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U.S. Department of Health and Human Services

Combination Products

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Frequently Asked Questions About Combination Products

General:

 

What is a combination product?

 

A combination product is a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product. Under 21 CFR 3.2 (e), a combination product is defined to include:

 

1. A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

 

2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;

 

3. A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where, upon approval of the proposed product, the labeling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose); or

 

4. Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

 

What are some examples of combination products?

 

Examples of combination products where the components are physically, chemically or otherwise combined (21 CFR 3.2(e)(1)):

 

  • Monoclonal antibody combined with a therapeutic drug
  • Device coated or impregnated with a drug or biologic
    • Drug-eluting stent; pacing lead with steroid-coated tip; catheter with antimicrobial coating; condom with spermicide
    • Skin substitutes with cellular components; orthopedic implant with growth factors
  • Prefilled syringes, insulin injector pens, metered dose inhalers, transdermal patches

 

Examples of combination products where the components are packaged together (21 CFR 3.2(e)(2)):

 

  • Drug or biological product packaged with a delivery device
  • Surgical tray with surgical instruments, drapes, and lidocaine or alcohol swabs

 

Examples of combination products where the components are separately provided but labeled for use together (21 CFR 3.2(e)(3) or (e)(4)):

 

  • Photosensitizing drug and activating laser/light source
  • Iontophoretic drug delivery patch and controller

 

Recent examples of combination product approvals may be found on the OCP website.

 

What are the roles of the Office of Combination Products?

 

The roles of the Office of Combination Products (OCP) are:

 

  • To serve as a focal point for combination product issues for agency reviewers and industry.
  • To develop guidance and regulations to clarify the regulation of combination products.
  • To assign an FDA center to have primary jurisdiction for review of both combination and single entity (i.e., non-combination) products where the jurisdiction is unclear or in dispute.
  • To ensure timely and effective premarket review of combination products by overseeing the timeliness of and coordinating reviews involving more than one agency center.
  • To ensure consistency and appropriateness of postmarket regulation of combination products.
  • To resolve disputes regarding the timeliness of premarket review of combination products.
  • To update agreements, guidance documents, or practices specific to the assignment of combination products.
  • To submit annual reports to Congress on the Office’s activities and impacts.

 

The legislation requiring FDA to establish the Office of Combination Products.

 

What staff members comprise the Office of Combination Products, and whom can I contact for specific issues?

 

The Office of Combination Products currently has 9 staff members:

 

Thinh X. Nguyen - Director

Patricia Y. Love, MD., MBA. - Deputy Director

John (Barr) Weiner, J.D. - Associate Director for Policy and Product Classification Officer

Leigh Hayes, J.D. - Senior Regulatory Council for Product Jurisdiction/Product Assignment Officer

Kristina J. Lauritsen, Ph.D. - Senior Scientific Reviewer

Joseph Milone, Ph.D. - Senior Scientific Reviewer

Bindi Nikhar, MD. - Associate Clinical Director

Michael Berman, Ph.D. - Senior Scientist

Bibi K. Jakrali - Management Analyst

 

Questions can be directed to any OCP staff by e-mail (combination@fda.gov) or by telephone (301-796-8930).

 

I have some questions about how a combination product will be regulated. What information will help OCP understand my product so they may respond to my inquiry?

 

OCP is available as a resource to help answer any question, general or specific, regarding combination product regulation/review or product jurisdiction. For questions about specific products, the following information will usually be helpful to relay to OCP: (1) a brief description of the product and its major components; (2) a description of the intended use of the product, (the clinical/therapeutic claims, including the types of patients it will be used for); (3) an explanation of the product’s modes of action (how the product works); and (4) any other information you think is relevant to your inquiry. The information outlined in 21 CFR 3.7 might also be appropriate.

 

How can I contact OCP?

 

You may e-mail OCP at combination@fda.gov , or call OCP at (301) 796-8930. Our mailing address is WO32, Hub/Mail Room #5129, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002. Our fax number is (301) 847-8619.

 

Where can I find out about workshops and public meetings on combination products?

 

FDA held a public hearing on the Regulation of Combination Products on November 25, 2002. The presentation materials and transcript for that meeting are posted at the above link.

 

FDA held a workshop titled FDA Workshop on Novel Drug Delivery Systems: Scientific, Clinical and Regulatory Challenges on July 8, 2003.  The slides and transcripts are at the link above.

 

FDA and DIA co-sponsored a public workshop titled Combination Products and Mutually Conforming Labeling on May 10, 2005. The agenda, presentation materials, transcript and the Federal Register notice announcing meeting are posted at the like above.

 

Future FDA-sponsored workshops will be announced in the Federal Register and on the Combination Products Website. In addition, OCP staff members often participate in workshops and educational meetings about combination product regulation.

 

How can I get copies of slides from OCP presentations?

 

Recent OCP presentations are posted on the Meetings, Conferences & Workshops section of the Combination Products Website.

 

Where can I find a summary of yearly OCP activities?

 

OCP’s most recent Report to Congress summarizes OCP’s activities and impacts. Much of OCP’s work is also posted on the Combination Products Website. In addition, the Office is currently developing guidance for adverse event reporting and for determining the appropriate number of marketing applications for combination products. We are also working to finalize guidance documents and regulations previously issued in draft form. Stakeholders have identified a number of other important issues that OCP will need to address, such as handling of post-approval changes, labeling format, registration and listing, and promotion and advertising. The Office will also evaluate the impact of the new policies, as well as the need for revisions or legislative changes. OCP is committed to continuing to seek input from stakeholders on its activities.

 

Product Jurisdiction/Assignment of Combination and Non-Combination Products:

 

How are combination products assigned for review?

 

A combination product is assigned to an Agency Center or alternative organizational component that will have primary jurisdiction for its premarket review and regulation. Under section 503(g)(1) of the Act, assignment to a center with primary jurisdiction, or a lead center, is based on a determination of the “primary mode of action” (PMOA) of the combination product. For example, if the PMOA of a device-biological combination product is attributable to the biological product, the Agency component responsible for premarket review of that biological product would have primary jurisdiction for the combination product.

 

A final rule defining the primary mode of action of a combination product was published in the August 25, 2005, Federal Register. The final rule defines primary mode of action as “the single mode of action of a combination product that provides the most important therapeutic action of the combination product.”

 

In some cases, neither FDA nor the sponsor can determine the most important therapeutic action at the time a request is submitted. A combination product may also have two independent modes of action, neither of which is subordinate to the other. To resolve these types of questions, the final rule describes an algorithm FDA will follow to determine the center assignment. The algorithm directs a center assignment based on consistency with other combination products raising similar types of safety and effectiveness questions, or to the center with the most expertise to evaluate the most significant safety and effectiveness questions raised by the combination product. The final rule is effective November 23, 2005.

 

Additional information about the final rule can be found on the Guidance & Regulatory Information section of the Combination Products Website.

 

How do I determine which Center will review my combination or non-combination product?

 

Requests for assignment of combination or non-combination products may be handled formally or informally. In some cases, jurisdiction may be determined informally based on FDA experience with similar products. Informal jurisdictional determinations are not binding on the agency. Sponsors wishing to discuss jurisdictional issues informally may contact the OCP Product Assignment Officer (for combination products) or the OCP Product Classification Officer (for non-combination/single entity products) 

 

The formal jurisdiction process for both combination and non-combination/single entity products is accomplished through the Request for Designation (RFD) process, described in 21 CFR Part 3. When the jurisdiction of a combination or non-combination product is unclear or in dispute, a formal request for designation should be submitted to the Office of Combination Products. Sponsors are encouraged to submit an RFD as soon as they have sufficient information for FDA to make a decision regarding assignment of a product.

 

How do I submit a Request for Designation for a combination or non-combination product?

 

The Request For Designation (RFD) process is outlined in 21 CFR Part 3, and the specific information to be included in the RFD is described in detail in 21 CFR 3.7. FDA also has issued a guidance document "How to Write a Request for Designation" to provide guidance to sponsors on the kind of information FDA needs in an RFD in order to make its jurisdictional determination. The guidance is available on the Combination Products section of the FDA website.

 

The RFD is limited to 15 pages and should include all information required by 21 CFR 3.7. On receipt of the RFD, OCP conducts a review to ensure the submission has all the information required by 21 CFR 3.7 in sufficient detail for FDA to make a determination. OCP has found that the most frequent sections of an RFD that are incomplete leading to non-filing are the following, so submitters are encouraged to pay close attention to these sections: the intended use of the product (what the product does), its modes of action (how the product works), its primary mode of action, and its recommendation as to which Agency Center should have primary jurisdiction, along with a statement of reasons supporting the recommendation. A final rule defining the primary mode of action of a combination product was published in the August 25, 2005, Federal Register, and is available on the Combination Products section of the FDA website. For non-combination products, submitters are encouraged to explain the reasons supporting their recommendation as to which Agency Center should have primary jurisdiction by explaining which medical product definition their product meets. For drugs and devices, these definitions are provided in 21 U.S.C. 321. For biological products, the definition is provided at 21 CFR 600.3.

 

How promptly will my RFD be reviewed?

 

The Office of Combination Products (OCP) will make its jurisdictional determination within 60 days of filing the RFD, as required by 21 CFR 3.8 and Section 563 of the Food, Drug and Cosmetic Act. OCP’s review performance for RFDs are available on the Combination Products section of the FDA website.

 

Premarket Review and Postmarket Regulation of Combination Products

 

What investigational application should I use for a combination product?

 

a. How many applications?

 

FDA only needs one investigational application for a combination product.  That application should include all information on the entire combination product.  For example, if the investigation is for a drug-device combination product, the application should include the details on the drug and device that typically would be submitted in an IND and IDE, respectively.

 

b. How to decide if an IND / IDE may be needed?

 

FDA considers the entire combination product in determining the need for an investigational application.  For example, in some investigational protocols one part of the combination product might be already approved but another part is new and raises safety risks.  Therefore, the entire combination product raises a safety risk and would be under an investigational application.

 

In some instances both the drug and device are already approved for different indications, but when the two are used together a new risk exists.  In such cases, the combination product as a whole would be under an investigational application submitted to the lead center.

 

c. Which center has the lead?

 

The lead center for the investigation of a combination product is determined by the primary mode of action (PMOA).  In most cases the type of investigational application is that typically required by the lead center.  For example, if the device is the PMOA, the lead center would be CDRH and the investigation would be under an IDE that includes the drug information.

 

What types of marketing applications are required for a combination product?

 

Depending upon the type of combination product, its approval, clearance or licensure may be obtained through submission of a single marketing application, or through separate marketing applications for the individual constituent parts of the combination product.

 

For most combination products, a single marketing application is sufficient for the product’s approval, clearance, or licensure. In some cases, however, a sponsor may choose to submit two marketing applications for a combination product when one application would suffice. For example, a sponsor may choose to submit two applications in order to receive some benefit that accrues only from approval under a particular type of application (e.g., new drug product exclusivity, orphan status, or proprietary data protection when two firms are involved). In other cases, FDA may determine that two marketing applications are necessary. For example, when one of the individual constituent parts of a combination product is already approved for another use, and where the labeling of the already approved product will need to be changed to reflect its new intended use in the combination product, FDA may determine that two applications are necessary if the labeling of the already approved product is subject to legal requirements different from those that will apply to the combination product. OCP is developing a guidance document for public review and comment addressing the factors FDA expects to consider in determining whether a single or multiple marketing applications should be submitted for a combination product.

 

Does OCP review marketing applications for combination products?

 

No. OCP does not review marketing applications for combination products. OCP assigns a lead Center (CBER, CDER or CDRH) that will have primary jurisdiction for the premarket review and regulation of a combination or single-entity product, and develops policy for combination product regulation. OCP is also responsible for ensuring timely and effective premarket review of combination products by overseeing the timeliness of and coordinating reviews involving more than one agency center. In addition, OCP is available as a resource to industry and agency reviewers to help facilitate the review process, to help clarify and/or develop appropriate regulatory pathways, or to provide any other assistance as appropriate to OCP’s mission.

 

What format should I use to submit a marketing application for a combination product?

 

OCP and the Centers are working on recommendations for formatting of marketing applications for combination products that will help facilitate review by all appropriate agency components. In the interim, sponsors are encouraged to discuss this issue during pre-submission meetings with the Agency.

 

What is the difference between consultative and collaborative reviews of combination products?

 

When combination products are assigned to a lead Center, that Center may consult or collaborate with another Center as part of the review process. FDA has a Standard Operating Procedure for the intercenter consultative and collaborative review process. The SOP includes the definitions of consultative and collaborative reviews, and sets out the procedures, policies and processes for Agency staff to use when requesting, receiving, handling, processing, and tracking formal consultative and collaborative reviews of combination products, devices, drugs and biological products. 

 

A consultative review, which is the most frequent process used for the review of combination products by a Center other than the lead Center, is a review activity in which a reviewer in one Center requests advice from a reviewer in another Center on a specific question or issue raised in the review of a submission. The consultative review is used to assist the requesting reviewer in making appropriate regulatory/scientific decisions.

 

In contrast, a collaborative review is a review activity in which reviewers in two or more Centers have primary review responsibilities, generally for a defined portion of a submission. Regulatory and scientific decisions will be made by the management of each Center for that portion of the review assigned to it, including the decision to approve or disapprove the product.

 

Where can I find guidance documents about combination products?

 

The Office of Combination Products has several draft guidance documents posted on the FDA website. In addition, links to a variety of guidance documents developed by CBER, CDER, and CDRH that might be of interest to combination product manufacturers are also available.

 

How do I request that OCP or review staff from a consulting Center attend a regulatory meeting, such as a pre-IDE or pre-IND meeting, with agency reviewers?

 

You can make such a request in your formal request to the lead Center for the meeting, and copy OCP or the consulting Center on the request, as appropriate.

 

What good manufacturing practice regulations apply to combination products?

 

OCP has published a draft guidance document for Current Good Manufacturing Practices for Combination Products. The guidance is posted on the Combination Products section of the FDA website.  OCP intends to publish a proposed regulation to clarify good manufacturing practice requirements for combination products.

 

How are adverse events reported for combination products?

 

OCP posted a request for comments for a concept paper about adverse event reporting for combination products.  Also, OCP intends to publish a proposed regulation to clarify adverse event reporting requirements for combination products.

 

Where can I get information about user fees for combination products?

 

OCP has published guidance document explaining how user fees are handled for combination products. The user fees guidance is posted on the Combination Products section of the FDA website.

 

Where can I find guidance for what kind of safety and effectiveness information is needed to support approval of a combination product?

 

The best approach would be to contact the lead Center review division to discuss this issue in conjunction with the consulting center or OCP as appropriate. In addition, by reviewing approval documentation for approved combination products (available on each of the Centers’ websites), you can often get insight into study design and related issues for products FDA has approved.

 

Where can I find guidance for how master files can be used in the submission of information relevant to my combination product?

 

Guidance for Drug Master Files and Drug Master File Binders, master files for biological products, and for master files for devices is available.

 

We have developed a new combination product and would like to initiate a dialogue with the appropriate FDA staff to obtain guidance on how to go about obtaining approval. However, we have limited experience in dealing with the FDA and do not know whom we should contact. Can the Office of Combination Products help?

 

Yes. One of OCP’s functions is to help facilitate meetings between industry and the Agency for combination products. You can contact OCP by either e-mail (combination@fda.gov) or telephone (301-796-8930) and, based on the composition of your product and its intended use, a member of our staff will work with you to identify the FDA staff with the appropriate scientific, clinical, and regulatory expertise to discuss your product, and to help organize and schedule the meeting.

 

How do I submit a formal request that OCP resolve a dispute regarding the timeliness of premarket review of a combination product?

 

OCP published guidance document describing the procedures for submission and FDA action on a formal request that OCP resolve a dispute regarding the timeliness of premarket review of a combination product. The document is available Guidances section of the FDA website

 

The Medical Device User Fee and Modernization Act (MDUFMA) requires FDA to report annually on the numbers and types of combination products reviewed, and the timeliness of such reviews. Where can I find these data, and how does FDA determine the types of combination products?

 

OCP reports annually to Congress on the numbers and types of combination products reviewed and the timeliness of such reviews. The Reports are posted on the Combination Products section of the FDA website.

 

FDA developed a method to help agency reviewers categorize products under review as to whether or not they concern a combination product, and if so, what type. The types of combination products include:

 

Convenience kit or co-package

Prefilled drug delivery device/system

Prefilled biologic delivery device/system

Device coated/impregnated/otherwise combined with drug

Device coated or otherwise combined with biologic

Drug/biologic combination

Separate products requiring mutually conforming labeling

Possible combination product based on mutually conforming labeling of separate products

Other type of combination product

Other Issues

 

How are products that combine two or more drugs regulated?

 

A product that combines two or more drugs (without including a device or biological product) is not a combination product as defined in 21 CFR 3.2(e). The Center for Drug Evaluation and Research (CDER) regulates combination drug products, including those that involve drugs provided in a single dosage form (“fixed combination” drug products) or as separate co-packaged drug products. 21 CFR 300.50 provides specific requirements for fixed combination prescription drug products. You should refer any specific questions about combination drug products to the responsible reviewing Division in CDER’s Office of New Drugs. If you are unsure which CDER Division would be responsible for the review of your product, or if you have a general inquiry, please contact the Regulatory Affairs Team in CDER’s Office of New Drugs at (301) 796-0700.

 

How are products that combine a drug and a cosmetic regulated?

 

A product that combines a drug and a cosmetic (without including a device or biological product) is not a combination product as defined in 21 CFR 3.2(e). Information about cosmetics may be found on the Cosmetics section of the FDA website. Specific information about drug-cosmetic products is provided. You should refer any specific questions about combination drug-cosmetic products to the responsible reviewing Division in CDER’s Office of New Drugs. If you are unsure which CDER Division would be responsible for the review of your product, or if you have a general inquiry, please contact the Regulatory Affairs Team in CDER’s Office of New Drugs at (301) 796-0700.

 

How are products that combine a drug and a dietary supplement regulated?

 

A product that combines a drug and a dietary supplement (without including a device or biological product) is not a combination product as defined in 21 CFR 3.2(e). Information about the regulation of dietary supplements is provided on the Dietary Supplements section of the FDA website. You should refer any specific questions about combination drug-dietary supplement products to the responsible reviewing Division in CDER’s Office of New Drugs. The contact information can be located on the CDER Reference Guide. If you are unsure which CDER Division would be responsible for the review of your product, or if you have a general inquiry, please contact the Regulatory Affairs Team in CDER’s Office of New Drugs at (301) 796-0700.

 

I believe my combination product may qualify for designation as an orphan drug or biological product, or as a humanitarian use device. Where can I find information about orphan product regulation?

 

Information about orphan product and humanitarian use device designation may be found on the Developing Products for Rare Diseases & Conditions section of the FDA website. If you are unsure whether your product is a drug, biological product, device or combination product (i.e., its regulatory identity is unclear), you are encouraged to submit a Request for Designation (see information above) prior to submitting an orphan product or humanitarian use designation request.

 

Where can I find more information about the regulation of nanotechnology products, including combination products involving nanotechnology?

 

Information about nanotechnology, including FDA regulation of nanotechnology products, is available on the Nanotechnology section of the FDA website. The FAQs also address combination products involving nanotechnology.