Setting the stage for biosimilar monoclonal antibodies

Abstract

CitationSetting This is a pre-or post-print of an article published in Schneider, C.K., Vleminckx, C., Gravanis, I., Ehmann, F., Trouvin, J.-H., Weise, M., Thirstrup, S. Setting the stage for biosimilar monoclonal antibodies (2012) Nature Biotechnology, 30 (12), pp. 1179-1185. Advice more than once). It is interesting to note that the scope of questions in these confidential Scientific Advice procedures for mAbs has shifted over time (Box 1). Development of a biosimilar frameworkThe current concept of development of biosimilar mAbs follows the principle that any analysis that compares the biosimilar mAb with its reference mAb aims to detect differences using state of the art technology, thus excluding to the best possible extent that there are any relevant differences (see Table 1 for a summary of the basic concepts). Slight differences, within known and controlled ranges, are a given fact for biologicals-including innovative mAbs in their batch-to-batch microheterogeneity and variability-and thus do not preclude the conclusion that a given mAb is a 'true' biosimilar, as recently defined 8 .The highest burden for a biosimilar development program is on the physicochemical and biological characterization (in regulatory jargon the 'quality programme') with various state-ofthe-art methodologies. First, the biosimilar mAb has to fulfil all relevant requirements for a mAb of the concerned class (stand alone properties); second, it has to be comparable with the reference mAb. In other words, the analytical package for a biosimilar mAb submission is considerably larger than for a 'stand-alone' mAb (blue plus orange segment in quality portion shown in Fig. 2a). Since the objective of a biosimilar development is to establish biosimilarity, not to re-establish benefit, the non-clinical and clinical development program is more focused and 'tailored' toward this objective 8-10 ( Fig. 2a), making in part reference to the already licensed original mAb. We have provided a comparison of regulatory reviews of (non-mAb) biosimilars to those of stand-alone biotechnological medicinal products, as this may throw light on issues that will be important for biosimilar mAbs (Box 2).The current concepts for biosimilar mAbs have evolved over time; indeed, several previous guidelines on specific product classes of biosimilars 11 introduced important milestones on non-clinical and clinical aspects that paved the way for more complex biosimilars, including mAbs (see Table 2 for an overview of the relevant guidelines). One area that illustrates this evolution is EMA stance on whether evidence from a clinical trial in one particular clinical condition can be considered sufficient for a biosimilar to be equally effective and safe in another clinical condition.This 'extrapolation' of indications was first applied to a wider extent to biosimilar low-molecular provide the basis for use in the prevention of arterial thromboembolism. Several guidelines introduced concepts around pharmacodynamic markers that are usually more sensitive as clinical endp...

Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

“…35 This is important when considering biosimilar products because different cell lines or culture conditions can modify the glycosylation of the antibodies produced, and, therefore, also their Fc-mediated functionality. 36 Indeed, removal of fucose, as is the case with obinutuzumab, results in an increase in its affinity for the FcγRIIIA receptor and increased ADCC. 17,20,37 Conversely, glycosylation is not important for binding to FcRn.…”

Clinical considerations for the development of biosimilars in oncology

“…Because clinicians will initially be unfamiliar with biosimilars as a new type of biological product, improved communication not only to physicians, but also to payers and patients about the labeling and the rigor of oversight for biosimilars, including post-marketing surveillance, is necessary. 34 …”

Regulatory considerations in oncologic biosimilar drug development

“…24 EU regulators believe that biosimilars are "therapeutic alternatives" to the reference product, which would allow a biosimilar to be switched for the reference product either at initiation or during therapy. 6,34 However, the European Consensus document released by the European Commission notes that interchangeability implies an initiative or agreement by the prescriber, and that patients should speak to their physician and pharmacist about switching decisions and changing therapy from one biologic product to another. 24 Consistently, the majority of the European physicians participating in the ASBM survey agreed that they should retain sole authority in the substitution process, specifying that they found it "critically important" (24% of responders), "very important" (48%), and "somewhat important" (23%) to retain such authority.…”

“…1,2,33 Extrapolation is allowed by both the EMA and FDA for biosimilars, although this must be based on a strong scientific justification, which leverages the complete comparability data set (quality, non-clinical and clinical evidence, as well as what is known on the mechanism of action [MOA]). 34 Of note, the EMA has recently allowed extrapolation of indication for rheumatologic and gastrointestinal inflammatory diseases at approval of the 2 infliximab biosimilar mAbs, Inflectra TM (Hospira UK Ltd, Royal Lemington Spa, UK) and Remsima TM (Celltrion Healthcare Hungary Kft, Budapest, Hungary). 35,36 In contrast, Health Canada did not agree that extrapolation to the inflammatory bowel disease indications (e.g., Crohn's disease and ulcerative colitis) was justified for Remsima.…”

“…In conclusion, it is clear that extrapolation is a complex area, as different regulatory agencies may arrive at different conclusions on whether extrapolation of indications is justified for a given biosimilar, and decisions are expected on a case-by-case basis. 34 …”