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Combination products raise a variety of regulatory and review challenges. Though the US regulation of drugs, devices and biological products shares many of the same basic features, each is also somewhat unique. Drugs, devices and biological products each have their own types of marketing applications, good manufacturing practice regulations and adverse event reporting requirements. When drugs and devices, drugs and biologics or devices and biologics are combined to create a new product, questions are sometimes raised about how the combination product as a whole will be regulated. For example, there is no special type of marketing application for combination products. Furthermore, although one Center will lead the premarket review, consultation is frequently required with another FDA Center.

Given the diversity in the types of combination products, a "one size fits all" approach to combination product regulation is probably not the answer. (See Sidebar: What is a Combination Product, page 31). A drug-device combination product, for example, may be comprised of a drug coated on a device, or a drug packaged with a device. Yet another type of drug and device combination is one in which the drug and device components are provided separately, perhaps even by different manufacturers, but are intended to be used together and labeled accordingly. Combination products may be relatively simple (such as a convenience kit with surgical supplies and alcohol wipes, or a syringe prefilled with a drug or biological product) or more complex (such as a drug-eluting coronary stent, a scaffold with live cellular components or a chemotherapeutic drug combined with a monoclonal antibody).

To address these issues and to ensure that combination product regulation is as clear, consistent and predictable as possible, FDA established the Office of Combination Products (OCP), as required by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA).1 OCP's primary responsibilities (See Sidebar: Roles of the Office of Combination Products, page 31) are to ensure the prompt assignment of combination products to agency Centers, and to oversee their "timely and effective" premarket review and "consistent and appropriate" postmarket regulation. OCP also develops guidance and regulations to help clarify combination product regulation. It should be noted that OCP does not review combination products; rather that responsibility is assigned by OCP to the agency's Center for Biologics Evaluation and and Research (CBER), the Center for Drug Evaulation and Research ( CDER) or the Center for Devices and Radiological Health (CDRH), based upon OCP's determination of the combination product's "primary mode of action" ²

OCP establihsed its initial priorities based upon direction from Congress in MDUFMA, as well as input from its stakeholders both within and outside the agency. This article focuses on the progress the agency has made in addressing these priorities.

Assignment of Combination Products

OCP has taken a multifaceted approach to ensuring the prompt assignment of combination products. Most importantly, FDA published a proposed regulation defining the primary mode of action of a combination product for stakeholder review and comment. This regulation is intended to provide a consistent, predictable and transparent approach to assign combination products to a lead agency component for regulatory oversight.

As described in that proposed regulation, primary mode of action would be defined as the “most important therapeutic action of a combination product.” For example, drug-eluting stents have been assigned to CDRH based upon the agency’s determination that the device’s role in physically maintaining vessel lumen patency provides the most important therapeutic action of the combination product, while the drug plays a secondary role in reducing restenosis caused by the body’s proliferative response to stent implantation.

When the most important therapeutic action of a combination product cannot be determined with reasonable certainty (e.g., the product has two independent modes action, neither of which is clearly subordinate to the other, or the way the product achieves its therapeutic effect is unknown), FDA would base the assignment on an algorithm proposed in the regulation. Under this algorithm, the agency would assign such a combination product to ensure consistency with the assignment of other combination products that present similar safety and effectiveness issues. When no such prior -product exists, FDA would assign the combination product to the agency component with the most expertise to evaluate the most significant safety and effectiveness questions presented by the combination product. FDA is considering stakeholder comments on the proposed regulation and expects to publish a final regulation defining primary mode of action in 2005.

FDA has also responded to stake­holder concerns about the transpar­ency of the jurisdictional process. OCP recently published approxi­mately 140 capsular descriptions of actual product jurisdiction decisions made since 1991.⁴ In determining whether web-publication of a prior jurisdictional determination is appro­priate for a particular product, FDA takes into account the extent to which the product can be suitably described, the extent to which the existence and description of the product or similarly described products has been made public and related factors. The descriptions are intentionally general to ensure the protection of trade secret and confidential commercial informa­tion. Jurisdictional determinations are often influenced by subtle distinctions in a product’s composition, mode(s) of action, intended use and related factors, which are not fully reflected in the capsular descriptions. It is possible that a product that fits within one of the general capsular descrip­tions provided might actually receive a different jurisdictional assignment, based upon the consideration of fac­tors not reflected in the brief capsular description.

To make the assignment process as efficient as possible, the agency has also improved its internal processing of formal requests for assignment (also called Requests for Designation or RFD’s). Thus far, OCP has issued 100% of its jurisdictional decisions within the 60-day timeframe required by law. The Sidebar: Combination Product Assignments (to the right) includes a summary of OCP’s formal jurisdictional assignments for combi­nation products in FDA’s Fiscal 2004, along with statistics on review time performance. Similar information for non-combination products is avail­able on OCP’s website at http://www. fda.gov/oc/combination.

Finally, OCP responds to external and internal stakeholder inquiries by providing advice, guidance and clari­fication on the assignment of both combination and non-combination products. These come to the office by telephone, email or through “pre-RFD” submissions.

Timely and Effective Premarket Review

OCP does not review combination products, but it is charged with ensuring their timely and effective premarket review by facilitating and coordinating the review process when more than one agency Center is involved. OCP performs a variety of activities intended to achieve this mission.

One of the first accomplishments was developing and implementing a Standard Operating Procedure for the IntercenterConsultative/Collaborative Review Process. 5 This SOP specifies the procedures and processes fol­lowed by CBER, CDER and CDRH staff when working together to review a combination product. This SOP also documents the policy that “Consults Count,” to ensure that the requesting Center receives timely and effective advice. OCP actively monitors the consultation process on combination products (See Sidebar: Intercenter Consultation Requests for Fiscal 2004 , page 32), and has also worked with the Centers to develop more spe­cific processes for particular product areas. OCP is piloting a new system for tracking intercenter consultation requests that will help automate the monitoring process.

One of the most significant ways that OCP helps ensure timely and effective premarket review is by help­ing applicants and agency reviewers determine the appropriate regulatory pathway for combination products when it is unclear. OCP often facili­tates meetings to discuss and resolve such issues at the request of the appli­cant or review staff. One issue that is sometimes raised concerns whether concomitant use of separately pro­vided drug and device components requires “mutually conforming” or “cross labeling,” thereby creating a combination product. This is a dif­ficult regulatory issue on which OCP cosponsored a workshop in May 2005 to obtain stakeholder input. Information about the workshop, including the workshop transcript, is available on the agency’s website at http://www.fda.gov/oc/combination. ¹

FDA is also drafting recommen­dations to help applicants determine whether single or separate marketing applications are most appropriate for individual combination products. 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 product designa­tion or proprietary data protection when two firms are involved). In other cases, FDA may determine that two marketing applications are neces­sary. FDA encourages applicants who are uncertain as to whether single or separate marketing applications should be submitted to discuss the issue with the lead reviewing division and/or OCP.

Other work remaining in this area is to better clarify how postap­proval modifications to combination products should be handled, i.e., when and how such changes should be submitted to the agency for prior review and approval. In addition, OCP is working with agency Centers to help clarify recommendations for the format and content of combination product marketing applications. As with product jurisdiction questions, applicants may contact OCP at any time if they have questions or would like to discuss whether the approach they are taking seems appropriate.

Consistent and Appropriate Postmarket Regulation

OCP is charged with ensuring the consistency and appropriateness of postmarket regulation of combina­tion products. OCP published a draft guidance document on good manu­facturing practice for combination products. 6 The draft makes recom­mendations for achieving compliance with applicable good manufacturing practice requirements for the drug, device or biological product constitu­ent parts of a combination product where such components are separately marketed. In addition, it makes recom­mendations for achieving compliance with applicable good manufacturing practice requirements for combina­tion products that are co-packaged or produced as a single entity. The agency believes the draft guidance is responsive to stakeholder concerns that it should generally not be neces­sary for manufacturers to maintain two separate manufacturing systems (e.g., 21 CFR Parts 210/211 for drugs/biological products and 21 CFR Part 820 for devices) for a com­bination product.

OCP is also working with other agency components in drafting policy on the application of adverse event reporting regulations for combination products. Guiding principles were developed on factors to be consid­ered when determining appropriate postmarket safety reporting require­ments for combination products.

Other Initiatives

OCP is responsible for resolving disputes regarding the timeliness of review of a combination product. While most issues can be resolved informally, the agency has also published guidance for applicants interested in filing a formal dispute. 7 Another guidance likely to be of interest to manufacturers addresses application user fees for combination products. 8 This guidance describes an Innovative Combination Product Waiver that may be appropriate for innovative combination products in the infrequent situation where FDA determines that two marketing appli­cations are necessary for the product. This waiver may reduce the applica­tion fee burden for certain innovative combination products.

OCP conducts a variety of train­ing and outreach sessions for both agency review staff and applicants to help raise awareness of combination product issues and keep stakehold­ers apprised of policy development. For example, in Fiscal 2004, OCP staff provided 30 presentations to external stakeholders and agency review staff and responded to a variety of press inquiries. OCP also participates in a variety of special agency initiatives of interest to com­bination product development, e.g., by participating in agency working groups on pharmacogenomic drug/ diagnostic device co-development and innovative delivery systems for drug and biological products. Finally, OCP reports to Congress on an annual basis on the office’s activi­ties and impact. These reports are available on the agency’s website at http://www.fda.gov/oc/combination.

Summary

OCP has made important strides in the two years since it was established, but a good deal of work remains. The agency must consider and incorporate stakeholder comments on all the draft documents published in the last year and issue them in final form. Several other draft documents currently in development still need to be published for stakeholder review and comment and, in turn, finalized. A variety of other issues must be clarified where applicability of current regulations to combination products is unclear. Importantly, FDA must evaluate the impact of all that has been done and determine whether any revisions are needed. Based upon that evaluation, the agency will decide whether any legislative changes should ultimately be recommended in order to achieve its goals of ensuring a comprehensive framework that provides for the most appropriate regulation of any given combination product.

OCP is available as a resource at any time during a combination product’s lifecycle. The staff is glad to help resolve questions, general or specific, or to receive comments about the work it is doing. OCP can be con­tacted by telephone at 301.427.1934 or by email at combination@fda.gov.

1. Information about the Designation and Regulation of Combination Products require­ments of MDUFMA is available at http://www.fda.gov/oc/combination/section204.html .
2. Section 503(g) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 353(g)).
3. The proposed rule was published in the May 7, 2004, Federal Register, and is available at http://www.fda.gov/oc/combination .
4. This information, along with other jurisdiction­al updates OCP has published, is available at http://www.fda.gov/oc/combination/updates.html . These capsular descriptions describe prior FDA decisions only and are not policy statements.
5. The SOP is available at http://www.fda.gov/oc/ombudsman/intercentersop.pdf.
6. Draft Guidance for Industry and FDA: Current Good Manufacturing Practice for Combination Products, available at http://www.fda.gov/oc/combination .
7. Guidance for Industry and FDA Staff: Submission and Resolution of Formal Disputes Regarding the Timeliness of Premarket Review of a Combination Product, available at http://www.fda.gov/oc/combination .
8. Guidance for Industry and FDA Staff: Application User Fees for Combination Products, available at http://www.fda.gov/oc/combination .

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