Lesson 1

Pharmacovigilance Fundamentals Cheat Sheet

Essential concepts and principles of drug safety monitoring and evaluation

📋 Definition and Scope

WHO Definition: “The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem.”

Core Activities:

Continuous monitoring of medicinal products after authorization
Evaluation of benefit-risk profiles over time
Implementation of risk minimization measures
Communication of safety information to stakeholders
Systematic approach to collecting, analyzing, and acting on safety data

Extended Scope:

Medication errors
Lack of efficacy
Misuse and abuse
Drug interactions
Counterfeit medicines
Quality defects affecting safety

🕰️ Historical Context

Thalidomide Tragedy (1950s-1960s): Marketed as a sedative and anti-emetic for pregnant women, caused approximately 10,000 cases of severe birth defects (phocomelia) worldwide before withdrawal in 1961.

1968

WHO Programme for International Drug Monitoring established

1970s

Spontaneous reporting systems implemented in multiple countries

1980s-1990s

Development of first computerized adverse event databases

1990

International Conference on Harmonisation (ICH) formed

2000s

Introduction of Risk Management Plans and proactive PV approaches

2010s

Integration of real-world data and advanced analytics

Evolution: Pharmacovigilance has progressed from reactive (waiting for problems to occur) to proactive (anticipating and preventing safety issues).

⚖️ Regulatory Framework

ICH Guidelines:

ICH E2A

Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

ICH E2B

Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports

ICH E2C

Periodic Benefit-Risk Evaluation Report (PBRER)

ICH E2D

Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting

ICH E2E

Pharmacovigilance Planning

ICH E2F

Development Safety Update Report

Region-Specific Regulations:

EU Good Pharmacovigilance Practices (GVP) modules
FDA’s Code of Federal Regulations (21 CFR parts 312 and 314)
Various national regulations across countries worldwide

👥 Stakeholders

Pharmaceutical Companies

Marketing Authorization Holders (MAHs) bear primary responsibility for product safety
Must maintain PV systems, collect and evaluate safety data, and report to authorities
Required to have Qualified Persons for Pharmacovigilance (QPPVs) in the EU

Regulatory Authorities

FDA (US): Oversees safety through Center for Drug Evaluation and Research (CDER)
EMA (EU): Coordinates the European pharmacovigilance network
PMDA (Japan): Regulates drugs and medical devices in Japan
WHO: Maintains global database and promotes international collaboration
National authorities: Implement country-specific requirements

Healthcare Professionals

Primary source of adverse event reports
Responsible for recognizing and reporting suspected adverse reactions
Key role in implementing risk minimization measures

Patients and the Public

Increasingly important source of direct adverse event reporting
Patient advocacy groups help shape safety policy
Recipients of safety communications

Academic Institutions

Conduct safety research and develop methodologies
Provide expertise for causality assessment
Contribute to signal detection through publications

🔄 Product Lifecycle

Pre-clinical Testing

Identifies potential toxicities and safety signals
Informs first-in-human dosing and monitoring parameters
Limitations include species differences and inability to detect rare effects

Clinical Development (Phases I-III)

Phase I: First-in-human studies assessing safety and tolerability
Phase II: Exploratory efficacy studies with continued safety monitoring
Phase III: Confirmatory efficacy trials with larger populations
Development Safety Update Reports (DSURs) required annually
Limitations include controlled populations and relatively short duration

Regulatory Review and Approval

Benefit-risk assessment based on available data
Establishment of initial product labeling
Agreement on post-approval safety commitments

Post-Marketing Surveillance (Phase IV)

Spontaneous adverse event reporting
Post-authorization safety studies (PASS)
Periodic safety update reports (PSURs/PBRERs)
Signal detection and evaluation
Regulatory actions (labeling changes, restrictions, withdrawals)

🔍 Signal Detection

Signal Definition: “Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.”

Signal Detection Methods:

Individual case review by medical professionals
Disproportionality analysis (statistical methods comparing observed vs. expected rates)
Longitudinal pattern recognition
Literature screening and evaluation
Data mining of large databases

Signal Management Process:

Signal detection

Signal validation

Signal analysis and prioritization

Signal assessment

Recommendation for action

Exchange of information

Importance: Signal detection represents the proactive element of pharmacovigilance, allowing early identification of potential safety concerns before they become widespread public health issues.

Pharmacovigilance and CDM

Curriculum

Lesson 1

Pharmacovigilance Fundamentals Cheat Sheet

Pre-clinical Testing

Clinical Development (Phases I-III)

Regulatory Review and Approval

Post-Marketing Surveillance (Phase IV)

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