What Are Combination Products and Why They Matter in 2025
Combination products, where a medical device, drug, or biologic come together to deliver a single therapeutic effect, are redefining how modern medicine reaches patients. From insulin pens and drug-eluting stents to AI-enabled inhalers, these hybrids represent the next frontier in precision treatment and patient convenience.
The global drug-device combination market was valued at USD 138.48 billion in 2023 and is projected to reach USD 251.9 billion by 2030, growing at a 9% CAGR. Nearly 30% of all medical product filings now involve some form of drug-device combination. These numbers reflect both scientific progress and regulatory complexity.
Despite years of harmonization efforts, each region continues to regulate the combination of products through distinct frameworks, definitions, and review mechanisms. For global manufacturers, the real challenge is no longer scientific feasibility, but regulatory navigation.
Understanding the Global Regulatory Framework for Combination Products
United States (FDA)
The U.S. FDA regulates combination products under 21 CFR Part 4, focusing on cGMP expectations. The Office of Combination Products (OCP) assigns a lead center, CDER, CBER, or CDRH, based on Primary Mode of Action (PMOA). The eSTAR submission system is now required for device components, improving consistency and transparency.
Europe (EMA and EU MDR)
In Europe, the EU MDR (2017/745) and Directive 2001/83/EC guide combination product oversight. The Committee for Advanced Therapies (CAT) supervises biologic or ATMP-based hybrids. However, custom-made, 3D-printed, and borderline products still face ambiguous pathways.
Global Harmonization Efforts
Organizations like the IMDRF and WHO’s Regulatory Convergence Network are promoting reliance and harmonization. The ICH Q12 and Q14 guidelines strengthen lifecycle and quality management integration across regions.
The frameworks share common principles, but implementation varies, turning global alignment into a balancing act of interpretation and adaptation.
Decoding the Right Regulatory Pathway: The PMOA Principle
Selecting the correct pathway is the strategic core of combination product regulation. The Primary Mode of Action determines both the lead authority and the submission type.
- Determine the PMOA: Identify whether the primary therapeutic effect is delivered by the drug, device, or biologic component.
- Assign the Lead Center: The FDA’s OCP allocates CDER, CBER, or CDRH oversight accordingly; the EMA uses a “principal vs ancillary” approach.
- Select the Submission Type: Depending on classification, the dossier could be an NDA, BLA, or PMA.
- Engage Regulators Early: Pre-submission meetings or Requests for Designation (RFDs) clarify jurisdictional boundaries and data expectations.
- Prepare a Unified Dossier: Combine drug CTD/eCTD modules with device technical documentation.
- Undergo Hybrid Inspections: Manufacturing sites are inspected under GMP, QSR, and relevant ISO standards.
- Approval and Lifecycle Control: Post-approval variations, device firmware updates, and component changes all trigger cross-domain review obligations.
An early, cross-functional regulatory strategy for bridging chemistry, engineering, and quality systems can save years of rework.
Global Convergence vs. Persistent Complexity
Regional Convergence Overview
Region | Signs of Convergence | Persistent Complexities |
United States (FDA) | Centralized oversight via OCP; clear PMOA-based classification; collaborative dialogues with EMA; WHO and IMDRF harmonization efforts. | Borderline classifications remain ambiguous; GMP and QSR overlap causes audit redundancies; differing review timelines among centers. |
Europe (EMA/EU) | MDR 2017/745 and Directive 2001/83/EC integrate assessments; ICH and WHO harmonization frameworks adopted. | Inconsistent national implementation; unclear pathways for 3D-printed or custom-made combinations; divergent PMOA interpretations. |
Asia-Pacific (Emerging Markets) | Rapid adoption of ICH and WHO reliance mechanisms; regional convergence through ASEAN and APEC initiatives. | Lack of standardized definitions; variable regulatory maturity; uneven coordination between drug and device regulators. |
These discrepancies can add 6–18 months to global launch timelines, especially when evidence requirements differ for identical products.
Why True Regulatory Convergence Remains Elusive
Several systemic issues prevent full alignment of combination product regulation:
- Rigid legal frameworks defining drugs and devices differently
- Inconsistent risk appetite for excipients or device safety
- Faster technology evolution than policy adaptation
- Lack of review expertise in emerging markets
- Conflicting standards (ICH vs ISO vs WHO)
- Terminology discrepancies between “borderline,” “hybrid,” and “ancillary” products
- Institutional Silos with drug, device, and biologics divisions still function separately in most agencies, slowing coordinated review.
A 2024 computational analysis of over 4 million regulatory entries across FDA, EMA, and NMPA databases found less than 45% semantic overlap in classification terminology, proof that convergence remains partial at best.
Emerging Regulatory Shifts Defining 2025 and Beyond
Recent policy moves suggest regulators are inching toward a more synchronized, data-driven model:
- Digital Health Integration: FDA and EMA are emphasizing connected combination products and AI-driven device modules.
- eSTAR and Structured Submissions: FDA’s digital format for device components is now required for combination filings.
- Advanced Therapy Hybrids: Cell and gene therapy combination products are being reviewed under hybrid frameworks that blend BLA and device guidance principles.
- Hybrid Inspections: Agencies are piloting integrated audits aligning GMP and QSR, with emphasis on data integrity.
- Nomenclature Harmonization: The Global Medical Device Nomenclature (GMDN) now serves as a standard in over 70 countries, simplifying device component traceability.
- Data-Driven Policy Mapping: AI tools are being used by regulators to compare rule alignment and close semantic gaps across jurisdictions.
These are encouraging signals, but convergence through data, rather than legislation, is what will likely define the next phase of global regulatory collaboration.
What Combination Product Manufacturers Should Do Now
For pharmaceutical and biotech companies, the regulatory map for combination products will continue to evolve faster than most organizations can adapt. Success will depend on how early and strategically companies engage with global agencies.
- Build a regulatory intelligence function capable of tracking updates across FDA, EMA, PMDA, and emerging markets.
- Align internal quality systems with both cGMP and ISO 13485 requirements from the outset.
- Use reliance and recognition mechanisms where possible to shorten approval cycles.
- Establish multidisciplinary development teams that include regulatory, engineering, and clinical experts.
- Maintain consistency in PMOA justification across all jurisdictions to minimize reclassification risk.
Conclusion
Combination product regulation stands at a crossroads. Global agencies share the same public health goals and are increasingly coordinating through WHO, IMDRF, and bilateral dialogues. Yet for manufacturers, operational complexity is still the lived reality.
The next frontier will be adaptive convergence, a model where regulators align dynamically through shared data standards and AI-based interpretation rather than static legal harmonization. As digital therapeutics and smart biologics expand, adaptive convergence will determine how fast innovation reaches patients.
For industry leaders, the strategy is clear: anticipate, not react. Those who invest in regulatory foresight grounded in science, supported by data, and guided by experience will shape how the future of global combination product regulation unfolds.
Read more from DDReg experts here: How AI-Driven Signal Detection Is Reshaping Pharmacovigilance Case Management