By Stacie Ropka, Ph.D., Ted Mathias, and Michelle Divelbiss, Axinn, Veltrop & Harkrider LLP
The Biologics Price Competition and Innovation Act (BPCIA) enacted in 2010 provides two abbreviated approval pathways for biological products (follow-on biologics). Developers of biologics can seek designation of their follow-on product as biosimilar to, or interchangeable with, a reference biological product approved by the Food and Drug Administration (FDA).1 Although the FDA has approved 23 biosimilars for nine reference products since 2015,2 the FDA has yet to designate a follow-on biologic as interchangeable. The interchangeable designation is more desirable because, unlike biosimilars, interchangeables can be substituted at the pharmacy without approval by a healthcare provider.
Here, we discuss the statutory and regulatory requirements for the interchangeability designation, describe how the designation has hampered development of the follow-on biologics market in the United States, and explain why real-world experience with biosimilars, supported by scientific studies, should allow the FDA to loosen the requirements for the interchangeability designation.
Biosimilar Versus Interchangeable Biologics
The BPCIA defines a biosimilar as a “product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.”3 An interchangeable, however, “can be expected to produce the same clinical result as the reference product in any given patient”4 and “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”5 The FDA further describes an interchangeable as “a biosimilar product that meets additional requirements outlined by the [BPCIA].”6
In 2019, the FDA provided a final guidance outlining the information required to support a demonstration of interchangeability to a reference product.7 An applicant seeking the designation of interchangeable must demonstrate that the biological product “can be expected to produce the same clinical result as the reference product in any given patient”8 and, for follow-on biologics administered more than once, applicants must also demonstrate 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.”9
To satisfy this switching requirement, applicants must conduct an immunogenicity switching study demonstrating that switching patients from the reference product to the interchangeable and back to the reference product does not impact safety or efficacy.10 The FDA guidance suggests, however, that advances in analytics might later obviate the need for switching studies.
The Follow-On Biologic Market Is Struggling To Form In The United States
The follow-on biologic market in the United States has not been well-served by the two-tiered biosimilars/interchangeables framework. The United States lags far behind Europe in follow-on approvals and adoption rates. Although there have been other contributing factors,11 Europe’s single-tier, “biosimilars-only” system simplifies physician and patient education regarding the safety and efficacy of follow-on biologics.
By contrast, the two-tiered approach has created confusion and resistance to biosimilars. Particularly for the first biosimilars but still to a lesser extent today, the medical community and patients equated “biosimilar” with lesser quality because they required less data than interchangeables. Physicians were often told that they should wait for interchangeables, suggesting that biosimilars would not meet patients’ needs.12 In 2018, FDA Commissioner Scott Gottlieb explained that “we [i.e., the FDA] are worried, and I’m worried in particular, that the market for these products is still not firmly established. And the ability of these products to penetrate clinical practice and gain acceptance in clinical practice isn’t yet firmed up.”13
Although the FDA’s efforts to educate the public and physicians have had some success in encouraging biosimilar adoption,14 a wave of approvals for interchangeables would surely accelerate the United States market’s development. Physicians and patients have already been conditioned to accept interchangeables.15 And at least for the growing number of self-administered biologics, the advent of interchangeables will lead to automatic substitution at the pharmacy. Adoption of these interchangeables will not be contingent on each individual physician deciding to affirmatively prescribe an alternative to the reference product.
How To Get Interchangeables On Track
The FDA’s delay in promulgating requirements for the interchangeable designation has undoubtedly discouraged companies from developing interchangeables. Now that it has issued the guidance, the FDA should use the flexibility it has built into the guidance to streamline the approval process.
Immunogenicity Concerns – In Theory
The FDA’s requirement that developers seeking an interchangeable designation undertake costly and time-consuming switching studies are driven by immunogenicity concerns, i.e., that patients could develop an immune response to the biologic that compromises its efficacy. At least in theory, a follow-on biologic could trigger an immune response different from that experienced with the reference biologic because of subtle differences between the two biologics.
The FDA and its European counterpart, the European Medicines Agency (EMA), have taken divergent approaches to the role of immunogenicity and its impact on automatic substitution at the pharmacy. The EMA delegates this responsibility to decide regarding automatic substitution to each of the 28 member states.16 The FDA has placed the burden on developers seeking an interchangeable designation to demonstrate that alternating or switching between the interchangeable and the reference product does not carry an increased risk.17 The FDA believes that immunogenicity is a concern with respect to automatic substitution, while the EMA recognizes that “[i]mmunogenicity is not a safety concern in itself.”18
Study Survey & Findings
The FDA now has years of experience and studies showing that immunogenicity has not impacted patient welfare. There are multiple biosimilars for each reference product, and it is highly likely that some patients have been switched in clinical practice, outside of switching studies. Nevertheless, “no new safety or efficacy concerns have been detected in the over 10 years and greater than 700 million days of patient experience with biosimilars.”19 The EMA’s director, Dr. Guido Rasi, has “confirmed that for the 29 biosimilar medicines in Europe... the EU monitoring system for safety concerns has not identified any relevant difference” between biosimilars and reference products.20 Additionally, Dr. Pekka Kurki, director and research professor at the Finnish Medicines Agency, has “stated that worries about immunogenicity are exaggerated and lack a solid theoretical background.”21
Cohen et al.’s meta-analysis reviewing nearly 100 switching studies and thousands of patients supports Dr. Kurki’s assessment. Three of the studies involved multiple switches. For filgrastim, researchers studied five switchover events and concluded that efficacy, safety, and immunogenicity were unchanged. Similarly, three-switch studies with both etanercept and adalimumab demonstrated similar efficacy, safety, and immunogenicity between the reference product and the biosimilar.
Scores of studies involving a switch from a reference product to a biosimilar reached similar results. For example, there were “14 studies that enrolled 5,256 patients who were switched from erythropoietin to darbepoetin” and 46 insulin switching studies involving more than 20,000 patients.22
Cohen et al. did identify two anomalous results in infliximab that involved a single switch from the reference product to the biosimilar. First, “a Turkish claims database where 148 patients were switched from reference infliximab to biosimilar infliximab… reported an 82 percent dropout rate in patients who were switched compared to a 24 percent dropout rate in control patients that remained on reference infliximab.”23 Second, Kang et al. identified an abnormality in which there was a “reported loss of efficacy in one of 17 patients in their study.”24 These two anomalies are not necessarily indicative of poor outcome or adverse reactions resulting from the switching itself.25 Cohen et al. stated that “[g]iven that the vast majority of other studies, irrespective of design or size, do not show immunogenicity or signs of intolerance after switching from reference biologic to biosimilar, it is most likely that these two reports are outliers.”26 Even though a few studies observed loss of responses, there were no identifiable patterns to explain why a patient might stop responding to treatment.27
Taking into account all of the data analyzed, Cohen et al. found that the studies “did not show loss of efficacy related to switching from reference medicines to biosimilars.”28 And perhaps more importantly, new adverse events were not detected when a patient was switched from a reference product to a biosimilar.29 Another group, Inotai et al., conducted a literature review of switching studies and concluded that preventing “switching to biosimilars due to anticipated risks seems to be disproportional compared to the cost savings and/or improved patient access.”30 Results from a study with five switching events “showed no differences in efficacy or overall safety,” and a study with three switching events also showed similar “safety, efficacy, and immunogenicity profiles.”31 Whether a study assesses single or multiple switching, these reviews have not found data to support the theory that switching will cause immunogenicity concerns.
The Future Of Interchangeables
Looking forward, there is reason for optimism. Boehringer Ingelheim began an interchangeability study in 2017 for BI 695501, a follow-on biologic of the blockbuster drug Humira. The study is slated for completion in 2020 and might lead to the first interchangeable biologic designation in the United States. If all goes well, it could pave the way for more biosimilar developers to seek an interchangeable designation.
The FDA can do much to facilitate the development of more interchangeables. The BPCIA requires that interchangeables “be expected to produce the same clinical result as the reference product in any given patient” and that the risk of switching between interchangeables and reference product is no greater than using the reference product alone.32 The FDA has discretion to determine how developers can meet those statutory requirements.
In addition, more data and new technologies could cause the FDA to conclude that switching studies are not the most effective or efficient method to produce data that satisfies the statutory requirements for an interchangeable designation. Improving technologies in detecting relative purity levels, impurities, and aggregates could allow regulators to give more weight to in vitro analyses and forgo costly and time-consuming clinical trials.33 Indeed, scientists from Colombia, India, Italy, the Netherlands, Spain, and the United States have urged the World Health Organization (WHO) to update its biosimilars guidelines to reflect that advancements in manufacturing “have greatly reduced the likelihood of a difference between [a biosimilar] and [a reference product] with a clinical impact.34
Looking forward, the FDA could require only a single pre-marketing switch study (where patients begin with the reference product and switch to the biosimilar product) and, potentially, post-marketing surveillance to assess ongoing safety and efficacy. It is more likely, however, that the FDA will not abandon multiple switch studies altogether and instead would decide whether to require them on a case-by-case basis. In any event, the FDA should continually reassess its requirements for interchangeability with the goal of encouraging development of interchangeable follow-on biologics.
About The Authors:
Stacie Ropka, Ph.D., is a partner at Axinn. Her practice focuses on intellectual property litigation, due diligence, and client counseling, with an emphasis on the life sciences. Ropka’s experience includes extensive counseling for product development efforts relating to biologics and reconstructive biomaterials, including products that utilize adult stem cells. Prior to attending law school, she held a faculty position at SUNY Upstate Medical University, and she also spent many years as a research scientist in the fields of neurology, virology, and immunology.
Ted Mathias is a partner at Axinn who focuses on trying patent cases. In just the last year, he tried two cases to judgment and served as lead counsel in a case involving 33 patents that favorably settled on the eve of trial. Mathias has litigated patent cases and handled successful appeals to the Federal Circuit in the areas of medical devices, pharmaceuticals, mechanical devices, e-commerce, and software. He has served as lead counsel in commercial disputes and litigated sham litigation, standards setting, patent pooling and IP licensing issues, other Sherman Act claims, insurance coverage, and environmental claims.
Michelle Divelbiss is an associate (not yet licensed to practice) in the Intellectual Property group in Axinn’s Washington, DC office. Prior to earning her JD from The George Washington University Law School, she was a research associate at a biotechnology company focused on the development and commercialization of diagnostic tests prognostic for risk of cancer metastasis, companion diagnostics to predict drug response, and anti-metastatic drugs.