The traditional boundaries separating pharmaceuticals, biologics, and medical devices have blurred. With the rise of combination products, from drug-eluting stents and prefilled autoinjectors to inhalers with embedded sensors, the regulatory landscape has undergone a seismic shift. While pharmacovigilance (PV) for pharmaceuticals is well-established, the safety monitoring of PV for devices and combination products introduces distinct technical and regulatory complexities.
Global health authorities now demand integrated, risk-based pharmacovigilance systems that capture both drug-related adverse events and device-specific performance failures. However, the frameworks vary significantly across regions, requiring manufacturers to navigate overlapping and sometimes divergent reporting obligations, timelines, and safety expectations.
This blog outlines the key global pharmacovigilance requirements for combination products and devices, highlighting region-specific nuances and best practices for unified, compliant safety oversight.
What Defines a Combination Product?
According to FDA (21 CFR Part 3.2) and increasingly adopted by other regulators, a combination product comprises any combination of:
- A drug and a device
- A biologic and a device
- A drug and biologic, with or without a device
They may be:
- Single-entity: e.g., a drug-eluting intrauterine device
- Co-packaged: e.g., a vaccine and its reconstitution syringe
- Cross-labeled: e.g., a phototherapy device approved for use with a specific topical agent
Each product must be assigned a Primary Mode of Action (PMOA), which determines the lead regulatory center and the primary regulatory pathway (drug-led, device-led, or biologic-led). However, pharmacovigilance services responsibilities are hybridized, often requiring compliance with multiple safety frameworks concurrently.
Global Regulatory Expectations for PV in Devices and Combination Products
United States – FDA (CDER, CDRH, CBER)
- Governed by the Combination Product Post Marketing Safety Reporting Rule (21 CFR Part 4 Subpart B)
- Applicants must comply with both:
- 21 CFR 314.80 / 600.80 for drug or biologic adverse event (AE) reporting (e.g., via FAERS)
- 21 CFR 803 for Medical Device Reporting (MDR) (e.g., via eMDR)
- Three safety reporting obligations exist:
- 5-day reports for unexpected deaths/serious injury related to the device
- 15-day reports for serious adverse drug reactions
- GMP and QMS compliance must adhere to 21 CFR 210/211 (drugs) and 21 CFR 820 (devices)—though streamlined CGMP (21 CFR Part 4) provisions exist for single-entity products.
European Union – EMA & EU MDR
- Governed under Regulation (EU) 2017/745 (MDR) for devices and Directive 2001/83/EC for medicinal products.
- Drug-device combinations are classified as:
- Integral (e.g., prefilled syringes): Regulated primarily under medicinal product legislation, with the device subject to General Safety and Performance Requirements (Annex I of MDR).
- Non-integral (e.g., reusable devices with drugs): Dual oversight by both EMA and Notified Bodies.
- Post-market surveillance must include:
- Periodic Safety Update Reports (PSURs) as per Article 86 of MDR
- Vigilance reporting (Article 87): Serious incidents and Field Safety Corrective Actions (FSCAs)
- Trend reports for increasing frequency of non-serious incidents (Article 88)
- EUDAMED will centralize vigilance reporting across Europe upon full implementation.
Japan – PMDA / MHLW
- Combination products are regulated under the Pharmaceuticals and Medical Devices Act (PMD Act).
- Good Vigilance Practice (GVP) Ordinance applies to all post-marketing safety management activities.
- Adverse events must be classified as:
- Level 1 (Serious; Fatal) – 15-day expedited reporting
- Level 2 (Moderate; Unexpected) – 30-day reports
- Level 3 (Minor; Known) – documented in reexamination/revaluation dossiers
- PMDA conducts post-marketing re-examinations and re-evaluations based on accumulated safety and effectiveness data over defined periods.
Global Harmonization – WHO, IMDRF, ICH
- IMDRF (International Medical Device Regulators Forum) supports harmonization of:
- Terminology for device safety
- Vigilance definitions, such as “serious public health threat” and “field safety corrective action”
- Standards for software as a medical device (SaMD)
- ICH E2E on pharmacovigilance planning is increasingly adapted to include combination product risk minimization measures.
- WHO’s Global Model Regulatory Framework for Medical Devices (2017) provides additional structure for LMICs developing device vigilance systems.
Key Technical Challenges in PV for Combination Products
- Safety Signal Attribution
Combination products require causality assessment to distinguish:
- Whether the AE stems from the active ingredient, the device mechanism, or the interaction between both.
This has implications for:
- Signal management processes
- Labeling updates and RMP revisions
- Regulatory reporting pathways
- Disparate Data Streams
Pharmaceutical PV systems (e.g., Argus, ArisG) are often siloed from device vigilance platforms. Data harmonization challenges include:
- Disconnected timelines and thresholds
- Lack of integrated narrative aggregation for benefit-risk assessment
- Global Timelines and Regional Nuance
Simultaneously meeting:
- FDA 15-day and 5-day reporting
- EU MDR Article 87 timelines
- Japan’s GVP 15-day/30-day cycle
…requires automated workflow orchestration, escalation matrices, and QPPV oversight across jurisdictions.
Best Practices for a Unified PV Approach
To meet complex global PV for devices and combination products, manufacturers should adopt:
Integrated Safety Governance
Form global PV-RA-QMS committees that jointly review signals, validate risk minimization measures, and align reporting priorities.
Harmonized SOPs
Implement SOPs that map overlapping obligations across:
- Drug/biologic safety (ICH E2E, E2D)
- Device vigilance (MDR, FDA 803, PMD Act)
Centralized, Dual-Class Safety Databases
Modern PV platforms should support multi-classification safety data (drug + device) and enable:
- MedDRA–IMDRF cross-mapping
- Shared signal management
- Real-time report generation per region
PMS Plan & RMP Alignment
Ensure that Post-Market Surveillance (PMS) plans required under EU MDR and Risk Management Plans (RMPs) for drug components reference shared signals, cross-component hazards, and interface risks.
How DDReg Drives Compliance Across the Combination Product Lifecycle
DDReg offers specialized pharmacovigilance and regulatory support for combination products, ensuring alignment with both drug and device expectations worldwide. Our capabilities include:
- PV system design tailored to hybrid product classes
- Vigilance and PMS plan development PV for medical devices and combination products aligned with MDR, FDA, PMDA
- E2E safety data integration for combination product portfolios
- Signal detection and management using AI-driven platforms
- Regulatory submissions & reporting (e.g., FAERS, eMDR, EUDAMED)
- Audit-readiness & inspection support (FDA, EMA, PMDA, Health Canada)
With deep cross-regulatory expertise, DDReg supports manufacturers in maintaining lifecycle compliance, from first submission to post-market benefit-risk reassessment.
Conclusion
As therapeutic innovation outpaces regulatory precedent, combination products represent both risk and opportunity. Sponsors who invest in globally harmonized pharmacovigilance frameworks will not only avoid compliance pitfalls, they will lead the next era of patient-centered safety innovation.