Additional Pharmacovigilance Activities

Introduction

The purpose of a Risk Management Plan is not merely to identify safety concerns. The purpose is to ensure that important risks and uncertainties are managed appropriately throughout the product lifecycle.

Routine pharmacovigilance activities provide the foundation of safety monitoring for all medicinal products. However, routine activities may not always be sufficient to address important uncertainties.

Additional Pharmacovigilance Activities are implemented when further information is required to better characterise a safety concern, reduce uncertainty or support ongoing benefit-risk evaluation.

These activities are among the most scrutinised sections of modern Risk Management Plans because they represent specific commitments undertaken by the Marketing Authorisation Holder to generate additional safety information.

Routine Versus Additional Pharmacovigilance

Understanding the distinction is critical.

Routine Pharmacovigilance

Examples include:

• ICSR collection
• Signal management
• Literature surveillance
• PSUR preparation
• Aggregate safety review

These activities apply to most products and generally do not require specific justification within the RMP.

Additional Pharmacovigilance

Additional activities are implemented because routine activities alone are insufficient.

The activity should address a defined uncertainty or safety concern.

A useful principle is:

Additional activities should answer a specific question.

Why Additional Activities Are Needed

Important uncertainties frequently remain after authorisation.

Examples include:

• Limited pregnancy exposure data
• Uncertain long-term safety
• Rare but serious adverse events
• Limited information in special populations
• Emerging safety concerns

Routine pharmacovigilance may identify problems but may not generate sufficient evidence to resolve them.

Additional activities are intended to close these knowledge gaps.

Regulatory Basis

Within the European Union, Additional Pharmacovigilance Activities are described within the RMP as part of the Pharmacovigilance Plan.

Activities should be linked directly to:

• Important Identified Risks
• Important Potential Risks
• Missing Information

Activities without a clearly defined purpose are difficult to justify.

Fundamental Principle

Every additional activity should be traceable to a safety concern.

The logic should be clear:

Safety Concern
        ↓
Knowledge Gap
        ↓
Additional Activity
        ↓
Expected Outcome

If this chain cannot be explained, regulators may question the necessity of the activity.

Common Objectives

Additional Pharmacovigilance Activities are generally designed to:

• Characterise risks
• Quantify risks
• Identify risk factors
• Evaluate outcomes
• Reduce uncertainty
• Support benefit-risk evaluation

The objective should be defined clearly before the activity begins.

Post-Authorisation Safety Studies (PASS)

PASS studies are among the most common Additional Pharmacovigilance Activities.

PASS may be conducted to:

• Investigate identified risks
• Evaluate potential risks
• Address Missing Information
• Characterise risk factors
• Estimate incidence

PASS studies may be:

• Interventional
• Non-interventional
• Registry-based
• Database studies

The design should match the scientific question being addressed.

Registries

Registries are often used when long-term observation or specialised populations are important.

Examples include:

• Disease registries
• Product registries
• Exposure registries
• Pregnancy registries

Registries can provide valuable information regarding:

• Real-world use
• Long-term outcomes
• Rare events
• Special populations

However, they require substantial resources and long-term governance.

Pregnancy Registries

Pregnancy exposure is a common area of Missing Information.

Pregnancy registries may be established to evaluate:

• Maternal outcomes
• Fetal outcomes
• Congenital anomalies
• Pregnancy complications

Such registries often require many years to generate meaningful data.

Drug Utilisation Studies

Drug Utilisation Studies examine how products are used in clinical practice.

These studies may evaluate:

• Off-label use
• Prescribing patterns
• Compliance with risk minimisation measures
• Use in specific populations

They are particularly useful when understanding exposure is important for risk evaluation.

Enhanced Follow-Up Activities

Enhanced follow-up may be implemented for specific adverse events.

Examples include:

• Targeted questionnaires
• Additional case information collection
• Structured follow-up programmes

These activities may improve understanding of:

• Event characteristics
• Risk factors
• Clinical outcomes

Enhanced follow-up is generally narrower in scope than formal studies.

Observational Studies

Observational studies may be used to evaluate:

• Incidence
• Comparative safety
• Long-term outcomes
• Risk factors

Because they reflect real-world practice, observational studies can complement information obtained from clinical trials.

Selecting the Appropriate Activity

The choice of activity should be driven by the question being asked.

Examples:

Unknown Pregnancy Outcomes

Possible activity:

Pregnancy Registry

Possible Long-Term Toxicity

Possible activity:

Long-Term Follow-Up Study

Suspected Class Effect

Possible activity:

Observational PASS

Uncertain Product Utilisation

Possible activity:

Drug Utilisation Study

The activity should fit the uncertainty.

Activities and Important Identified Risks

Not every Important Identified Risk requires additional activities.

Well-characterised risks may be managed adequately through:

• Routine pharmacovigilance
• Routine risk minimisation measures

Additional activities are generally justified only when important uncertainties remain.

Activities and Important Potential Risks

Potential risks commonly drive additional pharmacovigilance.

The objective is often to determine whether:

Potential Risk
        ↓
Identified Risk

or

Potential Risk
        ↓
Concern Refuted

Additional evidence supports this decision-making process.

Activities and Missing Information

Missing Information is frequently the strongest justification for additional pharmacovigilance.

Examples include:

• Pregnancy exposure
• Long-term safety
• Use in severe organ impairment
• Use in paediatric populations

Activities are designed to reduce uncertainty in these areas.

Lifecycle Management

Additional activities should not continue indefinitely.

They should be reviewed periodically.

Possible outcomes include:

Completion

Objectives achieved.

Modification

Objectives refined.

Replacement

Alternative approach required.

Discontinuation

Further activity no longer justified.

Lifecycle management is an important aspect of RMP governance.

Regulatory Commitments

Some Additional Pharmacovigilance Activities become formal regulatory commitments.

Examples include:

• Imposed PASS
• Agreed study obligations
• Specific authority requests

Such commitments require careful tracking and governance.

Failure to complete commitments may have significant regulatory consequences.

Common Regulatory Deficiencies

Several recurring issues occur.

Activity Without a Clear Question

The purpose of the activity is poorly defined.

Weak Linkage to Safety Concerns

Activities are not clearly connected to identified uncertainties.

Excessive Activities

Studies continue despite limited scientific justification.

Poor Lifecycle Management

Completed activities remain in the RMP indefinitely.

Failure to Use Results

Study findings do not influence risk management decisions.

These deficiencies frequently generate regulatory questions.

Inspection and Audit Considerations

Inspectors may review:

• Scientific rationale
• Study objectives
• Governance processes
• Progress tracking
• Commitment management
• Impact on risk management decisions

The key question is often:

How does this activity contribute to understanding or managing product risks?

Role of the QPPV

The QPPV should understand:

• Major Additional Pharmacovigilance Activities
• Key study objectives
• Regulatory commitments
• Significant study outcomes
• Impact on product risk management

Inspectors frequently explore how important study findings are incorporated into ongoing pharmacovigilance activities.

Characteristics of Well-Designed Activities

Well-designed Additional Pharmacovigilance Activities generally demonstrate:

• Clear objectives
• Direct linkage to safety concerns
• Appropriate methodology
• Defined success criteria
• Effective governance
• Lifecycle management

The objective is not to conduct studies for their own sake.

The objective is to generate information that improves understanding of product safety.

Key Takeaways

Additional Pharmacovigilance Activities are implemented when routine pharmacovigilance is insufficient to address important uncertainties.

Activities should be linked directly to Important Identified Risks, Important Potential Risks or Missing Information.

PASS studies, registries, pregnancy registries and Drug Utilisation Studies are common examples.

Each activity should address a specific scientific question and contribute meaningfully to risk management.

Effective governance and lifecycle management are essential throughout the duration of the activity.

References

1. EMA Good Pharmacovigilance Practices (GVP) Module V – Risk Management Systems.
2. EMA Good Pharmacovigilance Practices (GVP) Module VIII – Post-Authorisation Safety Studies.
3. EMA Risk Management Plan Template.
4. Commission Implementing Regulation (EU) No 520/2012.
5. ICH E2E Pharmacovigilance Planning.
6. CIOMS IX Practical Approaches to Risk Minimisation.