Pharmacovigilance Basics

Prepared By
Arfan Ahmed ShourovArfan Ahmed, Pharmacovigilance

Pharmaco + Vigilance
Arfan Ahmed, Pharmacovigilance
Pharmaco = Medicine
Vigilance = To watch

Pharmacovigilance Basics
Significance
AE & ADR Basics
ADR Reporting
Conclusion
Overview

Learning Objectives
At the end of the course, participants should be able to:
· Understand the basic concepts of pharmacovigilance
· Define key terms used in pharmacovigilance
· Identify pharmacovigilance methods applicable for data collection
for safety monitoring and national regulatory decision‐making
· Identify key stakeholders and understand how to work with them

Drug effects
Good
benefit
Bad
Adverse event
Expected Unexpected

The science & activities relating to the Detection,
Assessment, Understanding and Prevention of
adverse effects or any other drug related
problems

 WHO established its Programme for International Drug
Monitoring in response to the thalidomide disaster detected in
1961.
 Together with the WHO Collaborating Centre for International
Drug Monitoring, Uppsala
 At the end of 2010, 134 countries were part of the WHO PV
Programme.

Paracetamol tragedy in Bangladesh

Tuesday, August 25, 2009
Thursday, July 30, 2009

• Adulterated paracetamol (Adflame Pharmaceuticals ) syrup which
killed 76 children in the 1990s
• spurious paracetamol syrup (Rid Pharmaceutical ) causing the
deaths of 28 children in 2009

The Thalidomide Tragedy
Lessons for Drug Safety and Regulation
• Entered the German market in 1957 by gruenthal
• an OTC remedy
• 1960, marketed in 46 countries.
• 20,000 babies are affected

USA revised law requiring to prove safety and efficacy before issuing marketing authorization
1962
British Committee on safety of drug monitoring
1963
UK starts the “ YELLOW CARDS” system
1964
National ADR reporting system
UK, Australia, NZ, Canada, Germany, Sweden
1964-65
WHO center moved from GENEVA to UPPSALA
1978

Vioxx
• In Sep 30 2004, Merck withdrew the drug from the market
• doubled the risk of heart attacks and death.
• more than 38,000 deaths were related to Vioxx use

Drugs withdrawal from market by FDA
Drug Name Withdrawn Reason of Withdraw
Thalidomide 1950s–1960s risk of teratogenicity; returned to market for use
in leprosy and multiple myeloma under
FDA orphan drug rules
Lysergic acid
diethylamide (LSD)
1950s–1960s Marketed as a psychiatric drug; withdrawn after it
became widely used recreationally
Diethylstilbestrol 1970s risk of teratogenicity
Phenformin and Bu
formin
1978 risk of lactic acidosis
Ticrynafen 1982 risk of hepatitis
Zimelidine 1983 risk of Guillain-Barré syndrome

Drugs withdrawal from market by FDA
Drug Name Withdrawn Reason of Withdraw
Phenacetin 1983 An ingredient in “A.P.C.” tablet; withdrawn due to
the risk of cancer and kidney disease
Methaqualone 1984 risk of addiction and overdose
Nomifensine
(Merital)
1986 risk of hemolytic anemia
Troglitazone
(Rezulin)
2000 risk of hepatotoxicity; superseded
by pioglitazone and rosiglitazone
Rofecoxib (Vioxx) 2004 risk of myocardial infarction

CLASSIFICATION OF ADRS
(RAWLIN AND THOMPSON CLASSIFICATION)
Type A - Dose related – expected – extension of pharmacological effects
Salbutamol and tachycardia
Type B - Non dose related – bizarre – more serious
Penicillin rash
Type C - Dose and time related – related to cumulative drug use
NSAID’s induced Nephropathy
Type D - Delayed effects – carcinogenesis and teratogenicity
Thalidomide and phocomelia
Type E - End-of-use - due to withdrawal
Addisonian crisis after steroid withdrawal
Type F - Failure of therapy
Prescription, diagnosis, missed selection of the medicine or doses.

Why PV is Necessary?
Medicines are developed over a period of several years, while
efficacy & safety of new drug are tested in clinical trials.
Limitation of clinical trial:
Time limitation
Tested on healthy
volunteers
Age limitation Gender bias
This means they are not representative of real life users.
Concomitant
Medications
Narrow Set of Indications

Objective of PV
• assessment of
benefit, harm,
effectiveness
• Early detection of
unknown safety
problem
• Improve patient
care & safety
Patient
Care
Public
Health
Risk
Benefit
Assessment promote understanding,
clinical training
to health professionals
& Public

ADRs may cause 5700 deaths per year in UK.(Pirmohamedet al, 2004)
Up to 35% of hospitalized patients
experienced an ADR
350, 000 hospitalization due
to ADRs
100,000 Deaths/YR4th leading cause of
death

Analyzing Risk VS Benefit Ratio

Outcomes of Drugs
Indications
Mentioned in
insert
Desirable
Therapeutic
Effects
Unfavorable &
Unintended effects
In normal dose Not
mentioned
Undesirable
Adverse
Reactions

Any untoward medical occurrence
that may present during
treatment with a pharmaceutical
product but which does not
necessarily have a causal
relationship with this treatment.
“Does not imply causality”
Adverse Event Adverse Drug Reaction
“A response to a medicinal product
which is noxious and unintended.”
a causal role is suspected

Causal Relationship
Attributing ‘Cause-Effect’ relationship
is a medical testing protocol in which a medicine or drug is administered, withdrawn,
then re-administered, while being monitored for adverse effects at each stage
De-
challenge
Re-
challenge

Adverse drug reaction and causality assessment scales
 Naranjo’s algorithm
 Kartch Lasagna`s algorithm
 WHO probability scale
 Spanish quantitative imputation scale
 Kramer's scale
 Jones scale
 European ABO system
 Bayesian system

Special Situation
Medication Error
Misuse, Abuse
Lack of Efficacy
Off level use
Occupational Exposure

Classification of AE
Adverse
Event
Serious
Death
Anaphylaxis
Non
Serious
Skin Rashes
Nausea

•Related
•Un-related
•Expected
•Unexpected
•Non Serious
•Serious
•Mild
•Moderate
• Severe
Adverse
Event
Intensity Seriousness Expectedness Causality

Serious Adverse Event (SAE)
Death
Life
threatening
Hospitalization
or Prolongation
Birth
defect
Medical event
(Cancer)

Sources of Adverse Events (AE) reports
Spontaneous
reports
PSUR
by MA holder
ADR
case report

Sources of Adverse Events (AE) reports
Solicited reports:
–Clinical trials phases I-IV
–Observational Post-Marketing Surveillance (PMS) studies
Unsolicited report / spontaneous report :
–Patient support programs
–Disease management
–Marketing surveys
–Registries
–Pharmacoeconomics
–Quality of life questionnaires

Sources of AE Reports(Solicited Reports)
Solicited
Reports
Clinical
Studies
Phase I-IV
Investigator and
sponsor causality
required for
reporting purpose
Observational
Post
marketing
Surveillance

An
Adverse
Event
Valid
Case
An
Identifiable
patient
An
Identifiable
Reporter
A suspected
Drug

An adverse event report should contain the Four essential information
Patient’s Details Reporter’s Details
ADR
• Name
• Gender, age
• Contact number
• Pregnancy
• Name
• Occupation
• Address
• Contact number
Adverse Event
• Date of onset
• Symptoms
• Outcome
• Seriousness
Suspected Product(s)
• Brand name
• Dose, frequency
• Route
• Batch number
• Medical history

Doctors
Patients MIO
Medical Staff
Medical
Advisors Team
All Other
Sources
Who to Report?

When to
Report?
Within
of the Adverse Event

How to Report?
Phone
call
email SMS

Individual case data flow
Information
Received
Case initial entry
Duplicate check
Case
Registration
Case Triage
Data entry
& narrative
writing
Medical Review
Case closure
Reporting
(ICSR)

Reporting
Individual
Ex: Expedited
Reporting
Aggregate
Ex: PSUR
DSUR

Reasons for under reporting:
• Workload
• Uncertainty about causality
• Unsure of usefulness of information
• Lack of awareness
• Age of the molecules
Why Under Reporting?

• All ADRs are documented by the time the drug is
marketed
• Uncertainty about causality
• 1 reported case can’t make a difference
• ADRs should only be reported if certain
• Known side-effects shouldn’t be reported
The Myths……..?

Kazi Shamim, Pharmacovigilance

Pharmacovigilance Basics

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