The U.S. biopharma and medical device markets remain the largest and most robust in the world. The statistics on the size and potential growth of these markets are staggering: the pharmaceutical market size is currently $527 billion and expected to increase to $902 billion by 2030;1 the biologics market size is currently sitting at $264 billion, with growth expected to reach $719 billion by 2030;2 and the "medtech" device market size is currently $191 billion and anticipated to grow to $291 billion by 2030.3 The United States spent $717 billion in research and development in 2021, and this number continues to grow.4 The sheer size of these markets presents opportunities for firms to introduce breakthrough technology to compete with products that are already approved by the U.S. Food and Drug Administration. This competition can come in the form of innovations, but it can also be manifested by "me too" products that are the same as or similar to the FDA-approved, -licensed, or -cleared medical product.
The central questions for all medical research and development persist: Can we make a product better (or a better product), faster, or cheaper? In addition to seeking market advantages in answering these questions, the post-COVID-19 environment has created additional geographic factors that benefit firms looking to "on shore" critical medical products for manufacturing here in the United States. Also, certain sectors of the U.S. market present significant opportunities, such as platform technology, cell and gene therapy, telehealth, personalized medicine, portable diagnostics, and 3D printing. The largest retail spending in the United States continues to be for oncology, diabetes, autoimmune, and respiratory therapeutics, with a higher percentage of biologics license application (BLA) approvals than ever before.5 These demands for innovative and/or cheaper therapies in these product classes are not going away anytime soon. The combination of these factors makes the U.S. market an attractive destination for foreign medical product developers.
While the opportunity in the U.S. market is apparent to many pharma, biotech, and device companies, the route to market entry through the FDA is often unclear or overwhelming— especially to foreign firms. There is one unique area of U.S. food and drug law that is often overlooked by companies trying to access the U.S. market: abbreviated applications for drugs, biologics, and devices. This article describes the unique "abbreviated" legal pathways to marketing medical products in the United States and offers suggestions to firms navigating the U.S. FDA regulatory framework.
What is an "Abbreviated" Premarket Approval Pathway?
In the United States, Congress has created two statutes that regulate nearly all medical products. The Federal Food, Drug, and Cosmetic Act (FD&C Act)6 governs the approval of prescription drugs and medical devices, while the Public Health Service Act (PHSA)7 controls the approval of biologics. For each category of medical products—drugs, biologics, and devices—there are "full-scale" product applications that are required for novel products. These "full-scale" applications require full clinical investigations of safety and efficacy via adequate and well-controlled clinical trials, among other legal requirements. The primary approval pathway for novel drugs is the §505(b)(1) new drug application (NDA), whereas the primary full-scale biologics approval goes through the biologics license application (BLA) route at §351(a) of the PHSA. While devices are regulated based on the level of risk to the patient and the controls necessary to ensure the device is safe for patients' use,8 the full-scale premarket approval application for Class III (highest risk) medical devices is the Premarket Approval Application (PMA) under §515 of the FD&C Act. In these cases, the applicant is submitting a "soup to nuts" premarket approval application to the FDA for approval or licensure. FDA then makes approval decisions based on the data submitted to ensure the known benefits outweigh the known risks of the drug, biologic, or device. However, both the FD&C Act and the PHSA create shorter routes to market for medical products that are the same as or similar to products already approved, licensed, or cleared by the FDA. These application routes are, by statute, a shorter route to market because the applicant is relying, to some degree, on the safety and efficacy information related to a reference listed drug (RLD) (in the case of drugs or biologics) or a previously marketed "predicate" device and what FDA already knows about those predecessor products. This reliance on previously approved products often reduces the need to repeat costly clinical trials and allows a shorter route to market.
For prescription drug products, the abbreviated approval applications are the §505(b)(2) NDA and the §505(j) abbreviated new drug application (ANDA). For biologics, biosimilars are approved under §351(k) of the PHSA. While the device regulatory framework is different, there is an abbreviated approval mechanism for devices at §510(k) of the FD&C Act. We explore each of these mechanisms below.
What is a §505(b)(2) New Drug Application?
Section 505(b)(2) was added to the Act by the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Amendments) alongside the §505(j) ANDA provision that governs generic drug approvals.9 While the ANDA route for generic drugs— which are bioequivalent copies of the RLD—is well known, a less understood provision at §505(b)(2) expressly permits the FDA to rely, for approval of an NDA, on data not developed by the applicant. A §505(b) (2) NDA is an application for drug approval "based on investigations... relied on by the application for approval of the application [that] were not conducted by or for the applicant and for which the applicant has not obtained a right of reference."10 A §505(b)(2) applicant may rely on three categories of information for approval: (a) clinical data generated by the applicant; (b) published literature; and (c) FDA's prior safety and efficacy determination for the RLD to which the applicant's product can be compared.11 While some §505(b)(2) applicants are relying on data sets to which they do not have a right of reference12 and are not directly referencing an RLD, the most common type of §505(b)(2) applicant is relying on what FDA knows about an RLD. But §505(b) (2) NDAs are different from 505(j) ANDAs because, unlike ANDAs for generic drugs, §505(b)(2) applicants are demonstrating "similarity" to the RLD and not "sameness."
The §505(b)(2) NDA applicants are ideal for variations on an innovator drug product that require additional clinical efficacy data but would not need to repeat costly clinical safety studies. These are often referred to as "follow-on" or "me too" products. In this scenario, §505(b) (2) applications "may rely on FDA's finding only to the extent that the proposed product in the §505(b)(2) application shares characteristics (e.g., active ingredient, dosage form, strength, route of administration, indication, conditions of use) with the listed drug."13 To the extent that there are differences between the innovator RLD product and the 505(b)(2) applicant's product, sufficient data must be generated to demonstrate safety and efficacy.14 A §505(b)(2) NDA would be most appropriate where there is (i) a new indication for a previously approved drug; (ii) a change in dosage form, strength, formulation, dosing regimen, or route of administration from the RLD; (iii) a new combination product, including substitution of an active ingredient; (iv) a modified active ingredient; or (v) a switch from a prescription drug to an over-the-counter (OTC) drug, among other scenarios.15 Early engagement with the FDA regarding how it will weigh and balance the information—new clinical evidence, literature, and what it knows about the RLD—in the §505(b)(2) NDA is essential to this type of abbreviated application.
What is a 351(k) "Biosimilar" Application?
It was not until the Biologics Price Competition and Innovation Act of 2009 (BPCIA) that the FDA had the authority to approve abbreviated applications for biologics regulated under the PHSA.16 The BPCIA created an abbreviated approval path for biological products that are highly similar ("biosimilar") to or "interchangeable" with an FDA-approved biological product. The purpose of the BPCIA was—similar to the Hatch-Waxman Amendments of 1984—to incentivize new product innovation but also to allow competition in the market by "biosimilars." Biosimilars are defined as biological products that are "highly similar to the reference product notwithstanding minor differences in clinically inactive components" and where "there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency."17 A biosimilar BLA submitted under §351(k) of the PHSA must contain, among other things, information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies, animal studies, and clinical studies or studies.18
To meet the higher standard for "interchangeability," a biosimilar applicant must provide sufficient information to demonstrate biosimilarity to the reference product and to demonstrate that the biological product can be expected to "produce the same clinical result as the reference product in any given patient, and if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch."19 Interchangeable biosimilars may be substituted for the reference product at the pharmacy level without the intervention of the prescribing healthcare provider.20 A §351(k) biosimilar BLA must include information demonstrating that "the route of administration, the dosage form, and the strength" of the proposed biosimilar or interchangeable product "are the same as those of the reference product."21 The §351(k) biosimilar BLA is analogous to the FD&C Act's §505(b)(2) NDA insofar as the statute permits a comparison to a reference listed product. However there are important differences: a §351(k) biosimilar BLA may not seek approval for an indication, route of administration, dosage form, or strength that is different from that of the reference product.
FDA approved Sandoz Inc's Zarixo as the first biosimilar on March 6, 2015,22 and the first interchangeable biosimilar, Semglee, on July 28, 2021.23 There are now 46 FDA-approved biosimilars on the market in the United States.24 Because the BPCIA includes a patent infringement dispute resolution process (referred to as the "Patent Dance") and 12 years of marketing exclusivity for innovator products, this is a highly litigious environment, given that so much is at stake for innovator biologics whose patent terms are expiring and facing the threat of biosimilar competition. For biosimilar applicants, there is the prospect that, post-patent expiry, the §351(k) biosimilar BLA could be a means to add a lucrative product to a company's portfolio by competing with products that are often 20-fold more expensive than brand small- molecule drugs.25 As biologics are more complex, compared with small-molecule drug products regulated under the FD&C Act, a §351(k) biosimilar applicant still has a challenging road to BLA licensure, with a complex, carefully monitored and controlled manufacturing process.26 Early and regular interaction with the FDA's Center for Drug Evaluation and Research (CDER) (for therapeutic biologics) or the Center for Biologics Evaluation and Research (CBER) (for most other biologics) is essential for a §351(k) biosimilar BLA.
What is a 510(k) Premarket Notification?
Unlike drugs and biologics, the 1977 device amendments to the FD&C Act created a risk-based regulatory structure for devices. As described above, Class I medical devices are low-risk devices subject to "general controls" and generally do not require premarket approval before they may enter the U.S. market. Class III medical devices are high-risk and/or life-sustaining. Class III medical devices and other devices are determined to be "not substantially equivalent" to a "predicate device" and may not be marketed until the FDA has approved a PMA or "de novo" classification request.27 For Class II, moderate risk devices, Congress allowed for the submission of a premarket notification procedure widely referred to as the "510(k)" after its location—§510(k)—in the FD&C Act. FDA may clear devices via the §510(k) premarket notification process where the applicant can demonstrate that the device is "substantially equivalent" to a "predicate device."28 A "predicate" device is a legally marketed device against which the investigational device is compared. "Substantial equivalence" means the new device is "at least as safe and effective" as the predicate device and, compared with the predicate, has the same intended use and technological characteristics (or such changes raise no question of safety and effectiveness).29 FDA has classified over 1,700 distinct types of medical devices into 16 medical specialty "panels" and published regulations at 21 CFR Parts 862-892 that provide a description of each device and its classification.30 In short, the §510(k) pre-market notification is an abbreviated pathway to market, insofar as the framework allows device applicants to rely on previously approved devices.
Aspiring device manufacturers can search FDA's 510(k) Premarket Notification and PMA databases for potential comparisons to identify how FDA will regulate the device and, if it involves a Class II device, which predicate(s) may be appropriate to use in their own §510(k) submission.31 Companies interested in using the §510(k) premarket notification may first get feedback from FDA's Center for Devices and Radiological Health (CDRH) via a "Q-Sub," which is an opportunity for a submitter to obtain FDA feedback prior to an intended premarket submission.32 Q-Subs are voluntary submissions to the FDA to obtain early interaction and guidance on device development.33
Conclusions
The U.S. pharma, biotech, and medtech markets—soon to exceed $2 trillion combined—offer opportunities for drug, biologic, and device developers looking to capitalize on the need for innovative and cheaper therapeutics and devices. While there are myriad differences between the legal frameworks applicable to drugs, biologics, and devices under the FD&C Act and the PHSA, the law allows for abbreviated applications for all three medical products. These abbreviated approval pathways—the 505(b)(2) NDA for drugs, the §351(k) biosimilar BLA, and the 510(k) premarket notification for devices—provide an opportunity for companies to enter the market by relying, to some degree, on an innovator product that has previously been approved, licensed, or cleared by FDA. Use of these abbreviated approval pathways, generally, allows for a more efficient route to market at a lower cost and offers opportunities to introduce needed products to the U.S. market. While FDA-regulated medical product development is complex and challenging, do not overlook the abbreviated approval pathways unique to the U.S. regulatory framework.
Footnotes
1. https://www.insights10.com/report/us-pharmaceutical-market-analysis/ #:~:text=US%20
2. https://www.biospace.com/article/biologics-market-size-to-hit-usd-719-94-billion by-2030-/
3. https://www.fortunebusinessinsights.com/u-s-medical-devices-market-107009
4. See National Center for Science and Engineering Statistics, Jan. 4, 2023, available here: https://ncses.nsf.gov/pubs/nsf23320#:~:text=U.S.%20R%26D%20Increased%20by%20 %2451,Billion%20%7C%20NSF%20%2D%20National%20Science%20Foundation; see also U.S. and Global Research & Development, Jan. 2022, available at https://ncses.nsf. gov/pubs/nsb20221/u-s-and-global-research-and-development
5. Congressional Budget Office Report: Research & Development in the Pharmaceutical Industry, April 2021, at p. 6, available at https://www.cbo.gov/system/files/2021 04/57025-Rx-RnD.pdf.
6. FFDCA, June 25, 1938, c. 675, § 1, 52 Stat. 1040.
7. PHSA, July 1, 1944, ch. 373, 58 Stat. 682.
8. Class I low-risk devices must comply with "general controls"; Class II moderate-risk devices must comply with general controls and special controls listed in 21 CFR 8.
9. Hatch-Waxman Amendments, Pub. L. 98–417, Sept. 24, 1984, 98 Stat. 1585.
10. §505(b)(2) of the FD&C Act; see also Guidance for Industry: Applications Covered by Section
11. 505(b)(2) (December 1999) ("505(b)(2) Guidance") available at https://www.fda. gov/media/72419/download. 505(b)(2) Guidance at pp. 2-3.
12. A right of reference is permission, usually through a license agreement, to use and cite data in an applicant's NDA.
13. FDA Citizen Petition response regarding the scope of §505(b)(2) as it related to the Omnitrope NDA, May 30, 2006, at p. 6, available at https://downloads.regulations.gov/ FDA-2003-P-0003-0001/attachment_1.pdf
14. 21 CFR §314.54(a).
15. §505(b)(2) Guidance at pp. 4-5.
16. Pub. L. 111–148 (March 23, 2010); see also Krista Hessler Carver et al., An unofficial legislative history of the Biologics Price Competition and Innovation Act of 2009. 65 Food & Drug L.J. 671, 671 (2010).
17. §351(i) of the PHSA; 42 U.S.C. §262(i)(2); 42 USC §262(k)(2).
18. §351(k)(2)(A)(i)(I) of the PHS Act.
19. §351(k)(4) of the PHS Act.
20. §351(i)(3) of the PHS Act.
21. §351(k)(2)(A)(i)(IV) of the PHS Act; see also "Guidance for Industry: Questions and Answers on Biosimilar Development and the BPCIA Act," U.S. Food and Drug Administration (September 2021) at pp. 20-21, available at https://www.fda.gov/media/119258/ download.
22. Sandoz Inc.'s Zarixo was licensed as biosimilar to Amgen Inc.'s Neupogen as a treatment for patients who received forms of chemotherapy. See Novartis press release of March 6, 2015, at https://www.novartis.com/news/media-releases/fda-approves-first-biosimilar zarxiotm-filgrastim-sndz-from-sandoz
23. Semglee (insulin glargine-yfgn) is both biosimilar to, and interchangeable with (can be substituted for), its reference product Lantus (insulin glargine), a long-acting insulin analog. See FDA Press Release dated July 28, 2021, available at https://www.fda.gov/ news-events/press-announcements/fda-approves-first-interchangeable-biosimilar insulin-product-treatment-diabetes
24. See List of FDA-Approved Biosimilar Products, updated as of Nov. 1, 2023, available here: https://www.fda.gov/drugs/biosimilars/biosimilar-product-information
25. See Koyfman, Hannah, "Biosimilarity and Interchangeability in the Biologics Price Competition and Innovation Act of 2009 and FDA's 2012 Draft Guidance for Industry," Biotechnology Law Report, 2013 Aug; 32(4): 238–251.
26. See FDA's Biosimilars Info Sheet: Level 1: Foundational Concepts, which provides a great description of biosimilar manufacturing, available at https://www.fda.gov/ media/154913/download.
27. §21 USC § 360c(a)(1)(C); §21 USC 360c(f)(2)(A)(ii).
28. 21 USC § 360c(a)(1)(B); see also 21 CFR §807.92(a)(3).
29. See FDA's Premarket Notification 510(k) Overview, updated Oct. 3, 2022, available at https://www.fda.gov/medical-devices/premarket-submissions-selecting-and-preparing correct-submission/premarket-notification-510k#se
30. See Device Classification Panels, updated Aug. 31, 2018, available at https://www.fda.gov/ medical-devices/classify-your-medical-device/device-classification-panels
31. FDA's 510(k) database is searchable here: http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfPMN/pmn.cfm; FDA's PMA device database is searchable here: http://www. accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm
32. Premarket submissions include investigational device exemptions (IDEs), PMA, Humanitarian Device Exemptions (HDEs), De Novo Request, 510(k), and investigational new drug applications (INDs) for combination products, etc.
33. See FDA's Q-Sub Guidance here: https://www.fda.gov/media/114034/download
Originally Published by American Pharmaceutical Review
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