Regulation of Combination Products in the United States

Introduction to Combination Products

Combination products consist of two or more different types of medical products:
- Biologic and device
- Biologic and drug
- Device and drug
- All three combined
These products are regulated under distinct regulatory programs by different components of the FDA.
Combination products raise particular regulatory questions and challenges regarding regulatory standards, procedures, and coordination within the Agency and between the Agency and sponsors.
Combination products are a separate class of medical products, distinct from drugs, devices, and biological products.
Regulatory requirements, processes, and expectations address issues raised by each constituent part (drug, device, or biologic) and those arising from their combined use.
The goal is to ensure the safety and effectiveness of the combination product in light of its constituent parts and their interrelation/interaction.
The statutory authorities implemented by the FDA expressly state whether they apply to drugs, devices, and/or biological products, but not to combination products.
The FDA has promulgated only two regulations expressly stating how these various statutory provisions apply to combination products and is developing one other such rule.
The Agency has published some guidance expressly for combination products, and additional guidance is being developed and finalized.

Key Topics

Combination product classification and assignment
Regulation of combination products
The role of the Office of Combination Products (OCP)
Recent and upcoming developments
Practical considerations to help manage regulatory challenges for this class of products.
The OCP's Website offers reference materials.
The OCP serves as a contact point to obtain assistance from the Agency.

Combination Product Classification and Assignment

This section addresses determining whether a product is a combination product, how the Agency component with primary jurisdiction is determined, and how to obtain an agency determination of classification or assignment.

Classification: Is the Product a Combination Product?

The FD&C Act does not define "combination product," but agency regulations do.
Combination products include:
- Products that physically or chemically combine different types of medical products (single-entity combination products), such as prefilled syringes and drug-eluting stents
- Products in which different types of medical products are copackaged (copackaged combination products), such as a first aid kit or surgical procedure kit that includes both drugs and devices
- Certain products comprised of different types of medical products that are separately marketed but related through their labeling (cross-labeled combination products), as might be the case for a drug and a laser that activates it.
Single-entity or copackaged combination products generally are fairly readily identified.
Analysis can involve consideration of the composition of the articles in a product and the mechanism(s) by which the product accomplishes its intended effect(s), as well as parsing of the statutory definitions for biologic, device, and/or drug.
It can also involve comparing the product to existing products regulated by the FDA and reviewing prior agency classification determinations.
Product classification determinations are made with regard to investigational products and may remain confidential unless the product receives marketing authorization.
Classification often depends on product-specific characteristics that may not be readily apparent and may vary among otherwise similar products.
The Agency has published jurisdictional updates and intercenter agreements as an aid to determining the classification and assignment of products.
The Agency has noted that these agreements are incomplete and/or out of date and should not be read in isolation.
Members of the third category of combination products, cross-labeled combination products, can be difficult to identify because of the complexity of the regulatory language, which includes both objective elements (Are both products needed for the intended use?) and subjective ones (Is one product intended to be used only with the other?).
The FDA has announced its intention to develop guidance to clarify under what circumstances separately marketed products constitute cross-labeled combination products under the Agency’s regulations.

Assignment: Which Center Has the Lead for a Combination Product?

Medical products for humans are regulated by three “centers” within the FDA:
- The Center for Biologics Evaluation and Research (CBER)
- Center for Devices and Radiological Health (CDRH)
- The Center for Drugs Evaluation and Research (CDER).
The center with primary regulatory responsibility (the “lead”) for a combination product is determined based upon the “primary mode of action” (PMOA) of that product.
There are three types of modes of action:
- Biologic
- Device
- Drug
“Primary mode of action” is not defined by statute.
The FDA promulgated regulations in 2005 to define the term and address how to determine the PMOA of a combination product.
PMOA has been defined as the mode of action that provides the “greatest contribution to the overall therapeutic effects” of the combination product, with “therapeutic” effect or action defined to include any effect or action that is “intended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure or any function of the body.”
CBER generally has the lead for a combination product if it has a biologic PMOA, CDRH if it has a device PMOA, and CDER if it has a drug PMOA.
For some types of combination products, the constituent part that contributes the PMOA is well established.
For other types of combination products, a case-by-case analysis may be needed to determine PMOA.
PMOA can vary among similar combination products.
Two combination products that both include the same or similar drug and device constituent parts may have different indications, and the respective contributions of those constituent parts may differ depending on the indication.
If possible, PMOA is determined directly if the Agency can determine with reasonable certainty which constituent part appears to contribute the most to the product’s intended therapeutic effects.
In some cases, sufficient data may not exist, may not be generated by the sponsor, or may not be possible to generate.
In such instances, which center will have the lead is determined through a two-step algorithm established by regulation.
- The first step is to determine whether one of the centers is already regulating a combination product raising similar questions of safety and effectiveness.
- If not, the second step asks which center has the greatest expertise with respect to the most significant questions of safety or effectiveness raised by the combination product.
Under the 2005 PMOA rule, assignment of combination products is based, if possible, on determination of which constituent part contributes most to the product’s overall effects if that constituent part can be identified, regardless of which center may have the lead for similar combination products or which are the most challenging regulatory issues raised by the product.
Past assignments for combination products may not be a reliable indicator of the assignment, and similar combination products may be assigned to different centers.
The center assigned the product may not be the center with the most expertise with respect to the most challenging regulatory issues raised by that combination product.
The centers and other agency components work together to regulate combination products to ensure appropriate consideration of all regulatory issues.
Sponsors can also help ensure that appropriate offices and personnel from the nonlead center are playing an appropriate, timely role in the review and regulation of the combination product.

Obtaining an Agency Classification or Assignment Determination

If the classification or assignment is unclear or in dispute, a sponsor can seek an informal view or submit a request for designation (RFD) to the OCP for a formal determination.
Submitting a marketing application or clearance notification without seeking agency input poses some risk if the classification or assignment for the product is unclear.
Seeking input from the center to which the sponsor believes the product should be assigned poses less risk but can lead to delay if the center disagrees with the sponsor or is uncertain of the classification or assignment for the product.
Contacting the OCP is generally the most efficient, cost-effective means to determine the classification and/or assignment for a product if either is unclear.
The OCP is the office delegated authority to classify products as drugs, devices, or biological products, as well as to classify combination products, and assign such products to centers.
If the OCP has a ready answer, an informal inquiry can be the fastest way to confirm Agency thinking.
If the OCP does not have a ready answer, an informal query still can help the requester to determine what information to provide in an RFD to ensure an informed determination by the OCP.
The RFD process is a mechanism to obtain a formal classification or assignment determination from the Agency.
An FDA response to an RFD is binding and can only be changed with the consent of the RFD submitter or for public health reasons based on scientific evidence.
FDA must respond to an RFD within 60 days or the classification or assignment recommended in the RFD applies with the same binding effect.
Agency regulations stipulate the required elements of an RFD and establish a 15-page size limit.
The OCP has published a guidance titled “How to Write an RFD,” which elaborates upon the information that should be provided in an RFD.
Important elements include a detailed description of the product, its intended use(s), the mechanisms by which it achieves its intended use(s), and a recommendation for the lead center assignment based on the PMOA for the product or the algorithm if PMOA cannot be demonstrated directly.
OCP classification and assignment determinations reflect not only the judgment of the OCP but also the expertise and views of the interested centers.
When RFDs are submitted, current practice is for the OCP to circulate them to the jurisdiction officers for the interested centers for center input.
In some cases, the OCP also seeks the input of FDA’s Office of the Chief Counsel before issuing a determination.
If the RFD submitter disagrees with the OCP’s determination, it may submit a request for reconsideration of the RFD to the OCP within 15 days, to which the OCP must reply within 15 days.
The submitter may also appeal the OCP’s determination in accordance with 21 CFR 10.75.
If an RFD submitter believes that the OCP would have made a different decision if it had had additional information before it, the submitter can submit a new RFD presenting that information.

Regulation of Combination Products

This section discusses regulatory standards and procedures for combination products in the premarket and postmarket settings.
The marketing authorization pathways, regulatory standards, and procedures for combination products are essentially those for drugs, devices, and biological products.
The principal issues for combination products concern how to ensure that all of the regulatory issues raised by a combination product are appropriately addressed, regardless of the regulatory pathway by which it may enter the Agency.
Associated challenges include coordination across centers and between sponsors and the Agency.
This section focuses on regulatory issues for combination products in particular.

Premarket Regulation: Marketing Authorization Requirements and Processes

The PMOA standard determines which center will have the lead for regulation of a combination product.
It does not expressly address what types of investigational and marketing authorization submissions should be made for the product, what review standards or data requirements should apply, or how the lead and nonlead centers should coordinate.
Statutory language and agency policies, statements, and practice offer some insight.

Investigational and Marketing Submissions

The PMOA standard expressly addresses only center assignment.
CBER, CDER, and CDRH do not currently have the delegated authority to review all marketing authorization types.
CDER has the authority to review biologics licensing applications (BLAs), new drug applications (NDAs), Abbreviated NDAs (ANDAs), and investigational new drug applications (INDs).
CDRH has the authority to review PMAs, 510(k)s, Humanitarian Device Exceptions (HDEs), and IDEs.
CBER has the authority to review all of these types of submissions.
Key questions to consider in evaluating what investigational and marketing authorization submissions to make for combination products are:
- Which constituent part (drug, device, biological product) provides the PMOA
- Which submissions type(s) associated with that constituent part are available for the combination product.
If a drug–device combination product has a device PMOA, and it includes a drug that is a new molecular entity or the combination product has an indication for which the drug has not been approved, a PMA could be submitted but not a 510(k) because safety and efficacy would need to be demonstrated.
If a drug–device combination product with a drug PMOA includes the same drug but a different device than a previously approved combination product for the same indication, an NDA could be submitted, but submission of an ANDA would be possible only if the device is sufficiently similar in performance and design characteristics to the one included in the previously approved combination product.
If two marketing authorizations are permitted or required (e.g., for each constituent part of a cross-labeled combination product), the marketing authorization for each constituent part would be of a type normally associated with that kind of product.
The centers still coordinate as appropriate on the review of the product even though each would receive its own submissions to act upon.
To the extent it is relevant to review of each constituent part, the same data could be presented and relied upon for both marketing authorizations, though additional data might also be needed to support either authorization, or both, individually.
The type of submission(s) available may have other implications relevant to business judgments and product development planning.
User fees vary considerably for marketing submissions, with standard fees for NDAs currently ranging from ~$1 to $2 million, for PMAs being nearly $250,000, for ANDAs being over $50,000, and for 510(k)s being nearly $5,000.
Combination products reviewed under a single marketing authorization should be subject to the fee associated with that type of authorization; if two authorizations are reviewed, the fee associated with each applies.
Some marketing submission types offer protections from competition while others do not.
If a product is being marketed under an NDA or BLA, provisions would apply that facilitate protection of patent rights and grant periods of marketing exclusivity during which the Agency cannot approve follow-on products that seek to rely on the Agency’s prior approval of the same or a similar product.
If instead a product is marketed under 510(k), no marketing exclusivity applies, so a follow-on product could be cleared at any time.
For products marketed under PMA, no follow-on pathway has been made available to date.

Marketing Authorization Standards for Combination Products

The Agency has not published general guidance on what substantive requirements must be met to obtain marketing authorization for combination products.
The Agency has stated that the constituent parts of a combination product retain their legal status as a drug, device, or biologic.
The Agency has indicated in guidance that the review considerations raised by each constituent part should be addressed in keeping with standard approaches for such products.
Agency guidance on early development considerations also reflects the FDA’s view that marketing authorizations for combination products must address the various questions associated with the constituent parts of the combination product, as would be the case if the constituent parts were to be marketed independently, as well as the safety and effectiveness issues raised by their being combined.
Sponsors should look up to the standards and guidance applicable to the constituent parts as an aid in determining how to satisfy review requirements for the combination product.
In assessing what sort of data may be needed to support marketing authorization for a combination product, an important question is what kind of safety and effectiveness issues the combination product raises.
These issues may relate to the product as a whole, individual constituent parts, and the interaction of the constituent parts.
The more novel the combination product, the more issues may need to be addressed in supporting data.
Development challenges can arise due to new scientific or technical issues raised by the combining or combined use of the constituent parts.
Timely coordination with the Agency can be helpful in formulating an appropriate product development process and study designs.

Intercenter Coordination and Sponsor–FDA Interaction for Premarket Review of Combination Products

Coordination within the Agency and between the Agency and sponsors can be particularly important and complex for combination products.
Standard operating procedures (SOPs) and other established procedures and mechanisms facilitate intercenter coordination, agency–sponsor interaction, and coordination between sponsors and third parties important to the development of the product.
Premarket review systems for combination products provide for coordination between the lead center and the center(s) that typically regulate the other constituent part(s) included in the combination product.
One set of SOPs includes a formalized process for enabling the lead center to seek input from the secondary center(s).
OCP’s annual reports to Congress include data tracking the number of consults between centers.
Sponsors coordinate with the Agency through the lead center as a general matter.
Sponsors may work through the lead center to confirm participation in meetings and timely review of submissions by relevant offices and staff from the other center(s) with expertise and regulatory interest for the product.
The OCP is available as a resource to facilitate scheduling of meetings and other coordination with the Agency, and also to help resolve disputes regarding product review.
Strong business relationships can be important in general for FDA-regulated products but may be particularly significant for combination products because these products include two or more different types of regulated articles.
Development of combination products can often involve coordination between sponsors and manufacturers of different types of articles, such as a drug sponsor and device manufacturer.
This coordination can include providing rights of access for the Agency to rely on master files, investigational or marketing authorization files, and other sources of data needed to support the development and marketing authorization of the combination product.
Cooperation between product sponsors and manufacturers can be important not only to support development and pursuit of initial marketing authorizations for combination products, but also to enable agency consideration of postmarketing changes to the combination product.
Postmarket changes to one constituent part of a combination product may affect its interaction with the other constituent part, and thereby affect the safety and effectiveness of the combination product.
With respect to cross-labeled combination products, such considerations may inform decisions regarding whether it makes better sense to seek a single marketing authorization for the combination product or to seek separate marketing authorizations for each of the separately marketed constituent parts.
Separate applications may facilitate further development of these constituent parts for independent uses not involving the other constituent part.
Reliance upon separate applications may also pose challenges, for example, with respect to coordination of postmarket modifications to either constituent part, particularly if the applications are (or become) held by different sponsors.

Postmarket Regulation of Combination Products

The Agency has stated that constituent parts retain their legal status and, therefore, combination products are subject to regulatory requirements applicable to each of their constituent parts.
A final rule on current good manufacturing practices (cGMPs), a proposed rule on postmarketing safety reporting (PSR) for combination products, and a final rule on unique identification for devices as well as agency statements concerning product listing requirements, reflect a consistent analytical and policy approach to address these legal duties.
The Agency has attempted to simplify and streamline compliance with the regulatory requirements applicable to the constituent parts of a combination product, while ensuring that the regulatory needs to ensure that the safety and effectiveness of combination products are met.
In developing the cGMP and PSR rules for combination products, the OCP in conjunction with expert staff from the centers and other agency components has reviewed the underlying regulations applicable to drugs, devices, and biological products, to determine how best to ensure that the regulatory needs served by these regulations could be met for combination products while minimizing any unnecessary overlap or redundancy in their application to these products.
Based on such analysis, the cGMP rule, for example, offers a streamlined compliance option under which compliance with both the cGMP regulations for drugs and quality system regulations for devices can be demonstrated by fully implementing either of these two sets of regulations and implementing only specified provisions from the other.
The Agency’s final rule on unique identifiers (UDIs) for devices reflects a similar policy objective.
It establishes UDI duties for combination products and devices that are limited so as to ensure that a UDI is associated with all marketed devices through duties that apply either to the combination product or device constituent part, but not both.
Agency guidance issued to date on registration and listing for combination products addresses how to list combination products that have a device PMOA and states that facilities should list the product with the lead center for it, but also can choose to list with the secondary center(s) for the product.
Coordination across centers and other agency components is an important feature of postmarket regulatory activity for combination products, as it is for premarket activities.
Centers and the Office of Regulatory Affairs may coordinate on manufacturing facility inspection activities or on evaluation and response to postmarket safety reports.

What Is OCP and What Does It Do?

OCP is a statutorily mandated office, established in 2002 in response to industry calls to establish an office within the Office of the Commissioner to coordinate and oversee the regulation of combination products.
The OCP is tasked with ensuring timely, effective premarket review of combination products and consistent and appropriate postmarket regulation for these products.
The OCP pursues a variety of activities, including many designed to assist stakeholders to understand Agency policies and practices and to facilitate their interactions with the Agency.
Specifically, the OCP:
- Develops guidance and regulations for combination products with assistance from the centers and other relevant Agency components.
- Participates in the development of other guidance and regulation that may have implications for combination products.
- Makes medical product classification and assignment determinations both informally and in response to RFDs.
- Responds to public inquiries about the regulation of combination products.
- Assists regulated entities in identifying appropriate agency resources and components to address regulatory issues.
- Coordinates and participates in meetings of centers and other Agency components with product sponsors, to identify and resolve regulatory issues.
- Resolves disputes between sponsors and centers and between centers.
- Enhances transparency, including through postings and links on its Web page and through information technology enhancement efforts.
- Conducts outreach and seeks input and feedback through public presentations, publications, and meetings with stakeholder groups.
OCP is of particular note to stakeholders having questions or needing assistance navigating the FDA with regard to combination products.
OCP is an unusual resource that facilitates access to Agency staff and expedites Agency feedback on combination products.
OCP can enable timely scheduling of meetings and other measures to expedite resolution of challenging regulatory issues including differences of opinion between the Agency components and between the Agency and sponsors.
The value of the OCP to stakeholders is reflected in the volume of requests it receives and addresses.
The OCP typically addresses several hundred inquiries and requests for assistance each year.

Recent and Upcoming Developments

The Agency continues to pursue development of regulations and guidance on various issues relating to combination products.
Topics the Agency has announced it is addressing include:
- Cross-labeled combination product status
- When one or two marketing submissions may be appropriate for a combination product
- Postmarket changes to combination products
- Classification standards for drugs and devices
- Finalization and development of additional guidance on specific classes of products, including injectors, drug-eluting stents, imaging products, and companion diagnostics.
The Agency continues to address procedural and systems-related issues for combination products.
The Agency has recently updated its listing system for device-led combination products.
It has updated the search features for the Agency’s 510(k) and PMA online databases to enable the use of “combination product” as a search term.
Additional information technology projects are being pursued, including enhancing postmarket safety reporting quality and efficiency, and argumenting search capabilities on the Agency’s Website for information on combination products.
Efforts also continue to encourage coordination and convergence internationally on regulation of combination products.