Post-Authorisation Safety Studies (PASS): Their Role in Pharmacovigilance and Risk Management

Medicines continue to be monitored for safety after receiving marketing authorisation. Although clinical trials provide essential evidence before approval, they may not fully capture rare adverse reactions, long-term effects, or risks affecting specific patient populations. Post-authorisation safety studies (PASS) help address these gaps by generating additional evidence on the safety of medicines after approval.

For marketing authorisation holders (MAHs), PASS are an important component of pharmacovigilance and risk management. They can help clarify potential safety concerns, confirm aspects of a medicine’s safety profile, and evaluate the effectiveness of risk minimisation measures. Understanding when PASS are needed, how they are conducted, and how its findings inform regulatory decisions is essential for maintaining an appropriate benefit-risk balance throughout a medicine’s lifecycle.

What Are Post-Authorisation Safety Studies (PASS)?

Definition and Key Objectives of PASS

A post-authorisation safety study is conducted after a medicine has received marketing authorisation to obtain further information on its safety or to assess the effectiveness of risk management measures.

According to the European Medicines Agency (EMA), PASS have three main objectives:

• Identify, characterise, or quantify safety hazards.
• Confirm the safety profile of a medicine.
• Measure the effectiveness of risk minimisation measures.

These studies can investigate specific safety concerns, examine risks in particular patient populations, or assess interventions designed to promote safer medicine use. PASS findings contribute to the ongoing evaluation of a medicine’s benefit-risk balance and may support regulatory decisions, including updates to product information or risk management plans (RMPs).

Not every PASS has the same purpose. Its objectives depend on the safety question being investigated and the evidence already available.

Interventional vs Non-Interventional PASS

PASS can be interventional or non-interventional, depending on the study design.

In an interventional study, the research protocol specifies an intervention. When a PASS qualifies as a clinical trial, the applicable clinical trial requirements must also be followed.

In a non-interventional PASS, treatment is prescribed according to usual clinical practice, independently of the decision to include the patient in the study. Treatment decisions are not dictated by a research protocol, and patients do not undergo additional diagnostic or monitoring procedures solely for research purposes.

Non-interventional PASS may use medical records, patient registries, healthcare databases, or other appropriate data sources to investigate safety outcomes.

The choice of design depends on the research question, available data, feasibility, and applicable regulatory requirements. The study methodology must be appropriate for the safety concern being investigated.

Why Are PASS Important in Pharmacovigilance?

Identifying and Characterising Safety Risks

Spontaneous adverse reaction reports are essential for detecting potential safety signals. However, these reports may not provide sufficient information to determine how frequently an event occurs or which patients are most susceptible. They may also offer limited insight into other factors that contribute to the observed risk.

PASS can address these questions through systematic data collection and analysis. Depending on the study design, researchers may examine patient characteristics, treatment duration, concomitant medicines, underlying diseases, and clinical outcomes.

For example, if a potential association between a medicine and a particular adverse event is identified, a PASS could investigate the event in a defined population and compare its occurrence with an appropriate reference group.

Such findings can help clarify the nature and magnitude of a potential risk. However, conclusions depend on data quality, study design, and the control of bias and confounding.

PASS therefore complements spontaneous reporting and other pharmacovigilance activities rather than replacing them.

Confirming the Safety Profile of Medicines

Evidence collected before marketing authorisation cannot always capture the full range of conditions in which a medicine will be used. Clinical trials may have limited follow-up periods, relatively small populations, or eligibility criteria that exclude certain patients.

After authorisation, medicines may be used by people with different comorbidities, varying levels of organ function, and more complex treatment regimens. PASS can help investigate safety outcomes in these populations and examine effects that may emerge during longer-term use.

Depending on the research question, studies may assess the incidence of specific adverse events or compare outcomes across treatment groups. They may also investigate associations between treatment exposure and safety outcomes.

This additional evidence can strengthen the understanding of known risks and clarify unresolved safety questions. Importantly, a PASS does not automatically confirm or exclude a causal relationship. Its results must be interpreted alongside the totality of available clinical and pharmacovigilance evidence.

The Role of PASS in Risk Management

PASS Within the Risk Management Plan (RMP)

An RMP describes a medicine’s safety concerns, the activities planned to investigate or monitor those concerns, and the measures intended to minimise risks.

PASS may form part of an RMP when additional evidence is needed to characterise an important potential or identified risk, investigate missing information, or evaluate the effectiveness of risk minimisation measures.

For MAHs, the key consideration is whether existing evidence adequately addresses the safety concern. If important uncertainties remain, a PASS may provide a structured approach to obtaining the required information.

Study objectives should align with the identified safety concern, while the protocol should specify the study design, population, data sources, outcomes, analytical methods, and milestones.

Not every medicine requires a PASS, and not every RMP includes one. The need for a study depends on the medicine’s safety profile, available evidence, and applicable regulatory requirements.

Evaluating Risk Minimisation Measures

Risk minimisation measures aim to reduce the likelihood of adverse reactions or limit their consequences. They may include routine measures, such as product information and package leaflets, or additional measures, such as educational materials and controlled access arrangements. PASS can help determine whether these measures work as intended in clinical practice.

For example, a study might assess whether healthcare professionals follow recommended monitoring procedures, whether patients receive and understand educational materials, or whether a safety intervention changes prescribing practices.

Depending on the objective, researchers may examine healthcare utilisation patterns, adherence to recommendations, or relevant clinical outcomes before and after an intervention. The findings can reveal whether a measure achieves its intended effect or requires reassessment. However, observed changes do not necessarily establish that the intervention caused them. Study design, potential confounding factors, and the suitability of the selected outcomes must all be considered.

Regulatory Requirements for PASS in the EU

Imposed vs Voluntary PASS

In the European Union, PASS may be imposed by a competent authority or initiated voluntarily by a marketing authorisation holder.

Imposed PASS are studies that MAHs are legally required to conduct. Depending on the circumstances, they may be required as a condition of marketing authorisation, as a specific obligation associated with certain authorisation pathways, or in response to a regulatory request under the applicable legal framework.

Voluntary PASS are initiated, managed, or sponsored by MAHs on their own initiative. This category may also include non-imposed studies specified in an RMP.

The distinction matters because imposed PASS are subject to specific regulatory procedures, including protocol submission, assessment, and, where applicable, final study reporting.

MAHs should identify the legal basis of each study and determine the applicable submission requirements and deadlines. A study’s inclusion in an RMP alone does not necessarily mean that it has been formally imposed by a competent authority.

PASS Protocols, Reporting, and Regulatory Oversight

For imposed non-interventional PASS in the EU, MAHs must follow applicable procedures for protocol submission, assessment, and final study reporting. The Pharmacovigilance Risk Assessment Committee (PRAC) generally assesses these studies, although certain studies may fall under the responsibility of a national competent authority.

Protocols should describe the research objectives, design, population, data sources, outcomes, analytical methods, and planned milestones. Substantial protocol amendments may also require regulatory review.

The HMA-EMA Catalogue of real-world data studies is the current platform for registering and publishing relevant study information. Registration of non-interventional PASS imposed under the applicable EU legal provisions is mandatory. Registration of other relevant non-interventional PASS is strongly encouraged.

Since January 2025, MAHs should use the EMA IRIS platform to manage PASS following the initial submission, in accordance with the Agency’s procedural guidance. IRIS and the submission gateway serve different functions and are not interchangeable.

MAHs should consult current EMA guidance and the applicable procedural timetable to confirm the requirements and deadlines for each study.

Challenges and Best Practices in PASS

Common Challenges in PASS Design and Conduct

Conducting a reliable PASS requires careful planning. One major challenge is ensuring that the study design can adequately address the research question.

Observational studies may be affected by confounding, missing data, differences between patient populations, and incomplete recording of adverse events. These limitations can complicate the interpretation of associations between medicine exposure and clinical outcomes.

Other challenges include identifying suitable data sources, obtaining sufficient sample sizes, maintaining data quality, and meeting regulatory milestones.

Studies evaluating risk minimisation measures face additional difficulties because observed changes may reflect factors unrelated to the intervention. For example, changes in prescribing practices may coincide with updated clinical guidance or other healthcare initiatives.

Recognising these limitations early helps researchers select appropriate methods and establish realistic expectations. A well-designed PASS should clearly define its objectives, acknowledge potential sources of bias, and specify how findings will be analysed and interpreted.

Best Practices for Reliable PASS Results

Reliable PASS begin with a clearly defined research question linked to a specific safety concern or risk management objective.

The protocol should justify the selected study design, define the study population and outcomes, identify appropriate data sources, and describe the analytical methods before data collection or analysis begins, as applicable.

Additional good practices include:

• Involving experienced pharmacovigilance, epidemiology, biostatistics, and clinical experts.
• Establishing clear responsibilities, timelines, and quality control procedures.
• Documenting methodological decisions and protocol amendments.
• Ensuring appropriate data governance, privacy protection, and ethical oversight.
• Reporting limitations transparently and interpreting findings in the context of other evidence.

MAHs should also maintain appropriate oversight of studies conducted by external research organisations or other third parties. Following applicable regulatory guidance, including the EMA Good Pharmacovigilance Practices (GVP) Module VIII, supports scientific quality, transparency, and compliance throughout the study lifecycle.

Conclusion

Post-authorisation safety studies are an important component of pharmacovigilance because they generate additional evidence about the safety of medicines after marketing authorisation. By investigating potential risks, confirming aspects of the safety profile, and evaluating risk minimisation measures, PASS can support informed regulatory and risk management decisions.

For MAHs, effective PASS management requires more than meeting study deadlines. It involves selecting appropriate methods, maintaining scientific quality, complying with regulatory requirements, and translating findings into meaningful pharmacovigilance actions. When conducted and interpreted appropriately, PASS helps ensure that the safety of medicine continues to be evaluated as new evidence emerges throughout the product lifecycle.

Frequently Asked Questions About PASS

Are PASS Mandatory for All Medicines?

No. PASS may be imposed by a competent authority or initiated voluntarily by an MAH. Whether a study is required depends on the medicine, the identified safety concerns, the available evidence, and the applicable regulatory framework. Some studies are imposed as conditions or specific obligations associated with marketing authorisation, while others are undertaken to address safety questions identified by the MAH.

What Is the Difference Between PASS and a Clinical Trial?

PASS is a broad category of post-authorisation safety studies that can include clinical trials and non-interventional studies. In a non-interventional PASS, treatment is prescribed according to usual clinical practice and independently of study participation. In an interventional study, the research protocol specifies an intervention. The applicable regulatory requirements depend on the study design and its legal classification.

Who Is Responsible for Conducting a PASS?

The MAH is responsible for fulfilling applicable PASS obligations and ensuring that studies under its responsibility are appropriately designed, conducted, and reported. Studies may be carried out directly by the MAH or by external research organisations on its behalf. Competent authorities oversee studies that are imposed through the relevant regulatory procedures.

Where Can PASS Protocols and Results Be Found?

The HMA-EMA Catalogue of real-world data studies provides public access to information on relevant studies, including those with imposed non-interventional PASS. Protocols and results are made available in accordance with applicable legal requirements and transparency recommendations. EMA also publishes assessments of final results for imposed non-interventional PASS through relevant regulatory channels.