Navigating FDA Classification for Combination Products: PMOA, Submission Pathways, and Regulatory Strategy

Combination products are those composed of a drug, device, and biologic and present both exciting therapeutic potential and complex regulatory challenges. Once a product is confirmed as a combination product under 21 CFR 3.2(e), the next critical step is determining its Primary Mode of Action (PMOA). 

The PMOA drives which FDA center leads the review, what submission pathway is required, and what standards the sponsor must meet throughout development. 

 

Understanding the Primary Mode of Action (PMOA) 

PMOA is defined as the single mode of action that provides the most significant therapeutic benefit of the product. It serves as the foundation for FDA classification and regulatory oversight. 

• Drug-led PMOA: If the product’s primary therapeutic effect is achieved via chemical or metabolic action, the lead center is typically CDER (Center for Drug Evaluation and Research) or CBER (Center for Biologics Evaluation and Research). 

• Device-led PMOA: If the effect is mainly physical or mechanical, the product is reviewed by CDRH (Center for Devices and Radiological Health). 

Side-by-Side Comparison of Regulatory Pathways 

Feature	Drug-Led Product	Device-Led Product
PMOA	Chemical/metabolic action	Physical/mechanical action
Lead FDA Center	CDER or CBER	CDRH
Pathway	IND → NDA/BLA	Q-Sub → IDE (if needed) → 510(k), De Novo, or PMA
Focus	Drug safety, efficacy, pharmacology	Device performance, standards
Example	Prefilled syringe of monoclonal antibody	Drug-eluting stent

 

Borderline Products & Classification Gray Areas 

Innovative technologies increasingly blur traditional regulatory lines. Some examples: 

• Hydrogel-forming powders: May release drugs without chemical interaction, raising the question—is the delivery polymer a device? 

• Digital pills: A drug paired with an ingestible sensor (e.g., antipsychotic with adherence tracking) might be drug-led, but includes software and hardware requiring separate scrutiny. 

These edge cases underscore why early FDA engagement is critical. 

 

FDA Engagement: RFD vs. Pre-RFD 

To clarify classification and lead center assignment, FDA offers two pathways through the Office of Combination Products (OCP): 

1. Request for Designation (RFD)

• Formal process 

• Legally binding FDA decision within 60 days 

• Should be submitted when the classification is unclear or contested 

2. Pre-Request for Designation (Pre-RFD)

• Informal, non-binding communication 

• Allows early feedback from FDA on classification or PMOA 

• Useful for planning and refining your regulatory approach before committing to a full RFD 

 

Developing the Right Regulatory Strategy 

Once the PMOA is confirmed, sponsors must build a development program aligned with FDA expectations: 

Drug-Led Product Strategy: 

• IND submission 

• Clinical trials to establish safety and efficacy 

• NDA or BLA filing 

• Validate device components for usability, safety, and reliability 

Device-Led Product Strategy: 

• Q-Sub meeting to gather FDA feedback 

• IDE filing (if clinical data needed) 

• File a 510(k), De Novo, or PMA 

• Include drug safety data, even if drug is secondary 

Sponsors must also comply with hybrid quality systems, combining: 

• Drug GMP: 21 CFR Parts 210/211 

• Device QSR: 21 CFR Part 820
  → FDA’s 21 CFR Part 4 provides guidance on aligning these frameworks for combination products. 

 

Key FDA Guidances (2023–2025) 

Staying current with FDA updates ensures regulatory alignment. Recent publications include: 

• Combination Product User Fees (2024): Clarifies fee structures for joint submissions. 

• Use-Related Risk Analysis (2024, Draft): Prioritizes user interaction safety in auto-injectors and home-use devices. 

• Human Factors Engineering (2023): Q&A-style guide on usability study integration. 

• Drug-Device Software (2023, Draft): Regulatory expectations for digital components like sensors and apps. 

• Premarket Pathways for Combination Products (2022): Encourages single, streamlined submissions. 

 

Four Key Takeaways for Combination Product Developers 

• Start with Classification
  Use 21 CFR 3.2(e) to assess if your product qualifies as a combination product. If unclear, consult FDA via Pre-RFD or RFD early. 

• Understand PMOA Impact
  Your PMOA defines the lead FDA center and shapes submission timelines, clinical requirements, and quality standards. 

• Plan for Both Components
  Develop a regulatory strategy that addresses both drug and device requirements—no component can be overlooked. 

• Stay Updated on Guidance
  FDA expectations evolve. Risk management, usability, and digital integration are now central to regulatory review. 

 

Need Help with Your Combination Product Strategy? 

BioBoston Consulting provides expert CMC and regulatory support for combination products, helping sponsors: 

• Determine PMOA and regulatory classification 

• Navigate RFD and Pre-RFD processes 

• Design FDA-compliant development and submission strategies 

• Align drug and device quality systems 

• Avoid costly missteps and accelerate timelines 

📩 Contact BioBoston Consulting today for a free consultation and ensure your combination product is built on a strong regulatory foundation.