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Cutting Through the Red Tape of Combination Product Approvals

Wed, 10/11/2006 - 8:47am

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As the development and use of combination products increases, the FDA realizes it needs to establish specific guidelines to oversee this technology. This article explores some of the pivotal issues pertaining to how a combination drug-device, drug-biologic, or device-biologic is regulated.

By Suzan Onel
Getting combination products through the Food and Drug Administration (FDA) has recently become clearer and more predictable, but the pathway to product approval remains a challenge. Since drugs, devices, and biologics all have their own premarket applications, quality control regulations, and postmarket requirements, when these products are combined to create new products, complex questions arise.
What Is a Combination Product?
A combination product is a product that is comprised 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 Section 3.2(e), the combination does not need to be one integrated product, but may be (1) two or more separate products packaged together in a single package or as a unit, (2) a product composed of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity, or (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.

Some examples of combination products where the components are physically, chemically, or otherwise combined are drug-eluting stents, prefilled syringes, metered dose inhalers, condoms with spermicides, and chemotherapy drugs combined with monoclonal antibodies. Examples of combination products where the components are packaged together are convenience kits or surgical trays which contain surgical instruments and drugs, and a drug or biologic packaged with a drug delivery pump and/or catheter. Examples of combination products where the components are separately provided but labeled for use together are iontophoretic drug delivery patches and the iontophoresis device controller; and a lithotripter used in conjunction with a dissolution agent.
Which FDA Center Will Lead the Premarket Review?
Section 503(g) of the Federal Food, Drug, and Cosmetic Act requires that FDA assign a component of the agency to have “primary jurisdiction” for the regulation of a combination product. That assignment must be based on a determination of the primary mode of action (PMOA) of the product. For example, if the PMOA is that of a device, the combination product is to be assigned to the Center for Devices and Radiological Health (CDRH); if the PMOA is a drug, the combination product is to be assigned to the Center for Drug Evaluation and Research (CDER); and if the PMOA is a biologic, the combination product is to be assigned to the Center for Biologics Evaluation and Research (CBER).

For many years, CDRH, CDER, and CBER operated under three “Intercenter Agreements” (ICA) which generally guided FDA and industry as to which Center and regulatory authorities would lead the premarket review of such products. With the growth in the complexity and sheer number of combination products, the usefulness of the ICAs have become increasingly limited. As a result, in 2002, Congress created, as part of the Medical Device User Fee Modernization Act, an Office of Combination Products within FDA. The mission of this Office is to assist in the prompt assignment of combination products to the appropriate FDA Center and to oversee their “timely and effective” premarket review and postmarket regulation.

Currently Marketed Product Considerations

Prior FDA approval and/or clearance of a particular constituent part of a combination product is often an excellent starting point for considering the appropriate data to establish safety and effectiveness for its use in a combination product. FDA recommends that developers fully consider what is already established about a constituent part; i.e., what existing information and data are available, to avoid duplication and ensure a more timely and efficient development process. Throughout the development process, however, it is critical to recognize that it is the combination product that is being developed for approval/clearance, not just the constituent part. While this prior information is often very helpful, developers should recognize that additional data and information may be necessary to address the scientific and technical issues raised by the new use of the constituent in the combination product. These issues may be raised by combining the constituent parts or by new uses for the constituent in the combination product, such as a new indication for use, a different target population, a new route of administration, or by different local or systemic exposure profiles once the products are combined. For example, developers should consider:

  • Are the constituent parts already approved for an indication?
  • Is the indication for a given constituent part similar to that proposed for the combination product?
  • Does the combination product broaden the indication or intended target population beyond that of the approved constituent part?
  • Does the combination product expose the patient to a new route of administration or a new local or systemic exposure profile for an existing indication?
  • Is the drug formulation different than that used in the already approved drug?
  • Does the device design need to be modified for the new use?
  • Is the device constituent used in an area of the body that is different than its existing approval?
  • Are the device and drug constituents chemically, physically, or otherwise combined into a single entity?
  • Does the device function as a delivery system, a method to prepare a final dosage form, and/or does it provide active therapeutic benefit?
  • Is there any other change in design or formulation that may affect the safety/effectiveness of any existing constituent part or the combination product as a whole?
  • Is a marketed device being proposed for use with a drug constituent that is a new molecular entity?
  • Is a marketed drug being proposed for use with a complex new device?

  • Source: Excerpt from “Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Product” FDA Guidance Document; published September 2006.
    To further facilitate the process of assigning a Center with primary jurisdiction, FDA issued a final rule in August 2005 defining the PMOA of a combination product. According to this regulation, the PMOA is “the single mode of action of a combination product that provides the most important therapeutic action of the combination product.” [21 CFR Section 3.2(m); see also 70 Fed. Reg. 49848 (Aug. 25, 2005)] In some cases, a product’s PMOA is self-evident or the ICAs already provide guidance as to the Center with primary jurisdiction. In these cases, there is no need for a formal assignment of jurisdiction. For example, transdermal patches and nebulizers have typically been assigned to CDER based on the agency’s determination that the drug’s role provides the most important therapeutic action of the combination product. Similarly, wound dressings and bone cements containing antimicrobial agents are typically assigned to CDRH because the primary intended purpose of the product is to fulfill a device function.

    In other cases, it may be difficult for a company or FDA to determine the “most important” therapeutic action. For example, a product may have two independent modes of action, neither of which is clearly subordinate to the other; or the way the product achieves its therapeutic effect may not be known. In these situations, the sponsor may submit to the Office of Combination Products a formal request for designation (RFD) of jurisdiction pursuant to 21 CFR Section 3.7. According to 21 CFR Section 3.4, FDA will base its assignment of jurisdiction on an algorithm that would first assign a combination product to a Center that has had experience with combination products presenting similar safety and effectiveness issues. When no such prior product exists, FDA would assign the product to the Center with the most expertise to evaluate the most significant safety and effectiveness questions presented by the combination product. To assist sponsors in anticipating the most likely lead Center, FDA has issued over 128 capsular descriptions of its product jurisdiction decisions made since 1991 and its responses to formal RFD.1 This information is publicly available on FDA’s website.
    What Type of Premarket Submission Needs to be Filed?
    Once a combination product has been assigned a lead Center, that Center will have primary jurisdiction for the premarket review and regulation of the combination product. Generally, a single premarket submission is sufficient to obtain the combination product’s approval, clearance, or licensure. However, in some cases, a sponsor may need or want to submit two applications in order to receive a benefit that only accrues from approval under that type of application (e.g., new drug product exclusivity, orphan status, or proprietary data protection). In other cases, FDA may require two submissions, such as when one of the individual constituent parts of a combination product is already approved for another use and the labeling will need to change to reflect its new intended use in the combination product.

    As part of the review process, the lead Center may consult or collaborate with another Center. A consultative review is where a reviewer in one Center requests advice from a reviewer in another Center on a specific question or issue raised in the review of the submission. A collaborative review is where reviewers in two or more Centers have primary review responsibilities, generally for discrete portions of the submission. Both of these processes have to be closely managed because they have the potential for significantly lengthening the review time since the lead Center must wait for a response from the other Center before completing its review.

    In terms of user fees, generally combination products are subject to the user fee that applies to the particular type of premarket application that is submitted. For example, a drug-device combination product for which a Premarket Approval (PMA) Application is required would be subject to the PMA user fee. In situations where two applications are submitted to cover various components of the product, two application fees would be assessed, although fee waivers or reductions may be available.
    Which Quality Control Regulations Apply?
    FDA has not promulgated current good manufacturing practice regulations specifically for combination products. As a result, the question of which quality control regulation to use in the manufacture of a combination product is a pressing one for both pre-approval inspections and post-approval production.Based on a 2004 draft guidance, Current Good Manufacturing Practice for Combination Products (Sept. 2004), FDA has stated that each constituent part (i.e., drug, device, or biologic) remains subject only to its usual governing regulations as long as the parts remain separate. As a result, the drug constituent must comply with drug cGMP rules and the device constituent must comply with the device Quality System Regulation. If and when the constituent parts are joined into a single entity or packaged together as a single unit, both sets of manufacturing regulations would apply. However, FDA’s current thinking is that it is not necessary for a manufacturer to maintain two separate manufacturing systems; rather, companies can use the compliance system that is already operating at the manufacturing facility and add on any relevant requirements from the other set of regulations.

    Clearly this assessment will require frequent and candid discussions with the agency to ensure all parties are in agreement as to expectations and compliance.
    How Are Post-Market Requirements Implemented?
    While post-market requirements are typically clear for manufacturers of traditional drug, device, and biologic products, FDA is still developing its policies for combination products. For example, the agency is continuing to work on: (1) how companies should report adverse events for combination products; (2) how post-approval modifications or changes to constituent parts should be submitted and which Center would take the lead; (3) which Center’s regulations would apply to post-approval review of labeling and advertising; and (4) when do two different products need to be labeled for use together and which Center would take the lead on reviewing the cross-labeling.

    With few formal policies in place, forward-thinking companies have the opportunity to propose and help create the regulatory structure for combination products, whether it is through hands-on coordination with the agency on a particular product or the submission of stakeholder comments and recommendations.
    REFERENCES
    1 Performance Report to Congress for the Office of Combination Products FY 2005.
    ONLINE
    For additional information on the technologies and products discussed in this article, see Medical Design Technology online at www.mdtmag.com and the following websites:
  • www.klng.com
  • www.fda.gov/oc/combination/

    Suzan Onel practices in the areas of medical device, food, drug, and cosmetic law as a partner at Kirkpatrick & Lockhart Nicholson Graham LLP. She regularly advises international and domestic manufacturers, distributors, and researchers on market entry strategies, labeling and promotional activities, regulatory compliance, and enforcement defense. Onel assists clients with the preparation of FDA submissions, including 510(k) premarket notifications, premarket approval applications, adverse event reports, and product listings and establishment registrations. She has practiced in the medical device area for over 16 years. Onel leads the device portion of the firm’s FDA practice. She can be reached at 202-778-9134 or sonel@klng.com.
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