June 20, 2017
Law360
By Thomas L. Irving; Shana K. Cyr, Ph.D.
Authored by Shana K. Cyr, Ph.D. and Thomas L. Irving
In 2016, Congress enacted Section 3038 of the 21st Century Cures Act1to amend the portions of the Federal Food, Drug and Cosmetic Act(FDCA)2relating to the important and growing category of medical products that is combination products. Combination products include two or more regulated components (i.e., drug-device, biologic-device, drug-biologic or drug-device-biologic). Their regulation is complex because, in addition to many combination products involving new and complicated technologies, their components are subject to different premarket review pathways and regulations. According to the U.S. Food and Drug Administration, these "[d]ifferences ... can impact the regulatory processes for all aspects of product development and management."3
In response to the challenges presented by combination products, the FDA established the Office of Combination Products (OCP) in 2002 per the Medical Device User Fee and Modernization Act of 2002.4The OCP is tasked, for example, with assigning combination products to a lead center, coordinating premarket review of combination products by the various FDA centers, and developing consistent postmarket regulations. To assign a combination product to a lead center, the OCP examines the product’s intended use and each constituent part’s method of action (i.e., the means by which it achieves its intended therapeutic effect or action). The OCP then determines which component’s method of action is the primary mode of action (PMOA) by evaluating which is most responsible for the product’s intended use. The OCP then assigns the combination product to the FDA center corresponding to the PMOA for primary jurisdiction over premarket review and regulation.
The OCP generally assigns drug-lead combination products to the Center for Drug Evaluation and Research, biologic-lead combination products to the Center for Biologics Evaluation and Research and device-lead combination products to the Center for Devices and Radiological Health. In 2015, for example, the OCP assigned 185 combination-product applications to the CDER, 39 to the CBER, and 126 to the CDRH.5
The Cures Act codified the FDA’s definition of PMOA to be "the single mode of action ... expected to make the greatest contribution to the overall intended therapeutic effects of the combination product" and the FDA’s use of PMOA for assigning combination products to a lead center.6It also specified, consistent with guidance documents from the FDA, that the FDA cannot determine that a combination product’s PMOA is a drug or biologic solely because the combination product has any chemical action within or on the body.
Under the Cures Act, a sponsor who disagrees with the FDA’s lead-center determination can request a substantive rationale from the FDA that includes any scientific evidence the FDA relied on in making the determination. The sponsor can also propose and work with the FDA to develop studies for establishing the relevance of any chemical action to the combination product’s PMOA. In addition, sponsors can request meetings with the FDA to discuss issues relating to their combination products, including requirements related to marketing standards, postmarket modifications, and good manufacturing practices.
One of the complexities with combination products is that their constituent parts would otherwise be approved by the FDA through different types of marketing applications. For example, the FDA generally approves drugs through stand-alone new drug applications under Section 505(b)(1) of the FDCA, NDAs under Section 505(b)(2) of the FDCA, and abbreviated new drug applications under Section 505(j) of the FDCA.7It generally licenses biologics through biologic license applications under Section 351(a) of the Public Health Service Act and abbreviated biologic license applications under Section 351(k) of the Public Health Service Act.8And the FDA generally approves or clears medical devices through premarketing applications (PMAs) under Section 515 of the FDCA or premarketing notifications (PMNs) under Section 510(k) of the FDCA.9
The Cures Act provides that a sponsor can submit separate applications for a combination product’s constituent parts unless the FDA determines that a single application is "necessary."10It also directs the FDA to conduct the review of combination products under a single application, "whenever appropriate."11Further clarification of these provisions and when sponsors should submit multiple applications instead of one is expected through FDA guidance documents. The Cures Act further provides that if a combination product contains an already approved constituent part, the FDA may allow the sponsor to not submit data or information specific to that part. Instead, the FDA may require the sponsor to submit only data or information necessary to meet the standard for approval or clearance, including any incremental risks and benefits posed by the combination product.
One of the more interesting changes under the Cures Act for combination products is that certain device applications for drug-device combination products will be subject to some of the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act)12provisions of the FDCA that typically apply only to drugs. More specifically, under the Cures Act, PMAs and PMNs for drug-device combination products that include an approved drug will be treated like 505(b)(2) applications in some ways.
505(b)(2) applications were added by the Hatch-Waxman Act as a third type of new drug application in addition to stand-alone NDAs and ANDAs. 505(b)(2) applications are for proposed drugs that are similar enough to an approved drug to rely on at least some of the approved drug’s clinical and nonclinical investigations, but different enough that additional showings of safety and effectiveness are required. For example, a 505(b)(2) application should be submitted for a proposed drug that has a different dosage form, strength, or route of administration than an approved drug. A 505(b)(2) application may also be submitted for a proposed drug that contains a different quality or quantity of an excipient, dosing regimen, active ingredient (e.g., a different salt or enantiomer), or indication than an approved drug. Like stand-alone NDAs, 505(b)(2) applications must include full reports of investigations showing safety and effectiveness. But 505(b)(2) applicants need not perform all of the investigations themselves; they may, for example, rely on investigations reported in the literature or in a stand-alone NDA.
Drugs that are approved through a 505(b)(2) application may be eligible for patent protection, including for the drug itself or its method of use. Like stand-alone NDAs, 505(b)(2) applications should identify patents that cover the proposed drug or a method of using it in their application, and the FDA will list the patent information in its Approved Drug Products with Therapeutic Equivalence Evaluations publication (commonly referred to as the Orange Book).13The Cures Act does not indicate whether PMAs and PMNs for drug-device combination products that include an approved drug should identify relevant patents or whether the FDA will list those patents in the Orange Book.
The Cures Act is specific, though, that PMAs and PMNs for drug-device combination products that include an approved drug may be eligible for the same types of FDA marketing exclusivities as 505(b)(2) applications: five-year new chemical entity exclusivity, seven-year orphan drug exclusivity, three-year new clinical investigation exclusivity, and six-month pediatric exclusivity. These PMAs and PMNs are not, however, eligible for the 180-day exclusivity that may be given to a first ANDA that includes a paragraph IV certification.
Under the Cures Act, PMAs and PMNs for drug-device combination products that include an approved drug must include certifications as to each patent listed in the Orange Book for the approved drug. For example, the certification might be that the listed patent will expire before the proposed product is marketed (a paragraph III certification) or that the patent is invalid, unenforceable, or not infringed (a paragraph IV certification). Applicants that include a paragraph IV certification must provide notice to the NDA holder and patent owners. The patent owner (or exclusive licensee) then has 45 days to sue the applicant for patent infringement under the Hatch-Waxman Act litigation provisions. A suit within that time triggers a stay of 30 months or more, during which the FDA cannot approve the application while the litigation is pending. These provisions are not otherwise applicable to PMAs and PMNs for medical devices alone or in combination with a biologic.
Endnotes
121st Century Cures Act, Pub. L. No. 114-255, § 3038, 130 Stat. 1033, 1105-10 (2016) (codified as amended at 21 U.S.C. §§ 353(g), 360j(h)(4)).
2The Federal Food, Drug, and Cosmetic Act, Pub. L. No. 75-717, 52 Stat. 1040 (1938) (codified as amended at 21 U.S.C. § 301 et seq.).
3U.S. Food and Drug Administration, Commissioner’s Report, in FY 2015 Performance Report to Congress for the Office of Combination Products (2015), ("2015 OCP Performance Report").
4Medical Device User Fee and Modernization Act of 2002, Pub. L. No. 107-250, § 204, 116 Stat. 1588, 1611-12 (2002) (codified as amended at 21 U.S.C. § 353(g)).
52015 OCP Performance Report at 11.
621 U.S.C. § 353(g)(1).
7Id. § 355(b)(1), (b)(2), (j).
842 U.S.C. § 262(a), (k).
921 U.S.C. §§ 360e, 360(k).
10Id. § 353(g)(6).
11Id. § 353(g)(1)(B).
12Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (1984) (codified as amended at 21 U.S.C. § 301 et seq.).
13U.S. Food and Drug Administration, Approved Drug Products with Therapeutic Equivalence Evaluations, https://www.accessdata.fda.gov/scripts/cder/ob/.
505(b)(2) application, Biologic License Application (BLA), combination product, Food and Drug Administration (FDA), new drug application (NDA), premarketing application (PMA), premarketing notification (PMN)
Originally printed in Law360 on June 20, 2017. This article is for informational purposes, is not intended to constitute legal advice, and may be considered advertising under applicable state laws. This article is only the opinion of the authors and is not attributable to Finnegan, Henderson, Farabow, Garrett & Dunner, LLP, or the firm's clients.
Due to international data regulations, we’ve updated our privacy policy. Click here to read our privacy policy in full.
We use cookies on this website to provide you with the best user experience. By accepting cookies, you agree to our use of cookies. Please note that if you opt not to accept or if you disable cookies, the “Your Finnegan” feature on this website will be disabled as well. For more information on how we use cookies, please see our Privacy Policy.
Finnegan is thrilled to announce the launch of our new blog, Ad Law Buzz, devoted solely to breaking news, developments, trends, and analysis in advertising law.