GYANA JYOTHI COLLEGE OF PHARMACY

Affiliated By PCI& JNTUH Hyderabad

Address:Bus depot,7-48/1, Gyana Jyothi Nagar, uppal, hyd,Telangana 500098

PHARMACOVIGILANCE

B. pharmacy IV/I sem

Unit-I

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a. Changes in the labelling of medicines indicating restrictions in use or statuary warning , precautions, or even withdrawal or the drug, by the

regulatory decision making authority.

Phamacovigilance centers have been set up in most countries. The Uppsala Monitoring Centre (Sweden) is the international collaborating centre. In

India. the Central Drug standard Control Organization (CDSCO) is coordinating the pharmacovigilance programme, under “which peripheral, regional

and zonal monitoring centres have been set up along ” with a national Pharmacovigilance advisory committee.

The pharmacovigilance centers collect, communicate and disseminate ADR data by linking with hospitals as well as practitioners and are also

expected to provide experts for assessing causality and severity of ADRs by using standard algorithms and rating scales like the ‘ Naranjo algorithm’

(causalihy assessment) and modified Hartwig scale (severity grading).

The etymological roots for the word Pharmacovigilance are: Pharmakon (Greek) = medicinal substance, and Vigilia (Latin) = to keep

watch.

• Pharmacovigilance is branch of pharmacoepidemiology but is restricted to the study, on an epidemiological scale, of drug
events or adverse reactions.

• Here ‘events’ means, recorded happenings during a period of drug monitoring in the patients notes, it may be due to the
disease for which the drug is being given.

Major aims of Pharmacovigilance are as follows:

– Early detection of unknown adverse reactions andinteractions.

– Identification of risk factors and possiblemechanisms underlying adverse reactions.

– Estimation of quantitative aspects of benefit/risk analysis and dissemination of information needed to improve drug
prescribing and regulation.
 • Pharmacovigilance promotes the systematic, rational use and assures the confidence for the safety of drugs. It improves
Patient care and safety, Public health and safety.

• The related fields to promote or encourage the Pharmacovigilance studies are Pharmaceutical industry, Paramedics,
Pharmacists, andPracticing Clinicians etc.
• AE/ADR REPORTS: SOURCES

– Reporting Systems: From Health care Professionals(voluntary)-high incidence of under reporting

– Published scientific literature: From Pubmed, Scopus etc.

– Periodic Safety Update Reports (PSUR)

IMPORTANCE OF PHARMACOVIGILANCE

• Complete information of unintended and severe adverse events could be finding through the Pharmacovigilance. It could not be
done through clinical trials which are conducted in an In vivo method.
SCOPE IN PHARMACOVIGILANCE

• Pharmacovigilance conducting advanced drug monitoring study based Adverse drug reactions, adverse events report of new
drugs include:

– 1. Medication errors and irrational use of medicines

– 2. Herbal, traditional and complimentary medicines

– 3. Substandard medicines and counterfeit medicines

– 4. Blood products, biologicals, medical devices and vaccines ADR

 • Pharmacovigilance main aim is to give clear information regarding drug safety and its risk or benefits of drugs to the patients.

The activities involved in pharmacovigilance are:

b. Post marketing surveillance and other methods of ADR monitoring such as voluntary reportingby doctors (e.g. yellow card system of UK), prescription

event monitoring, computerized medical record linkage and other cohort/case control studies as well as anecdotal case reports by doctors. Voluntary

reporting depends on the initiative and willingness of the health professionals. It is minimal in India, while even in the developed country only ~ I 0%

ADRs are reported voluntarily. Immediately occurring reactions and those that are dramatic are mostly reported. Though even rare reactions can be

detected by this method, it does not provide incidence of the reaction.

c. Dissemination of ADR data through ‘drug alerts’. ‘medical letters’ , advisories sent to doctors by pharmaceuticals and regulatory agencies (such as

FDA in USA. committee on safety o f medicines in UK).

History and development of Pharmacovigilance

• The history of Pharmacovigilance started 169 years ago, on Jan 29, 1848, when a young girl (Hannah Greener) from the north
of England died after receiving chloroform anesthetic beforeremoval of an infected toenail.

• Sir James Simpson had discovered that chloroform was a safer and powerful anesthetic, and he had introduced it in clinical
practice.

• The causes of Hannah’s death was investigated to understand whathappened to Hannah, but it was impossible to identify what
killedher. Probably she died of a lethal arrhythmia or pulmonary aspiration
 Thalidomide: the tragedy of birth defects

• Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnantwomen.

• It became apparent in the 1960s that thalidomidetreatment resulted in severe birth defects in thousands of children (teratogenicity).

• Though the use of thalidomide was banned in most countries at that time, thalidomide proved to be a useful treatment for
leprosy and later, multiple myeloma.
ThalidomideDisaster:

The thalidomide tragedy marked a turning point in toxicity testing, as it prompted United States and international regulatory agencies to
develop systematic toxicity testing protocols; the use of thalidomide as a tool in developmental biology led to important discoveries in
the biochemical pathways of limb development.Importance of safety monitoring of medicine

• The US Federal Food and Drug Act was formed on June 30, 1906, and it established that drugs must be pure and free of any
contamination. Furthermore, in 1911, this organizationforbade false therapeutic indications of drugs.

• Drug safety monitoring is a risk mitigation exercise in which the ADRs caused by therapeutic drugs, biologicals or devices
can be explored, prevented or minimized.

• It is the process of identifying expected and unexpected adverse reactions resulting from the use of medicines in the post-marketing phase.
• It is known, that the medicines developed for treatment ofdiseases, have also side effects, sometimes dangerous for life.

• Revealing, registration and analysis of the ADR (Pharmacovigilance) are necessary for the subsequent specification of the
drugs’ indications, contra-indications, side effects, dosages, etc.

• “Health care institutions, drug stores, institutions and the organizations which are consuming and using medicines, are obliged to
inform the authorized governmental body about all cases of development of unknown adverse reactionsimmediately”.
• Other relevant issues regarding safety monitoring of medicine

– Substandard medicines

– Medication errors

– lack of efficacy reports

– use of medicines for indications that are not approved and for whichthere is inadequate scientific basis

– case reports of acute and chronic poisoning

 – assessment of drug-related mortality

– abuse and misuse of medicines

– adverse interactions of medicines with chemicals, other medicines,and food

Report Form: The Report Form has four sections:

A. INFORMATION ABOUT PATIENT: This section includes the personalinformation of the patient:
– Name, surname (may be encoded in purpose of keeping confidentiality)

– Age or date of birth

– Sex

– Weight

B. ADVERSE DRUG REACTION OR MANUFACTURING PROBLEM

: This section isfor the description of the adverse drug reaction or manufacturingproblem and includes the following information:

– Marking of adverse reaction or manufacturing problem

– Date of event

– Date of report

– Motivation for sending the report (death, life-threatening, hospitalization, disability,congenital anomaly, other)

– Description of adverse reaction or manufacturing problem

– Used diagnostic methods

– Short description and peculiarities of the disease

C.SUSPECTED DRUG(S)

This section is for pointing out the suspected drug or drugs that are related to the adverse reactions. The section includes the
following information:
– Name, drug form, manufacturer, batch
– Dose

– Indications for use

– Duration
D. INFORMATION ABOUT THE REPORTER

This information has to be introduced completely, in case it is necessary to contact the reporter for getting detailed data of the
case. The section includes the following information:
-Name, address, phone no.

– Profession

– Occupation
 Functions of WHO programme for internationaldrug
monitoring
It includes:

• Identification and analysis of new adverse drug reaction signal from the case report information submitted to the national
centers and from them to the database.

• Information exchange between WHO and national centers mainly through VIGIMED and email informationexchange system.

• Publication of periodical news letters, guidelines and

• Supply of tools for management of clinical information including ADR case reports

– WHO drug dictionary

– WHO ADR terminology

• Provision of training and consultancy support to the national centers and countries establishing PVsystems.

• Computer software for case report managements design to suit the needs of national centers(VIGIFLOW).

WHO & UMC

• UMC (Uppsala Monitoring Centre) is a field name of the WHO collaborating centre forInternational Drug Monitoring.

• It is responsible for the management of the WHO programme for International Drug Monitoring.

Functions of UMC
• To coordinate the WHO programme for International Drug Monitoring and its more than eighty member countries.

• To collect, assess and communicate information from member countries about the benefits, harms and risks of drugs
 and other substances used in medicine to improve patient therapy and public health world wide.

• To collaborate with member countries in the

development and practice of the science of PV.

Pharmacovigilance Program of India(PvPI)

• The Central Drugs Standard Control Organization (CDSCO), New Delhi, under the aegis of Ministry of Health & Family
Welfare, Government of India has initiated a nation-wide Pharmacovigilance programme in July, 2010, with the All India
Institute of Medical Sciences (AIIMS), New Delhi as the National Coordinating Centre (NCC) for monitoring Adverse Drug
Reactions (ADR) in the country to safe-guard Public Health.

• In year 2010, 22 ADR monitoring centers (AMCs) including AIIMS, New Delhi had been setup under this Programme.

• To ensure implementation of this programme in a more effective way, the National Coordinating Centre was then shifted
from the All India Institute of Medical Sciences (AIIMS), New Delhi to the Indian Pharmacopoeia Commission (IPC),
Ghaziabad, (U.P.) in April, 2011.

Mission and vision of PvPI

• The mission of PvPI is to safeguard the health of the Indian population by ensuring that the benefit of use of medicine
outweighs the risks associated with its use.

• Since there exist considerable social and economic consequences of adverse drug reactions and the positive benefit/cost ratio of
implementing appropriate risk management
 – there is a need to engage healthcare professionals and the public at large, in a well structured programme to build
synergies for monitoring adverse drug reactions in the country.
• The vision of PvPI is to improve patient safety and welfare in Indian population by monitoring drug safety and thereby
reducing the risk associated with use of medicines.

• The ultimate safety decisions on medicines may need considerations of comparative benefit/risk evaluations
between products for similar indications, so the complexity is great.
• The purpose of the PvPI is to collate data, analyze it and use the inferences to recommend informed regulatory
interventions, besides communicating risks to healthcareprofessionals and the public.

• The broadened patient safety scope of Pharmacovigilance includes the detection of medicines of substandard quality aswell
as prescribing, dispensing and administration errors.

• Counterfeiting, antimicrobial resistance, and the need for real time surveillance in mass vaccinations are other Pharmacovigilance
challenges which need to be addressed.

Scope and Objectives

• To create a nation-wide system for patient safety reporting

• To identify and analyze new signal from the reported cases

• To analyze the benefit – risk ratio of marketed medications

• To generate evidence based information on safety of medicines

• To support regulatory agencies in the decision-making process on use of medications

• To communicate the safety information on use of medicines to various stakeholders tominimize the risk

• To emerge as a national centre of excellence for Pharmacovigilance activities

• To collaborate with other national centers for the exchange of information and datamanagement

• To provide training and consultancy support to other national Pharmacovigilance centersacross globe

• To promote rational use of medicine

Short Term Goals

• To develop and implement pharmaco-vigilance system in India

• To enroll, initially, all MCI approved medical colleges in the program covering north, south, east and west of India

• To encourage healthcare professionals in reporting ofadverse reaction to drugs, vaccines, medical devices and biological products

• Collection of case reports and data

Long Term Goals

• To expand the Pharmacovigilance programme to all hospitals (govt. & private) and centers of public health programs located
across India

• To develop and implement electronic reporting system (e-reporting)

• To develop reporting culture amongst healthcare professionals

 • To make ADR reporting mandatory for healthcare professionals

Functions of a National Pharmacovigilance System

• To create a nation-wide system for patient safety reporting

• To identify and analyze the new signal (ADR) from the reported cases

• To analyze the benefit – risk ratio of marketed medications

• To generate the evidence based information on safety of medicines

• To support regulatory agencies in the decision-making process on use of medications

• To communicate the safety information on use of medicines to various stakeholders tominimize the risk

• To emerge as a national centre of excellence for Pharmacovigilance activities

• To collaborate with other national centers for the exchange of information and datamanagement

• To provide training and consultancy support to other National PharmacovigilanceCenters

located across globe

Pharmacovigilance system

• Pharmacovigilance activities may be undertaken by several organizations, individuals and agencies. The Pharmacovigilance Programme of India
fulfills the minimum requirements that should be present in any functional national Pharmacovigilance system, as per
 WHO, which include the following:
1. A national Pharmacovigilance centre with designated staff (at least one full time), stable basic funding, clear mandates,
well defined structures and roles and collaborating with the WHO Programme forInternational Drug Monitoring.

2 .The existence of a national spontaneous reportingsystem with a national individual case safety report (ICSR) form i.e. an
adverse drug reaction (ADR) reporting form.
• A national database or system for collating and managing ADR reports (Vigibase database and Vigiflow software for PvPI)

• 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.
 INTRODUCTION TO ADVERSE DRUGREACTION

– Definitions and classification of ADRs

• An adverse drug event is “any untoward medical occurrence that may present during treatment with a pharmaceutical product
but which does not necessarily have a causal relationship with this treatment” (WHO definition, 2005)

• An adverse drug reaction is “a response to a drug which is noxious and unintended and which occurs at doses normally used
in man for prophylaxis, diagnosis, ortherapy of disease or for the modification of physiologic function.” (WHO definition, 2005)
Traditionally, ADRs have been classified into two types:

• Type A reactions – sometimes referred to as augmented reactions – which are ‘dose-dependent’ and predictable on the basis
of the pharmacology of the drug.

• Type B reactions – bizarre reactions – which are idiosyncratic and not predictable on the basis of the pharmacology.
Drug reactions may be classified as:

• Type A: Dose-related reactions (adverse effects at either normal dose or overdose), eg. serotonin syndrome or anticholinergic
effects of tricyclics

• Type B: Non-dose-related reactions (i.e. any exposure is enough to trigger such a reaction), eg. allergic or anaphylaxis reactions

• Type C: Dose and time-related reactions, eg due to dose accumulation, or with prolonged use (eg. adrenal
suppression with corticosteroids)

• Type D: Time related reactions, i.e. due to prolonged use in a drug which doesn't tend to accumulate (eg. Tardive dyskinesia
from antipsychotics/ neroleptics)

• Type E: Withdrawal reactions, i.e. the undesired effectsof ceasing the drug (for example, opiate withdrawal)

• Type F: Unexpected failure of therapy, where a drug undesirably increases or decreases in efficacy- for example, the
decreased clearance of a drug by dialysis, or the decreased effect of antibiotics due to resistance.
etection and reporting of ADR
Pharmacovigilance system: Constitution and functioning
 Methods in causality assessment

• Causality assessment is the method by which an association is evaluated between a drug and a suspected reaction.

• It assesses the relationship between a drug treatment and the occurrence of an adverse event and establishes the same.

• It is an important tool which is used in Pharmacovigilance programmers for evaluating suspected ADR reports for
assessingthe safety of drugs for use & for regulatory purposes also.

• This assessment may be undertaken by clinicians, academics, pharmaceutical industry, and regulators.
• Causality assessment can be done by treating health professionals as a tool for decision making regarding a drug treatment &
by regulators as a help in signal detection and assist in risk-benefit decisions regarding medicines.

• Algorithms, structured tools specifically designed forthe identification of an ADR, should theoretically make a more objective
decision on causality.

The objective of causal assessments are based on four basic principles:

• Temporal eligibility

• Dechallenge and outcome

• Rechallenge and outcome

• Confounding factors

• It is often difficult to decide if an adverse clinical event is because of therapeutic failure or an ADR and therefore in a patient who is on a
drug treatment, the differential diagnosis should include the possibility of an adverse drug reaction.
 • Immediately after an adverse event it is wise that the first step is to find out whether a patient is taking a medicinal product, including
over-the-counter formulations.

• The next step is to assess the possibility of the effectbeing caused by the medicine and in cases of poly pharmacy it is often a
denting task to pinpoint the causative drug.

• There are many characteristics looked for assigning probability of causation to a suspected adverse drug reaction.

• Timing- The time relation between the use of the drug and the occurrence of the reaction should be assessed.

• Pattern recognition- The pattern of the adverse effect may match the known pharmacology or allergy pattern of one of the suspected
medicines, or of chemically related or pharmacologically related compounds.

• Investigations- It is wise to establish baseline functions likeliver function & kidney function tests, allergic tests etc. at the start of
therapy in anticipation of an adverse drug reaction.

• A number of algorithms or decision support have been published including the Jones algorithm, Naranjo algorithm, the Begaud
algorithm, the Karch algorithm, the Yale algorithm, the WHO-UMC and a newer quantitativeapproach algorithm. Each of
these algorithms has similarities and differences.

• WHO-UMC system has been developed in consultation with the National Centers participating in the Program for International Drug
Monitoring and is meant as a practical tool for the assessment of case reports.

• The most commonly used algorithms is the Naranjo algorithm which is a questionnaire designed by Naranjo et al for
determining the possibility of whether an ADR is actually due to the drug rather than the result of other factors.

• The Naranjo criteria classify the probability that an adverse event is related to drug therapy based on a list of weighted
questions, which examine factors such as the temporal association of drug administration and event occurrence,
alternative causes for the event, drug levels, and previous patient experience with the medication.
• Probability is assigned via a score termed definite, probable, possible or doubtful. It is also called the Naranjo Scale or Naranjo
score.
Severity and seriousness assessment
Predictability and preventability assessment
 • BASIC TERMINOLOGIES USED IN PHARMACOVIGILANCE

– Terminologies of adverse medication relatedevents

– Regulatory terminologies

Eudravigilance medicinal product dictionary

• 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

Glossary of important terms used in Pharmacovigilance

• Adverse Event/ Adverse Experience: Any untoward medical occurrence that

may present during treatment with a pharmaceutical product but which does not
necessarily have a causal relationship with this treatment.

• Adverse Drug Reaction: A response to a drug which is noxious and unintended,

and which occurs at doses normally used in humans for the prophylaxis, diagnosis
or therapy of disease, or for the modification of physiological function.

• An adverse drug reaction, contrary to an adverse reaction, is characterized by the

suspicion of a causal relationship between the medicine and the occurrence, i.e.
judged as being at least possibly relatedto treatment by the reporting or a
reviewing health professional.
• Individual Case Safety Report (ICSR): A document providing the most
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 complete information related to an individual case at a certain point of time.
An individual case is the information provided by a primary source to
describe suspected adverse reaction(s) related to the administration of one
or more medicinal products to an individual patient at a particular point of
time.

• Lack of Efficacy: Unexpected failure of a medicine to produce the intended

effect as determined by previous scientific investigation.
• National Pharmacovigilance Centre: A single, governmentally recognized
centre (or integrated system) within a country with the clinical and scientific
expertise to collect, collate, analyze and give advise on all information related
to medicine safety.Pharmacoepidemiology: The study of the use and
effects of medicinesin large numbers of people.

• Prescription Event Monitoring: A system created to monitor adverse drug

events in a population. Prescribers are requested to report all events,
regardless of whether they are suspected adverse events, for identified
patients receiving a specified medicine.

• Record Linkage: Method of assembling information contained in twoor

more records, e.g., in different sets of medical charts, and in vital records
such as birth and death certificates. This makes it possible to relate significant
health events that are remote from one another in time and place.

• Serious Adverse Event or Reaction: A serious adverse event or reaction is any

untoward medical occurrence that at any dose results in:

– Death

– Is life-threatening

– Requires inpatient hospitalization or prolongation of existing hospitalization

– Persistent or significant disability/incapacity

– Congenital Anomaly

– Medically important event or reaction

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 • To ensure no confusion or misunderstanding of the difference between the
terms

‘serious’ and ‘severe’, the following note of clarification is provided:

• The term “severe‟ is not synonymous with serious. In the English language,
„severe‟ is used to describe the intensity (severity) of a specific reaction (as in
mild, moderate or severe); the reaction itself, however, may be of relatively
minor medical significance (such as severe headache). Seriousness (not
severity) which is based on patient/reaction outcome or action criteria serves as
guide for defining regulatory reporting obligations.

• Case Control Study: Study that identifies a group of persons with the
unintended medicine effect of interest and a suitable comparison group of
people without the unintended effect. The relationship of a medicine to the
medicine reaction is examined by comparing the groups exhibiting and not
exhibiting the medicine reaction with regard to how frequently the medicine
ispresent.

• Cohort Study: A study that identifies defined populations and follows them
forward in time, examining their rates of disease. A cohort study generally
identifies and compares exposed patients to unexposed patients or to
patients who receive a different exposure.

• Causality assessment: The evaluation of the likelihood that a medicine

was the causative agent of an observed adverse reaction. Causality
assessment is usually made according established algorithms.

• Clinical Trial: A systematic study on pharmaceutical products in human

subjects (including patients and other volunteers) in order to discover or verify
the effects of and/or identify any adverse reaction to investigational products,
and/or to study the absorption, distribution, metabolism and excretion of the
products with the objective of ascertaining their efficacy and safety.

• Clinical trials are generally classified into Phases: I to IV. Phase IV trials are
studies performed after marketing of the pharmaceutical product. They are
carried out on the basis of the product characteristics for which the marketing
authorization was granted and are normally in theform of post-marketing
surveillance.

• Drug/ Medicine: Any substance in a pharmaceutical product that is used to modify or

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 explore physiological systems or pathological states for the benefit of the recipient.
The term drug/medicinal product is used in a wider sense to include the whole
formulated and registered product, including the presentation and packaging, and the
accompanying information.

• Drug Alerts: The action of notifying a wider audience than the initial information
holder(s) of a suspected association between a drug and an adverse reaction. Note
that the term is used in different contexts that can be confusing, for example, an alert
may be from a manufacturer to a regulator or from a regulator to the public.

• Dechallenge: The withdrawal of a medicine from a patient; the point at which the
continuity, reduction or disappearance of adverse effects may be observed.

• Rechallenge: The point at which a medicine is again given to a patient after its
previous withdrawal.
• Individual Case Safety Report (ICSR): A document providing the most
complete information related to an individual case at a certain point of time.
An individual case is the information provided by a primary source to
describe suspected adverse reaction(s) related to the administration of one
or more medicinal products to an individual patient at a particular point of
time.

• Lack of Efficacy: Unexpected failure of a medicine to produce the intended

effect as determined by previous scientific investigation.

• National Pharmacovigilance Centre: A single, governmentally recognized

centre (or integrated system) within a country with the clinical and scientific
expertise to collect, collate, analyze and give advise on all information
related to medicine safety.
• Pharmacoepidemiology: The study of the use and effects of medicines in
large numbers of people.

• Prescription Event Monitoring: A system created to monitor adverse drug

events in a population. Prescribers are requested to report all events,
regardless of whether they are suspected adverse events, for identified
patients receiving a specified medicine.

• Record Linkage: Method of assembling information contained in twoor

more records, e.g., in different sets of medical charts, and in vital records
such as birth and death certificates. This makes it possible to relate significant
health events that are remote from one another in time and place.
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 • Side Effect: Any unintended effect of a pharmaceutical product occurring at
doses normally used in humans, which is related to the pharmacological
properties of the medicine.

• Signal: Reported information on a possible causal relationship between an adverse reaction

and a drug, the relationship being unknown or incompletely documented previously.

Usually more than a single report is required to generate a signal, depending upon the

seriousness of the reaction and the qualityof the reaction.

•
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