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The authors discuss regulatory and patent issues with combination products.
Products involving combinations of drugs, biological products, and medical devices are becoming increasingly prominent. Combination products can involve components that are physically, chemically, or otherwise combined (e.g., a monoclonal antibody with a therapeutic drug); components that are packaged together (e.g., a drug packaged with a delivery device); or components that are provided separately but intended to be used together (e.g., a photosensitizing drug and activating light source) (1).
Combination products can follow a variety of regulatory pathways, each with its own benefits and shortcomings. FDA notes that a product’s pathway “can impact the regulatory processes for all aspects of product development and management, including preclinical testing, clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, and post-approval modifications (2).” The most successful companies begin targeting a regulatory pathway from the earliest stages of development, based at least in part on the regulatory and patent considerations discussed in this article.
A combination product’s regulatory pathway generally depends on its primary mode of action (PMOA), recently defined in the 21st Century Cures Act as “the single mode of action of a combination product expected to make the greatest contribution to the overall intended therapeutic effects of the combination product (3, 4).” FDA’s Office of Combination Products (OCP) examines the product’s modes of action, determines which is the PMOA, and then uses that to assign the product to a particular FDA center for premarket review and regulation (5).
Classification is more complicated if the PMOA is not clearly identified or there are two independent, equally important modes of action. In these cases, OCP generally looks to the product’s most critical safety and efficacy issues, classifying the product either in accordance with other products raising the same issues or based on which FDA center is most experienced with such issues (6).
Drug-lead products. If a combination product is classified as a drug lead, OCP assigns it to FDA’s Center for Drug Evaluation and Research (CDER) for premarket review and regulation (7). Companies with an innovative drug-lead product generally must file a new drug application (NDA), which can cost up to $2.4 million in FDA application fees alone and take one year or more for FDA review (8, 9). This is in addition to the years and millions of dollars spent in development before the NDA is even filed (10).
Combination products approved under an NDA may be eligible to receive five years or more of exclusivity from FDA (11). But the primary advantage of having a drug lead in a combination product can be summarized in three words: the Orange Book. The FDA Orange Book lists drug-lead products, along with patents covering the products, their active ingredients, and methods of use (12, 13). Companies benefit from these listings, because they provide notice of the patents to the public and give rise to the patent-related protections of the Hatch-Waxman Act (14).
Under Hatch-Waxman, an NDA holder can sue a company seeking to market a generic version of its drug-lead product before it otherwise might be able to. More specifically, a company seeking to market a generic version of a drug can avoid the lengthy and costly NDA process by filing an abbreviated new drug application (ANDA), which relies on the data reported in the NDA (15). An ANDA filer must certify that each patent listed in the Orange Book either will expire before the generic product goes on the market (paragraph III certification), or is invalid, unenforceable, or will not be infringed by the product (paragraph IV certification) (16). If the ANDA filer makes a paragraph IV certification, the NDA holder can sue for patent infringement before the proposed generic product is made, used, or sold. In addition, paragraph IV suits trigger a stay where FDA cannot approve the generic product application for up to 30 months (17, 18).
Biological-lead products. If a combination product is classified as a biological-product lead, it is not eligible for listing in the Orange Book, and OCP will assign it to FDA’s Center for Biologics Evaluation and Research (CBER) for premarket review and regulation (19). Companies with an innovative biological-lead product generally must file a biologic license application (BLA), which can cost more than $260,000 in FDA application fees alone and take one year or more for FDA review (9, 20). This is in addition to the years and millions of dollars spent in development before the BLA is even filed (21).
Combination products approved under a BLA may be eligible for 12 years or more of FDA exclusivity (22). FDA lists the products and some of their exclusivities in its Purple Book publication (23). Unlike the Orange Book for drug-lead products, the Purple Book does not include patents. BLAs instead implicate the patent protections of the Biologics Price Competition and Innovation Act (BPCIA) (24).
Under BPCIA, a BLA holder can sue a company seeking to market a generic version of its biological-lead product before it otherwise might be able to. Similar to drug-lead products, a company seeking to market a generic version of a biological-lead product might be able to avoid part of the time and cost associated with filing a BLA by filing an abbreviated application that relies on the BLA holder’s data (25). This filing may trigger a “patent dance” whereby the applicant and BLA holder exchange information and arrive at a list of patents subject to a patent-infringement action (26). Unlike with Hatch-Waxman litigation for drug-lead products, BPCIA patent litigation does not trigger a regulatory stay of approval for the generic product.
Medical-device lead products. If a combination product is classified as a medical-device lead, it is not eligible for listing in the Orange Book or the Purple Book, and OCP will assign it to FDA’s Center for Devices and Radiological Health (CDRH) for premarket review and regulation (27). Companies with an innovative medical-device-lead product generally must file a premarket approval application (PMA), which can cost more than $260,000 in FDA application fees alone and take about one year for FDA review (9, 20). Although this is in addition to the time and money spent in development (28), such time and cost are generally less than with drug-lead and biological-lead products. In addition, if the product contains only a small change over a previously approved device, the company can reduce time and cost even further by filing a premarket notification (PMN) instead of a PMA.
Combination products with medical-device leads do not receive FDA exclusivities, and their only patent-related protection is the patent term itself. As such, a company might need to wait until the medical-device-lead product is made, used, or sold before suing for patent infringement. Medical-device-lead products are generally listed in the FDA Global Unique Device Identification Database (GUDID), which does not include patent information, although one of the database’s goals is better detection of counterfeit devices (29).
Companies should decide which regulatory pathway to pursue early on, based on their time and cost goals and their patent portfolios. While development and approval for drug-lead and biological-product-lead combination products is lengthy and expensive, pursuing them may come with FDA data exclusivities and patent-related protections, as discussed above, that make the time and cost worthwhile. Pursuing a drug lead or biological-product lead is more likely a strong choice if the combination product enjoys a robust patent portfolio. On the other hand, if the product does not have a robust patent portfolio, or a more timely approval at a lower cost is the goal, pursuing the medical-device-lead pathway might be the best strategy.
Once a company decides which pathway will likely be most beneficial for its product, it should take steps to ensure that OCP assigns the product to that pathway. The most obvious way to do this is to ensure that the product’s PMOA corresponds to the desired lead. To the extent that a product’s PMOA is unclear, a company can ask OCP to assign the product to its preferred pathway in a Request for Designation (RFD). A company might be able to influence OCP’s decision about product lead by consistently characterizing the product’s therapeutic effect as attributed to the preferred lead, by analogizing the product to other products that OCP previously assigned to that lead, or by emphasizing safety and effectiveness issues that call for the expertise of the preferred center. For example, if a company consistently emphasizes the product’s drug component during patent prosecution as providing the most important therapeutic action, OCP might be influenced to assign the product to CDER. Under the recent 21st Century Cures Act, FDA now must provide a substantive rationale when it disagrees with a company’s determination of a combination product’s PMOA (30).
The choice of regulatory pathway must be balanced against the ability to obtain and leverage a robust patent portfolio. The ability to obtain a robust portfolio might depend on whether the company disclosed the product or its therapeutic action before it filed the patent application with the US Patent and Trademark Office (USPTO). For example, statements about a product at a trade show or in a peer-reviewed publication might preclude a company from securing a patent for the product. The ability to leverage a robust patent portfolio might depend on whether the company made statements to FDA that contradict statements in the patents or made to the USPTO during prosecution. For example, companies should take care in making statements when seeking authorization for human testing of a drug-lead product, submitting proposed labels to FDA for biological-lead products, or seeking approval for a new medical-device-lead product that relies on a predicate device. Companies developing combination products should strive for open communication and strategic coordination among scientists, individuals tasked with preparing FDA submissions, and individuals tasked with obtaining and leveraging the company’s patents.
Although combination products raise challenges for FDA and companies alike, they also can provide opportunities for companies that strategize from the earliest stages to pursue the most beneficial regulatory pathway for their products. In developing a combination-product strategy, companies should consider regulatory and patent issues, including how these issues might be affected by ever-changing laws and regulations.
1. FDA, Frequently Asked Questions About Combination Products (Oct. 20, 2016) (citing Code of Federal Regulations, Title 21, Section 3.2(e)), accessed Feb. 6, 2017.
2. FDA, About Combination Products (Sept. 8, 2016), accessed Feb. 6, 2017.
3. 21st Century Cures Act of 2016, Pub. L. No. 114-255, § 3038 (amending United States Code, Title 21, Section 353(g)).
4. Code of Federal Regulations, Title 21, Section 3.2(m).
5. Code of Federal Regulations, Title 21, Section 3.4.
6. Code of Federal Regulations, Title 21, Section 3.4(b).
7. Code of Federal Regulations, Title 21, Section 3.4(a)(1).
8. FDA, Prescription Drug User Fee Rates for Fiscal Year 2016, Fed. Reg. 80 (148), 46028–46031 (Aug. 3, 2015).
9. FDA, FY2015 Performance Report to Congress for the Office of Combination Products 14-15 (2016), accessed Feb. 6, 2017.
10. J. A. DiMasi et al., J. Health Econ. 47 (20) (2016).
11. Code of Federal Regulations, Title 21, Section 314.108.
12. Code of Federal Regulations, Title 21, Section 314.53(b).
13. FDA, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, accessed Feb. 6, 2017.
14. Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (amending United States Code, Title 21, Section 355).
15. United States Code, Title 21, Section 355(j).
16. United States Code, Title 21, Section 355(j)(2)(A).
17. United States Code, Title 21, Section 355(j)(5)(B)(iii).
18. United States Code, Title 21, Section 355(c)(3)(E)(ii) (providing that the thirty-month period is extended in certain circumstances).
19. Code of Federal Regulations, Title 21, Section 3.4(a)(3).
20. FDA, Medical Device User Fee Rates for Fiscal Year 2016, Fed. Reg. 80 (148), 46033–46035 (Aug. 3, 2015).
21. J. A. DiMasi and H. G. Grabowski, Manage. Decis. Econ. 28 (469) (2007).
22. United States Code, Title 42, Section 262(k)(7)(A).
23. FDA, Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations.
24. Biologics Price Competition and Innovation Act of 2009, in the Patient Protection and Affordable Care Act, Pub. L. No. 111-148, 124 Stat. 119, 804-21 (2010) (amending United States Code, Title 42, Section 262).
25. United States Code, Title 42, Section 262(k).
26. United States Code, Title 42, Section 262(l).
27. Code of Federal Regulations, Title 21, Section 3.4(a)(2).
28. Josh Makower, et al.,
(November 2010), accessed Feb. 6, 2017.
29. FDA, Unique Device Identification System, Fed. Reg. 78 (185), 58786–58787 (Sept. 24, 2013).
30. 21st Century Cures Act of 2016, Pub. L. No. 114-255 § 3038(a)(4) (amending United States Code, Title 21, Section 353(g)).