The Biologics Price Competition and Innovation (BPCI) Act defines a biosimilar as a product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and without clinically meaningful differences in terms of safety, purity, and potency. Although draft guidances issued by FDA do begin to clarify the issue, little or no discussion regarding how similar is considered highly similar is given in the BPCI Act and no criteria for assessing biosimilarity were mentioned.
Criteria for biosimilarity
In practice, the terms biosimilarity (similarity), bioequivalence (equivalence), and comparability (consistency) are used interchangeably in pharmaceutical research and development. For comparison between drug products, some criteria for assessment of bioequivalence (e.g. drug absorption profiles comparison), similarity (e.g. dissolution profiles comparison), and comparability or consistency (e.g. comparison between product protein structures and function) are available in either regulatory guidelines/guidances or literature. These criteria, however, can be classified into either: 1) absolute change versus relative change; 2) aggregated versus disaggregated; or 3) moment-based versus probability-based. In this section, different categories of criteria are briefly reviewed.
Absolute change versus relative change
In clinical research and development, for a given study end point, post-treatment absolute change from baseline or post-treatment relative change (% change) from baseline is usually considered for comparison between treatment groups.
For generic drugs assessment of bioequivalence is carried out in this way. For example, when the pharmacokinetic response, such as area under the blood or plasma-concentration time curve, between the generic and reference product falls within 80% and 125% bioequivalence is concluded.
Aggregated versus disaggregated
Bioequivalence can also be assessed by evaluating differences in averages, intra-subject variabilities and variance due to subject-by-formulation interaction between drug products separately.
In this type of bioequivalence analysis FDA and WHO, for example, require the log-transformed pharmacokinetic responses, such as area under the blood or plasma concentration time curve, of the generic and reference product to fall between 80% and 125%.
Although the recent FDA draft guidances did provide some insights regarding the assessment of biosimilarity of biosimilars, many scientific issues such as the definition of highly similar, criteria for biosimilarity, the feasibility of the stepwise approach, statistical tests for comparability in quality attributes, and the assessment of totality-of-the-evidence still remain unresolved for meeting regulatory expectations within the US.
Conflict of interest
The authors declared that there were no conflicts of interest.
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Professor Shein-Chung Chow is a member of the International Editorial Advisory Board of GaBI Journal; an expert in bioavailability/biosimilarity and bioequivalence; and is the Guest Editor of the Special Issue (educational editorial series) on ‘Biosimilarity and Interchangeability‘ currently under production by GaBI Journal, contact us for more information on this Special Issue.
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