UNIT II

Pharmacovigilance

(Adopted from https://xcelcareer.com/pharmacovigilance-course/accessed on 01.05.2020)

SUBJECT Pharmacovigilance
PROGRAMME/COURSE Pharmacy/B. Pharmacy
SEMESTER Eight (8)
DEVELOPED BY Dr. Kunjbihari Sulakhiya, Assistant Professor,

Pharmacology
DEPARTMENT Pharmacy
INSTITUTION Indira Gandhi National Tribal University,

Amarkantak (MP) -4848487, India

Disclaimer: The presented matter is compilation of various online materials
available on the topic with modification and simplification. The content is
presented here for student’s easy accessibility as online study material and not for
commercial purpose.

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Contents:
A. Drug and disease classification

Anatomical, therapeutic and chemical classification of drugs
International classification of diseases
Daily defined doses
International Non proprietary Names for drugs

B. Drug dictionaries and coding in pharmacovigilance
WHO adverse reaction terminologies
MedDRA and Standardised MedDRA queries
WHO drug dictionary
Eudravigilance medicinal product dictionary

C. Information resources in pharmacovigilance
Basic drug information resources
Specialised resources for ADRs

D. Establishing pharmacovigilance programme
Establishing in a hospital
Establishment & operation of drug safety department in industry
Contract Research Organizations (CROs)
Establishing a national programme

[A] Drug and disease classification –

Anatomical, Therapeutic and Chemical Classification of Drugs (ATC)
o In the ATC system the active substance is divided into

different groups according to the organ or system on which they
act and their therapeutic, Pharmacological and chemical properties.

 ATC / DDD Methodology
o Drug utilization research uses the Anatomical Therapeutic

Chemical (ATC) as the classification system and Defined Daily
Dose (DDD) as a unit of measure.

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o DDD is the assumed average maintenance dose per day for a drug
used for its main indication in adults.

o The methodology is endorsed by WHO and is recommended as the
international standard for drug utilisation monitoring and research.

 Why ATC/DDD ?

o ATC/DDD methodology facilitates the presentation and
comparison of drug consumption statistics at international, national
and regional levels despite differences in nomenclature (both
branded & generic), packing sizes, pricing and customary
dosages.

o This methodology is useful for valid presentation & comparison of
drug utilization within and across countries to support better
outcomes & quality use of medicines.

 General Principles for ATC Classification

o Drugs are classified based on their main therapeutic use
o Only one ATC code for each ROA (route of administration).
o Several ATC code: if clearly different therapeutic uses reflected in

different
 Routes of administration (e.g. topical, systemic)
 Strengths

 ATC Groups
In the Anatomical Therapeutic Chemical (ATC) classification system, the
active substances are divided into different groups according to the organ
or system on which they act and their therapeutic, pharmacological and
chemical properties.

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Drugs are classified in groups at five different levels.
1. ATC 1st level
 The system has fourteen main anatomical or pharmacological groups

(1st level). The ATC 1st levels are shown in the figure.
2. ATC 2nd level
 Pharmacological or Therapeutic subgroup
3. ATC 3rd & 4th levels
 Chemical, Pharmacological or Therapeutic subgroup
4. ATC 5th level
 Chemical substance

The 2nd, 3rd and 4th levels are often used to identify pharmacological
subgroups when that is considered more appropriate than therapeutic or
chemical subgroups.

Figure : Coding of drugs based on their anatomical groups

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Table : Coding of drugs based on their anatomical groups

The complete classification of metformin illustrates the structure of the code:

(ATC, https://www.who.int/medicines/regulation/medicines-safety/toolkit_atc/en/Accessed on

25/04/2020)

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Thus, in the ATC system all plain metformin preparations are given the code
A10BA02. For the chemical substance, the International Nonproprietary Name
(INN) is preferred. If INN names are not assigned, USAN (United States Adopted
Name) or BAN (British Approved Name) names are usually chosen. The coding is
important for obtaining accurate information in epidemiological studies. The five
different levels allow comparisons to be made at various levels according to the
purpose of the study.

Applications of ATC/DDD

(https://www.who.int/medicines/regulation/medicines-safety/toolkit_atc/en/Accessed on

25/04/2020)

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International Classification of Diseases
The ICD is originally designed as a health care classification system,
providing a system of diagnostic codes for classifying diseases, including
nuanced classifications of a wide variety of signs, symptoms, abnormal
findings, complaints, social circumstances, and external causes of injury or
disease.

Classification of Diseases

(https://www.dimdi.de/dynamic/en/classifications/icd/icd-10-

who/history/family/accessed;25/04/2020

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Importance of ICD
The ICD is important because it provides a common language for

reporting and monitoring diseases. This allows the world to compare
and share data in a consistent and standard way- between
hospitals, regions and countries and over periods of time.

History of ICD
 In 1860, Floresence Nightingale, made 1st model of systemic

collection of hospital data.
 In 1893, French Physician Jacques Bertillon introduced bertillon

classification of cause of death.
 In 1898, American public health association recommended revision of

ICD system every 10 years
 The revision followed minor changes untill 6th version of ICD,

morbidity & mortality conditions and section on mental disorders
 WHO has responsibility of preparing & publishing the ICD revision

every 10 years.

Who uses ICD ?
1. Users include physicians, nurses, other providers, researchers, health

information managers and coders, health information technology
workers, policy-makers, insurers and patient organizations.

2. ICD has been translated into 43 languages and it is being used by all member
States. Most countries (117) use the system to report mortality data,
a primary indicator of health status.

3. All Member States are expected to use the most current version of the
ICD for reporting death and disease statistics (according to the WHO

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Nomenclature Regulations adopted by the World Health Assembly in
1967).

International Non Proprietary Names for Drugs (INN)
INN facilitates the identification of pharmaceutical substances or active
pharmaceutical ingredient. Each INN is a unique name that is globally recognized
& is public property. A nonproprietary name is also called generic name.
It provides clear identification, safe prescription and dispensing of medicines to
patients. It is also important for the communication and exchange of information
among health professionals worldwide.

History of INN
 The system was established in 1950 by World Health Assembly and the

first list of International Nonproprietary Names for pharmaceutical
substances was published in 1953.

 The cumulative list of INN now stands at some 7000 names designated
since that time, and thus number is growing every year by 120-150 new
INN.

Uses of INN
Nonproprietary names are intended for use in pharmacopoeias, labeling, product
information, advertising and other promotional material, drug regulation and
scientific literature and as a basis for product names.

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[B] Drug dictionaries and coding in pharmacovigilance
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/spponsors
of clinical trials‰
 Within regions and between regions

A single terminology for use through all phases of development cycle
(both pre- and post-marketing)
 Clinical Trials (medical information, adverse events)
 Registration (study reports, analyses, summary of product

characteristics/labeling – undesirable effects section)
 Post-authorization (adverse events)

Support for electronic submissions
 Each MedDRA term is assigned a unique 8-digit numeric code

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 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

(https://www.meddra.org/sites/default/files/page/documents_insert/pharmacon_conferen
ce_meddra_belgrade_thouvay_2012.pdf/accessed on 24.04.2020)

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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).

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

ICH MedDRA Management Board
Six Parties: EU, EFPIA, FDA, MHLW, JPMA, PhRMA,
Three Observers: WHO, EFTA, Canada European

1. Commission – European Union (EU)
2. European Federation of Pharmaceutical Industries and Associations

(EFPIA)

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3. US Food and Drug Administration (FDA)
4. Pharmaceutical Research and Manufacturers of America (PhRMA)
5. Ministry of Health, Labor and Welfare, Japan (MHLW)
6. Japan Pharmaceutical Manufacturers Association (JPMA)

(https://www.who.int/medicines/areas/quality_safety/regulation_legislation/WB_2.pdf?ua=1/acces
sed on 24.04.2020)

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

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– Unique 8-digits codes for all terms
– For data fields in e- submission types (e.g. E2B)

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.

(https://www.meddra.org/browsers/accessed on 02.05.2020)

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WHO Drug Dictionary
The WHO Drug Dictionary is an international classification of the

medicines created by the WHO Programme for International Drug Monitoring
(IDM) and managed by Uppsala Monitoring Centre (UMC).
 A database with information about medical products from all over the

world.
 It contains medicinal products and information related to the mina

relational database system.
 Information is provided in a consistent and structured way
 It provides useful groupings of data useful for both data input and out put.
 It is continuously updated.

Eudravigilance medicinal product dictionary
Glossary
 EudraVigilance: European Union Drug Regulating Authority

Pharmacovigilance
 ATC: Anatomical Therapeutic Chemical
 CIOMS: Council for International Organisations of Medical Sciences
 EEA: European Economic Area
 EMA: European Medicines Agency
 ESTRI: Elecronic Strandards for the Transfer of Regulatory Information
 EVDAS: Eudravigilance Data Analysis System
 EVCTM: Eudravigilance Eudravigilance Clinical Trial Module
 EVPM: Eudravigilance Post-Authorisation Modole
 ICH: International Conference of Harmonisation

Introduction

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The history of pharmacovigilance is closely linked to the history of drug safety
crises. With each crisis, the public and the media have demanded, and the
legislators and regulators have provided, improved safety monitoring. The media
and the public appear to expect zero-risk medicines. In the real world, zero risk
medicines do not exist. For each new drug presented to the regulators for
approval, the potential benefits for public health need to be balanced against
known safety risks. Information on safety risks at the moment of approval comes
from pre-clinical and more importantly, clinical data originating from clinical
trials. As the time intervals and the number of patients involved in clinical trials
are necessarily limited, the benefit risk balance must be continuously monitored
after authorising a new medicinal product. The new medicines legislation also
explicitly provides for risk management plans to be submitted by the applicants
for marketing authorisation. It is therefore essential that we have in place systems
which will allow us to collect, validate, store and process reports on adverse drug
reactions for investigational and authorised medicinal products. The better the
data quality and the larger the number of such reports received and processed the
earlier will significant signals be detected. In view of the number of adverse drug
reactions reported, this has to be carried out using modern tools of information
and communications technology.

EUDRAVIGILANCE: (European Union Drug Regulating Authority
Pharmacovigilance) is the European data processing network and management
system for reporting and evaluation of suspected adverse reactions to medicines
which have been authorized or being studied in clinical trials in the European
Economic Area (EEA). The European Medicines Agency (EMA) operates the
system on behalf of the European Union (EU) medicines regulatory network.
The European Eudravigilance system deals with the :
• Electronic exchange of individual case safety reports (ICSR, based on the ICH

E2B specification):

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Eudravigilance Clinical Trials Module (EVCTM) for reporting Suspected
Unexpected Serious Adverse Reactions (SUSARs).

Eudravigilance Post-Authorisation Module (EVPM) for post-
authorization ICSRs.

• Early detection of possible safety signals from marketed drug for human use.
• Continous monitoring and evaluation of potential safety issues in relation to

reported adverse reactions.
• Decision-making process, based on broder knowledge of the adverse reaction

profile of drugs.
• The first operating version was launched by EMA in December 2001

(http://eudravigilance.emea.europa.eu/human/index.asp/accessed on 2.05.2020)

Eudravigilance medicinal product dictionary (EVMPD):
The EudraVigilance Medicinal Product Dictionary (EVMPD) has been designed
to support in a standardised and structured way the collection, reporting, coding
and evaluation of data on authorised medicinal products and investigational
medicinal products.

The EVMPD offers:
• A distributed and common approach for data collection through user-friendly

and easy accessible software solutions available free of charge for
pharmaceutical companies

• Integrated standard terminology to code e.g. active ingredients, excipients,
pharmaceutical forms, routes of administrations, concentration ranges and
units, country codes, marketing authorisation holders and sponsors.

• A hierarchical data structure accommodating coding requirements in
pharmacovigilance to reliably capture product information in safety reports

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taking into account the possible vagueness of the reported data by the primary
source .

• A hierarchical, multi-axial data structure to support scientific data analysis of
medicinal product data and grouping of data based on ingredients, strengths
and pharmaceutical forms.

• Automated data import and systematic workflow with integrated quality
control and audit checks.

• A standardised XML schema to support the collection and exchange of
structured medicinal product information.

• Defined data ownership ensuring controlled data update through the
respective product owner.

• A standardised approach to support updates, variations and withdrawals to
medicinal product through the defined responsible product owner.

• Traceable and auditable regulatory changes to product information (recording
of medicinal product history).

EudraVigilance contains other dictionaries:
MedDRA:

MedDRA is the Medical Dictionary for Regulatory Activities. It was
developed in the frame of the ICH M1 activities as a clinically validated
international medical terminology for regulatory authorities, and is maintained by
the MedDRA’s Maintenance and Support Services Organisation (MSSO).
MedDRA is used by regulators and pharmaceutical industry for data entry,
retrieval, evaluation and presentation during all phases of the drug regulatory
process i.e. the pre- and post-authorisation phase. These processes include clinical
studies, reports of spontaneous adverse reactions, events, regulatory submissions
and regulated product information.

o VEDDRA

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o Routes of Administration
o Dosage Units
o Pharmaceutical forms
o ATC

Purpose of Eudravigilance
• To support the public health of EU citizens by collecting safety information

on medicines and making this available for scientific assessment.
• This assessment is carried out by regulatory authorities in the EU that

supervise and monitor the correct use of the medicines in all EU countries on
a continuous basis.

• Medicinal product authorization information.
• Pharmacovigilance information.

Eudravigilance support
• Electronic exchange of suspected adverse reaction reports (referred to as

Individual Case Safety Reports) between European Medicines Agency
(EMA), National Competent Authorities (NCA’s), Marketing Authorization
holders, and sponsors of clinical trials in the EEA.

• Early detection of possible safety signals from marketed drug for human use.
• Continuous monitoring and evaluation of potential safety issues in relation to

reported adverse reactions.
• Decision-making process, based on brooder knowledge of the adverse reaction

profile of medicinal products especially in the frame of risk Management.

Conclusion
• EudraVigilance is a powerful tool for monitoring the safety of medicinal

products

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• Once the complete feed of data has been established, it will be the largest
database of its kind in the world.

• It will become an extremely useful resource for academic and commercial
research once full access to data mining and statistical evaluation can be
provided.

Information resources in pharmacovigilance
 DEFINTION:-The branch of science who`s activities relating to the

detection, assessment, understanding, and prevention of adverse effects or
any other drug related problem.

 ORIGIN OF PHARMACOVIGILANCE:-
 The Thalidomide disaster in 1956 – Thalidomide launched in market and

in 1956-61 report of foetal abnormalities (20000 cases) maximum in
Germany.

 In 1962 USA revised law requiring proving the safety and efficacy before
issuing marketing authorization.

 In 1963 British committee on safety of drug monitoring.
 In 1964 UK starts the “YELLOW CARDS” system.
 In 1964-65 National ADR reporting system UK, Australia, New Zealand,

Canada, West Germany, Sweden .

 OBJECTIVE:
1- To know what are the various sources of drug information.
2- To select the appropriate source depending on the information.

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 BASIC DRUG INFORMATION RESOURCES- Drug information is

current, critically examined, relevant data about drugs and drug use in a
given patient or situation.

 Current information uses the most recent, up-to-date sources possible.
 Critically examined information.
 Relevant information must be presented in a manner that applies directly

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

 TYPES OF RESOURCES:-
(I) Primary resources
(II) Secondary resources
(III) Tertiary resources

(I) PRIMARY RESOURCES-

• Researcher`s and manufacturer`s information.
• Patents containing original information regarding the discovery of drug.

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• Reports containing scientific data before product can be sold, supplied or

represented.
• Scientific Journals
• Provide original studies or reports

 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.

(II) SECONDARY RESOURCES-
• Abstract or index which summarizes the information arising in

primary resource.
• Indexing and abstracting services are valuable tools for quick and

selective screening of the primary literature for specific information,
data, citation, and article.

• Bibliographic database that provide abstract or full-text of studies.
 ADVANTAGES-

• Find specific information at high granularity.
• Pick out key point.
• Quick to read.

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 DISADVANTAGES-

• Detail missing.
• Two different authors can interpret the same piece of original material

in two widely different ways.
• May be inaccurate.

(III) TERTIARY RESOURCES-

• Compilation of knowledge in the field. e.g. Textbooks, handbook, online
drug compendia.

 ADVANTAGES-
• Provide comprehensive information.
• Information reflects views of multiple experts in field.
• Fast, easy to use, and may be good for patients.

 DISADVANTAGES-
• Information may be dated due to gap between when resources is written

and published.
• Chances of distorting a topic.

 OTHER SOURCES-
• Libraries
• Research association
• Government bodies
• Information center in industries

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ADVERSE DRUG REACTION

Any noxious change which is suspected to be due to drug , occur at doses
normally used in man,require treatment or decrease in dose or indicates caution in
future use of the same drug.

CLASSIFICATION:-

1. Type A effect:- Augmented pharmacologic effects – dose dependent and
predictable are those which are due to pharmacologic effects.

2. Type B effect:- Bizarre effects(idiosyncratic)- dose independent and
unpredictable .

3. Type C effect:- Chronic effect refer to situation where the use of a
medicine, often for unknown reasons, increase the frequency of a
“spontaneous” disease.

4. Type D effect:- Delayed effects.
5. Type E effect:- End-of-treatment effect.
6. Type F effect:- Failure of therapy.

 SPECIALISED RESOURCE OF ADR
• Individual reporting
• Comprehensive Monitoring
• Population Monitoring
• Individual case safety report (ICSR)
• Spontaneous Reporting

 INDIVIDUAL REPORTING
• In individual reporting Doctor are the major source of report.
• The physician, during an outpatient or inpatient examination, may decide

that the patient has a recognizable syndrome of signs, symptoms and/or

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UNIT II
laboratory finding and that this syndrome may be associated with a
previously administered drug.

• Since most severe reaction are seen in hospitals, physicians who are
Hospital-based are often able to ascertain previous drug administration,
link it to the reaction, and submit a report.

 COMPREHENSIVE MONITORING:-
• Comprehensive monitoring is typically performed in a hospital setting and

the input of abstract of patient identification, drug administration, and
patient reaction.

• Specialised method are used to ensure that this information is complete,
and case report or tabulated summary data can be supplied to the national
centre.

 POPULATION MONITORING:-
• In population monitoring the record of hospital or clinic patients, or of the

entire population of a district, may be employed.
• Such monitoring could be effective when a large stable population is

surveyed in an organized medical care system.

 INDIVIDUAL CASE SAFETY REPORT (ICSR):-
• Individual Case Safety Report is a report which contains information

describing suspected adverse drug reaction related to administration of one
or more medicinal product.

• A document providing the most complete information related to an
individual case at a certain point of time.

 SPONTANEOUS REPORTING:-

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• Spontaneous reporting is a system whereby case report of adverse drug

event are volunteer submitted by healthy professionals, pharmaceuticals
companies or consumers to the national pharmacovigilance centre.

• It is basically the reporting of a suspected adverse reaction on the
initiative of the health professional who became aware of the problem, or
the patient initiative. These report can be communicated by any means,
but in countries with a well developed pharmacovigilance system they are
most often reported on the country- specific reporting card.

• Such reporting is sometime referred to as intensified spontaneous
reporting, or ideally, prospective

[D] Establishing pharmacovigilance programme

Established pharmacovigilanace program in a hospital and national
programme

PV is a major post-marketing tool to ensure the safety of a medicinal product.
Apart from the respective drug regulating authorities in each country,
International Conference on Harmonization (ICH) of Technical Requirements for
Registration of Pharmaceuticals for Human Use, Pharmacovigilance Planning-
ICH E2E and World Health Organization-Uppsala Monitoring Centre (WHO-
UMC) also play key roles towards developing, enhancing and monitoring global
PV system. A PV system is defined as a system used by an organization to fulfill
its legal tasks and responsibilities in relation to PV that monitors authorised
medicinal products’ safety and detect if any change to risk benefit balance.

After the thalidomide disaster in the year 1961, WHO worked along with
its Collaborating Centre to establish a programme for International Drug
Monitoring and through this programme, WHO promoted PV at the country level.
At the end of 2010, 134 countries were part of the WHO-PV Programme. To give

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it a further impetus and fortify the drug regulatory framework in the country, the
Drug Controller General of India (DCGI) has announced the CDSCO’s “VISION
2020” which proposes to create a PV center in every medical college in the
country which is an ambitious task keeping in view the fact that it is still at low
ebb in many government medical colleges and the condition is the same or may
be worse in the private institutes. Therefore, it is likely that the proposal may have
to negotiate many bottlenecks to pay some dividends. In this backdrop, the article
discusses the essentials of setting up a PV center and getting it operational

Essential for a Pharmacovigilance program:-
Pharmacovigilance is all about drug regulations and is based on thorough
collaborative ties, coordination, communications, and public relations. The most
suitable location for setting up a PV centre is dictated by the political governance
and its healthcare priorities, including willingness to do, law enactment, its
enforcement, funding, organisation, staffing, training, and development.

To Ensure a Good PV System, Certain Operational Requirements must be
met, which include:-
 A properly structured drug safety management team to intensify the

communication among the PV network. This will assure an organised
structure and smooth functioning. Meetings among the PV physicians,
managers, and technical agencies need to be held from time to time

 A countrywide database which provides provision for collating and
managing ADR reports

 A national PV advisory committee
 A clear approach, to be communicated in detail, in regular situations as

well as situations of crisis
 Funding to run different grounds of a system.

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Basic Steps in Setting up a PV System Include:-

(https://www.pharmafocusasia.com/strategy/setting-pharmacovigilance-system/accessed on

02.05.2020)
Developing guidelines and communications with the health authorities-a general
guideline is a standard strategy to confirm that the PV system at all levels meets
the national and international standards and regulations. Getting into regular
communications with the health authorities, local, regional and national bodies,
and professionals involved in clinical medicine, pharmacology, toxicology,
epidemiology, briefing them about the importance of the project and its
applicability in modern therapeutics.

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Minimum requirements for a functional national pharmacovigilance system
The following are the minimum requirements that WHO and partners agree
should be met in any 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, and collaborating with the WHO Programme for International Drug
Monitoring;
2. A national spontaneous reporting system with a national individual case safety
report (ICSR) form, i.e. an ADR reporting form;
3. A national database or system for collating and managing ADR reports;
4. A national ADR or pharmacovigilance advisory committee able to provide
technical assistance on causality assessment, risk assessment, risk management,
case investigation and, where necessary, crisis management, including crisis
communication;
5. A clear communication strategy for routine communication and communication
during crises.

1. The Manpower and the machinery
a) Adequate qualified and experienced man power to run the system – PV staff
should have complete knowledge regarding data collection and verification,
coding of drugs and adverse events, causality assessment, signal detection, risk
management, interpreting the data obtained etc.
*Staff
The expertise desirable in the routines of a pharmacovigilance centreincludes:
Clinical medicine, pharmacology, toxicology, epidemiology. However, a new
pharmacovigilance centre often starts with only a part-time expert

• usually a physician or a pharmacist
• and some secretarial support.

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It may soon become necessary to have one expert who is responsible for
pharmacovigilance for most of his/her time and for secretarial assistance to be
expanded. When the reporting of adverse reactions increases, staff resource
requirements may be calculated by assuming that the average assessment time per
case report is about one hour.

2. Planning the basics
A blueprint should be drawn up to establish and get a PV system to work. Care
needs to be taken to establish the following:
a) Advisory Committees
A multi-disciplinary advisory committee is desirable, to support the
pharmacovigilance centre with regard to the quality of the procedures in:

1. Data collection and assessment
2. Data Interpretation
3. Information publication

A network of experienced advisors in various specializations is helpful

b) Communication process
Getting in conversation with health authorities and local, regional, national bodies
and groups engaged in clinical medicine, pharmacology, toxicology,
epidemiology, briefing them about 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 for the dissemination of information.
Prompt data-sheet amendments are important, but data-sheets may be printed
infrequently and their educational impact may not be large. In urgent cases of
sufficient importance ‘Dear Doctor’ letters may alert the profession

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c) 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 center.

d) 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 times.

e) Establishment
Hiring the right qualified and interested staff, getting suitable place for
accommodating them as well as the center, making arrangements for telephones,
computers, printers, word processors, database management, bibliography support
services and an internet.

f) Internal education
Ensuring proper education and frequent updating of the staff belonging to the PV
centers by training them 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 categorizing the data and summarizing identified relationships.

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g) Database and information serivce
Creating a safely stored, classified database which is retrievable and guarded by
required degrees of confidentiality. The provision of a high quality information
service to healthcare professionals is a basic task of a pharmacovigilance centre
and a major instrument in the stimulation of reporting. For this purpose and for
the assessment of case reports the centre should have access to a comprehensive
and up-to-date literature source and information database.
Location of the centre in a large hospital usually has the advantage of a library
within reach. National pharmacovigilance centres can have online access to the
database of the UMC and be on the mailing lists of adverse drug reaction and
drug bulletins produced by the World Health Organization and many national or
regional centers.

h) Promotion
To inculcate and promote the habit of reporting ADRs to the higher center,
medical journals, health bulletins and other professional healthcare publications.

I) Networking
To encourage healthcare professionals to contact institutions working on a global
scale in PV e.g. Uppsala Monitoring Centre (UMC) WHO department of
Essential Medicines and Medicines Policy, Geneva, and net groups like
International Network for the Rational Use of Drugs (INRUD), E-drug, and
Network for Rational Use of Medicines (NetRUM)

3. Data
Pharmacovigilance at present thrives heavily on a regional/country wide reporting
of suspected ADRs through spontaneous reporting system from motivated
reporters. It usually picks up signals of rare, serious, unprecedented ADRs.

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Reports of suspected ADRs are taken in case report forms (CRF) which in PV is
defined as a notification relating to a patient with an ADE (or laboratory test
abnormality) suspected to be induced by a medicine. The CRF should be
distributed to health care professionals across the area covered by a particular PV
center regularly, and a suitable system has to be developed to ensure that the filled
forms are either collected or could be posted free, or sent by e mail/FAX to the
center, so that there is an uninterrupted and free flow of data.
A CRF should contain minimum following information

• Patient: Age, gender, medical history in brief, ethnic origin (in some countries)
• ADE monitoring: Detailed description (nature, localization, severity,

characteristics), reports of investigations and tests, date of appearance, course,
outcome

• Suspected medicines: Name (brand, formulation, ingredient, concentration,
manufacturer), dose, route of administration, date of initiation of therapy/date of
withdrawal of therapy, indications for use, and rechallenge in case of non serious
ADEs

• Other medicines: All other medicines used by the patient (including self
medication) including their name, dose, route, date of initiation and withdrawal

• Risk factors: e.g. impaired renal function, past exposure to suspected medicines,
history of allergy, and social drug use

• Reporter: Name and address of the reporter (confidential and to be used for data
completion, verification, and follow up)
Health care professionals e.g. practicing physicians, pharmacists, nurses, dentists,
and midwives are reliable sources of information. Pharmacists and nurses can
illuminate on concomitant medication and history of medicine usage. It is
imperative for pharmaceutical companies to report any ADRs of their products to
regulatory authorities. In the event of patients directly reporting ADRs, it is

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always better to communicate with their physicians for better understanding and
verification of data.
The reporting can be done from peripheral to the regional PV centers, which
sweep a particular region, which in turn pool into the zonal database, the analysis
of which reflects a gross national overview. The entire national data should be
reported to UMC.

4. Bringing a reporting culture
Reporting of ADR is a continuous process and important to cultivate and sustain
the attention and interest of healthcare workers so that it gets incorporated as a
routine procedure in healthcare. The following measures may be adopted to give a
fillip to reporting:

• Easy and free availability of prepaid reporting forms and other modes of reporting
• Duly acknowledging the receipt of ADR reports telephonically or through

personal communication
• Providing journal articles, ADR bulletins, newsletters to reporters
• Actively involving the PV center staff in scientific meetings, undergraduate and

postgraduate education
• Collaborating with other PV committees, It is always ideal to look out for other

organizations that may be able to collaborate with your PV Centre to reduce the
financial and logistic burden. For example, poison control and drug information
centres share similar PV interests. It may be useful to develop a PV system in
conjunction with these centres.

• Collaborating with professional associations
• Utilizing PV data for development of clinical pharmacy and clinical

pharmacology

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5. Tasks for pharmacovigilance
a) Information service
One of the primary responsibilities of a center is to make high quality credible and
latest medicine information available to health care professionals. For this, the
center should have access to up-to-date and comprehensive literature database.
The national centers should preferably have an online access to UMC database
and be on the mailing list of ADR bulletins of WHO.

b) Reaching out
Newsletters, medicine bulletins, columns from reputed medical or pharmaceutical
journals may be chosen as routes of effective propagation of latest developments
in medicine research and therapy to the healthcare professionals.

c) Appraisal
The ADR case reports obtained are evaluated by the center staff, employing the
collective know-how of clinical medicine, pharmacology, toxicology, and
epidemiology.

d) Secondary prevention of ADRs
Secondary prevention of ADRs can be attempted by distribution of “patient alert
cards” which are pocket size cards and could be carried around by patients. They
provide relevant information about the medicines including ADRs and go a long
way in preventing ADRs.

e) Data processing
Data is best managed electronically by computer, wherein, data is entered in a
hierarchical format according to product name, medicine name or therapeutic
category. This facilitates recording detailed case information and easy retrieval.

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Internationally accepted terminologies regarding classification of medicines
(Anatomical Therapeutic Chemical [ATC], International Nonproprietary Names
[INN]) and ADRs e.g. WHO Adverse Reaction Terminology (WHO ART),
Medical Dictionary for Regulatory Activity (MedDRA) should be used, so that
the data can be globally shared.

f) Hypothesizing
This is one of the chief goals of PV center. Based on the case reports, the center
should be able to generate hypothesis or detect a signal with regard to probable
ADRs.

e) Medicine regulation
It is PV center’s duty to keep a close eye on the new medicines launched in the
market and follow them up to look for newer ADEs, issue warnings, unmask
newer indications or changes or to advocate withdrawal of medicines in extreme
cases. A center should actively take up activities towards furthering the role of PV
with periodic safety update reports (PSURs), registries, risk management-
minimization plans, and improved communication with changes in label of
medicines.
The PV system needs to deal with large population and the rate of reporting
governs the estimation of the money needed to run the complete system. Huge
investment is required in terms of collection of data from the actual source to
transforming it into a Regulatory reportable format. Funding can be obtained from
various parties, such as drug Regulatory authority, university departments, health
insurance companies, and professional associations.

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Fig :-Pharmacovigilance system: Constitution and functioning

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Establishment & operation of drug safety department in industry
Introduction:-

• Pharmacovigilance has grown as a discipline over the past 10 to 15 year.
• An educational survey in 1994 revealed that more than 320 people

currently worked in company pharmacovigilance function in the UK
alone.

• Pharmaceutical companies are international, hence the number of staff
working in this field within the industry,particularly in other European
countries and USA.

• A major pharmaceutical company such as Astra has over 100 permanent,
experienced staff in pharmacovigilance within its research and
development organisation in Sweden and the UK and US similar number
in local operating companies worldwide

• 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 harmby identifying previously
unrecognised drug hazards.

• Refuting false safety signals and quantifying risk in relation to benefit.

Scientific characteristics:-

• Pharmacovigilance is related to a number of scientific disciplines
i. Clinical medicine

ii. Clinical and preclinical pharmacology

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iii. Immunology
iv. Toxicology
v. Epidemiology ,

Identification and analysis of the safety characteristics of medicine .
• In two distinct stage:-
1. Before marketing:-

The main methodology is experimental with clinical trial comparing the new
treatment to existing alternative treatment.

2. After marketing:-
Introduction of a new medicine into you generally use, the main safety
methodology is observational i.e. uses data from observation of patients
treated in clinical practice rather than from 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 (eg. 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 authorisation
application submitted by the company and will be the basis of ADR,
warning and precaution include in the prescribing informationi.e data
sheet.

Methods of post marketing surveillance (PMS) used by the pharmaceutical
industry:-

1. First step in signal generation:- Processes that can identify possible new
ADR.

Signal generated through four different methods
• Spontaneous reporting

o Recording and reporting clinical observation of a suspected ADR with
a marketed drug is known as spontaneous reporting.

o The National system in the UK is the yellow card.
o Where doctors, dentists and recently hospital pharmacist are

encouraged to report all suspected reactions to new medicines and
serious suspected reactions to established medicines.

• Published case reports
• Publishing case reports of suspected ADR in medical journals is an

establish a way of alerting other to possible drug hazards.
• A more recent development is report of possible ADR appearing on

the internet and money companies are still determining how they
should best handle them.

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• Cohort studies
o Companies may set up or sponsor prospective, non interventional

cohort type studies to answer safety question rose after marketing or
general hypothesis generating and testing tool to be used as need arises.

• Post marketing clinical trials
o Large randomised clinical trials with wide entry criteria can be valuable

in assessing the safety of marketed products as well as confirming
efficacy.

Companies can use to set up or sponsor search studies to address particular safety
issues.

2. Second step in signal generation:- Signals are subjected to hypothesis testing
i.e. processes that determine whether the single-dose indeed indicate a new ADR
or whether it is false.
• The hypothesis testing process:-A typical situation in company

pharmacovigilance is that a small number of reports have been received,
showing that the patients have developed a serious medical condition e.g.-liver
function disturbance, convulsion.

• Using spontaneous reporting data for hypothesis testing:-It is common
place in clinical practice to make decisions and take actions based on
assessment of causality between an event and a certain drug in individual
cases.

• Epidemiological studies:- during the last decade pharmacoepidemiology, the
study of the use and effect of drugs in large populations e.g- NSAID treatment
and gastrointestinal ulceration and bleeding.

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• National and international regulatory requirements:-
The reporting of safety information from clinical trials and with marketed
product by pharmaceutical companies to regulatory authority has been
mandatory for many years but with each National authority having different
requirements.

Pharmacovigilance is not just about reporting cases to the regulatory
authority the result of post marketing surveillance and hypothesis testing
should provide useful information.

• Issue and crisis management:- The signal generation and hypothesis testing

processes are long-term and continuous throughout the lifetime of a product
resulting in a gradual buildup of knowledge of safety properties.

• The future:- Pharmacovigilance in the industry will continue to grow and

develop as a discipline. The strong development towards international
harmonization will result in much more international requirement and the very
rapid development in electronics communication will allowautomated
distribution of case reports within companies and to regulatory authorities.

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