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The Food and Drug Administration (FDA) has approved biosimilars for adalimumab, etanercept, filgrastim, and infliximab; and approval of bevacizumab and trastuzumab biosimilars is recommended. More are expected as other biologic medications lose patent exclusivity by 2020. In May the Pharmacy & Therapeutics Committee approved the replacement of filgrastim with one of the approved biosimilar prod- ucts, tbo-filgrastim.
A biosimilar medication is a biologic medication that is highly similar to, and has no clinically meaningful differences in terms of safety, purity, potency and effectiveness from the original reference biologic.1 Biologic medications include protein-containing products such as monoclonal antibodies, cytokines, growth factors and other non-vac- cine immunotherapies. It is not possible to produce exact copies of biologics, only similar ones, because the molecules are complex and differences in the biologic can arise during the manufacturing process that involves production in living cells or organisms. These differ- ences can occur between product batches or when the production process is changed. Thus, protocols for establishing comparability of biosimilars are more detailed than those for establishing therapeutic equivalence of smaller molecule nonbiologic medications. Approval
of generic oral small molecule medications requires only that the rate and extent of absorption of the generic product is within the bioequiv- alence margin for the brand reference product.
There are two pathways for approval of a copy of a marketed biologi- cal product.2 One is the same pathway by which the original product was approved that requires a full evaluation of the product’s safety and efficacy for the indications approval is sought. Tbo-filgrastim was approved by this pathway. Biobetters, biologics that have been altered and demonstrate better efficacy for the same or different indications than a similar biologic are also approved by this pathway.3 Obinutu- zumab is an example of a biobetter. It is a more effective treatment for chronic lymphocytic leukemia than rituximab, another anti-CD20 monoclonal antibody. The other pathway is an abbreviated application that demonstrates biosimilarity with the reference biologic. As with bioequivalence, the underlying assumption for biosimilarity is that the same active ingredient does the same thing when administered to an individual. The aim of establishing biosimilarity is not to reestablish clinical benefit that was established with the reference biologic, but
to demonstrate the degree the molecules of the biosimilar and the reference biologic are the same.4
The basis for establishing biosimilarity is the comparability protocol the FDA established for approving changes in the manufacturing pro- cess for a biological product.4 A stepwise approach is taken to reduc-
References
1. Food and Drug Administration. April 2015. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry. Retrieved from https://www.fda. gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128. pdf
2. Lucio SD, Stevenson JG and Hoffman JM. Biosimilars: Implications for health-system pharmacists. Am J Health-Syst Pharm. 2013; 70:2004-2017.
3. de Mora F. Biosimilar: what it is not. Br J Clin Pharmacol. 2015; 80(5): 949-956.
ing uncertainty about the similarity of the biosimilar and the reference biologic.5 The type and volume of data required to demonstrate this varies with the complexity of the biologic and how well its properties are characterized. The first step is to compare the structural, phys- iochemical, and functional characteristics of the potential biosimilar and the reference biologic using advanced analytical techniques. Structural differences between the biosimilar and the reference biologic are only acceptable if they are consistent with the pattern of heterogeneity within the molecules.
The next steps are to compare the in vivo pharmacokinetics, pharma- codynamics, immunogenicity, and safety of the potentially biosimilar medication and the reference biologic. Human immunogenicity data are usually required for biosimilar approvals.
Then, clinical equivalence of the biosimilar and reference biologic is evaluated in populations sensitive to potential differences in effica-
cy, safety and immunogenicity between them. Primary endpoints in these trials are biomarkers that correlate with efficacy, such as the absolute neutrophil count, response rate and disease activity scores. The comparability margins for the endpoints represent the largest dif- ference in efficacy that would not be clinically meaningful. Sometimes post-marketing safety surveillance studies are requested.
When the FDA determines that the totality of the scientific evidence demonstrates the similarity of the biosimilar and the reference biolog- ic, it may approve the biosimilar both for the indications studied and for the other indications the reference product is approved. However, not all biosimilars are automatically interchangeable with the refer- ence product.
The FDA has proposed that for a biosimilar to be interchangeable, the biosimilar must produce the same clinical result as the reference product; and for a biosimilar product administered more than once to an individual, the risk of adverse events or diminished efficacy of switching between the reference biologic and biosimilar is not greater than the risk of using only the reference product.6 The sponsor of the biosimilar must submit the results of a randomized controlled switch- ing study to support interchangeability. The aim of a switching study is to determine the impact of alternating between the biosimilar and the reference biologic.2 Study endpoints include measures of safety, pharmacokinetics, pharmacodynamics and efficacy. The FDA has
not designated any biosimilar products interchangeable yet because it only released draft guidance in January 2017. Information on the biosimilarity and interchangeability of biologic products can be found in the Purple Book on the FDA website. ●
4. McCamish M and Woollett GR. Molecular “sameness” is the key guiding principle for extrapolation to multiple indications. Clin Pharmacol Ther. 2017; 101(5):603-605.
5. Declerck P, Danesi R, Petersel D and Jacobs I. The language of biosimilars: clarification, definitions and regulatory aspects. Drugs. 2017; 77:671-677.
6. Food and Drug Administration. January 2017. Considerations in Demonstrating Interchangeability with a Reference Product. Guidance for Industry. Retrieved from https:// www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ ucm537135.pdf
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Biosimilar, bioequivalent and biobetter — what does it all mean? Jeff Reitz, Pharm.D, MPH
NOVEMBER 2017 FOCUS • 27