functional characterization ( often binding affinity for the target receptor ) and comparison with the reference product . This is different to the approach for the reference biologic and for originator small molecule drugs , where Phase III clinical trials are paramount . First , physicochemical similarity is confirmed for the biosimilar . Additional studies are also required because physicochemical data alone are not sufficient to determine biosimilarity . Animal and clinical studies assessing pharmacokinetic ( PK ) and pharmacodynamic ( PD ) characteristics , and immunogenicity are followed by limited clinical trials . Figure 1 illustrates the difference in the approach to the reference biologic compared with approval of the biosimilar .
As previously described , biosimilars are required to be highly similar to the existing , FDAapproved reference biologic . As biologics have natural variations in the manufacturing process , a biosimilar is required to have no meaningful clinical differences in the amino acid sequence , the final functional activity of the drug , or the mechanism of action . The biosimilar must also have the same route of administration , dosage form , and strength as the reference product . Other areas of the manufacturing process might contain slight differences , including the host cell line that produces the drug , the protein structure , and inactive ingredients .
The clinical trials required for biosimilar approval are minimized in this abbreviated regulatory framework . The biosimilar candidate is assumed to be highly similar to the reference product in the physicochemical analysis and PK and PD studies . The clinical trials determining efficacy and safety for the molecule can therefore be inferred from those studies used for approval of the reference product , and do not need to be replicated . Instead , the clinical trials are designed to focus on assuring that there are no clinically meaningful differences between the biosimilar and the reference product – not in re-establishing the safety and efficacy of the molecule in specific indications . This can often be accomplished by designing studies in sensitive patient populations and with sensitive endpoints that may be different than the endpoints that were used in the reference product approval . With these studies in sensitive populations , the FDA can determine whether the biosimilar will produce safety and efficacy outcomes that are not clinically different than the reference product . Within the biosimilar label , the FDA has ruled that data on the safety and efficacy from the reference product may be utilized .
Extrapolation Given the abbreviated regulatory approval process and limited clinical trials , the FDA uses a process referred to as ‘ extrapolation ’ to determine which indications to approve for the biosimilar . 17 The FDA considers the totality of what is known about the mechanism of action of the compound and the patient populations related to each of the approved indications . It determines whether to grant approval for indications beyond those for which clinical trial data is submitted in the biosimilar data package . This practice is one that has been somewhat controversial . Yet , the FDA and the European Medicines Agency ( EMA ) have approved all biosimilars to date for the same range of indications as the reference biologics , with the exception of those indications that may have existing patent protection . The process of extrapolation is one of the key elements that allows approval of biosimilars at a lower cost than the reference biologic . The FDA considers comparative PK and PD data and at least one clinical trial in a sensitive population to remove any uncertainty about the clinical equivalence of the biosimilar and the reference biologic . 18
As mentioned , unlike Europe , where the EMA has only one approval category for biosimilars , in the US , the BPCIA allowed for the creation of a second category , referred to as an ‘ interchangeable ’. An interchangeable product must meet additional requirements regarding switching studies and is intended to show that the interchangeable
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