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Reproduced from the Journal of Medical Device Regulation, 2005, 2(3), 3 with the kind permission of Global Regulatory Press, London, UK (www.globalregulatorypress.com).
Combination products raise a variety of regulatory and review challenges. Though the US regulation of drugs, dev ices and biological products share many of the same basic features, they are also each 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 Food and Drug Administration (FDA) Center will lead the premarket review, consultation is frequently required with another 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. 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 may be one in which the drug and device components are separately provided, perhaps even by different manufacturers, but are intended to be used together and labelled accordingly. Combination products may be relatively simple (such as a convenience kit with surgical supplies and alcohol wipes, or a syringe pre-filled 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 the regulation of combination products is as clear, consistent and predictable as possible, the FDA established the Office of Combination Products (OCP), as required by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). The OCP’s primary responsibilities 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. The OCP also develops guidance and regulations to help clarify the regulation of combination products. It should be noted that the OCP does not review combination products; rather that responsibility is assigned by the OCP to the Agency’s Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER) or the Center for Devices and Radiological Health (CDRH), based on the OCP’s determination of the ‘primary mode of action’ of the combination product.
The OCP established its initial priorities based on direction from Congress in MDUFMA, as well as input from its stakeholders both within and outside the Agency. Each of these priorities is addressed below.
The OCP has taken a multifaceted approach to ensuring the prompt assignment of combination products. Most importantly, the FDA published for stakeholder review and comment, a proposed regulation defining the ‘primary mode of action’ of a combination product 1 . 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’. When the most important therapeutic action cannot be determined with reasonable certainty (e.g. the product has two independent modes of action, neither of which is clearly subordinate to the other, or the way the product achieves its therapeutic effect is unknown), the 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 or effectiveness issues. When no such prior product exists, the 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. The FDA is considering stakeholder comments on the proposed regulation and expects to publish a final regulation defining primary mode of action in 2005.
The OCP has also responded to stakeholder concerns about the transparency of the jurisdictional process. The FDA recently published approximately 140 capsular descriptions of actual product jurisdiction decisions made since 1991 2 . These descriptions are general in nature in order to protect trade secret and confidential commercial information.
To make the assignment process as efficient as possible, the Agency has also improved its internal processing of formal requests for designation (RFD) or assignment. Thus far, the OCP has issued 100% of its jurisdictional decisions within the 60-day timeframe required by law. The OCP publishes a summary of its formal jurisdictional assignments, along with statistics on review time performance, on its website at www.fda.gov/oc/combination/. In addition, the OCP responds to external and internal stakeholder enquiries by providing advice, guidance and clarification on the assignment of combination products. These frequently come to the office by telephone, email or through ‘pre-RFD’ submissions.
The OCP does not review combination products, but it is charged with ensuring their timely and effective premarket review by facilitating and co-ordinating the review process when more than one Agency Center is involved. The OCP performs a variety of activities intended to achieve this mission. One of the first accomplishments was the development and implementation of a Standard Operating Procedure [SOP] for the Intercenter Consultative/Collaborative Review Process 3 . This SOP specifies the procedures and processes for CBER, CDER and CDRH staff to follow when working together in the review of a combination product. This SOP also documents the policy that ‘Consults Count’, to ensure that the requesting Center receives timely and effective advice. The OCP actively monitors the consultation process on combination products (there were over 200 such intercenter consultations in FDA’s fiscal year 2004), and has also worked with the Centers to develop more specific processes for particular product areas. The 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 the 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. The 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 the concomitant use of separately provided drug and device components requires ‘mutually conforming’ or ‘cross’ labelling, thereby creating a combination product. This is a difficult regulatory issue and the OCP co-sponsored a workshop on this topic in May 2005 to obtain stakeholder input. Information about the workshop is available on the Agency’s website.
The FDA is also drafting guidance to help applicants determine whether single or separate marketing applications are most appropriate for a combination product. 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, the FDA may determine that two marketing applications are necessary. The FDA encourages applicants who are uncertain as to whether single or separate applications should be submitted for a combination product to discuss the issue with the lead reviewing Division and/or the OCP.
Other work remaining in this area is to clarify better how post-approval 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, the OCP is working with the Agency Centers to help clarify recommendations for the format and content of combination product marketing applications.
As with product jurisdiction questions, applicants may contact the OCP at any time when they have questions or would like to discuss whether the approach they are taking seems appropriate.
The OCP is charged with ensuring the consistency and appropriateness of postmarket regulation of combination products. The OCP published a draft guidance document on Good Manufacturing Practice for combination products, available on the OCP website. The draft guidance 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, the draft guidance document makes recommendations for achieving compliance with applicable Good Manufacturing Practice requirements for combination products that are co-packaged or produced as a single entity. We believe the draft guidance is responsive to stakeholder concerns and 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.
The 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 the factors to be considered when determining the appropriate postmarket safety reporting requirements for combination products. The OCP also provides support to Centers and sponsors to ensure the consistency and appropriateness of postmarket regulation of combination products.
The OCP is responsible for resolving disputes regarding the timeliness of review of a combination product. While most issues can be resolved informally, guidance for applicants interested in filing a formal dispute is available on the OCP website. Another guidance document that will likely be of interest to manufacturers addresses application user fees for combination products. This guidance describes an Innovative Combination Product Waiver that may be appropriate for innovative combination products in the infrequent situation where the FDA determines that two marketing applications are necessary for the product. This waiver may reduce the application fee burden for certain innovative combination products.
The OCP conducts a variety of training and outreach for both Agency review staff and applicants to help raise awareness of combination product issues and keep stakeholders informed about policy development. For example, in FDA’s fiscal year 2004, OCP staff provided 30 presentations to external stakeholders and Agency review staff, and responded to a variety of press enquiries. The 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, the OCP reports to Congress on an annual basis on the activities and impact of the Office. These reports are available on the Agency’s website.
We believe that the OCP has made important strides in the two years since its implementation, but a good deal of work remains. We must consider and incorporate stakeholder comments on all our pending draft documents and finalise them. Several other draft guidance documents currently in development still need to be published for stakeholder review and comment and, in turn, finalised. We must clarify other issues where applicability of current regulations to combination products is unclear. Importantly, we must evaluate the impact of all that we have done, and determine whether any revisions are needed. Based on that evaluation, we will need to determine whether any legislative changes should ultimately be recommended in order to achieve our goals of ensuring a comprehensive framework that provides for the most appropriate regulation of any given combination product.
The OCP is available as a resource at any time during the life cycle of a combination product. We are happy to help resolve questions, general or specific, or to hear your comments about the work we are doing. You can contact us by telephone at +1 301 427 1934 or by email at combination@fda.gov.
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