ect based on therapeutic e ect:
• Atropine (preanaesthetic)-dryness of mouth
• Acetazolamide (diuretic-bicarbonate excretion) -Acidosis
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Drug intolerance: Appearance of characteristic toxic e ects of a drug in an individual at thera-
peutic doses. Intolerance can happen in individuals with a low threshold
Example: Tri upromazine (single dose) can cause Muscular dystonias in some individuals
Drug allergy/Drug hypersensitivity: Immunologically mediated reaction producing stereotype

symptoms, unrelated to the pharmacodynamic pro le of the drug. Generally occur even with
much smaller doses
• Types of drug allergy:
• Type I: Immediate, anaphylactic (IgE) - E.g:Penicillins – Anaphylaxis
• Type II: Cytotoxic antibody (IgG, IgM) - E.g: Methyldopa – hemolytic anemia
• Type III: Serum sickness (IgG, IgM) Antigen-antibody complex - E.g: Procainamide-in-
duced lupus
• Type IV: Delayed hypersensitivity (T cell) - E.g: Contact dermatitis
Drug dependence: Drugs capable of altering mood and feelings are liable to repetitive use to
derive euphoria, withdrawal from reality, social adjustment, etc.
• Psychological dependence: Individual believes that optimal state of well being is

achieved only through the actions of the drug. Example: Opioids, Cocaine.
• Physical dependence: Altered physiological state produced by repeated administration

of a drug which necessitates the continued presence of the drug to maintain physiologi-
cal equilibrium. Discontinuation of the drug results in a characteristic withdrawal (ab-
stinence) syndrome. Example: Opioids, Barbiturates, Alcohol, Benzodiazepines
Drug abuse: Use of a drug by self medication in a manner and amount, that deviates from the
approved medical and social patterns in a given culture at a given time. Drug abuse refers to
any use of an illicit drug.
Drug addiction: Compulsive drug use characterized by overwhelming involvement with the
use of a drug.
Drug habituation: Less intensive involvement with the drug, withdrawal produces only mild
discomfort. Habituation and addiction imply di erent degrees of psychological dependence.
Drug misuse: Situations where the medicinal product is intentionally and inappropriately used
not in accordance with the terms of the marketing authorisation.
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Drug withdrawal reactions: Sudden interruption of therapy with certain drugs result in adverse
consequences, mostly in the form of worsening of the clinical condition for which the drug
was being used.
Examples:
• Corticosteroid can cause Adrenal insu ciency
• β-blockers can cause worsening of angina, precipitation of MI
• Clonidine can cause severe HTN, restlessness, sympathetic over activity
Teratogenicity: Capacity of a drug to cause foetal abnormalities when administered to the

pregnant mother.
Drugs can a ect the foetus at 3 stages:
1. Fertilization and implantation (Conception to 17 days): failure of pregnancy which often

goes unnoticed.
2. Organogenesis(18 days to 55 days): most vulnerable period, deformities are produced.
3. Growth and development (> 56 days): developmental and functional abnormalities can
occur.
Examples:
• Thalidomide – Phocomelia, multiple defects
• Anticancer drugs – Cleft palate, hydrocephalus, multiple defects
• ACE inhibitors – Hypoplasia of organs (lungs, kidney)
Mutagenecity and Carcinogenicity:
Capacity of a drug to cause genetic defects is called mutagenecity and causing cancer is
called Carcinogenicity. Chemical carcinogenesis generally takes several (10-40) years to de-
velop.
Examples:
• Anticancer drugs,
• Radio-isotypes,
• Estrogens,
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• Tobacco.
Drug induced disease: Also called Iatrogenic(Physician induced) diseases.
These are functional disturbances caused by drugs which persist even after the o ending
drug has been withdrawn and largely eliminated
Examples:
• Salicylates, Corticosteroids – Peptic ulcer
• Phenothiazines, other antipsychotics – Parkinsonism
Medication error: A medication error is an unintended failure in the drug treatment process
that leads to, or has the potential to lead to, harm to the patient. A failure in the drug
treatment process does not refer to lack of e cacy of the drug, rather to human or process
mediated failures.
O -label use: Situations where a medicinal product is intentionally used for a medical pur-
pose not in accordance with the terms of the marketing authorisation.
Examples include the intentional use of a product in situations other than the ones de-
scribed in the authorised product information, such as:
• Medicine used for disease or medical condition that it is not approved to treat
• Medicine administration through di erent route or method of administration
• Medicine used with di erent dose (posology)
• Medicine used in di erent group of patients (population)
Overdose: Administration of a quantity of a medicinal product given per administration or

cumulatively which is above the maximum recommended dose according to the authorised
product information. Clinical judgement should always be applied.
Causal relationship: Causal assessment is determined based on temporal relationship, alterna-

tive explanations, and (if possible) dechallenge and rechallenge. According to the WHO, the
causal relationship between an adverse event and a suspected drug can be:
• certain
• probable/likely
• possible
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• unlikely
• conditional/unclassi ed
• unassessable/unclassi able.
Important medical event (IME): The EudraVigilance Expert Working Group has co-ordinated
the development of an important medical event (IME) terms list based on the Medical Dic-
tionary for Regulatory Activities (MedDRA). This IME list aims to facilitate the classi ca-
tion of suspected adverse reactions, the analysis of aggregated data and the assessment of
ICSRs in the framework of the day-to-day pharmacovigilance activities.
Identi ed risk: An untoward occurrence for which there is adequate evidence of an association
with the medicinal product of interest.
Potential risk: An untoward occurrence for which there is some basis for suspicion of an asso-
ciation with the medicinal product of interest but where this association has not been con-
rmed.
Important risk: An identi ed risk or potential risk that could have an impact on the risk-bene-
t balance of the product or have implications for public health.
Risk-bene t balance: An evaluation of the positive therapeutic e ects of the medicinal product
in relation to the risks, i.e. any risk relating to the quality, safety or e cacy of the medicinal
product as regards patients’ health or public health
Safety concern: An important identi ed risk, important potential risk or missing information
Signal: Information arising from one or multiple sources, including observations and exper-
iments, which suggests a new potentially causal association, or a new aspect of a known as-
sociation between an intervention and an event or set of related events, either adverse or
bene cial, that is judged to be of su cient likelihood to justify further investigation
CCDS: Company Core Data Sheet: The CCDS is a document that re ects the full company’s
knowledge and data evaluation for a medicinal product
CCSI: Company Core Safety Information: The CCSI is the safety information contained in
the CCDS
DLP: Data Lock point: The DLP represents the cut-o date for data and analyses presented
in a document.
DSUR: Development Safety Update Report: Comprehensive, thoughtful annual review and eval-
uation of pertinent safety information collected during the reporting period related to a drug
under investigation, whether or not it is marketed
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IB: Investigator ś Brochure: The IB is a compilation of the clinical and nonclinical data on the
investigational product(s) that are relevant to the study of the product(s) in human sub-
jects.
International Birth Date: The date of the rst marketing authorisation for any product contain-
ing the active substance granted to any company in any country in the world
Periodic Safety Update Report (PSUR) / Periodic Bene t-Risk Evaluation Report (PBRER): Pharma-
covigilance document intended to provide an evaluation of the risk-bene t balance of a med-
icinal product for submission by marketing authorisation holders at de ned time points dur-
ing the post-authorisation phase
Risk management system: The RMS covers the entire life-cycle of a medicinal product.
Risk Management Plan: A set of pharmacovigilance activities and interventions designed to

identify, characterise, prevent or minimise risks relating to medicinal products, including
the assessment of the e ectiveness of those activities and interventions. The RMP is a dy-
namic, stand-alone document that should be updated throughout the life-cycle of the medic-
inal product to re ect the increasing knowledge on risks and bene ts and the post-market-
ing experience with the product.
Summary of Product Characteristics: The SmPC is the basis of information for the healthcare
professional on how to use the medicine. Its information is updated throughout the life-cy-
cle of the product as new data emerge. The SmPC is a legal document approved as part of
the marketing authorisation of a medicinal product in the European Union.
Medical Con rmation: A situation in which a healthcare professional, preferably one directly
involved in the care of the patient (primary healthcare provider), con rms (i.e., agrees) that
the circumstances as reported by or on behalf of the patient occurred and that the facts, as
amended or updated in the con rmation process, constitute an adverse event case for which
there is a suspicion by that healthcare professional of drug causality (thus, it should be con-
sidered an ADR).
Individual case safety report (ICSR): This is an adverse drug reaction report, involving the re-
porting of one or several suspected adverse reactions in relation to a medicinal product that
occur in a single patient at a speci c point of time. A valid report should include at least one
identi able reporter, one single identi able patient, at least one suspect adverse reaction and
at least one suspect medicinal product. "
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SOURCES OF INDIVIDUAL CASE RE-
PORTS
The source of a report can be an important factor for the evaluator; awareness of the source
contributes to an understanding of the quality and value of the information for assessing a
case. The nature, amount and even feasibility of any needed follow-up will also be highly
dependent on the source. Depending on the source of adverse event information the correct
report type need to be selected.
Below are the sources for individual case reports;
1. Spontaneous / Voluntary Reports
2. Literature Reports
3. Reports from other sources (social media/press, etc.,)
4. Solicited Reports
5. License partner reports
6. Regulatory Authority reports
7. Legal Reports
SPONTANEOUS REPORTS:
A spontaneous report is an unsolicited communication by a healthcare professional or con-

sumer to the Agency or the marketing authorization holder that describes one or more sus-
pected adverse reactions in a patient who was given one or more medicinal products and
that does not derive from a study or any organized data collection program.
Reports that follow a direct healthcare professional communication, publication in the

press, questioning of healthcare professionals by company representatives, including prod-
uct promotion representatives, communication from patients’ organizations to their mem-
bers, or class action lawsuits should be considered spontaneous reports. Unsolicited con-
sumer adverse reaction reports should be handled as spontaneous reports, irrespective of
any subsequent ‘medical con rmation.’
LITERATURE REPORTS:
The scienti c and medical literature is a signi cant source of information for the monitoring
of the safety pro le and of the risk-bene t balance of medicinal products, particularly in re-
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lation to the detection of new safety signals or emerging safety issues. Marketing authoriza-
tion holders are therefore expected to maintain awareness of possible publications through a
systematic literature review of widely used reference databases (e.g. Medline, Excerpta Med-
ica or Embase) no less frequently than once a week. The marketing authorization holder
should ensure that the literature review includes the use of reference databases that contain
the largest reference of articles in relation to the medicinal product properties. In addition,
marketing authorization holders should have procedures in place to monitor scienti c and
medical publications in local journals in countries where medicinal products have a market-
ing authorization, and to bring them to the attention of the company safety department as
appropriate.
Reports of suspected adverse reactions from the scienti c and medical literature, including
relevant published abstracts from meetings and draft manuscripts, should be reviewed and
assessed by marketing authorization holders to identify and record ICSRs originating from
spontaneous reports or non-interventional post-authorization studies .
REPORTS FROM OTHER SOURCES
If a marketing authorization holder becomes aware of a report of suspected adverse reac-

tions originating from a non-medical source (e.g. the press or other media), it should be
handled as a spontaneous report. Every attempt should be made to follow-up the case to ob-
tain the minimum information that constitutes a valid ICSR. The same reporting time
frames should be applied as for other spontaneous reports.
Information on suspected adverse reactions from the Internet or digital media: Marketing
authorization holders should regularly screen the Internet/digital media under their man-
agement or responsibility, such as web sites, web pages, blogs, vlogs, social networks, Inter-
net forums, chat rooms, or health portals, for potential reports of suspected adverse reac-
tions. In this aspect, digital media is considered to be company sponsored if it is owned,
paid for and/or controlled by the marketing authorization holder. A donation ( nancial or
otherwise) to an organization/site by a marketing authorization holder does not constitute
ownership, provided that the marketing authorization holder does not control the nal con-
tent of the site.
If a marketing authorization holder becomes aware of a report of suspected adverse reaction

described in any non-company sponsored digital medium, it should assess the report to de-
termine whether it quali es for reporting.
Unsolicited cases of suspected adverse reactions from the Internet or digital media should
be handled as spontaneous reports. The same reporting time frames as for spontaneous re-
ports should be applied.
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REPORTS ORIGINATING FROM SOLICITED SOURCES:
Solicited reports of suspected adverse reactions are those derived from organized data col-
lection systems, which include clinical trials, non-interventional studies, registries, o -label
or named patient use, other patient support and disease management programs, surveys of
patients or healthcare providers, compassionate use programs or information gathering on
e cacy or patient compliance. Adverse reactions reports obtained from any of these data
collection systems should not be considered spontaneous. This is with the exception of sus-
pected adverse reactions originating from o -label use where adverse events are not actively
sought. Reports from clinical trials should be conducted according to the “Regulation on
Clinical Trials” and related guidelines.
LICENSE PARTNER REPORTS:
A Pharma company get into a licensing agreement with third party to produce or market a
drug formulation that the other company has developed. Each license partners does have
pharmacovigilance agreement to meet safety requirements in marketing country.
Pharmacovigilance Agreement means an agreement entered into by the Pharma companies

to set forth the protocols and procedures for reporting adverse events and complying with
reporting requirements set forth by Regulatory Authorities. The cases received from other
pharmaceutical company which has PVA agreement need to be handled as license partner
cases.
REGUL ATORY AUTHORIT Y REPORTS:
If consumer or healthcare professional directly report adverse events to regulatory authority

(i.e, FDA, EMA etc..) not to marketing holder (pharmaceutical company), then those re-
ports will be shared to marketing holders by regulatory authorities. This type of cases which
were received by companies from regulatory authority are to be handled as regulatory au-
thority cases.
LEGAL REPORTS:
The safety information reported by lawyer on behalf of individual patient or group of pa-
tients concerned with occurrence of adverse reactions associated with medical product use
are to be handled as legal reports.
The reports originating from solicited sources (Interventional clinical trials, non-interven-
tional studies, registries, o -label or named patient use, other patient support and disease
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management programs, compassionate use programs, marketing program and patient sup-
port, investigator initiated trials) are called Solicited ICSR reports and other source of re-
ports (Spontaneous, Literature, Regulatory Authority, Legal, License partner, Internet etc.,)
are considered as non solicited ICSR reports."
PHARMACOVIGIL ANCE PROCESS
Pharmacovigilance includes multiple steps through which a case pass from initial receipt to
reporting to Regulatory Authority.
Below are the steps in Pharmacovigilance process;
1. Individual case safety report
2. Aggregate Reporting
3. Signal Management
4. Risk Management
INDIVIDUAL CASE SAFET Y REPORT (ICSR):
ICSR is an adverse drug reaction report, involving the reporting of one or several suspected
adverse reactions in relation to a medicinal product that occur in a single patient at a speci c
point of time. A valid report should include at least one identi able reporter, one single
identi able patient, at least one suspect adverse reaction and at least one suspect medicinal
product.
ICSR Processing includes multiple steps:
1. Case receipt / Triaging
2. Case validity check
3. Data Entry and Duplicate check
4. Coding of Drugs
5. Coding of Adverse events
6. Seriousness, causality and labelling assessment
7. Case Narrative
8. Case follow up
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AGGREGATE REPORTING:
Aggregate reporting is the process that reviews the cumulative safety information from a
wide range of sources, on a periodic basis and submits the ndings to regulators worldwide.
Types of Aggregate reports: Based on marketing authorisation status, di erent types of re-
ports are prepared by MAH, which includes pre marketing aggregate reports and post mar-
keting aggregate reports.
Pre Marketing Aggregate reports:
1. Annual Safety report in Europe
2. IND annual reports in United States
However these two documents were replaced by a well harmonised document, Developmen-
tal Safety Update Report (DSUR), in which health regulators in ICH regions can receive the
same information at the same time.
Post Marketing Aggregate reports:
1. Periodic Safety Update Reports (PSUR)/Periodic Bene t- Risk evaluation reports (PBR-
ER)
2. Periodic Adverse Drug Experience Report (PADER)
3. NDA and ANDA Annual Reports in US
4. Addendum Clinical Overviews (ACO)
5. Risk Management Plans (RMP)
SIGNAL MANAGEMENT:
As per GVP Module VI, a signal is de ned as Information arising from one or multiple
sources, including observations and experiments, which suggests a new potentially causal
association, or a new aspect of a known association between an intervention and an event or
set of related events, either adverse or bene cial, that is judged to be of su cient likelihood
to justify further investigation.
Signal Management Include Activities of;
1. Signal Detection
2. Signal Validation
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3. Signal prioritisation
4. Signal Assessment
5. Exchange of information
6. Recommendation for action
ICSR - CASE PROCESSING
Individual case safety report (ICSR) is an adverse drug reaction report, involving the report-
ing of one or several suspected adverse reactions in relation to a medicinal product that oc-
cur in a single patient at a speci c point of time. A valid report should include at least one
identi able reporter, one single identi able patient, at least one suspect adverse reaction and
at least one suspect medicinal product.
The rst step in ICSR case processing is checking validity of received adverse event report.
VA L I DAT I O N O F R E P O R T S :
Only valid ICSRs should be reported and all reports of suspected adverse reactions should
be validated before reporting them to the Agency to make sure that the minimum criteria
for reporting are included in the reports. The minimum criteria include the following:
1. Identi able Reporter:
Below criteria are used to check validity of reporter:
• Report must have one identi able reporter (primary source), characterized by professional
quali cation (e.g. physician, pharmacist, dentist, nurse, midwife, lawyer, consumer or oth-
er non-healthcare professional) name, initials or address.
• Whenever possible, contact details for the reporter should be recorded so that follow-up
activities can be performed. However, if the reporter does not wish to provide contact de-
tails, the party receiving the report should con rm this with the reporter, and indicates it
on the ICSR.
• All parties providing case information should be identi able, not only the reporter.
• The reporter should have rst hand knowledge on event experience.in the event of second-
hand reports, every reasonable e ort should be made to verify the existence of an identi -
able patient and reporter.
2. Identi able patient:
• One single identi able patient characterized by initials, le number, date of birth, age, age
group or address. The information should be as complete as possible.
• Incase of absence of any of the above patient details, the case can still be considered as
valid if report clearly de nes there is a patient who experienced event with suspect prod-
uct.
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Criteria for non Identi able patient:
• A report referring to a de nite number of patients should not be regarded as a case until
the minimum four criteria for case reporting are met. For example, “Two patients experi-
enced…” or “ a few patients experienced” should be followed up for patient-identi able
information before regulatory reporting.
• Medical inquiries about AEs with no patient
3. Suspect product:
• Report must have one or more suspected substance/medicinal product (the classi cation
of medicinal products as suspect, interacting or concomitant should be based on the in-
formation provided by the primary source). If the case received by any marketing holder
then it is the company responsibility to check if the product which caused adverse event
belong to their company to not.
Below criteria are used to check validity of suspect product:
• Product registered status, marketing status, in-licensed, or co- promoted by company

or MAH (globally or locally)
• If only generic formulation is mentioned in report without manufacturer name then

marketing status of a generic formulation will be checked.
• For clinical trial cases if patient enrolled in trial and receiving study medication/blinded
product/placebo then it is considered as valid report.
Criteria for not a valid suspect drug:
• A generic formulation of a company product (manufacturer known)
• No event reported to company drug (in this situation report will be sent to marketing
holder of suspect product)
4. Adverse event:
• The report must have one or more suspected adverse reaction.
• For an event to be considered reportable to regulatory authority it should meet all of the
following criteria.
- An event must have occurred after receiving product. Typical events can be:
1. A speci c symptom or diagnosis
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2. Abnormal laboratory nding
3. Drug/food interaction
4. Lack of e cacy or lack of expected therapeutic e ect (as de ned in the product label),
disease aggravation, aggravation of pre existing condition.
5. Medication errors
6. Pregnancy
7. Overdose, Abuse, dependencies, withdrawal syndrome, accidental administration
8. Product quality errors, an inaccuracy in the labelling, instructions for use and/or in
promotional materials. Inaccuracies include omissions and de ciencies.
9. An identi ed medical device is associated with the event.
10.The death of a patient, user, or other person
11.Serious injury to a patient, user, or other person. Serious injury being a life threatening
illness or injury; permanent impairment of a body function or permanent damage to a
body structure; a condition necessitating medical or surgical intervention to prevent
permanent impairment of a body function or permanent damage to a body structure.
!
The lack of any of these four elements means that the case is considered incomplete and
does not qualify for reporting. Marketing authorization holders are expected to exercise due
diligence in following up the case to collect the missing data elements. Reports, for which
the minimum information is incomplete, should nevertheless be recorded within the mar-
keting authorization holder’s pharmacovigilance system for use in on-going safety evalua-
tion activities.
FOLLOW-UP OF REPORTS
When rst received, the information in suspected adverse reactions reports may be incom-
plete. These reports should be followed-up as necessary to obtain supplementary detailed
information signi cant for the scienti c evaluation of the cases. This is particularly relevant
for monitored events of special interest, prospective reports of pregnancy, cases notifying
the death of a patient, cases reporting new risks or changes in the known risks. This is in
addition to any e ort to collect missing minimum information. Any attempt to obtain fol-
low-up information should be documented.
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Follow-up methods should be customized for the case to optimize the collection of missing
information. This should be done in ways that encourage the primary source to submit rele-
vant new information. Requesting the primary source to repeat information already provid-
ed in the initial report and/or to complete extensive questionnaires should be avoided, as
this may discourage future spontaneous reporting by this source. Therefore, consideration
should be given to pre-populating some data elds in those follow-up report forms to make
their completion by the primary source more convenient.
If the information received directly from a consumer is incomplete but suggests that an ad-
verse reaction may have occurred, attempts should be made to obtain consent to contact a
nominated healthcare professional to obtain further follow-up information. When such a
case, initially reported by a consumer, has been con rmed (totally or partially) by a health-
care professional, this information should be clearly highlighted in the ICSR.
For suspected adverse reactions relating to biological medicinal products, the de nite identi-
cation of the concerned product with regard to its manufacturing is of particular impor-
tance. Therefore, all appropriate measures should be taken to clearly identify the name of
the product and the batch number.
DUPLIC ATE SEARC H
A duplicate case refers to the same individual case reported by di erent senders, through
di erent routes to describe suspected adverse reaction(s) related to the administration of
one or more medicinal products to an individual patient at a particular point of time.
Common causes of duplicate reports are:
• A consumer and healthcare professional reporting the same event/reaction occurrence
• Multiple healthcare professionals treating the same patient reporting the same event/
reaction occurrence
• An event/reaction occurrence being reported by the original reporter to both the MAH
and the NCA
• Literature reporting of the same event/reaction occurrence for generics.
Impact of duplicate cases:
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Detection and handling of duplicates by National Competent Authorities (NCAs), Market-
ing Authorisation Holders (MAHs) and Sponsors of clinical trials is an important element of
good case management.
The presence of duplicates in any pharmacovigilance system can create misleading signals
and therefore impact on the safety monitoring and potential regulatory actions.
CODING IN DRUG DICTIONARIES:
Medicinal products or drugs are coded using drug dictionaries integrated in drug safety
database.
The safety database comprise of two drug dictionaries
1.WHODD for coding products which are not manufactured by company
2.Company drug dictionary for coding of products manufactured by company
1. WHODD: WHODrug Global is the international reference for medicinal product infor-
mation and it is maintained by the Uppsala Monitoring Centre. With its unique drug
code hierarchy and extensive coverage, it provides a consistent drug dictionary with ex-
act terminology when coding concomitant medications. The dictionary is used to identi-
fy drug names and evaluate medicinal product information, including active ingredients
and products’ anatomical and therapeutic classi cations, from nearly 150 countries.
• WHODrug data covers both conventional medicines and herbal remedies. The conven-
tional medicines include prescription-only products, over-the-counter (OTC) and phar-
macist-dispensed preparations, as well as biotech and blood products, diagnostic sub-
stances and contrast media. Products and substances registered by the US Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) are also routinely
recorded.
• It is created in 1968 and the data is continuously updated, with new releases twice a year,
on 1 March and 1 September, and available to subscribers either as text and csv les or
via our browsing tool, WHODrug Insight.
• Since 2005 there have been major developments in the forms of
• WHO Drug Dictionary Enhanced
• WHO Herbal Dictionary (covers traditional and herbal medicines)
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• Regulators around the world (FDA, PMDA, EMA) recommend using WHODrug En-
hanced Dictionary
WHODrug dictionary
• is an unique hierarchical drug-code system
• contains exact terminology
• helps to identify product names
• lists active ingredients
• delivers the preferred term/name for a medication
• It uses the Anatomical Therapeutic Chemical (ATC) classi cation system
ATC Classi cation System:
ATC is used for the classi cation of active ingredients of drugs according to the organ or
system on which they act and their therapeutic, pharmacological and chemical properties
ATC contains 5 level:
• First level indicates the anatomical main group (there are 14 groups)
• Second level of the code indicates the therapeutic main group
• Third level indicates the therapeutic/pharmacological subgroup
• Fourth level indicates the chemical/therapeutic/pharmacological subgroup
• Fifth level of the code indicates the chemical substance
Structure of an ATC code for "Furosemide":
• rst level consists of one letter, e.g. “C” for Cardiovascular system
• second level consists of two digits, e.g. “C03” for Diuretics
• third level consists of one letter, e.g. “C03C” for High-ceiling diuretics
• fourth level consists of one letter, e.g. “C03CA” for Sulfonamides
• fth level consists of two digits, e.g. “C03CA01” for Furosemide
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But: there may be di erent codes for the same drug available when it is used for a di erent
purpose, route or dosing:
Acetylsalicylic acid code is “B01AC06” as platelet aggregation inhibitor
and “A01AD05” as a drug for local oral treatment (stomatology)
and “N02BA01” being used as pain killer.
2. Company Drug Dictionary: All company suspect products must be coded with company
drug dictionary.
EVENT CODING AND MEDDRA:
Adverse event coding is the process by which information from an adverse e ect reporter, is
coded using standardized terminology from a medical coding dictionary, such as MedDRA
(the most commonly used medical coding dictionary). The purpose of medical coding is to
convert adverse event information into terminology that can be readily identi ed and ana-
lyzed.
For instance, Patient 1 may report that they had experienced “a very bad headache that felt
like their head was being hit by a hammer” [Verbatim 1] when taking Drug X. Or, Patient 2
may report that they had experienced a “slight, throbbing headache that occurred daily at
about two in the afternoon” [Verbatim 2] while taking Drug Y. Neither Verbatim 1 nor Ver-
batim 2 will exactly match a code in the MedDRA coding dictionary. However, both quotes
describe di erent manifestations of a headache. As a result, in this example both quotes
would be coded as PT Headache (PT = Preferred Term in MedDRA).
Medical Dictionary for Regulatory Activities (MedDRA):
ICH MedDRA Management Committee appointed by the ICH Assembly to provide over-
sight of MedDRA related activities and the Maintenance and Support Services Organization
(MSSO)
De nition: MedDRA is a clinically-validated international medical terminology used by regulatory au-

thorities and the regulated biopharmaceutical industry. The terminology is used through the entire regula-
tory process, from pre-marketing to post-marketing, and for data entry, retrieval, evaluation, and presen-
tation.
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MedDRA is updated by the MSSO twice yearly. The rst annual release in the spring in-
cludes changes to all levels in MedDRA (if any occur). The second release in the autumn is
minor and only includes changes to terms at the PT and LLT levels (e.g., new terms, spelling
changes, non-current LLTs).
Where MedDRA is Used:
• Regulatory Authority and Industry Databases
• Individual Case Safety Reports and Safety Summaries
• Clinical Study Reports
• Investigators’ Brochures
• Core Company Safety Information
• Publications Prescribing Information
• Marketing Applications
• Advertising
Purpose of MedDRA:
• To Facilitate the exchange of clinical information through standardization
• Important tool for product evaluation, monitoring, communication, electronic records ex-
change, and oversight
• Supports coding (data entry) and retrieval and analysis of clinical information about hu-
man medical products including pharmaceuticals, biologics, vaccines, and drug-device
combination products
Scope of MedDRA:
In-scope: MedDRA is used to code medical conditions, indications, investigations (tests, re-
sults), medical and surgical procedures, medical, social, family history, medication errors,
product quality issues, device-related issues, product use issues, pharmacogenetic terms,
toxicologic issues and standardized queries
Out of scope:
• MedDRA is not a frequency quali ers
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• Numerical values for results cannot be coded using MedDRA
• It can not describe severity
• It is not an equipment, device or diagnostic product dictionary,
• Clinical trial study design terms, Patient demographic terms and drugs cannot be coded
using MEdDRA
For example if we receive the case with below information then all highlighted information
has to be coded with MedDRA.
Sample Narrative: A 75-year-old male receiving Drug X for rheumatoid arthritis developed
symptomatic aortic valve stenosis. The patient’s medical history is signi cant for colon
cancer and cigarette smoking. He underwent an aortic valve replacement and developed
a sternal wound infection three days post-surgery.
MedDRA Structure:
MedDRA can be used to analyse individual medical events (e.g., In uenza) or issues involv-
ing a system, organ or etiology (e.g., Infections) using its hierarchical structure.
It has 5 levels and is hierarchical totalling over 80000 terms:
System organ classes (SOCs)
Higher level group terms (HLGTs)
Higher level terms (HLTs)
Preferred terms (PTs)
Lowest level terms (LLTs)
1. “Lowest Level Terms” (LLTs): re ects how information is reported by reporter (verba-
tim). It is most speci c and most accurate to the reported term.
2. “Preferred Terms” (PTs) are single concepts for symptoms, signs, disease diagnoses,
therapeutic indications, investigations, surgical or medical procedures, and medical, so-
cial or family history characteristics.
3. Related PTs are grouped together into “High Level Terms” (HLTs) based upon anatomy,
pathology, physiology, etiology or function. HLTs are in turn linked to “High Level
Group Terms” (HLGTs).
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4. Finally, HLGTs are grouped into “System Organ Classes” (SOCs) which are grouped by
etiology (e.g., Infections and infestations), manifestation site (e.g., Gastrointestinal
disorders) or purpose (e.g., Surgical and medical procedures).
SERIOUSNESS ASSESSMENT
One of the main objectives of ADR monitoring is to avoid any delay in decisions a ecting
the public health with regard to the use of medicines. However, for products under devel-
opment as well as for marketed drugs, the typically large volume of clinical safety informa-
tion precludes the ability to document, validate, evaluate and report all experiences with the
same degree of priority. It is necessary to select information which might require urgent de-
cisions, i.e., information regarding events that create a threat for patients’ life or function
(‘‘seriousness criteria’’), previously undocumented events (‘‘expectedness criteria’’).
As per ICH guideline (E2A) a Serious Adverse Event is:
Any untoward medical occurrence or e ect that at any dose results in
1. death,
2. life-threatening,
3. requires hospitalisation or prolongation of existing hospitalisation,
4. results in persistent or signi cant disability or incapacity,
5. congenital anomaly or birth defect,
6. any event that may not result in death/be life threatening/require hospitalisation may
be considered a serious adverse drug experience when, based upon medical judgment,
it may jeopardise the patient or subject and may require medical or surgical interven-
tion to prevent one of the outcomes listed in this de nition.
Common Terminology Criteria for Adverse Events:
The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology
which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provid-
ed for each AE term.
Grades: Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with
unique clinical descriptions of severity for each AE based on this general guideline:
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Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; in-
tervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age- ap-
propriate instrumental Activities of Daily Living.
Grade 3: Severe or medically signi cant but not immediately life-threatening; hospitalisation
or prolongation of hospitalisation indicated; disabling; limiting self care ADL.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE
LISTEDNESS/EXPECTEDNESS ASSESSMENT
There are two principal criteria that control the priority for documenting, validating, evalu-
ating and regulatory-reporting of ADR cases: seriousness and expectedness.
The concept of expectedness refers to events that may or may not have previously been ob-
served and documented. It does not refer to what might be anticipated (expected in a di er-
ent sense) from the known pharmacological properties of the medicine. Nor does it refer to
what may occur in the course of the treated disease such as in the case of disease progres-
sion and/or lack of drug e ect.
An adverse reaction will be unexpected in the regulatory sense unless it is mentioned in the
appropriate reference safety information (RSI) document(s) for the drug, even if it is a med-
ical occurrence expected for the disease being treated.
Depending on the status and circumstances of the drug, RSI may be one or more of the fol-
lowing:
• Investigator Brochure (IB)
• CCSI for investigational drugs that have not been approved or pre-marketed drugs.
• RSI can also be a CCDS, IB, SmPC, package insert (USPI) and product insert and these
apply to drugs that have been approved or post-marketing drugs.
Investigator Brochure (IB): a compilation of the clinical and nonclinical data on the investiga-
tional product(s) that are relevant to the study of the product (s) in human subjects.
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Company Core Safety Information (CCSI): a clinical safety reference of all relevant safety infor-
mation contained in the company core data sheet prepared by the MAH and that the MAH
requires to be listed in all countries where the company markets the drug, except when local
regulatory authority speci cally requires a modi cation. It is the reference information by
which listed and unlisted are determined for the purpose of periodic reporting for marketed
products, but not by which expected and unexpected are determined for expedited report-
ing.
Company Core Data Sheet (CCDS): a document prepared by the manufacturer, containing all
relevant safety information, such as adverse drug reactions, which the manufacturer requires
to be listed for the drug in all countries where the drug is marketed. It is the reference doc-
ument by which labeled and unlabelled are determined for the purpose of international ADR
reporting. Also referred to as CCSI.
According to ICH E2C, the CCDS covers material related to safety, indications, dosing,
pharmacology, and other information concerning the product.
Development of Core Safety Information (DCSI): an independent section of an IB identical in

structure to the CCSI that contains a summary of all relevant safety information that is de-
scribed in more detail within the main body of the IB. It is the reference safety document
that determines whether an ADR is listed or unlisted.
Region-Speci c Labelling documents:
Each Marketing Authorisation Holder (MAH) maintains a reference safety document speci c
to the region. Also, each national regulatory authority maintains product speci c mono-
graphs which includes drug safety information.
Some of the region-speci c labelling documents presented below-
1. Summary of Product Characteristics (SmPC): The RSI for European Medicines Agency
(EMA) region or any country speci c document for national competent authorities in
Europe.
2. United States Prescribing Information (USPI): Country speci c labelling document for
United States of America.
3. Japanese Prescribing Information (JPI): Country Speci c labelling Document for Japan.
4. Canadian Monographs (CM): Country Speci c labelling Document for Canada.
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Many di erent terms are currently used to indicate expected or unexpected:
The terms ‘Listed/Labelled” are used during assessment for the “Marketed products”.
The term “Expectedness” is used during assessment for “Developmental drugs or Investiga-
tional molecules.”.
1. Expectedness means the AE whether serious or not is already listed in the IB or CCSI.
2. Unexpectedness: the AE whether serious or not is not listed in the IB or CCSI.
3. Labeled/Unlabeled: For a product with an approved marketing application, any reaction

which is not mentioned in the o cial product information is unlabeled. If it is includ-
ed, it is termed labeled. O cial product information refers to SmPCs, package inserts,
or product data sheets.
4. Listedness/Unlistedness: any reaction which is not included in the Company Core Safe-
ty Information within a company’s core data sheet for a marketed product is unlisted. If
it is included it is termed listed.
What is Expectedness?
Expectedness refers to the AE being previously observed and documented in Reference Safe-
ty Information (i.e. IB, SmPC, Package Insert, CCSI).
What is not Expectedness?
1. Expected does not mean that the AE could have been anticipated, e.g., from the known
pharmacological properties of the medicine.
2. Expected does not refer to what may occur in the course of the treated disease such as
in the case of disease progression and/or lack of e ect.
What is Unexpectedness?
Unexpectedness refers to AE not being observed or documented in the Reference Safety In-
formation.
What is Unexpectedness Assessment?
1. Unexpectedness assessment is deciphering whether the reported adverse event is dif-

ferent in its nature, severity, speci city or usual outcome relative to the term/descrip-
tion used in Reference Safety Information. This is determining unexpectedness.
2. An AE will be unexpected in the regulatory sense unless it is mentioned in the appro-

priate RSI, even if it is a medical occurrence expected for the disease being treated.
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CAUSALIT Y ASSESSMENT
Causality is an assessment procedure used for the determination of relationship between a

drug treatment and the occurrence of an adverse drug event.
When a causal relationship is identi ed, then adverse drug event (ADE) would be called as
adverse drug reaction (ADR).
The assessment of causality is a common procedure in pharmacovigilance, which is done at

di erent levels which included physicians, investigators, professionals working in drug safe-
ty department of a pharmaceutical company and national health authorities which can assist
in taking regulatory decisions.
Causality is the key factor for identi cation of new signals, measuring the strength of evi-
dence, and in evaluating bene t risk pro le of pharmaceutical medicinal products.
Methods of causality assessment
There are several methods published to perform causality assessment. However, there were
no internationally agreed upon standards or criteria for assessing causality in ICSRs.
Below two methods are widely accepted and used for assessing causality globally.
1. WHO UMC causality assessment
2. Naranjo causality assessment
1. WHO UMC causality assessment
The World Health Organisation (WHO) and Upsala Monitoring center (UMC) at Sweden
has developed a system for causality assessment in consultation with the National Centers
participating in the International Drug Monitoring Programme.
It is meant as a practical tool for the assessment of causal relationship in ICSRs.
It is basically a combined assessment considering the clinical-pharmacological aspects of the

case history and the quality of the documentation of the observation.
The following causality terms are de ned based on their respective assessment criteria.
Causality term Assessment criteria
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Certain ◦ Event or laboratory test abnormality, with plausible time relation-
ship to drug intake
◦ Cannot be explained by disease or other drugs
◦ Response to withdrawal plausible (pharmacologically, pathological-
ly)
◦ Event de nitive pharmacologically or phenomenologically (i.e. an
objective and speci c medical disorder or a recognised pharmaco-
logical phenomenon)
◦ Rechallenge satisfactory, if necessary
Probable / Likely ◦ Event or laboratory test abnormality, with reasonable time relation-
ship to drug intake
◦ Unlikely to be attributed to disease or other drugs
◦ Response to withdrawal clinically reasonable
◦ Rechallenge not required
Possible ◦ Event or laboratory test abnormality, with reasonable time relation-

ship to drug intake
◦ Could also be explained by disease or other drugs
◦ Information on drug withdrawal may be lacking or unclear
Unlikely ◦ Event or laboratory test abnormality, with a time to drug intake that
makes a relationship improbable (but not impossible)
◦ Disease or other drugs provide plausible explanations
Conditional / Un- ◦ Event or laboratory test abnormality

classi ed ◦ More data for proper assessment needed, or
◦ Additional data under examination
Unassessable / Un- ◦ Report suggesting an adverse reaction

classi able ◦ Cannot be judged because information is insu cient or contradicto-
ry
◦ Data cannot be supplemented or veri ed.
Below table will aid in identi cation of causal criteria based on the assessment of various
factors.
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Category Temporal Rela- Concomitant medica- Dechallenge Rechal-
tionship tion use/Concurrent positive lenge pos-
Diseases (Alternative itive
causalities)
Certain Yes Yes Yes Yes
Probable Yes Yes Yes No
Possible Yes No No No
Unlikely No No No No
Unclassi able NA NA NA NA
2. Naranjo causality assessment
In the year 1991, Naranjo and co-workers from the University of Toronto developed the Ad-
verse Drug Reaction (ADR) Probability Scale to determine the likelihood of whether an
ADR is due to the medicinal product rather than the result of other contributory factors.
It is often referred to as the Naranjo Scale which is simple to apply and widely used.
ADR probability scale: The Naranjo Algorithm, or Adverse Drug Reaction Probability Scale,
is used to assess whether there is a causal relationship between an adverse drug experience
and a drug using a simple questionnaire to assign probability scores.
The questionnaire scale consists of 10 questions that are answered as either “Yes”, “No”, or
“Do not know”. Di erent point values (-1, 0, +1 or +2) are assigned to each answer.
Listed below are the ’10’ questions:
Question Yes No Do Not Score

Know
1. Are there previous conclusive reports on this reac- 1 0 0

tion?
2. Did the adverse event appear after the suspected 2 -1 0

drug was administered?
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3. Did the adverse event improve when the drug was 1 0 0
discontinued, or a speci c antagonist was adminis-
tered?
4. Did the adverse event reappear when the drug was 2 -1 0

re-administered?
5. Are there alternative causes that could on their own -1 2 0

have caused the reaction?
6. Did the reaction reappear when a placebo was given? -1 1 0
7. Was the drug detected in blood or other uids in 1 0 0

concentrations known to be toxic?
8. Was the reaction more severe when the dose was in- 1 0 0
creased or less severe when the dose was decreased?
9. Did the patient have a similar reaction to the same 1 0 0

or similar drugs in any previous exposure?
10. Was the adverse event con rmed by any objective 1 0 0

evidence?
Total Score:
The total scores range from “-4 to +13”
Criteria based on score:
Based on the total score, causality is assessed, and the strength of relationship is de ned.
De nite: If total score is ‘greater than or equal to 9’. A strong temporal relationship, positive
dechallenge and rechallenge scenarios. No alternative explanation for attribution/absence of
confounding factors.
Probable: If the total score lies in ‘between 5 and 8’. A reasonable temporal sequence, and a
recognised response of reaction outcome with respect to action taken on suspected drug.
Presence of alternative explanatory conditions like patient current conditions, medical histo-
ry etc.,
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Possible: If the total score lies in ‘between 1 and 4’. Attribution due to a reasonable tempo-
ral association or presence of positive reaction outcomes with respect to action on drug ad-
ministration (dose reduction/suspension/withdrawal)
Doubtful: If the total score is ‘less than or equal to 0’. Having alternative explanations with
a strong confounding factors which included medical history, concurrent illness, age group,
population (paediatric, geriatric), social habits (alcohol, tobacco use) etc.,
NARRATIVE WRITING
Narrative writing is an important part of Pharmacovigilance and in patient safety as well.
A narrative is a brief summary of speci c events experienced by patients, during the course
of a clinical trial/treatment. Narrative writing involves multiple activities such as generation
of patient pro les, review of data sources, and identi cation of events for which narratives
are required.
Purpose:
To provide a concise summary of identi ed/speci c adverse events (AEs) occurring in a pa-
tient to conclude causal relationship between the drug and event.
Objective:
The objective of the narrative is to summarize all relevant clinical and related information,
including patient characteristics, therapy details, prior medical history, clinical course of the
event(s), laboratory evidence and any other information that supports or refuses a diagnosis
for an ADR. The information should be presented in a logical time sequence.
Regulatory Perspectives:
The ICH guideline (E2B) on data elements and speci cations for electronic reporting of in-
dividual ADR cases states that company narratives are required for all serious reactions.
Narratives are expected to be submitted for all cases reported expeditiously to any regulato-
ry authority, but are useful and should be made available when needed for other types of re-
ports and purposes.
Most of the safety database include auto narrative option and after auto generating narrative
it is safety reviewer responsibility to optimise it according to company speci c format.
As per International Conference on Harmonisation (ICH) E3, a patient narrative should de-
scribe :
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• The nature, intensity and outcome of the event
• Clinical course leading to the event
• Timing of study drug administration
• Relevant laboratory measures
• Counter measures
• Action taken with the study drug in relation to the event
• Post mortem ndings (if applicable)
• Investigator’s and sponsor’s opinion on causality
• Additionally, patient identi er, age, gender, clinical condition, disease being treated,
relevant medical history, concomitant and prior medications should be included.
• All this information is extracted from the source les (e.g. Council for International
Organisations of Medical Sciences [CIOMS] form.
• The narrative preparer’s (sponsor’s) medical evaluation and comment.
Example of a Standard Narrative Template:
Case reference number XXXX is a spontaneous case report sent by a hospital pharmacist.
This report refers to an 84-year-old Caucasian male patient who experienced myocardial in-
farction while on qweasytrol.
The patient’s past medical history included gastric ulcer, asthma, and hypertension. At the
time of the event the patient had Lyme Disease and severe headache. The patient previously
took steroids (1990), cimetidine (1996), and tetracycline (09-Sep-1999). The patient had a
history of allergy to penicillin and gin.
The patient started taking qweasytrol from 01-Jan-2000 at 1:00 PM, at an unspeci ed dose
for vomiting. Some 12 hours later, and 10 minutes following the latest dose, the patient de-
veloped rash, dyspnea and queasiness. Over the period of the next two days, the patient also
developed chest pain and later unconsciousness.
Relevant laboratory test results include elevated CK-MB and relevant physical signs were
hypertension, fourth heart sound and bradycardia. The patient was hospitalized. Qweasytrol
was discontinued on 08-Jan-2000. The eventual diagnosis made on the 10-Jan-2000 was
myocardial infarction. The patient was treated for the event with a beta-blocker.
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The patient died on 12-Jan-2000 from myocardial infarction; no autopsy was done. Death
occurred 12 days after the treatment with qweasytrol began and 4 days after it was discon-
tinued.
The cardiologist cited in the pharmacist’s report considered the myocardial infarction possi-
bly related to qweasytrol. In his opinion, other possible etiological factors include hyperten-
sion and the patient’s age.
The company believes the following facts were also relevant in this case: as a highly selective
epsilon G2 receptor antagonist, there was no known plausible mechanism by which the drug
would cause a myocardial infarction.
REGUL ATORY REPORTIN G RE-
QUIREMENTS FOR ICSR
What Events should be Reported?
Each Regulatory authority has speci c requirement on ICSR reports submission, below are
the common requirements from di erent regulatory authorities:
1. For “new” drugs - report all suspected reactions, including minor ones (products on the
market less than ve years are usually considered “new” drugs)
2. For established or well-known drugs - report all serious or unexpected (unusual) sus-
pected ADEs;
3. Report if an increased frequency of a given reaction is observed;
4. Report all suspected ADEs associated with drug-drug, drug-food or drug- food supple-
ment interactions;
5. Report ADEs in special elds of interest such as drug abuse and drug use in pregnancy
and during lactation;
6. Report when suspected ADEs are associated with drug withdrawals;
7. Report ADEs occurring from overdose or medication error;
8. Report when there is a lack of e cacy or when suspected product quality problems are
observed.
9. Report any concerns about product presentation e.g. confusing labeling, packing
10. Report counterfeit products
11. Report reactions suspected of causing death, danger to life, admission to hospital, pro-
longation of hospitalization, birth defeats. !
When should an ADR be reported?
Regulatory reporting timeline start with initial receipt date ‘day 0’ of the ICSR. Day 0, is the
date when manufacturer received information about valid adverse event report.
The timelines for submitting an ICSR depends on country speci c regulatory requirements.
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Globally ICSR are reported under 3 categories :
1. Clinical trial - Death/Life threatening cases and SUSAR (Suspected Unexpected Seri-
ous Adverse Reaction) cases are reported within 7 calendar days to the HA (health au-
thorities.
2. Clinical trial other Serious cases and safety issues are reported in 15 calendar days
timeframe.
3. Serious post marketing cases are reported within 15 calendar days to the HA
4. Non-Serious cases are reported within 90 calendar days to the EU health authority
(EMA). Not mandatory for non-EU countries.
Characteristics of a Good Case Report
1. Adverse event(s) details
2. Baseline patient characteristics
3. Therapy details
4. Time to onset of symptoms and signs
5. Diagnosis of the event
6. Clinical course of the event and outcomes
7. Laboratory data
8. Any other relevant information !
REPORTS OF SPECIAL SITUATIONS
USE OF A MEDICINAL PRODUCT DURING PREGNANCY
OR BREASTFEEDING:
Pregnancy
Reports, where the embryo or fetus may have been exposed to medicinal products (either
through maternal exposure or transmission of a medicinal product via semen following pa-
ternal exposure), should be followed-up in order to collect information on the outcome of
the pregnancy and development of the child after birth. When an active substance or one of
its metabolites has a long half-life, this should be taken into account when assessing the
possibility of exposure of the embryo, if the medicinal product was taken before conception.
When pregnant women or healthcare professionals contact marketing authorization holders

to request information on the teratogenicity of a medicinal product or experience of use dur-
ing pregnancy, reasonable attempts should be made to obtain information on any possible
medicinal product exposure to the embryo or fetus and to follow-up on the outcome of the
pregnancy.
Reports of exposure to medicinal products during pregnancy should contain as many de-
tailed elements as possible in order to assess the causal relationships between any reported
adverse events and the exposure to the suspected medicinal product.
Individual cases with an abnormal outcome associated with a medicinal product following
exposure during pregnancy are classi ed as serious reports and should be reported.
This especially refers to:
• reports of congenital anomalies or developmental delay, in the fetus or the child;
• reports of fetal death and spontaneous abortion; and
• reports of suspected adverse reactions in the neonate that are classi ed as serious.
Reports of induced termination of pregnancy without information on congenital malforma-

tion, reports of pregnancy exposure without outcome data or reports which have a normal
outcome should not be reported since there is no suspected adverse reaction. These reports
should however be collected and discussed in the periodic safety update reports. !
However, in certain circumstances, reports of pregnancy exposure with no suspected reac-
tions may need to be reported. This may be a condition of the marketing authorization or
stipulated in the risk management plan. Examples include pregnancy exposure to medicinal
products contraindicated in pregnancy, or medicinal products with a special need for sur-
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veillance because of a high teratogenic potential (e.g. thalidomide, isotretinoin). !
A signal of a possible teratogenic e ect (e.g. a cluster of similar abnormal outcomes) should
be noti ed immediately to the regulatory authority.
Breastfeeding
Suspected adverse reactions which occur in infants following exposure to a medicinal prod-
uct from breast milk should be reported to the regulatory authorities.
USE OF A MEDICINAL PRODUCT IN THE PEDIATRIC OR

E L D E R LY P O P U L A T I O N
The collection of safety information in the pediatric or elderly population is important. Rea-
sonable attempts should therefore be made to obtain and report the age or age group of the
patient when a case is reported by a healthcare professional, or consumer in order to be able
to identify potential safety signals speci c to a particular population.
REPORTS OF OVERDOSE, ABUSE, OFF -L ABEL USE, MIS-

USE, MEDIC AL ERROR OR OCCUPATION EXPOSURE
Medication error refers to any unintentional error in the prescribing, dispensing, or adminis-
tration of a medicinal product.
Reports of overdose, abuse, o -label use, misuse, medication error or occupational exposure
with no associated adverse reaction should not be reported as ICSRs. They should be con-
sidered in periodic safety update reports as applicable. When those reports constitute safety
issues impacting on the risk-bene t balance of the medicinal product, they should be noti-
ed to the regulatory authorities.
Reports associated with suspected adverse reactions should be followed-up to ensure that
the information is as complete as possible with regards to the symptoms, treatments, out-
comes, context of occurrence (e.g., error in prescription, administration, dispensing, dosage,
unauthorized indication or population, etc.).
If a case of overdose, abuse, o -label use, misuse, medication error or occupational exposure
is reported with clinical consequences, the MedDRA (Lowest Level Term) code, correspond-
ing to the term closest to the description of the reported overdose, abuse, o -label use, mis-
use, medication error or occupational exposure should be selected.
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L AC K OF THERAPEUTIC EFFICACY
Reports of lack of therapeutic e cacy should be recorded, followed-up if data is incomplete,

and reported to the regulatory authorities within a 15-day time frame. Special care should
be taken with reports involving medicinal products used in critical conditions or for the
treatment of life-threatening diseases, vaccines, contraceptives are examples of such cases.
This applies unless the reporter has speci cally stated that the outcome was due to disease
progression and was not related to the medicinal product.
Clinical judgment should be used when considering if a case of lack of therapeutic e cacy
qualify for reporting. For example, an antibiotic used in a life-threatening situation where
the medicinal product was not in fact appropriate for the infective agent should not be re-
ported.
However, a life-threatening infection, where the lack of therapeutic e cacy appears to be

due to the development of a newly resistant strain of a bacterium previously regarded as
susceptible, should be reported within 15 days.
For vaccines, cases of lack of therapeutic e cacy should be reported, in particular with re-
gard to potential signals of reduced immunogenicity in a sub-group of vaccinees, waning
immunity, or strain replacement. With regard to the latter, it is considered that sponta-
neously reported cases of lack of therapeutic e cacy by a healthcare professional may con-
stitute a signal of strain replacement. Such a signal may need prompt action and further in-
vestigation through post-authorization safety studies as appropriate.
REPORTS REL ATED TO QUALIT Y DEFECTS OR COUNTER-

FEIT MEDICINAL PRODUCTS
When a suspected adverse reaction is associated with a suspected or con rmed counterfeit
medicinal product or quality defect of a medicinal product, an ICSR should be reported. The
seriousness of the ICSR is linked to the seriousness of the reported suspected adverse reac-
tions.
In order to protect public health, it may become necessary to implement urgent measures
such as the recall of one or more defective batches of a medicinal product from the market.
Therefore, marketing authorization holders should have a system in place to ensure that re-
ports of suspected adverse reactions related to counterfeit medicinal products or to quality
defects of a medicinal products are investigated in a timely fashion and that con rmed quali-
ty defects are noti ed separately to the manufacturer and to the regulatory authorities.
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REPORTS OF SUSPECTED TRANSMISSION OF AN INFEC-
TIOUS AGENT VIA A MEDICINAL PRODUCT
Any suspected transmission of an infectious agent via a medicinal product should be consid-
ered as a serious adverse reaction and such cases should be reported within 15 days. If no
other criterion is applicable, the seriousness of this ICSR should be considered as an impor-
tant medical event. This also applies to vaccines.
Marketing authorization holders should therefore have in place a system to inform con-
sumers, regulatory authorities of any transmission of an infectious agent via a medicinal
product.
Any organism, virus or infectious particle (e.g. prion protein transmitting Transmissible
Spongiform Encephalopathy), pathogenic or non-pathogenic, is considered an infectious
agent.
A transmission of an infectious agent may be suspected from clinical signs or symptoms, or

laboratory ndings indicating an infection in a patient exposed to a medicinal product.
Emphasis should be on the detection of infections/infectious agents known to be potentially

transmitted via a medicinal product, but the occurrence of unknown agents should also al-
ways be considered.
In the context of evaluating a suspected transmission of an infectious agent via a medicinal

product, care should be taken to discriminate, whenever possible, between the cause (e.g.,
injection/ administration) and the source (e.g., contamination) of the infection and the clin-
ical conditions of the patient at the time of the infection (immunosuppressed /vaccinee).
Con rmation of contamination (including inadequate inactivation/attenuation of infectious

agents as active substances) of the concerned medicinal product increases the evidence for
transmission of an infectious agent and may therefore be suggestive of a quality defect.
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VAC C I N E P H A R M AC OV I G I L A N C E
A higher standard of safety is expected of immunizations compared with medications be-
cause vaccines are given to healthy persons to prevent disease. The general public has low
tolerance to any adverse events following vaccination, this lower tolerance for risks from
vaccines translates into a greater need to detect and investigate any adverse event following
immunization (AEFI) than is generally expected for other pharmaceutical products.
Vaccine pharmacovigilance is de ned as the science and activities related to the detection, assessment, un-
derstanding and communication of adverse events following immunization and other vaccine-related or
immunization-related issues, and to the prevention of untoward e ects of the vaccine or immunization.
ADVERSE EVENTS FOLLOWIN G IMMUNIZATION (AEFI):
AEFI is any untoward medical occurrence which follows immunization and which does not
necessarily have a causal relationship with the usage of a vaccine. The adverse event may be
any unfavourable or unintended sign, abnormal laboratory nding, symptom or disease.
AEFIs are divided in 5 categories.
Vaccine product-related reaction: An AEFI that is caused or precipitated by a vaccine due to one
or more of the inherent properties of the vaccine product.
• Example: Extensive limb swelling following DTP vaccination.
Vaccine quality defect-related reaction: An AEFI that is caused or precipitated by a vaccine that is
due to one or more quality defects of the vaccine product including its administration device
as provided by the manufacturer.
• Example: Failure by the manufacturer to completely inactivate a lot of inactivated polio

vaccine leads to cases of paralytic polio.
Immunization error-related reaction: An AEFI that is caused by inappropriate vaccine handling,

prescribing or administration and thus by its nature is preventable.
• Example: Transmission of infection by contaminated multidose vial.
Immunization anxiety-related reaction: An AEFI arising from anxiety about the immunization.
• Example: Vasovagal syncope in an adolescent during/following vaccination.
Coincidental event: An AEFI that is caused by something other than the vaccine product, im-
munization error or immunization anxiety.
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• Example: A fever occurs at the time of the vaccination (temporal association) but is in
fact caused by malaria.
REPORTABLE AEFIS:
1. Serious AEFIs
2. Signals and events associated with a newly introduced vaccine
3. AEFI's caused because of immunisation errors
4. Signi cant events of unexplained cause occurring within 30 days of vaccination
5. Events causing signi cant parental/community concern
6. Injection site reactions lasting for more than 3 days
MATERIOVIGIL ANCE
Global Harmonization Task Force (GHTF) de ned a medical device as any instrument, appa-
ratus, implement, machine, appliance, implant, in vitro reagent or calibrator, software, ma-
terial, or other similar or related article, which is thereby intended to be used by the manu-
facturer for human beings for one or more of the speci c purposes of:
1. Diagnosis, prevention, monitoring, treatment, or alleviation of disease or compensation

for an injury
2. Investigation, replacement, modi cation, or support of the anatomy or of a physiologi-

cal process
3. Supporting or sustaining life
4. Control of conception
5. Disinfection of medical devices
6. Providing information for medical purposes by means of in vitro examination (such as

reagents, calibrators, sample collection kits, control materials, and related instruments)
of specimens derived from the human body and which does not achieve its primary in-
tended action in or on the human body by pharmacological, immunological, or meta-
bolic means, but which may be assisted in its function by such means.
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Medical device vigilance, as known as materiovigilance, is the collection, assessment, reporting and identi-
cation of trends in incidents resulting from the use of medical devices. Its primary purpose is to protect
and improve safeguards for patients, users and others by preventing or reducing the likelihood of reoccur-
rence of incidents elsewhere.
The purpose of materiovigilance is to study and follow incidents that might result from us-
ing medical devices. It enables dangerous devices to be withdrawn from the market and to
eliminate faults in medical devices with the intention of constantly improving the quality of
devices and providing patients and users with increased safety.
File a report with a medical device Regulatory Authority when:
• A death or serious deterioration of health has occurred.
• A serious public health threat has emerged.
• A sustained negative trend has developed.
• A recall or eld safety corrective action (FSCA) has been issued.
Generally, if labeling is su cient, reporting is not required when:
• There is a very small likelihood of death or serious injury.
• The incident was caused by patient/user error.
• The service life or shelf life of the device was exceeded.
• The side e ects were predictable and disclosed.
• A device problem was discovered by the user prior to use.
• The device shuto or fault mechanism worked as designed.
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PHARMACOVIGIL ANCE INSPECTION
AND AUDITS
PHARMACOVIGIL ANCE INSPECTIONS:
In order to determine that Marketing Authorisation Holders (MAHs) of human medicinal

products comply with pharmacovigilance obligations, and to facilitate compliance, pharma-
covigilance inspections of MAHs or any rms providing pharmacovigilance services to
MAHs are performed.
The objectives of pharmacovigilance inspections are;
• to determine that the marketing authorisation holder has personnel, systems and facil-
ities in place to meet their pharmacovigilance obligations,
• to identify, record and address non-compliance which may pose a risk to public health,
• to use the inspection results as a basis for enforcement action, where considered nec-
essary.
PHARMACOVIGIL ANCE AUDITS:
The audit in general is a systematic and independent examination of activities to determine

whether the evaluated activities were performed according to de ned requirements.
The PV audit activities verify, by evaluation of objective evidence, the appropriateness and
e ectiveness of the implementation and operation of a PV system including its quality sys-
tem for PV activities. The audit evidence can be relevant and veri able records, statements
or any other information.
In accordance with the EU Guideline on good pharmacovigilance practices, Marketing Au-

thorisation Holders (MAHs) are required to perform regular risk-based audits of their PV
system, and can any time be inspected by a governmental or o cial drug regulatory authori-
ty, by license partners, internal auditors or others.
The aim of these audits is to conduct a systematic, independent, disciplined and document-
ed process to obtain evidence of a functioning PV system; to evaluate the evidence objective-
ly and determine whether the system meets its goals; and then to contribute to improving
risk management, control, and governance processes.
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CASE SCENARIO
Read below adverse event reports and answer the questions following guidelines
C ASE SCENARIO : SPONTANEOUS ADVERSE REPORT

RECEIVED FROM A CONSUMER:
I (patient initials: CN) have SEVERE low potassium attacks since having the Mirena insert-
ed. I have had my Mirena for 5 years for contraception and just got another inserted less
then 6 months ago. I have experienced the following symptoms the past 5 years with this
IUD: Severe low potassium attacks wherein I was hospitalized 5 times. The symptoms of
low potassium are: headaches, dizziness, blurred vision, the chills, diarrhea, shallow breath-
ing, cramping in the tummy. Weight Gain. I have personally gained 60 pounds since this de-
vice has been inserted. Bloating in the abdomen area and lower back pain. I am planning to
have this device removed and pray that my health goes back to normal.
Check case validity criteria:
Validity Criteria YES NO
Identi able Reporter
Identi able patient
Suspect product
Adverse event
Select the seriousness of the case:
Seriousness Criteria YES NO
Death
Life-threatening
Hospitalization
Congenital anomoly
Disability
Important medical event
Non - serious
Write Case narrative:
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Answers:
• The case has identi able reporter (consumer details were provided), Identi able patient
(Consumer / patient details are available, gender can be considered as female based on re-
ported information) and the patient had experienced valid adverse events after using IUD
Mirena.
• The case has one serious event low potassium attacks (including symptoms) with serious-
ness criteria of hospitalisation and remaining events are non serious.
Narrative:
This is an initial spontaneous report from a consumer (patient) received on date (XXXX).
This report refers to a female patient who experienced low potassium, weight gain, bloating
in the abdomen area and lower back pain with Mirena (levonorgestrel-releasing intrauterine
device). The patient’s medical history and concomitant medication were not reported. The
patient had started using Mirena (levonorgestrel-releasing intrauterine device) since ve
years at an unknown dose for contraception. The patient had inserted new one less then 6
months ago. The patient had experienced severe low potassium attacks, for which she was
hospitalized 5 times. The patient experienced symptoms of headaches, dizziness, blurred vi-
sion, chills, diarrhea, shallow breathing and cramping in the tummy due to low potassium.
The patient had also experienced weight gain (gained 60 pounds since this device has been
inserted), bloating in the abdomen area and lower back pain. The patient had all these
events for 5 years. As of reported date (xxxx), no action was taken to drug due to events but
reported that she was planning to remove this device. The outcome of the event was not
mentioned.
The reporter considered event (low potassium) as serious and other events as non serious.
The reported assessed the events as related to Mirena.
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PHARMACOVIGIL ANCE INTERVIEW QUESTIONS
1. What are the Phases in a Clinical Trial ?
Answer: After preclinical research, tests and treatments go through a series of clinical trials.
Clinical trials assess if tests or treatments are safe for and work in people. Clinical trials
have four phases.
Phase 0: These trials are the rst clinical trials done among people. They aim to learn how a
drug is processed in the body and how it a ects the body. In these trials, a very small dose of
a drug is given to about 10 to 15 people.
Phase I
Phase I trials aim to nd the best dose of a new drug with the fewest side e ects. The drug
will be tested in a small group of 15 to 30 patients. Doctors start by giving very low doses of
the drug to a few patients. Higher doses are given to other patients until side e ects become
too severe or the desired e ect is seen. The drug may help patients, but Phase I trials are to
test a drug’s safety. If a drug is found to be safe enough, it can be tested in a phase II clinical
trial.
Phase II
Phase II trials further assess safety as well as if a drug works. The drug is often tested
among patients with a speci c type of cancer. Phase II trials are done in larger groups of pa-
tients compared to Phase I trials. Often, new combinations of drugs are tested. Patients are
closely watched to see if the drug works. However, the new drug is rarely compared to the
current (standard-of-care) drug that is used. If a drug is found to work, it can be tested in a
phase III clinical trial.
Phase III
Phase III trials compare a new drug to the standard-of-care drug. These trials assess the side
e ects of each drug and which drug works better. Phase III trials enroll 100 or more pa-
tients. Often, these trials are randomized. This means that patients are put into a treatment
group, called trial arms, by chance. Randomization is needed to make sure that the people in
all trial arms are alike. This lets scientists know that the results of the clinical trial are due
to the treatment and not di erences between the groups. A computer program is often used
to randomly assign people to the trial arms. There can be more than two treatment groups
in phase III trials. The control group gets the standard-of-care treatment. The other groups
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get a new treatment. Neither you nor your doctor can choose your group. You will also not
know which group you’re in until the trial is over.
Every patient in a phase III study is watched closely. The study will be stopped early if the
side e ects of the new drug are too severe or if one group has much better results. Phase III
clinical trials are often needed before the FDA will approve the use of a new drug for the
general public.
Phase IV
Phase IV trials test new drugs approved by the FDA. The drug is tested in several hundreds
or thousands of patients. This allows for better research on short-lived and long-lasting side
e ects and safety. For instance, some rare side e ects may only be found in large groups of
people. Doctors can also learn more about how well the drug works and if it’s helpful when
used with other treatments.
2. What is the di erence between NDA and ANDA ?
Answer: NDA means New Drug Application. When the sponsor of a new drug believes that
enough evidence on the drug’s safety and e ectiveness has been obtained to meet the FDA’s
requirements for marketing approval, the sponsor submits to the FDA a new drug applica-
tion (NDA). In other words, when a pharmaceutical company creates a new drug, the com-
pany must contact the FDA and demonstrate that the new drug has a particular quality and
that the drug is safe and e ective.
ANDA means Abbreviated New Drug Application. An abbreviated new drug application
(ANDA) contains data that, when submitted to the FDA, provides for the review and ulti-
mate approval of a generic drug product. Generic drug applications are called “abbreviated”
because they are not required to include preclinical (animal) and clinical (human) data to
establish safety and e ectiveness. Instead, a generic applicant must scienti cally demon-
strate that its product is bioequivalent (i.e., performs in the same manner as the original
drug). Once approved, an applicant may manufacture and market the generic drug product
to provide a safe, e ective, low cost alternative to the public.
3. What is IND approval ?
Answer: The FDA’s Investigational New Drug (IND) approval is the means by which
a pharmaceutical company obtains permission to start human clinical trials and to ship an
experimental drug across state lines (usually to clinical investigators) before a marketing
application for the drug has been approved.
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4. What is a AE and how is it di erent from ADR ?
Answer: An adverse drug reaction (ADR) refers to an adverse physical episode following
consumption of a medication. These reactions may occur acutely or chronically and can re-
sult from interactions with multiple medications. An adverse event (AE) is any negative
medical occurrence that is associated with the use of a medication or a medical error. An AE
can be life-threatening. An ADR di ers from an AE in that an ADR is associated with a cau-
sational relationship between the medication and the injury. Within AEs, such events are
viewed as side e ects and causative relationships between a drug and the event cannot be
established. AEs can also be related to medical procedures.
5. What is the de nition of AE as per GVP?
Answer: As per Guideline on good pharmacovigilance practices (GVP) Adverse event is “Any
untoward medical occurrence in a patient or clinical trial subject administered a medicinal
product and which does not necessarily have a causal relationship with this treatment”.
An adverse event can be any unfavourable and unintended sign (e.g. an abnormal laboratory
nding), symptom, or disease temporally associated with the use of a medicinal product,
whether or not considered related to this medicinal product (as per GVP Annex IV, ICH-
E2D Guideline).
6. What are the 4 subsets if ICH ?
Answer: The International Council for Harmonisation of Technical Requirements for Phar-
maceuticals for Human Use (ICH) is an initiative that brings together regulatory authorities
and pharmaceutical industry to discuss scienti c and technical aspects of pharmaceutical
product development and registration.
The ICH topics are divided into four categories and ICH topic codes are assigned according
to these categories:
• Q : Quality Guidelines
• S : Safety Guidelines
• E : E cacy Guidelines
• M : Multidisciplinary Guidelines
7. Under ICH guidelines, which document outlines the basic guidelines for pharmacovigi-
lance ?
Answer: E cacy Guidelines
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The work carried out by ICH under the E cacy is concerned with the design, conduct, safe-
ty and reporting of clinical trials. ICH E2A to E2F covers pharmacovigilance guidelines.
8. What are the regulatory reporting timelines?
Answer: Regulatory reporting timeline start with initial receipt date ‘day 0’ of the ICSR. Day
0, is the date when manufacturer received information about valid adverse event report. The
timelines for submitting an ICSR depends on country speci c regulatory requirements.
Globally ICSR are reported under 3 categories :
• Clinical trial - Death/Life threatening cases and SUSAR (Suspected Unexpected Serious
Adverse Reaction) cases are reported within 7 calendar days to the HA (health authorities.
• Clinical trial other Serious cases and safety issues are reported in 15 calendar days time-
frame.
• Serious post marketing cases are reported within 15 calendar days to the HA
• Non-Serious cases are reported within 90 calendar days to the EU health authority !
(EMA). Not mandatory for non-EU countries. !
9. Name the regulatory of US, Canada, Japan, Germany, China, Switzerland, France, Cana-
da, Denmark, etc.,
Answer:
USA: United States Food and drug administration (USFDA).
UK: European Medicines Agency (EMEA).
Japan: Ministry of Health, Labour and Welfare (MHLW).
India: Central Drugs Standard Control Organization (CDSCO)
10. What is MedDRA and which is the current version of MedDRA?
Answer: Medical Dictionary for Regulatory Activities (MedDRA) is a clinically-validated in-

ternational medical terminology used by regulatory authorities and the regulated biophar-
maceutical industry. The terminology is used through the entire regulatory process, from
pre-marketing to post-marketing, and for data entry, retrieval, evaluation, and presentation.
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MedDRA is updated by the MSSO twice yearly. The rst annual release in the spring in-
cludes changes to all levels in MedDRA (if any occur). The second release in the autumn is
minor and only includes changes to terms at the PT and LLT levels (e.g., new terms, spelling
changes, non-current LLTs).
The September 2020 Version 23.1 release is the current version.
11. Outline the MedDRA hierarchy?
Answer: It has 5 levels and is hierarchical totalling over 80000 terms:
• System organ classes (SOCs)
• Higher level group terms (HLGTs)
• Higher level terms (HLTs)
• Preferred terms (PTs)
• Lowest level terms (LLTs)
12. Mention 5 seriousness criteria for classifying ICSR?
Answer: As per ICH guideline (E2A) a Serious Adverse Event is:!

Any untoward medical occurrence or e ect that at any dose results in
• death,
• life-threatening,
• requires hospitalisation or prolongation of existing hospitalisation,
• results in persistent or signi cant disability or incapacity,
• congenital anomaly or birth defect,
• any event that may not result in death/be life threatening/require hospitalisation may be
considered a serious adverse drug experience when, based upon medical judgment, it may
jeopardise the patient or subject and may require medical or surgical intervention to pre-
vent one of the outcomes listed in this de nition. !
13. What is a causality and what are the di erent scales used ?
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Answer: Causality is an assessment procedure used for the determination of relationship be-
tween a drug treatment and the occurrence of an adverse drug event. When a causal rela-
tionship is identi ed, then adverse drug event (ADE) would be called as adverse drug reac-
tion (ADR).
Scales for causality assessment:
1. De nite (>95% con dence in causality)
2. Probable (50 - 90 % con dence in causality)
3. Possible (5 - 50 % con dence in causality)
4. Unlikely (< 5% but not 0 % con dence in causality)
5. Not related
14. What is expectedness and what is listedness and the di erence between them (if any)?
Answer: Expectedness means the AE whether serious or not is already listed in the IB or
CCSI. Listedness/Unlistedness: any reaction which is not included in the Company Core
Safety Information within a company’s core data sheet for a marketed product is unlisted. If
it is included it is termed listed. !
15. What is a SUSAR? Reporting timelines for SUSARs?
Suspected Unexpected Serious Adverse Reactions (SUSARs) are any serious events suspect-
ed to be caused by a medicinal product, but which are not consistent with information about
the medicinal product (these are the most serious of events and are subject to expedited re-
porting procedures). SUSAR cases are reported within 7 calendar days to the HA (health au-
thorities).
16. Why do you opt for pharmacovigilance and what do you know about PV?
Answer: Safety is what an individual seeks. From our day to day living and more importantly
in the drugs we consume for our bene ts. It would be surprising to know that the drugs/
medicines we consume at times can cause adverse reactions in certain individuals. This is
where Pharmacovigilance plays a very important role in detecting, analyzing, assessing and
preventing adverse drug reactions and in turn improving the patient care and public health
by following stringent steps to curb unintended and harmful e ects of the drug by dealing
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with every aspect of the drug lifecycle – from preclinical development to post-market sur-
veillance – making it an essential element in drug research.
I chose to opt PV to be medically and scienti cally stimulated dealing with everyday a new
adverse reactions and analysing its impact.
17. Explain about interventional and non-interventional studies?
Answer:
A “non#interventional study” is a study where the medical product(s) is (are) prescribed in-
dependent to inclusion of the participant in the study and as part of a therapeutic strategy,
including diagnostic and monitoring procedures, which is not decided in advance by a study
protocol but is applied according to the current clinical practice. As such, these studies seek
to understand the use of a marketed product in real-world conditions, including risk/bene-
t, healthcare resource utilization, and patient/caregiver satisfaction, as examples.
Interventional studies, also called experimental studies, are those where the researcher in-
tercedes as part of the study design. These trials use authorized drugs (excluding placebos)
in accordance with the marketing authorization, or non-authorized drugs, if their use is evi-
dence-based and supported by the published scienti c evidence. These trials should not
pose more than a minimal additional safety risk or burden to participants compared to nor-
mal clinical practice. As in all clinical trials, the assessment and treatment procedures of
low-intervention clinical trials are to be determined by the protocol. However, less stringent
requirements may be applicable.
18. What is case validity criteria?
Answer: Only valid ICSRs should be reported and all reports of suspected adverse reactions
should be validated before reporting them to the Agency to make sure that the minimum
criteria for reporting are included in the reports. The minimum criteria include the follow-
ing:
• An identi able reporter
• An identi able patient
• A suspect product
• An adverse drug event
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PHARMACOVIGIL ANCE

Pharmacovigilance - Introduction ............................5

History and evolution of Pharmacovigilance ..........8

Major Drug recalls ................................................14

Drug development and Role of Pharmacovigilance19

Drug Discovery: ...........................................................19

Terms and De nitions in Pharmacovigilance .........26

Sources of Individual Case Reports .......................33

Spontaneous reports: ...................................................33

Pharmacovigilance Process ...................................37

Individual case safety report (ICSR): .............................37

ICSR - Case processing ...........................................41

Validation of reports: ...................................................41

Regulatory reporting Requirements for ICSR ........61

Reports of special situations .................................63

Use of a medicinal product during pregnancy or breastfeeding: 63

Vaccine Pharmacovigilance ...................................67

Adverse events following immunization (AEFI): ..............67

Pharmacovigilance Inspection and audits .............70

Pharmacovigilance Inspections: ....................................70

Case Scenario : Spontaneous Adverse Report received from a consumer: 71

• Identify previously unknown adverse e ects

• Recognize changes in the frequency or severity of known adverse e ects

• Assess a drugs risk/bene t to determine if action is required to improve safety

• Ensure the accuracy of information communicated to healthcare professionals and pa-

Why is pharmacovigilance important?

• Therefore, post-marketing surveillance is important to permit detection of less common

• Thus, post-marketing surveillance is important to permit detection of less common, but

The aims of pharmacovigilance are to:

Products Covered by Pharmacovigilance:

In 1949, Council for International Organizations of Medical Sciences (CIOMS) established

In 1961, a big change of Pharmacovigilance happened following the tragedy of Thalidomide.

• Identify early warning signals of serious adverse reactions to medicines;

• Evaluate the hazard;

In 1990, CIOMS I: International reporting of adverse drug reaction released.

• Modi cation of the de nition of adverse drug reactions (ADR);

• Greater involvement of patients and citizens in Pharmacovigilance activities;

• Strengthening of the Eudravigilance database containing reports of suspected reactions

• Increasing transparency and timeliness of important information on Pharmacovigilance

• Establishment within the EMA of the Pharmacovigilance Risk Assessment Committee

Manufacturer: Eli Lilly

Recalled: 1975 (after 37 years on the market)

3. Fen uramine/phentermine (Fen-Phen)

Manufacturer: Wyeth-Ayerst Laboratories

Manufacturer: Hoechst Marion Roussel (now Aventis)

Recalled: 1997 (after 13 years on the market)

Recalled: 1998 (after one year on the market)

Recalled: 2000 (after one year on the market)

Manufacturer: No principal manufacturer, widely manufactured across the industry

Recalled: In 2000 (at least 60 years on the market)

Recalled: 2001 (after four years on the market)

Baycol, prescribed to patients as a treatment for high cholesterol, is reportedly responsible

Recalled: 2004 (after ve years on the market)

Recalled: In 2005 (after just one year on the market)

11. Able Laboratories Generic Prescription Drugs

Manufacturer: Able Laboratories

In September 2020, The Therapeutic Goods Administration (TGA - Australia) withdrawn

They aim to nd the best ways to:

• Treat illness to improve survival or increase the number of people cured

• Diagnose diseases and health problems.

Why are clinical trials important?

PHASES OF CLINICAL TRIALS: