Regulatory And Legislative Actions Set The Tone For Biosimilars In 2021
By Philip Chen, Kayleigh McGlynn, and Jenny Shmuel, Fish & Richardson P.C.
The abbreviated biosimilar licensure pathway created by the Biologics Price Competition and Innovation Act (BPCIA) in 2010 was designed to increase competition for biologics and reduce healthcare costs. Already, FDA has licensed almost 30 biosimilars, nearly 20 of which are available to patients in the United States. While 2020 saw a slowdown in FDA approvals and biosimilar product launches from previous years, market uptake of biosimilars increased—and more biosimilars are sure to come. FDA has reported numerous biosimilar-related submissions in its pipeline for Fiscal Year (FY) 2020, including seven original biosimilar biologics license application (BLA) submissions in FY 2020. As of FY 2020 Q4, there were 84 biosimilar development programs enrolled in the biosimilar biological product development (BPD) program. In addition, with the BPCIA’s 10-year anniversary on March 23, 2020, insulin and other biological products previously regulated as “drugs” transitioned to regulation as biologics, paving the way for increased biosimilar diversity.
This article focuses on regulatory and legislative actions in 2020 that may impact the burgeoning biosimilars space in 2021 and beyond. In particular, we review FDA’s preparation for the March 23, 2020 transition date, as well as FDA’s efforts to address biosimilar competition, interchangeability, and the COVID-19 pandemic. We also look to lawmakers at the federal and state levels, who considered a variety of legislative proposals relating to biologics and biosimilars designed to improve patient access, encourage commercialization, and reduce costs.
Biosimilar Regulatory Updates
In 2020, FDA focused on a range of biosimilar-related issues through guidance documents, citizen petitions, and other mechanisms.
FDA Addresses Biosimilar Competition
In February 2020, FDA and the Federal Trade Commission (FTC) issued a Joint Statement of the Food & Drug Administration and the Federal Trade Commission Regarding a Collaboration to Advance Competition in the Biologic Marketplace. The statement advanced four stated goals: (1) to promote greater competition in biologics markets, (2) to deter behavior that impedes access to samples needed for biologic development, (3) to take appropriate action against false or misleading communications about biologics, and (4) to review patent settlement agreements involving biologics for antitrust violations.
Coinciding with this announcement, FDA issued draft guidance addressing promotional labeling and advertising considerations for prescription biological reference and biosimilar products. The guidance explains that determining whether promotional material is truthful and non-misleading involves a “fact-specific” analysis based on a number of factors, including “how the information is presented,” “the type and quality of the data relied on,” and “contextual and disclosure considerations.” The guidance further states that promotional material may be false or misleading if it creates an impression that there are clinically meaningful differences between the reference product and the biosimilar in terms of safety, purity, or potency, such as representations that a reference product is safer or more effective than its biosimilar product, or suggestions that a biosimilar is not highly similar to its reference product.
Around that same time, FDA responded to Pfizer’s August 2018 citizen petition in which the company asked the agency to issue guidance “to ensure truthful and non-misleading communications by sponsors concerning the safety and effectiveness of biosimilars, including interchangeable biologics, relative to reference product(s).” FDA granted Pfizer’s citizen petition in part to the extent that Pfizer requested draft guidance regarding promotional labeling and advertising considerations for biologics and biosimilars but denied Pfizer’s request to include specific content in the guidance, which was to be determined by FDA after consideration of public comments on the draft guidance.
FDA may soon weigh in again on issues relating to biosimilar competition. In December 2020, Boehringer Ingelheim (BI) filed a citizen petition asking FDA to change its interpretation of the term “strength” as used in the BPCIA for parenteral solutions to mean “total drug content” without regard to concentration. BI argued that a change in interpretation is necessary to, among other things, “prevent abusive ‘evergreening’ tactics from stifling competition of affordable biosimilar and interchangeable biological products” and “maintain fair and consistent treatment of all similarly situated parenteral biological products.” BI contended that FDA’s current interpretation “encourages, or at least permits, brand sponsors to use minor concentration changes as an anticompetitive tactic.” BI pointed to Humira (adalimumab) as an example. BI and other biosimilar manufacturers have approved Humira biosimilars with 50 mg/mL concentrations, but as of July 2018 Humira is now also marketed at a 100 mg/mL concentration—and BI alleged “no currently approved [original concentration] adalimumab product can be considered biosimilar or interchangeable to Humira’s [high concentration] formulation because the products have different concentrations.” FDA has acknowledged receipt of BI’s petition but has not yet provided any substantive feedback.
FDA Issues Draft Guidance on Biosimilarity and Interchangeability
In February 2020, FDA issued draft guidance in which it confirmed that “[a] biosimilar or interchangeable biosimilar may be licensed only for conditions of use that have been previously licensed for the reference product.” However, FDA also acknowledged that a “variety of circumstances,” such as orphan-drug exclusivities and patent protections, may cause applicants to seek licensure for fewer indications. The draft guidance provides suggestions on how to plan for approval of fewer than all indications.
In November 2020, FDA released new draft guidance for industry describing its current thinking on, among other things, seeking FDA review of biosimilar and interchangeable biosimilar BLAs and labeling of interchangeables. The draft guidance states, for example, that FDA intends to review new BLAs submitted under Section 351(k) as biosimilars (as well as interchangeables, if indicated), unless the cover letter clearly states that the applicant is only seeking licensure as an interchangeable. The guidance also provides exemplary language for indicating interchangeability on a label and clarifies that many of the guidelines for biosimilar labels also apply to interchangeable labels.
FDA Facilitates the Transition of Insulin and Other Biological Products Previously Regulated as “Drugs” to Biologics Regulation
As noted above, the “deemed to be a license” provision of the BPCIA went into effect on March 23, 2020, changing the way insulin and certain other biological products are reviewed and approved. Typically, “drugs” and “biologics” are subject to different laws and regulations. While drugs are regulated under the Food, Drug & Cosmetic Act (FD&C Act) through new drug applications (NDAs), biologics are regulated under the Public Health Service Act (PHS Act) through BLAs. A subset of biologics, including insulin and human growth hormones, historically were approved through NDAs under the FD&C Act and not through BLAs under the PHS Act. As a result, applicants could not seek approval of biosimilars or interchangeables of these products under the BPCIA. As of the March 23, 2020 transition, however, approved NDAs to “biological products” were “deemed” BLAs under the PHS Act, and companies can now seek biosimilars and interchangeables of these biological products.
FDA facilitated this transition by issuing relevant guidance and promulgating a final rule addressing the definition of “biological products” subject to the transition. Under that rule, FDA aligned the regulatory definition of “biological product” with the definition under the statute, which provides that a “biological product” includes a “protein.” For example, FDA interpreted the term “protein” to mean “any amino acid polymer with a specified defined sequence that is greater than 40 amino acids in size.”
Companies are already taking advantage of these new designations. For example, Mylan has announced its submission of “all necessary documentation” to FDA for approval of Semglee, an insulin product, as a biosimilar referencing Sanofi’s Lantus.
FDA Updates the Purple Book
Over the past year, FDA transitioned the so-called “Purple Book” to a searchable, public-facing online database. The database now contains information on “all FDA-licensed (approved) biological products regulated by the Center for Drug Evaluation and Research (CDER), including licensed biosimilar and interchangeable products, and their reference products” and “all FDA-licensed allergenic, cellular and gene therapy, hematologic, and vaccine products regulated by the Center for Biologics Evaluation and Research (CBER).” The Purple Book currently includes information such as the date of approval, the type of BLA approved, and whether there are approved biosimilars. The Purple Book does not currently include any patent information, but that will change in the future per recent legislation, as discussed below.
FDA Addresses the COVID-19 Global Pandemic
While FDA delayed inspections last year due to the ongoing global COVID-19 pandemic, the agency took steps to help companies navigate new challenges and minimize the impact of the pandemic on development and production of FDA-regulated products. To that end, FDA issued a steady stream of guidance documents that, for example:
- Provide recommendations to drug and biological product manufacturers regarding manufacturing controls to prevent contamination, risk assessment of SARS-CoV-2 as it relates to drug safety or quality, and continuity of manufacturing operations.
- Clarify FDA’s handling of site inspections and provide insight into those inspections that are deemed “mission critical.”
- Describe “how to evaluate and prioritize remediation of [current good manufacturing practice (CGMP)] activities that were necessarily delayed, reduced, or otherwise modified” during the COVID-19 pandemic “in order to maintain production and the drug supply.”
- Provide considerations to assist in ensuring safety and compliance with good clinical practice (GCP) in clinical trials conducted during COVID-19.
Biosimilar-Related Legislative Updates
In 2020, federal and state lawmakers considered a variety of legislative proposals relating to biologics and biosimilars designed to improve patient access, encourage commercialization, and reduce costs.
On Dec. 27, 2020, the president signed a second COVID-19 stimulus bill that included amendments to the BPCIA and updates to the Purple Book that bring the Purple Book closer to the analogous Orange Book for small molecule drugs. Under the new amendments, reference product sponsors (RPSs) must provide FDA with copies of any patent lists, along with patent expiration dates, within 30 days of when they were first provided to biosimilar applicants as part of the patent dance (pursuant to 42 U.S.C. § 262(l)(3)(A) or (l)(7)). FDA must then include this patent information in a public “searchable, electronic” database (i.e., the Purple Book) along with the nonproprietary name, date of licensure and application number, licensure and marketing status, and exclusivities of each approved biologic product.
Several legislative proposals directed to biosimilars were not enacted by the 116th Congress, but nevertheless provide insight into issues that may be the focus of future legislation:
- The proposed Increasing Access to Biosimilars Act of 2020 (H.R. 6179/S. 4134) would have directed the Centers for Medicare & Medicaid Services (CMS) to implement a “shared savings” model to encourage physicians to prescribe lower-cost biosimilars by offering providers a percentage of any net savings realized resulting from their efforts to reduce healthcare spending by patients.
- The proposed ACCESS for Biosimilars Act of 2020 (S. 3466/H.R. 4597) would have waived all out-of-pocket expenses for biosimilar products for beneficiaries of Medicare Part B programs for the first five years that a biosimilar is on the market.
- The proposed Biosimilar Insulin Access Act of 2020 (H.R. 8190) would have allowed for biosimilar insulins to automatically be granted interchangeability designations to their reference products.
While many states have enacted laws directed to biosimilars, specifically future interchangeables, California has enacted a number of additional unique laws. Most notably, California recently enacted two laws impacting biosimilars:
- California Assembly Bill 824 (AB 824) went into effect on Jan. 1, 2020 and regulates anticompetitive patent settlements. Sometimes referred to as “pay-for-delay” agreements, these settlements arise when brand name pharmaceutical companies or RPSs pay generic drug or biosimilar product manufacturers to slow or stop lower-cost medications from entering the market. Under the new law, such settlements are presumptively anticompetitive and unlawful if the generic or biosimilar receives “anything of value.” This presumption is a departure from the traditional framework for analyzing the legality of patent settlements set forth by the Supreme Court in the 2013 case FTC v. Actavis. AB 824 also provides that the State of California may obtain significant civil penalties for violations. The Association for Accessible Medicines (AAM) has challenged AB 824 as unconstitutional and preempted by federal law.
- In September 2020, California Governor Gavin Newsom signed into law the California Affordable Drug Manufacturing Act of 2020 (SB 852), which would allow the state’s Health and Human Services Agency to contract with drug manufacturers and suppliers to produce and distribute its own label of biosimilars, biosimilar insulins, and generic drugs. In a statement announcing the new legislation, Governor Newsom said that the bill would “help inject competition back into the generic drug marketplace – taking pricing power away from big pharmaceutical companies and returning it to consumers.”
In 2020, FDA remained an active participant in the biosimilar space, facilitating the transition of insulin and other “drugs” to regulation under the biologics statutory framework and providing new guidance on several different issues, such as biosimilarity, interchangeability, and promotional labeling and advertising. Federal and state lawmakers also continued to consider legislation designed to improve patient access, reduce drug prices, and increase competition.
While 2020 saw few new biosimilar approvals (potentially due in part to the COVID-19 pandemic), the slowdown may reflect a pause between an initial period of challenges to decades-old biologics and an anticipated second chapter focused on challenges to insulin and other biological products that are now deemed to be approved as BLAs and challenges to newer biologics that are reaching the end of their 12-year statutory period of exclusivity.
Looking ahead to 2021, FDA has already begun reviewing BLAs for biosimilars of reference products without previously approved biosimilars, such as Samsung Bioepis and Biogen’s SB11, a biosimilar referencing Lucentis (ranibizumab). Insulin interchangeables, for example Semglee, also may be on the horizon. FDA is also likely to issue additional guidance clarifying its approach to biosimilars and interchangeables. From a legislative perspective, it is likely that federal and state lawmakers will continue to pursue efforts to encourage competition and reduce the costs of biosimilars.
About The Authors:
Philip K. Chen is an associate at Fish & Richardson P.C., where he works on various patent litigation matters including pharmaceutical and biosimilar litigation. He can be reached at email@example.com.
Kayleigh McGlynn is an associate at Fish & Richardson P.C., where she works on a wide range of patent litigation matters including life sciences and pharmaceutical litigation. Before becoming a lawyer, she worked as a research scientist at a biotechnology company focused in the area of molecular diagnostics. She can be reached at firstname.lastname@example.org.
Jenny Shmuel, Ph.D., is a principal at Fish & Richardson P.C., where she has helped build the firm’s biologics and biosimilar litigation practice. She also represents pharmaceutical clients in competitor litigation and Hatch-Waxman litigation. Shmuel has extensive experience in all phases of litigation and, over the last several years, has helped successfully defend a large pharmaceutical franchise and secure a significant damages award for a medical device manufacturer. She can be reached at email@example.com.
The opinions expressed are those of the authors on the date noted above and do not necessarily reflect the views of Fish & Richardson P.C., any other of its lawyers, its clients, or any of its or their respective affiliates. This post is for general information purposes only and is not intended to be and should not be taken as legal advice. No attorney-client relationship is formed.