Marketing authorization marks a critical regulatory milestone, but it does not conclude the safety evaluation of a medicinal product. Real-world use often reveals safety information that controlled clinical trials cannot fully capture. Regulatory authorities therefore rely on Post-Authorization Safety Studies (PASS) as a core pharmacovigilance instrument to assess risks that emerge or evolve after approval.
PASS requirements now form an integral part of lifecycle safety management across major regulatory regions. Authorities expect sponsors to treat these studies as structured, auditable commitments rather than post-approval formalities. This article outlines the regulatory framework governing PASS, clarifies when such studies become mandatory, and explains how sponsors can maintain compliance across jurisdictions.
What Are Post-Authorization Safety Studies (PASS)?
A Post-Authorization Safety Study is a pharmacoepidemiological or clinical investigation conducted after a medicinal product receives marketing authorization. The primary objective is to characterize, quantify, or confirm a safety concern in routine clinical practice.
Regulators may request PASS to:
- Evaluate identified or potential risks
- Assess the effectiveness of risk minimization measures
- Study long-term safety outcomes
- Investigate safety in specific populations under-represented in pre-approval trials
PASS may use interventional or non-interventional designs, depending on the research question and regulatory mandate.
Regulatory Basis for PASS Across Key Jurisdictions
European Union (EU)
The EU has established the most structured PASS framework under Regulation (EC) No 726/2004 and Directive 2001/83/EC, reinforced by Good Pharmacovigilance Practices (GVP) Module VIII.
PASS becomes mandatory when:
- The European Medicines Agency (EMA) or a national competent authority imposes a specific obligation as a condition of marketing authorization
- A safety concern requires further evaluation post-approval
Key regulatory expectations include:
- Submission of the PASS protocol to the Pharmacovigilance Risk Assessment Committee (PRAC)
- Registration of the study in the EU PAS Register
- Defined timelines for protocol approval, progress reports, and final study results
- Public disclosure of study outcomes
Non-compliance can lead to regulatory action, including variation requests, penalties, or authorization suspension.
United States (FDA)
In the United States, PASS obligations arise under the FDA Amendments Act (FDAAA) and fall within the Risk Evaluation and Mitigation Strategy (REMS) framework.
The FDA may require postmarketing safety studies to:
- Assess known serious risks
- Evaluate signals detected through spontaneous reporting
- Confirm safety in broader or vulnerable populations
Sponsors must:
- Submit study protocols for FDA review
- Provide periodic status reports
- Adhere to agreed milestones
Failure to meet postmarketing requirements may result in warning letters, civil penalties, or product withdrawal.
United Kingdom (MHRA)
Following Brexit, the UK Medicines and Healthcare products Regulatory Agency (MHRA) maintains PASS requirements aligned with EU principles, though oversight now occurs at a national level.
The MHRA may impose PASS:
- As a condition of UK marketing authorization
- In response to emerging safety concerns within the UK population
Sponsors must notify the MHRA, submit protocols where required, and provide final study outcomes within agreed timelines.
Other Regulatory Markets
Many global regulators, including Health Canada, TGA Australia, PMDA Japan, and several Middle East and Latin American authorities, now integrate PASS or equivalent post-marketing safety studies into approval conditions.
Although terminology and procedural details vary, common expectations include:
- Clear safety objectives
- Regulatory oversight of study design
- Submission of interim and final reports
- Alignment with international pharmacovigilance standards
Types of Post-Authorization Safety Studies (PASS)
PASS has been classified into four types based on study design and legal obligation.
- Non-Interventional PASS
These studies observe routine clinical practice without influencing treatment decisions. Examples include cohort studies, registries, and database analyses. - Interventional PASS
These studies involve protocol-driven interventions and follow clinical trial standards. Authorities request them when observational data cannot address the safety question. - Mandatory PASS
These arise from a formal regulatory obligation and carry enforceable timelines and reporting requirements. - Voluntary PASS
Sponsors initiate these studies proactively to strengthen the safety profile or support regulatory dialogue.
PASS and Risk Management Plans (RMPs)
PASS plays a central role within the Risk Management Plan lifecycle. Regulators often link PASS obligations directly to:
- Safety concerns listed in the RMP
- Additional pharmacovigilance activities
- Evaluation of risk minimization effectiveness
Any modification to a PASS protocol may require prior regulatory approval, particularly when the study supports a legally binding obligation.
Data Transparency and Reporting Obligations
Authorities increasingly emphasize transparency in PASS execution and reporting.
Regulatory expectations include:
- Public registration of mandatory PASS
- Timely submission of progress reports
- Submission of final study reports with scientific conclusions
- Reflection of results in product labeling, when applicable
Incomplete reporting or delayed submission may raise inspection findings during pharmacovigilance audits.
Compliance Challenges in PASS Execution
Sponsors often face operational and regulatory challenges, such as:
- Multi-country protocol alignment
- Data quality management in real-world settings
- Coordination between safety, clinical, and regulatory teams
- Inspection readiness across regions
Regulators now assess not only study outcomes but also governance, documentation quality, and adherence to approved protocols.
Strategic Approach to PASS Compliance
An effective PASS strategy requires:
- Early regulatory engagement during protocol development
- Clear governance and oversight mechanisms
- Robust data management and quality controls
- Integration of PASS outcomes into ongoing benefit-risk evaluation
Organizations that treat PASS as a strategic safety activity achieve smoother regulatory interactions and stronger inspection outcomes.
Conclusion
Post-Authorization Safety Studies have evolved into a cornerstone of modern pharmacovigilance services. Regulatory authorities expect scientifically sound study designs, disciplined execution, and transparent reporting. PASS obligations now influence approval sustainability as much as pre-authorization evidence.
Sponsors that invest in compliant, well-governed PASS programs protect both patient safety and long-term product viability in an increasingly vigilant regulatory environment.
Frequently Asked Questions (FAQs)
When is a PASS legally mandatory?
Are PASS required for all approved medicines?
What is the difference between PASS and PAES?
Why Choose DDReg ?
DDReg provides end-to-end support for Post-Authorization Safety Studies with a strong focus on regulatory compliance and inspection readiness. From PASS protocol development and global regulatory submissions to progress reporting and final study close-out, DDReg ensures alignment with EMA, FDA, MHRA, and other global authority expectations. Our regulatory-first approach helps sponsors generate credible real-world safety evidence while maintaining lifecycle compliance.