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
 y ou
an k
Th
Pharmacovigilance
Before drugs become available to the patients, they are subjected to
rigorous clinical studies.

However, some adverse drug reactions

(ADRs) are often detected ONLY after
marketing.
The study of ADRs is
the concern of the
field known as
pharmacovigilance
Adverse drug reactions
• ADR is defined as any harm associated with the use of
given drugs at a normal dosage during normal use.

• ADRs may occur following a single dose or prolonged

administration of a drug or result from the
combination of two or more drugs.
• The meaning of ADR differs from the meaning of "side
effect ", as this last expression might also imply that
the effects can be beneficial.
 Types of ADRs
1. Type A: Augmented pharmacologic
effects (dose dependent and
predictable)
2. Type B: Bizarre effects (dose independent
& unpredictable)
3. Type C: Chronic effects
4. Type D: Delayed effects
5. Type E: End-of-treatment effects
6. Type F: Failure of therapy
7. Type G: Genetic reactions
 Serious and severe
Serious (FDA): when the patient outcome:

1. Death
2. Life-threatening
3. Hospitalization
4. Disability - or permanent change, impairment, damage or
disruption in the patient's body function/structure, physical
activities or quality of life
5. Congenital abnormalities
6. Requires intervention to prevent permanent damage

Severity: intensity of the adverse effect

Possible causes of ADRS
1. Intrinsic
Idiosyncrasy Mutagenicity Carcinogenicity
Teratogenicity
2. Extrinsic
Adulterations, contamination
3. Underlying medical conditions
4. Interactions
5. Wrong use
Economic impact of ADRs
• In the USA, the cost of drug-related morbidity and mortality
exceeded 177.4 billion dollars in 2000
(Ernst FR & Grizzle AJ, 2001: J American Pharm Assoc)

• The cost to the country of ADRs may exceed the cost of the
medications themselves

• 30-60 % of ADRs may be preventable

Definition of Pharmacovigilance
PV is the science and activities dealing with the detection,
assessment, understanding and prevention of adverse effects
of drugs.
It has been widened to include biological products, herbals,
traditional and complementary medicines.
Pharmaco - Vigilance
Pharmaco (Greek): drug
Vigilance (Latin):
• to keep awake or alert
• to keep watch
• the process of paying close and
continuous attention
Why do we need
pharmacovigilance?
Reason 1: Insufficient evidence of safety
• Animal experiments
• Clinical trials prior to marketing

Reason 2: Dying from a disease may be inevitable, dying from a

medicine is unacceptable (WHO,2005)

Reason 3: ADR are expensive

Limitations of clinical trials

1. Number of patients is limited: ~ 5000

2. Narrow population: Specific age and sex
3. Narrow indications: only those having the specific disease
studied
4. Short duration: often no longer than a few weeks
 A lesson from history
1959 – 1961 thalidomide 4,000 - 10, 000 cases of
phocomelia (congenital limb defects)

This lead to withdrawal of the drug from the market

 Pharmacovigilance is gaining
importance as the number of stories
of drug recalls increases
Examples of product recalls due
to toxicity
1. Thalidomide (1965) Phocomelia
2. Practolol (1975) Sclerosing
peritonitis
3. Phenformin (1982) Lactic acidosis
4. Rofecoxib (2004) cardiovascular
effects
5. Veralipride (2007) Anxiety,
depression,
movement disorders
6. Rosiglitazone (2010( Increased risk of
MI and death
from CV causes
Pharmacovigilance
 Aims of Pharmacovigilance
 Pharmacovigilance cycle
 Regulatory actions to minimize risk
 WHO members of the drug monitoring programme
 The Egyptian Pharmacovigilance Center
 Middle East Members
 Top 10 contributors to the WHO database
 Yellow Card Scheme
 What should be reported?
 Who can report?
 Report to whom?
 Causality assessment
 Aims of pharmacovigilance
1. Identify previously unrecognized adverse effects or
changes in the patterns of adverse effects

2. Assess the risks and benefits of medicines in order to

determine what action, if any, is necessary to
improve their safe use

3. Provide information to healthcare professionals and

patients to optimize safe and effective use of
medicines
• Thus, the ultimate purpose of ADR reporting and monitoring is to
reduce risks associated with drug prescribing and administration

• Improve patient care and patient safety

• Communication with international institutions working in
pharmacovigilance
Pharmacovigilance cycle
Collecting the data

Analysis of the data

Acting to protect public health

Decision making with regard to safety issues
Changes that occur from the PV findings
include
1. Restriction in use
2. Changes in the specified dose of the medicine
3. Introduction of specific warnings in the product
information
4. Changing the legal status of a medicine, e.g., from
over-the-counter to prescription only
5. In rare cases, removal of the medicine from the
market, if the risks of a medicine are found to
outweigh the benefits
International collaboration
in the field of pharmacovigilance
• WHO runs the Uppsala Monitoring Centre (Started in 1968,
Located in Uppsala Sweden)
• European Union runs the European Medicines Evaluation Agency
(EMEA)
• United States, the FDA is responsible for monitoring post-
marketing studies.
• Egyptian PV center
Growth of membership of International
Drug Monitoring Programme since 1968
WHO drug monitoring programme, 2001

As for August 2011: 106 members and 33

awaiting for full membership
Establishment of the Egyptian
Pharmacovigilance Center (EPVC)
The Egyptian Pharmacovigilance Center (EPVC)
December 2009
‫مركز اليقظة الدوائية المصري‬
2009 ‫ديسمبر‬
http://epvc.gov.eg
Middle East Members
1. Morocco 1992
2. Tunisia 1993
3. Oman 1995
4. Iran 1998
5. Egypt 2001
6. Jordan 2002
7. Sudan 2008
8. Saudi Arabia 2009
9. Iraq 2010
Why is it important for countries to
support their own PV programs?

1. Citizens may have unique traditions and diets

influencing reactions to medications
2. ADRs may be associated with traditional or herbal
remedies unique to each country
3. In some cases, ADRs to certain drugs may only occur
in particular ethnic groups
4. Alternate brands of therapy may be imported or
manufactured & differ in ingredients or production
processes
Yellow Card Scheme
• The Yellow Card Scheme is the UK system for collecting information on
suspected ADRs.

• The Scheme was founded in 1964 after the thalidomide disaster.

Essential information to include
on a yellow card
1. Patient details
2. Suspected drug
3. Suspected reaction
4. Reporter details
Why is the yellow card scheme
important?
1. The scheme acts as an early warning system for the
identification of previously unrecognised reactions

1. It enables to identify risk factors, outcomes of the ADR and

other factors that may affect clinical management
What should be reported?
1. All suspected reactions including minor ones
2. All serious, unexpected, unusual ADRs
3. Change in frequency of a given reaction
4. All suspected drug-drug, drug-food, drug food
supplements interactions
5. ADRs associated with drug withdrawal
6. ADRs due to medication errors
7. ADRs due to lack of efficacy or suspected
pharmaceutical defect
Who can report?
• Patients, patients relatives or patients carers
• Health care professionals (physicians, dentists, pharmacists,
radiographers, nurses)
• Manufacturers
• Authorities
Report to whom?
► Regulatory Authority
► Industry, manufacturers
► Health professionals
► Patient organizations
► General public
► Social security
Cumulative reports as of April
2004
Causality assessment
How likely is this medication the cause of this problem in this
particular patient?
Naranjo’s algorithm
Questionnaire
1. Are there previous conclusive reports on this
reaction?
2. Did the adverse event appear after the suspected
drug was given?
3. Did the adverse reaction improve when the drug was
discontinued or a specific antagonist was given?
4. Did the adverse reaction appear when the drug was
readministered?
5. Are there alternative causes that could have caused
the reaction?
Questionnaire (cont)
6. Did the reaction reappear when a placebo was given?
7. Was the drug detected in any body fluid in toxic
concentrations?
8. Was the reaction more severe when the dose was
increased, or less severe when the dose was
decreased?
9. Did the patient have a similar reaction to the same or
similar drugs in any previous exposure?
10. Was the adverse event confirmed by any objective
evidence?
Scoring
Definite ADR >9

Probable ADR 5-8

Possible ADR 1-4

Doubtful ADR 0
Take home message
• Pharmacovigilance is a dynamic clinical and scientific discipline
• ADR reporting is the cornerstone pharmacovigilance activity
• The majority of global information related to ADRs arises from
Western countries
• Each country should support its own PV program
 A successfully implemented pharmacovigilance centre can
minimize, prevent and improve the use of drugs by discovering
ADRs at the level of general public use.
PHARMACOVIGILANCE

1
Medicine Safety

To undergo treatment you have to be

very healthy, because apart from your
sickness you have to withstand the
medicine.

Molière

2
 PHARMAKON - Drug safety
VIGLARE - to keep watch
• Pharmacovigilance is defined by WHO as “the science and activities related to the
detection, assessment, understanding and prevention of adverse drug reaction or
any other possible drug-related problems”.
• Products covered by pharmacovigilance:
• Medicines
• Herbals
• Traditional
• Biologicals
• Vaccines
• Blood products
• Medical devices
World Health Organization. The Importance of Pharmacovigilance - Safety Monitoring of medicinal products. Who [Internet]. 2002;1–52.
3
Available from: http://apps.who.int/medicinedocs/pdf/s4893e/s4893e.pdf
Pharmacovigilance at different stages of drug
development

4
 AIM OF PHARMACOVIGILANCE
• Improve patient care and safety in relation to use of medicines in medical and
paramedical interventions, including vaccination.

• Improve public health and safety.

• Contribute to assessment of benefit, harm, effectiveness and risk of medicines

• Encourage safe, rational and effective (includes cost effective) use of medicines

• Promote understanding, education and clinical training in pharmacovigilance and

effective communication of it’s surveillance role to the public.
5
 Adverse drug
reactions

Interaction of Medication
medicines Errors

Scope of
Pharmacovigilance

Counterfeit
Lack of efficacy
medicines

Abuse and
misuse of
medicines

World Health Organization. Pharmacovigilance Indicators: A practical manual for the assessment of pharmacovigilance systems. WHO [Internet]. 2015. Available from: 6
http://apps.who.int/medicinedocs/documents/s21970en/s21970en.pdf
 Why is Pharmacovigilance required?
I. {a} Pre-marketing safety data
• Animal Experiments: Relevant?
• Clinical Trials: Complete?

I. {b} Post Marketing Topics

• Unexpected adverse reactions
• Interactions
• Risk factors
• Quality of life
• Long-term efficacy
• Cost assessment
7
II. Medicines are supposed to save lives

III. Economic Impact-

IV. Promoting rational use of medicines and adherence

V. Ensuring public confidence

VI. Ethics- to know of something that is harmful to another person who

does not know, and not telling, is unethical
WHO. Joining the WHO Programme for International Drug Monitoring. Uppsala Monitoring Centre [Internet]. Available from: http://www.who- 9
umc.org/DynPage.aspx?id=98081&mn1=7347&mn2=7252&mn3=7322&mn4=7325
 Pharmacovigilance Programme of India (PvPI)
• Launched with a broad objective to safe guard the health of the people of India
• The Central Drugs Standard Control Organisation (CDSCO) initiated a nation-wide
pharmacovigilance programme under the Ministry Of Health & Family Welfare in
2010 with AIIMS as National Coordinating Centre (NCC) for monitoring ADRs
• Adverse drug Reactions are reported from all over the country to NCC-PvPI
• It work in collaboration with the global ADR monitoring centre (WHO-UMC),
Sweden to contribute in the global ADRs data base
• NCC-PvPI monitors the ADRs among Indian population and helps the regulatory
authority of India (CDSCO) in taking decision for safe use of medicines

10
• Mission-
Safeguard the health of the Indian population by ensuring that the
benefits of use of medicine outweigh the risks associated with its use.

• Vision-
To improve patient safety and welfare in Indian population by
monitoring the drug safety and thereby reducing the risk associated
with use of medicines.

11
 Centre of
Excellence
Nation-
Training and
wide
consultancy
system

Collaborate
with other Identify new
centers Signals
OBJECTIVES

Communicate
Benefit-Risk
safety
ratio
information
Evidence
Support based
regulatory information
agencies on medicine
12
safety
 GOALS

• Develop and implement pharmaco-vigilance system

• Enrol all MCI approved medical colleges
• To encourage healthcare professionals in reporting of adverse reaction
Short term
Goals • Collection of case reports and data

• Expand the pharmacovigilance programme to all hospitals and centres of

public health programs
• Develop and implement electronic reporting system
Long term Goals • Develop reporting culture
• Make ADR reporting mandatory

13
 ORGANIZATION INVOLVED IN PvPI

• The Central Drugs Standard Control Organization Headquarters

• Indian Pharmacopoeia Commission
• WHO Collaborating Centre for International Drug Monitoring: The
Uppsala Monitoring Centre
• WHO Country Office for India
• National Institute of Biologicals
• AEFI surveillance
• Participation of nursing professionals

14
 Identify and evaluate
signals from ICSR
PvPI
administered
and monitored

Review quality,
causality and
completeness of ICSR
Give technical
inputs to CDSCO

15
National Coordination Centre
• NCC shifted from AIIMS to Indian Pharmacopeia Commission (IPC),
Ghaziabad on 15th April 2011

• Committees under NCC:

• Steering committee

• Working group

• Quality review panel

• Signal review panel

• Core Training panel

16
 NCC- Responsibilities
• Preparing standard operating procedures (SOPs), guidance document and training manual
• Enrolment of new ADR Monitoring Centres (AMCs)
• Reviewing and analysing Individual Case Safety Report (ICSRs)
• Forwarding ICSRs to WHO-UMC
• Communicate with WHO-UMC for administrative logistic and technical issues
• Organising Continuous Medical Education (CME) on Pharmacovigilance
• Conducting periodic training and workshops
• Publishing the PvPI newsletter
• Reporting all concerned issues to CDSCO HQ
• Provide procurement, financial and administrative logistic with respect to PV
• Token of appreciation for ADR reporters

17
ORGANOGRAM OF NCC
NCC

National
Scientific Advisor
Coordinator

Secretary-Cum- Director, National

Scientific Institute of
Director, IPC Biologicals

Senior Scientific Finance and

officer Account Officer

Scientific
Assistant

Technical
Associates
18
 UMC
• Independent foundation and a centre for international service and
scientific research

• Vision- safeguarding patients

• It provides a forum for WHO member states to collaborate in the monitoring of

drug safety

• Within the Program, individual case reports of suspected adverse drug reactions
are collected and stored in a common database

• Presently containing over 3.7 million case reports

19
• It is responsible for the collection of data about ADRs from around the world

• Member countries send their reports to the Uppsala Monitoring Centre where they
are processed, evaluated and entered into the WHO International Database

• When there are several reports of adverse reactions to a particular drug this
process may lead to the detection of a signal — an alert about a possible hazard
communicated to member countries

• Through membership of The WHO International Drug Monitoring Program, a

country can know if similar reports are being made elsewhere

20
 WHO-UMC collaboration PvPI
VigiFlow:
• Web based ICSR management system
• It offers simple, fast and secure web based solution for ADR reporting
• Once completed and committed ICSR will automatically save in VigiBase

VigiBase:
• WHO global ICSR database
• Receives reports of ADRs from member countries
• Developed and maintained by UMC
• Computer based system which allows retrieval and analysis of data

VigiSearch:
• It is a search tool, provides access to all case reports in VigiBase
• Enables international comparison
21
 WHO-UMC collaboration PvPI
VigiMine:
• Gives access to statistical data on all drug-ADR pairs reported to VigiBase
• Allows filtering as well as stratification of reports
• Used to compare with national database

VigiMed:
• Web based forum for national centres
• Easy access to safety concerns
• Checks regulatory status

VigiLyze:
• Search and analysis tool
• Includes data on conventional and traditional medicines as well as biological
medicines and vaccine
22
The responsibilities of WHO-UMC towards NCC are as follows:

• Training of the staff at the PvPI NCC at IPC

• Monitoring centres in medical colleges across the country

• Usage of UMC’s Vigiflow software (for medicines) at no cost to PvPI

• Access to Vigi-base, which contains worldwide medicines safety data

• Access to early information about potential safety hazards of medicines (worldwide data)

• Technical collaboration for a regular publication that will be issued by the PvPI NCC for
distribution to the AMCs and other stakeholders

• CDSCO Headquarters has held several meetings with UMC over the past few years to
discuss the potential role and approach for technical collaboration
23
 NATIONAL REGULATORY AUTHORITY
• Responsible for ensuring that every pharmaceutical product used within
the country is:
• Of good quality,
• Of known potency,
• Safe for the purpose or purposes for which it is proposed.

• They may conduct:

• Post-licensure surveillance of ADRs,
• Data collection on AEFIs using standardized methodologies,
• Data analysis,
• Regular communications with NCC to update safety profiles.
 CDSCO Headquarter
Mission
• To safeguard and enhance the public health by assuring the safety, efficacy and quality of
drugs, cosmetics and medical devices

Responsible for:
• Facilitate in Uniform implementation of the provisions of the Drugs & Cosmetics Act
1940 and Rules 1945
• Regulatory control over the import of drugs, approval of new drugs and clinical trials
• Central license Approving Authority
• Taking appropriate regulatory decision and action regarding drug safety
• Propagating medicine safety related decisions to stakeholders
• Provide administrative and technical support to run PvPI
• Collaboration with WHO-uppsala monitoring centre – Sweden
• Providing training to the Indian regulatory personnel 25
 ORGANIZATIONAL CHART OF CDSCO

http://www.cdsco.nic.in/forms/list.aspx?lid=2121&Id=0 26
The Zonal/ Sub-zonal CDSCO office is responsible for:

• Reporting all drug safety issues to the CDSCO headquarter and NCC-PvPI

• Providing administrative and logistic supports to the AMC at their zone

• Auditing AMC in their respective zonal and submitting the inspection report to
CDSCO HQ

27
 Regional Resource centres
• EASTERN REGION: Department of Pharmacology, IPGMER, Kolkata

• WESTERN REGION: Department of Clinical Pharmacology, Seth GS Medical

College and KEM Hospital, Mumbai

• NORTHERN REGION: Department of Pharmacology, PGIMER, Chandigarh

• SOUTHERN REGION: Department of Clinical Pharmacy, JSS Medical College

Hospital, Mysore
28
 Adverse drug reaction Monitoring Centre
AMCs are the Medical Council of India (MCI) approved:
• Medical colleges & hospitals
• Medical/central/autonomous institutes
• Public health programmes
• Corporate hospitals

They are responsible for:

• Collecting the adverse event information from the patients
• Performing follow up with them to check the completeness of the ADR reports as per standard
operating procedures (SOPs)
• Entering information in the prescribed software (Vigiflow)
• Sending the information to NCC via the same software
• Some AMCs are also responsible for providing training and technical support at regional level.

29
• PvPI started with the enrolment of 22 ADR monitoring centres across
the country in the year 2010, which has increased to 90 by the end of
2012

• 90 AMCs are categorised into four zones i.e. North, South, East and
West as per zonal offices of CDSCO in India and are functioning
under NCC

30
• The main benefits include

• Access to Vigiflow and VigiBase

• Early information about potential safety hazards (based on analyses of country’s data
and communications from other AMCs)

• Terminologies and software (tools for carrying out national medicine safety tasks)

• Support, guidelines and resources (on pharmacovigilance practice) and access to the
national network (knowledge and expertise of other AMCs).

• Chance to contribute towards the public health safety and improving patient safety in
Indian population.

• In addition, members of the PvPI meet at various conferences and meetings to share
information and network.

31
32
AMCs Enrolled ICSRs reported

33
AMCs in Delhi

34
35
36
Who can report?
• Any healthcare professional (Doctors including Dentists, Nurses and Pharmacists)

How to report?
• Suspected adverse drug reaction reporting form’ to report any ADR
• Form available in all AMCs or download from www.ipc.nic.in or www.cdsco.nic.In

Whom to report?
• The filled reporting form can be submitted to the AMC or directly to the NCC
• A reporter can also mail the form at pvpi.Ipcindia@gmail.Com
• A list of nationwide AMCs is available at: http://ipc.nic.in and also at
http://cdsco.nic.in/pharmacovigilance.htm
• Toll free number 1800-180-3024 for reporting ADR

37
Channels:

• Suspected ADR form

• Helpline (1800-180-3024)

• Mobile Application
Launched on 22nd May 2015.
Joint venture of IPC and
NSCB Medical College, Jabalpur

• Medicines Side Effect Reporting Form

patients/ consumer
ten local languages
38
What happens to the submitted information?

• Causality assessment is carried out at AMCs by using WHO-UMC scale

• Analysed forms are forwarded to NCC through the ADR database
• Data is again analysed and forwarded to the Global Pharmacovigilance Database managed by
WHO UMC in Sweden
• Reports are periodically reviewed by the NCC (IPC). The information generated on the basis
of these reports helps in continuous assessment of the benefit-risk ratio of medicines.
• Information is submitted to the Steering Committee of PvPI constituted by the Ministry of
Health and Family Welfare
• The Committee is entrusted with the responsibility to review the data and suggest any
interventions that may be required

39
 Causality Assessment of Adverse Event
• It is the evaluation of likelihood that a medicine was the causative
agent of an observed adverse event

• WHY???
Most case reports as suspected ADR
Some are certain or unlikely / possible or probable

AMC is responsible for performing causality assessment of reports

which are reviewed at NCC

40
• PvPI follows WHO-UMC causality assessment scale to establish a
relationship

• What it can do:

• Decrease disagreement between assessors
• Classify relationship likelihood
• Mark Individual case reports
• Improvement of scientific evaluation

41
WHO-UMC Causality Assessment Scale

42
Signal Generation and
Risk Management
strengthening

UTLIZATION OF
THE DATA

Drug Regulation Education

43
 Haemovigilance Programme of India
• HvPI is a process of data collection and analysis of transfusion-related
adverse reactions in order to investigate their causes and outcomes and
prevent their occurrence.
• IPC in collaboration with National institute of Biology (NIB) has
launched haemovigilance under PvPI to:
• Track Adverse Reactions/ Events and incidence associated with blood transfusion and
blood product administration
• Help in identifying trends, best practices and interventions required to improve patient
care and safety
• HvPI was launched on 10th Dec 2012 as an integral part of PvPI
• NIB functions as NCC to collate and analyse data
44
 Vaccine Pharmacovigilance

Defined as “the science and activities relating to the

• Detection,
• Assessment,
• Understanding and
• Communication
of adverse events following immunization and other vaccine- or
immunization-related issues, and to the prevention of untoward effects
of the vaccine or immunization”.

Vaccine Safety Basics 45

 Categories:
• Vaccine product – related
reaction

• Vaccine quality defect- related

AEFI- any untoward medical reaction
occurrence which follows
immunization and which • Immunization error-related
does not necessarily have a reaction
causal relationship with the
usage of the vaccine. • Immunization anxiety-related
reaction

• Co-incidental event

46
 Serious AEFI

Signals and events associated with a newly introduced vaccine

AEFIs that may have been caused by an immunization error

REPORT

Significant events of unexplained cause occurring within 30 days after a

vaccination

Events causing significant parental or community concern

Swelling, redness, soreness at the injection site IF it lasts for more than 3
days

Swelling at injection site extends beyond the nearest joint

47
• AEFI surveillance:
• monitors all aspects of immunization safety
• detects and responds to adverse events contributes to the quality
of immunization activities
• corrects unsafe immunization practices
• reduces negative impact of the event on health

• Vaccine safety in India is monitored by division of AEFI, Ministry of

health and family Welfare and PvPI
• Reporters report AEFI to either AMC or NCC
• Cases reported are further coordinated with AEFI committee and State
Expanded programme immunization officer for investigation
• The committee with local AEFI team furnish FIR/PIR/DIR to do the
causality assessment
48
Components of global vaccine safety monitoring, investigation
and response system

49
 • Licensing
• Post marketing surveillance
• Vaccine lot release
NRA • Laboratory access
• Regulatory inspection
• Oversight of clinical trails

• Makes sure that health staff respond to AEFI

NIP • Makes sure that health staff is trained
• Responsible for storage, handling and administration

• Review individual AEFI

AEFI • Assess causal link between vaccine and AEFI
• Monitor AEFI data for signals
Review • Provide recommendation for investigation, corrective action and
communication
committee • Records it’s decision and feedback to all stakeholders
50
51
VACCINE PHARMACOVIGILANCE-
THREE STEPS

DEVELOPMENT TESTING
SIGNAL
OF CAUSALITY CAUSALITY
DETECTION
HYPOTHESIS HYPOTHESIS

52
PvPI Collaboration
with

53
 RNTCP
• Collaboration between RNTCP and PvPI in relation to the use of anti-tubercular
drugs. RNTCP formally collaborated with PvPI on October 11th , 2013

• PvPI as a core component of joint monitoring mission of RNTCP

• MoHFW and WHO Country Office (India) along with other technical partners
conducted a JMM to review India’s RNTCP from 10th April 2015.

54
• Guidelines for Prevention and Management of Adverse reactions associated with
Anti TB drug’ and launched Bedaquiline – new drug for MDR TB as part of
RNTCP

• Developed a bridge application to ensure data flow

55
 Challenges for PV in India
• Gross underreporting of adverse effects
• Lack of medical expertise in drug administration
• Inadequate skilled resources in PV
• Inadequate nationwide awareness of PV.
• Lack of infrastructure
• Orthodox attitude to new drug research and PV
• Less regulatory inspections
• IT collaborations
• Easy access to Over The Counter medicines.

56
 “Gaps in the system mean the
government has less data to
determine whether drugs might
have harmful side effects. Also,
relatively little information flows
from one of the world's largest
pharmaceutical markets to the
WHO database of over 12
million suspected adverse drug
reactions.”

Huffington Post, 16/02/2016

57
58
• When her father's lung cancer worsened, Yin Min, a 51-year-old financial broker
from Shanghai, faced a choice: pay nearly $3,000 a month for an approved drug or
pay a fraction of the price for a generic drug not approved for use in China.
• Yin, like many families in China, turned to the increasingly popular, unregulated
market of online pharmacies, agents and peer groups for drugs.
• She bought a generic version of Iressa, not approved for use in China, directly
from a manufacturer in India.

• HEALTH NEWS | Mon Dec 26, 2016 | 2:13pm EST

59
60
 Future Prospects
• Strengthening the system- to detect new ADRs

• Generating information that can assist a healthcare professional or a

patient in the decision-making process.

• Integrating Good Pharmacovigilance Practice (GPP) into the processes

and procedures to help ensure regulatory compliance and enhance
clinical trial safety and post marketing surveillance.

• Transparency and communication would strengthen consumer

reporting.
61
• Role of social media

62
63
64
65
THANKYOU
66
 1

Drug Safety &

Pharmacovigilance
 2
History of Drug Safety - I

 1848 – 15 year old Hannah Greener died in course of routine anaesthesia

with chloroform (problem: ingrown nail of toe; fibrillation of ventricles?).

 1893 - Lancet initiated foundation of a commission and starting collection of

notifications about side effects

 1906 - US Federal Food and Drug Act - required, that the pharmaceuticals
should be “pure” and “free of any contamination” (nothing about the
efficacy)

 1936 - USA-s 107 lethal cases after sulphanilamides (diethylene glycol was
used to solubilize);

 1938 - Food, Drug, and Cosmetic Act, 1938. Firms had to prove to FDA that
any new drug was safe before it could be marketed: the birth of the new
drug application.
Katalyst Healthcares & Life Sciences 12/10.16
 3
History of Drug Safety - II
 1961 - Dr William McBride (Australia) reported 20% increase in foetal abnormalities and
phocomelia in relation with thalidomide use, later numerous reports from other countries (more
than 4000 cases)

 1962 - USA Kefauver-Harris amendment to the law (requirement to prove safety and efficacy
before issuing MA)

 1963 - resolution WHA 16.36 reaffirmed the need for early action in regard to adverse drug
reactions

 1964 - UK started “yellow cards” system

 1965 - European Union issued EC Directive 65/65 - first European pharmaceutical directive. The
directive was a reaction to the Thalidomide tragedy in the early 1960s, and aimed to establish and
maintain a high level of protection for public health in Europe.

 1968 - start of WHO Programme for International Drug Monitoring

 1990 - ICH - elaboration of intra-regional requirements for safety starts. ICH Safety Guidelines
Katalyst Healthcares & Life Sciences 12/10.16
 4
Are Drugs Safer Today?

 During 1960-1999 there were 121 safety related

withdrawals Worldwide
 Market life less than 2 years 31%
 Market life less than 5 years 50%
 Fung et al. Drug Information Journal, 2001; 35:293-317

 During 1972-1994 in 583 new active substances were

approved
 Of these 59 were withdrawn later

Katalyst Healthcares & Life Sciences 12/10.16

 5
Recent Drug Withdrawals
Drugs withdrawn from market due to Safety Issues

Terfenadine (Seldane) 1998 Withdrawn due to risk of cardiac arrhythmias;

Mibefradil (Posicor) 1998 Withdrawn due to dangerous interactions with other drugs

Trovafloxacin (Trovan) 1998-1999 Withdrawn due to risk of liver failure

Withdrawn due to risk of hepatotoxicity; superseded by
Troglitazone (Rezulin) 2000
pioglitazone and rosiglitazone

Withdrawn in many countries due to risk of cardiac

Cisapride (Propulsid) 2000s
arrhythmias
Cerivastatin (Baycol,
2001 Withdrawn due to risk of rhabdomyolysis
Lipobay)

Rofecoxib (Vioxx) 2004 Withdrawn due to risk of myocardial infarction

Katalyst Healthcares & Life Sciences 12/10.16

 6
Drug Safety

 No medicine is absolutely safe and all pose some magnitude

of safety and health risks

 Making sure that medicines are safe for their intended use is
an on-going process that starts in the developmental stage
& continues long after medicine is in the market.

 The process is closely monitored by manufactures and the

Regulatory Agencies.

Katalyst Healthcares & Life Sciences 12/10.16

 7
Pharmacovigilance

Investigational Products Marketed Products

Development phase Post-marketing

Vigilance: Watching carefully in order to avoid danger

Katalyst Healthcares & Life Sciences 12/10.16

 8
Drug Development

Katalyst Healthcares & Life Sciences 12/10.16

 9
What is Pharmacovigilance?

Pharmacovigilance is a science and activities relating to the

detection, assessment, understanding and prevention of adverse
effects or any other possible drug-related problems (e.g.
interactions, misuse, medication errors, abuse, overdose, addiction
potential).

Katalyst Healthcares & Life Sciences 12/10.16

 10
Drug Safety – some definitions

 Adverse event/adverse experience (AE)- Any untoward medical

occurrence that may occur during treatment with a pharmaceutical
product but which does not necessarily have a causal relationship
with this treatment
 undesirable signs & symptoms
 disease or accidents
 abnormal lab finding ( leading to dose reduction / discontinuation / intervention )
 Side effect - Any unintended effect of a pharmaceutical product
occurring at doses normally used in man, which is related to the
pharmacological proprieties of the drug
 Adverse drug reaction (ADR) - A response to a drug which is noxious
and unintended, and which occurs at doses normally used in man for
the prophylaxis, diagnosis, or therapy of disease, or for modification of
physiological function – causal role is suspected

Katalyst Healthcares & Life Sciences 12/10.16

 AEs Versus
AEs versus ADRs
ADRs

AE

ADR

12/10.16 Katalyst Healthcares & Life Sciences

11
 12
Drug Safety – some definitions

SAE (Serious Adverse Event) - an AE or ADR that is associated with

 Death
 Life threatening
 Results in hospitalization /Prolongs existing hospitalization
 Persistent or significant disability or incapacity
 Congenital anomaly or birth defect
 Medically significant

SUSAR (Serious, unexpected, suspected adverse reaction)

 Serious
 Not included in Product Core Safety Data Sheet
 Suspected link to the drug

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Serious vs Severe

The term "severe" is often used to describe the intensity (severity) of

a specific event (as in mild, moderate, or severe pain); the event
itself, however, may be of relatively minor medical significance (such
as severe headache).

This is not the same as "serious" which is based on patient/event

outcome or action criteria usually associated with events that pose
a threat to a patient's life or functioning.

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Safety Signal

 Safety Signal - information on a possible causal

relationship between an adverse event and a drug, the
relationship being unknown or incompletely
documented previously.

 Detected / generated during pharmacovigilance

 Usually more than a single report is required to generate a signal,

depending upon the seriousness of the event and the quality of
the information

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Drug Safety – 15
Main sources of information

Pre-marketing (During Development)

 Pre-clinical (animal / in-vitro) studies
 Clinical studies – Phase I – III

Post-marketing
 Spontaneous adverse reaction reporting
 national and international
 Regulatory authorities
 Contractual partners
 Published medical literature
 Clinical trials - PMS & Phase IV studies, epidemiological studies
 Data collected for other purposes
 routine statistics
 special purpose registries
 databases of prescription and outcomes
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 Limitations of pre-approval clinical 16
trials

 Size (maximum 3,000-5,000 subjects)

 Sometimes larger for vaccines

 Narrow Population
 Often does not include special groups
(e.g., children, elderly)

 Narrow indications not covering actual evolving uses in practice

 Short Duration (1-3 years)

 Latent effects not directly measured

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No. of patients required to be 95% certain
of detecting 1, 2 or 3 ADRs

No. of patients required

Incidence of
One Case Two Three Cases
ADR
Cases
1 in 100 300 480 650
1 in 1,000 3,000 4,800 6,500
1 in 2,000 6,000 9,600 13,000
1 in 10,000 30,000 48,000 65,000

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Rationale for continued
Pharmacovigilance
Information obtained prior to first marketing is inadequate to
cover all aspects of drug safety:
 Tests in animals are insufficiently predictive of human safety,
 In clinical trials patients are selected and limited in number,
 Conditions of use in trials differ from those in clinical
practice,
 Duration of trials is limited
 Information about rare but serious adverse reactions,
chronic toxicity, use in special groups (such as children, the
elderly or pregnant women) or drug interactions is often not
available.

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Why Pharmacovigilance

Impact of ADRs
 4-6th leading cause of death (Lazarou et al, JAMA; 1998)
 Upto 19 % of in-patients will have an ADR (Davies et al, J Clin
Pharm & Ther; 2006);
 up to 70 % ADRs are preventable (Pirmohamed et al, BMJ; 2006.

The cost factor

 588 million $ / year in Germany (1997),
 > $ 177.4 billion in the US in 2000,
 $847m / year in the UK (2006, BMJ)

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Classification of ADRs

 Type A

 Type B

 Type C

 Type D

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Type A

Augmented reactions - pharmacologically

predictable from the known activity of the drug,
and are usually discovered during early research.

They are common, dose related, but are usually

benign with a low mortality and morbidity.

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Type B

Bizarre reactions which are unpredictable and

are rare, often at rates of less than 1:1000
patients per annum.
 areusually dose-independent
 have a high morbidity or mortality.

Eg Agranulocytosis with Clozapine, Anaphylaxis

with Penicillins

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Type C

Type C or chemical reactions are those reactions

whose biological characteristics can be either
rationalized or even predicted based on the
chemical structure of the parent drug, or of
reactive intermediates and metabolites.

Example: hepatotoxicity caused by high doses of acetaminophen

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Type D

Delayed effects

E.g. the development of vaginal cancer of the offspring

where the mothers had received the drug
Diethylstilbestrol during pregnancy between 1938 &
1971

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Pharmacovigilance Aims

 Early detection of unknown safety problems

 Detection of increases in frequency

 Identification of risk factors

 Quantifying risks

 Preventing patients from being affected unnecessarily

Rational and Safe use of Medicines

Combined responsibility of Industry & Regulators

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 Pharmacovigilance 26
MAH*Responsibilities

 Timely collection of data, recording and notification

(reporting) – PV systems & processes, safety database
 Appropriate assessments (data completeness,
seriousness, relatedness, expectedness, medical
significance, reporting requirements & timelines)
 Expedited and periodic reporting to RA
 Signal detection & proactive risk management

* Marketing Authorization Holder

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Assessing Adverse Reactions

 Nature, organ/system involved, severity, duration

 Serious / not serious

 Causality – relationship to the drug (definite, probable,

possible, unlikely)

 Expected / unexpected (as per known safety profile of the

drug)

 Medical significance (significant / not significant)

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Regulatory Reporting of Adverse
Reactions

Why Report?
 Ethical requirement
 Regulatory requirement
 Legal requirement

Who Reports?
 Company (post marketing),
 Company & investigator joint responsibility (clinical trials)

When to Report?
 Expedited – 7 to 15 days
 Periodic – depending on when launched / region

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Reporting Adverse Reactions

What to report?
- Patient details: Pt. identifier, initials, sex, age etc
- Suspected drug: generic name, indication, dates of admin., dose, starting & stopping
date and time
- Other treatments
- Details of suspected ADR – nature, severity, duration, relationship to drug, action
taken
- Outcome
- Details about the reporter/ investigator

 Formats for reporting

 Expedited reports – ICSR, MedWatch 3500A, CIOMS I & II
 Periodic reports – annual safety reports, PSUR, NDA PADER
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Minimum Data for a Reportable ADR

 Identifiable patient
 AE/ADR
 Suspected Medicinal Product
 Reporter (HCP)

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PV Regulations

Main Players – EMEA (EU), US FDA, MHRA (UK),

TGA (Australia), Japan

Slightly different regulations, based on ICH

guidelines

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EU Requirements

 Applicable Regulations / Guidelines:

 Pre-authorization - Clinical Trials Directive 2001/20/EC
 Post-marketing - Volume 9A Eudralax
 ICH guidelines - E2A (pre-approval safety data management); E2D (post-approval safety
data); ICH E2B (electronic reporting); ICH E2C (PSURs)
 Expedited Reporting to RA
 Timelines - 7 days for Fatal or Life threatening events; 15 days for other SUSARs
 Mandatory e-reporting of Individual Case Safety Reports (ICSR) in pre & post-authorization phase

 Regulatory-compliant ADR database

 QPPV
 Main contact for the RA on pharmacovigilance issues
 Residing in the EU region with access to medically qualified safety expert

 PSURs
 Pre- authorization : EU Annual Safety Reports (ASR)
 6 monthly for 1st two years after authorization ; Yearly for next 2 years ; 3 yearly thereafter

 Signal generation & ongoing communication with RA

 Risk Management Plan

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US Requirements

 Applicable Regulations / Guidelines

 21 CFR parts 310, 312, 314, 320, 600, 601, 606
 FDA Guidance for Industry on Good Pharmacovigilance Practices and Pharmacoepidemiologic
Assessment – March 2005
 ICH guidelines - E2A (pre-approval safety data management); E2D (post-approval safety
data); ICH E2B (electronic reporting); ICH E2C (PSURs)
 Expedited Reporting to RA
 Timelines – 7 days for Fatal or Life threatening events; 15 days for other SUSARs
 Electronic reporting possible but not mandatory
 21 CFR Part 11 compliant safety database
 Safety Reports - NDA PADERs (post approval), ASRs (pre-approval)
 Quarterly for first 3 years after approval, yearly thereafter in NDA PR format
 PSURs in ICH format accepted on agreement with FDA
 Annual Safety Reports (pre-approval) - yearly
 Signal generation, ongoing communication with RA
 RiskMAPs – Risk Minimization Action Plans (REMS)
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Clinical Trial Safety Monitoring

Adverse Event experienced by Patient

Medical evaluation and patient safety decisions (Investigator)
AE noted in CRF / SAE reported to Company / CRO within protocol-specified timelines

Data Capture & Entry (Receive SAE & assign Unique ID No / Data entry in ADR
Database) (Company / CRO)

Medical Evaluation & Reporting Assessment

Preparing reports in CIOMS / MedWatch / SAE narrative format (Com / CRO)

Reporting to Reg Authority within prescribed timelines, if reportable (Com / CRO)

Reporting to IRB & DSMB Reporting to other investigators

Data Mining, Safety Signal & Report Writing - Annual Safety Reports (Com / CRO)

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Drug Safety Post Marketing

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Safety Reports & Documents

 Individual Case Safety Reports (ICSR)

 Paper or electronic

 MedWatch 3500 / CIOMS forms

 Patient safety narratives (individual reporting / incl in CSR)

 Periodic / Aggregate Safety Reports

 Annual safety reports, DSURs (EU) – pre-marketing

 IND Annual Safety Reports (US) – per-marketing

 Periodic Safety Update Reports - PSUR (EU) – post-marketing

 NDA PADER (US) – post-marketing

 Canadian Annual Report (CAR)

 Integrated safety summary (US) – for NDA

 Safety overview (EU) – for NDA

 Risk Management Plan (EU)

 RiskMAP or REMS (US)

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Drug Safety Requirements

 Understanding of global requirements & regulations

 Workflow management SOPs for collection of ADRs, collation,
assessment, reporting , risk management
 Validated database e.g. Arisg, Argus, Oracle AERS
 Data / documents management systems, storage, security
 Data back-up & disaster management
 People
 Drug Safety Associates - Medical (allopathic or integrated
alternative system BAMS, BHMS) or Life Sciences graduates
 Drug Safety Physicians – Medical graduates / post-graduates with
experience in safety assessment
 Medical / Safety Writers
 Drug safety expert –experienced drug safety physician
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Thank You
&
Questions

Contact:
Katalyst Healthcare’s & Life Sciences
South Plainfield, NJ, USA 07080.
E-Mail: info@KatalystHLS.com 12/10/2016