Fixing The Follow-On Insulin Regulatory Approval "Dead Zone"

By Chad A. Landmon and Christopher M. Gallo, Ph.D., Axinn, Veltrop & Harkrider LLP

With all the attention on the costs of pharmaceutical products, there is an upcoming regulatory “dead zone” that will potentially delay market entry of certain insulin products, adversely impacting insulin prices for consumers and payors. A recent Senate bill has been proposed to address this regulatory anomaly. Industry players should monitor this bill and other efforts to address the insulin dead zone, given how critical this product is to so many people.

Nearly 30 million Americans have diabetes,¹ with approximately 30 percent of diabetic adults either taking insulin alone or in combination with oral medication, based on data collected between 2007 and 2010.² Between 2002 and 2013, the list price for insulin products nearly tripled,³ and the list price of insulin typically increases between 15 and 17 percent annually.⁴ Currently, only three drug manufacturers (Eli Lilly, Novo Nordisk, and Sanofi) provide insulin to the U.S. market.⁵

Insulin products are biological products, but they have traditionally been approved as drugs under section 505 of the Federal Food, Drug, and Cosmetic Act (FDCA). But on March 23, 2010, Congress enacted the Biologics Price Competition and Innovation Act (BPCIA), which mandated that all applications to market biological products be submitted for approval under section 351 of the Public Health Service (PHS) Act.⁶ The BPCIA provided an exception for this requirement for applications (1) seeking to market a biological product that is “in a product class for which a biological product in such product class is the subject of an application approved under such section 505 [of the FDCA] not later than” March 23, 2010, e.g., insulin, and (2) that were submitted to the FDA before March 23, 2010 or no later than March 23, 2020.⁷ The BPCIA also prevents the submission of any application under section 505 of the FDCA if a licensed biologic product that can serve as a reference product exists.⁸ Notably, the BPCIA further provides that applications for biological products that have been approved under section 505 before March 23, 2020 will be deemed licensed biologic products after March 23, 2020.⁹

Taken together, the provisions discussed above effectively create a dead zone where an application for a generic insulin product that: (1) has already been submitted under section 505 of the FDCA and remains pending or tentatively approved as of March 23, 2020 and (2) references an insulin product that will transition to the status of a licensed biologic is not approvable under the FDCA. And indeed, the FDA has provided final guidance stating that any such applications that remain pending or tentatively approved as of March 23, 2020 will receive a complete response letter requiring resubmission of the application under the approval pathways for biologic products outlined in section 351 of the PHS Act.¹⁰

The FDA has stated that it “intends to assist applicants” who may be affected by the dead zone created by the transition provisions of the BPCIA, “where feasible and appropriate.”¹¹ But it is likely that resubmission of applications seeking to market generic insulins will result in unwelcome delays in approval that will ultimately prolong getting generic insulin products to market, which in turn prevents a slowdown in the continually rising prices for insulin paid by patients.

In an effort to prevent such delays and speed up the approval of generic insulin products already undergoing review by the FDA, Senators Dick Durbin (D-IL), Kevin Cramer (R-N.D.), and Tina Smith (D-MN) recently introduced Senate Bill 2103 (S. 2103; the Affordable Insulin Approvals Now Act).¹² The bill specifically exempts from the dead zone applications for generic insulin products that were submitted under section 505 of the FDCA before Dec. 31, 2019 and that remain unapproved as of March 23, 2020.¹³ Per the bill’s current text, the FDA must continue to review such applications under section 505 and treat any reference product in the application as a listed drug under the FDCA, even if the reference product has transitioned to a licensed biological product after March 23, 2020. The bill also directs the FDA to deem any such application eventually approved under section 505 as a licensed biological product after the March 23, 2020 transition date.

As discussed above, keeping generic insulin applications in the section 505 approval pipeline and exempt from the dead zone should speed up approval of generic insulin products that otherwise may be delayed by resubmission for approval under section 351 of the PHS Act. Indeed, while the FDA may intend to avoid any such delays, it has stated that any reviews under section 505 will only be considered to the extent they are relevant and consistent with the requirements of section 351 of the PHS Act.¹⁴ Further, resubmissions under section 351 may require the performance of additional clinical studies to demonstrate that the generic product is highly similar to the reference product, with no clinically meaningful differences as to safety, purity, or potency. And importantly, the FDA has stated that patent exclusivities associated with reference products approved under the FDCA will cease upon transition of the product to a licensed biologic.¹⁵ So, by removing the dead zone, S. 2103 will also to serve to speed up approval of any tentatively approved generic insulin products that are only blocked from final approval by such patent exclusivities and otherwise would have to be resubmitted for review under section 351. All in all, S. 2103 should help bring lower-cost generic insulins to market in a timely manner that does not disrupt the current standing of these applications at the FDA.

In July, S. 2103 was referred to the Committee on Health, Education, Labor, and Pensions, from which it will need to be reported out for ultimate consideration by the full Senate and then the House of Representatives. Industry players will want to keep apprised of the status of S. 2103 as the March 23, 2020 transition date approaches. Also, should the bill not become law, the FDA may see lawsuits challenging its interpretation of the BPCIA’s transition provisions when it begins requiring resubmission of applications not approved before March 23, 2020.

Notes:

1. Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency’s continued efforts to bring competition to the insulin market to lower prices and expand access (available at https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-continued-efforts-bring-competition-insulin (last accessed Aug. 20, 2019)) (“Gottlieb Statement”).
2. Sharon H. Saydah, Medication Use and Self-Care Practices in Persons With Diabetes, Chapter 39 in Diabetes in America, 3rd ed., Cowie CC et al., Eds. Bethesda, MD, National Institutes of Health, NIH Pub No. 17-1468 (2018).
3. Cefalu, W.T., et al., “Insulin Access and Affordability Working Group: Conclusions and Recommendations,” Diabetes Care, 41: 1299-1311 (2018).
4. Gottlieb Statement.
5. Baxter recently obtained approval in July 2019 to market human insulin for intravenous administration in hospital and acute care settings. See https://www.baxter.com/baxter-newsroom/baxter-announces-us-fda-approval-myxredlin-first-and-only-ready-use-insulin-iv (last accessed Aug. 20, 2019).
6. BPCIA, Pub. L. No. 111-148, § 7002(e)(1) (124 Stat. 817) (codified at 42 U.S.C. § 262).
7. BPCIA, Pub. L. No. 111-148, § 7002(e)(2) (124 Stat. 817) (codified at 42 U.S.C. § 262).
8. BPCIA, Pub. L. No. 111-148, § 7002(e)(3) (124 Stat. 817) (codified at 42 U.S.C. § 262).
9. BPCIA, Pub. L. No. 111-148, § 7002(e)(4) (124 Stat. 817) (codified at 42 U.S.C. § 262).
10. Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009: Guidance for Industry (Dec. 2018), at 6 (available at https://www.fda.gov/media/119590/download (last accessed Aug. 20, 2019)).
11. Id. at 7.
12. S. 2103 is also currently co-sponsored by Senators Cindy Hyde-Smith, Shelley Moore Capito, Mitt Romney, Jeanne Shaheen, and Doug Jones.
13. Affordable Insulin Approvals Now Act, S. 2103, 116th Cong. (2019).
14. Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009: Guidance for Industry (Dec. 2018), at 7.
15. Id. at 8-9.

About The Authors:

Chad Landmon is a partner at Axinn, where he chairs the firm’s Food and Drug Administration and Intellectual Property Practice Groups. He focuses his practice on patent litigation and counseling and food and drug law, with an emphasis on pharmaceuticals, biologics, regenerative medicine, and human tissue products. Landmon also maintains a particular focus on Paragraph IV patent litigation, having litigated dozens of cases on blockbuster products. By coupling his patent litigation experience with his FDA expertise, he enables pharmaceutical clients to develop and execute on patent and FDA strategies to bring products to market.

Christopher Gallo holds a Ph.D. in biochemistry and molecular genetics and is an associate at Axinn, where he focuses on patent counseling and litigation for biological and drug products. His experience includes matters before federal district courts and the United States International Trade Commission, in which he has been heavily involved in all aspects of litigation. Christopher also has experience in patent reexaminations and in inter partes review proceedings before the Patent Trial and Appeal Board.