QPPV.COM

PASS and Risk Management Plans

A practical guide to the role of PASS studies in Risk Management Plans, including study selection, regulatory expectations, governance and lifecycle management.

PASS and Risk Management Plans

Introduction

Post-Authorisation Safety Studies (PASS) are among the most important Additional Pharmacovigilance Activities used within modern Risk Management Plans (RMPs). They are designed to generate information that cannot be obtained adequately through routine pharmacovigilance activities alone.

PASS studies are frequently used to investigate Important Identified Risks, Important Potential Risks and Missing Information. They may help quantify risks, characterise risk factors, evaluate long-term outcomes or assess safety in specific populations.

Within an RMP, a PASS should never exist without a clear scientific purpose. The study should address a defined uncertainty and contribute directly to risk management objectives.

What Is a PASS?

A PASS is a study conducted after marketing authorisation with the objective of obtaining additional information about the safety of a medicinal product.

The purpose may include:

PASS studies may be imposed by regulators or proposed voluntarily by the Marketing Authorisation Holder.

Why PASS Studies Are Included in RMPs

Routine pharmacovigilance activities provide valuable information but have limitations.

Examples include:

PASS studies are used when additional evidence is needed to address an important uncertainty.

A useful principle is:

A PASS should answer a question that routine pharmacovigilance cannot answer adequately.

Relationship Between Safety Concerns and PASS

PASS studies should be linked directly to safety concerns.

Examples include:

Important Identified Risks

To better characterise frequency, severity or risk factors.

Important Potential Risks

To determine whether a suspected association is genuine.

Missing Information

To generate data in populations where knowledge is limited.

The connection between the safety concern and the study objective should be explicit.

PASS and Important Identified Risks

A PASS may be used to investigate:

Example:

Important Identified Risk:
Serious hepatotoxicity

PASS Objective:
Characterise incidence and predictors of severe liver injury.

The objective is not necessarily to prove the risk exists but to understand it more completely.

PASS and Important Potential Risks

Potential risks are among the most common reasons for PASS studies.

Example:

Important Potential Risk:
Major cardiovascular events

PASS Objective:
Determine whether use of the product is associated with increased cardiovascular risk.

The study may ultimately:

All three outcomes are valuable.

PASS and Missing Information

PASS studies frequently address Missing Information.

Examples include:

The objective is to reduce uncertainty regarding safety in these populations.

PASS Study Designs

Several study designs may be used.

Cohort Studies

Useful for estimating incidence and comparing outcomes.

Case-Control Studies

Useful when outcomes are rare.

Registry Studies

Useful for long-term follow-up and specialised populations.

Database Studies

Useful when large populations are required.

Hybrid Designs

Some studies combine multiple approaches.

The selected design should match the scientific question.

Imposed Versus Voluntary PASS

PASS studies may be:

Imposed

Required by a regulatory authority.

Voluntary

Proposed by the Marketing Authorisation Holder.

Imposed studies usually become regulatory commitments and require formal tracking.

PASS Protocols

Protocols should define:

The protocol should clearly demonstrate how the study addresses the relevant safety concern.

PASS Milestones in RMPs

RMPs frequently include:

These milestones allow regulators to monitor progress.

Governance processes should ensure milestone compliance.

PASS and Benefit-Risk Evaluation

PASS findings may influence benefit-risk evaluation.

Potential outcomes include:

Consequently, PASS results often have implications extending beyond the RMP itself.

PASS and Signal Management

Signal management and PASS activities are closely linked.

Signals may trigger PASS studies.

PASS findings may generate new signals.

PASS findings may also resolve signal-related uncertainties.

These interactions should be reflected within governance processes.

PASS and Product Information

PASS results may support changes to:

The impact depends on study findings and regulatory assessment.

PASS Lifecycle Management

PASS studies should be reviewed throughout their lifecycle.

Possible outcomes include:

Ongoing

Objectives not yet achieved.

Completed

Objectives achieved and study finalised.

Modified

Design adjusted to address emerging issues.

Terminated

Scientific or operational justification for continuation no longer exists.

Lifecycle management should be documented clearly.

PASS Results and RMP Updates

PASS findings often trigger RMP revisions.

Examples include:

A completed PASS should generally result in evaluation of RMP impact.

Regulatory Commitment Tracking

Where PASS studies are commitments, organisations should track:

Regulatory commitment tracking is frequently reviewed during inspections.

Common Regulatory Deficiencies

Several recurring problems occur.

Weak Scientific Rationale

The study objective is unclear.

Poor Linkage to Safety Concerns

The study does not address the stated uncertainty.

Inappropriate Study Design

Methodology does not answer the scientific question.

Delayed Milestones

Commitments are not met.

Failure to Use Results

Findings do not influence risk management decisions.

These deficiencies often generate regulatory questions.

Inspection and Audit Considerations

Inspectors may review:

The focus is often on whether the study contributes meaningfully to risk management.

Role of the QPPV

The QPPV should understand:

Inspectors frequently assess QPPV awareness of important post-authorisation safety activities.

Characteristics of Effective PASS Programmes

Effective PASS programmes generally demonstrate:

The objective is to generate information that improves understanding of product safety and supports informed benefit-risk evaluation.

Key Takeaways

PASS studies are important Additional Pharmacovigilance Activities used to investigate Important Identified Risks, Important Potential Risks and Missing Information.

They should address specific uncertainties that cannot be resolved adequately through routine pharmacovigilance activities.

PASS findings may influence safety concerns, product information, risk minimisation measures and benefit-risk evaluation.

Strong governance, milestone tracking and integration with the RMP are essential throughout the study lifecycle.

References

  1. EMA Good Pharmacovigilance Practices (GVP) Module VIII – Post-Authorisation Safety Studies.
  2. EMA Good Pharmacovigilance Practices (GVP) Module V – Risk Management Systems.
  3. Commission Implementing Regulation (EU) No 520/2012.
  4. ENCePP Guide on Methodological Standards in Pharmacoepidemiology.
  5. ICH E2E Pharmacovigilance Planning.
  6. EMA Risk Management Plan Template.

Related Articles

Additional Pharmacovigilance Activities

A practical guide to Additional Pharmacovigilance Activities, including PASS studies, registries, enhanced monitoring and regulatory expectations.

Risk Minimisation Effectiveness Evaluation

A practical guide to evaluating whether risk minimisation measures achieve their intended objectives and improve safe use of medicinal products.

Additional Risk Minimisation Measures

A practical guide to Additional Risk Minimisation Measures, including educational materials, pregnancy prevention programmes, controlled access systems and effectiveness evaluation.

Last reviewed: 2026-06-11