Understanding PMCs and PASS in Phase 4 Clinical Trials: Compliance and Design Essentials

What Are Post-Marketing Commitments and PASS?

After a new drug or biologic is approved, regulatory agencies often require further studies to confirm its long-term safety, effectiveness, or optimal usage. These obligations fall under two categories: Post-Marketing Commitments (PMCs) and Post-Authorization Safety Studies (PASS). Both are conducted during Phase 4 and play a crucial role in lifecycle drug management.

While PMCs may be voluntarily undertaken or required, PASS is usually mandated by regulators when there is a known or potential safety concern. These studies ensure that drugs continue to offer favorable benefit-risk ratios in real-world populations.

Why PMCs and PASS Are Important

• Validate real-world safety: Confirm risk profiles in broader populations
• Fulfill regulatory obligations: Comply with EMA, FDA, CDSCO, PMDA, etc.
• Support pharmacovigilance programs: Collect long-term adverse event data
• Enable label updates or withdrawal: Modify indication, dosage, or risk warnings

Types of Post-Marketing Commitments

1. Clinical PMCs

• Confirmatory efficacy trials (e.g., for conditional approvals)
• Studies in special populations (e.g., pediatric, geriatric)

2. Non-Clinical PMCs

• Carcinogenicity, reproductive toxicity, or drug interaction studies

3. Chemistry, Manufacturing, and Controls (CMC) PMCs

• Stability studies, validation of manufacturing processes

What Constitutes a PASS?

PASS is a type of post-authorization study designed to monitor safety and detect known, potential, or emerging risks associated with a product. It can be initiated by:

• Regulators (obligatory or “imposed” PASS)
• Sponsors (voluntary or “agreed” PASS)

Examples of PASS Triggers

• Unexpected adverse events in early trials
• Use in vulnerable populations (e.g., pregnant women)
• Need to confirm effectiveness of risk minimization strategies

Study Designs Commonly Used

For PMCs:

• Randomized or open-label interventional trials
• Dose-finding or titration studies

For PASS:

• Prospective observational cohort studies
• Case-control or nested case-control studies
• Drug utilization studies (DUS)
• Patient registries or database analysis

PASS Registration and Transparency

• EU: All imposed and voluntary PASS must be registered in the EU PAS Register
• FDA: PMRs and PMCs must be listed in Drugs@FDA and tracked annually
• PMDA: PASS submissions required for conditional or early approvals

Examples of PMCs and PASS in Practice

PMC Example:

A sponsor received FDA approval for a biologic based on Phase 2 efficacy. A confirmatory Phase 4 trial in a broader population was a required PMC. The sponsor submitted data within 3 years, confirming efficacy and leading to full approval.

PASS Example:

EMA required a PASS for a newly approved antipsychotic due to potential cardiac risk. A 5-year observational study involving 10,000 patients assessed QT prolongation and sudden cardiac death, with outcomes leading to a black box warning update.

Reporting and Compliance Timelines

• FDA: Annual status reports on all PMRs and PMCs
• EMA: Protocol approval before study initiation; final report timelines depend on risk
• CDSCO (India): Requires PSURs every 6 months for the first 2 years post-approval

Challenges and Solutions

• Challenge: Delays in study initiation or reporting
  Solution: Develop internal regulatory trackers and escalation protocols
• Challenge: Low engagement in long-term observational studies
  Solution: Use mobile apps, home visits, and patient portals to maintain engagement
• Challenge: Data harmonization across regions
  Solution: Use global data standards (CDISC, MedDRA) and centralized databases

Best Practices for Executing PMCs and PASS

• Engage with regulatory authorities early to align study objectives
• Choose pragmatic and scalable study designs
• Use validated tools for adverse event collection and signal detection
• Maintain transparency through public registries

Final Thoughts

Post-Marketing Commitments and PASS are not just regulatory formalities—they are essential tools for ongoing patient safety and data-driven therapeutic improvements. Successfully navigating these Phase 4 obligations requires proactive planning, cross-functional collaboration, and a deep understanding of evolving regulatory expectations.

At ClinicalStudies.in, we support pharmaceutical professionals in the strategic design, execution, and compliance management of Phase 4 post-marketing studies across global markets.