INTRODUCTION TO PHARMACOVIGILANCE

IMPORTANCE OF SAFETY MONITORING OF MEDICINE

The safety monitoring is defined as the monitoring of all the important aspects of
the medicines during their pre phase so that it becomes a good or effective product
when it introduces in the market. There are several aspects of drug safety that
have been neglected till now. It is an important step to make the drug effective.
These are basically used for clinical trials.

➢ Till a medicine is not approved for sale, it remains protected under

scientific environment of clinical trials.
➢ Before release for sale, a medicine is tested using a limited population
ranging from 500 to 5000.
➢ Once the medicine comes into the market, it becomes legally available for
consumption by the general population.
➢ The population may be children, pregnant women, patients suffering from
other diseases and the elderly.
➢ It may be given separately or in combination with other medicines. Thus,
the drug is taken in different therapeutic situations and
physiological conditions
➢ It is therefore, very much necessary to observe and record the effectiveness
and safety of the medicine under real life conditions.
➢ In fact, diverse effect, interactions with foods or with other medicines, and
risk factors are to be noticed only during its real use over the years.

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In general, the stakeholders who need to collaboratively work are:
1. Government
2. Industry
3. Hospitals and academia
4. Medical and pharmaceutical associations
5. Poisons and medicines information centres
6. Health professionals
7. Patients
8. Consumers
9. The media
10. World Health Organization

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 WHO INTERNATIONAL DRUG MONITORING PROGRAMME

1) The WHO Programme for International Drug Monitoring (PIDM) was

established in 1968. This Programme provides a forum for Member States of
WHO for working together in monitoring of drug safety. It also facilitates in
identifying and analysing the adverse reaction signals from the documented data
handed over to the WHO global individual case safety report (ICSR) database by
the respective member countries.

2) There are more than 150 countries in the WHO Programme for International
Drug Monitoring. All these countries have a common vision of safer and more
effective use of medicines. They operate their working nationally and
internationally work as a team for identification and monitoring the harm caused
by medicines, to reduce patient’s risks and to establish the pharmacovigilance
systems and standards globally. However, since 1978 the Uppsala Monitoring
Centre (UMC) controls and operates all the technical and operational aspects of
the programme.

3) In 1968 the WHO programme was established to make sure that all the data on
adverse reactions on patients was collected from maximum sources. This would
allow the individual countries to become alert about the pattern of adverse
reactions occurring all over the world and that may not be evident from the local
reported adverse drug reactions only.

4) The WHO programme includes three-part network:

(i) The headquarters of WHO located in Geneva, Switzerland manages all the
issues related to any type of policy.

(ii) National pharmacovigilance centres from member countries of WHO

coordinated for all the case reports sent to the WHO Individual Case Study Report

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(ICSR) database. The Uppsala Monitoring Centre (UMC) located in Sweden
manages all the reports.

(iii) The Uppsala Monitoring Centre (UMC) supervises the WHO programme
operations, including:

a) Collection, assessing and communicating the information from all the WHO
member countries about the effectiveness, toxic effect, benefits, and risks of
medicinal products,

b) Collaboration with member countries for practice and developing

pharmacovigilance,

c) Warning the National Regulatory Authorities (NRAs) of member countries

about probable drug safety problems through WHO signal process.

5) As per the data, more than 100 countries joined the WHO programme till June
2012, and more than 30 members associated were waiting for compatibility
between the national and international formats of reporting

MISSION OF UMC

1. Mission of UMC is to promote rational drug therapy.

2. Collection and analysing of reports about drug safety at the international

level.

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3. Collection of the data regarding national activities concerning the drug safety
and classifying this information.

4. Developing more expertise professionals to improve the analysing process for

better results.

5. Developing new methods for use in work regarding drug safety.

6. To develop new standards for assessment of risk and use of drug therapy in
trials.

7. To improve the education or the communication for relevant interest of

concerning risks of the drug treatment.

8. Research and development improvement.

9. Collections of the ADR reports on a wide scale and maintain the database for
the world.

PHARMACOVIGILANCE PROGRAMME OF INDIA (PvPI)

Directorate General of Health Services, Central Drugs Standard Control

Organization (CDSCO), under the guidance of Ministry of Health & Family
Welfare, Government of India in collaboration with Indian Pharmacopeia
commission, Ghaziabad initiated a nation-wide Pharmacovigilance Programme
(PVPI) for the protection of patient’s health by providing safety from the drugs.
However, Indian Pharmacopeia commission (IPC), Ghaziabad coordinates these
Programs as a National Coordinating Centre (NCC).

1) On 14th July 2010 the Government of India started the Pharmacovigilance

Programme of India (PvPI) with All India Institute of Medical Sciences (AIIMS),
New Delhi as its first National Coordination Centre (NCC) for monitoring
Adverse Drug Reactions (ADRs) in the country for purpose of safety and
protection of public health.

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2) 22 ADR monitoring centres including AIIMS, New Delhi in the year 2010 were
set up under this Programme.

3) However, on 15th April 2011 the National Coordination Centre was later
shifted to Indian Pharmacopoeia Commission (IPC), Ghaziabad, Uttar Pradesh
from All India Institute of Medical Sciences (AIIMS, New Delhi) in order to
safeguard and protect implementation of this programme in a better way

4) July, 2015 onwards Indian Pharmacopoeia Commission- Pharmacovigilance

Programme in India (IPC-PvPI) became the National Coordination Centre (NCC)
for Materiovigilance Programme of India (MvPI).

5) In July, 2017 Indian Pharmacopoeia Commission (IPC), National Coordination

Centre for Pharmacovigilance Programme in India (NCC-PvPI) became a WHO
Collaborating Centre for Pharmacovigilance in Public Health Programmes &
Regulatory services.

Mission: To protect the health of Indian population by ensuring that the benefits
of medicine used overshadow the risks associated with its use.

Vision: To improve patient safety and welfare in Indian population by monitoring

the drug safety and thereby reducing the risk associated with use of medicines.

Objectives

1) A nation-wide system must be formed for reporting of patient safety

2) Identification and analysis of new ADR (signal) from the reported cases

3) Analysis of benefit - risk ratio of marketed pharmaceutical products

4) Evidence based information must be generated on safety of medicines

5) Supporting the regulatory agencies in the process of decision making on use

of medicines.

6) Emerging as a national centre of excellence for pharmacovigilance activities

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7) Communicating over the safety information on use of medications to different
stakeholders for minimizing the risk

8) Collaborating with other national centres for data management and exchange
of information.

9) Providing consultancy and training support to other National Coordination

Centre for Pharmacovigilance Programme in India located across the world

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INTRODUCTION TO ADVERSE DRUG REACTION

DEFINITION

Adverse drug reactions can be defined by different terms by different scientists.

1) Schatz et al in 2015 defined ADR as “undesirable, unwanted effect of any drug

that occurs when used at any usual clinical condition".

2) Edwards et al in 2000, defined adverse drug reaction as “an unpleasant or

appreciably harmful reaction occuring due to an intervention related to
medication use, which might predict harm from forthcoming administration and
permits specific treatment or prevention, or change in the dosage regimen, or
product withdrawal.”

3) Adverse drug reactions as per WHO (2005) can be defined as “any response to
a drug which is noxious and unintended and which occurs or doses normally used
in a man of prophylaxis diagnosis or therapy of disease or for the modification of
physiologic function”.

Classification of ADRs

Based on Type of Reactions:

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Objectives of ADR Monitoring

1) To identify the nature and frequency of ADRs

2) To assist the Drug Regulatory Authority, Public Health Programmes, Scientists

and Consumer Society to minimise ADRs.

3) To deliver updated Drug Safety Information to Health Care Professionals.

4) To spread information by organising proper education programme to

consumers.

5) To find the risk factors which can predispose induce or influence the
development, severity and incidence of ADRs.

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Benefits of ADR Monitoring

1) It provides information regarding quality and safety of pharmaceuticals

products.

2) It introduces risk management plans.

3) It inhibits the possible adverse effects and assists in determining ADR

occurrence.

4) It provides information to health care team, patients, pharmacists and nurses

regarding adverse drug effects and spread awareness about ADRs

DETECTION OF ADRS

Drug and Therapeutic Committee (DTC) is a policy framing and recommending

body established at any facility with representative members with the aim of
managing therapeutic use of drug. The DTC include various activities such as

I] Process to detect ADRs

The DTC should implement various healthcare programs, which will help to
detect ADRs, medication errors, product quality defect etc. Such health care
program may include- review of ADES, medicament error, physical inspection
of drug and patient review.
A. Detection methods of ADRS include various steps:
B. Pre-marketing studies
C. Post-marketing surveillance
D. Assessing causality
E. Communicating ADRs
F. Portal survey method

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A. Pre-marketing studies
➢ Whenever there is a development of new medicine, its safety is first tested
in the animal models
➢ Studies like drug carcinogenicity, teratogenicity and mutagenicity are done
in specific animal
➢ Normally, a clinical trial identifies ADRs of frequency greater than 0.5-
1.0%
➢ These trials are carried out in three different phases

B. Post-Marketing Surveillance
➢ For the detection of risk and collection of risk information
Pharmacovigilance
➢ methodologies are used.
➢ Spontaneous reporting system is done to detect out the ADR. It is also
known as
➢ Drug Safety Signal.
➢ It is a duty of health care practitioner to check out and report ADR result
in a patient under his/her care.
➢ It includes reporting of product defect, intoxicants and abuse and
unexpected lack of therapeutic effect.
➢ Two epidemiological methods are most commonly used.

(i) Cohort-studies- In this study, two groups are made, the first group of patient
exposed to a particular drug and the other group is unexposed to a drug. Both the
group is compared with the ADR frequencies.

(ii) Case-control studies

➢ Individuals affected by the adverse event being studied are identified each
case is matched with various disease

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 ➢ Both cases and controls are investigated their exposure to possible
causative agents prior to occurrence of the event
➢ The odd ratio is calculated on the basis of exposure data

C.ASSESSING CAUSALITY
Causality assessment is the method by which the range of bonding between the
drug and adverse reaction is established. If an adverse drug reaction is suspected
in the patient, the identification of ADRs is started with following data collection.
a) Patient history
b) Medication taken (including OTCs)
c) Time of onset
d) Duration of ADRs
e) Treatment data
f) Its outcome and reports
In the case of causality assessment, following approaches may be beneficial.
▪ Expert opinion
▪ Penal of Expert opinion
▪ Formal algorithms (data is assessed by using standard algorithms)

COMMUNICATING ADRS
As the name suggests, in communicating ADRs the knowledge about the safe and
effective use of medicines must be provided to the patient and medical staff,
during training program of professionals or throughout the education programmes
of health professionals, in the drug information centres, and through packaged
inserts and patient counselling.

PORTAL SURVEY METHOD

Portal survey method involves questionnaires related to drugs. This method is
used after the drug is launched into the market for the duration of about 1-2 years

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to monitor the drug related ADRs. The questionnaire about the drug involves
following:
a) Drug detail
b) Dose of drug
c) Brand name
d) Drug used for number of patient (Given period)
e) Common ADRs
f) Duration of drug action

Note: Questionnaire is filled and prepared envelope is mailed to practitioners all

over the city or state

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METHODS IN CAUSALITY ASSESSMENT

Causality assessment can be defined as the assessment of relationship between

the treatment with any drug treatment and incidence of an adverse reacion or
event. It helps in checking and also evaluating that whether the particular
treatment due to which an adverse event or reaction has occured is co-related with
the drug or not.

Objectives

1) Setup relationship between the medicine and events.

2) Detection of signal (“a possible causal corelation between the drug and an
adverse event, the relationship being either incompletely documented previously
or unknown".)

3) Better evaluation of the toxic or beneficial effects of drugs.

4) Plays an important part for evaluating ADR reports for regulatory purposes and
in early warning system

Methods

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EXPERT JUDGEMENT / 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.

There are two methods based on expert opinion or global introspection:

1.Swedish method by Wilholm et al.:

2. World Health Organization (WHO) - Uppsala Monitoring Centre (UMC)

Causality Assessment Criteria

World Health Organization (WHO) - Uppsala Monitoring Centre (UMC)

Causality Assessment Criteria

i) This method is globally and worlwide accepted.

ii) WHO-UMC system provides practical tool for assessing the case
reports for International monitoring of drugs.
iii) System helps in detecting the unexpected and unknown adverse
reactions
iv) The assessment is based on following four criteria:

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 a) Absence of other competing causes like, medications, disease process
itself, etc.
b) Time relationships between the use of drug and adverse drug reaction
or event.
c) Response to re-administration of drug (re-challenge).
d) Response to dose reduction or withdrawal of drug (de-challenge).

Based on number of the above criteria that match, the level of causality
association is grouped further into four categories as follows:

i) Certain: When all the four criteria (a,b,c,d) match

ii) Probable: When criteria a, b and c meet
iii) Possible: When only criteria a is met
iv) Unlikely: When criteria a and b are not met

However, ADR can also be classified into following classes:-

1. Unclassified/Conditional: Applied when more data is needed and such data

is being sought or is already under examination.
2. Unclassifiable: Finally when the information in a report is incomplete or
contradictory and cannot be verified, then it is unclassified

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Algorithms

✓ Algorithms are sets of specific questions with associated scores for

calculating the likelihood of a cause-effect relationship.
✓ It consists of a problem-specific flow chart with step-by-step instruction on
how to arrive at an answer.
✓ Actually, its form contain some questionnaire, whose answers provide the
causality of particular ADR.
✓ It give structured and standardized methods of assessment in a systematic
approach.

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 ✓ Assessment of ADRs based on parameters such as Time to onset of the
ADR or temporal sequence, Previous drug/adverse reaction history,
Dechallenge and Rechallenge.

1.Naranjo et al. Method (Naranjo Scale)

1) This method is widely accepted

2) This method facilitates in determining the likelihood of whether an adverse

drug reaction (ADR) is actually due to the therapeutic drug rather than the other
factors result.

3) It consists of ten questions that are answered as “yes", “no", and “unknown”
(don"t know)

4) These answers are assigned by a score termed as: Definite, Probable, Possible
Or Doubtful.

i) Definite- when a total score of > 9.

ii) Probable- when a total score of 5-8.

iii) Possible- when a total score of 1-4.

iv) Doubtful- when a total score of < 0.

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SEVERITY ASSESSMENT AND SERIOUSNESS

SEVERITY OF ADRs

Severity defines the extent to which the ADRs effects livelihood of the patient

Severity describes the extent to which the ADRs influence the everyday life of
the patients. According to Hartwig’s Severity Assessment Scale adverse drug
reactions was categorized into 7 levels of severity by J Seigel and PJ Schneider:

1 ) Level 1: In this level no change is needed in treatment with the suspected drug
in case of ‘mild' type reaction.

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2) Level 2: In this level, the ADR requires that the suspected drug to be withdrawn
or changed. Antidote or other treatment is not required, and the patient does not
require further hospitalisation.

3) Level 3:It is same as level 2

4) Level 4: It is classified in two parts:

i) Level 4(a):The patient requires further hospitalisation (at least for a day)
because of level 3 reactions.

ii) Level 4(b): The patient can be hospitalised due to ADR.

5) Level 5: In this level the produced reactions may need an intensive care unit
attention in the severe type of ADR.

6) Level 6: In this level the reactions may cause permanent harm to the patient.

7) Level 7: In this level the patient may die directly or indirectly due to ADR.

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Seriousness of ADRs

The seriousness of any adverse drug reaction is associated with the life
threatening nature of that adverse reaction. It can be defined as any unwanted,
undesired or untoward reaction of the therapeutic or medicinal drug that can cause
death, requires hospitalization of the patient, extended hospitalization of the
existing admitted patient, resulting in tenacious or significant disability, is a birth
defect or congenital anomaly, or is a medically important event or reaction.

A serious adverse event or reaction is any untoward medical occurrence

associated with the use of a medical product in a patient that at any dose, the
outcome is one of the following:

1) Death: Report if the patient's death is suspected as being a direct outcome of

the adverse reaction.

2) Life-Threatening: Report if the patient was at substantial risk of dying at the

time of the adverse reaction or it is suspected that the use or continued use of the
product would result in the patient's death.

3) Hospitalization (Initial or Prolonged ): Report if admission to the hospital or

prolongation of a hospital stay results because of the suspected adverse reaction

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4) Disability: Report if the adverse reaction resulted in a significant, persistent,
or permanent disability/ incapacity; (change, impairment, damage, or disruption
in the patient's body function/structure, physical activities, or quality of life).

5) Congenital Anomaly: Report if there are suspicions that exposure to a medical

product prior to conception or during pregnancy resulted in an adverse outcome
in the child (birth defect).

6) Medically Important Event or Reaction: Medical and scientific judgment

should be exercised in deciding whether other situations should be considered
serious such as important medical events that might NOT be immediately life-
threatening or result in death or hospitalization but might cause danger to the
patient or might require intervention to prevent one of the other outcomes as listed
above

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PREDICTABILITY AND PREVENTABILITY ASSESSMENT

The expectedness of the reaction is assessed in accordance with the approved

product information; the reaction is defined as expected if it is included in
package insert or the summary of product characteristics (SPC)

ADRs are difficult and sometimes impossible to distinguish from the disease
being treated since they may act through the same physiological and pathological
pathways. However, the following approach is helpful in assessing possible drug-
related ADRs

1. Ensure that the medicine ordered is the medicine received and actually taken
by the patient at the dose advised
2. Take a proper history and do a proper examination of the patient
▪ A full medicine and medical history should be taken
▪ An ADR should be your first differential diagnosis at all times
▪ Ask if this adverse reaction can be explained by any other cause e.g.
patient's underlying disease, other medicines including over-the-counter
medicines or traditional medicines, toxins or foods
▪ It is essential that the patient is thoroughly investigated to decide what the
actual cause of any new medical problem is.
▪ A medicine-related cause must be considered, especially when other causes
do not explain the patient's condition
3. Establish time relationships by answering the following question: Did the ADR
occurs immediately following the medicine administration?
Some reactions occur immediately after the medicine has been given while others
take time to develop
4. Carry out a thorough physical examination with appropriate laboratory
investigations if necessary;

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 ▪ Remember only a few medicines produce distinctive physical signs
▪ Exceptions include medicine eruptions, steroid-induced dermal atrophy,
acute extra-pyramidal reactions
▪ Laboratory tests are important if the medicine is considered essential in
improving patient care or if the laboratory tests results will improve
management of the patient.
▪ Try to describe the reaction as clearly as possible- Where possible, provide
an accurate diagnosis.
5. Effect of Dechallenge and Rechallenge should be determined:

a] Dechallenge (withdrawal of the suspected medicine). Positive dechallenge is

the improvement/resolution of ADR when the suspected medicine is withdrawn
in a strong, though not conclusive indication of medicine induced reaction.

b] Rechallenge (re-introducing the suspected medicine after a dechallenge)

Rechallenge is only justifiable when the benefit of reintroducing the suspected
medicine to the patient overweighs the risk of recurrence of the reaction, which
is rare. In some cases, the reaction may be more severe on repeated exposure.
Rechallenge requires serious ethical considerations.
6 Check the known pharmacology of the medicine
▪ Check if the reaction is known to occur with the particular suspected
medicine as stated in the package insert or other reference.
▪ Remember, if the reaction is not documented in the package insert, it does
not mean that the reaction cannot occur with that particular suspected
medicine
7. Report any suspected ADR to the person nominated for ADR reporting in the
hospital

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Preventability Assessment Scale

1) According to WHO factsheet, it is assessed that at least 60% of ADRs are

preventable. In several countries ADR-related costs like hospitalisation, surgery
and lost productivity, goes beyond the cost of the medications.

2) From the previous studies it is found that 20% to 80% of ADEs and ADRs are
preventable having majority of later studies showing around 60-70%
preventability.

By using Schumock and Thornton scale preventability of ADRs can be evaluated

(Table 1). Any answer of “yes” to any question in this scale proposes that the
ADR might have been preventable. ADRs can be categorised as definitely
preventable, probably preventable or not preventable.

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In 2002, Olivier proposed a method for preventability assessment. It consisted of
three sets of questions;

1. Related to patient,

2. Related to drug, and

3. Related to prescription.

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MANAGEMENT OF ADRS

➢ Rapid action towards the management of adverse drug reaction is

important because if the serious nature of suspected adverse drug reaction.
Ex- Anaphylactic Shock
➢ In the case of Dermatologic (Skin) adverse effect, Flushing is bothersome
to the patient, as antihistamine may be administered to treat or prevent the
reaction.
➢ In the case of Gastrointestinal adverse effects, common adverse effect like
nausea vomiting, diarrhea, hepatitis etc. can be cure by withholding drug
until such problem resolves.
➢ If several medicines could be causative, the non-essential medicines should
be Withdrawn first, preferably one at a time, depending on the severity of
the reaction.
➢ Many prescribers unnecessarily withhold a drug when inter-actions are
suspected, rather than adjusting the dose.
➢ The patient should be observed during withdrawal of the drug
➢ If the patient is getting better, in keeping with the prediction, alternative
medicines for the basic can be introduced if necessary.
➢ If the patient is not doing well after withdrawal of the first drug, the next
most Likely the culprit should be considered and the process repeated.
➢ Monitoring patient who are at greater risk of developing ADRs.
➢ Monitoring patients who are prescribed with drugs highly likely to cause
ADRs.
➢ Assessing and documenting the patient’ s previous allergic status.
➢ Assessing patient’s drug therapy for its appropriateness
➢ Changing dose of drug
➢ Replacement with alternate medicine
➢ Use of prophylactic regimen

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 ➢ Assessing possible drug interactions in multiple therapies
➢ Assistant health care professionals in the detection and assessment of
ADRs
➢ Stimulating health care professionals in reporting an ADR

REPORTING OF ADRS

For new drugs, all suspected reactions including, minor as well as major ones are
reported, for establishment or well-known of the drug, while reporting an ADR.
A professional should keep in mind that only suspected association of drug which
has caused particular adverse event should be reported.

1. What to report?
Any undesirable adverse event other than the therapeutic effect begins with the
use of drug which can be herbal, cosmetics, or medical device should be reported.
They should include,
a) All ADRs
b) All suspected ADRs and product detailed provided by the company
c) Unexpected reaction
d) Increase of reaction
e) ADRs associated with drug-drug, food-drug, drug-food interactions
f) ADR occurring from overdose
g) ADR due to pharmaceutical defects
h) ADR associated during pregnancy, lactation or drug-abuse

2. How to report an ADR?

For reporting an ADR, one should have local Case Report Form (CRF) which is
obtained from the National Drug Regulatory Authority. There are different case

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report format in different countries but all must have at least four major sections
having;

i) Patient information
▪ Identify of Patient
▪ Age/Date of Birth
▪ Sex
▪ Weight

ii) Adverse event/reaction

▪ Brief description of ADR
▪ Date of ADR
▪ Time of ADR
▪ Laboratory data
▪ Patient-history (Medical history)
▪ Outcomes attributed to adverse event

iii) Suspected medication

▪ Name of suspected medication
▪ Dose/route of administration/frequency of drug
▪ Date of therapy from the suspected medication
▪ Event abated(subside) after dose decreased or stopped
▪ Expire date of dose
▪ Provide relevant information on medical devices

iv) Reporter
▪ Detail of reporter
▪ Name of the reporter
▪ Address of the health facility
▪ E-mail address
▪ Signature, telephone number

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 ▪ Date of reporting the reaction

3. When to report?
All the suspected adverse reactions that are clinically important should be
reported as soon as possible, delay in the process of reporting will make the report
inaccurate. If possible, report should be sent while the patient is still under
examination, it will help the reporter to clear any ambiguity by re-examining the
patient.

4.How to Report
1) Standardised ADR reporting form should be used for reporting.
2) ADRs in the reporting from should be filled appropriately in case an ADR is
encountered.
3) Separate forms with complete information should be used for every individual.
4) The completely filled ADR form should be then returned to the nearest adverse
drug reaction monitoring Centre (AMC) or to National Coordinating Centre.
5) Any follow-up information should be forwarded by another ADR form, in case
of an ADR case that has been reported already. It can also be communicated by
telephone, fax or e-mail.
6) Follow-up reports should be recognisable including following points:
i) Follow-up Information
ii) Date of Original Report
iii) Patient Identity

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DRUG AND DISEASE CLASSIFICATION

ANATOMICAL, THERAPEUTIC AND CHEMICAL CLASSIFICATION

OF DRUGS

The ATC system classifies therapeutic drugs. The purpose of the ATC system is
to serve as a tool for drug utilization research in order to improve quality of drug
use.
The Anatomical Therapeutic Chemical Classification System (ATC) is used for
the classification of active ingredients of drugs according to the organ or system
on which they act and their therapeutic, pharmacological and chemical properties.
It is controlled by the World Health Organization Collaborating Center for drug
statistics methodology (WHOCC), and was first published in 1976

CLASSIFICATION STRUCTURE

In this system, drugs are classified into groups at five different levels

First level
The first level of the code indicates the anatomical main group and consists of
one letter.
There are 14 main groups:

CODE CONTENTS
A Alimentary tract and metabolism
B Blood and blood forming organs
C Cardiovascular system

D Dermatological

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 G Genitourinary system and sex hormones
H Systemic hormonal preparations, excluding sex hormones and
insulin’s
J Anti invectives for systemic use
L Antineoplastic and immunomodulation agents
M Musculo-skeletal system
N Nervous system
P Antiparasitic production, insecticides and repellents
R Respiratory system
S Sensory organs

Second level
The second level of the code indicates the therapeutic subgroup and consists of
two digits for example-CO3 Diuretics.
Third level
The third level of the code indicates the therapeutic/pharmacological subgroup
and consists of one letter.
Example CO3C High-Ceiling diuretics
Fourth Level
The fourth level of the code indicates the chemical/therapeutic/ pharmacological
subgroup and consists of one letter.
Example-C03CA Sulfonamides
Fifth level
The fifth level of the code indicates the chemical substance and consists of two
digits. Example COSCAOI Furosemide

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INTERNATIONAL CLASSIFICATION OF DISEASES

The (ICD) International Classification of Diseases is the international "standard

diagnostic tool for epidemiology, health management and clinical purposes".
Its full official name is International Statistical Classification of Diseases and
Related Health Problems.
The ICD is maintained by the World Health Organization (WHO) which is the
directing and coordinating authority for health within the United Nations system.

HISTORY OF THE ICD

In the year 1893, a French physician, Jacques Bertillon, introduced the Bertillon
classification of causes of Death at a congress of the International Statistical
Institute in Chicago Organization of the League of Nations.
In 1948, the WHO assumed responsibility for preparing and publishing the
revisions to the ICD every ten years.
The ICD is currently the most widely used statistical classification system for
diseases in the world.

DESIGN OF THE ICD

The ICD contains a description of all known diseases and injuries. Each disease
is detailed with diagnostic characteristics and given a unique identifier that is used
to code mortality data on death certificates identifier that is used to code mortality
data on death certificates and morbidity data from patient and clinical records.
The core of the ICD 10 uses one single list of four alphanumeric-character codes
from A00.0 to 299.0.
The first letter of the code designates a different chapter; there are 22 chapters in
total (several letters are included in the single chapter together) within each
chapter, The fourth character codes divided so that they specify different

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classification axes, the fourth character. (The number after the decimal) is not
required for reporting and is used in various ways.

USE OF THE ICD

Every country subscribing to the ICD system uses it is varying degrees. Most
countries subscribe to the entirely of the ICD system, whereas some use the ICD
in hospitals only and others for morbidity only.
Some countries have chosen to implement partial code use. Differences in
mortality classification coding between ICD-9 and ICD-10 prevented direct
comparisons between the two, though a method to adjust for the change was
introduced.

VERSIONS OF ICD
The years for which, causes of death in the United States have been classified by
each revision as follows
ICD 1 = 1900
ICD 2 = 1910
ICD 3 = 1921
ICD 4 = 1930
ICD 5 = 1939
ICD 6 = 1949
ICD 7 = 1958
ICD 8A = 1968
ICD 9 = 1979
ICD 10 = 1999

Cause of death on United States death certificates, statistically compiled by the

Centers for Disease Control and Prevention (CDC), are coded in the ICD, which

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does not include codes for human and system factors commonly called medical
errors.

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 DAILY DEFINED DOSES

Definition: The defined daily dose (DDD) is the assumed average maintenance
dose per day for a drug used for its main indication in adults.
The ddd is a unit of measurement and does not necessarily reflect the
recommended or prescribed daily dose. Therapeutic doses for individual patients
and patient groups will often differ from the ddd as they will be based on
individual characteristics (such as ago, we ethnic differences, type and severity
of disease) and pharmacokinetic considerations

GENERAL PRINCIPLES FOR DDD ASSIGMENT

DDD are only assigned to drugs with an ATC code and a DDD will normally not
be assigned for a substance before a product is approved and marketed in at least
one country
The basic principle is to assign only one DDD per route of administration within
an ATCcode
DDDs are not established for topical products, sera vaccines, antineoplastic
agents, allergen extracts, general and local anaesthetics and contrast media. The
designed DDD is based on the following principles
a. The average adult dose recommended for the main indication as reflected by
the ATC code.
b. The recommended maintenance dose (10mg term therapeutic dose) is usually
preferred when establishing the DDD.
c. For some groups of medicinal products specific principles for DDD assignment
are established (example- the DDDs for the selective serotonin agonists in the
treatment of migraine are based on the approved initial dose)
d. The treatment dose is generally used.

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e. A DDD is usually established according to the declared content (strength) of
the product.
f. Parenteral drugs that have different routes of administration have same DDD.

APPLICATION FOR DDD

Data requirements
Following are requirement when requesting a new DDD.
i) Dose ranges and dosing instructions of product information approved by one
or more major regulatory authorities.
ii) Proposal for a DDD.
iii) Status concerning marketing authorization.
iv) Doses used in clinical trials.
v) Market research data on doses.
vi) Fitting the drug in ATC classification.

INTERNATIONAL NON -PROPRIETARY NAMES (INN)

▪ International Non -Proprietary Names (NN) identifies pharmaceutical
substances or active pharmaceutical substances or active pharmaceutical
ingredients, Drugs are generally marketed by their brand names though
there is a legal requirement to mention generic names in the labels.
▪ However, countries have their own systems of generic nomenclature for
▪ pharmaceutical substances. Each INN is a unique name that is globally
recognized and is public property A non-proprietary name is also known
as a generic name.
▪ The WHO administers an international generic nomenclature system called
INNs also known as rINN (For recommended international non-proprietary
name or PINN for proposed International Non-Proprietary name). Example
of INNS- Paracetamol
▪ Chemical name- N (4-hydroxyphenyl acetamide) INN-Paracetamol

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HISTORY OF INNS
The INN system initiated in 1950 by World Health Assembly resolution, it begins
operating in year 1953. The cumulative list of INN now stands at some 7000
names designated since that time, and this number is growing every year by some
120-150 new INN.

AIMS OF THE INN SYSTEM

● To provide health professionals with a unique and universal available
designated name to identify each pharmaceutical substance.
● For the clear identification, safe prescription and dispensing of medicines to
patients
● . For communication and exchange of information among health professionals
and scientists worldwide.
● Non-proprietary names are intended for use in pharmacy, labelling, product
information, advertising and other promotional material, drug regulation and
scientific literature, and as a basic for product names.

PROTECTION OF INN

▪ As a result of gong collaboration, national names such as British Approved

Name (BAN), Dominations Communes Franchiser DCF), Japan Adopted
Names (JAN), and United States Accepted Names (USAN) are identical to
INN To avoid confusion, trade-marks cannot be derived from INN and in
particular, must not include their common stems.
▪ Encourage manufacturers to rely on their corporate name and the
international
▪ Non-proprietary names, rather than trademarks

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 ▪ Develop policy guidelines on the use of INNA

RIGHTS OF TRADE-MARK OWNERS

▪ In the process of INN selection, the rights of existing trade-mark owners
are fully protected
▪ If in the period of four months following the publication of a proposed
INN, a formal objection is filed by an interested person who considers that
the proposed INN is in conflict with an existing trade-mark
▪ WHO will actively pursue an arrangement to obtain a withdrawal of such
an objection or will reconsider the proposed name.
▪ As long as objection exists, WHO will not publish it as a recommended
INN.

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 DRUG DICTIONERIES AND CODING IN PHARMACOVOGILANCE

WHO ADVERSE REACTION TERMINOLOGIES (WHOART)

1) The WHO Adverse Reactions Terminology (WHOART) is a dictionary

developed to serve as a basis for rational coding of adverse reaction terms for the
WHO drug monitoring programme.

2) This system is maintained by the Uppsala Monitoring Centre (UMC), the

World Health Organisation Collaborating Centre for International Drug
Monitoring.

3) This system was developed in 1968 and is hierarchical in nature with 4 level
hierarchical structures. It is used both by regulatory agencies and pharmaceutical
manufacturers.

4) There are about 6000 terms included in the WHO Adverse Reactions
Terminology (WHOART) dictionary.

5) It has been developed in different languages like, English, Chinese, French,

Portuguese and Spanish translations.

6) Used by drug regulatory agencies and pharmaceutical manufacturers in many

countries.

7) The whole Structure of WHO ART Dictionary includes:

i) 23 SOCs: Body organ groups.

ii) 339 HLTs: For grouping preferred terms.

iii) 2123 PTs: Principal terms for describing ADR.

iv) 3925 Its: Synonyms to preferred terms

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Definitions and Uses

1) Preferred Terms: These are the primary terms used for describing adverse drug
reactions. They are the main terms used at the input side. Nevertheless, it can also
be used for output purposes.

2) Included Terms: These terms are closely related to preferred terms. They are
used to help in finding the equivalent preferred term for proper coding of reported
adverse reaction.

3) High Level Terms: These are group terms of related or similar conditions,
which are used for easy retrieval of information. For example, thrombophlebitis
leg and thrombophlebitis arm represent two different preferred terms but are both
grouped under thrombophlebitis as a high-level term. All Preferred terms may not
have been assigned a high-level term.

4) System-Organ Classes: These are groups of adverse reaction Preferred terms

pertaining to the same system-organ, and are for some purposes used at the output
side. A Preferred term can be allocated to a maximum of three different system-
organ classes, e.g., respiratory depression is coded both under Respiratory
disorders and Central nervous system disorders. The allocation of a preferred term

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to system-organ classes is fixed and does not change with specific reports. The
first System Organ class listed for each preferred term is considered the most
important one. A complete list of the classes and their codes is given at the end of
this introduction.

MedRA AND STANDARDISED MedRA QUERIES

What is MedDRA?

• Med Medical • D=Dictionary • R=Regulatory • A=Activities

Definition:

The MedDRA is a medical terminology used to classify adverse event

information associated with the use of biopharmaceuticals and other medical
products (e.g., medical devices and vaccines).

It is used to classify the adverse drug events (ADES) data from clinical trials,
spontaneous adverse event reports by healthcare professionals, patients and
others; and from other sources of the ADES.

MedDRA has been developed by an ICH Working Group to provide:

➢ An international, multi-lingual, medical terminology%

▪ Medical personnel can code ADR data in their native language
▪ Safer-less likely to miscode data
➢ Standardized communication between regulators and industry/sponsors of
clinical trials%0
▪ Within regions and between regions

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A single terminology for use through all phases of development cycle (both
pre- and post-marketing)

➢ Clinical Trials (medical information, adverse events).

➢ Registration (study report, analyses, summary of product
characteristics/labelling- undesirable effects section).
➢ Post-authorization (adverse events).

Support for electronic submissions

➢ Each MedDRA term is assigned a unique 8-digit numeric code

➢ Codes can fill certain data fields in e-submission types (E2B: ICSR-
Individual Case Safety Reports, eCTD: e-Common Technical Document)
➢ Codes easier to transmit as no language boundaries

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Who develop MedDRA?

It is developed by the International Council for Harmonization (ICH) of Technical

Requirements for Pharmaceuticals for Human use.

ICH has created a governance structure to nature and protects the integrity of
MedDRA.

ICH Med DRA committee oversees all the activities of the MedDRA maintenance
and support services organization.

The Maintenance and Support Service Organization (MSSO)

➢ MSSO is the management Board appointed by ICH steering committee.

➢ Maintain and upgrades MedDRA.
➢ Releases updated MedDRA versions twice a year (in March and
September).

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MedDRA MSSO
➢ MedDRA is actively developed and maintained
▪ Two releases per year
▪ Evolves to meet needs of regulators, industry, other users
▪ Success depends on these activities
➢ ICH contracted MSSO for this purpose
➢ MSSO activities are governed by ICH MedDRA Management Board

Objectives of MedDRA's Development

➢ International multi-lingual terminology

❖ Used in 60 countries.
❖ Available in 11 languages.
➢ Standardised communication between industry and regulators Application
throughout all phases of development Classification of a wide range of
clinical information.
➢ Support multiple medical product areas Support electronic submissions
❖ Unique 8-digits codes for all terms.
❖ For data fields in e- submission types (e.g., E2B)

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MED-DRA CODE

➢ Unique number assigned to each term in the dictionary

➢ 8-digit number
➢ Starts with 10000001, initially started alphabetically
➢ As term added, codes assigned sequentially.

STANDARDISED MEDRA QUERIES(SMQs)

1. Standardised MedDRA Queries (SMQs) are groupings of MedDRA terms,

ordinarily at the Preferred Term (PT) level that relate to a defined medical
condition or area of interest.
2. SMQs are proposed to help in the identification and retrieval of potentially
relevant individual case safety reports.
3. The included terms may relate to signs, symptoms, diagnoses, syndromes,
physical findings, laboratory and other physiologic test data, etc.
4. The only Lowest Level Terms (LLTs) represented in an SMQ are those that
link to a PT used in the SMQ.
5. The hierarchical structure of MedDRA facilitates data retrieval by
providing grouping terms (High Level Terms (HLTs) and High-Level
Group Terms (HLGTs) that aggregate the very specific terms used for
coding into broader medical categories.
6. SMQs are tools developed to facilitate retrieval of MedDRA-coded data as
a first step in investigating drug safety issues in pharmacovigilance and
clinical development.
7. SMQs include:
i) Narrow Terms: These are those that are highly likely to represent
the condition of interest. For example, the PTs Pancreatitis acute

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 and Pancreatitis haemorrhagic are narrow terms for the SMQ
Acute pancreatitis.
ii) Broad Terms: PT Blood bilirubin increased is a broad term
because not all instances of increased blood bilirubin are
indicative of acute pancreatitis.
8. Example of a simple SMQ of narrow and broad terms includes lactic
acidosis. Description of lactic acidosis are as follows:
i) Lactic acidosis is a form of high anion gap metabolic acidosis.
ii) Intrinsic cardiac contractility may be depressed, but inotropic
function can be normal because of catecholamine release.
iii) Peripheral arterial vasodilatation and central vasoconstriction can
be present.
iv) Central nervous system function is depressed, with headache,
lethargy, stupor, and, in some cases, even coma.
v) Glucose intolerance may occur.
vi) Characterised by an increase in plasma L-lactate.
vii) Acidosis is seldom significant unless blood lactate exceeds 5
mmol/1,
viii) Clinical presentation in type B lactic acidosis:
a) Symptoms: hyperventilation or dyspnoea, stupor or coma,
vomiting, drowsiness, and abdominal pain.
b) Onset of symptoms and signs is usually rapid, accompanied
by deterioration in the level of consciousness. 70
Pharmacovigilance
9. Over 100 SMQs have been created in the current situation as per the
requirement. The following are a small sample of SMQs available:
i) Anaphylactic reaction
ii) Central nervous system vascular disorders
iii) Convulsions

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 iv) COVID-19

v) Depression and suicide/self-injury

vi) Drug abuse, dependence and withdrawal

vii) Hyperglycaemia/new onset diabetes mellitus

viii) Hypersensitivity

ix) Ischaemic heart disease

x) Lack of efficacy/effect

Development of SMQs

1) A focus of the early phase of SMQ development was to identify which areas
of interest were candidates for development.

2) On an average about 100 possible topics were initially identified.

3) The CIOMS Working Group continuously reviews this list and prioritises
topics for development.

4) Sub-teams work on each candidate SMQ prior to review and approval by the
entire CIOMS Working Group.

5) The definitions, inclusion and exclusion criteria, hierarchy (if required), and
algorithm (if appropriate) for each SMQ are included in this Introductory Guide.

6) Much of this information was derived from the anonymised SMQ CIOMS
Working Group detailed documentation.

Design Concepts for SMQ

Content SMQs may have a mixture of very specific terms and less specific terms
that are consistent with a description of the overall clinical syndrome associated
with a particular adverse event and drug exposure. Some SMQs are a

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straightforward collection of terms; others have been designed to accommodate
combinations of terms from more than one group.

WHO DRUG DICTIONARY

1) The WHO Drug Dictionary is an international classification of medicines

created by the WHO Programme for International Drug Monitoring and managed
by the Uppsala Monitoring Centre.

2) The WHO Drug Dictionary was created in 1968 and is updated regularly. Since
2005 there have been major developments in the form of a WHO Drug Dictionary
Enhanced and a WHO Herbal Dictionary, which covers traditional and herbal
medicines.

3) However, since 2016 all of the WHO Drug products have been available in a
single subscription service called WHO Drug Global.

4) The dictionary is used by drug regulatory authorities, clinical trial

organisations and pharmaceutical companies to identify drug names in
spontaneous ADR reporting, pharmacovigilance and in clinical trials.

5) It is a source of international drug names in which:

i) Substance names are given according to International Non-Proprietary

Names (INN).

ii) Drugs are classified according to the Anatomical -Therapeutic Chemical

(ATC) classifications system.

iii) Information on companies and reference sources

6) Medicinal product names are given according to:

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 i) Proprietary Names: a) Single-ingredient b) Multiple-ingredient

ii) Non-proprietary/Generic Names: a) Single-ingredient b) Multiple-

ingredient

7) The majority of the entries refer to conventional (chemical substance)

medicinal products but the WHO-DD also includes: i) Herbal remedies

ii) Vaccine iii) Blood products iv) Homeopathic remedy v) Dietary supplement.

Organisation of WHO - DD
1) WHO Drug drug code consists of 11 characters (alphanumeric code).

2) It Has 3 Parts:

i) Drug Record Number (DrugRecNo),

ii) Sequence number l(Seql ) and

iii) Sequence number 2 (Seq2).

3) DrgRec No consists of 6 characters. It uniquely identifies active moieties,

regardless of salt form or plant part and extract.

4) Seql is used to uniquely identify different variations (e.g. salts and esters), plant
parts and extraction methods, thereby defining active substances or a combination
of active substances.

5) WHO Drug records sharing the same DrugRec No and Seql contain the same
variation/plant part/extract variation of the same active moiety.

6) For single-ingredient records, if

i) Seql =01, it identifies a specific active moiety.

ii) Seql > 01, it refers to variations of that active moiety.

7) For multi-ingredient records, if

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 i) Seq1 =01, it identifies a combination of active moieties.

ii) Seql > 01, it refers to variations of one or more of the active moieties in
the combination.

iii) Seq2 uniquely identifies the name of the record in WHO Drug.

For example, The Drug Code for the substance Ibuprofen is 001092 01 001. The
Drug Code for the trade name Advil infants’ pain & fever relief is 001092 01 A3D

ATC in WHO Drug Dictionary (Relationship of ATC with WHO-DD)

1) WHO Drug records are classified with at least one code from Anatomical
Therapeutic Chemical Classification System (including the HATC which stands
for Herbal ATC and which is treated as part of ATC for mapping purposes).

2) Preferably, a fourth level ATC code is assigned.

3) ATC assignments in WHO Drug are marked as ‘official’ or ‘UMC-assigned’.

4) Official ATC codes are classifications included in the official ATC index, while
UMC-assigned ATC codes are classifications NOT included in the official ATC
index.

5) In addition, a separate cross reference called "Cross Reference ATC 5".

6) In this additional reference, WHO Drug records are matched to fifth level ATC
codes (where relevant).

7) It helps in drug utilisation research.

8) Hierarchical classification provided is useful for navigation and aggregation.

9) It remains applicable to both single and multiple ingredient drugs.

10) Medicinal products are classified according to the main therapeutic use.

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EUDRAVIGILANCE MEDICINAL PRODUCT DICTIONARY

1) EudraVigilance is the European Union pharmacovigilance database and data-

processing network, known as the ‘EudraVigilance database'. It supports the
detection, evaluation and management of signal,

2) Proactive information release on adverse drug reactions in compliance with

personal data protection legislation in the European Union,

3) Secure exchange, processing and evaluation of Individual case safety reports

(ICSRs) related to therapeutic products authorised in the European Union (EU)
and investigational medicinal products (IMPs) studied in authorised clinical trials
in the European Union,

4) Electronic submission of information about the therapeutic drugs authorised in

the European Union,

5) Provision of information on IMPs by the sponsor before completing a clinical

trials application in the EU.

6) The European EudraVigilance system deals with:

i) electronic exchange of Individual Case Safety Reports (ICSR, based on

the ICH E2B specifications):

a) EudraVigilance Clinical Trial Module (EVCTM) for Suspected

Unexpected Serious Adverse Reactions (SUSARs) reporting.

b) EudraVigilance Post-Authorisation Module (EVPM) for post

authorisation ICSRs.

ii) Early detection of possible safety signals from marketed drugs for
human use.

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 iii) Regular evaluation and monitoring of potential safety issues with
respect to reported adverse drug reactions.

iv) Decision-making processes based on wide-ranging knowledge of the

adverse drug reactions profile of medicinal products/drugs.

Main Components of EudraVigilance

1) EudraVigilance (EV) Gateway: A data-processing network for the secure

electronic exchange of adverse reaction data

2) EudraVigilance Post-Authorisation Module (EVPM): Dedicated to the

collection of Individual case safety reports (ICSRs) related to all therapeutic
products authorised in the EEA in line with Regulation (EC).

3) EudraVigilance Clinical Trial Module (EVCTM): This indicates the

collection of Individual case safety reports ICSRs of Suspected Unexpected
Serious Adverse Reactions (SUSARs) in accordance with Directive 2001/20/EC
and Regulation (EU) No 536/2014 of the European Parliament and of the Council
of 16 April 2014 on clinical trials on medicinal products for human use, and
repealing Directive 2001/20/EC.

4) EudraVigilance Data Analysis System (EVDAS): This system supports the

European Union pharmacovigilance safety monitoring activities with the primary
focus on signal detection and evaluation of Individual case safety reports
(ICSRs).

5) Adrreports.eu portal: This portal will allow in searching and viewing data on
suspected adverse reactions for authorised medicinal products in the EEA and
provides general information to help in understanding of the reports.

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6) extended EudraVigilance Medicinal Product Dictionary (XEVMPD): It is a
reference source for substances coding and medicinal products reported in ICSRs
based on the provided information given by MAHs in line with Article 57(2)

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 INFORMATION RESOURCES IN PHARMACOVILANCE

BASIC DRUG INFORMATION RESOURCES

Drug information is defined as recent, critically observed, relevant data regarding
drugs and their administration in a particular situation.

1) Current information uses the possible updated and latest sources.

2) Critically examined information should meet the following criteria:

i) More than one source should be used when appropriate.

ii) The determination of extended agreement of the sources should be done.

iii) The probability of information, based on clinical circumstances should

be facilitated.

3) Significant information should be delivered in a way that directly relates to the

circumstances under consideration (e.g., patient parameters, therapeutic
objectives, alternative approaches)

TYPES OF RESOURCES

1.Primary Resources

1) Researcher’ s and manufacturer’s information.

2) Patents containing original information related to the discovery of drug.

3) Reports including scientific data before product can be retailed, delivered or

represented.

4) Scientific journals.

5) Provide original studies or reports, e.g., clinical trial, case series, case report.

6) Scope is narrow.
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7) Good when topic is new or when new data has been published

Advantages

▪ Most current evidences.

▪ Provide data on new drugs
▪ Original document that was created at the time of the actual events.

Disadvantages

▪ Data can be controversial

▪ Every study has limitation
▪ Complicated
▪ Time consuming

2.Secondary Resources

It is an abstract or index which concludes the information rising in primary

source.

2) For specific information, data, citation, and articles, indexing and abstracting
services are valuable tools for quick and selective screening of the primary
literature.

3) There are following three types of abstracts:

i) Telegraphic abstract (only string of words).

ii) Indicative abstract (structured in sentence).

iii) Informative abstract.

4) It contains bibliographic databases that provide abstracts or full text of studies.

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Advantages

▪ Find specific information at high granularity.

▪ Pick out key point.
▪ Quick to read.

Disadvantages

▪ Detail missing.
▪ Two different authors can interpret the same piece of original material in
two widely different ways.
▪ May be inaccurate.

3.Tertiary Resources

1) It is compilations of knowledge in the field, e.g., textbooks, handbooks, online

drug compendia.

2) This resource is good for background questions.

3) Its scope is wide.

Advantages

1) It provides comprehensive information.

2) The information provided by this source facilitates reflection views towards

multiple experts in field. 3) It is fast, easy to use, and may be good for patients.

Disadvantages

1) It is generally not relevant for at least 2 years by publication.

2) It is highly dependent on the interpretation of the authors.

3) It can be addressed by pharmacists after consulting at-least 2 tertiary resources.

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Others Resources

1) Libraries.

2) Research associations.

3) Government bodies.

4) Information centre in industries.

5) Analyst labs.

6) Poison centres.

Specialised Resources of ADRs

Specialised resources of ADR are as follows:
1) Individual reporting.
2) Comprehensive monitoring.
3) Population monitoring.
4) Individual Case Safety Report (ICSR).
5) Spontaneous reporting.

1.Individual Reporting

1) In individual reporting Doctor are the major source of report.

2) The doctors, who mainly practice outside the hospital, provide therapy to the
patients for prolonged periods of time can easily monitor the occurrence of
gradually developing or delayed reactions.

3) As most severe reactions may be found in hospitals, then hospital - based

practitioners can submit a report by determining previous drug administration and
relating it to the reaction.

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4) During external and internal examination, the practitioner may determine that
the patient has a recognisable syndrome of signs, symptoms and/or laboratory
findings and then this syndrome can be linked with a previously administered
drug.

5) Further this information should be reported to the centre

2.Comprehensive Monitoring

1) It is carried out normally in a hospital setting and its input consists of abstracts
of patient identification, drug administration, and patient reactions.

2) To ensure that the information delivered is complete, specialised methods can

be used. Then the case reports or summary data can be forwarded to the national
center

3.Population Monitoring

1) In population monitoring the record of hospital or clinic patients, or of the

entire population of a district, can be maintained.

2) Such monitoring can be effective in case a large stable population is surveyed

in an organised medical care system.

3) Because of the advanced electronic processing of patient documentation and

records, the opportunities to integrate a drug observing element in these systems
can be rare.

4) It seems to have much to offer in those actual rates of reactions being obtained
and truly unexpected reactions can be recognised.

5) The patient population can-not be more for the detection of rare (1 in 10000-
50 000) reactions because of its complexity and high charges.

6) Drug use and patient syndromes or events can be recorded automatically in

this system and then examines the links between the two.

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7) The results of such searches should be reported to the national centre

4. Individual Case Safety Report (ICSR)

1) It is a report which includes information describing suspected adverse drug

reaction associated with the administration of one or more medicinal product.

2) This document offers the most comprehensive information allied to an

individual case at a definite point or time

5.Spontaneous Reporting

1) It is a system by which the case report of adverse drug event can be voluntarily
submitted through healthy professionals, pharmaceuticals companies as well as
consumers to the national pharmacovigilance centre.

2) In this mainly the reporting of a suspected adverse reaction on the initiative of

the health professional who might be aware of the problem, or the patient
initiative. These reports can be forwarded through any means, still in several
countries they are communicated with a well-developed pharmacovigilance
system; they are mostly reported on the country-specific reporting card.

3) Such reporting can also be stated as intensified spontaneous or ideally

prospective reporting.

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 ESTABLISHING PHARMACOVIGILANCE PROGRAMME

ESTABLISHING PHARMACOVIGILANCE IN A HOSPITAL

A PV centre can be established in a hospital or at any department, mainly in

pharmacology, medicine, clinical pharmacy or clinical toxicology.

At the initial stage locally, it can be started in one hospital and by the time it can
extend to other hospitals for covering the entire region.

This helps in close communication with the zonal centre. One by one all zonal
centres should report to the national nodal centre.

There the gathered data from the entire country is organised. For global
referencing and use, the organised data are forwarded to the Uppsala Monitoring
Centre (UMC), Sweden, in definite time line.

To start the process at least one clinical pharmacologist, clinical pharmacist or a

physician should be present in the centre

Requirements

Basic requirement to start a PV centre are a physician or clinical pharmacist along

with the secretarial support. Progressively, a full time professional should be
appointed to manage the increase in the data traffic. This can be processed to
maintain the advancement in the centre and secretarial support. The increase in
the quantum of work, staff resource requirements are calculated by flatly
assuming the time of assessment of a single case as one hour. The involvement of
professionals with expertise in pharmacology, clinical medicine, epidemiology,
toxicology can be beneficial in the smooth functioning of a PV centre.

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Moreover, for successful functioning of the centre, a permanent secretariat can be
required in the centre who can handle the phone calls, database, and
documentation of literature. They are also needed for coordinating some activities
such as interfacing with related departments so that secretarial continuity can be
maintained.

An advisory committee assists to acquire funds and support for the centre,
monitoring, and evaluation. It also helps in keeping a tab in the quality of the
procedures linked with the data collection and mining, data interpretation and
publication information. Disciplines of clinical medicine, pharmacology,
toxicology, epidemiology, phytotherapy, pathology, drug regulation and quality
assurance can represent advisory committee.

PV centre also requires some technological requirements like continuous electric

supply, intercom, multi connection telephone, computer, printer, FAX, internet,
photocopier. These technologies should be taken care of and made available for
working at all times. In case of sudden breakdowns, sufficient back up facilities
should be present to avoid interruption in the work.

Steps Recommended by WHO for Establishing a PV Centre

1) To ensure approval for the centre by outlining the importance of the centre and
its purpose, one should contact to the relevant authorities.

2) ADR reporting form should be designed and the data should be collected by
distributing the form to the hospital departments, family practitioners, etc.

3) A printed material should be produced for informing health professionals

regarding definitions, aims and methods of the pharmacovigilance system.

4) Centre should be formed including staff, accommodation, phone, word

processor, database management capability, bibliography, etc.

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5) Pharmacovigilance staff should be educated on the following topics:

i) Data collection and verification.

ii) Case causality assessment.

iii) Interpreting and coding of adverse reaction descriptions.

iv) Signal detection.

v) Coding of drugs.

vi) Risk management.

6) Database should be established for the storage and recovery of ADR data.

7) Routine meetings should be organised in the hospitals, academia and

professional associations, for explaining the principles of pharmacovigilance and
the importance of reporting.

8) The importance of reporting adverse drug reactions through medical journals,

other professional publications, and communications activities should be
promoted.

Plan

For establishing and getting a smoothly working PV system, a blueprint should

be formed. Following methods should be established carefully:

1) Communication Process: Communication with health authorities and local,

regional, national bodies and groups engaged in clinical medicine i.e.,
pharmacology, toxicology, epidemiology, should be done. They should be briefed
regarding the importance of the project and its applicability in modern
therapeutics. A bulletin or newsletter distributed to all healthcare professionals or
a regular column in reputed medical and pharmaceutical journals are good means

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for the disseminating information. Although the prompt data-sheet amendments
are important, still data-sheets should be irregularly printed and also their
educational effect might not increase. ‘Dear Doctor' letters should alert the
profession in urgent cases of appropriate importance.

2) Data Acquisition: Designing a template for ADR reporting and making

available ADR reporting forms at all times, to hospital departments and general
practitioners, on which they can furnish relevant information to the data bank of
the centre.

3) Dissemination: producing printed handouts as well as conducting meetings or

workshops in hospitals and academia to acquaint health care professionals about
the definitions, goals, scope, and methodology of the PV system to create
awareness about its relevance in present time.

4) Establishment: Well qualified and interested staff should be hired and a

suitable place for accommodating them as well as the centre should be provided.
Arrangements for telephones, computers, printers, word processors, database
management, bibliography support, and internet services should be done.

5) Internal Education: The staff of PV centres should be educated properly,

updated regularly by providing them training in data collection, filtration, mining,
verification, interpretation and coding of ADRs, medicines coding, causality
assessment, signal detection, risk management, and action in case of serious/fatal
adverse drug events (ADE). Data mining is a relatively nascent interdisciplinary
area which involves finding correlations and patterns among many fields in large
databases with the aim of categorising the data and summarising identified
relationships.

6) Database and Information Service: A safely stored and classified database

should be created which can be retrievable and secured by required degrees of
confidentiality. The basic task of a pharmacovigilance centre is to deliver a high-

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quality information service to healthcare professionals and a major instrument in
the stimulation of reporting. For this purpose and also for the assessment of case
reports, the centre should have access to a comprehensive and updated literature
source as well as information database

7) Promotion: The habit of reporting ADRs should be inculcated and promoted

to the higher centre, medical journals, health bulletins and other professional
healthcare publications.

8) Networking: Healthcare professionals should be encouraged to contact

institutions who are working on a global scale regarding PV e.g., Uppsala
Monitoring Centre (UMC), WHO department of Essential Medicines and
Medicines Policy, Geneva, and net groups e.g., International Network for the
Rational Use of Drugs (INRUD), E-drug, and Network for Rational Use of
Medicines (NetRUM).

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 ESTABLISHMENT AND OPERATION OF DRUG SAFETY
DEPARTMENT IN INDUSTRY

Introduction: -

1) Pharmacovigilance has grown as a discipline over the past 10 to 15 years.

2) An educational survey in 1994 revealed that more than 320 people
currently worked in company pharmacovigilance function in the UK alone.
3) Pharmaceutical companies are international, hence the number of staff
working in this field within the industry, particularly in other European
countries and USA.
4) A major pharmaceutical company such as Astra has over 100 permanent,
experienced staff in pharmacovigilance within its research and
development organization in Sweden and the UK and US similar number
in local operating companies worldwide
5) The number of individual reports of possible adverse drug reaction can be
considerable, for key marketed products often more than 1000 case reports
a year are received worldwide from healthcare professionals and other
sources.

Aim of pharmacovigilance within the industry

✓ Protect patients from unnecessary harm by identifying previously

unrecognized drug hazards.
✓ Refuting false safety signals and quantifying risk in relation to benefit.

Scientific and Safety Characteristics

1) Pharmacovigilance is related to the following number of scientific disciplines:

i) Clinical medicine.

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 ii) Clinical and preclinical pharmacology.

iii) Immunology.

iv) Toxicology.

v) Epidemiology,

2) Safety characteristics of medicine should be identified and analysed in two

distinct stages:

i) Before Marketing: Comparing the new treatment to current alternative

treatment, the main methodology can be experimental with clinical trial.

ii) After Marketing: While administrating a new medicine, the main safety
methodology should be observed i.e., data used from observation of
patients treated in clinical practice instead of experimental situations

Pre-marketing clinical trials: -

❖ Safety monitoring in clinical trials involves collecting adverse event,

laboratory investigation and details of the clinical examination of patients.
❖ Pharmacovigilance may be involved to varying degrees all phases of
clinical trials including planning, execution, data analysis, reporting of
safety information.
❖ Safety issues from animal pharmacology and toxicology studies, finding in
phase-1 studies, ADR with similar drugs, signals from other studies and
special patient group (e.g., elderly).
❖ The practice of collecting all adverse events rather than suspected ADR
arose from the failure of clinical trials to detect serious reaction with
protocol and after several years’ experience this is now the approach
adopted by company in most studies.

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 ❖ The involvement of pharmacovigilance staff in clinical trials also includes
an important responsibility for the expedited reporting of individual cases
and safety update required by the UK medicine control agency and other
regulatory authorities.
❖ Safety analysis and clinical expert report in the marketing authorization
application submitted by the company and will be the basis of ADR,
warning and precaution include in the prescribing information i.e., data
sheet.

Methods of Post Marketing Surveillance (PMS) in Industry

1) First Step in Signal Generation: Processes by which possible new ADR can
be identified should be carried out. The signal generated through following four
methods:

i) Spontaneous Reporting:

a) It is the process of recording and reporting clinical observation of a

suspected ADR along with a marketed drug.

b) yellow card is the National system in the UK is the.

c) It is the reporting in which the doctors, dentists and recently hospital

pharmacist are encouraged to report all suspected reactions caused because
of use of new medicines and serious suspected reactions to established
medicines.

ii) Published Case Reports:

a) In this the case reports of suspected ADR are published in medical

journals as it is an established way of alerting others regarding possible
drug hazards.

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 b) The report of possible ADR appearing on the internet is the latest
advancement that is a serious problem for many companies and they are
still determining how well they should handle them.

iii) Cohort Studies: The prospective might be organised or sponsored by the

companies. The interventional cohort type studies can be introduced to answer
safety question that may arise after marketing or after generating general
hypothesis. The testing tool can also be used according to the need.

iv) Post Marketing Clinical Trials: While evaluating the safety of marketed
products and confirming the efficacy, the large randomised clinical trials with
wide entry criteria can be useful. Search studies to address particular safety issues
can be carried out and sponsored by Companies.

2) Second Step in Signal Generation: Signals are subjected to hypothesis

testing, i.e., processes that determine whether the indication of new ADR by the
single-dose is true or false.

i) The Hypothesis Testing Process: A small number of reports are received by

the Pharmacovigilance Company showing that the patients have developed a
serious medical condition, for example, liver function disturbance or convulsion.

ii) Using Spontaneous Reporting Data for Hypothesis Testing: It is a common

place in clinical practice where the decision can be made and action can be carried
out on the basis of causality evaluation between an event and a certain drug.

iii) Epidemiological Studies: These studies are the use and effect of drugs in large
populations, e.g., NSAID treatment and gastrointestinal ulceration and bleeding
are studied during the last decade pharmacoepidemiology.

iv) National and International Regulatory Requirements: To regulatory

authority, the reporting of safety information from clinical trials and with
marketed product by pharmaceutical companies has been mandatory for many

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years but with each National Authority having different requirements.
Pharmacovigilance is not only about the reporting cases to regulatory authorities
but it also provides the useful information from the post marketing surveillance
and hypothesis testing.

v) Issue and Crisis Management: Throughout the lifetime of a product, long

lasting and continuous processes of signal generation and hypothesis testing are
carried out that may result in a gradual build-up of knowledge about safety
properties.

vi) The Future: In the industry pharmacovigilance can continue to grow and
develop as a discipline. The strong advancement towards international
harmonisation might lead to increase the international requirement and fast
development in electronics communication. This may permit automated
distribution of case reports within companies and also to the regulatory
authorities.

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CONTRACT RESEARCH ORGANISATIONS (CROS)

A Contract Research Organisation (CROs) is a service organisation that provides

support to the pharmaceutical and biotechnological industries in the form of
obtaining pharmaceutical research services (for both drugs and medical devices).
It is also known as Clinical Research Organisation (CRO). CROs range from
large, international full-service organisations to small and niche specialty groups.
They may provide the experience to their client of moving a new drug or device
from its conception to FDA marketing approval, without maintaining a staff for
these services by the drug sponsor.

Roles

1) Even though different types of CROs and diverse levels of specialisation

(distinct therapeutic areas for instance) are present still typical CRO services
include regulatory affairs, recruitment support, clinical monitoring, data
management, trial logistics, pharmacovigilance, biostatistics, medical writing,
project management and site selection and activation, among others.

2) During clinical trial, CROs should be hired by sponsors for carrying out a set
of tasks and takes various technical and administrative responsibilities on the
behalf of the sponsor.

3) Being a central contact point between the sponsor and other trial actors (e.g.,
ethics committees, regulatory agencies, vendors, and hospitals), the main role of

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the CRO is to plan, coordinate, execute, and supervise the processes involved in
the advancement of a clinical trial.

4) Since CROs have the knowledge and the capabilities required for the proper
advancement of a clinical study, therefore they are the key players in clinical
research. While ensuring trial quality and compliance with national and
international standards, they also decrease the workload of the sponsors.

5) To raise efficiency in the study processes, many CROs supply innovative

technological tools at the same time that translates into cost reductions.

Advantages

1) Reduced Need for Staffing or Infrastructure Upgrades: The need to acquire

the manpower, infrastructure, office space (to carry out drug or device design),
development, and testing by the sponsors decreases after contracting with an
outside company. This characteristic is especially favourable for smaller firms
who may face difficulties in recruiting the specialised talent that are required to
bring a new product in the market.

2) Faster Clinical Trials: CRO trade groups state that when firms or public
entities outsource to a CRO, it decreases the time it takes to conduct a trial in
comparison of doing it in-house and translating it to the market in lesser time.

3) Lower Costs without Shrinking Profits: The pharmaceutical and medical

devices organisation continues searching different ways to decrease the cost of
prescribed drug without losing profits, as they face increasing pressure related to
high drug costs. Outsourcing clinical trial management to CROs contributes in
lowering the overhead costs considerably and also helps them to recover the loss
that occurred because of reducing drug prices. Faster clinical trials can also help
reducing prices.

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Disadvantages

1) Poor-quality Work: Even if one is selective while hiring of a CRO can guard
against it, unsatisfactory work done by CRO can become a risk for companies.
For example, a work produced by CRO can be of poor quality which may require
repeating the work.

2) Delays in Commercialisation: In case CRO fails to identify the milestone or

has to perform the same work, the launch of the product might be delayed because
of which sponsor will not be able to become the first firm to bring a product in
the market.

3) Potential for Financial Losses: Both repeat work as well as delays may lead
to lose both time and money for the sponsor that disproves the benefit of selecting
a CRO to initiate with.

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14 | P a g e
 ESTABLISHING A NATIONAL PHARMACOVIGILANCE
PROGRAMME

Country's central drug regulatory agency sponsors and coordinates the

nationwide programme. In India Central Drugs Standard Control Organisation
(CDSCO) is responsible for establishing and managing the data base of Adverse
Drug Reactions (ADR). To ensure safety of the drugs and takes informed
regulatory decisions related to marketing drug authorisation. The National
Pharmacovigilance Centre organises the programme at CDSCO. The procedures
and guidelines regarding regulatory interventions are recommended by the
National Centre that works under the supervision of the National
Pharmacovigilance Advisory Committee (NPAC).

Objectives of the Programme

Broad Objectives of the Programme

1) To foster the culture of AE notification and reporting.

2) To establish a viable and broad-based ADR monitoring program in India.

Specific Objectives of the Programme

1) To create an ADR database for the Indian population.

2) To create awareness of ADR monitoring among people.

3) To ensure optimum safety of drug products in Indian market.

4) To create infrastructure for on-going regulatory review of PSURs.

Operational Requirements for Establishing a National Pharmacovigilance

Programme

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Pharmacovigilance is all about drug regulations and is based on thorough
collaborative ties, coordination, communications, and public relations. The
political governance commands about the most suitable location for setting up a
PV centre. Its healthcare priorities involve the willingness to do, law enactment
as well as its enforcement, finding, organisation, staffing, training, and
development.

To ensure a good PV System, certain operational requirements should meet

the following criteria:

1) To intensify the communication among the PV network a well-structured drug

safety management team should be present. With this an organised structure and
smooth functioning of the centre is ensured. Meetings among the PV physicians,
managers, and technical agencies should be conducted from time to time.

2) A countrywide database which provides provision for collating and managing

ADR reports should be present.

3) A national PV advisory committee should be made.

4) In regular situations as well as situations of crisis, a clear approach should be

communicated in detail.

5) To run different grounds of a system, funding should be collected.

6) A general guideline can be a standard strategy for confirming that the PV

system meets the national and international standards and regulations at each
level. Thus, the guidelines and communications should be developed with the
health authorities.

7) To know about the importance of the project and its applicability in modem
therapeutics, a regular communication should be done with the health authorities,

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local, regional and national bodies as well as professionals involved in clinical
medicine, pharmacology, toxicology, and epidemiology.

Minimum Requirements for a Functional National Pharmacovigilance

System

1) A national pharmacovigilance centre with designated staff (at least one

fulltime), stable basic funding, clear mandates, well-defined structures and roles
should be present. For International Drug Monitoring it should also collaborate
with the WHO Programme.

2) A national spontaneous reporting system should include national individual

case safety report (ICSR) form, i.e., an ADR reporting form.

3) A national database or system should be provided for organising and managing

ADR reports.

4) A national ADR or pharmacovigilance advisory committee facilitates with

technical assistance on causality assessment, risk assessment, risk management,
case investigation, crisis management (including crisis communication) and
where ever required.

5) A clear communication strategy should be facilitated for routine

communication and communication during crises.

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 VACCINE SAFETY SURVEILLANCE

VACCINE PHARMACOVIGILANCE
Vaccine Pharmacovigilance is defined as "The Science and activities relating to
the detect assessment understanding and communication of adverse events
following immunization and other vaccine related problems or issues and their
prevention".

Importance of Pharmacovigilance study of Vaccines:

❖ To monitor all Adverse Events Following Immunization (AEFI).

❖ To monitor all the aspects and factors which contribute in occurrence in
AEFI
❖ To provide better results with person safety.
❖ To promote education clinical training in Pharmacovigilance and the
communication to the public.
❖ To give new proposals regaining the vaccine safety.
❖ To provide summarized feedback of AEFI to the regulatory authorities.
❖ To compile all the new and old events related to the AEFI.

Goals

1) Vaccine pharmacovigilance aims to minimise negative effect of adverse events

by detecting the risk early and providing appropriate response (risk management)
to the problem.

2) To lessen the potential negative impact on immunisation programme is another

goal of vaccine programs

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Objectives

1) To promote the safe use of vaccines for its consumer.

2) To detect the adverse event early.

3) To make sure that healthy people usually receive the vaccines.

4) To ensure that infants and children consume most of the vaccines.

5) To administer the vaccines globally to a large population.

6) To ensure that vaccines are often administered concomitantly with other

vaccines

7) To make sure that vaccines are complex biological products

Steps of Vaccine Pharmacovigilance

Elements to Consider in Vaccine PV

A very high level of safety is required for vaccines. Therefore, elements to

consider when conducting vaccine pharmacovigilance include the following:

1) Generally, healthy people including infants receive vaccines.

2) Vast majority of the population or of a birth cohort or to group at high risk for
the disease complications receives the vaccine.

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3) Several adverse events following immunisation may be more susceptible for
the subpopulation to experience

4) The emergency of certain age-related diseases like neurodevelopment disorder

may coincide with the age at the time of immunisation.

5) Immunisation with certain vaccines is mandated in some countries.

6) If the target disease incident is low, the benefits of the immunisation may not
be visible immediately.

7) Intensive investigation of serious adverse events (even if rare) following

immunisation is necessary due to low acceptance of risks.

8) Non-serious adverse events following immunisation may signal a potentially

large complication with the vaccine or immunisation or may generally have an
impact on the acceptability of immunisation so it should be monitored carefully.

9) Any potential causal association of serious, rare, and/or delayed adverse events
or of advance events in subgroups with immunisation should be detect with
appropriate methods.

10) Consideration of dechallenge and rechallenge differs for vaccines compared

with other medicinal products. Vaccines are often administered only once or with
long term intervals, and severe adverse events following immunisation often to
avoid further administration. Dechallenging may not be applied to vaccines,
reason being long term immunological effects, and rechallenging details are only
hardly available.

11) Vaccines are administered concomitantly with other vaccines, making causal
attribution to a specific vaccine difficult.

12) The use of live vaccine can result in diseases caused by the attenuated
organism in vaccine or their contacts, this should be separated form coinciding
natural infection

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Pharmacovigilance of Vaccines in India

1) One of the largest manufacturer and exporters of vaccine is India.

2) One of the largest immunisation programs in the world is run by India

(Universal Immunisation Program, UIP.)

3) Every year, UIP targets 27 million newborns and 30 million pregnant women

4) The Government of India in 1986 initiated AEFI (Adverse Events Following

Immunisation Program) surveillance program.

5) In 2008 national and state AEFI were set up by the government.

6) In Health and Family Welfare department, national AEFI Secretariat was

established.

7) At Lady Harding Medical College, New Delhi, AEFI Technical Collaborating

Centre was established.

8) The response and Surveillance of AEFI is reported in pharmacovigilance.

9) Auxiliary Nurse Midwife, Medical Officers, Health Workers, District Health

Authority.

10) Immediate serious AEFI and monthly routine reporting is done in this.

11) Primary Health Centre, Community Health Centre, District Immunisation

Centre are included in vaccine programs under pharmacovigilance

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 VACCINATION FAILURE

Vaccine is defined as a biological product that helps to improve and increase

immunity to a disease. A vaccine is used for improving the immunity in body
against the disease. Vaccine may be monovalent and multivalent.

REASONS FOR VF
Vaccination failure includes many points some of them are:
1) Vaccine failure
2) Failure to vaccinate
3) Other factors
1) Vaccine failure:
1) Vaccine-Related or host related. These can be
a) Due to immunodeficiency
b) Due to age related response
c) Due to suboptimal immune responses
d) Due to other infectious agents
e) Due to sub health status (under lying disease) and waning immunity
f) Due to immunological interference. Etc.
2) Vaccine Related:
Vaccines are not 100% efficient against antigens. In some cases, incomplete
coverage of strains, genotypes or escape mutants can cause vaccine preventable
diseases. Sometimes manufacturing related problem can cause disease. In the
manufacture defects can be known as batch variations or quality defects etc.
3) Other factors:
There are other factors which can affect vaccine failure related problems. They
are given below
a) Usage issues
b) Immunization programme-related issues.

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a) Usage issues: This includes various steps related to administration of vaccines,
incomplete series of vaccination and sometimes storage related problems. These
all errors can affect the vaccines performance and lead to vaccination failure.
There is one more factor which plays important role in vaccination failure that is
expiry date of vaccine.
b) Immunization programme related issues: There are various reasons which are
related to vaccines failure or vaccinate failure.
There are various cases came which are related to the incomplete vaccination or
some of them are related to time period of the vaccination.
In the immunization programme there are specified points of starting vaccines
and ending in specified.
So that it is necessary to obey or complete the time schedule of vaccination
according to guidelines.
According to the guidelines given by CIOMS there are specified conditions of
vaccination failure. To specify the condition on which the vaccines fail to perform
are categorized as:
a) Confirmed clinical vaccine failure
b) Suspected clinical vaccine failure
c) Confirmed immunological vaccine failure

Types of Vaccine Failure

1) Primary Vaccine Failure: This failure occurs when a person is unable to

produce antibodies or does not produce enough antibodies considered necessary
to protect from the diseases.

2) Secondary Vaccine Failure: This failure occurs when a person stops

producing antibodies in response to vaccination and the level declines at a faster
rest then normally expected. Even after booster shots antibodies to almost all
vaccines decline over time this is reason of vaccine failure in the outbreak of
disease amongst the vaccinated is frequent.

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Other reason for vaccine failure

1) From the time of manufacture till vaccination there is a lack of maintenance.

2) If repeatedly thawed and cooled the quality of the vaccine will deteriorate.

3) In case of stain variation there may be low efficiency or ineffective vaccine.

For example, FMD.

4) Poor vaccine storage

5) Unsuitable vaccine transportation

6) The quality of water is poor for reconstitution of vaccine.

7) UV (direct sunlight) light exposure

8) Vaccine condition is poor.

9) Incorrect vaccination timing

10) Wrong vaccination technique

11) Improper duration of vaccination

12) Poor health status

13) Presence of respiratory diseases

14) Immunosuppression.

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 ADVERSE EVENTS FOLLOWING IMMUNISATION (AEFI)\

Any untoward medical existence which follows vaccination and which does not
necessarily have a causal association with the usage of the vaccine is defined as
Adverse Events Following Immunisation (AEFI)

Classification

AEFIs are divided in following five categories:

1) Vaccine Product-Related Reaction: It is a precipitation triggered by vaccine

due to one or more of the inherent properties of the vaccine product. Example,
extensive limb selling following DTP vaccination.

2) Vaccine Quality Defect -Related Reaction: It is 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. For
example, failure by the manufacturer to completely inactivate a lot of inactivated
polio vaccine leads to cases of paralytic polio.

3) Immunisation Error-Related Reaction: It is an AEFI that is caused by:

inappropriate vaccine management, prescribing or administration and thus by its
nature is preventable. For example, transmission of infection by contaminated
multi - dose vial.

4) Immunisation Anxiety-Related Reaction: It is an AEFI caused from anxiety

about the immunisation. For example, vasovagal syncope in an adolescent
during/following vaccination.

5) Coincidental Event: It is an AEFI that is triggered by something other than the

vaccine product, immunisation error or immunisation anxiety. For example, a
fever occurs at the time of the vaccination (temporal association) but is in fact
caused by malaria. Coincidental events reflect the natural occurrence of health
problems in the community with common problems being frequently reported.

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Objectives of AEFI Surveillance

The objectives for an effective AEFI surveillance system are to (WHO, Vaccines
safety):

1) To identify problems related with vaccine lots or brands leading to vaccine

reactions caused by the inherent properties of a vaccine.

2) To detect, correct and prevent immunisation errors caused by errors in vaccine

preparation, handling, storage or administration.

3) To prevent false blame caused due to coincidental adverse events following

immunisation, which may have a known or unknown cause that might be not
related to the immunisation.

4) To minimise the incidence of injection reactions resulted from anxiety or pain

associated with immunisation, by educating and reassuring vaccines,
parents/guardians and the general public about vaccine safety.

5) To enhance the awareness about risks of vaccine among public uphold

confidence by appropriately responding to parent and community concerns. To
create new theories for vaccine reaction that is definite to the population of the
country/region living in.

6) To estimate rates of occurrence of AEFIs in the local population compared with

trial and international data, mainly for new vaccines that are being introduced.

Components of AEFI Surveillance

Components of adverse event following immunisation surveillance (WHO,

vaccine safety):

1) Detection and reporting,

2) Investigation,

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3) Causality assessment of AEFIs, and

4) Risk/benefit assessment.

1.Detection and Reporting

The AEFIs when firstly occur are mostly detected or recognised by the parents of
vaccinated infants/children, health workers at immunisation services and staff of
the accident and emergency rooms in the hospital.

Detection of AEFI requires effective staff training and education to ensure

accurate diagnosis of AEFI based on clear case definitions, which can be
included on the AEFI reporting form and national AEFI guideline.

Health works and staff are responsible to detect, report, and treat patients for
AEFI. For detecting AEFI by identifying adverse events of importance to the
immunisation program in the country, the immunisation program managers
should create suitable criteria.

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It is important that immunisation program managers define the roles and
responsibilities of stakeholders, simplify on the process of reporting, and how
to ensure/encourage reporting, in addition to determining which adverse events
should be reported. The following questions should monitor the immunisation
program manager when setting up and preserving detection and reporting
mechanism.

Who should Make the AEFI Report and to Whom?

Make sure that health workers are aware of their responsibility to report AEFI.

How should Reporting Occur?

Reporting should be as standardised as possible, best done through an

unambiguous and standardised reporting form.

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What should the Route of Reporting Be?

This may depend on the local context. Keep in mind that with unclear
responsibilities among stakeholders, there is the danger of double-reporting or
under-reporting. Make sure that reporting lines are simple and direct and clear to
all stakeholders involved.

When should AEFIs be Reported?

Any AEFI that is of concern to the parents or to the healthcare worker should be
reported. See above for a list of events that must be reported.

How to Reporting? Improve/Encourage reporting.

Health workers may be afraid of getting penalised for reporting. It is important

that reporting health workers understand that adverse events following
immunisation - related to the vaccine or not-must be expected and can happen
independent of the health worker’ s action.

2.Investigation

Conducting an AEFI Investigation Some AEFI reports will need further

investigation. The purpose of an AEFI investigation is to:

1) To confirm the diagnosis (or propose other diagnoses) and to determine the
outcome of the adverse event,

2) To detect specifications of implicated vaccine(s) used to immunise patient(s),

3) To examine operational aspects of the immunisation program that may cause

immunisation errors,

4) To justify the search for other AEFI cases/clustering, and

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5) To compare background risk of adverse event (occurring in unimmunised
people) to the reported rate in the vaccinated population.

AEFI Reports to be Investigated

Not all AEFI will need investigation; reported events requiring the initiation of
an investigation are as follows:

1) Serious AEFIs, i.e., adverse events or reactions that result in death,

hospitalisation (or prolongation of existing hospital stay), persistent or significant
disability or incapacity (e.g., paralysis), or are potentially lifethreatening.

2) Clusters of minor AEFIs. All signs and actions related to the new presented
vaccines.

3) Other AEFIs as recommended by WHO:

i) AEFIs that might be caused by immunisation error like bacterial abscess,

severe local reaction, high fever or sepsis, BCG lymphadenitis, toxic shock
syndrome, clusters of AEFIs.

ii) Significant events of unexplained cause occurring within 30 days after

a vaccination.

iii) Parental and community concerns causing event.

Vaccine Testing in an AEFI Investigation

To authorise or rule out a possible vaccine-related cause of the AEFI, if it is

suitable to react, collect and test the vaccine specimen according to the working
hypotheses. If possible, collect a vial of the residual vaccine from the healthcare
service for testing the vaccine. In case the vaccine is reconstitute, then dilute the
vials and retain suitable sample from the same site of unopened vaccines. Until a

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verdict on testing is collected, the sample should be maintained under right
storage condition.

It is hardly essential to examine the vaccine quality, which should by now be part
of the national regulatory rules if a vaccine is implication an AEFI case. To
determine reasons for lack of vaccine efficacy, potency testing is of little value.

To examine the vaccine (and where suitable, the diluent), the test(s) selected are
based on the nature of the adverse event and the functioning hypotheses on the
likely reasons. One or more of the following tests may be carried out:

1) Visual Test: it is carried out for clarity, presence of foreign matter, turbulence
or discolouration,

2) Sterility Testing (Vaccine and/or Injection Equipment): It is carried out if an

infectious cause is suspected,

3) Chemical Composition Analysis: It is carried out to test preservatives,

adjuvant level, etc., (e.g., aluminium content); abnormal components (e.g.,
suspect drug used instead of vaccine or diluent),

4) Biological Tests: It is carried out in case of abnormal toxicity is suspected to

detect foreign substances or toxins, and

5) Vaccine manufacturer should provide additional field performance

information.

3.Causality Assessment of AEFIs

The systemic review of the data about an AEFI case is called causality
assessment. It controls the possibility of a causal association between the event
and the vaccine received. Causality assessment helps to determine:

1) If an AEFI is attributable to the vaccine or the vaccination program, and

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2) What possible steps need to be taken to address the event. 8.3.5.3. The quality
of a causality assessment depends on:

i) AEFI case report quality.

ii) AEFI reporting system effectiveness.

iii) Causality review process quality.

There are following five principles that underpin the causality assessment of
vaccine adverse events:

1) Consistency: The administration of the vaccine and the association of the

claimed AEFI should be consistent. The findings should lead to the same
conclusion after being replicable in different localities, by different methods and
investigators.

2) Strength of Association: In terms of magnitude and the dose-response the

relationship between the AEFI and the vaccine should be strong.

3) Specificity: The adverse event should specifically be connected with the

vaccine other than occurring frequently, spontaneously or commonly in
association with the other external stimuli or conditions.

4) Temporal Relation: The relationship between the vaccine and the adverse
event should have a temporal relation. For example, the vaccine receipt should
head the earliest sign of the event.

5) Biological Plausibility: The relationship between plausible and explicable

should be coherent in accordance with the known facts of the natural history and
biology of the diseases.

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4.Risk/Benefit Analysis

To strengthen the confidence in immunisation programs continuous evaluation of

risks and benefits of vaccines is required. Following things should be assured by
the risk/benefit assessment:

1) The population (not individual) at risk should be addressed

2) Contextual issues should be taken into consideration. (Factors like economics,

culture, socio-political, available of alternative vaccine)

3) Must remain holistic after stimulating a newly discovered risk (e.g., the entire
safety profile of the vaccine should be considered)

4) Active enquiry, cooperation and exchange of information should run in parallel

Evaluation benefits begin with knowledge of epidemiology and natural history of

a vaccine that conserves unvaccinated population from diseases. It involves the
size of the reduced risk of morbidity and mortality form diseases in vaccinated
population that depends on the efficacy of the used vaccine.

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 PHARMACOVIGILANCE METHODS

Introduction Various pharmacovigilance methods are used to generate safety data.

Regulatory authorities monitor safety of the product under the duties of the
sponsor.

The sponsor provides the safety data by conducting non-clinical and clinal trials
on the product before it is approved.

Safety data for marketed product is collected from sources using several
pharmacovigilance’s methods that are not limited to passive surveillance,
solicitation reports, comparative observational studies, observational prescription
event monitoring, registries, etc.

It is vital for drug safety specialist to consider the key method used in
pharmacovigilance according to their advantages, limitations, background
information, so that these methods can be used to extract further information on
safety of the required medical products.

Methods used in pharmacovigilance are to identify risks, confirm potential risks,

or to collect missing information on adverse effect.

Objectives

1) To monitor the safety of all medicines a functional reporting system is to be

established.

2) To study about the safety profile of new medicines in the early postmarketing
phase.

3) To study about the ADR profile of a specific medicine(s) in the population.

4) To evaluate the incidence of a known ADR to a specific medicine in the

population.

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5) To collect more information on the safety profile of a new chemical entity in
early post-marketing phase.

6) To support pharmacovigilance activities by using the current electronic health

records and register

Methods

1) Passive Surveillance:

i) Spontaneous reports

ii) Case series

2) Stimulated reporting

3) Active Surveillance:

i) Sentinel sites

ii) Drug event monitoring

iii) Registries

4) Targeted clinical investigations.

5) Comparative Observational Studies:

i) Cross sectional study

ii) Case control study

iii) Cohort study

6) Descriptive Studies: Natural history of disease. Drug utilisation study

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PASSIVE SURVEILLANCE

Passive surveillance means that no active measures are taken to manage the
adverse effects other than the encouragement of health professionals and others
to report safety concerns. In this the reporting is completely dependent on the
initiative and motivation of the potential reporters.

It is also called spontaneous or voluntary reporting and the most common form
of pharmacovigilance. Clinicians, pharmacists and community members should
be trained on how, when and what to report

Spontaneous Reports

An unsolicited communication by the health care expert or consumers that

describes one or more ADR in a patient who was administered one or more
medical products that is not derived form a study or any organisation data
collected scheme is called a spontaneous report.

purpose

Pharmacovigilance system is designed using a spontaneous reporting system to

examine ADRs that were not reported earlier in the clinical or pre-clinical trials.
It is used to enhance the knowledge of the possible risks, drug interaction
reactions to provide a basis for the effective drug regulation, education,
consequent changes in practices by prescribers and consumers.

Purpose Reporting Requirements

According to WHO criteria, the following basic information is required before a

report is acceptable:

1) A source of information that can be identified.

2) A patient that can be identified.

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3) Name(s) of the suspected product(s); and

4) The suspended reaction description

Other Practical Conditions

1) The system functions on written records with the help of standard reporting
form. For this reason, the reporter should be literate and the reporting system
should extend only to the clinic and dispensary level of the health care system.

2) Informal health care experts cannot act as reporters because of their varying
degrees of literacy, but can play an important role in referring patients to health
facilities where reports can be made

Method of Reporting

Reporting Form

Number of different reporting forms available are over 100 that are separately
developed by each country that has set-up a PvC. For effective reporting the form
needs to be available in the local language(s) and should have features related to
the responsible authority like logo, address, contact details of the issuing
institution. Some features are as follows:

1) PvCs should have or develop their own national reporting forms.

2) The forms should be simple and easy to complete.

3) The requested information should be relevant as well as easy to find and record.

4) The form should have sufficient space in which the suspected reaction(s) can
be described.

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5) There is difficulty in finding a reporting form therefore they should be
distributed among all the health care experts who are treating AID/HIV and
working privately.

6) The form should be easily folded and sealed if printed on a single paper.

7) The return address should be mentioned on the outside, with postage pre-paid.

8) Only one type of reporting form should be available in the country for the use
for all the medicine with ARVs

Other Options for Reporting

The methods for reporting should be as convenient as possible and should be

completely confidential. If it is not so then the other methods that are available
for reporting may be preferred by health experts varying between clinical and
hospital, private or government facilities. The methods should include:

1) Telephone: The person making the report should record the details and assure
that important data is not missed.

2) Fax: It is a very important method for a national PvC and its major sentinel
sites as it is fast and equivalent to posting the report.

3) E-Mail: A written case-report submitted by e-mail can be acceptable.

4) Internet Site: It is a valuable asset for a PvC and through which a reporting
form could be made available for downloading or for completion online (entering
data through web-based data entry) if it is secure

Where to Report

1) Report should be submitted to the PvC.

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2) If practically it is not possible to send the forms directly to the centre, then it
is necessary to arrange points of collection at other sites such as specific hospital
or clinics.

3) To maintain privacy the reports should be kept securely.

When to Report

1) After the reaction the report should be completed immediately.

2) The additional details like final result or hospital letter can be sent later to the
PvCs, and the reporters should not wait as the report may be forgotten.

Who should Report

The following is a list of potential reporters who may work in the public or private
health sectors:

1) Physicians.

2) Pharmacists.

3) Nurses.

4) Other (literate) health and community workers should be encouraged to detect

and report, rather the clinician who prescribed for the treatment, or directly to the
PvC.

5) Public health programmes.

6) Pharmaceutical companies.

7) Patients or patient representatives.

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Elements of Report

1) Patient Details:

i) Health Number: It is a national identifier (preferred), hospital, clinic, or

programme number.

ii) Name: The full name of the patent is asked as an accurate identifier for
follow-up purposes and avoidance of duplication.

iii) Address: It is asked to permit for follow-up and accurate identification.

This may take various forms depending on the location.

iv) Sex.

v) Date of birth (preferred) or age (add esf if age is estimated).

vi) Weight and height.

2) Patient Medical History of Significance, for e.g.,

i) Renal Disease.

ii) Liver Disease.

iii) Malnutrition.

iv) Tuberculosis.

3) Details of Medicines:

i) Name(s): This may be brand or generic and formulation (e.g., tablets,

syrup, injection). Providing the brand name gives detailed information. The
use of standard abbreviations for the ARV medicines or regimens would
make recording easy. The best way to record ARV would be a part of the
standard operating procedure (SOP)for finishing the report.

ii) Mode of administration (e.g., oral, rectal, injection).

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 iii) Indication(s) for use.

iv) Dose: It is easy to record the total daily dose of the medicines that have
fixed doses. The best way to record ARV, is that the recording dose should
be a part of the standard operating procedure (SOP) and it could be referred
to by regimen for the appropriate age group. The recording should be
accurate and simplified.

v) Date of commencement.

vi) Date of withdrawal.

vii) Duration of use, if dates of commencement and withdrawal are not

available.

viii) All medicines thar are administered at the time of the event should be
listed. Each suspect medicine can be indicated by an asterisk.

4) Reaction Details:

i) Date of onset.

ii) A short clinical description should be provided by the reports without

the official pharmacovigilance reaction terms being included.

iii) The laboratory tests results with units.

iv) Outcome of Event: resolved, resolving, no change, disabling,

worsening, death (with date), congenital anomaly.

v) Effect of rechallenge (if any).

5) Reporter Details:

i) Name.

ii) Contact details.

iii) Status, e.g., physician, nurse, patient.

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6) Date and place of report.

Advantages

1) It is administratively simpler and less labour intensive than CEM.

2) It is less costly than CEM.

3) It is the most commonly used method of pharmacovigilance.

4) PvCs and health professionals are more likely to be familiar with this method.

5) It offers safety surveillance throughout the marketed life of all medicines.

Disadvantages

1) The information provided by this method is unfinished. In the evolving

countries less than 5% of the reactions are informed. The WHO filariasis program
suggests that compliance with the reporting in the public health is said to be much
less than this, leaving many doubts.

2) The risk cannot be measured and risk factors cannot be established with
confidence as reliable rates cannot be calculated.

3) The reporting is highly biases.

4) Deaths are not well reported.

5) To obtain data on regions of specific interest,

Case Series

A series can deliver the sign of a link between a medicine and an adverse effect.
Therefore, these case-reports are more important for producing theories than for

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authorising a link between medicines, exposure and outcome. Some distinct
adverse events like anaphylaxis, aplastic anaemia, toxic epidermal necrolysis and
Steven Johnson Syndrome occurs more frequently with drug therapy. These
events are reported for detailed and rapidly followed up.

STIMULATED REPORTING

Stimulated reporting is a method used to encourage and facilitate reporting by

health professionals for new products, or for limited period. Types of methods
have been used to confirm and simplify reporting by health experts in specific
situation for new product or for partial time duration. Such systems comprise
online reporting and methodical motivation of reporting of adverse event based
on a per designed method.

Drawback

These methods have been used for advanced reporting not for passive
surveillance discriminating reporting and imperfect information. It should be
considered as a procedure of spontaneous event reporting and thus data acquired
from stimulated reporting cannot be used to make accurate incident rates, but for
projecting reporting rate.

ACTIVE SURVEILLANCE

Active Surveillance, in contrast to passive surveillance, peruses to control the

particular number of adverse events using a constant per- organised procedure.
Usually, it is more attainable to acquire wide-range data on discrete adverse event
reporting through an active surveillance system than through a passive reporting
system. Active (or proactive) safety surveillance is the active precautions are
taken to control adverse effect that is managed by active follow-up after

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treatment. The events can be management is done by active patient directly or
screening patents records.

Sentinel Sites

✓ Active surveillance can be accomplished by revision of medical records or

questioning the patient or the physician in a sentinel site to guaranteed that
comprehensive and accurate data on the reported events.
✓ The picked sites can deliver the data from the specific patient group that
will not be accessible in the passive immediate reporting system.
✓ Sentinel sites weakness comprises difficulties with selection bias, a smaller
number of patients and augment costs.
✓ Active surveillance with sentinel sites is most affected for those medicines
that are mostly used in institution settings like hospitals, nursing home, and
health care centre.
✓ Some medical item is more usually used in institutional setting that
provides an argument for excited reporting. It is supportive in identifying
the risks among patients taking orphan medication in intensive care
medicines.

Drug Event Monitoring

✓ Drug Event Monitoring Surveillance is the of active pharmacovigilance

surveillance.
✓ Patient can be recognised from electrical or automated health insurance
claims for medication event monitoring.
✓ Studies using this process are cohort-based and prospective and
observational.

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 ✓ Over the period of observing a single prescription or a series might be
composed.
✓ Each physician or patient at pre-specific intervals received a follow up
questionnaire to acquire outcome data.
✓ The questionnaires can request for the data on clinical events, dosage,
duration of treatment, reason for termination, patient demographics,
indication for treatment and applicable past history.
✓ The poor physician and the patients reply rates can lead to the restriction
of Medicine Event Monitoring.

Registries

✓ A list of the patients presenting with the identical representation is called a

registry. This representation can be a disease (disease registry), or a specific
exposure (medicine registry), both type of registrations can gather cordless
of information, using standardised questionnaires in a prospective fashion.
✓ Disease Registries like blood dyscasias, severe cutaneous reaction, or
congenital malfunctions can help gather data on medicine exposure and
other factors related to the clinical condition. A disease that has been
registered might also be a veil for a case control study associating the
medicine exposure of cases recognised from the registry with controls
selected either patient with another condition within the registry, or from
patients outside registry.
✓ Exposure (medicine) registries are a registry that report populations
exposed to the medicines of interest to evaluate the different effect of
medicine on any particular group of patients. Some exposure (medicine)
registries address drug exposures in specific populations like pregnant
women. To collect data on adverse events using standardised

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 questionnaires patients can be followed over time and included in a cohort
study.
✓ Single cohort studies can quantity incidence, but, without a comparison
group, cannot deliver proof of association. This type of registry is very
effective while examining the safety of an orphan medicine indicated for a
specific condition. Customary epidemiological methods are a key
constituent in the evaluation of adverse events.
✓ There are many observational study projects that are effective in
authenticating signals from spontaneous reports, case series or medicine
event monitoring. The most imperative of these designs is cross-sectional
studies, case-control studies and cohort studies.

TARGETED CLINICAL INVESTIGATIONS

✓ To evaluate the mechanism of action for the adverse reaction clinical

studies are called in in case the significant risks are identified from pre-
approval clinical trials.
✓ To define whether specific dosing instructions can put patients at an
increased risk of adverse events PK and PD studies can be carried out.
✓ Additionally, on the basis of pharmacological properties and the
predictable use of the medicine in general practice, performing specific
studies to examine potential medicine-medicine interactions and food-
medicine interactions can be entitled to.
✓ These studies consist of population pharmacokinetics studies and medicine
concentration monitoring in patients and normal volunteers.
✓ One drawback is that the outcome measure might be too reduced and this
might have an effect on the quality and eventual worth of the results of the
trial for this method. Large, basic trials are similarly resource-intensive.

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COMPARATIVE OBSERVATIONAL STUDIES

Observational study designs are suitable for validating signals from spontaneous
reports or case series. Traditional epidemiologic methods are important in the
evaluation of adverse events.

Types of designs:

1) Cross-sectional study.

2) Case-control study.

3) Cohort study (both retrospective and prospective).

Cross-sectional Study

✓ Data collected on inhabitants of patients during a specified interval of time

is irrespective of exposure or disease status establishes a cross-sectional
study.
✓ These types of study are mainly used to collect data for surveys or for
ecological analyses. When data for serial time points can be collected then
these studies are par amounted to scrutinise the prevalence of a disease at
one time point or to inspect trends over time.
✓ Cross-sectional studies are utmost important when exposures do not
change over time.
✓ These studies can also be used to observe the crude relationship between
exposure and outcome in ecological analyses.
✓ The cross-sectional studies are the temporal relationship between exposure
and outcome that cannot be straight addressed which a major disadvantage
of this study.

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Case-Control Study

✓ In a case-control study, cases of disease (or events) are recognised in

patients or the control having disease or event of interest that has not
occurred.
✓ These controls and patients are carefully chosen from the source population
that gave rise to the cases. The control is selected in such a way that the
prevalence of exposure among the controls exemplifies the prevalence of
exposure in the source population.
✓ The status of exposure for the two groups is paralleled using the odds ratio,
which is an evaluation of the comparative risk of disease in the two groups.
✓ For the purpose of the study the patients can be recognised from an existing
database or using data collected unambiguously.
✓ In case a safety data is sought for special populations, the cases and
controls can be stratified on the basis of the population of interest.
✓ For rare adverse events, prevailing large population-based databases are a
valuable and effective method of providing the required data on medicine
exposure and medical outcome is relatively quick.
✓ To examine whether there is a relationship between a medicine (or
medicines) and one specific rare adverse event, as well as to identify risk
factors for adverse events then case-control studies are mainly effective.
✓ Risk factors can include conditions like renal and hepatic dysfunction,
which might alter the relationship between the medicine exposure and the
adverse event.
✓ A case-control study can deliver the complete incidence rate of the event
under particular conditions.

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Cohort Study

✓ A population at risk for the disease (or event) is observed over time to
record the occurrence of the disease (or event) in a cohort study.
✓ Exposure status information is available during the follow-up period for
each patient. A patient might be exposed to a medicine at one time during
follow-up, but not exposed at another time.
✓ Meanwhile the population exposure during follow-up is acknowledged,
incidence rates can be calculated, concerning medicine exposure, appraisal
cohorts of interest are selected on the basis of medicine use and monitored
over time in many cohort studies.

Objectives

CEM and spontaneous reporting has the same objective which is more effective.

1) To provide incidence rates for adverse events as a measure of risk.

2) To characterise the known adverse reactions.

3) To identify signals of unrecognised reactions.

4) To detect interactions with other medicines, complementary and alternative

medicines, foods and concomitant diseases.

5) To identify risk factors and therefore offer evidence on which to base effective
risk management.

6) To evaluate safety in pregnancy and lactation.

7) To give a measure of comparative risks between medicine

8) To provide cohorts for additional study of safety issues.

9) To detect inefficacy, which might be due to:

i) Faulty administration;

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 ii) Poor storage conditions;

iii) Poor quality product;

iv) Counterfeit product; and

v) Interactions

Epidemiology

The main epidemiological characteristics of CEM can be described as follows:

1) Observational: Observational studies are “non-interventional” and are

undertaken in real-life situations. Patients are not selected as per any criteria - all
patients who receive ART are considered until the desired cohort size is reached.
This contains patients of all ages, those with other diseases and those on other
medicines. Treatment is given according to the usual local strategies.

2) Prospective: This means that CEM is planned before the patients are treated
and ART is observed until the end of the programme, or until they cease to receive
treatment for whatever reason.

3) Inceptional: It is similar to prospective i.e., from the time of commencement

of their treatment every patient is followed-up for adverse events.

4) Dynamic: This means that due to sufficient numbers in the cohort new patients
are added as the study continues until dynamic time.

5) Longitudinal: This means that the events occurrence in patients are evaluated
over a period of time until the end of the programme, or until they cease to receive
treatment with the monitored medicines.

6) Descriptive: This means that all events are recognised and termed, their
frequency is calculated and their distribution in different subgroups of interest in
the cohort is recorded and analysed.

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Advantages

1) They can produce rates.

2) They can produce a new profile of the adverse events and/or adverse reaction
for the interested medicines.

3) They can recognise signals very effectively at an early stage.

4) They can characterise reactions in terms of age, sex and duration to onset, and
dose, and other related factors. Other important data can be collected like weight,
comorbidity or region to provide the opportunity for determining other risk
factors.

5) They are capable of making accurate comparisons between medicines.

6) The are capable of establishing a pregnancy register and recognising problems

with pregnancy and common congenital abnormalities.

Disadvantages

1 ) It is more costly and more labour intensive than spontaneous reporting.

2) Training in its use will be necessary as it is new to healthcare Experts and PvCs.

DESCRIPTIVE STUDIES

In Pharmacovigilance, Descriptive studies play an important role in acquiring the

circumstantial rate of outcome events to inaugurate the prevalence of the use of
medicine in the selected population.

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1) Natural History of Disease:

Epidemiology initially concentrated on the natural history of disease, including

the features of diseased patients and the distribution of disease, in particular
populations, as well as assessing the incidence and prevalence of possible
outcomes of interest.

These outcomes comprise a narrative of disease treatment outlines and adverse

events. Studies that inspect precise facts of adverse events, like the contextual
incidence rate of, or risk factors for, the adverse event of interest, can contribute
in placing spontaneous reports into viewpoint.

2) Drug Utilisation Study (DUS):

It defines marketing, prescribing and administration of medicine in a population

and its factors affecting outcomes (like clinical, social and economic outcomes).

These studies deliver data on definite populations, like the elderly, children, or
patients with hepatic or renal dysfunction, habitually stratified by age, sex,
concomitant medication and other characteristics.

It can be used to define if a product is being used in these populations. It is useful

in defining the effect of regulatory action, media courtesy on the use of medicine,
to improve estimation of economy in terms of medicine and also to scrutinise the
relationship between optional and definite clinical practice.

These studies provide help to judge whether a medicine has been abused or
delicately prescribed. An absence of clinical outcome data or material on the
indication for use of a product is the only limitation offered by these studies

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COMMUNICATION IN PHARMACOVIGILANCE

Pharmacovigilance communication is an interactive process in which information

is exchange which can be beneficial for veterinarians and other health-care
professionals for preventing and responding to any concerns that arises from
pharmacovigilance.

Need of Improvement in Communication

1) To improve patient care and understanding.

2) To eliminate disease or improving disease control.

3) To uphold transparency and liability.

Need of Communications in Drug Safety

1) For the welfare of millions of people worldwide.

2) To overcome severe risks of failure.

3) For improving the health care quality, communications are modified that
are commonly poorly executed, second-rate and ineffective.

EFFECTIVE COMMUNICATION IN PHARMACOVIGILANCE

➢ Effective communication in Pharmacovigilance is the communication

which is about the desired information.
➢ This communication is held between healthcare professional and the
marketing authorization holders about the important aspects of medicines.
➢ These types of communications have brief information about the medicines
including doses, effects, side effects, adverse effects and specifications.
➢ These factors are characteristics of medicines and help to develop a brief
profile of the drug including their solutions of a disease.

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 ➢ It is an easy method for conveying the message to market stakeholders and
the marketing authorization holders about the outcomes of the drugs.

PRINCIPLES OF EFFECTIVE COMMUNICATION

The main purpose of taking effective communication in Pharmacovigilance is to

prepare a brief data of ADRs of drugs and to prepare the cure of these ADRs
before the drug is available in the market or as soon as possible. The principles
of effective communications are:
● Be clear about your purpose of communication
● Specify your group of audience from which you want to communicate
● To choose the right method for communication to patients Make the benefits
clear to the people
● To ensure that people should understand about information you are sharing
● To take feedback of ADR's
● To provide a brief knowledge of benefits to peoples

In today's world there are various methods to give right information about
anything to people. Modern communication methods describe how to give your
message in clear and simple way so that people should get the message easily and
act on them. There are various
newsletters in today's world which are publishing the interesting articles on the
effects and uses of new drugs with pictures so that people should read the
information with interest and remember the information clearly.

COMMUNICATION IN DRUG SAFETY CRISIS MANAGEMENT

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Communication in drug safety crisis management is defined as the
communication or exchange of information between healthcare professionals and
marketing authorization holders; about the adverse effects of medicines and other
information about the crisis occurring from the medicinal products. It included
various issues related to the medicines like ADRs, product safety, unexpected
effects or other possible effects of medicine which is not appropriate as per
specifications and the drug can be banned.
Crisis management is the process of steps taken by the company to overcome the
failure outcomes of the medicinal product. It also includes the detection of the
crisis of products.

Crisis:
A crisis is defined as "A situation where; after assessment of the associated risks,
urgent and coordinated actions with regulatory authorities are required to manage
and control the situation for the welfare of medicines for human use"

Crisis communication:
Crisis communication is defined as the process of managing the strategy,
messages distribution channels which are necessary to communicate effectively
with media and employees, advocacy groups or stakeholders or policy makers for
the betterment of the product and their outcomes.

Crisis can create three types of threats:

1) Public safety
2) Reputation loss
3) Financial loss
To overcome these crises; companies have to make crisis management plan so
that they can overcome the outcomes of this crisis.

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Role of communication drug safety crisis management in
Pharmacovigilance:
Communication drug safety crisis management plays an important role in
Pharmacovigilance studies or their regulations. By the help of drug safety crisis
management, the regulatory can-do early studies or detection of adverse drug
reactions and their other roles are

Early detection of ADR's and events

➢ To detect the frequency of adverse events
➢ Identification of risk factors affecting adverse events or reactions
➢ Preventions of ADR's.
➢ To communicate with nationally and international organizations, working
on Pharmacovigilance concept
➢ To enhance drug safety and quality surveillance programmes
➢ Encourage rational and safer use of drugs

CRISIS MANAGEMENT
It is the process for preventing the damage a crisis which can inflict on a company
or stakeholders.
Crisis management is divided into three phases:
1) Pre-crisis
2) Crisis response
3) Post-crisis
1) Pre-crisis: In this process, the prevention of known risks which may lead to
crisis is done. This process includes various steps which are helping to maintain
data for the prevention risks which leads to crisis. For this an organization have
to make a crisis management plan committees or team so that they are working,
is one direction for betterment in a crisis management programme. By pre-crisis

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programme it is easy to make effective decision about the crisis and for
conducting exercises to test the crisis management plan.

2, Crisis Response: Crisis response is defined as the response from the

Management, after the crisis hits. For this response public play the key role to
help in developing, the messages to public.
Crisis response is further divided into two sections:
i) Initial crisis response
ii) Reputation repair and behaviour intentions

3) Post Crisis: Post crisis phase is the phase where the organization returns to
business. An organization processes various steps to return to the actual state of
business after crisis. The organization needs to release various updates for the
recovery process, and other corrective actions. This process effort about the
processes which needs to improve the organization in business level,
communicate with regulatory agencies, business partners, healthcare facilities &
media.
This section of communication describes the conversation of information
between the
company and regulatory authorities, business partners, healthcare facilities and
media. Each and every class is having their own importance in communication
and exchange of the information

COMMUNICATION WITH REGULATORY AGENCIES BUSINESS

PARTNERS HEALTHCARE FACILITIES AND MEDIA.

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Pharmacovigilance in the Regulation of Medicines The foundation for a national
ethos of medicine safety as well as public confidence in medicines are given by
robust regulatory arrangements. For being effective, the drug regulatory
authorities should go further than the approval of new medicines, to include a
wider range of issues related to the safety of medicines, that are namely:

1) Clinical trials
2) The safety of complementary and traditional medicines, vaccines and
biological medicines.
3) The advancement of lines of communication between all parties which
contribute in medicine safety, ensuring the efficient and ethical functioning of the
drugs, mainly at the time of crisis.

Pharmacovigilance programmes and drug regulatory authorities should be

supporting each other mutually in order to achieve their respective objectives. On
one side, pharmacovigilance programmes require to maintain strong links with
the drug regulatory authorities for ensuring that the latter are well described on
safety issues in everyday clinical practice.
To conclude that whether these issues are relevant to future regulatory action or
to concerns that arise in the public domain. On the other side, regulators require
to understand about the specialised and pivotal role played by pharmacovigilance
to ensure the ongoing safety of medicinal products.

Pharmacovigilance in Clinical Practice

Observation of the medicines in common use should be the fundamental part of
clinical practice. The degree to which clinicians are informed about the principles
of pharmacovigilance, and practice according to them, has a great effect on the
quality of health care. To enhance effective patient care, the education and

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training of health professionals in medicine safety, exchange of information
between national pharmacovigilance centres, the coordination of such exchange,
and associating clinical experience of medicine safety with research and health
policy are required. Therefore, a continuous flow and exchange of information
means that the national pharmacovigilance programmes are ideally placed to
identify gaps for understanding medicine-induced diseases

Pharmacovigilance in Disease Control Public Health Programmes

In countries having no regulatory or safety monitoring system, and in rural areas
having little or no health care surveillance and infrastructure; evaluation of
medicine safety is recognised as a matter for concern. Therefore, the problems
are influenced in this situation which involve the use of medicines in treatment
of specific communities, e.g., in the treatment of tropical diseases like malaria,
leishmaniosis Ans schistosomiasis, HIV/AIDS and tuberculosis.
The administration of medicines to large communities in settings several of
disease control initiatives are being implemented within the same population
along with little knowledge and concern regarding the interaction of the
medicines with each other. Along with the public health disease control
programme, pharmacovigilance should be a priority for every country.

Communication with Media

Who are the Media
1) Print: magazines, newspapers, community newspapers.
2) Electronic: radio, TV, internet.
3) Local and national levels.
Some Basic Questions a Reporter will Ask You
1) Who is affected, responsible?
2) What has happened and what is being done about it?
3) Where has it happened?

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4) When did it happen?
5) Why did it happen?
6) Will it happen again?
Communications Practices to Avoid
1) “Spinning” (distortion or decoration of facts for beneficial effects).
2) All communications are subjective, but cannot be manipulative or false.
3) It should avoid “No comment”; rather say why there is nothing to say and what
is being done.
4) It should avoid confusing statistics.
5) It should not avoid taking responsibility.
6) It should not attack the messenger or accuser.
7) It should not disagree, explain or excuse the mistakes

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