Global Combination Products 2025: Regulatory Convergence, PMOA Strategy & Compliance Trends

Combination products — the integration of drugs, biologics, and medical devices into a single therapeutic solution — are transforming how healthcare innovation reaches patients. From drug-eluting stents and insulin pens to connected inhalers and AI-driven autoinjectors, these products exemplify precision medicine and patient-centric design.

The global drug–device combination product market, valued at USD 138.48 billion in 2023, is projected to exceed USD 251.9 billion by 2030, growing at a CAGR of 9%. Nearly one in three global medical product submissions now includes a combination of components — underscoring both the scientific potential and regulatory complexity of this domain.

While science continues to advance rapidly, regulatory frameworks remain fragmented, requiring manufacturers to navigate diverse jurisdictional pathways, classification systems, and compliance expectations.

Global Regulatory Frameworks: Navigating Divergence and Alignment

United States (FDA)

In the U.S., combination products are regulated under 21 CFR Part 4, with oversight from the Office of Combination Products (OCP). The Primary Mode of Action (PMOA) determines which center — CDER, CBER, or CDRH — assumes lead responsibility.

The FDA’s eSTAR electronic submission system is now mandatory for device components, promoting greater review of consistency and transparency. In addition, hybrid GMP/QSR compliance is expected across manufacturing systems to ensure integrated quality oversight.

European Union (EMA / EU MDR)

In the EU, combination products are regulated under Regulation (EU) 2017/745 (MDR) and Directive 2001/83/EC. Oversight of biologic or ATMP-based hybrids is coordinated through the Committee for Advanced Therapies (CAT).

However, borderline classifications, custom-manufactured, and 3D-printed combinations remain in areas of regulatory ambiguity, creating additional complexity for manufacturers and Notified Bodies.

Global Convergence and Harmonization Efforts

Organizations such as the International Medical Device Regulators Forum (IMDRF), International Council for Harmonization (ICH), and the World Health Organization (WHO) continue to advance regulatory reliance and harmonization frameworks. Initiatives such as ICH Q12 (lifecycle management) and ICH Q14 (analytical procedure development) are helping align global expectations for quality and risk management.

Despite progress, true regulatory convergence remains partial — varying implementation timelines, inconsistent terminology, and diverging legal frameworks continue to challenge global product alignment.

Decoding the Primary Mode of Action (PMOA): The Strategic Core of Compliance

Selecting the correct regulatory pathway is the foundation of any global submission strategy for combination products.

Key considerations include:

1. Determine the PMOA — Identify whether the primary therapeutic effect arises from the drug, device, or biologic component.
2. Assign the Lead Authority — In the U.S., the OCP assigns CDER, CBER, or CDRH oversight. In the EU, classification is determined by whether the medicinal or device component is principal or ancillary.
3. Select the Submission Pathway — Depending on classification, the application may follow NDA, BLA, or PMA pathways (or the corresponding CE Mark for technical documentation).
4. Engage Regulators Early — Conduct pre-submission meetings or submit a Request for Designation (RFD) to clarify regulatory expectations and jurisdiction.
5. Develop a Unified Dossier — Integrate CTD/eCTD modules with technical documentation and design control evidence to ensure a seamless review process.
6. Plan for Hybrid Inspections — Expect multi-framework audits covering GMP, QSR, and ISO 13485.
7. Lifecycle and Post-Market Oversight — Manage firmware changes, component updates, and post-approval variations across both drug and device domains.

A proactive, cross-functional strategy integrating regulatory, quality, and engineering expertise is key to reducing rework and accelerating market entry.

Regulatory Convergence vs. Compounding Complexity

Discrepancies between these frameworks can extend global launch timelines by 6–18 months, underscoring the importance of early regulatory intelligence and harmonized dossier planning.

Why True Global Alignment Remains a Challenge

Despite collaborative intent, several systemic barriers continue to limit regulatory convergence:

• Inflexible legal definitions distinguishing drugs, devices, and biologics.
• Differing risk tolerance across regions for device safety and excipients.
• Rapid technological evolution outpacing legislative adaptation.
• Limited review of expertise in emerging markets.
• Conflicting global standards (ICH vs. ISO vs. WHO) and terminology of inconsistencies.
• Persistent organizational silos within agencies hindering integrated review.

A 2024 data analysis of regulatory databases (FDA, EMA, NMPA) revealed less than 45% overlap in terminology alignment, confirming the ongoing divergence of classification and review methodologies.

Emerging Regulatory Trends Reshaping 2025 and Beyond

1. Digital Health Integration – Regulators increasingly emphasize AI-enabled and connected combination products, driving new guidance on cybersecurity, data governance, and interoperability.
2. Structured Electronic Submissions – FDA’s eSTAR, EMA’s Structured Application Data Initiative (SADI), and MHRA’s digital frameworks are redefining submission architecture.
3. Advanced Therapy Hybrids – Combination products incorporating cell or gene therapy components are evaluated under hybrid models merging BLA and device guidance principles.
4. Hybrid Inspections – Regulatory authorities are conducting integrated GMP/QSR audits, with a growing focus on data integrity and digital traceability.
5. Nomenclature and Data Harmonization – Adoption of the Global Medical Device Nomenclature (GMDN) across 70+ jurisdictions improves traceability and post-market surveillance consistency.

These developments point toward adaptive regulatory convergence, where data standardization and AI-assisted intelligence replace static legislative harmonization.

Strategic Recommendations for Manufacturers

To stay ahead in an evolving regulatory landscape, pharmaceutical and medical device companies should:

• Establish a Regulatory Intelligence Function to monitor and interpret evolving global policies.
• Integrate cGMP and ISO 13485 Systems from the earliest development stage.
• Leverage Reliance Mechanisms (IMDRF, WHO, ASEAN) to shorten approval timelines.
• Build Multidisciplinary Teams including regulatory, engineering, clinical, and quality specialists.
• Maintain PMOA Consistency across jurisdictions to prevent reclassification of risks.
• Invest in Digital Dossier Infrastructure for efficient lifecycle and variation management.

Conclusion: Toward Adaptive Convergence

A global combination of product regulation is entering a transformative era — one characterized by collaborative intelligence, structured data, and technology-enabled compliance.

Regulators across the FDA, EMA, and global networks share a unified vision: advancing patient safety and innovation through regulatory alignment. Yet, achieving operational convergence requires adaptive frameworks that evolve with technology, not lagging it.

At Maven Regulatory Solutions, we partner with global life sciences organizations to build regulatory resilience — combining deep scientific understanding, data-driven strategy, and hands-on experience to navigate the complexities of combination product compliance in 2025 and beyond.