An Introduction to

PHARMACOVIGILANCE
dr. J.W.S. Hajadi

Zero risk doesnt exist !

Survival
Cure
Quality of Life
Conmfort
BENEFIT
RISK
DRUG

Prevention
Side Effect
Toxicity
Drug Interaction

Drug Effect
Environment

Patient

Drug

Illness

Pharmacovigilance - WHO
Definition :
Is the pharmacological science relating to the
detection, assessment, understanding and
prevention of adverse effects, particularly longterm and short-term side effects of medicines.
Etymological roots :
pharmacon (Greek) = drug
vigilare (Latin) = to keep awake or alert, to keep
watch
Importance of PV,WHO - 2002

Definition of Pharmacovigilance - MHRA

Pharmacoviglance is the process of :
Monitoring medicines including traditional herbal medicines
as used in everyday practice to identify previously
unrecognised risks or changes in the patterns or frequency
of their adverse effects.
Assessing the risks and benefits of medicines in order to
determine what action, if any, is necessary to improve their
safe use.
Providing information to users to optimise safe and
effective use of traditional medicine.
Monitoring the impact of any action taken.
Medicine and Healthcare products Regulatory Agency

What is Pharmacovigilance ?
Generally speaking, PV is the science of :
- collecting,
- monitoring,
- researching,
- assessing , and
- evaluating
information from healthcare providers and patients on the
adverse effects of medication, biological products, herbalism
and traditional medicines with a view to :
Identifying new information about hazards associated with
medicines,
preventing harm to patients.

Safety of Medicines
WHO / Geneve 2002 - Guide to detecting and
reporting adverse drug reactions :
The objective of the Guide are to raise awareness of the
magnitude of the drug safety problem and to convince
health professionals that reporting of adverse drug
rections is their moral and professional obligation.
The ultimate goal of the Guide is to reduce drug morbidity
and drug mortality by early detection of drug safety problems
in patients and improving selection and rational use of drugs
by health professionals.

Marketing Authorisation
Is granted by the Regulatory Authority
after rigorous evaluation of data on :

SAFETY
EFFICACY
QUALITY

Main steps of Pharmaceutical R&D

1000000

Research (2-10 years)

< 5%

5%

100

Preclinical testing (3-4 years)

Laboratory and animal testing

Phase I (1 year)

10

10% 20-80 Healthy volunteers used to

determine safety and dosage

Phase II (2 years)

20% 100-800 Patient volunteers used to look for

Relative
Cost

efficacy and side effects

Phase III (3 years)

5050-70%

1000-8000 Patient volunteers used to

monitor adverse reactions to long-term use

Agencies Review/
Approval
0

10

Years

14

12

16

Drug Safety Evaluation along the

value chain
Clinical Phases

Preclinical Phases
Phase I
(safety)

Phase II

Phase III

Phase IV

(safety/efficacy) (safety/efficacy)Pharmacovigilance

Pharmacovigilance
Mechanistic Toxicology
Genetic Tox
Screening
Genetic Toxicity
1 month Tox
SD Expl
2-week Expl Tox Acute Toxicity
Tox
Teratology
Female Fertility

3/6 month Tox

Male fertility

carcinogenicity
Chronic Tox

GLP

First Dose in Human

Pre- Post NatalIty

PMS

Exploratory Safety Pharmacology

Safety
Pharmacology

Safety Data : CT vs Post-marketing

Clinical Studies

Marketed drugs

) Limited number of exposed patients

) Large number of exposed patients

) Blinded or open studies

) Uncontrolled co-medications (self

medication)

) Well-defined daily dose

) Limited number of prescribers
(investigators)

) Variable compliance
) Off label use

) Well-defined indication

) Limited monitoring

) Well-defined inclusion and non-inclusion

criteria to be enrolled in the study

) Difficult evaluation of the number of

exposed patients

) Controlled co-medications
) Strict clinical and/or biological monitoring

Specific regulations, Internal interfaces:

Clinical development, projects, toxicology,
regulatory affairs

Specific regulations, Internal interfaces:

Regulatory affairs, Business units,

Current Drug Safety issues

Recent reports in the media on new, unexpected
and severe ADRs with new or existing products
leading to widespread publicity has become part of
our daily life.
Affecting :
patients,
their doctor,
pharma company,
regulatory agencies,
legal system.

Need for Postmarketing Surveillance and

ADR reporting
The information collected during the pre-marketing phase of
drug development is inevitably incomplete with regard to
possible ADRs. This is mainly because :

Animal tests are insufficient to predict human safety;

Patients used in clinical trials are selected and limited in number,
the conditions of use differ from those in clinical practice and the
duration of trials is limited;
By the time of licensing, exposure of less than 5000 human
subjects allows only the more common ADRS to be detected;
At least 30.000 people need to be treated with a drug to be sure
that you do not miss at least one patient with an ADR which has an
incident of 1 in 10,000 exposed individuals;
Information about rare but serious adverse reaction, chronic
toxicity, use in special groups (i.e. children, elderly, pregnancy) or
drug interactions is often incomplete or not available.

Thus, post-marketing surveillance is important to permit

detection of less common but sometimes very serious ADRs.

Current PV issues
First World August 14, 2007
FDA : Stronger warning to be added to some type 2 diabetes
drugs
The FDA announced that a stronger warning on the risk of heart
failure will be added to the thiazolidinedione class of type 2
diabetes drugs (rosiglitazone and pioglitazone).

First World October 18, 2007

EU regulator confirms benefit-risk profile for rosiglitazone and
pioglitazone
The EMEA concluded that the benefits pf rosiglitazone and
pioglitazone outweigh the risk in approved indications. The agency
stated that it conducted a review of thiazolidinediones because of
new information on potential side effects including bone fractures
in women and ischemic heart disease

Current PV issues
First World September 17, 2007
New York City, State suing Merck&Co. over Vioxx
The city and state of New York filed a lawsuit against Merck&Co.
over allegations that the drug maker misrepresented the risks of
Vioxx. The suit is seeking tens of millions of dollars in damages and
civil penalties as restitution for money spent on prescriptions for the
COX-2 inhibitor therapy through healthcare program.

First World November 09, 2007

Merck&Co. to settle Vioxx lawsuits, shares rise
To pay 4.85 billion to settle state and federal claims related to Vioxx
in the US (as of October 9 : 27,000 lawsuits 47,000 plaintiff
groups as well as 264 class-action suits).

Current PV issues
Buletin BERITA MESO, Vol 25 No 2,
November 2007

Pembatalan ijin edar dan penarikan produk yang

mengandung Clobutinol HCl dari peredaran
.....karena adanya informasi potensi efek samping KV.
Walaupun belum ada laporan efek samping tersebut oleh
Pusat MESO Nasional, namun keputusan ini merupakan
bagian dari keputusan global.........
Rosiglitazone terkait efek samping pada KV
Metoklopramide terkait peningkatan laporan gejala ekstrapiramidal

Magnitude of the Problem

Estimated that ADRs are the 4th 6th largest
cause for mortality in the USA
Percentage of hospital admissions due to ADRs in
some countries is about or more than 10% :
Norway 11.5% France 13.0% UK 16.0%
A high financial burden on health care for drug
related problems. Medicine related problems
include drug abuse, misuse, poisoning,
therapeutic failure and medication errors.
Lazarou J. et al, 1998. Incidence of ADR in hospitalized patients : a metaanalysis of prospective studies.JAMA, 1998,279 (15) 1000-5.

Why PV is needed in every country

There are differences among countries (and even
regions within countries) in the occurence of ADRs
and other drug-related problems. This may be due
to differences in eg :
diseases and prescribing practices;
genetics, diet, traditions of people;
drug manufacturing processes used which influence
pharmaceutical quality and composition;
drug distribution and use, including indication, dose and
availability;
the use of traditional and complementary drugs (e.g. herbal
remedies) which may pose specific toxicological problems,
when used alone or in combnation with other drugs.

How voluntary reporting on ADRs can prevent new medicine

tragedies from developing
It took many decades before the deleterious effects of aspirin on the G-I
tract became apparent or that the protracted abuse of phenacetin could
produce renal papillary necrosis. 35 five years elapsed before it became
clear that amydopyrine could cause agranulocytosis; and several years
before the association of phocomelia and thalidomide became obvious.
Withdrawals from the market as a result of spontaneous reporting
INN
(brand name)

Reason for
withdrawal

Year of
marketing

Year of
withdrawal

bromfenac (Duract)

serious hepatotoxic effect

1997

1998

encainide (Enkaid)

excessive mortality

1987

1991

flosequinan (Manoplax)

excessive mortality

1992

1993

temafloxacin (Omnifox)

haemolytic anemia

1992

1992

benoxaprofen (Oraflex)

liver necrosis

1982

1982

mibefradil (Posicor)

multiple drug interaction

1997

1998

terfenadine (Seldane)

fatal cardiac arrhytmias

1985

1998

How voluntary reporting on ADRs can

influence labelling

Cyclophosphamide has been on the market for several years in

many countries. In January 2001 there were some new reactions
included in the labels : Steven-Johnson syndome and toxic
epidermal necrolysis; they were not included in the PDR 1995.
For example : EPIDERMAL NECROLYSIS
ERYTHEMA MULTIFORME
STEVEN-JOHNSON SYNDROME

Losartan was marketed in the USA since 1995. Some of the new
reactions that have been discovered after launch and included in
the PDR are :
VASCULITIS
PURPURA ALLERGIC (incl. Henoch-Schoenlein purpura)
ANAPHYLACTIC SHOCK
ANAPHYLACTOID REACTION

Levofloxacin was launched in the USA in 1997. In February 2000

the label
TORSADES DES POINTES

was included.

How to recognize ADRs (1)

1.
2.

3.
4.

5.

Ensure that the medicine ordered is the medicine received

and actually taken by the patient at the dose advised;
Verify that the onset of the suspected ADR was after the
drug was taken, not before and discuss carefully the
observation made by the patient;
Determine the time interval between the beginning of drug
treatment and the onset of event;
Evaluate the suspected ADR after discontinuing the drugs
or reducing the dose and monitor the patients status. If
appropriate, re-start the drug treatment and monitor
recurrence of any adverse events.
Analyse the alternative causes (other than drug) that could
on their own have caused the reaction;

How to recognize ADRs (2)

6.

7.

Use the relevant up-to-date literatures and personal

experience as a health professional on drugs and their
ADRs and verify if there are previous conclusive reports
on this reaction. The manufacturer of the drug can also be
a resource to consult;
Report any suspected ADR to the person nominated for
ADR reporting in the hospital or directly to the National
ADR Center.

What should be reported ?

For new drugs report all suspected reactions, including minor

ones (In many countries drugs are still considered new up to 5
years after marketing authorization);
For established or well-known drugs report all serious or
unexpected (unusual) suspected ADRs;
Report if an increased frequency of a given reaction is observed;
Report all suspected ADRs associated with drug-drug, drug-food or
drug-food supplement (including herbal and complementary
products) interactions;
Report ADRs in special field of interest such as drug abuse, drug
use in pregnancy and during lactation;
Report when suspected ADRs are associated with drug
withdrawals;
Report ADRs occuring from overdose or medication error;
Report when there is a lack of efficacy or when suspected
pharmaceutical defetcs are observed.

Thus, report all suspected adverse reaction that you consider

clinically important as soon as possible !

How to report ADRs ?

There are different Case Report Forms used in
different countries. Basically all of them have at
least 4 sections which should be completed :
1. Patient Information
2. Adverse Event or product problem
3. Suspected Medication(s)
4. Reporter

1. Patient Information

Patient identifier
Age at time of event or date of birth
Gender
Weight

2. Adverse event or product problem

Description of event or problem

Date of event
Date of this report
Relevant tests/laboratory data (if available)
Other relevant patients information/history
Outcomes attributed to adverse event

3. Suspected medication(s)

Name (INN and brand name)

Dose, frequency & route of administration
Therapy date
Diagnosis for use
Event abated after use stopped or dose reduced
Batch number
Expiration date
Event reappeared after reintroduction of the
treatment
Concomitant medical products and therapy dates

4. Reporter
Name, address and telephone number
Speciality and occupation

Company A

Where to send ADR reports

National Drug Regulatory Authority (in
Indonesia : Badan POM, Jl. Percetakan
Negara No. 23, Jakarta Pusat).
The manufacturer of the suspected
product.

Systems for PMS of drug-associated

events

Voluntary reporting
Intensified adverse drug reaction reporting
Special regiestries of drug-associated disorders
Intensive hospital monitoring
Multiple case control surveillance
Disease-based case control surveillance
Medical record linkage
Prescription event monitoring
Computers in physicians office

Terminology in PV

Adverse events
Adverse drug reactions
Side effects
Seriousness
Causality
Expectedness

Terminology
Adverse events (experience)
Any untoward medical occurence in a patient
treated with a pharmaceutical product wich is not
necessarily suspected as being due to the drug.

Adverse drug reaction

Side effect

Terminology
Adverse events
Adverse drug reactions
A response which is due to the drug and
considered noxious and unintended.
WHO : occures at doses normally used in man.

Side effects

Terminology
Adverse events
Adverse drug reactions
Side effects
broad term to express any untoward event
occuring with the use of a product.
(therapeutic effect = an unintended/undesirable
consequence of medical treatment),
(unintended consequence = effect that is unforeseen,
regardless of type / quality).

Severe vs Serious Event

Severe :
Term to describe the intensity (severity) of a
specific event.
Grading : mild moderate severe
Serious :
Term which is based on patient outcome criteria,
serves as a guide for defining regulatory reporting
obligations.

Seriousness Criteria
A serious medical occurence is one that at any dose
results in death
requires in-patient hospitalisation or
prolongation of current hospitalisation,
results in persistent or significant
disability/incapacity,
is life-threatening,
cancer and congenital anomaly,
any event which suggests a significant hazard
to a patient.

Expectedness

From the perspective of previously observed, an

event could be :
- Expected (= labelled)
The event is consistent with the available data in
the official product information (e.g. Investigators
Brochure, Core Data Sheet, Product
Information/label, etc.).
- Unexpected (= unlabelled)
The event has not been recorded previously

Causality

Certain
Probably / likely
Possible
Unlikely
Unclassified

Causality
Certain
Implies a plausible time relationship to drug
administration which cannot be explained by
concurrent disease or other drugs/chemicals.
Response to dechallenge (= drug withdrawal)
should be clinically plausible.
Event must be definitive pharmacologically, using
a satisfactory rechallenge procedure if necessary.

Causality
Probable / likely
Event had a reasonable time sequence to
administration of drug which is unlikely to be
attributed to concurrent disease or other
drugs/chemicals.
There must be a reasonable response on drug
withdrawal.
Rechallenge is not required to fulfil this definition.

Causality
Possible
Event had a reasonable time sequence to
administration of drug, but it could also be
explained by concurrent disease or other drugs /
chemicals.
Information on dechallenge may be lacking or
unclear.

Causality
Unlikely
Temporal relationship to drug administration
makes a causal relationship improbable, or
Other drugs / chemicals, underlying disease or
other factors provide a more plausible explanation.

Causality
Unclassified
There is insufficient information to decide on other
options, or unclassifiable if the required
information in not likely to be forthcoming.

Category of Report
CRITERIA
Seriousness

SERIOUS

NON-SERIOUS

Expectedness

UNEXPECTED

EXPECTED

Relatedness

RELATED

UNRELATED

Source of Report (unsolicited)

Health Care professionals :
physicians, dentists, nurses, pharmacists, midwife,
etc.
Consumer (patient, lawyer, etc.)
Health Authorities
Literatures (journals, newspapers, etc.)
Internet
Etc.

Source of Report (solicited)

Clinical trials
Registries
Post-approval programs
Disease management
Etc.

Reporting Procedures
Form MESO

National Drug Safety

(BPOM)

Physician
MR

Local Industry/Affiliate

HQ

Intl Agencies

Timeframe for Reporting

In SERIOUS cases :
International Companies have to report to their
HQ within 24 hours.
HQ has the obligation to report to the European
Agency or FDA within 15 days.

Closing notes
Continuous monitoring on the safety aspects of a drug (and
device) is important to secure the safety of patients/
consumers.
Roles of regulatory agencies, physician, consumers and
industry are complementory and important
To ensure more active participation in PV activities (e.g.
reporting), National Center for Drug Safety to conduct
regular training on PV and establish a system to collect
reports on adverse event at least for those meeting SUR
criteria.

Thank You for Attention,

SAFETY FIRST !

Biodata
Name

: Wiriadi S. Hajadi (James)

Place & DoB : Jakarta, June 22, 1951

Education
: Medical Doctor, ATMA JAYA Catholic University
Jakarta (1980)
Working experience :
1990 2007 : sanofi-aventis Group (Medical & Regulatory
Director, Affiliate Pharmacovigilance Head, Member
of Management Committee)
1985 1990 : WKS / Dokter Puskesmas Jakarta Selatan
1979 1985 : Ciba-Geigy Pharma (Associate Medical Director)
1978 1979 : Le Laboratoires Servier (Scientific Coordinator)