Table 1. Biosimilarity Concepts and Terms.

Topic	Brief explanation
What is a biosimilar?	A biosimilar is a “highly similar” version of a single FDA-licensed biologic (i.e., an RP), notwithstanding minor differences in clinically inactive components. No clinically meaningful differences are permitted between the biosimilar and the RP in terms of safety, purity, and potency.
What makes biosimilars different from generic drugs?	Biosimilars are: Produced from living organisms Relatively large complex molecular structures Molecules with minor natural structural heterogeneities Sensitive to storage and handling conditions Approved based on “high similarity” to the RP and demonstrating comparable safety, purity, and potency	Generics are: Synthesized chemically Simple small-molecule drugs Structurally well defined Relatively stable and predictable Approved based on structural identicalness and “bioequivalence” to the RP
What differences are permitted between approved biological products such as biosimilars?	Minor differences, or “acceptable within-product variations,” are anticipated between each biosimilar and its RP during manufacture. Acceptable within-product lot-to-lot and batch-to-batch differences are a natural occurrence, even when RPs are manufactured. All within-product variations must be marginal, vigilantly monitored, and stringently controlled so as not to affect the biologically active parts of the molecule implicated in biological functionality (i.e., no meaningful impact on clinical efficacy, safety, and immunogenicity).
How are biosimilars developed?	Biosimilars are reverse-engineered from an original biological product for which the proprietary formulation is unavailable to the biosimilar sponsor. The goal is to minimize potential variations between the proposed biosimilar and the RP.
How does the development of biosimilars proceed?	A comprehensive stepwise development program is implemented. Step 1. Molecular structure and function assessments Step 2. Nonclinical assessments (including animal studies) Step 3. Clinical pharmacology assessments (pharmacokinetic and pharmacodynamic studies in addition to the assessment of immunogenicity in an adequately sensitive population) Step 4. A comparative clinical trial(s) (biosimilar vs. the RP) to confirm efficacy, safety, and immunogenicity in a population sufficiently sensitive to the detection of any clinically meaningful product differences while simultaneously mitigating patient- or disease-related issues
What is the approval process for biosimilars?	Biosimilars are approved based on an array of scientific data referred to as the totality-of-the-evidence (outlined in Steps 1–4) as opposed to a single test. Analytical studies lay the groundwork for determining biosimilarity. Substantive evidence based on analytical similarity—with a focus on biological functionality—can provide the rationale for reducing the amount of preclinical and clinical data/studies required. FDA approval of a biosimilar signifies that there are no clinically meaningful differences associated with its efficacy and safety compared with the RP.
Why are there fewer clinical studies for a biosimilar compared with a reference product?	A biosimilar is always compared with a RP that previously underwent extensive clinical study before its approval by the FDA and has been in clinical use for many years. The foundation of the biosimilar development program is an extensive comparison to show that the biosimilar and its RP are highly similar in structure and function. After the demonstration of high similarity in structure and function, a more tailored clinical development program can be utilized to probe for any clinical meaningful differences between the products. It is not necessary to recreate the entire development program.
Why is the cost of biosimilars lower?	Abbreviation of the approval process for biosimilars occurs because of the nature of the clinical development program and the approval pathway. Multiple, large, and costly clinical trials are not necessary and so this can generate health-care cost savings.
Treatment changes
Substitution	The practice of a retail or hospital pharmacist dispensing one biological product for another clinically equivalent or interchangeable biological product without (automatic substitution) or with the agreement of the prescriber. Substituting a biosimilar for a RP is a matter of state pharmacy law; it varies from state to state and is not within the purview of the FDA. However, only when biosimilars meet the FDA-approved interchangeable criteria will pharmacy-level substitution without consulting with the prescriber be permitted.
Switching	A decision made by the treating provider (physician/AP) to exchange one biological product with another (i.e., a biosimilar to replace a RP) with the same therapeutic intent. Ideally, switches are done in consultation with the patient. » Reverse-switching refers to a switch back from the biosimilar to the RP. » Cross-switching refers to switching from one biosimilar to another biosimilar of the same originator biologic.
Extrapolation	When the sponsor of a proposed biosimilar elects to expand the indication(s) covered to include another one (or more) of the indications held by the RP, but for which direct tests in a comparative clinical trial(s) specific to that indication(s) were not conducted. Scientific justification must be provided in order to extrapolate an indication (e.g., pharmacokinetic bioequivalence must be established and the existing indication must have been sensitive enough to detect any clinically meaningful differences).
Interchangeability	Interchangeability is when the FDA considers that a biosimilar “can be expected to produce the same clinical result as the reference product in any given patient” and that “when administered more than once to an individual, the risk in terms of safety or diminished efficacy or 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.” Interchangeability would allow a substitution of the RP with a biosimilar without the prescribing health-care provider intervening. A designation of interchangeable requires additional clinical switching studies
Immunogenicity
What are ADAs?	ADAs are anti-drug antibodies; they can develop when biological drugs become recognized as non-self and a humoral immune response occurs. If a patient develops ADAs to a particular RP or biosimilar, the likelihood that they develop ADAs to other biosimilars of that RP is high. ADAs may be a medical concern if they are associated with drug inactivation, increased clearance, and subsequent loss of efficacy, and/or toxicity of a biologic. The extent of ADA formation varies among biologic class, disease state, and patient characteristics. Modern biologics are designed to minimize the formation of ADAs.
What are NAbs?	NAbs are neutralizing ADAs. If high titers of high-affinity NAbs develop, they can reduce the therapeutic activity of a biological drug by speeding up its clearance from the body, and by binding to variable regions of the antibody to prevent targeting of the biological effect.

Note. ADAs = anti-drug antibodies; AP = advanced practitioner; FDA = US Food and Drug Administration; NAbs = neutralizing antibodies; RP = reference product. Information from American Society of Clinical Oncology (2015); Blevins (2019); Chiu & Gilliland (2016); Christl (2018); Christl & Lim (2018); Cuellar et al. (2019); Curigliano et al. (2016); Demler (2018); FDA (2015, 2017b, 2019b, 2020b); Gabay (2017); Grampp & Ramanan (2015); Isaacs et al. (2017); Kim et al. (2020); Krishna & Nadler (2016); Lyman et al. (2018); Markus et al. (2017); Mayden et al. (2015); McClellan et al. (2019); McMahon Publishing (2013); NIH National Cancer Institute (2019); Pittman et al. (2016, 2019); Schellekens et al. (2016); Stanton (2017); Stebbing et al. (2020); Thill et al. (2019); Rumore et al. (2016); Webster et al. (2019); Welch (2017); van Brummelen et al. (2016).