Principal Mode of Action (PMOA): How to Determine the Regulatory Pathway for Drug-Device Combinations

You're in a regulatory strategy meeting. The product development team presents their new combination product - a wound dressing that incorporates an antimicrobial agent. Someone asks: "So is this a device or a drug?"

You pause. The answer isn't obvious. The antimicrobial could be acting pharmacologically, or it could be providing a physical barrier. And getting this wrong doesn't just mean paperwork headaches - it means choosing the wrong regulatory pathway entirely, potentially adding years and millions to your timeline.

PMOA determination is the first and most consequential decision in drug-device classification. This guide gives you the framework to make that decision with confidence.

What Is Principal Mode of Action?

The principal mode of action is the primary mechanism by which a product achieves its intended therapeutic effect. For combination products that incorporate both medicinal and device components, PMOA determines which regulatory framework governs the entire product.

The concept is straightforward in principle: identify what's doing the therapeutic heavy lifting. But in practice, combination products often have multiple mechanisms working simultaneously, and determining which one is "principal" requires careful scientific analysis.

Why this matters: Your PMOA determination cascades through every subsequent regulatory decision - from the dossier structure to which authorities review your submission to whether you need a Notified Body or EMA scientific opinion.

The Three Key Criteria for PMOA Assessment

Why this matters: These aren't just definitions - they're the scientific arguments you'll need to defend in your regulatory dossier and potentially in discussions with competent authorities.

1. Pharmacological Action

Pharmacological action involves interaction between the substance and a cellular component, usually a receptor, resulting in a direct response or blocking of another agent's response. The key characteristic is interaction at the molecular or cellular level that triggers a biological cascade.

2. Immunological Action

Immunological action involves stimulating, modifying, or replacing the immune system's function. This includes vaccines, immunomodulators, and products that trigger or suppress immune responses.

3. Metabolic Action

Metabolic action involves the substance being chemically altered in the body or participating in chemical reactions that produce the therapeutic effect. The substance becomes part of the body's biochemical processes.

How to Use This: When assessing your product, examine each therapeutic claim and ask: "Is this effect achieved through molecular/cellular interaction (pharmacological), immune modulation (immunological), biochemical transformation (metabolic), or physical/mechanical means?"

The critical insight here: if you can describe the mechanism without referencing receptors, enzymes, immune cells, or metabolic pathways, you're likely looking at a device. If the scientific explanation inherently requires these biological concepts, you're in medicinal product territory.

Practical Assessment Framework

Why this matters: This is the systematic approach that experienced regulatory professionals use - and that assessors expect to see documented in your submission.

Step-by-Step Assessment Questions

The last two questions are particularly revealing. If removing the substance would fundamentally change the therapeutic outcome, that's strong evidence the substance's action is principal. If the device would still provide meaningful therapy (just less effectively), the device action may be principal.

Documentation Requirements for PMOA Justification

Why this matters: A weak PMOA justification invites regulatory questions and potential classification disputes. Strong documentation preempts challenges.

The EMA and MDCG guidance are clear: the manufacturer bears the burden of proof for demonstrating that a product qualifies as a medical device rather than a medicinal product. This means your documentation must affirmatively establish the non-pharmacological nature of your product's principal action.

Common Challenges and How to Address Them

Challenge 1: Multiple Mechanisms Working Simultaneously

Many combination products have several mechanisms that all contribute to the therapeutic effect. A wound dressing might provide physical barrier protection, moisture management, and antimicrobial activity. Determining which is "principal" requires analyzing which contributes most to the intended therapeutic outcome.

Solution: Focus on the claimed indication. If your indication claims rely primarily on the antimicrobial effect, the pharmacological action is likely principal regardless of the physical barrier function. If the claims focus on wound bed protection with antimicrobial as an additional benefit, the device action may be principal.

Challenge 2: Concentration-Dependent Classification

Some substances can act mechanically at low concentrations but pharmacologically at higher concentrations. Hyaluronic acid, for example, can be a device component (viscoelastic properties) or a medicinal substance (biological activity) depending on concentration and molecular weight.

Solution: Document the concentration used and provide scientific evidence demonstrating that at your specific concentration, the action is mechanical rather than pharmacological.

Challenge 3: Evolving Scientific Understanding

What was considered mechanical ten years ago may now be understood to have pharmacological components. Your PMOA justification must reflect current scientific understanding, not historical assumptions.

Borderline Products: When PMOA Is Unclear

Why this matters: Borderline cases require additional regulatory engagement. Knowing when to seek guidance - and from whom - can prevent costly misclassification.

Despite careful analysis, some products genuinely fall in the grey zone. For these borderline cases, EU regulations provide mechanisms to obtain binding classification decisions.

The MDCG has published a Manual on Borderline and Classification that includes worked examples and precedent decisions. Before seeking formal advice, review this document - your product's situation may already have established precedent.

When Borderline Advice Is Essential