The question of biosimilar interchangeability – whether or not a biosimilar can safely be switched with another biosimilar or with the originator product – is a thorny one. In fact, write Hans C Ebbers and Paul Chamberlain [1], striving for some of the standards suggested to certify interchangeability may not be in a patient’s best interests.
There has been considerable debate around the topic of interchangeability in Europe and the US. In the European Union (EU), approved ‘biosimilar’ status signifies that a biosimilar can be prescribed interchangeably with the originator product. However, automatic substitution by pharmacists does not follow because there is no implication of interchangeable status for substitutability within EU Pharmaceutical Law governing Similar Biological Medicinal Products [2].
In the US, the Food and Drug Administration (FDA) does have the power to classify biosimilars as interchangeable, which means that substitution by pharmacists would be possible (unless state legislature outlawed such substitution or the prescribing physician had specified ‘do not substitute’ on the prescription form).
There have been no biosimilar approvals in the US, and it is difficult to see how biosimilars could ever be interchangeable at the pharmacy level. Even if studies showed that treatment with a biosimilar had the same clinical efficacy and safety as the originator, those studies would only look at the patient population – not individual patients. Similarly, such studies would overlook post-authorization changes likely to occur over time, such as changes in manufacture or formulation. And, as we know, due to the fact that biological drugs are complex mixtures, even small changes in the manufacturing process can cause changes in the final molecule.
‘At the time of registration, not all clinical variables will have been tested, such that uncertainties may remain to be addressed via heightened pharmacovigilance and post-authorization studies,’ write the authors. Very large numbers of patients would need to be followed up to identify or exclude differences in risk of a biosimilar over its reference product. Looking at the example of biosimilar monoclonal antibodies, enhanced monitoring of immunogenicity, drug levels, sustainability of efficacy and incidence and severity of adverse events would be required in order to follow-up longer-term interchangeability.
At the same time, discriminating between interchangeable and non-interchangeable products could disqualify potentially beneficial products for which it is hard to demonstrate interchangeability, or that are currently marketed without the status of interchangeability.
In the US, an interchangeable product is expected to produce the same clinical result as the originator ‘in any given’ patient. Importantly, write Ebbers and Chamberlain, this does not mean that a product will produce the same clinical result as the reference product in every patient. For all these reasons, argue the authors, the ‘higher’ standard required for designation of interchangeability/substitutability will not necessarily benefit patients.
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References
1. Ebbers HC, Chamberlain P. Interchangeability. An insurmountable fifth hurdle? Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):88-7. doi:10.5639/gabij.2014.0302.022
2. GaBI Online - Generics and Biosimilars Initiative. Efficacy, extrapolation and interchangeability of biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Jun 20]. Available from: www.gabionline.net/Biosimilars/Research/Efficacy-extrapolation-and-interchangeability-of-biosimilars
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