PHARMACOVIGILANCE
CONTENTS:
Introduction.
Collection of data.
Reporting of ADRs.
Pharmacovigilance method.
Assessment.
Periodic safety update report(psur).
Risk-benefit assessment and management.
Pharmacovigilance program of India.
INTRODUCTION:
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
DEFINITION:
Pharmaco (Greek): drug
Vigilance (Latin): –to keep awake or alert
–to keep watch
–the process of paying close and continuous
attention
Definition: 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.
WHY DO WE NEED PHARMACOVIGILANCE?
• Insufficient evidence of safety.
Reason 1
• Dying from a disease may be inevitable, dying
Reason 2: from a medicine is unacceptable (WHO,2005)
• ADR are expensive.
Reason 3:
AIMS OF PHARMACOVIGILANCE
Identify previously unrecognized adverse effects
Assess the risks and benefits of medicines in order to determine what
action, if any, is necessary to improve their safe use
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
WORK FLOW
Data collection Aggregate reporting Regulatory
(icsr) (PSUR) authorities
Data entry in
Signal detection Actions
database
Review panel
Case processing ( NCC)
(AMC) Casuality
assessment
PHARMACOVIGILANCE FRAMEWORK
COLLECTION OF DATA:
Passive data collection
Mandatory data collection
Active data collection
PASSIVE DATA COLLECTION:
Voluntary case reporting.
Requires health care professionals to be active participant in safety.
Encouraged – improving patient care and reducing the risks of
ADRs.
Barrier
s:
Liability
Incidence of occurrence
Facilities (reporting method)
Lack of time.
MANDATORY DATA COLLECTION:
Manufacturers
and distributers post marketting
submit ADE
of surveillance.
pharmaceuticals
Official
Regulatory
Ex: PSUR. recognition of the
authorities
drug
ACTIVE DATA COLLECTION:
Focused and structured activity.
More reliable calculated event occurrence rate.
Direct
Patient chart observation
Trigger tools
audits
methods
TYPES OF TRIGGER:
Laboratory triggers
• Identifies defined parameter-ADR reported.
• Ex: serum glucose(<50), WBCs(<3000)
Medication order triggers
• Prescription orders for antidotes/reversal agents.
• Sudden change/stoppage of medication(“discontinue digoxin)
Clinical triggers
• Patients condition associated with ADRs
• Ex: rash, lethargy
PATIENT CHART AUDITS:
Identify potential ADRs, medication interaction and errors.
Conducted prospectively, concurrently, retrospectively
• ADR in patients receiving new medicine
• Ghana national centre for pharmacovigilance
Prospective
• Ex: pregnant women- chloroquine to sulphadoxine pyremethamine
• Combined with demographic information
• Unrecognised ADRs dtected
concurrent • Recognised before they happen (Harm minimized)
• Widely used
• More convenient
retrospective • Depth investigation difficult
DIRECT OBSERVATION:
Requires abundant of data on medication errors.
Helps identify weaknesses in medication use process.
Verify
Observer physician Data use to
Observer collect data in order in calculate
select preprinted for patient error in
Nurses specific chart(dose, specific
medication route, focus area
frequency etc)
DATA COLLECTION TOOLS:
Filling standardized forms
Adapted from standards of practice and procedures
Country have pharmacovigilance program(own standard form)
For ADR data, identifying specifics about patient is important
Concominent therapies and conditions
Patient’s reaction to medicine
Medicine suspected for causing reaction
Manufacturer and batch number, if available
REPORTING:
Spontaneous reporting
Expedited reporting
Clinical trial reporting
Aggregate reporting
others
SPONTANEOUS REPORTING:
Clinician's normal diagnosis of a patient.
Relies on vigilant physicians and other healthcare
professionals, generate a suspicion of an ADR, but
also report it.
core data-generating system of international
pharmacovigilance and WHO Database, 4.6
million reports growing annually by about
250,000.
EXPEDITED REPORTING:
Involve a serious and unlisted event.
The timeframe for reporting expedited cases
7/15 calendar days
Within clinical trials - SUSAR (a Suspected Unexpected
Serious Adverse Reaction).
SUSAR, life-threatening or fatal, subject to a 7-day
"clock".
CLINICAL TRIAL REPORTING
Also known as SAE (serious adverse event) reporting.
key component that drug regulatory authorities consider in
the decision-making - to grant or deny market authorization
for a drug.
SAE reporting occurs as a result of study patients (subjects)
who experience serious adverse events during the
conducting of clinical trials.
AGGREGATE REPORTING
Also known as periodic reporting.
key role in the safety assessment of drugs
compilation of safety data for a drug over a
prolonged period of time (months or years)-
(broader view)
Example: PSUR.
PHARMACOVIGILANCE METHODS:
Passive Surveillance
Spontaneous reporting
Case Series
Stimulated Reporting
Active Surveillance
Sentinel Sites
Drug Event Monitoring
Registries
Comparative Observational Studies
Cross-sectional Study (Survey)
Case-control Study
Cohort Study
Targeted Clinical Investigations
Descriptive Studies
Natural History of Disease
PASSIVE SURVEILLANCE:
Spontaneous reporting
• A report of an ADR received directly from healthcare
professionals/consumers/patients.
Case series:
• Series of case reports can provide evidence of an association
between a drug and an adverse event
• more useful for generating hypotheses than for verifying an
association between drug exposure and outcome
STIMULATED REPORTING:
Reporting by health professionals in specific situations (e.g., in- hospital
settings) for new products or for limited time periods.
on-line reporting of adverse events and systematic stimulation of reporting
of adverse events based on a predesigned method.
ACTIVE SURVEILLANCE:
Sentinel Sites Drug Event Monitoring Registries
Patients –electronic A registry is a list of patients
The selected sites can provide prescription. presenting with the same
information, such as data from Questionairre -specified time characteristic(s).
specific patient subgroups. details about patients disease (disease registry)
demographic,indication of Ex: registries for blood
treatment, duration of therapies, , dyscrasias, severe cutaneous
dosage, clinical events, and reactions
reasons for discontinuation can a specific exposure (drug
be included in the questionnaire registry).
Ex: registry of rheumatoid
more detailed information on arthritis patients exposed to
adverse events from a large drugs of interest.
number of physicians and/or
patients might be collected.
COMPARATIVE OBSERVATIONAL STUDIES
Cross-sectional Study Case-control Study Cohort Study
(Survey)
Data collected on a population cases of disease are identified a population-at-risk for the
of patients at interval of time Controls,are then selected disease (or event) is followed
regardless of exposure or disease from the source population that over time for the occurrence of
status constitute a cross- gave rise to the cases. the disease (or event).
sectional study. exposure status of the two Information on exposure
Drawback: groups, compared using the odds status is known throughout the
temporal relationship between ratio, an estimate of the relative follow-up period for each patient
exposure and outcome cannot be risk of disease in the two groups. and hence incidence rate is
directly addressed particularly useful-investigate known.
So best utilised when an association between a drug A patient might be exposed to
exposures do not change over and one specific rare adverse a drug at one time during
time. event, & identify risk factors for follow-up
adverse events. comparison cohorts of interest
are selected on the basis of drug
use and followed over time.
FORMS FOR REPORTING ADRs IN
DIFFERENT COUNTRIES:
Yellow Card Scheme
UK system for collecting information on suspected ADRs.
Founded in 1964 after the thalidomide
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?
Acts as an early warning system for the identification of previously
unrecognised reactions
Enables to identify risk factors, outcomes of the ADR and other factors
that may affect clinical management
ADR REPORTING THROUGH VIGIFLOW
VigiFlow is a web-based Individual Case Safety Report (ICSR)
management system
Specially designed for use by national centres in the WHO Programme
for International Drug Monitoring.
VigiFlow 5.1(Released on 14 June 2013)
Subscription for Vigiflow is free in India.
Other tools:
ARISg (mainly used by Drug manufacturer in Europe)
Argus (mainly used by Drug manufacturer in USA)
ASSESSMENT
Routine procedure in pharmacovigilance.
The WHO-UMC system has been developed in consultation with the
National Centres participating in the Programme for International Drug
Monitoring.
practical tool for the assessment of case reports.
combined assessment - clinical-pharmacological aspects of the case
history and the quality of the documentation of the observation.
guidance - which should be used to select one category over another.
CAUSALITY ASSESSMENT
KEY QUESTIONS
Can the drug cause the adverse reaction?
Has the drug caused the adverse reaction?
Will the drug cause the adverse reaction?
how likely is it that this medication is the cause of this problem in this particular
patient?
making a differential diagnosis
VARIOUS CAUSUALITY CRITERIA:
PERIODIC SAFETY UPDATE REPORT
(PSUR)
OVERVIEW OF PSUR:
Important Aggregate Reporting
Key role in safety assessment of Drugs.
It involves compilation of safety data of drug over a prolonged period of time.
Advantages: Provides broader view of safety profile of a drug.
(PSURs) now called as PBRER (Periodic benefit risk evaluation report):
are Pharmacovigilance documents intended to provide an evaluation of the risk-
benefit balance of a medicinal product for submission at defined time points during the
post- authorisation phase.
The PSUR should focus on summary information, scientific safety assessment and integrated
benefit-risk evaluation.
PERIODIC SAFETY UPDATE REPORT
(PSUR) cont…
As per Schedule Y, PSUR includes all safety reports
Spontaneous AE reports,
PMS studies,
Safety info from other sources
published articles etc.
After approval of the product, new drugs should be closely monitored for
their clinical safety once they are marketed.
CONT..
The applicants shall furnish Periodic Safety Update Reports (PSURs) in order to –
Report all the relevant new information from appropriate sources;
Relate these data to patient exposure;
Summarize the market authorization status in different countries and any
significant variations related to safety; and
Indicate whether changes should be made to product information in order to
optimize the use of the product.
Cont..
Submission frequency for PSURs:
First 2 yrs: every 6 month
Next 2 yrs: every year
After that every 3 years.
On the basis of PSURs: Regulatory Authorities take the appropriate decision
for marketing of particular medicinal product.
RISK BENEFIT ASSESSMENT AND
MANAGEMENT:
Risk management
responsible for signal detection and the monitoring of the risk-benefit
profile of drugs.
compilation of Risk Management Plans (RMPs)
Signal detection:
Signal detection (SD) involves a range of techniques (CIOMS VIII).
The WHO defines a safety signal as: "Reported information on a possible causal
relationship between an adverse event and a drug, the relationship being unknown
or incompletely documented previously".
Usually more than a single report is required to generate a signal, depending upon
the event and quality of the information available.
SIGNAL DETECTION (CONT..)
Individual Case Safety Reports (ICSRs) in these databases are retrieved.
converted into structured format, and statistical methods (usually a mathematical
algorithm) are applied to calculate statistical measures of association.
If the statistical measure crosses an arbitrarily set threshold
A signal is declared for a given drug associated with a given adverse event.
SD is an essential part of drug use and safety surveillance.
Ideally, the goal of SD is to identify ADRs that were previously considered unexpected
provide guidance in the product's labeling as to how to minimize the risk of using the drug in a
given patient population.
RISK MANAGEMENT PLANS:
Documented plan that describes the risks (adverse drug reactions and potential
adverse reactions) associated with the use of a drug and how they are being
handled
overall goal of an RMP is to assure a positive risk-benefit profile once the drug
is marketed.
risks described in an RMP fall into one of three categories:
o Identified risks - Preclinical findings not adressed/resolved in clinical phase
o Potential risks -General pharmacology, Interactions, Toxicity; and
o Unknown risks - Populations not studied
RISK MANAGEMENT PLANS: (cont..)
The Market Authorization Holder,
usually a pharmaceutical company, will undertake measures
to minimize
the risks associated with the use of the drug.
These measures are usually focused on the product's
labeling and healthcare professionals.
The risks that are documented in a pre-authorization RMP
will inevitably become part of the product's post-marketing
labeling
RISK MANAGEMENT PLANS: (cont..)
In the US, the FDA may require a company to submit a document
called a Risk Evaluation and Mitigation Strategies (REMS) for a
drug that has a specific risk that FDA believes requires
mitigation.
REMS can require a sponsor to perform certain activities or to
follow a protocol, referred to as Elements to Assure Safe Use
(ETASU), to assure that a positive risk-benefit profile for the drug
is maintained for the circumstances under which the product is
marketed.
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
PHARMACOVIGILANCE PROGRAM OF
INDIA (PvPI)
launched with a broad objective to safe guard the health of 1.27 billion
people of India.
Adverse drug Reactions (ADRs) are reported from all over the
country to NCC-PvPI, which also 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.
REFERENCES:
Management science for health USA, chapter 35 Pharmacovigilance, by
Christopher olsan.
ICH E2E guidelines.
Clinical causality assessment by I. Ralph Edwards, R.H.B Meyboom
The use of the WHO-UMC system for standardised case causality assessment –
the uppsala monitoring centre.
Risk Benefit Assessment and Risk Management, National Regulatory
Conference 2013, Kuala Lumpur, Pia Caduff-Janosa MD; the uppsala
monitoring centre.
Pharmacovigilance Wikipedia.
Pharmacovigilance program of india (PvPI)
