The European Union has led the way in establishing
regulations for biosimilars. In 2005, the EMA established the first regulatory
pathway for biosimilars that is distinct from the generic pathway [9-13]. The
biosimilar manufacturer should assemble all available knowledge of the
reference product with regard to the type of host cell, formulation and
container closure system, and submit a complete description and data
package delineating the whole manufacturing process including obtaining and
expression of target genes, the optimization and fermentation of gene
engineering cells, the clarification and purification of the products, the
formulation and testing, aseptic filling and packaging.
Furthermore, non-clinical evaluations should be undertaken
both in vitro and in vivo. In terms of the clinical evaluation, the
comparability exercise should begin with pharmacokinetic (PK) and
pharmacodynamic (PD) studies followed by the pivotal clinical trials. PK
studies should be designed to enable detection of potential differences between
a biosimilar and the reference product. Singledose, cross-over PK studies in
homogenous population are recommended.
The manufacturer should justify the choice of singledose
studies, steady-state studies, or repeated determination of PK parameters and
the study population. PD studies and confirmatory PK/PD studies may be
appropriate if there are clinically relevant PD markers, but if there is lack
of them, the traditional 80-125% equivalence range is often used. In addition,
similar efficacy of biosimilar and reference product has to be demonstrated in
randomized and well controlled clinical trials, which should preferably be
double blind or at least observer blind. The pre licensing safety data and the
immunogenicity data should be obtained from the comparative efficacy trials.
Finally, applicants also need to present an ongoing risk management and
pharmacovigilance plan, since data from pre-authorized clinical studies are
usually too limited to identify all potential side effects of the biosimilar.
Clinical management
Due to their special characteristics, there is the need to
pay even more attention when using biosimilars than when using small chemicals.
Most biopharmaceuticals induce immune responses, which in many cases do not
have clinically relevant consequences but in some situations the consequences
can be more relevant and potentially lethal, causing a loss of efficacy of the
drug or even leading to autoimmunity to endogenous molecules. The
immunogenicity to biopharmaceuticals is based on their foreign nature, being of
exogenous origin (neo-antigens or non-self antigens) or in their similarity to
self molecules (self antigens). Anyway, it is the activation of
antibody-secreting B cells which is the main reason that causes the clinical
manifestation of immunogenicity. There are two ways in which such
immunogenicity can occur. On the one hand, impurities, such as endotoxins or
denatured proteins within a biopharmaceutical may provide a signal to T cells,
that may then send activating signals to B cells and hence, break B cell
tolerance. On the other hand, B cell tolerance can be broken via a T cell
independent response. If a biopharmaceutical is not uniformly soluble it can
form aggregates and they can be confused with viruses, activating
B cells to produce auto reactive binding antibodies
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