Biologic-Device Combination Products: Jurisdiction

For Life Science Companies

More and more companies are developing combination products for many life-threatening and unmet medical needs. One area that holds much promise is the development of tissue engineered products which contain living cells or tissues combined with a device. As with any novel technology, questions regarding what the requirements will be by the regulators to obtain market approval is always an issue. This has been a changing dynamic in other parts of the world but the Food and Drug Administration (FDA) has dealt with these products for some time and has developed a reasonable approach to regulating combination products. This article will focus on the FDA approach to jurisdiction of cell and device combination products.

What a combination product is not is a drug-drug combination, biologic-biologic combination, or device-device combination. Many people are under the impression that they have a combination product if the two components are regulated by two different centers.

What is a combination product?

The definition for what constitutes a combination product is defined in the Code of Regulations (CFR) at 21 CFR 3.2(e). It basically is the combination of two or more regulated components i.e. drug-device, device-biologic, drug-biologic, drug-device-biologic. The components can be physically or chemically combined, co-packaged in a kit, or sold separately but the two components must be cross labeled for use together. What a combination product is not is a drug-drug combination, biologic-biologic combination, or device-device combination. Many people are under the impression that they have a combination product if the two components are regulated by two different centers. However, with the transfer of some biologic products to the Center for Drug Evaluation and Research (CDER) in 2001 and the fact that the Center for Biologics Evaluation and Research (CBER) regulates both biologics and devices, this is not the case. One can develop a biologic-drug combination product where both components are regulated individually by the same center. Many examples of combination products can be found on the FDA website (https://www.fda.gov/oc/combination/determinations.html). Some of the cell device combination products include such products as autologous chondrocytes and scaffold for repair of cartilage defects, autologous cell therapy and delivery device to treat cardiovascular disease, cultured bone marrow cells and bone void filler with handling agent for bone repair, and dental implant coated with autologous cells to name a few. Companies are developing combination products as metabolic support systems for hepatic and renal indications and many tissue repair/replacement products to treat cardiovascular disease, orthopedic indications, musculoskeletal problems, neurologic and wound healing indications.

How does FDA regulate combination products?

Because of the complexity of these products, it is sometimes difficult to understand which regulatory requirements apply to combination products. As a result of this confusion, Congress mandated in the Medical Device User Fee and Modernization Act of 2002 that FDA establish an Office of Combination Products (OCP) within the Office of the Commissioner. This office was established on December 24, 2002. The role of this office is to make jurisdictional determinations, oversee/help coordinate premarket review, ensure consistent/appropriate postmarketing regulation, develop policy, guidance, and regulations, serve as a resource for industry and the FDA review staff, and resolve timeliness disputes. This office has no direct responsibility for the review and regulation of the actual products but instead works with industry and the three medical product centers (CBER, CDER and CDRH). The objective of OCP is to ensure that the regulations for combination products are clear, consistent, appropriate, predictable, and transparent. One area of confusion is understanding the jurisdictional process and decisions. OCP has taken great strides in publishing the final rule on determination of the primary mode of action (PMOA), listing over 200 jurisdictional decisions on their webpage, providing jurisdictional updates that cover classes of products, providing redacted requisition for designation (RFD) decision letters for approved products and working with the centers to define the intercenter agreements.

What is the process for deciding who will have regulatory oversight?

There are two pathways a sponsor can take to determine which center will have primary responsibility for regulating a combination product. One avenue is an informal process which involves calling or emailing OCP and briefly describing the product and how it works. In some cases, OCP can make a determination. However, this decision is not binding on the agency and no letter is sent by the agency confirming the decision. If a sponsor does not like the decision through the informal process, they can always go through the formal process known as a request for designation. In this case there is a formal submission to the agency of less than 15 pages. The decision made by the agency is binding and therefore a letter is issued to the company. If the company still disagrees with the decision, there is an appeal process.

When should an RFD be submitted?

A company should submit an RFD for any product where the jurisdiction is unclear or is in dispute. This submission should be before the filing of an application for premarket review but where there is sufficient information for FDA to make a determination it is probably not a good idea to submit an RFD for a concept product. Scientific data definitely help FDA make a determination. It is not a good idea to send an application to a particular center if there is not a clear jurisdiction for your product. If this happens, FDA can make a determination later that your product has been reviewed by the wrong center and they will change the lead center. This can cause significant delay in development, change in regulatory requirements, and can cost the company a significant amount of money.

What is the RFD process?

The submission of an RFD is voluntary. The requirements are described in 21 CFR 3.7. In general, as indicated above, the submission of less than 15 pages is sent to OCP. They have 60 days from the filing date to make a decision and issue a letter with the final decision. During the 60-day review clock, they will review the RFD, sending it to appropriate center jurisdiction officers for their review and input. In the case of cells/tissue and device combination products, the RFD would be sent to CBER and CDRH for input on the jurisdictional decision. Most of the time the center jurisdictional officer will involve appropriate review staff to provide scientific rationale to support the center decision. In addition, for really difficult decisions, there may be internal meetings between the different centers and OCP to better understand the product and the mode of action. If a letter is not issued within 60 days, the sponsor's recommendation of the center with primary jurisdiction shall become the designated agency component.

What should be included in an RFD?

In August 2005, FDA issued a final guidance document that described the content of an RFD ("Guidance for Industry and FDA Staff: How to Write a Request for Designation (RFD) (https://www.fda.gov/oc/combination/howtowrite.html). The key elements of an RFD include a description of the product; how the product will be used; how the product works; the product's most important therapeutic action; the basis for the company's determination of PMOA; and how the company thinks the product should be assigned—and why—based on the algorithm outlined in the final rule for PMOA.

How does FDA decide the lead center?

Regulation 21 CFR 3.4(a) says that FDA should determine the lead center based on the product's "primary mode of action." However, the regulation does not define PMOA. This has caused some confusion over how FDA makes this determination. In August 2005, FDA issued a final rule defining PMOA for combination products. In some cases it is very difficult to assign a single PMOA to a combination product. In those instances, FDA has outlined an algorithm for establishing the lead center. This final rule defines PMOA as the single mode of action of the combination product that provides the most important therapeutic action of the combination product. That is, what mode of action makes the greatest contribution to the overall intended therapeutic effect. If the PMOA is dependent on the biologic, the combination can be assigned to CBER or CDER, depending of the type of biologic in the combination product. If the PMOA is dependent on the drug, the combination product will be assigned to CDER. If the PMOA is dependent on the device, the combination product will be assigned to either CDRH or CBER, depending on the type of device. For cell and device combination products, generally the primary jurisdiction for the premarket review and regulatory oversight will be assigned to CBER. However, if the cells are present to enhance the function of the device, the jurisdiction will be assigned to CDRH. An example of this is the dental implant coated with autologous cells.

However, in those cases where the PMOA cannot be determined, the FDA will then make an assessment regarding the safety and effectiveness questions for the product and the center that has similar products will be assigned the lead center. If it is a novel product and there aren't similar products at the agency, then FDA assesses which center has the expertise to address the issues of safety and effectiveness (Figure 1).

What is in an RFD letter issued by FDA?

The letter issued by FDA will describe FDA's understanding of the product and the PMOA. It will designate the lead center and in some cases will indicate the regulatory pathway. However, the lead center has the authority to dictate the regulatory pathway. It will also include language to indicate whether the review will be under the consultation process or will be a collaborative review between two or more centers. This is an important distinction because under consultative review, one center has the regulatory responsibility and sign-off and the other center serves as a consult to the lead center. The lead center can accept the consult review or make changes. However, rarely does the lead center overturn the consult center's review and recommendations. Under collaborative review, both centers have regulatory responsibility and sign-off. So if one center decides that there are concerns and doesn't allow a study to proceed, the other center cannot override that decision.

Conclusions

As these types of products move forward in development, there has been a lot of progress toward making the regulatory requirements much more transparent. When issues or uncertainty arise, FDA has instituted a clear process for resolution of those issues through the help of OCP interacting with industry and review staff at FDA. There are still many concerns, such as post-marketing requirements, adverse event reporting and cross labeling, that still need to be resolved. However, there is a clear process for obtaining a jurisdiction decision by the agency so that companies can be assured that they are talking and interacting with the appropriate agency components.