Important Potential Risks

Introduction

Important Potential Risks are among the most difficult safety concerns to classify correctly within a Risk Management Plan (RMP).

Unlike Important Identified Risks, a causal relationship has not been established. Unlike Missing Information, the concern relates to a specific potential adverse outcome rather than a gap in available data.

The category exists to capture safety concerns that may represent genuine risks but for which available evidence remains insufficient to confirm a causal association.

The challenge for RMP authors is determining when available evidence justifies inclusion as an Important Potential Risk and when a concern should remain outside the Safety Specification.

This distinction is important because Important Potential Risks frequently drive additional pharmacovigilance activities, influence benefit-risk evaluation and attract regulatory scrutiny.

Regulatory Concept

An Important Potential Risk is:

A risk for which there is some basis for suspicion of an association with the medicinal product, but where the available evidence is insufficient to establish causality.

Two elements are required:

Potential Risk
        +
Important
        =
Important Potential Risk

Evidence suggesting a possible association is required.

Importance for risk management purposes is also required.

Neither criterion alone is sufficient.

The Position of Potential Risks in Risk Management

Potential risks sit between uncertainty and confirmation.

A simplified progression is:

Observation
      ↓
Signal
      ↓
Potential Risk
      ↓
Identified Risk

Not every signal becomes a potential risk.

Not every potential risk becomes an identified risk.

Many concerns are ultimately dismissed following further evaluation.

The purpose of the category is to ensure that potentially important concerns receive appropriate attention while uncertainty remains.

Sources of Potential Risks

Potential risks may originate from multiple sources.

Signal Management

The most common source.

A validated signal may suggest an association but lack sufficient evidence for confirmation.

Clinical Trials

Imbalances observed during development may indicate possible risks requiring further evaluation.

Non-Clinical Studies

Animal or laboratory findings may raise concerns requiring monitoring after authorisation.

Class Effects

Safety concerns observed with related products may indicate possible risks for a new product.

Scientific Literature

Published observations may suggest emerging concerns.

Regulatory Reviews

Health authority assessments may identify potential risks requiring ongoing monitoring.

Not Every Signal Is a Potential Risk

One of the most common RMP writing mistakes is automatic promotion of signals into the Safety Specification.

Signals represent observations requiring evaluation.

Potential risks represent safety concerns considered sufficiently plausible and important to justify ongoing risk management consideration.

Many signals are:

• Refuted
• Explained by confounding
• Explained by background incidence
• Determined to be non-causal

Such concerns should not automatically become Important Potential Risks.

Not Every Potential Risk Is Important

Potential risks must also satisfy the importance criterion.

Considerations may include:

• Seriousness
• Public health impact
• Potential effect on benefit-risk balance
• Need for additional monitoring
• Potential need for risk minimisation

A theoretical concern with minimal clinical significance may not justify inclusion.

The Safety Specification should remain focused on concerns requiring active management.

Common Examples

Examples that may become Important Potential Risks include:

• Malignancy signals
• Serious cardiovascular outcomes
• Severe hepatic injury
• Severe neurological disorders
• Class-related safety concerns
• Pregnancy-related risks

Whether inclusion is appropriate depends on available evidence and product context.

No event is automatically an Important Potential Risk.

Relationship to Important Identified Risks

Potential risks and identified risks represent different stages of evidence.

Important Potential Risk

Possible association
Evidence incomplete
Uncertainty remains

Important Identified Risk

Association established
Evidence sufficient
Risk characterised

As evidence accumulates, a potential risk may be reclassified as an identified risk.

This is a normal component of RMP lifecycle management.

Relationship to Missing Information

Potential risks are often confused with Missing Information.

The distinction is important.

Important Potential Risk

A specific adverse outcome is suspected.

Example:

Potential severe hepatotoxicity

Missing Information

The problem is insufficient knowledge regarding a population or setting.

Example:

Use during pregnancy

One describes a suspected risk.

The other describes a knowledge gap.

Additional Pharmacovigilance Activities

Important Potential Risks commonly drive additional pharmacovigilance activities.

Examples include:

• PASS studies
• Disease registries
• Pregnancy registries
• Long-term follow-up studies
• Enhanced monitoring programmes

The purpose of these activities is usually to reduce uncertainty.

A useful question is:

What evidence would be needed to determine whether this concern is a true risk?

Additional Risk Minimisation Measures

Potential risks may occasionally justify risk minimisation measures.

However, regulators generally expect proportionality.

Extensive risk minimisation activities are usually more common for identified risks than for potential risks.

The available evidence should justify any proposed intervention.

Risk Characterisation

Even where causality remains uncertain, organisations should attempt to characterise:

• Nature of the concern
• Available evidence
• Susceptible populations
• Potential severity
• Remaining uncertainties

This information supports governance and benefit-risk evaluation.

Lifecycle Management

Potential risks require periodic review.

Possible outcomes include:

Reclassification as an Important Identified Risk

Evidence becomes sufficient to establish causality.

Retention as an Important Potential Risk

Uncertainty remains.

Removal

Available evidence no longer supports concern.

A potential risk should not remain indefinitely without review.

Removal of Potential Risks

Removal is often appropriate when:

• New evidence refutes the association.
• Studies fail to support concern.
• Sufficient experience accumulates without evidence of risk.
• Regulatory agreement is obtained.

Removal should be justified scientifically.

The objective is to maintain a focused and current Safety Specification.

Common Regulatory Deficiencies

Several recurring problems are observed.

Excessive Numbers of Potential Risks

The RMP becomes a repository for every unresolved question.

Weak Scientific Justification

Concerns are included without clear supporting evidence.

Failure to Remove Obsolete Risks

Potential risks remain long after uncertainty has been resolved.

Confusion With Missing Information

Knowledge gaps are incorrectly classified as risks.

Signal Inflation

Signals are automatically converted into RMP safety concerns.

These issues frequently generate regulatory questions.

Inspection and Audit Considerations

Inspectors may review:

• Supporting evidence
• Signal-to-RMP decision-making
• Governance records
• Reclassification decisions
• Removal rationale

The ability to explain why a concern is considered both potential and important is often more important than the concern itself.

Role of the QPPV

The QPPV should understand:

• Major Important Potential Risks
• Associated uncertainties
• Planned pharmacovigilance activities
• Significant changes to the Safety Specification

Inspectors may explore how emerging safety concerns move from signal management into risk management processes.

Key Takeaways

Important Potential Risks represent safety concerns for which evidence suggests a possible association with the medicinal product but remains insufficient to establish causality.

Not every signal becomes an Important Potential Risk.

Not every potential risk is important enough to justify inclusion within the Safety Specification.

Potential risks frequently drive additional pharmacovigilance activities intended to reduce uncertainty.

Appropriate classification, periodic review and scientifically justified lifecycle management are essential for maintaining a focused and effective Risk Management Plan.

References

1. EMA Good Pharmacovigilance Practices (GVP) Module V – Risk Management Systems.
2. EMA Risk Management Plan Template.
3. Commission Implementing Regulation (EU) No 520/2012.
4. ICH E2E Pharmacovigilance Planning.
5. EMA Guidance on Safety Concerns and Risk Management Planning.