4.8 Biosimilarity tetrahedron

Understanding biosimilarity

The changes made by the originator in the comparability protocol exercises are generally available in regulatory documents, and these documents along with establishment inspection reports (EIRs) of the facilities where the originator product is made are excellent sources of information for the biosimilar product developer. The EIRs are available under the Freedom of Information Act. It is noteworthy that these reports provide great insight into what is considered a critical attribute and how it is controlled in a risk-based evaluation of the development plan of the biosimilar product developer. The use of comparability has speci c meaning for postapproval changes and should be discouraged when compiling documents for the FDA ling. Figure 4.10 shows an example of variability in the comparability protocol presentation to FDA; differences arising out of changes are acceptable as long as they do not have any clinically meaningful difference. The reason why the regulatory agencies let a manufacturer make changes without necessarily having to demonstrate clinical similarity is that the manufacturer knows its molecule well and is able to satisfy the regulatory agencies that these changes are not critical to the safety and the ef cacy of the product. Much of published literature, however, ignores this differentiation. However, this should not be confused with the use of comparison, which is an evaluation of two products at any stage. Compare to is used to liken two things or to put them in the same category. Compare to is a proper choice when you intend to simply assert that two things are alike. Compare with is used to place two things side by side for the purpose of examining their similarities or differences as is the case in biosimilarity testing; so use compared with instead of compared to and never comparability. An example of an improper choice is “Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab” (Visser et al. 2013).

Realizing that there is a signi cant difference in the development of biological drugs and a biosimilar, there is a need to add a fourth classi cation of attributes, identity, to the existing list of safety, purity, and potency that the FDA prescribes for biological drugs. And this allows us to create a tetrahedron, wherein each of these categories of attributes is equally important, and must be checked off for similarity to demonstrate overall biosimilarity to qualify approval under the 351(k) statute. Figure 4.11 shows the tetrahedron of biosimilarity. A keen understanding of each of the four pillars of this tetrahedron and its three components is required to execute a successful biosimilarity demonstration program.

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