CHAPTER ONE: INTRODUCTION

Pharmacovigilance (PV) is defined 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 benefits of medicines”. The international PV systems aim to monitor the
risk/benefit ratio of drugs as well as improve patients’ safety and their quality of life.
The etymological roots for the word “pharmacovigilance”
are: Pharmakon (Greek) = medicinal substance, and Vigilia (Latin) = to keep a watch.
It includes:
 Collecting and managing data on the safety of medicines.
 Looking at individual case reports to detect new “signals”, pro–active risk
management to minimize any potential risk associated with the use of medicines.
 Communicating and informing stakeholders and patients.

Aim of the study

Pharmacovigilance was studied to measure the safety of medicine. To measure the adverse
effect and problems caused by medicine. To measure pharmacovigilance of drug I analysed the
data of national drug regulatory authority, international health organization, world health
organization and clinical practice of pharmacovigilance and other international research work.
And more objective are:

1|P ag e
Objective of Pharmacovigilance

Adverse Drug Reactions:

Harmful, unintended reactions to medicines that occur at doses normally used for
treatment are called adverse drug reactions (ADRs).

2|P ag e
Type A ADR There are two subclasses:
 Exaggerated Desired Effect- The undesirable exaggeration of a desired pharmacologic
effect after a normal dose in a susceptible subject or after a higher than normal dose. This
results from the excess stimulation of targeted receptors by the therapeutic agent. Orthostatic
hypotension with an antihypertensive, daytime somnolence after a sedative-hypnotic taken for
sleep, and hypoglycaemic shock after insulin is examples of this phenomenon.

 Undesired Effect- The appearance of an undesired pharmacologic effect, known as lateral

or parallel stimulation, can be seen after a normal dose or a higher than normal dose in a
susceptible subject; it is due to the stimulation of untargeted receptors by the therapeutic agent.
Examples include constipation due to morphine, gastrointestinal irritation with non-steroidal
anti-inflammatory drugs (NSAIDs), hair loss from chemotherapy, and loss of libido with
antidepressants.

Type B ADR There are two subclasses:

 Immunologic- An allergic or hypersensitivity reaction occurs as a result of an immunologic
mechanism. A pseudo allergy or anaphylactic reaction is the result of a mechanism involving
the release of the same mediators released during an immunologic reaction due to
immunoglobulin E (IgE). Such reactions can occur with radio contrast agents, NSAIDs.
 Idiosyncratic- The term idiosyncratic is often used in a broad sense to designate qualitatively
abnormal adverse reactions that occur in a given individual and whose mechanism is not yet
understood. These reactions are usually quite rare and in some cases may be due to a genetic
or acquired enzyme abnormality with the formation of toxic metabolites. This is also known as
primary toxicity. Congenital enzyme abnormalities may produce adverse reactions such as the
haemolytic anaemia due to glucose-6- phosphate dehydrogenase (G6PD) deficiency.5

Some of the ADRs could not be explained by the mechanism of either type A or B reactions
which led to ABCDEF classification:

1. Dose-related (Augmented)
2. Non-dose-related (Bizarre)
3. Dose-related and time-related (Chronic)
4. Time-related (Delayed)
5. Withdrawal (End of use)
6. Failure of therapy (Failure)

Type of Features Examples Management

Reaction
Dose related Common Related to Dry mouth with tricyclic Reduce dose or
(Augmented) the pharmacologic antidepressants, withhold drug
action of the drug – respiratory depression Consider effects of

3|P ag e
 exaggerated with opioids, bleeding concomitant
pharmacologic with warfarin, serotonin therapy
response Predictable syndrome with SSRIs,
Low mortality digoxin toxicity
Non–dose Uncommon Not Immunologic reactions: Withhold and avoid
related related to the anaphylaxis to penicillin in future
(Bizarre pharmacologic action Idiosyncratic reactions:
of the drug malignant hyperthermia
Unpredictable High with general anesthetics
mortality
Dose related Uncommon Related Hypothalamic-pituitary- Reduce dose or
and time to the cumulative adrenal axis suppression withhold;
related dose by corticosteroids, withdrawal may
(Chronic) osteonecrosis of the jaw have to be
with bisphosphonates prolonged
Time related Uncommon Usually Carcinogenesis Tardive Often intractable
(Delayed) dose related Occurs dyskinesia Teratogenesis
or becomes apparent Leucopenia with
sometime after use of lomustine
the drug
Withdrawal Uncommon Occurs Withdrawal syndrome Reintroduce drug
(End of use) soon after withdrawal with opiates or and withdraw
of the drug benzodiazepines (e.g., slowly
insomnia, anxiety)
Unexpected Common Dose Inadequate dosage of an Increase dosage
failure of related Often caused oral contraceptive when Consider effects of
therapy by drug interactions used with an enzyme concomitant
(Failure) inducer Resistance to therapy
antimicrobial agents

Detection of ADRs
Improve detection and accurate diagnosis of ADRs by healthcare providers and patients.
Encourage active surveillance of specific drug safety concerns through epidemiological
methods such as case control studies, record linkage and epidemiological studies.
Adverse drug reactions-Methods of Detection

4|P ag e
The pharmaco-epidemiological methods are used now days to detect new signals of possible
adverse drug reactions (ADRs) and these methods can either be ‘hypothesis generating’ where
the aim is to detect new & previously undetected ADRs with a new drug or ‘hypothesis testing’
where these methods aim to prove whether any suspicions that may have been raised are
justified.

Detection Method of ADRs

1) Pre-marketing studies
2) Post-marketing surveillance
3) Assessing Causality (Causality Assessment)
4) Communicating ADR
5) Postal Survey Method.
1. Pre-marketing Studies: Pre-marketing evaluation involves animal studies and
clinical trials in human. Studies in two or more animal species are conducted to test
whether the drugs are harmful and whether they may for instance induce cancer
(Carcinogenic), damage and malformations in the unborn child (Teratogenic) etc.
Once scientists are sure that a drug is safe, they start studies in human beings and these
studies are known as clinical trials. Pre-marketing clinical trials take place in three
phases (I, II and III). These trials are studies on the effects of drug on humans under
rigorously controlled conditions. All clinical trials will assess safety of the drug in
question. A brief description of each phase of clinical trial is given below:

 Phase I –Single or multiple dose studies in healthy volunteers, using low doses of the drug.
Subsequently, large doses and multiple sequence are evaluated.

 Phase II –Efficacy is the primary objective of phase II trials, but safety is also continuously
monitored and evaluated.

 Phase III- Evaluations of safety in groups of patients with the disease. Each phase involves
increasing number of patients and by the end of full pre-marketing clinical trials about 5000
patients would have taken the medicine. However, when the drug is marketed millions of
people will take the medicine. There is therefore the question of whether clinical trials
involving just about 5000 people provided enough information to extrapolate the safety of a
new medicine to millions of people through pre-marketing safety. Pre-marketing safety
evaluation have two significant drawbacks:

2. Post Marketing Drug Surveillance in Pharmacovigilance

Post Marketing Surveillance (PMS) refers to the monitoring of the drugs when they reach the
market for performing in the individuals under a wide range of circumstances. This surveillance

5|P ag e
is more likely to detect the positive and negative effects of the drugs. The post-marketing
surveillance concerns with the ADR monitoring of drug in the market.
The issues like the unapproved or off-label drug use, problems with an orphan drug, and lack
of pediatric formulation, as well as issues concerning with international clinical trials in
paediatrics population, are concerned with the post-marketing surveillance.

 Case-Control Studies- In case control studies the research compares the exposure rate in the
cases with the exposure rate in the control.

 Cohort Studies- These studies involve a group of patients (cohort) followed up for a time
duration long enough to detect the outcome of interest.

3. Causality assessment: is a process of establishment of a relationship between a

drug and a suspected reaction.
In case an ADR is suspected, then the assessment starts with the collection of the
relevant data related to patient’s demographics like medications including OTCs; time
of onset and duration of reaction; treatment of reaction and its outcome and reports.
3Following approaches may be appropriate in assessing causality:
i) Opinion of individual experts.
ii) Opinion of penal of experts.
iii) Formal algorithm

4. Communicating ADRs:
By the following ways the knowledge about rational and safe use of medicines are
provided:
1) At the time of basic training of health professionals.
2) By conducting constant education programmes for health professionals.
3) By specifically designated drug information centres.
4) By inserting package (document having information about that drug and its use) and
by counselling the patient as well.

5. Postal Survey Method:

1) This method comprise of a specific drug related questionnaire.

2) It is mainly used for monitoring ADR of new drugs i.e. within 1 to 2 years after the drug
has been launched.
3) The questionnaire should inquire the details about drug, usage, dose, brand used, and
number of patients treated in a given period.

6|P ag e
4) As mentioned in the literature, the common ADRs seen along with the drug should be
listed at the end of questionnaire.

5) The questionnaire including a prepaid envelope should be mailed to medical practitioners

all over the city/state who are likely to use the drug.

Approaches of Pharmacovigilance:

Who should report Healthcare Professionals are the preferred source of information in
pharmacovigilance, for example physicians, family practitioners, medical specialists, and
dentists. Nurses and other health workers may also administer medicines and should report
relevant adverse drug reactions experienced by the patients. Pharmacists can play an important

7|P ag e
role in the stimulation of reporting and in the provision of additional information (for example,
on co-medication and previous medicine use). Patients & their relatives can also report their
experienced adverse drug reactions directly to JPC, or through their healthcare professionals.
In this case seek the patient permission to contact their healthcare professionals for additional
information and data verification. Marketing authorization holder (MAH), being primarily
responsible for the safety of their products, they are obligated to report serious adverse drug
reactions they receive about their products to JPC. While the Non-serious ADRs should be
included in the periodic safety update report (PSURs).

What should be reported If it is suspected that a patient has experienced an ADR it should be
reported using a Yellow Card. ADRs resulting from prescription medicines, herbal remedies,
and OTC medications can all be reported. Causality does not need to have been established.

 For new medicines report all the suspected reactions, including minor ones. (Medicines are
considered “new” up to five years after marketing authorization)

 For established medicines or well-known medicines report all serious or unusual suspected
adverse reactions, (see definition of a serious reaction, expectedness of reactions.

 Report if an increased frequency of a given reaction is suspected.

 Report all suspected ADRs associated with drug-drug, drug food or drug-food supplements
(including herbal and complementary products) interactions.

 Report when suspected ADRs are associated with medicine withdrawals.

 Report ADRs occurring from overdose or medication error.

 Report ADRs in special fields of interest such as medicine abuse and medicine use in
pregnancy (teratogenicity) and during lactation.

 In children under the age of 18, all suspected ADRs occurring, should be reported regardless
of whether the medicine is licensed for use in children. Children are often not exposed to
medicines during clinical trials and many medicines are used in children even if they are not
licensed for this purpose. This means that monitoring of medicine safety is particularly
important for this age group.

Causality Assessment in Pharmacovigilance: Concept & Methods

Causality is an assessment procedure used for the determination of relationship between a
drug treatment and the occurrence of an adverse drug event.

The assessment of causality is a common procedure in pharmacovigilance, which is done at

different levels which included physicians, investigators, professionals working in drug safety

8|P ag e
department of a pharmaceutical company and national health authorities which can assist in
taking regulatory decisions.

Causality is the key factor for identification of new signals, measuring the strength of evidence,
and in evaluating benefit risk profile 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 individual case safety
reports.

Below two methods are widely accepted and used for assessing causality globally.

1. Clinical judgment or global introspection

2. Algorithms

3. Probabilistic methods

1. Clinical judgment or global introspection

Expert Judgment/Global Introspection Expert judgments are individual evaluation on the basis
of previous knowledge and experience in the field. These judgments are made without using
any standardized tool for getting the conclusions regarding causality. In this process, the expert
considers all the relevant and available data about the possibility of causing the drug event and
the expresses the judgment. Adverse drug reaction is assessed either by individual expert
evaluator or by a group of evaluators (experts). However, the assessment and evaluation of
adverse drug reactions by the evaluators (experts) is based totally on the knowledge, experience
and subject of interest of individual expert.

a. WHO UMC causality assessment

The World Health Organisation (WHO) and Uppsala Monitoring centre (UMC) at Sweden has
developed a system for causality assessment in consultation with the National Centres
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 defined based on their respective assessment criteria.

9|P ag e
Assessment criteria: Below key points will aid in ease understanding of various criteria for
assessing causality.

1. Temporal relationship: It is the time relationship between the drug administration (Date
of therapy start date, therapy duration) and occurrence of adverse event (Event onset date/date
of initial symptoms observed).

2. Abnormal Laboratory tests: There are some adverse event incidences which cannot be
ruled out from the causal relation with drug based on unusual or abnormal values in the
laboratory investigation.

3. Dechallenge: The assessment of the outcome of adverse event followed by

suspension/withdrawal of drug/reduced dose of drug in response to the adverse event. Based
on outcome of AE, it is further classified into two categories:

I. Positive Dechallenge: The complete or partial resolution of adverse event followed by

suspension/withdrawal of drug/reduced dose of drug

II. Negative Dechallenge: There is no change in the outcome of AE. It is persisting

irrespective of drug suspension/withdrawal and reduced dose.

4. Rechallenge: This is applicable in the positive dechallenge scenario. The

re-introduction/restarting of drug therapy after the event resolution. It also can be classified
into below two categories:

10 | P a g e
 I. Positive Rechallenge: Re-occurrence of adverse event after restarting of drug.

II. Negative Rechallenge: Adverse event has not recurred even after drug restart.

5. Alternative causality: Other contributory factors for the cause of adverse event. Below are
the possible contributors attributed to an AE.

I. Medical conditions: Underlying concurrent medical conditions of patient (e.g., diabetes,

heart diseases, autoimmune disease etc.,) or past medical history and prior or ongoing surgical
procedures.

II. Other medicinal product use: Concomitant medication details and past drug history.

III. Social life: Alcohol use, smoking (both history & concurrent use), obesity, diet,
profession etc.,

IV. Risk factors: Age (both paediatric and geriatric patients), hepatic and renal impairment
patients etc.

Below table will aid in identification of causal criteria based on the assessment of various
factors.

2. Algorithms

a. Naranjo causality assessment

In the year 1991, Naranjo and co-workers from the University of Toronto developed the
Adverse 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.

11 | P a g e
The questionnaire scale consists of 10 questions that are answered as either “Yes”, “No”, or
“Do not know”. Different point values (-1, 0, +1 or +2) are assigned to each answer.

Listed below are the 10 questions:

The total scores range from “-4 to +13”

Total Score ADR Probability Classification
 9 Highly Probable (Definite)
 5–8 Probable
 1-4 Possible
 0 Doubtful

Criteria based on score:

Based on the total score, causality is assessed, and the strength of relationship is defined.

Definite: 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.
Suspicious presence of alternative explanatory conditions like patient current conditions,
medical history etc.

Possible: If the total score lies in ‘between 1 and 4’. Attribution due to a reasonable temporal
association or presence of positive reaction outcomes with respect to action taken on drug
administration (dose reduction/suspension/withdrawal).

12 | P a g e
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.,

3.Probabilistic Method: This method is used in case of specific findings while transforming
the estimate of prior probability into posterior probability of drug causation. With the help of
epidemiological information, prior probability can be calculated and posterior probability combines
with the previous information along with the evidence of the particular case to find out an approximate
of causation.

a.Bayesian Adverse Reactions Diagnostic Instrument (BARDI):

1) It is established to overcome the numerous limitations allied with expert judgements and algorithms.

2) It is used for calculating the odds of a specific drug by comparing adverse event with an alternative
cause. These odds can be known as posterior odds. The posterior odds factor is calculated by
considering six assessment subsets i.e., one deals with background epidemiologic or clinical trials
information (the prior odds) and the other five deal with case specific information (the likelihood ratios).
With the help of six assessment subsets, the posterior odds factor can be calculated. In this, one deal
with background epidemiologic or clinical trials information which is said to be the prior odds and the
other five deal with case specific information that are known as likelihood ratios. The Five Likelihood
Ratios (LRs):

i) Patient history (Hi).

ii) Timing of the adverse event with respect to drug administration (Ti).

iii) Characteristics of the adverse event (Ch).

iv) Drug dechallenge (De), (any signs, symptoms, or occurrences after drug withdrawal)

. v) Drug re-challenge or re-administration (Re) of the suspected causal drug(s). The product of these
factors is the prosterior odds (PsO). PsO = PrO x LR (Hi) x LR (Ti) x LR (Ch) x LR (De) x LR (Re)

vi) On either paper or computer, the Bayesian approach can be implemented as a spreadsheet
programme.

vii) It calculates and provides instant numerical and graphical feedback immediately after new pieces
of evidence of the suspected ADR are evaluated.

Glossary of important terms used in Pharmacovigilance

Adverse Event/ Adverse Experience: Any untoward medical occurrence that may present
during treatment with a pharmaceutical product but which does not necessarily have a causal
relationship with this treatment.

Adverse Drug Reaction A response to a drug which is noxious and unintended, and which
occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease,
or for the modification of physiological function. An adverse drug reaction, contrary to an

13 | P a g e
adverse reaction, is characterized by the suspicion of a causal relationship between the
medicine and the occurrence, i.e. judged as being at least possibly related to treatment by the
reporting or a reviewing health professional.

Case Control Study Study that identifies a group of persons with the unintended medicine
effect of interest and a suitable comparison group of people without the unintended effect. The
relationship of a medicine to the medicine reaction is examined by comparing the groups
exhibiting and not exhibiting the medicine reaction with regard to how frequently the medicine
is present.
Clinical Trial A systematic study on pharmaceutical products in human subjects (including
patients and other volunteers) in order to discover or verify the effects of and/or identify any
adverse reaction to investigational products, and/or to study the absorption, distribution,
metabolism and excretion of the products with the objective of ascertaining their efficacy and
safety. Clinical trials are generally classified into Phases: I to IV. Phase IV trials are studies
performed after marketing of the pharmaceutical product. They are carried out on the basis of
the product characteristics for which the marketing authorization was granted and are normally
in the form of post-marketing surveillance.
Cohort Study A study that identifies defined populations and follows them forward in time,
examining their rates of disease. A cohort study generally identifies and compares exposed
patients to unexposed patients or to patients who receive a different exposure.
Causality assessment The evaluation of the likelihood that a medicine was the causative agent
of an observed adverse reaction. Causality assessment is usually made according established
algorithms.
Drug/ Medicine Any substance in a pharmaceutical product that is used to modify or explore
physiological systems or pathological states for the benefit of the recipient. The term
drug/medicinal product is used in a wider sense to include the whole formulated and registered
product, including the presentation and packaging, and the accompanying information.
Drug Alerts The action of notifying a wider audience than the initial information holder(s) of
a suspected association between a drug and an adverse reaction. Note that the term is used in
different contexts that can be confusing, for example, an alert may be from a manufacturer to
a regulator or from a regulator to the public.

Pharmacoepidemiology The study of the use and effects of medicines in large numbers of
people. Pharmacovigilance The science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other medicine-related problem.
Prescription Event Monitoring A system created to monitor adverse drug events in a
population. Prescribers are requested to report all events, regardless of whether they are
suspected adverse events, for identified patients receiving a specified medicine.
Adverse Drug Reaction (ADR)

14 | P a g e
• A response to a drug that is noxious and unintended and occurs at doses normally used in man
for the prophylaxis, diagnosis, or therapy of disease or for modification of physiological
function (WHO)
• An appreciably harmful or unpleasant reaction, caused by an intervention related to the use
of a medicinal product, which predicts hazard from future administration and warrants
prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the
product (Edwards)
• Any unexpected, unintended, undesired, or excessive response to a drug that requires
discontinuing the drug (therapeutic or diagnostic), requires changing the drug therapy, requires
modifying the dose (except for minor dosage adjustments), necessitates admission to a hospital,
prolongs stay in a health care facility, necessitates supportive treatment, significantly
complicates diagnosis, negatively affects prognosis, or results in temporary or permanent harm,
disability, or death (ASHP)
• Harm directly caused by a drug at normal doses (Edwards)
Adverse Drug Event (ADE)
• Any untoward occurrence that may present during treatment with a pharmaceutical product
but that does not necessarily have a causal relation to the treatment (WHO) a
• Injuries caused by medical interventions related to a drug. Adverse drug events may result
from medication errors or from ADRs in which there was no error (Bates) Unexpected Adverse
Reaction
• An adverse reaction, the nature or severity of which is not consistent with domestic labeling
or market authorization, or expected from characteristics of the drug (Cobert) Serious Adverse
Effect
• Any untoward medical occurrence that at any dose results in death, requires hospital
admission or prolongation of existing hospital stay, results in persistent or significant
disability/incapacity, or is life threatening (Edwards) Signal
• Reported information on a possible causal relation between an adverse event and a drug, the
relation being previously unknown or incompletely documented (Edwards) Medication Error
• Any preventable event that may cause or lead to inappropriate medication use or patient harm
while the medication is in the control of the health care professional, patient, or consumer (NCC
MERP)
• Errors in the process of ordering or delivering a medication, regardless of whether an injury
occurred or the potential for injury was present (Bates)
• Inappropriate use of a drug that may or may not result in harm

15 | P a g e