This document discusses pharmacovigilance, which involves monitoring the safety of medical products. It defines pharmacovigilance and outlines its history, purpose, and key processes. These include collecting adverse event reports, detecting safety signals, evaluating risks, and implementing risk minimization measures. The document also discusses challenges such as distinguishing true safety signals from background noise and standardizing signal evaluations.

1. Pharmacovigilance
Processes & Challenges

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• Definition
• History
• Purpose
• The pharmacovigilance process
• Pharmacovigilance data sources
• Signal detection
• Risk minimisations measures
Index
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3. WHO definition
Pharmacovigilance is the science and activities relating to the detection, assessment,
understanding and prevention of adverse reactions and other medicine-related problems.
Pharmacovigilance is related to a number of scientific disciplines:
• Clinical medicine
• Clinical and pre-clinical pharmacology
• Immunology, toxicology and epidemiology
FDA definition
Drug Safety Science is the strengthening of the science that supports the medical product safety
system at every stage of the product life cycle, from pre market testing and development through
post-marketing surveillance and risk management.
Definition
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4. Next to drugs and medicines, pharmacovigilance concerns also include:
• Herbals
• Traditional and complementary medicine
• Blood products
• Biologicals
• Medical devices
• Vaccines
Side effect or adverse reactions
Medicines may affect the body in unintended, harmful ways. These effects, called side effects or
adverse reactions, represent risks of medicines.
Definition
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5. The Thalidomide disaster (1961)
• An unsafe drug was marketed as safe for pregnant women, resulting in the birth of thousands of
congenitally deformed infants.
• 1st resolution adopted at WHA 16.63*: rapid dissemination of information on adverse drug reactions
• WHO Pilot Research Project for International Drug Monitoring in 1968: development of an international
system for detecting previously unknown or poorly understood adverse effects of medicines
From these beginnings emerged the practice and science of pharmacovigilance. Systems and central
databases were developed in Member States for the collection and the evaluation of individual case histories of
ADRs**. The purpose was to improve the safety profile of medicines, and avoid further disasters
History
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*The sixteenth World Health Assembly in 1963
**ADRs: adverse drug reactions
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6. The Thalidomide case proved that a strong and effective pharmacovigilance system is required to protect
patients from any unexpected emerging safety signals associated with the use of any medical product.
According to the CIOMS VI working group, a signal is a single report or a batch of reports of an adverse
event with an unknown causal relationship to treatment that is judged as worthy of further analysis and
continued surveillance
• The signal suggests a new risk or an increase of an already known risk of Adverse Event (AE) detected either
statistically (trend analysis) or by individual cases depending on the severity.
• Not every signal is casually related to the use of the product therefore a careful evaluation is necessary
before taking any action or decision
Purpose
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7. Pharmacovigilance process
Data
Collection
Signal
Detection
Evaluation
Communication
Intervention
• Post marketing spontaneous
reporting (ADR reporting
system)
• Clinical development and
pharmacology studies
• Interventional and
Observational studies
• Epidemiology data and
registries
• Pre-clinical information:
animal, toxicology and
pharmacology information
• Literature
• Web, blogs, social networks…
• Statistical analysis
• Disproportionality
analysis
• Cluster detection
analysis
• Quantitative strength
of association (time
to onset, biological
plausibility)
• Safety aggregate reports
• Risk management plan
• Dear Healthcare Provider Letter
• License Renewal
• Label change
• Marketing authorisation
withdrawal or cancellation
• Causality assessment
of the Individual Case
Safety Report
• Signal evaluation
• Benefit-risk evaluation
• Risk management
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8. Preclinical studies:
• Animal studies - in vivo studies
Clinical studies:
• Phase 0: pharmacokinetic and
pharmacodynamic studies
• Phase 1: dose ranging studies to determine
the optimal therapeutic dose
• Phase 2: efficacy studies
• Phase 3: comparison with other products
• Phase 4: post marketing studies
Pharmacovigilance data sources
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Product Development phase Post Marketing phase
• Mandatory reporting (MAH periodic safety
reports)
• Voluntary reporting (healthcare professionals and
consumers)
• Data analysis from authorities or MAH
• Communications (webinars, blogs, podcasts,
video and social media)
• Postmarketing surveillance (post marketing
studies or clinical trials)
• Safe use initiative (misuse or errors)
• Sentinel system (e-system for monitoring of
product safety)
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9. The European Medicines Agency (EMA), together with the regulatory authorities in the Member
States and Marketing Authorisation Holders are responsible for detecting and managing safety
signals
The presence of a safety signal does not directly mean that a medicine has caused the
reported adverse event. An illness or another medicine taken by the patient could also be the
cause. Therefore the assessment of safety signals is important, the signal evaluation establishes
whether or not there is a causal relationship between the medicine and the reported adverse
event.
Signal detection
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10. Process
Signal management
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Selection Review Documentation Tracking Control
Selection of the
appropriate signal
detection methods
according to the size of
data
• Adaptability of the
method to the
nature of the source
data (spontaneous
reports Vs clinical
trial reports)
Signal review,
prioritisation and
assessment
Tracking system
to capture the
evaluations of
closed and
ongoing signals,
communication
to authorities if
applicable
(PBRER, PSUR,
DSUR, RMP,
Q&A…)
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Documentation of
the signal output
activities
• Rational,
method and
periodicity
Quality control of
the signal detection
activity
• Metrics,
deadlines

11. Challenges
• Make the distinction between a true signal with a causal relationship to the medicinal product and background noise due to media
alert or increased awareness in a region or a country
• Select the appropriate method to detect signals related to drug co-administration (collaboration between different MAH is
necessary)
• Select the signals of interest and provide a rational for non selected signals
• Prioritisation of signals
• Standardisation of signal evaluations (a reproducible approach) within the company for different evaluators
• Find a way to shorten the time delay from the time of occurrence of the AE until the data are processed
• Fulfil the quality requirements:
• Documentation systems to archive the signal evaluations: Tracking of the efforts, archive of the evaluations
• Audit trail of the signal management activities
• Staff appropriate trainings
Signal detection & management
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12. The aim of risk management is to ensure that the benefit of the medicinal product exceed the risks by the
greatest achievable margin.
A risk management plan (RMP) is intended to describe the risk management planning throughout a medicinal
product’s life cycle. The RMP must contain the following:
•An identification of the safety profile of the medicinal product: describe what is known and not known
about the safety profile
•Measures taken to prevent or minimise the risks associated with the medicinal product and an
assessment of the effectiveness of those interventions
•Obligations that have been imposed as a condition of the marketing authorisation
•Rational for additional measures (post marketing studies on efficacy, patient registry…)
Risk minimisation measures
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Risk minimisation measures are the interventions intended to prevent or reduce the
occurrence of AE caused by treatment, or to reduce their impact of severity
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13. Risk minimisation measures
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TOOLS
Routine tools Other tools
• SmPC, leaflet
• Labelling
• Pack size and design,
• Legal (prescription)
• Status of product
• Educational program (for HCP, patients or sales
representative) and tools targeting HCP or patients
(guidance on prescription, management of risks,
reporting of event of interest, patient alert card)
• Controlled access program
• Pregnancy prevention program
• Controlled distribution system
• Dear HCP letters: direct HCP communication for
punctual safety issues (quality issue or supply issue)
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14. Challenges
• Selection of the most suitable and applicable measures according to the seriousness and
severity of the identified risk
• Surveillance of specific populations:
• pregnant women, children and patients with specific underlying conditions
• Deal with patient privacy and data protection obligations
• Personal identifiable information: important for signal detection assessment like date of
birth and address zip codes
• Adaptability according to the country and the cultural differences
• Differentiate the RMP educational tools from promotional documents (especially if distributed by
sales rep)
Risk minimisation measures
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15. • Pharmacovigilance in the EU: roles and responsibilities by Henry Fitt
• Guideline on good pharmacovigilance practices (GVP)Module I – Pharmacovigilance systems and their quality systems by HMA and EMA
• Signal Management
• Pharmacovigilance during the Pre-Approval Phases
• WHO Drug Information Vol. 16, No. 1, 2002
Sources
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