Biosimilars in rheumatology: the wind of change.

The wind of change is blowing in rheumatology. Rheumatologists may soon be exposed to ‘biosimilars’ of the medicines they routinely use as the European Medicines Agency (EMA) has recently issued its final guideline on biosimilar monoclonal antibodies (mAbs)—a product class of utmost importance for rheumatologists—and a biosimilar infliximab is currently under evaluation for marketing authorisation in Europe, and more will come. Rheumatologists, as it appears, are especially challenged these days as many of their patients are already successfully put on long term treatment with individualised drug regimens, including biologicals such as tumour necrosis factor α inhibitors. Apparently, introduction of ‘copy ’ versions of the medicines they already know may be seen as a critical issue, although economic considerations suggest major cost savings in healthcare. ‘Concerns’, ‘challenges’ and ‘critical issues’: these are terms with which the term ‘biosimilar ’ is often combined in papers written by clinicians and discussions at conferences. We read about the ‘complexity’ of biological medicines, and that it is difficult to replicate their exact structure. Also in clinical literature in rheumatology, we read about ‘small variations’ that can impact the activity and function of a biosimilar, and ‘major safety and efficacy concerns’ that have to be addressed before clinicians can use biosimilars. In their review in this issue, Dörner et al report on a roundtable discussion on the advent of biosimilars in rheumatology recently held at the Charité in Berlin (Germany). I note at least one aspect in this review that is worth emphasising— the paper puts scientific facts into perspective. For example, it reports about the complexities and microheterogeneity of mAbs/cepts but also puts it into perspective with the so-called ‘originator ’ mAbs/cepts that are likewise complex. As a regulator, I have been deeply involved in the design of guidelines around biosimilars (including biosimilar monoclonal antibodies), and in discussions around public perception of biosimilars that I have experienced, it has been my impression that scientific facts are often discussed in isolation. For example, it is true that biologicals such as mAbs and -cepts are complex, and that small changes in their manufacturing process can have a large impact on their function (although I have also seen a few cases where larger changes had only little impact). This has often had the connotation to implicitly assume that biosimilars therefore may have an undetected ‘inferior ’ quality compared with the established originators, or that at least there is more uncertainty around them. The sentence ‘biosimilar and biological reference medicines are similar but not identical’ (also used by Dörner et al) is perhaps one of the most frequently misunderstood sentences in the history of biosimilars and has almost become a mantra when raising concerns around biosimilars. It comes from a previous version of the EMA ‘Questions and answers’ document on biosimilars (the document has been updated so the sentence can no longer be found there), and its intention had rather been to clarify that due to inherent complexity and inherent variability of biologicals, any biosimilar can never be ‘identical’ to its reference product (and therefore the ‘generic pathway ’ is not possible). One would have to add that also no batch of any reference product is ‘identical’ to the previous one—‘non-identicality ’ is a normal feature of biotechnology that has to be controlled by tight specifications of critical product attributes, within current technical and scientific limitations (inherent variability). The ‘art’ for a biosimilar is to demonstrate that the biosimilar is as close as possible to its reference product in all relevant functional and structural aspects, again within current technical and scientific possibilities and its inherent variability. What is often not mentioned (but mentioned by Dörner et al; this is also acknowledged in other papers such as Scheinberg and Kay) is that originator mAbs/cepts have undergone changes after their approval—this is what regulators call the ‘life cycle’ of a medicine. This is normal—manufacturing processes are updated during the life cycle of any medicine, and this is welcome as these are often improvements. A recent publication suggested that licensed biologics undergo changes in relevant molecular attributes over time. In fact, the seminal regulatory guideline ICH Q5E, issued by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), an internationally agreed standard that sets the data requirements for changes to the manufacturing process for biotechnological and biological products, stipulates that “The demonstration of comparability does not necessarily mean that the quality attributes of the prechange and post-change product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product”. This is called the ‘comparability exercise’, and the determination of comparability is usually based on a combination of physicochemical and analytical testing, biological assays and, in some cases, non-clinical and clinical data. In other words, clinical data (especially from new randomised controlled clinical studies) have not always been part of a dossier for a biological medicine that underwent changes in its manufacturing process because such data were in many cases not necessary to demonstrate that the preand post-change product are comparable. Such changes in manufacturing can be seemingly small (ie, change in the supplier of cell culture media) and range to major ones (ie, introducing new purification steps or implementing new manufacturing sites). It is true that even small changes can have a large impact. But this would certainly be picked up in the comparability exercise and regulatory assessment, and via implementation of correct regulatory measures for post-approval surveillance. In fact, all of the licensed mAbs and -cept fusion proteins used in rheumatology have had changes in their manufacturing processes after their initial approval (figure 1A). For several years, EMA has published a regularly updated list of ‘steps taken after approval’, for any medicine. These can Correspondence to Dr C K Schneider, Danish Health and Medicines Authority, Medicines Assessment and Clinical Trials, Copenhagen 2300, Denmark, and Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany;[email protected]