As more biosimilars are granted interchangeability status, 2 representatives from Samsung Bioepis stop misinformation in its tracks by clarifying that the designation will primarily impact pharmacy dispensing instead of prescription habits.
In July 2021, Semglee (insulin glargine-yfgn) was approved by the US FDA as the first interchangeable biologic in the United States. In October 2021, Cyltezo (adalimumab-adbm) was approved as the first interchangeable monoclonal antibody. In less than 6 months, the first adalimumab biosimilar is expected to launch in the United States, followed by 6 to 9 more launching in the second half of 2023.
Will the FDA designation of interchangeability matter commercially? No one knows, but it is important to clarify what interchangeability means from a clinical and regulatory perspective. This is especially the case as biosimilars are introduced to a wider pool of health care professionals in diverse specialties who may have less familiarity with what biosimilars are and the benefits they offer to their patients.
Biosimilars and Interchangeable Biologics from Legal Perspective
In the United States, in Europe, or elsewhere when the biologic product is approved by the governing regulatory agency as a “biosimilar,” they are already “interchangeable” with their reference biologic as a clinical matter., Many countries, including the United States, have created mechanisms to transition patients to biosimilars to provide greater and earlier access to these medicines.
In the United States, interchangeability is a legal distinction, and the term “interchangeability” is defined under section 351(k) of the Public Health 24 Service Act (PHS Act). The law enables the interchangeable biologic product to “be substituted for the reference product without the involvement of the prescriber.” This concept of interchangeability for biologics corresponds to automatic substitution for generic small molecule drugs.
In Europe, the law is silent on interchangeability because approvals are centralized, whereas how the medicines are purchased, distributed, and prescribed is made separately by each country’s health authority.
As stated in the article published in BioDrugs titled Interchangeability for Biologics is a Legal Distinction in the USA, Not a Clinical One, an FDA designation of interchangeability is only relevant to dispensing decisions and not prescribing ones, and hence not applicable to physician-administered biologics.
The US Congress added the additional category of “interchangeable biologic” to create the generic-like opportunity for biologics that are dispensed in retail or specialty pharmacies. The states govern substitution of medicines by other than the prescriber through their practice of pharmacy laws. The interchangeability designation was expected to act like FDA’s designation of therapeutic equivalence for generic small molecule drugs and offer opportunities for greater market competition and wider access to biologics for patients.
The existence of a legal statute and an additional regulatory designation for interchangeability seems to have triggered misunderstanding around interchangeable biologics as representing a "higher" standard. This is not the case—biosimilars and interchangeable biologics are approved under the same biologics license application (BLA) and both are safe, pure and potent just like every other FDA approved biologic. The same quality manufacturing standards that apply to the original biologic also apply to the interchangeable biologic and the biosimilar.
Biosimilars and Interchangeable Biologics from Clinical Perspective
Biosimilarity is based on the well-established regulatory concept of comparability. Comparability has been used successfully for several decades to ensure consistency between biological products before and after a manufacturing change. Both biosimilarity and comparability are grounded on the scientific fact that biologically active parts of the molecule, “critical quality attributes,” having consistent composition and conformation will govern the clinical outcome. If critical quality attributes are shown to be comparable then the same clinical results can be expected. This has been shown to be true in practice with both originator and biosimilar products, and hence as a scientific matter, comparability and biosimilarity apply the same principles.
Interchangeable biologics are the very same biosimilars upon which additional studies may have been done, to satisfy the statutory requirements for an interchangeable biologic to demonstrate “the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.”
Decades of experience with manufacturing changes to marketed reference products are useful for assessing the potential clinical implications of “switching” between reference products and biosimilars, especially potential risks associated with immunogenicity. No reasons for concern have been seen, and the observation and surveillance with the marketed products have been extensive and intense, especially since biosimilars became possible.
Since the approval of the first biosimilar in Europe in 2006, multiple biosimilars have become available, and their use is widespread. Biosimilars are now available in more than 100 countries around the world, and the accumulated patient treatment experience with biosimilars is over 2 billion patient days of treatment through 2020 in Europe alone. Because many countries use centralized or regional tender systems, large-scale transitions of treatment have occurred over many years, including switching from the reference product to a biosimilar, vice versa, and multiple switches between biosimilars. Despite diverse cases of transitions occurring frequently, patients’ treatment experience has remained consistent because the active moieties in each product give the same clinical results—that is what the regulators expected upon their approval and that is what has been shown to be the case in practice.
And to further confirm expectations, European Public Assessment Reports (EPARs) and European Medicines Agency post-marketing surveillance reports of approved biosimilars, along with real-world studies conducted by third-party investigators, show that the accumulated experience with biosimilars do not result in unexpected outcomes compared to using the reference product alone.
This is consistent with what has been observed with reference products going through manufacturing changes. Science is a universal language and the same science is applied around the world, irrespective of a given sponsors business model. This can be a further source of great confidence for all biologics.
Education is the Key
As biosimilars become more widely used in the market, they become more familiar and so more accepted. We have seen this with oncology biosimilars—trastuzumab, bevacizumab, and rituximab—and they are now having 50% to 70% of the market share by volume in the US. Understanding biosimilars and experience with them, especially by health care providers and their patients is the key.
Health care providers and their patients must be confident that biosimilars are approved to the same quality standards as every other biologic, and know that the FDA is confident that they will perform clinically in the same manner as their reference product. Otherwise, they would not have been approved. And it is imperative that health care professionals involved in the prescription and dispensing of biologics have adequate and accurate information about the product’s clinical profile as well as logistical and supply chain considerations in order to guide their patients’ choices. As adalimumab biosimilars start to become dispensed in pharmacies, pharmacists can play an important role in providing information and addressing questions about the equivalence of quality, efficacy, and safety of biosimilars and especially regarding interchangeability.
Consequently, it is increasingly urgent that semantic games cease, and in particular the implication that interchangeable biologics are better biosimilars be dismissed. We need to reduce barriers to patient access to these life-changing treatments, and work together to improve medical care for many chronic and acute diseases through affordability and accessibility to all biologics, including originator biologics, biosimilars and interchangeable biologics. That way everyone can benefit.
Gillian Woollett, MA, DPhil, is the the vice president and head of regulatory strategy and policy at Samsung Bioepis. Prior to her work at Samsung Bioepis, she served as Avalere Health's senior vice president for over 10 years.
Joseph Park, PhD, is the senior manager of regulatory strategy and policy at Samsung Bioepis. Park obtained his PhD from the Korea Advanced Institute of Science and Technology.
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