1.

INTRODUCTION
2.AIMS
3.RESPONSIBILITIES
4.NEED OF PHARMACOVIGILANCE
5.GOVERNING BODIES
6.METHODS OF PHARMACOVIGILANCE
7. PHARMACOVIGILANCE INSPECTION
8.ADVERSE DRUG REACTION
9.APPLICATION OF PHARMACOVIGILANCE
10.TERMINOLOGY
11.POST MARKETING SURVEILLANCE
12. PHARMACOVIGILANCE PROGRAMME IN INDIA
13.WHO PROGRAMME FOR INTERNATIONAL DRUG
MONITORING
14.PHARMACOVIGILANCE OF MEDICAL DEVICES
15.PHARMACOVIGILANCE OF HERBAL MEDICINES
Pharmacovigilance(PV) also called as drug
safety
Pharmakon-------in greek----drug
Vigilare -----------in latin------to keep watch

def: Pharmacovigilance is the science &activities

relating to the detection , assessment,
understanding and prevention of adverse effects
(WHO collaborating centre for international
drug monitoring)
 AIMS
 To improve patient care and safety
 To improve public health and safety
 To contribute to the assessment of benefit,
harm ,effectiveness and risk of medicines
 To promote education and clinical training
 To promote rational and safe use of
medicines
 RESPONSIBILITIES

 Timely collection of data ,recording and

notification
 Appropriate assessments
(data completeness , seriousness)
 Expedited and periodic reporting
 Creates appropriate structures for
communication
1.HUMANITARIAN CONCERN
-Animal toxicology is often not a good
predictor for human effects .
-Evidence of safety from clinical trials is
insufficient due to some limitations
 LIMITATIONS (phase 1-3): limited size ,
narrow population (age &sex specific),
narrow indications (only specific disease),
short duration
2. SAFE USE OF MEDICINES
it has been suggested that ADRs may cause
5700 deaths per year in UK
3.ADRs ARE EXPENSIVE
4.PROMOTING RATIONAL USE OF MEDICINES
5.ENSURING PUBLIC CONFIDENCE
6.ETHICAL CONCERN
not reporting is serious reaction is unethical
 The pharmaceutical industry
 Regulatory authorities
 WHO collaborating centre for international
drug monitoring
 CIOMS(Council for International
Organization of Medical Sciences )
METHODS 0F PHARMACOVIGILANCE

1. Individual case safety reports

2. Clinical review of case reports
3. Cohort event monitoring
4. Longitudinal electronic patient records
5. Spontaneous reporting
6. Periodic Safety Update Reports (PSUR)
7. Expedited report
8. Record linkage
1.INDIVIDUAL CASE SAFETY REPORTS:

-Like yellow card system of the

Pharmacovigilance section of the U.K.

-Their strength in signaling causal associations

depend on the skill and experience of the
reporter and the documentation and
characteristics of the event.
2.CLINICAL REVIEW OF CASE REPORTS:
-The quality of reports is variable , large national
and international organizations collect
hundreds of thousands of reports each year ,
every one of which can’t possibly be reviewed
by the available experts.
-Even if each report could be reviewed ,
important reporting patterns would be missed.
-Computational have therefore been developed
to help highlight the most urgent problems .
3.COHORT EVENT MONITORING:

-Cohort Event Monitoring (CEM) systems for

intensified follow up of selected medicinal
products.

-The main limitations are its restriction to small

subset of medicinal products , the relatively small
fraction of the population covered .
4.LONGITUDINAL ELECTRONIC PATIENT
RECORDS:
-It is extremely valuable but underused.

-They cover large populations, provide detailed

information on both exposed and unexposed
patients.

-Information is extracted directly from the

computer systems in which physicians store
patient’s data.

-Privacy protection for patients and physicians is

of the utmost importance.
5.SPONTANEOUS REPORTING:

-The reporting might be directly to the

company , or it could be to the regulatory
authority.

-Main limitation is under reporting.

-However , their main purpose is not the

quantification of the frequency, but
identification of signals.
-When becoming aware of a serious adverse drug
reaction , health care providers, pharmacies,
pharmaceutical companies shall report to the
health authority.

-Time frame of reporting , report within a specific

time frame(ex:7days) upon knowing of any serious
ADR.
 -REPORTING METHODS AND TEMPLATE : shall submit
reports by post, fax or internet .

-A verbal report is acceptable in urgent situations, but

written submission should be completed before the
deadline.

-Additional information on a serious ADR report, not

available at the time of the initial report , should be
provided in follow up reports.
6.PERIODIC SAFETY UPDATE REPORTS(PSUR):
-Pre marketing clinical trials may not be
sufficient to reflect the product safety profile.

-Therefore medically advanced countries

impose the “post marketing drug safety
monitoring period ” on new drugs.

-license holders shall proactively collect post

marketing safety data, prepare PSUR and
submit them to the health authority.
 -According to the “regulation of medical
products under safety monitoring” ,if
pharmaceutical companies fail to submit PSUR
as required , then the health authority may
reassess the safety of the concerned product.

-The last PSUR should be submitted before the

expiration of the drug safety monitoring period.

-The “summary bridging report” provides

summarized information of the PSURs.
7.EXPEDITED REPORT:
-If there has been spontaneous reporting of a
suspected ADR to a pharmaceutical company ,
there are legal obligations on the company to
report serious reactions within a specified time
frame to the regulatory authority.

-based on the results of drug safety assessment ,

license holders shall report to the health
authorities in an expedited manner
8.RECORD LINKAGE:

- Bring together a variety of patient

records .

-A specific example is prescription event

monitoring scheme.

-It is less expensive but time consuming

method.
 PHARMACOVIGILANCE INSPECTION
two types -
1.routine inspection
2.targeted inspection

1.Routine inspections
- To make sure that pharmaceutical companies
have the ability in performing Pharmacovigilance
activities
2.targeted inspections
a) inspections irrelevant to drug safety
-companies that have not yet been inspected
-companies that launch their first product
-companies which are newly merged

b) inspections relevant to drug safety

-companies that delay or fail to take their obligations on
safety monitoring
-companies that delay to submit or submit incomplete
periodic safety update reports
-companies that failed to report drug safety related
issues (like drug withdrawal with out reporting )
 ADVERSE DRUG REACTIONS

Adverse event reporting –comprises 4

elements

1.an identifiable patient

2.an identifiable reporter
3.a suspect drug
4.a suspected adverse event
 TYPES OF ADR
 non immunological
a) TYPE A (or) predictable
b) TYPE B (or) unpredictable

 immunological a) TYPE -I (Ig E mediated)

b) TYPE -II (cytotoxic)
c) TYPE -III (immune complex)
d) TYPE -IV (cell mediated)
 miscellaneous a) jarisch - herxheimer
reaction
b) infectious mononucleosis
 NON IMMUNOLOGICAL
TYPE A (or) predictable
1.side effects
2.secondary effects
3.toxic effects
4.mutagenicity&carcinogenicity
5.drug interactions
6.teratogenicity
7.nonimmunological activation of effector
pathways
8.exacerbation of disease
9.Metabolic alterations
10.drug induced chromosomal damage
11.effect on spermatogenesis
TYPE B (or) unpredictable
1. intolerance
2. idiosyncrasy
 Type A
1.Side effects :
- undesirable and unavoidable effects of
drugs due to their pharmacological property at
recommended doses.
Ex-dry mouth from atropine therapy
2.Secondary effect:
-Indirect effects of drug due to its principal
action.
Ex-occurrence of TB in corticosteroid
therapy.
3.toxic effect:
-It is a pharmacological action due to over
dosage or prolonged usage.
Ex-coma with barbiturates

4.mutagenicity & carcinogenicity:

-metabolites from drugs can cause
structural changes in chromosomes to produce
mutations.
Ex-anti cancer drugs
5.drug interactions:
-Can occur before its absorption into systemic
circulation .
Ex- phenobarbitone inhibits griseofulvin
absorption from intestine

6.teratogenicity:
-Fetal abnormalities produced due to drug
intake by the pregnant woman
Ex-androgens cause virilization of fetus
7.non immunological activation of effector
pathways:
-Some drugs cause release of mediators
from mast cells resulting in urticaria.
Ex-radio contrast media

8.exacerbation of disease :
-Barbiturates precipitate symptoms of
porphyria
9.metabolic alterations :
Ex- isotretinoin interferes with VLDL
metabolism and causes xanthoma

10.drug induced chromosomal damage:

-Also called clastogens
Ex-antibiotics, anticonvulsants

11.effect on spermatogenesis:
-Cytotoxic drugs causes oligospermia.
 Type B
1.intolerance:
-Appearance of toxic effects in a recipient to
therapeutic doses of drug
Ex- trifluperazine single dose causing
muscle dystonia in children
2.idiosyncrasy:
-Uncertain reaction to a drug in a genetically
defect patient
Ex-chloramphenicol causes bone marrow
depression
 IMMUNOLOGICAL
1.Type 1 (immediate or anaphylactic):
Earlier exposure

AB formed
Re exposure to the
AG:AB reaction
same Drug (AG)
mast cells

Mediators
urticaria

Ex:-penicillin, lignocaine
2.Type 2 (cytotoxic):
Drug + particular tissue AB
(AG)

AG:AB reaction

complement

cytolysis

Ex: blood transfusion reactions, cephalosporins

3.Type 3 (retarded or arthus ):
Drug (AG) AB

AG : AB complex

Complement

Inflammatory reaction

Ex:- acute interstitial nephritis with NSAIDs

4.Type 4 (delayed hypersensitivity reactions ):

Prior sensitization T lymphocytes c receptors

(AB)

Re exposure of the drug AG:AB reaction

(AG)

Release of lymphokines

Attracts granulocytes

Inflammatory response
Ex:-contact dermatitis
 MISCELLANEOUS
1.jarisch-herxheimer reaction:
-This is seen when an infective disease is
treated with antimicrobials , due to release of
active substances from dead micro organisms
and injured tissue resulting in focal
exacerbation of the lesions.
2.infectious mononucleosis:
-Ampicillin induced morbilliform rash in
patients suffering from infectious
mononucleosis.
Steps of ADR monitoring:
1.identifying adverse drug reactions

2.assessing causality

3.documentation of ADR

4.reporting serious ADRs to PV centres/ADR

regulatory authorities
 NARANJO algorithm

For assessing the causality-

-definite = 9
-probable = 5-8
-possible = 1-4
-doubtful =  0
 Hartwig and Seigels scale
For assessing the severity-
1.mild ADRs-are self limiting and do not
contribute to prolongation of length of hospital
stay.
2.moderate ADRs- require therapeutic
intervention or hospital admission or prolonged
hospital stay by at least one day .
3.severe ADRs- life threatening, requiring
intensive medical care or produce disability or
lead to death.
APPLICATION OF PHARMACOVIGILANCE

1. in national drug policy

2.in the regulation of medicines
3.in clinical practice
4.in disease control public health programmes
(problems are apparent in situations for the
treatment of tropical diseases)
 TERMINOLOGY

1.SIGNAL-reported information on a possible

causal relationship which is being unknown or
incompletely documented previously.

-usually more than 1 report is required to

generate a signal

-before signals are published they are first

clinically assessed by PV experts at
UMC(Uppsala monitoring centre ,Sweden)
-there are 3types of signals
1.confirmed signals-causal relationship
between the drug and adverse event

2.refuted(false) signals-no causal

relationship

3.unconfirmed signals-require further

investigation
2.TRIAGE-process of placing a adverse event
report into one of these 3 categories .
a) non serious case
b)serious case
c)no case
3.ADVERSE DRUG REACTION –any noxious
change which is suspected to be due to a drug,
occurs at doses normally used in man , requires
treatment or decrease in dose or indicates
caution in the future use of the same drug.
4.ADVERSE DRUG EVENT-any untoward
medical occurrence that may present during
treatment with a medicine , but which does
not necessarily have a causal relationship
with the treatment.
5.WHOART-WHO Adverse Reaction
Terminology is dictionary for coding adverse
reactions . This system is maintained by the
UMC.
6.COSTART-COding Symbols for a Thesaurus
of Adverse Reaction Terms developed by
USFDA . But recently COSTART was replaced
by MedDRA.
7.MedDRA-Medical Dictionary for Regulatory
Activities
- International medical terminology dictionary
-Originally available in English &Japanese
- MedDRA is organized as System Organ
Class(SOC).which is divided into
a)high level group terms(HLGT)
b)high level terms(HLT)
c)preferred terms(PT)
d)lower level terms(LLT)
-MedDRA is managed by MSSO(Maintenance
and Support Services Organization)

-MSSO releases new version in twice a year

(march& September)

-March release is the main ,contains changes at

the HLT level &above

-September release contains changes at the PT

level
-Latest version(16.1) was updated on sept 2013
8.DATA MINING-extract information from a
data and transform it into an understandable
structure for further use
-it is practical machine learning tools
&techniques with java
-the term data mining appeared around
1990.
-currently data mining and knowledge
discovery are used interchangeably
Six tasks-
a)anomaly detection –identification of unusual
data &data errors that require further
investigations.
b)association rule learning-searching
relationship between variables
c)clustering-discovering groups that are in some
way similar
d)classification-to apply to new data
e)regression-models the data with least error
f)summarization-compact representation of data
-Medical data mining-HITECH act(Health Information
Technology for Economic and Clinical Health act)
-by this data mining opportunities are maximized
a)Free open source data mining soft ware & applications-
carrot 2
GATE
Orange
rapid miner
b)Commercial data mining software & application
-clara bridge
-oracle data mining
-statistica data miner
9.VIGI FLOW-it is a web based ICSR(Individual Case Safety
Report) system designed for national centres ,which does
not have ICH-E2B compatible data base.
-ICH-International Conference on Harmonization
-Vigiflow is based on ICH-E2B
-ICH-E1-E2F -----clinical safety
-E3 ----------clinical study reports
-E4 ----------dose response studies
-E5 ----------ethnic factors
-E6 -----------good clinical practice
-E7-E11 -----clinical trials
-E12 ---------clinical evaluation by therapeutic
category
-E14 ---------clinical evaluation
- E15-16 ----pharmacogenomics
 a)input-ICSR data can be manually entered
into vigiflow with support from the latest
version of terminologies such WHO-ART
or MedDRA

b)handling of ICSRs-it is easy to communicate

within the vigiflow by adding a digital
note to the ICSR.

- once a report is complete the first version of

the ICSR is considered to be finalized.
c)analysis-search& statistics module is part of
vigiflow .the results can be exported in
different output formats.
d)communication-data can be sent to external
contacts such as companies or other
regulatory agencies.
-Technical information-requirements are web
browser , internet connection.
- information stored in vigiflow is only accessible
by users within the same country.
-There are downloadable pdf information sheets
available here
10.VIGIBASE-a unique collection of
international drug safety data.Vigibase is the
name of the WHO ICSR data base . Its consists of
reports of adverse reactions
common uses-
-signal detection
-updating product safety update reports
-compare the reports
- WHO member countries have access to the
collected data and analyze
- Vigibase comprises 8million reports in which
2 lack new reports are added quarterly
11.VIGI SEARCH- a search service for accessing
ICSRs stored in the vigibase , offered by UMC
to national centres.

12.VIGIMED-share point based conferencing

facility ,exclusive to member countries of the
WHO. For fast communication .

13.VIGIMINE-a statistical tool within vigisearch.

It allows filtering of the results by age , sex ,
country.
14.VIGILYZE- during may & June 2013
vigisearch & vigimine were replaced by this.
Its a search and analysis tool that provide
access to vigibase.

15.DECHALLENGE AND RECHALLENGE-a

drug being stopped &restarted in a patient
to confirm causal relationship.

16.PHARMACOEPIDEMIOLOGY- study of the

incidence of adverse drug reactions in
patient populations.
17.PHARMACOGENETICS-genetic variation that
gives rise to differing responses to drugs
including ADR.

18.PHARMACOGENOMICS-application of
genomic technologies to new drug discovery.

19.PHARMACOENVIRONMENTOLOGY-form of
pharmacovigilance which deals specifically
with those pharmacological agents that have
impact on the environment via elimination
through living organisms subsequent to
pharmacotherapy.
 Post marketing surveillance(PMS)

-Is the practice of monitoring the safety of a

pharmaceutical drug or medical device often it has
been released on the market and is an important part
of the science of Pharmacovigilance.

-Since drugs are approved on the basis of clinical

trials, which involve relatively small numbers of
people & do not have other medical conditions.

Approaches are –spontaneous reporting database

- prescription event monitoring
-electronic health records
-patient registries
Uses-no fixed duration or patient population
starts immediately after marketing
report all ADRs
helps to detect rare ADRs
PMS-consists of 3 systems
1.ADR collecting and reporting system
2.reexamination system
3.reevaluation system
Sources-focus groups
- customer surveys
- customer complaints& warranty claims
- literature reviews
- media
Benefits-improvement of medical device quality
-verification of risk analysis
-detection of chronic complaints
-performance in different user
population
- customer satisfaction
Needs of PMS-
-to develop information about drug effects
- to find rare adverse events
-assess to more patient data
Methods of surveillance-
-controlled clinical trials
-spontaneous recording
-cohort studies
-case control studies
-All adverse events occurring in a PMS
should be submitted to UMC in the form of
fact sheet.
 Fact sheet should be-email to
vigibase@whoumc.org
- confirmation will be sent of received cases
within 3 days
-case report format-ICH E2B
-both serious and non serious cases should
be submitted
-reporter qualification should be specified in
the ICSR
-ICSR on veterinary medicines , cosmetics
should not be submitted to UMC
-either of the two ADR terminologies WHOART
(or)MedDRA can be used .
 Pharmacovigilance programme of India
(PVPI)
Introduction –
-officially started on 23 November 2004 at new
Delhi

-pharmaceutical industry in India is valued at

90,000crore and is growing at the rate of 12-14%
per annum

-total export of pharma products is to the extent of

40,000crore.

- India is now being recognized as the “global

pharmacy of generic drugs”
-India is also emerging rapidly as a hub of
global clinical trials & destination for drug
discovery and development

-In a vast country like India with a population of

over1.2 billion with vast ethnic variability
,different disease prevalence patterns ,
practice of different systems of medicines,
different SES , it is important to have robust
Pharmacovigilance and drug safety monitoring
programmes.
PVPI is under control of-
1.CDSCO(Central Drugs Standard Control
Organization)
2.directorate general of health services
3.indian pharmacopeia commission
(Ghaziabad)

-The programme is conducting by

NCC(National Coordinating Centre) .
Goals & objectives-
goal- to ensure that the benefits of use of medicine outweighs the risks

objectives-
1. to monitor ADRs

2. to create awareness among health care professionals about

ADRs

3.to monitor benefit –risk profile of medicines

4. generate independent ,evidence based recommendations

5.support the CDSCO

6.communicate findings with all stake holders

7.create a national centre

PVPI will be administered and monitored by
the following committees
1.steering committee
2.strategic advisory committee

Technical support by –
1.signal review panel
2.core training panel
3.quality review panel
 STEERING COMMITTEE
Chairman-drugs controller general (India), New Delhi
Members-
1.scientific director , Indian pharmacopoeia commission ,
Ghaziabad

2.head of dept of pharmacology ,AIIMS

3.Nominee of director general ,ICMR

4.Assisstant director general as representative of directorate

general health services

5.under secretary as representative of the ministry of

health & family welfare

6.nominee of vice chancellor of medical/pharmacy university

7.nominee of the medical council of India

8.nominee of the pharmacy council of India

-PVPI is a 3 layered structure consisting of
1.peripheral
2.regional
3.zonal centres
programme road map
 Collaboration with WHO- UMC
Long term objective of the PVPI is to establish a
centre of excellence- for that
 training of the staff at the PVPI NCC
 Usage of UMC s vigiflow (for medicines),
paniflow (for vaccines)
 Access to vigibase
 Access to early information about safety
hazards
 OPERATIONAL ASPECTS
 Roles and responsibilities of different
personnel in PVPI
 Centre management
 Processing and reporting of suspected ADRs
 Quality assurance in the programme
 Regulatory decision making
 Communication among various stake holders
 Risk management
 Ensure availability and management of
funds
 Conduct frequent training and awareness
 Detect and respond to under reporting
ADRs
 Quality review of filled ADR forms
 Proper supervision of the centres
 Feed back to the health care professionals
 Programme communications

A,B,C,D,E- programme communications

1,2,3,4- ADR reporting

 Monitoring and evaluation
1.Process indicators –
-number of ADR monitoring centres
participating
-number of personnel trained in a year
-funds budgeted and spent
2. Out come indicators –
-number of ADR reports received in year
-number of ADR reports processed in year
-number of ADR reports submitted to vigiflow
3. Impact indicators –
-number of signals generated and confirmed
-number of safety related alerts issued by
CDSCO
 WHO Pharmacovigilance programme
Introduction : -Started in 1978
- Known as WHO programme for international
drug monitoring, which is located in Uppsala, Sweden.
-As of October 2013, 117 countries have
joined

Functions –
1. identification and analysis of new ADR signals from
national centres & sent to the WHO ICSR database

2. provision of the WHO database as a reference source.

3. information exchange between WHO UMC , national

centres through vigimed
4. Publications, news letters, guidelines and books in
the pharmacovigilance

5. supplying tools like WHO drug dictionary and WHO

adverse reaction terminology

6. training to national centres

7. Maintaining of computer software(vigiflow)

8. annual meetings

9. research on Pharmacovigilance
REPORTING TRENDS:
1. preferred report format is the ICH E2B

2.but some members still use the old WHO

format(INTDIS)

3.ICSRs should be sent once every month but

at least every quarterly
DISTRIBUTION OF ICSR WORLD WIDE
PHARMACOVIGILANCE OF MEDICAL DEVICES
- medical device reporting(MDR) which is the
reporting of adverse events with medical
devices

PHARMACOVIGILANCE OF HERBAL MEDICINES

- the safety of herbal medicines has become a
major concern to both national health
authorities and public
-however mass media reports of adverse
events with herbal medicines can be
incomplete and therefore misleading regarding
the use of herbal medicines