PASS and Risk Management Plans
A post-authorisation safety study (PASS) is a study relating to an authorised medicinal product that is conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile, or measuring the effectiveness of risk-management measures. In an RMP, a PASS is not an ornament attached to a safety concern. It should exist because a specific uncertainty remains and a defined study can realistically reduce that uncertainty.
- PASS and Risk Management Plans
- Purpose and Regulatory Framework
- Why a PASS May Be Needed
- Relationship With RMP Safety Concerns
- From Safety Concern to Research Question
- Choosing a Study Design
- Protocol and Methodological Quality
- Imposed and Non-Imposed PASS
- Ethics, Data Protection and Scientific Independence
- Study Registration and Transparency
- Conduct, Changes and Milestones
- Role of the QPPV
- When Study Results Change the RMP
- Potential Failure Modes
- Inspection Considerations
- Practical Review Checklist
- Key Takeaways
- References
- Regulatory Note
Purpose and Regulatory Framework
The EU framework for PASS arises from Directive 2001/83/EC, Regulation (EC) No 726/2004 and Commission Implementing Regulation (EU) No 520/2012. GVP Module VIII — Post-authorisation safety studies provides detailed guidance on the design, conduct, supervision and reporting of PASS, while GVP Module V — Risk management systems explains how additional pharmacovigilance activities are incorporated into the RMP.
The legal and procedural status of a study matters. A PASS may be:
- imposed as a condition of the marketing authorisation or subsequently imposed by a competent authority under the applicable legal framework; or
- conducted voluntarily by the marketing-authorisation holder, including as an additional pharmacovigilance activity proposed in the RMP.
These categories can have different procedural requirements. The scientific principle, however, is the same: the study objective should be linked to an important question about the medicinal product's safety or the effectiveness of risk management.
Why a PASS May Be Needed
Routine pharmacovigilance is essential but has methodological limits. Spontaneous reporting is effective for detecting unusual clinical patterns but generally cannot provide a reliable denominator, is affected by under-reporting and reporting bias, and may be poorly suited to estimating incidence or comparing exposed and unexposed populations.
A PASS becomes useful when the remaining uncertainty requires a method that routine surveillance cannot adequately provide.
Examples include questions such as:
- Is a suspected association real?
- How large is an established risk?
- Which patients are most susceptible?
- Does risk vary with dose, duration or cumulative exposure?
- What is the safety profile in a clinically relevant population with limited evidence?
- Are additional risk-minimisation measures changing clinical behaviour or reducing harm?
The study should therefore be question-driven, not category-driven.
Relationship With RMP Safety Concerns
A PASS can address different types of RMP safety concern, but the objective changes according to the state of knowledge.
| Safety concern | Typical uncertainty | Possible PASS objective |
|---|---|---|
| Important identified risk | risk exists but is incompletely characterised | estimate incidence, identify risk factors, characterise severity or outcomes |
| Important potential risk | causality remains uncertain | estimate association using an appropriate comparative design |
| Missing information | safety profile in a relevant use/population is insufficiently known | collect or analyse data capable of characterising that population or situation |
The presence of a safety concern does not automatically require a PASS. GVP Module V distinguishes routine from additional pharmacovigilance activities. A PASS is justified when it contributes information that the pharmacovigilance system otherwise cannot obtain adequately.
From Safety Concern to Research Question
The most important design step occurs before the protocol is written: translating the RMP uncertainty into a researchable question.
A weak objective states: "To monitor hepatotoxicity."
A stronger objective states: "To estimate the incidence of severe drug-induced liver injury among new users of Product X and compare it with an appropriate active-comparator population, while evaluating prespecified clinical risk factors."
The second formulation identifies the outcome, population, comparison and intended decision value. It also makes it easier to determine whether the proposed data source and study design can answer the question.
Choosing a Study Design
No single PASS design is preferred in all situations. GVP Module VIII permits interventional and non-interventional approaches where appropriate, although many regulatory PASS are non-interventional pharmacoepidemiological studies.
Design selection should follow the causal and descriptive question.
| Question | Designs that may be appropriate |
|---|---|
| estimate incidence | cohort, registry, database cohort |
| compare risk between treatments | active-comparator cohort, case-control, other comparative observational design |
| evaluate an acute transient exposure-outcome relation | self-controlled or case-crossover design where assumptions are met |
| characterise rare clinical cases | structured case series or registry |
| assess pregnancy outcomes | pregnancy cohort/registry or population-data approach depending on feasibility |
| evaluate effectiveness of a risk-minimisation measure | drug-utilisation study, knowledge/behaviour study, clinical-outcome study, or mixed methods depending on objective |
Methodological sophistication is not itself a quality criterion. A simpler design that directly answers the regulatory question can be superior to a complex design with poor validity or inadequate data.
Protocol and Methodological Quality
A PASS protocol should be detailed enough to show that the proposed method can answer the research question. GVP Module VIII describes the expected content for protocols of non-interventional PASS, including title and administrative information, rationale and background, research question and objectives, study design, setting, variables, data sources, study size, data management, analysis, quality control, limitations, protection of human subjects and plans for dissemination.
These elements should not be turned into a universal corporate checklist detached from the study. Their purpose is methodological transparency.
Data-source suitability
Before selecting a database, registry or primary-data collection system, the sponsor should determine whether it can capture:
- the exposure with adequate accuracy;
- the clinical outcome or a valid proxy;
- relevant confounders and effect modifiers;
- sufficient follow-up;
- an appropriate comparator where needed; and
- a population large enough to answer the question with useful precision.
Large size does not compensate for missing variables or poor outcome validity.
Bias, confounding and misclassification
Observational PASS frequently face confounding by indication, channeling, immortal-time bias, outcome misclassification, exposure misclassification and informative loss to follow-up. The protocol should identify the important threats to validity and explain how design and analysis will address them.
Methods such as active comparators, new-user designs, matching, stratification, propensity scores, inverse-probability weighting or self-controlled designs can be useful, but none is automatically required. The appropriate approach depends on the causal structure of the study question and the available data.
Sample size and precision
A PASS should justify whether the available study population and expected event count are capable of producing a meaningful result. Depending on the objective, this may involve power calculations, confidence-interval precision, detectable relative risks or expected event accrual.
There is no universal PASS sample-size threshold. A study can be large yet uninformative if the outcome is poorly defined or confounding cannot be controlled.
Imposed and Non-Imposed PASS
The distinction between imposed and non-imposed studies affects procedure and oversight.
For certain imposed non-interventional PASS, EU legislation and GVP Module VIII establish specific requirements for submission and endorsement of protocols, substantial amendments and final study reports. The exact route depends on the legal basis under which the study was imposed and whether the authorisation concerns one Member State or more than one.
A voluntarily initiated PASS does not automatically acquire those same procedural requirements merely because it appears in an RMP. It remains subject to the applicable legal, ethical, pharmacovigilance and data-protection obligations, and any commitments agreed with regulators should be tracked accurately.
This distinction should be explicit in internal governance so that a regulatory commitment is neither under-managed nor treated as more prescriptive than it actually is.
Ethics, Data Protection and Scientific Independence
PASS may involve secondary use of routinely collected data, prospective observational data, patient contact or interventional procedures. Ethical review, informed consent and data-protection requirements therefore depend on study design, jurisdiction and data source.
GVP Module VIII also emphasises that non-interventional PASS should not promote use of a medicinal product and that remuneration should be limited to compensation for time and expenses incurred. Scientific objectives and methodological decisions should not be distorted by commercial considerations.
Study Registration and Transparency
The EU framework promotes transparency of non-interventional PASS. Studies within the scope of GVP Module VIII should be entered in the appropriate EU study register when required, and final results should be made available according to the applicable procedure.
Operational systems should therefore be able to reconcile the RMP, protocol status, study registry information, major milestones, final report and regulatory outcome.
Conduct, Changes and Milestones
Once a PASS begins, governance should focus on whether the study remains capable of answering its question.
Relevant controls include:
- protocol version control;
- documentation and assessment of important amendments;
- monitoring of recruitment, exposure or event accrual where relevant;
- data-quality controls;
- oversight of vendors and data providers;
- timely escalation of methodological or operational problems; and
- tracking of authority-agreed milestones and submission commitments.
There is no universal requirement for a particular committee, meeting frequency or QPPV signature on every protocol amendment. Governance should be proportionate to study status, regulatory importance and risk.
Role of the QPPV
The QPPV should have sufficient oversight of PASS that materially affect the pharmacovigilance system or benefit-risk profile. This includes awareness of important study objectives, significant delays or failures, major emerging results and the regulatory consequences of study conclusions.
That does not make the QPPV the principal investigator, epidemiologist or operational study manager. Good governance preserves scientific accountability while ensuring that information relevant to benefit-risk and pharmacovigilance obligations reaches the QPPV.
When Study Results Change the RMP
A PASS is valuable only if its conclusions are connected back to risk management.
Possible consequences include:
- confirming an important potential risk and reclassifying it as identified;
- reducing concern sufficiently to remove an important potential risk;
- refining incidence or risk factors for an identified risk;
- resolving or narrowing missing information;
- changing the pharmacovigilance plan;
- strengthening, modifying or removing risk-minimisation measures; or
- supporting a conclusion that no change is required.
A null or inconclusive study is not automatically a failed PASS. The key question is whether the study was methodologically capable of addressing the uncertainty and how much uncertainty remains after its completion.
Potential Failure Modes
The following are illustrative failure modes, not published inspection findings.
| Failure mode | Why it weakens the RMP | Better approach |
|---|---|---|
| Adding a PASS because a safety concern exists | Confuses risk classification with evidence needs | Define the uncertainty first and ask whether a study is necessary |
| Choosing a database before defining the research question | Encourages method-driven rather than question-driven design | Define population, exposure, outcome and comparison before selecting data |
| Treating PASS as synonymous with registry | Ignores other valid designs | Select the design according to the causal or descriptive question |
| Requiring every PASS to have the same governance structure | Creates bureaucracy without scientific value | Match governance to legal status, complexity and risk |
| Assuming statistical significance proves causality | Confuses association with causal inference | Interpret effect estimates with bias, confounding and clinical coherence |
| Treating an inconclusive result as evidence of no risk | May overstate what the study could detect | Assess study validity, precision and residual uncertainty |
| Completing the final report without updating the RMP | Disconnects evidence generation from risk management | Translate study conclusions into the safety specification and PV/RMM plans |
Inspection Considerations
A pharmacovigilance inspector may examine whether PASS are scientifically justified, procedurally compliant and effectively integrated into the pharmacovigilance system.
Relevant inspection questions can include:
- Why was the study selected for this safety concern?
- Can the protocol answer the stated RMP uncertainty?
- Are imposed-study obligations and authority commitments correctly tracked?
- Are protocol changes controlled and, where required, submitted or endorsed appropriately?
- Are outsourced study activities subject to effective MAH oversight?
- Are important delays, deviations or emerging results visible to relevant governance and the QPPV?
- Is the final study conclusion reflected in the RMP, aggregate reports and product information where appropriate?
The inspection emphasis is therefore on scientific traceability, execution, legal status and lifecycle integration.
Practical Review Checklist
This checklist is recommended operational practice, not a prescribed regulatory template.
- What exact RMP uncertainty is the PASS intended to address?
- Could routine pharmacovigilance answer the question adequately?
- Is the research question specific enough to guide design?
- Is the selected population relevant to the safety concern?
- Can exposure, outcome and key confounders be measured adequately?
- Is the comparator appropriate where causal estimation is intended?
- Are the main sources of bias anticipated and addressed?
- Is study size adequate for a meaningful conclusion?
- Is the legal status of the PASS correctly identified?
- Are authority-agreed milestones and procedural obligations tracked?
- Are governance and vendor oversight proportionate?
- Will the final result feed explicitly back into the RMP and benefit-risk evaluation?
Key Takeaways
A PASS should begin with an important unresolved safety question, not with a preferred study type. The RMP defines the uncertainty; the PASS is one possible method for reducing it.
Important identified risks, important potential risks and missing information can all be addressed by PASS, but the research objective differs according to the state of knowledge.
Imposed and voluntary PASS should not be treated as procedurally identical. The legal basis determines specific regulatory obligations, while GVP Module VIII provides the scientific and operational framework.
The quality of a PASS depends on whether its design can answer the question credibly and whether the results are translated back into risk management.
References
- European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VIII — Post-authorisation safety studies (Rev. 3). EMA/813938/2011.
- European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module V — Risk management systems (Rev. 2). EMA/838713/2011 Rev. 2.
- European Union. Directive 2001/83/EC, as amended, including provisions on imposed post-authorisation safety studies.
- European Union. Regulation (EC) No 726/2004, as amended.
- European Union. Commission Implementing Regulation (EU) No 520/2012, consolidated version current at 12 February 2026.
- European Medicines Agency. EU PAS Register / HMA-EMA Catalogue of real-world data studies and related PASS transparency information.
Regulatory Note
This article distinguishes legal requirements, GVP guidance and recommended operational practice. As of 8 September 2026, EMA continues to list GVP Module VIII Rev. 3 as the published PASS module. EMA's risk-management information day on 8 September 2026 includes updates on GVP Modules V and VIII, and future adopted revisions should be checked before relying on this article for a live regulatory procedure.