Combination Product FDA: Classification, Assignment, and Regulatory Pathway

Combination Product FDA: Classification, Assignment, and Regulatory Pathway

Key Takeaways

What Is a Combination Product

Section 503(g) of the FD&C Act and 21 CFR 3.2(e) define a combination product as a product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are:

Type 1: Single-Entity Combination Products

Products in which two or more regulated components are physically, chemically, or otherwise combined or mixed and produced as a single entity. The components cannot be physically separated without affecting the product's function.

Examples:

• Drug-eluting coronary stent (drug + device)
• Prefilled syringe (biologic + device)
• Antimicrobial wound dressing (drug + device)
• Bone graft with growth factor (biologic + device)
• Transdermal patch with active pharmaceutical ingredient (drug + device)

Type 2: Co-Packaged Combination Products

Products in which two or more separate regulated components are packaged together in a single package or unit, and the components are intended to be used together.

Examples:

• Drug and delivery device packaged together (e.g., epinephrine auto-injector)
• Surgical kit containing both a device and a drug or biologic
• Diagnostic test kit containing both the test device and a reagent (drug)

Type 3: Cross-Labeled Combination Products

Products in which two or more separate regulated components are not packaged together but are intended to be used together, as indicated in the labeling of at least one of the components.

Examples:

• A drug whose labeling specifies that it must be administered using a specific device
• A device whose labeling indicates it is intended for use with a specific biologic
• An IVD test whose labeling references a specific companion diagnostic device

Distinguishing Combination Products from Non-Combination Products

Not every product that involves both a drug and a device (or a biologic and a device) is a combination product. Key distinctions:

Primary Mode of Action

Definition

The primary mode of action (PMOA) is the single mode of action of a combination product that provides the most important therapeutic action. FDA uses the PMOA to determine which FDA center has primary jurisdiction over the combination product.

Mode of Action Categories

PMOA Determination

21 CFR 3.4 describes the PMOA determination process:

Step 1: Identify all modes of action of the combination product.

Step 2: Determine which mode of action provides the most important therapeutic action. "Most important" is assessed based on which mode of action makes the greatest contribution to the overall intended therapeutic effect.

Step 3: Assign the product to the center responsible for regulating that mode of action:

When PMOA Is Unclear

If the PMOA cannot be determined with reasonable certainty, 21 CFR 3.4(b) provides a secondary algorithm based on which center has the most expertise with the type of product:

1. Assign to the center that regulates other combination products with similar questions of safety and effectiveness
2. If no similar products exist, assign to the center with the most expertise regarding the most significant safety and effectiveness questions

In practice, PMOA disputes between FDA centers are resolved by the Office of Combination Products (OCP).

The Office of Combination Products

Role and Authority

The Office of Combination Products (OCP) was established by Section 503(g) of the FD&C Act, as added by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). OCP is located within the Office of the Commissioner and has the following responsibilities:

OCP Contact

OCP provides informal guidance through Pre-RFD meetings and written correspondence. Manufacturers with questions about whether a product is a combination product, which center has jurisdiction, or what regulatory pathway applies can contact OCP before submitting a formal Request for Designation.

Request for Designation (RFD)

When to File an RFD

A Request for Designation (RFD) is a formal submission to OCP requesting FDA to determine:

1. Whether a product is a combination product (as opposed to a single-component drug, biologic, or device)
2. Which FDA center has primary jurisdiction
3. The product's classification/regulatory identity

An RFD is recommended when:

• The PMOA is genuinely unclear
• The product has characteristics of multiple regulated categories
• The manufacturer disagrees with a center's preliminary jurisdictional determination
• The product is novel and has no precedent for center assignment

RFD Content Requirements

Per 21 CFR Part 3, Subpart A, an RFD must include:

RFD Timeline

The 60-day timeline is statutory. OCP issues a designation letter within 60 days of receiving a complete RFD. The designation is binding on all FDA centers.

Designation Outcomes

The designation letter specifies:

• Whether the product is a combination product
• The product's regulatory identity (drug, biologic, device, or combination)
• The lead center
• The participating center(s) (if applicable)

The manufacturer may request reconsideration within 15 days if it disagrees with the designation. Under 21 CFR 3.8, the reconsideration is reviewed by the supervisory official within the Office of the Commissioner.

Intercenter Agreements

How Centers Collaborate

When a combination product is assigned to a lead center, the lead center has primary responsibility for premarket review and post-market regulation. However, the participating center(s) provide expertise on the components within their jurisdiction.

The collaboration is governed by intercenter agreements, which define how the centers share review responsibilities:

Consultation and Collaboration

In practice, the intercenter review process works as follows:

1. Lead center receives and manages the marketing application (NDA, BLA, PMA, or 510(k))
2. Lead center identifies sections requiring participating center expertise
3. Participating center reviews relevant sections and provides feedback to the lead center
4. Lead center incorporates participating center's recommendations into the review decision
5. Both centers coordinate on post-market requirements

The lead center makes the final regulatory decision, but it must consider the participating center's input. Disagreements between centers are escalated to OCP.

Regulatory Pathways for Combination Products

Which Application to Submit

The premarket application type depends on the lead center and the PMOA:

Combination Products with Drug PMOA (CDER Lead)

When the drug component provides the PMOA:

• Application: NDA under Section 505 of the FD&C Act
• Drug requirements: Full chemistry, manufacturing, and controls (CMC); nonclinical pharmacology/toxicology; clinical trials demonstrating safety and efficacy
• Device requirements: Device design, verification, and validation data included in the NDA; CDRH provides consultation on device-specific aspects
• Example: Drug-eluting stent where the drug's antiproliferative effect is the PMOA

Combination Products with Biologic PMOA (CBER Lead)

When the biologic component provides the PMOA:

• Application: BLA under Section 351 of the PHS Act
• Biologic requirements: Full characterization, manufacturing, nonclinical, and clinical data
• Device requirements: Device component data included in the BLA; CDRH provides consultation
• Example: Cell therapy product delivered via a scaffold device where the cells provide the therapeutic action

Combination Products with Device PMOA (CDRH Lead)

When the device component provides the PMOA:

• Application: PMA, 510(k), or De Novo (depending on device classification)
• Device requirements: Full device submission including design, performance testing, biocompatibility, clinical evidence (if PMA)
• Drug/biologic requirements: Chemistry, pharmacology, and safety data for the drug or biologic component; CDER or CBER provides consultation
• Example: Antimicrobial bone cement where the device's structural function is the PMOA and the drug prevents infection

CGMP Requirements for Combination Products

21 CFR Part 4

21 CFR Part 4 establishes current good manufacturing practice (CGMP) requirements for combination products. The regulation requires compliance with the CGMP requirements applicable to each component type:

Streamlined Approach

21 CFR 4.4 provides a streamlined approach for combination product CGMP:

For co-packaged or single-entity combination products:

• The manufacturer must comply with the CGMP requirements of the constituent part that is the product's PMOA
• For the other constituent part(s), the manufacturer may comply with the CGMP requirements for that part type OR demonstrate that compliance with the PMOA component's CGMP provides equivalent controls

Example: A drug-device combination product with drug PMOA must comply with drug CGMP (21 CFR Parts 210/211). For the device component, the manufacturer can either comply with the device QSR (21 CFR Part 820) or demonstrate that drug CGMP controls cover the device manufacturing adequately. In practice, most manufacturers comply with both sets of requirements.

Practical CGMP Challenges

Post-Market Requirements

Adverse Event Reporting

Combination product adverse event reporting follows the rules for the application type:

OCP's guidance "Postmarketing Safety Reporting for Combination Products" (March 2019) provides additional detail on reporting requirements, including situations where both drug and device reporting may be required.

Labeling Changes

Post-market labeling changes for combination products follow the rules of the lead center:

• CDER lead: Changes in labeling follow the CBE-0/CBE-30/PAS framework under 21 CFR 314.70
• CDRH lead: Labeling changes may require a 510(k) supplement, PMA supplement, or De Novo amendment depending on the nature of the change

Manufacturing Changes

Post-market manufacturing changes to combination products must comply with both the lead center's change reporting requirements and 21 CFR Part 4 CGMP requirements. Changes to the drug or biologic component of a CDRH-led combination product must still be evaluated against drug CGMP standards.

Common Combination Product Issues

Issue 1: Constituent Part vs Accessory

A constituent part of a combination product is integral to the product's function and is included in the combination product classification. An accessory is a separate device used with but not part of the combination product. Accessories are regulated independently.

Issue 2: Drug-Device or Drug-with-Device

The distinction between a combination product and a drug packaged with a non-specific device depends on whether the device is specifically designed for or essential to the drug's use. A drug packaged with a generic, widely available device (e.g., a standard syringe) is not a combination product unless the labeling creates a cross-labeled relationship.

Issue 3: Companion Diagnostics

Companion diagnostics (CDx) are in vitro diagnostic devices used to identify patients most likely to benefit from a specific drug. While CDx are sometimes cross-labeled with a drug, they are typically regulated as standalone devices (Class III, PMA pathway) rather than as combination products. The co-development of a CDx and a drug involves coordination between CDER/CBER and CDRH, but the products are usually submitted as separate applications.

Strategic Considerations

Pre-Submission Planning

Before submitting an RFD or marketing application:

1. Identify all components and their individual regulatory identities
2. Determine the PMOA based on scientific evidence
3. Consult OCP informally if the PMOA or classification is unclear
4. File an RFD if formal designation is needed
5. Submit Pre-Submission (Q-Sub) to the lead center to align on:

- Clinical evidence requirements

- Testing requirements for each component

- CGMP strategy

- Post-market reporting approach

Common Mistakes

1. Starting development without determining regulatory classification: The choice of lead center and application type determines the entire development and regulatory strategy
2. Ignoring the device constituent part: In drug-led combination products, device design controls and testing requirements are often underestimated
3. Filing with the wrong center: Submitting directly to a center without confirming jurisdiction can result in refusal or transfer, causing delays
4. Treating CGMP as single-framework: Combination products must address CGMP requirements for each constituent part type

Key Regulatory References

References