By Jennifer Fox and Joshua Ney, Ph.D., Brinks Gilson & Lione
In July 2018, the FDA unveiled a Biosimilar Action Plan (BAP) intended to “facilitate the efficient development and approval” of biosimilar products. When FDA Commissioner Scott Gottlieb introduced the BAP, he emphasized the importance of building a market for biosimilar products and expressed concern that the market is not yet established.
The BAP lays out four areas of focus: (1) improving the efficiency of the biosimilar and interchangeable product development and approval process; (2) maximizing scientific and regulatory clarity for the biosimilar product development community; (3) developing effective communications to improve understanding of biosimilars among patients, clinicians, and payors; and (4) supporting market competition by reducing gaming of FDA requirements or other attempts to unfairly delay competition.1
For each area of focus, the BAP identifies several “priority deliverables” the FDA intends to provide to achieve the goals of the BAP. Some of the deliverables are specific. For example, the BAP states the FDA is developing application review templates to increase the efficiency of reviewing biosimilar product applications and education materials to improve understanding of biosimilars among patients, clinicians, and payors. However, many of the deliverables outlined in the BAP are framed in broad terms and do not reveal the specific policies the FDA is contemplating. This article discusses two elements of the BAP that have significant potential to shape the incentives for innovator biologic and biosimilar development, but which the FDA has not yet translated into specific policy proposals.
Reference Product Exclusivity
The BAP indicates the FDA plans to “clarify [its] position on issues affecting reference product exclusivity to better effectuate balance between innovation and competition.” Under the “reference product exclusivity” provisions of the Biologics Price Competition and Innovation Act (BPCIA), a section 262(k) application cannot be submitted until at least four years, and cannot be approved until at least 12 years, after the reference product was first licensed under section 262(a).2 Although the duration of reference product exclusivity is fixed by statute, considerable discussion has been devoted to the criteria for determining whether a given product is eligible for reference product exclusivity, as well as the start date for the exclusivity period.
The BAP does not identify the reference product exclusivity issues the FDA intends to address or the position it may take on those issues, but much of the discussion surrounding reference product exclusivity has focused on the “first-licensure” provision of the BPCIA. The “first-licensure” provision states reference product exclusivity shall not apply to licenses for “supplements” to a prior reference product or to licenses for certain “subsequent applications” filed by the sponsor of a prior reference product (or a related entity).3 The sponsor of an approved reference product may file a supplement or subsequent application to make certain changes or improvements to the approved product, such as manufacturing changes, labeling changes, and new indications. The FDA issued draft guidance interpreting the “first-licensure” provision in August 2014.4
Several issues surrounding reference product exclusivity, and particularly the “first-licensure” provision, appear to be candidates for clarification:
- Umbrella Exclusivity – The existing draft guidance does not state whether approved “supplements” and “subsequent applications” that are not eligible for their own reference product exclusivity period will be awarded the remaining exclusivity of the prior reference product (“umbrella exclusivity”). For example, if the sponsor of an approved reference product that received first licensure exclusivity files a supplement or subsequent application for a new indication of that approved reference product, will any remaining exclusivity on the approved reference product extend to the later-approved new indication? The availability of umbrella exclusivity can have a profound effect on the potential date of biosimilar entry for a given biologic product, and some public comments submitted in connection with the existing draft guidance have argued the absence of umbrella exclusivity would provide a disincentive for sponsors to make improvements to existing products.5 The FDA recently solicited additional public comments as to whether umbrella exclusivity should be available,6 suggesting this issue is likely to be addressed in the FDA’s new guidance.
- Procedural Aspects of Exclusivity Determination – The FDA may also consider clarifying or revising the rights and obligations of reference product sponsors and biosimilar applicants to participate in FDA exclusivity determinations. The existing draft guidance suggests product sponsors should provide certain information (e.g., a list of structurally related biological products) to the FDA “[t]o assist FDA in evaluating the date of first licensure” of the product because sponsors “generally have superior information … relevant to the date of first licensure.”7 This aspect of the existing guidance has generated extensive public commentary. Some commenters have stressed that section 262(k)(7) should be interpreted to confer a “presumption” of exclusivity and that a reference product sponsor should not be required to “apply” for exclusivity or provide evidence to establish its eligibility for exclusivity.8 Other commenters have suggested the FDA should provide a mechanism for biosimilar applicants to submit information relevant to exclusivity determinations, since the FDA’s exclusivity determinations substantially impact biosimilar applicants.9 The FDA’s possible clarification of these procedural issues has the potential to shape both the burden of proof and the information available to the FDA in making exclusivity determinations.
Given the importance of reference product exclusivity, both in the incentives it provides to developers of new biological products and in its effect on the timing of biosimilar competition, the above issues are worth watching as the FDA implements the BAP.
The BAP also states the FDA plans to “[p]rovide additional clarity for product developers on demonstrating interchangeability,”10 but does not elaborate on the FDA’s specific plans. By statute, interchangeable products “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”11 In addition, the first biosimilar product approved as interchangeable for a given reference product is entitled to a period of regulatory exclusivity during which no other biosimilar product may be approved as interchangeable for the same reference product.12 Accordingly, biosimilar sponsors have a significant financial incentive to achieve the interchangeable designation.
The FDA previously issued draft guidance discussing certain scientific considerations and requirements involved in demonstrating a biosimilar product is interchangeable with its reference product.13 While the existing draft guidance provides some insight into the FDA’s potential thought process in evaluating applications for interchangeable status, the guidance also raises significant questions the FDA may address in its implementation of the BAP:
- Applicability – By its terms, the existing draft guidance is specific to therapeutic protein products.14 The FDA has not issued guidance discussing the considerations pertinent to interchangeability determinations for other biologics, and it remains to be seen whether the considerations outlined in the existing guidance will be applied broadly.
- Factors Impacting the Type of Data Needed – The existing draft guidance stresses that the type and amount of data needed to demonstrate a biosimilar product meets the requirements for interchangeability depends on the “residual uncertainty” about the interchangeability of the biosimilar product with the reference product.15 The residual uncertainty, in turn, depends on factors such as the structural complexity of the product, the degree of analytical similarity between the biosimilar and reference products, and the existence of any product-specific immunogenicity risks.16 The guidance recommends the analytical similarity of the biosimilar product to the reference product be determined by a “fingerprint-like characterization,”17 but provides little detail as to what fingerprint-like characterization entails, how it should be conducted, and how the results would be applied to a determination of interchangeability. Indeed, many of the public comments on the existing draft guidance have called for the FDA to clarify these issues.18
- Studies Needed to Demonstrate that Product Meets “Any-Given-Patient” Standard – The existing draft guidance explains that the sponsor of a product intended to be administered to an individual more than once will be expected to conduct a switching study. This should demonstrate the product meets the statutory requirement that “the risk in terms of safety or diminished efficacy of alternating or switching between 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 However, the draft guidance does not discuss whether separate studies, in addition to the switching studies, would need to be conducted to demonstrate a product meets the other statutory requirement for interchangeability — that the product “can be expected to produce the same clinical result as the reference product in any given patient.”20 It is unclear from the draft guidance whether the FDA interprets the “any-given-patient” standard to impose an additional requirement beyond the requirements for demonstrating biosimilarity.21
In implementing the BAP, the FDA may clarify these aspects of its guidance for demonstrating interchangeability of a biosimilar product with a reference product. The choices the FDA makes in addressing these issues likely will have a profound effect on the ability of biosimilar products to qualify for interchangeable status.
The FDA’s pledge to clarify its guidance regarding reference product exclusivity and interchangeability determinations are just two of the many deliverables outlined in the BAP that have the potential to shape the incentives and procedures for biosimilar development in the coming months and years. These issues bear watching as the FDA translates the broad goals outlined in the BAP into concrete policies.
- U.S. Food & Drug Admin., Biosimilar Action Plan: Balancing Innovation and Competition 5 (July 2018) [hereinafter BAP].
- 42 U.S.C. § 262(k)(7)(A) & (B). Section 262 of Title 42 of the U.S. Code corresponds to section 351 of the Public Health Service Act. For consistency, all statutory references in this article refer to the U.S. Code provision.
- 42 U.S.C. § 262(k)(7)(C).
- U.S. Food & Drug Admin., Guidance for Industry: Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (Aug. 2014) [hereinafter Draft Exclusivity Guidance] (draft).
- Pharm. Research & Mfrs. of Am., Comment Letter on Guidance for Industry Entitled “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act” (Docket No. FDA-2013-D-1165) 17-19 (Oct. 6, 2014) [hereinafter PhRMA Exclusivity Comments].
- Request for Comments, 83 Fed. Reg. 35,154, 35,156 (July 25, 2018).
- Draft Exclusivity Guidance at 1, 7-8.
- See, e.g., Biotech. Indus. Org., Comment Letter on Guidance for Industry Entitled “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act” (Docket No. FDA-2013-D-1165) 2, 4 (Oct. 6, 2014) [hereinafter BIO Exclusivity Comments]; PhRMA Exclusivity Comments at 2-3.
- Generic Pharm. Assoc., Comment Letter on Guidance for Industry Entitled “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act” (Docket No. FDA-2013-D-1165) 2 (Oct. 6, 2014) [hereinafter GPhA Comments]; Hospira, Inc., Comment Letter on Guidance for Industry Entitled “Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act” (Docket No. FDA-2013-D-1165) 1-2 [hereinafter Hospira Comments]; Mylan Comments at 4.
- BAP at 3.
- 42 U.S.C. § 262(i)(3).
- 42 U.S.C. § 262(k)(6).
- U.S. Food & Drug Admin., Guidance for Industry: Considerations in Demonstrating Interchangeability with a Reference Product (Jan. 2017) [hereinafter Draft Interchangeability Guidance] (draft).
- Draft Interchangeability Guidance at 1.
- Draft Interchangeability Guidance at 5.
- Draft Interchangeability Guidance at 5-7.
- Draft Interchangeability Guidance at 6.
- See, e.g., Assoc. for Accessible Meds. et al., Comment Letter on Guidance for Industry Entitled “Considerations in Demonstrating Interchangeability With a Reference Product” (Docket No. FDA-2017-D-0154) 9-10 (May 19, 2017); Biotech. Innov. Org., Comment Letter on Guidance for Industry Entitled “Considerations in Demonstrating Interchangeability With a Reference Product” (Docket No. FDA-2017-D-0154) 5 (May 19, 2017); Pharm. Research & Mfrs. of Am., Comment Letter on Guidance for Industry Entitled “Considerations in Demonstrating Interchangeability With a Reference Product” (Docket No. FDA-2017-D-0154) 10 (May 19, 2017).
- Draft Interchangeability Guidance at 12.
- Existing Draft Guidance at 9-15.
- See Johnson & Johnson, Comment Letter on Guidance for Industry Entitled “Considerations in Demonstrating Interchangeability With a Reference Product” (Docket No. FDA-2017-D-0154) 2-3 (May 19, 2017).
About The Authors:
Jennifer Fox is a shareholder at Brinks Gilson & Lione, where she is a co-chair of the firm’s biopharma practice group. With over two decades of experience in the pharmaceutical and biotechnology industries, her practice includes patent portfolio procurement and management, IP due diligence and transactional support, and post-grant proceedings.
Joshua Ney, Ph.D., is an associate at Brinks Gilson & Lione, where he focuses his practice on patent litigation and prosecution in the pharmaceutical, biotechnology, and chemical industries.