As with generics, the bioequivalency of biosimilars must be tested, but the complexity of biological drugs necessitates side-by-side clinical trials. The bioequivalency of biosimilars must be established through assays using antibodies to “extract” the biologic from the sample. Using a biologically derived technique to assess a biologically derived drug further complicates testing.
Biologic drug assays are highly diverse and results vary from test to test. For example, an assay that shows similar profiles between an originator and biosimilar does not necessarily indicate that the two are bioequivalent. If the antibody binds to the same molecular component in both the originator and the biosimilar, though it may be “seeing” the drugs in the same way, differences may still exist in the other parts of the drug.
On the other hand, an antibody may bind differently to an originator and biosimilar due to their unique glycosylation patterns. Though they may be bioequivalent, they cannot be considered biosimilar because the antibodies “see” them differently. These differences may affect the effectiveness of biosimilars and the way the body reacts to them.
Immunogenicity tests for generics are not necessary because small molecule drugs do not typically cause an immunogenic response. With biological drugs, the slightest presence of any impurities, degraded protein, or aggregates can trigger an antibody response. An antidrug antibody response can lead to a range of outcomes from neutralization of the drug’s therapeutic action to more serious consequences such as a cross-reaction with an endogenous protein.
Another challenge for biosimilars is that methods currently required for immunogenicity testing must meet more rigorous performance expectations than those that were in effect for the originator. For example, if the originator reported an immune response of 2% then, and if the same set of samples were tested on methods meeting current standards, a rate of 5% to 10% may have to be reported now. As a result, side-by-side testing is necessary for comparing rates of immunogenicity; otherwise, the follow-on may paradoxically appear to have a greater immune potential.
With the announcement that EMA will be adopting new biosimilar guidelines at the end of 2010, European pharmaceutical companies will most likely be required to perform separate clinical trials for different diseases addressed by the same antibody. The FDA should take a page from EMA and follow suit with a similarly cautious approach. The testing needed will be time-consuming and makes biosimilars a more expensive venture than generics.
Innovation of biosimilars should continue because it is precisely their complex nature that makes it so difficult to establish biosimilarity that also makes them valuable. Patients who take biologics may begin to experience decreased therapeutic efficacy as their immune system begins to adjust by producing antibodies against the biologic or the related impurities. Patients that become antibody positive to the originator have an option for an alternative therapy provided by the biosimilar. Since the biosimilar is not likely to be identical to the originator, there is a good chance that the antibodies to the originator will not interfere with the efficacy of the biosimilar.