May 15, 2005 (Vol. 25, No. 10)
Initiatives Continue to Evolve
Combination products, i.e., those containing any combination of a drug, device, or biological, constitute a growing category of innovative medical products. Examples include a drug with an implantable delivery device, drug-eluting cardiovascular stents, and autologous cells with scaffolds for orthopedic use.
While these products contribute to advancing medical care, they also pose a challenge for the FDA since, by definition, they straddle existing statutory classifications of regulated products, thereby complicating the selection of the appropriate review and approval pathway.
Congress recognized the existence of such combination products (CPs) when it enacted The Safe Medical Devices Act of 1990 and established that the FDA shall classify a CP according to its primary mode of action [see Section 503(g) of the Federal Food, Drug, and Cosmetics Act (21 USC 353(g)].
To implement this new regulatory authority, the FDA defined a CP in 21 CFR 3.2(e), as:
a product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed as a single entity; or
two or more separate products packaged together; or
a product packaged separately but intended for use only with an approved, individually specified 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 where both products are investigational.
From its determination of the primary mode of action (PMOA) of the CP, the Agency could then assign jurisdiction over the product to one of its established Centers.
For example, if the PMOA is that of a drug, the product is assigned to CDER, with similar assignments of devices to CDRH, and biological products to CBER. In 1991, FDA issued a final rule establishing the process (known as a Request for Designation; RFD) by which a product sponsor could petition the Agency to make such an assignment.
The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) modified Section 503(g) of the Act to require the FDA to establish an office with the primary responsibility for providing regulatory oversight of CPs.
The Office of Combination Products (OCP), located within the Office of Commissioner, assigns a CP to the appropriate FDA Center, ensures timely and effective premarket review as well as appropriate and consistent postmarket regulation, resolves any disputes, reviews/updates guidances, agreements, and practices, and is a valuable resource for industry and the FDA Center(s) review staff.
OCP reports to Congress on an annual basis. Although OCP does not actually perform the review process for market clearance or approval, there has been much progress since this Office was established in making this often complex regulatory area more efficient, transparent, and better understood.
Assignment of product to a center
Clearly the most important issue for a sponsor of a CP is the assignment of the product to a Center for regulatory review. As indicated, the RFD process, which is voluntary, can be used by sponsors to obtain a formal determination of which FDA Center will have primary jurisdiction (the lead Center) for premarket review and regulation of their CPs.
Details of the RFD process can be found at 21 CFR 3.7 and on the OCP website (www.fda.gov/ oc/combination).
Typically, an RFD of no more than 15 pages is submitted to OCP before filing a premarket review application and as soon as there is sufficient information for the Agency to make a determination.
In addition to the product description, status of developmental work and description of the manufacturing process, the RFD should include a description of all known components modes of action (MOA), the sponsors identification of the CPs PMOA and the basis for this determination, and the sponsors recommendations as to which FDA Center should have primary jurisdiction.
Upon receipt, OCP has 60 days to render a decision. Sponsors can request reconsideration of the decision within 15 days and, the FDA must respond to this within 15 days.
Because of its important role in overseeing jurisdictional determinations, OCP has become the focus and, often, primary point of entry for sponsors of CPs. For its part, OCP encourages informal as well as formal (through the RFD process) interactions with sponsors regarding jurisdictional issues/questions.
In an effort to enhance transparency of the jurisdiction process, OCP has published (via their website) capsular descriptions of selected jurisdictional decisions. These descriptions include only prior RFD decisions and are not policy statements.
They are intentionally general to ensure protection of trade secret and confidential commercial information. However, the list of CPs assigned to the regulatory Centers can be helpful to sponsors in anticipating the assignment of their particular CPs. OCP also publishes recent examples of CP approvals and reports on its RFD review performance.
As indicated, the FDA has traditionally required sponsors submitting a RFD to identify the PMOA of the product and recommend an FDA Center to take the lead in premarket product review and regulation. However, there is no statutory definition of what constitutes the PMOA.
PMOA Proposed Rule
In fact, many in the industry have indicated that, without a statutorily codified definition, the CP assignment process has at times appeared arbitrary. To address these concerns and to simplify and clarify the designation process, OCP published a proposed rule on May 7, 2004, to amend its CP regulations to define/codify MOA and PMOA (Definition of Primary Mode of Action of a Combination Product, Proposed Rule, 69 FR 25527).
In addition to these definitions, the PMOA Proposed Rule describes an algorithm that the Agency would use to assign a CP to a Center for regulatory oversight when it cannot determine with reasonable certainty which MOA provides the most important therapeutic action of the product.
The Proposed Rule would require a sponsor to base its recommendation of the Center with primary jurisdiction for its CP by using the PMOA definition and, if appropriate, the assignment algorithm.
Under the Proposed Rule, MOA would be defined as the means by which a product achieves a therapeutic effect. Therapeutic includes any effect or action of the product intended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure or any function of the body.
There are three types of MOA, corresponding to the existing statutory definitions of regulated medical products, i.e., that of a drug, device, or biological product.
Since a CP consists of more than one type of regulated component, it will typically have a combination of drug, device, or biological product MOAs corresponding to the definitions of its regulated components. The PMOA of this CP would be defined as the single MOA that provides the most important therapeutic action of the CP.
The assignment algorithm is followed in cases where it is not possible to determine the most important therapeutic action of the CP with reasonable certainty. This may occur in cases where there are two important, independent MOA, neither of which is subordinate to the other or when it is too early in product development to know this with any certainty.
The CP would then be assigned to the Center that regulates other CPs that present similar questions of safety and effectiveness with regard to the CP as a whole. In other words, assignment would be to the Center with direct experience in that type of CP.
If there are no other CPs that present similar questions of safety and effectiveness with regard to the CP as a whole, for example, when it is the first such CP or where differences in intended use or design present different safety and effectiveness questions, then the algorithm continues with assignment to the Center with the most expertise related to the most significant safety and effectiveness questions presented by the CP. In other words, assignment would be to the Center with the most related experience for the product.
Simplifying Designation Process
In summary, the goal of the Proposed Rule is to simplify the designation process for sponsors by providing a defined framework sponsors may use when recommending and/or considering the PMOA and assignment of a CP to a Center.
The framework is based on an assessment of the CP as a whole; its intended use and effect; consistency with assignment of similarly situated products; and safety and effectiveness issuesall of which have been recommended by the industry and others as key factors for consideration through comments to the docket and at public hearings (May 15, 2002; November 25, 2002) and workshops (July 8, 2003).
Information about and presentations given at these hearings and workshops can be obtained through the OCP website. These requirements would affect RFDs submitted after the effective date of a final rule based on the Proposed Rule. OCP projects a final rule will be published by this summer.
The numbers and types of CPs developed will, most likely, continue to grow, given the research advances in many technology areas over the last few years. Recognizing this, the FDA, through its Office of Combination Products, continues, to its credit, to work on different ways to make the CP jurisdiction/ assignment process clearer and more predictable, the consultation process more systematic, and provide continued opportunities for industry input.
For example, the Office is currently working on initiatives in Good Manufacturing Practices/ Quality Systems Regulations (GMP/QSR), adverse event reporting, and cross-labeling issues, among others.