Missing Information

Introduction

Missing Information is one of the three categories of safety concerns used within the Safety Specification of a Risk Management Plan (RMP).

Unlike Important Identified Risks and Important Potential Risks, Missing Information does not describe a specific adverse event or safety outcome. Instead, it describes an important gap in knowledge that may affect understanding of the product's safety profile or benefit-risk balance.

Historically, RMPs often contained extensive lists of populations with limited clinical experience. Modern regulatory practice has moved toward a more focused approach. The existence of limited data alone is not sufficient to justify inclusion as Missing Information.

The critical question is whether the lack of information creates uncertainty that is important for risk management purposes.

Regulatory Concept

Missing Information refers to:

Gaps in knowledge concerning the safety of a medicinal product for particular patient populations, clinical situations or treatment conditions that are relevant to the product's safety profile or benefit-risk evaluation.

Two components are required:

Knowledge Gap
        +
Risk Management Importance
        =
Missing Information

Both elements are necessary.

A simple absence of data is not enough.

Why Missing Information Exists

At the time of authorisation, medicinal products are rarely studied under every possible condition of use.

Clinical development programmes have practical limitations.

Common limitations include:

• Restricted study populations
• Limited treatment duration
• Exclusion criteria
• Limited sample sizes
• Limited special population exposure

As a result, uncertainties often remain.

The purpose of the Missing Information category is to identify uncertainties that may require additional monitoring or further investigation.

Missing Information Versus Lack of Data

One of the most important principles in RMP writing is:

Not all missing data represents Missing Information.

For example:

No clinical trial participants older than 92 years

This may represent limited data.

However, it does not automatically represent Missing Information.

A knowledge gap should only be included if resolving it is important for understanding product safety or benefit-risk.

Why Modern RMPs Contain Fewer Missing Information Categories

Earlier RMPs often included extensive lists such as:

• Elderly patients
• Adolescents
• Renal impairment
• Hepatic impairment
• Pregnancy
• Lactation

sometimes regardless of actual clinical relevance.

Regulatory expectations have evolved.

Current practice generally focuses on:

• Clinically meaningful uncertainties
• Safety-relevant knowledge gaps
• Areas requiring active management

The emphasis is on relevance rather than completeness.

Common Categories of Missing Information

Examples may include:

Pregnancy Exposure

Limited information regarding safety during pregnancy.

Breastfeeding

Limited information regarding exposure during lactation.

Long-Term Use

Insufficient information regarding prolonged treatment.

Severe Organ Impairment

Limited experience in patients with severe hepatic or renal dysfunction.

Paediatric Populations

Limited information in children when use is expected or foreseeable.

Rare Patient Populations

Limited information in clinically important subgroups.

Whether these categories qualify depends on product-specific circumstances.

Relationship to Important Potential Risks

Missing Information is often confused with Important Potential Risks.

The distinction is fundamental.

Important Potential Risk

A specific adverse outcome is suspected.

Example:

Potential severe hepatotoxicity

Missing Information

The uncertainty relates to insufficient knowledge.

Example:

Limited safety data in severe hepatic impairment

One describes a possible risk.

The other describes a knowledge gap.

Relationship to Important Identified Risks

Identified risks involve established associations.

Missing Information involves uncertainty.

For example:

Identified Risk:
Anaphylaxis

Missing Information:
Use in patients with severe allergic disease

These concepts may coexist but they address different questions.

How Missing Information Is Identified

Potential sources include:

Clinical Development Programmes

Underrepresented populations.

Regulatory Reviews

Questions raised during assessment.

Signal Management Activities

Identification of knowledge gaps requiring further evaluation.

Scientific Literature

Recognition of areas where evidence remains limited.

Expert Review

Clinical assessment of remaining uncertainties.

Identification should be systematic and evidence-based.

Does Missing Information Require Action?

Not always.

However, Missing Information frequently influences:

• Routine pharmacovigilance
• Additional pharmacovigilance activities
• PASS studies
• Registries
• Long-term follow-up programmes

The objective is often to reduce uncertainty over time.

Additional Pharmacovigilance Activities

Missing Information is a common justification for:

PASS Studies

To obtain additional safety data.

Pregnancy Registries

To evaluate maternal and fetal outcomes.

Disease Registries

To collect information in specific populations.

Long-Term Follow-Up

To assess extended exposure.

The selected activity should address the specific knowledge gap identified.

Additional Risk Minimisation Measures

Missing Information does not automatically justify additional risk minimisation measures.

In many cases, routine measures are sufficient.

Additional interventions may be appropriate when uncertainty itself creates significant clinical concern.

The decision should be proportionate and scientifically justified.

Relationship to Benefit-Risk Evaluation

Missing Information may influence benefit-risk assessment.

Examples include:

• Unknown long-term toxicity
• Limited pregnancy experience
• Limited use in vulnerable populations

The significance depends upon:

• Expected product utilisation
• Severity of the condition treated
• Availability of alternatives
• Magnitude of uncertainty

Not all knowledge gaps have equal importance.

Lifecycle Management

Missing Information should be reviewed regularly.

Possible outcomes include:

Resolution

Additional data become available.

Retention

Uncertainty remains relevant.

Reclassification

Information suggests a potential or identified risk.

Lifecycle management is an essential component of RMP maintenance.

Removal of Missing Information

Removal is often appropriate when:

• Sufficient data have been generated.
• Relevant studies have been completed.
• Clinical experience has expanded substantially.
• Regulatory agreement has been obtained.

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

Historical uncertainties should not remain indefinitely.

Common Regulatory Deficiencies

Several recurring issues occur.

Excessive Missing Information Categories

Every data limitation becomes a safety concern.

Lack of Clinical Relevance

Knowledge gaps are included without demonstrating importance.

Duplication of Potential Risks

Potential risks are incorrectly classified as Missing Information.

Failure to Remove Resolved Issues

Categories remain despite substantial accumulated evidence.

Weak Justification

Insufficient explanation of why the uncertainty matters.

These deficiencies frequently generate regulatory comments.

Inspection and Audit Considerations

Inspectors may review:

• Justification for inclusion
• Linkage to pharmacovigilance activities
• Lifecycle management decisions
• Removal rationale
• Governance processes

The emphasis is often on scientific justification rather than the number of categories included.

Role of the QPPV

The QPPV should understand:

• Major areas of Missing Information
• Activities intended to reduce uncertainty
• Significant updates to the Safety Specification
• Implications for benefit-risk evaluation

Inspectors may explore how important knowledge gaps are monitored and managed within the pharmacovigilance system.

Characteristics of Well-Justified Missing Information

Well-justified Missing Information generally demonstrates:

• A genuine knowledge gap
• Clinical relevance
• Importance for safety evaluation
• Potential impact on benefit-risk assessment
• Appropriate linkage to pharmacovigilance activities

The objective is not to document every limitation in available data.

The objective is to identify uncertainties that require ongoing consideration within the risk management strategy.

Key Takeaways

Missing Information describes important gaps in knowledge relevant to product safety or benefit-risk evaluation.

Limited data alone is insufficient to justify inclusion.

The uncertainty must be important for risk management purposes.

Missing Information differs from both Important Identified Risks and Important Potential Risks because it describes a knowledge gap rather than a specific adverse outcome.

Appropriate classification and lifecycle management help maintain a focused and scientifically justified 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.
6. EMA Guideline on Good Pharmacovigilance Practices.