By: Brandon D. Burch, M.S., Ph.D. Senior Manager, Scientific Writing & Regulatory Affairs
Drug, biologic and device combinations have the potential to make treatments safer, more effective and/or more convenient for patients. But obtaining approval for a combination product involves complexities beyond a typical development program. The first key to success is understanding what FDA considers to be a combination product and how these products are regulated.
Combination Products Defined
In 1990, the US Congress amended the Federal Food, Drug and Cosmetic Act to introduce the concept of combination products and to clarify product jurisdiction issues. Put simply, a combination product is a product comprised of two or more FDA-regulated components (i.e., drug/device, biologic/device, drug/biologic or drug/device/biologic) that are intended for use together. Importantly, products consisting solely of components of the same class (i.e., drug/drug, biologic/biologic or device/device) are not considered to be combination products. Within the Code of Federal Regulations, 21 CFR 3.2(e) considers combination products to include:
1) Single Entity Combinations: 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. Examples: Drug conjugated to an antibody, prefilled syringe, transdermal patch, drug eluting stent, metered dose inhaler
2) Separate Products Packaged Together: 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. Examples: Drug or biologic packaged with a delivery device; Surgical tray with instruments, drapes, and lidocaine or alcohol swabs
3) Products Packaged Separately but Intended for Use Together (2 Types, Depending upon the Regulatory Status of the Components):
- A drug, device or biological product that is packaged separately and intended for use only with an individually specified approved drug, device or biological product where both are required to achieve the intended use, indication or effect and whereupon approval of the proposed product the labeling of the approved product would need to be changed to reflect, for example, a change in intended use, dosage form, strength, route of administration or significant change in dose, or
- Any investigational drug, device or biological product that is packaged separately and intended 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. Examples: Photosensitizing drug and specified activating laser/light source; Iontophoretic drug delivery patch and controller
Navigating the Regulatory Landscape
Despite being comprised of two or more regulated components, combination products generally proceed through a single approval pathway, either as a drug, biologic or device. This product classification is based upon the primary mode of action of the product and determines the FDA center with primary jurisdiction over the product (CDER for drugs, CBER for biologics and CDRH for devices), although other centers may be utilized in an advisory capacity.
While the primary mode of action of a combination product is often clear, it may not be readily apparent for all products, may be the subject of dispute, or otherwise may not be covered by existing FDA intercenter agreements. In such cases, FDA encourages sponsors to confirm their product’s classification early in product development. Doing so can save both time and money and facilitate a more streamlined development program.
Confirming your Product’s Classification
Submit a Request for Designation, also known as a “letter of request,” to FDA’s Office of Combination Products (OCP). Within 60 days, OCP will respond with a Letter of Designation that specifies the center with primary jurisdiction and any consulting centers.
When it comes time to submit for marketing approval, a single application to the lead center at FDA is generally sufficient, although there may be select cases where two applications may be desirable to the sponsor or required by FDA. Two applications may allow the sponsor to claim some benefit that accrues only from approval under a particular type of application, for example, new drug product exclusivity, orphan status, or proprietary data protection when two firms are involved. On the other hand, FDA may require two applications under the following scenarios:
- If a constituent part is already approved for another use, its label will need to be changed to reflect its use in the combination product, and the approved label is subject to legal requirements different from those of the combination product,
- If a constituent part has been approved for the intended use, but that approved agent is not licensed for use in the combination product, or if it is further processed as part of combination product manufacturing, or
- If the product pairs a therapeutic product with an in vitro diagnostic device (IVD). Note that while FDA expects that most such products will not meet the statutory definition of “combination product,” FDA currently intends to require separate marketing applications for these products regardless of combination product status.
Importantly, if multiple applications are filed, the sponsor will be responsible for application fees for both applications unless a fee waiver is obtained.
Combination products present an exciting opportunity for improving medical treatment safety, efficacy, and convenience. Understanding what combination products are and how they are regulated is the first step toward an efficient development and approval process.
A future post will explore important considerations and guidelines for combination product development.