R. C.

Patel Institute of Pharmaceutical Education and Research, Shirpur

Pharmacovigilance:
Database & Signal Detection

Jinal Vaghela
Deputy Safety Lead/Manager- Pharmacovigilance
Merck Sharp & Dohme
Australia & New Zealand

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Know my Audience

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Learning objective

 Understand the pharmacovigilance database’s core functions

 Identify key features of modern PV databases
 Explain signal detection methodologies
 Analyse real-world case studies
 Discuss emerging trends in drug safety monitoring

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Introduction to Pharmacovigilance

Pharmacovigilance is the science and activities related to the detection, assessment,

understanding, and prevention of adverse effects or any other drug-related problems.

 Ensures patient safety and public health by monitoring drug safety throughout
the product lifecycle.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Module 1: Pharmacovigilance Databases

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

What are PV safety databases

 Centralized repositories for storing Individual Case Safety Reports

(ICSRs) from various global sources

 pharmacovigilance (PV) safety databases , powerful tools that

allow for the continuous monitoring and management of adverse
drug reactions. These databases help pharmaceutical companies
maintain regulatory compliance, detect risks, and ultimately
safeguard patient health.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Key stakeholders: Types of data stored:

Regulators, Adverse Event Reports (AEs)

Clinical trial data
Pharma companies
Literature reports
Healthcare providers Product quality complaints

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Key Features:

Automated Collection and Processing: Enables efficient case

management and reduces processing time.

Regulatory Compliance: It is essential for databases to remain

up to date with the latest regulatory requirements and
international standards, such as those of the International
Conference on Harmonization (ICH) and regulations from the Food
and Drug Administration (FDA), the European Medicines Agency
(EMA), and local authorities.

Signal Detection and Analysis: Ensures the identification of

potential risks associated with a drug, allowing for appropriate
decision-making and actions to protect public health.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Audience Poll

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

 Leading PV Safety Databases

Oracle Argus Safety: Industry leader, suitable for large enterprises.

Veeva Vault Safety: Cloud-based, ideal for small to mid-sized companies.

Aris Global LifeSphere Multi-Vigilance: Comprehensive features for global compliance.

Vigilazierta R3: Modular solution for scalability.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Global Pharmacovigilance Databases

Category Database Name Region/Owner Description

Largest global ADR database

Global Databases VigiBase WHO-UMC (Global) managed by Uppsala
Monitoring Centre (UMC)

European Union's
EudraVigilance EMA (Europe) pharmacovigilance database
for ADR reporting

US-based adverse event

FAERS (FDA Adverse Event
USA (FDA) reporting system for drugs
Reporting System)
and biologics

Global safety database for

WHO ADR Database WHO
monitoring ADRs

Supports global PV data

Uppsala Monitoring Centre WHO
management and analysis

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Industry-Specific Databases

Database Name Owner/Region Description

Leading drug safety software used

Argus Safety (Oracle) Industry (Pharma)
by pharmaceutical companies

Comprehensive PV database for case

ARISg (Aris Global) Industry (Pharma)
management and signal detection

Cloud-based pharmacovigilance
SafetyEasy Industry (Pharma) database for case tracking and
analysis

MedDRA (Medical Dictionary for Standardized medical terminology

ICH (Global)
Regulatory Activities) for PV databases

Cloud-based PV system for global

Veeva Vault Safety Industry (Pharma)
safety data management

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

National Databases

Database Name Country/Regulatory Authority Description

India PvPI (Pharmacovigilance India’s national PV database for ADR

India (IPC)
Programme of India) monitoring

Canada Vigilance Canada (Health Canada) Canada’s ADR reporting system

UK’s national reporting system for

Yellow Card Scheme UK (MHRA)
suspected adverse reactions

Japan JADER Japan (PMDA) Japan’s ADR reporting database

China National ADR Monitoring China’s PV system for monitoring

China (NMPA)
System drug safety

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Implementation Best Practices

 Scalability: Ensure the system can handle increased data volumes.

 Regulatory Compliance and global reach: Meet FDA, EMA, and local standards.

 Data Quality: Implement validation processes to ensure accuracy.

 Automation Capabilities: Automation reduces the risk of manual errors and accelerates case processing

 Cost and Maintenance: Total cost of ownership is another important consideration, encompassing setup,
licensing, support, and ongoing updates.

 Audit: Implement audit trails, secure access, and electronic signatures.

 Disaster Recovery Protocols: Regular data backups and a tested disaster

recovery plan to ensure 99.9% uptime.

 Continuous User Training : Provide comprehensive training on database use and

compliance, with regular refreshers.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Audience stretch / break

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Module 2: Signal Detection in Pharmacovigilance

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Introduction to Signal Detection

What is a pharmacovigilance signal?

A pharmacovigilance signal is a more or less strong hypothesis of a possible correlation between a

drug and an adverse event that emerged from the analysis of one or more sources

 Signal Detection is an analysis activity performed in pharmacovigilance for the identification of an

unexpected result with respect to the safety profile of a drug. This is a continuous monitoring
activity, which is performed throughout the life cycle of the drug, from the clinical development
phase to marketing.

 Signal Detection is the first of the Signal Management activities, a process of determining new
risks or changes to known risks. According to module IX of GVP (Good Pharmacovigilance
Practices), signal management consists of

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Signal Management Process Description

Identification of new or known risks from various data sources

Signal Detection (spontaneous reports, literature, clinical trials, etc.).

Assessment of the data to determine whether the detected signal

Signal Validation
is valid and requires further investigation.

Additional review of validated signals using more extensive

Signal Confirmation
datasets or expert evaluation to confirm relevance.

Signal Analysis and Prioritization Evaluation of the clinical impact, severity, frequency, and regulatory
importance of the confirmed signal.

Signal Assessment Comprehensive investigation of the signal, including benefit-risk

evaluation and possible regulatory action.

Decision-making on necessary risk minimization measures (e.g.,

Recommendation for Action
label updates, warnings, restricted use, or withdrawal).

Sharing of signal-related information with regulatory authorities,

Communication of Signal
healthcare professionals, and the public.

Ensuring all steps in the signal management process are

Record Keeping and Documentation
documented and maintained for future reference and audits.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Signal Detection regulations

Signal Detection in pharmacovigilance is regulated at both international and national levels:

WHO provides global guidelines and manages

VigiBase for international drug monitoring.
ICH developed global safety guidelines, while
CIOMS issued key reports on practical aspects of
Signal Detection.

FDA (USA) regulates post-marketing drug

surveillance.

EMA (Europe) oversees EudraVigilance and

EVDAS, with guidelines in GVP Module IX.
AIFA (Italy) enforces pharmacovigilance through
the National Pharmacovigilance Plan and EU
regulations.

These systems ensure early detection and management of drug safety risks worldwide.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Audience quiz

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

In India, Signal Detection in pharmacovigilance is regulated by the Pharmacovigilance Programme of
India (PvPI) under the Indian Pharmacopoeia Commission (IPC) and the Central Drugs Standard Control
Organization (CDSCO).

Key regulatory aspects include:

 PvPI monitors adverse drug reactions (ADRs) and maintains the India Adverse Drug Reaction
Monitoring Database.
 CDSCO oversees post-marketing surveillance and enforces pharmacovigilance guidelines for
pharmaceutical companies.
 PvPI collaborates with WHO and contributes data to VigiBase for global drug safety monitoring.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Importance of Signal Management in Pharmacovigilance

 Critical for Updating Drug Safety Profiles: Helps identify new risks or changes in known risks,
ensuring timely updates to product labeling, risk minimization measures, and regulatory actions.

 Enhances Patient Safety: By detecting and mitigating potential adverse drug reactions (ADRs), it
reduces harm to patients and improves overall drug safety.

 Regulatory Compliance: This function ensures adherence to Good Pharmacovigilance Practices

(GVP) and helps pharmaceutical companies meet regulatory requirements.

 Improves Benefit-Risk Assessment: Facilitates informed decision-making by continuously evaluating

the benefits and risks of medicinal products.

 Supports Transparent Communication: Ensures that healthcare professionals, regulatory

authorities, and the public receive timely safety information about drugs.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

The sources of pharmacovigilance signals

 Clinical studies. The data is characterized by low number and high reliability.

 Scientific literature (case reports and systematic reviews). Like clinical studies, they are characterized
by low numbers and high reliability. Also, often only new and egregious cases are published, so they are
limited.

 Spontaneous reports. They have a high number and fairly good reliability. However, they may be
subject to underreporting or duplication.

 Cases from healthcare databases. Common databases are large and highly reliable.

 Other sources (market research, analysis of drug consumption, and social media).

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Signal detection Methods

 Qualitative Methods
✔ Expert Review – Manual assessment of case reports, literature, and clinical data.
✔ Case-by-Case Analysis – Individual Case Safety Reports (ICSRs) evaluation.

 Quantitative Methods (Statistical & Data Mining Techniques)

✔ Proportional Reporting Ratio (PRR) – Compares ADR frequency for a drug vs. all drugs.
✔ Reporting Odds Ratio (ROR) – Measures the likelihood of ADR occurrence with a drug.
✔ Bayesian Confidence Propagation Neural Network (BCPNN) – Uses Bayesian statistics to identify ADR
patterns.
✔ Multi-item Gamma Poisson Shrinker (MGPS) – Detects rare ADR signals using data mining.
✔ Empirical Bayes Geometric Mean (EBGM) – Adjusts disproportionality for small sample sizes.

 Hybrid Approach

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Approach Description Examples
Expert case review, literature Manual assessment of Individual
Qualitative Analysis evaluation, and clinical Case Safety Reports (ICSRs),
assessment. medical literature review.
Statistical disproportionality
Quantitative Analysis methods to detect unexpected PRR, ROR, BCPNN, MGPS, EBGM.
patterns.
Integrates expert assessment AI-assisted signal detection,
Hybrid Approach with statistical techniques to automated flagging combined
validate signals. with human review.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Method Description Commonly Used In

Qualitative Methods Manual review of individual case safety reports Case-by-case analysis, spontaneous reporting
(ICSRs), literature, and expert judgment. systems (e.g., FAERS, EudraVigilance).

Disproportionality Analysis Statistical methods to compare observed vs. Large-scale spontaneous reporting databases (e.g.,
expected ADR frequencies in databases. VigiBase, FAERS).

Proportional Reporting Ratio (PRR) Measures if an ADR is reported more frequently Used by regulatory agencies (e.g., MHRA, EMA).
for a drug compared to all other drugs.

Reporting Odds Ratio (ROR) Compares the odds of reporting an ADR for a Common in European pharmacovigilance
particular drug versus other drugs. (EudraVigilance, WHO-UMC).

Bayesian Confidence Propagation Neural Uses Bayesian statistics to assess ADR signals and WHO’s VigiBase and some AI-driven PV systems.
Network (BCPNN) associations.

Multi-item Gamma Poisson Shrinker (MGPS) Detects rare or emerging ADRs using a data mining FDA’s FAERS and large pharma company
algorithm. databases.

Time-to-Onset Analysis Analyzes the time between drug exposure and Clinical trials, post-marketing studies.
ADR occurrence.

Machine Learning & AI Models Uses AI algorithms to detect complex patterns in Big data pharmacovigilance, automated ADR
real-world data. detection.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Quiz

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Why Use a Hybrid Approach?

 Ensures both statistical significance and clinical relevance.

 Balances automation with human expertise for better decision-making.

 Combining Quantitative and Qualitative Methods: Enhances detection accuracy

and reduces false positives.

 Role of AI and Machine Learning: Automating data analysis for faster signal
identification

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

 Case Studies in Signal Detection

Example : Detection of Liver Toxicity Using Veeva Vault Safety

• Context: A pharmaceutical company noticed an increase in liver-related adverse events following the
use of a newly marketed drug.

• Signal Detection:
• Veeva Vault Safety (cloud-based PV system) was used to analyze Individual Case Safety
Reports (ICSRs).
• The system applied disproportionality analysis and flagged an unexpected frequency of liver
toxicity in the database.

• Outcome:
• The signal was validated and confirmed through further analysis.
• Regulatory authorities were notified, and additional safety warnings were added to the
product label, including monitoring for liver function during treatment.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Real scenario

Detection of Liver Toxicity with Rosiglitazone (Avandia)

• Context: Rosiglitazone (Avandia), a drug used to treat type 2 diabetes, was suspected of causing liver
toxicity after being marketed.

• Signal Detection:
• FDA Adverse Event Reporting System (FAERS) data was analyzed for reports of liver-related
adverse events.
• The Proportional Reporting Ratio (PRR) identified a disproportionality in the reporting of liver
toxicity in patients taking rosiglitazone compared to other antidiabetic drugs.

• Outcome:
• The signal led to further investigation, and although no definitive causal link was confirmed,
black box warnings and liver monitoring guidelines were added to the drug’s labeling.
• In 2010, the FDA restricted its use due to safety concerns, including liver toxicity.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

AI, Big Data, and Future Directions in Pharmacovigilance

• Machine Learning & Automation in ADR Detection

• Use of AI to automate ADR detection by identifying patterns in large data sets.
• Machine learning algorithms improve the accuracy and speed of signal detection, reducing
manual review.

• Integration of Real-World Evidence (RWE)

• Integration of data from EHRs, insurance claims, and patient registries to provide a
comprehensive view of drug safety.
• Helps assess safety in diverse populations beyond clinical trials, improving post-marketing
surveillance.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Challenges and Future Directions

Addressing Challenges & Future Trends in Pharmacovigilance

Challenges in Signal Detection

 Data Quality: Improve data standardization and advanced data cleaning techniques for more accurate
ADR reports.
 False Positives/Negatives: Combine manual review with AI algorithms and use advanced statistical
methods to reduce biases in detection.

Future Trends in Pharmacovigilance Technology

 AI & Deep Learning: Use large datasets for training AI, with continuous learning to detect emerging
ADRs accurately.
 Blockchain: Ensure data transparency and integrity using decentralized, immutable records.
 Real-Time Monitoring: Integrate wearables, mobile apps, and telemedicine for continuous ADR data
collection and faster detection.

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

Key take aways , Poll

CERTIFICATE COURSE IN CLINICAL RESEARCH AND PHARMACOVIGILANCE

THANKYOU!!!