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Biosimilar terms you should know
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“Biosimilars” are a relatively new concept to many physicians in the U.S., and an extensive inventory of associated terminology may be equally unfamiliar. Below is a glossary of key terms essential to understanding what biosimilars are and how they may be developed, regulated and prescribed to patients.
Biobetter
While a biosimilar seeks to establish high similarity to a reference product, a biobetter seeks to establish superiority in one or more aspects of its clinical profile, including structure, function or formulation, that may improve safety or efficacy. A full biologics license application (BLA) and development through existing regulatory pathways for new products are required.
Biosimilar
A biosimilar is a biologic submitted in a 351(k) application that is approved based on evidence it is “highly similar” to its reference product, aside from small differences in clinically inactive components, and with no clinically meaningful differences in safety, purity and potency. A biosimilar is not expected to be identical to its reference product, as all biologics have inherent variability in structure and function. Biosimilars should have the same known mechanism(s) of action as the reference product for each indication, and they must meet the same product and manufacturing quality standards required for any biologic by the FDA. They have been available in Europe since 2006 and have been approved in many other countries. Since the Biologics Price Competition and Innovation Act enacted the abbreviated licensure pathway for biosimilars in 2010 as part of the Affordable Care Act, the first biosimilar in the U.S. was approved in 2015, and many others are currently under review by the FDA.
Critical quality attributes
Based on public data and hands-on testing of the reference product, the biosimilar manufacturer can identify structural attributes of the reference product that can impact clinical safety and effectiveness, the most important of which are called “critical quality attributes.” These are used to guide the measurement of equivalence in structure and function between the biosimilar and the reference product. Highly critical attributes must be equivalent, while differences in clinically unimportant attributes are permitted.
Extrapolation
A biosimilar may be approved for an indication for which its reference product is approved despite the absence of a comparative clinical trial in that indication. This is based on the concept of “extrapolation,” a common principle in the development of biologics, and critical for the expedited development and expanded access of biosimilars. Extrapolation to an indication must be scientifically justified based on known mechanisms of action and the “totality of evidence” supporting biosimilarity.
Immunogenicity
Immunogenicity refers to the relative human immune response to the biosimilar and its reference product. The development of antidrug antibodies can interfere with biologic activity and cause loss of response, and it is expected that antidrug antibodies against the reference product may cross-react with the biosimilar. Moreover, as the development of antidrug antibodies is related to structural aspects of a biologic, minor variations in the biosimilar’s structure could potentially lead to significant variations in immunogenicity. Potential development of immunogenicity remains a key concern regarding the interchangeability of biosimilars. As part of the “totality of evidence” approach to biosimilar development, comparative immunogenicity studies should be performed in healthy volunteers or in patients with functional immune systems to ensure the study population is sensitive to detect potential differences that could lead to immunogenicity.
Interchangeability
Biosimilars that produce the same clinical results as their reference products in any patient may be deemed “interchangeable” based on criteria in section 351(k)(4) of the Public Health Service (PHS) Act, and can be switched with the reference product at the pharmacy without the prescriber’s intervention. For a biologic to be considered interchangeable, alternating or multiple switching with the reference product must provide the same level of safety and effectiveness as the reference product. In the U.S., “interchangeable” is a separate designation for biologics, and the FDA has issued guidance on interchangeability for biosimilars. State laws regulating pharmacy substitution must be updated to include interchangeable biologics, and many have or are in the process of passing such legislation.
Nonproprietary/proper name
According to FDA guidance issued in August 2015, the agency intends to designate a nonproprietary or “proper” name to all previously and newly licensed biologics. This will include a “core name” shared among related biologics and a unique 4-letter suffix, and aims to ensure clear identification, promote pharmacovigilance and prevent inadvertent substitution of biologics that have not been deemed interchangeable. A unique suffix will be applied to originator, related and biosimilar products, but the FDA has not decided whether interchangeable products should share the same suffix as their reference product.
Reference/originator product
Biological medications are extracted from living cells or produced by recombinant DNA technology, and include antibodies, gene and plasma therapies, proteins and vaccines. They are more complex than small molecule drugs in terms of size, structure, variability, stability and manufacturing, and treat diseases like cancer and autoimmune disorders by mediating natural processes and signals in the body. They are typically delivered via IV infusion or injection. Approved biologics serve as the “reference products” for biosimilars. Similarly, “originator products” are biologics submitted in a BLA under section 351(a) of the PHS Act when there is no previously licensed related biologic submitted under the same section.
Related biological product
A related biologic is one submitted in a BLA under section 351(a) of the PHS Act when there is a previously licensed biologic in a different section 351(a) BLA containing a drug substance whose classification may stipulate use of the same drug substance name.
Totality of evidence
The FDA considers the “totality of evidence” that a biosimilar is “highly similar” to its reference product before approval. This begins with public data on the reference product’s structure, function and mechanisms of action, and peer-reviewed data from observational and clinical trials. These data, in addition to the biosimilar sponsor’s hands-on testing of the reference product’s structure and function, inform the development of the biosimilar candidate. Then a “stepwise approach” is used to establish analytical data comparing the structure and function of the biosimilar to the reference product, followed by additional comparative animal, human clinical and immunogenicity data to reduce residual uncertainty of sufficient similarity. This approach considers that modern analytical testing and pharmacology assays provide such robust data that fewer comparative clinical data may be needed to address this residual uncertainty, and the FDA can therefore determine that comparative data elements are unnecessary based on data established in a preceding step.
References:
Academy of Managed Care Pharmacy. https://www.biosimilarsresourcecenter.org/faq/what-is-a-biobetter/. Accessed October 17, 2016.
Anour R. Generics and Biosimilars Initiative Journal. 2014;doi:10.5639/gabij.2014.0304.039.
Biosimilars Forum: Overview. Biosimilars Forum website. http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_overview_032816opt_-_copy_0.pdf. Accessed October 1, 2016.
FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. Accessed January 17, 2017.
FDA. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241719.htm. Updated May 10, 2016. Accessed October 1, 2016.
U.S. Department of Health and Human Services. Nonproprietary Naming of Biological Products: Guidance for Industry. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf. Accessed October 1, 2016.