HPE HPE Fresenius Kabi handbook - Page 15

LEGISLATION/REGULATORY EU regulatory framework for biosimilars The regulatory policy for biosimilars is outlined mainly in general and product class-specific guidelines issued by the European Medicines Agency, addressing quality, non-clinical and clinical issues Paolo Rocco PhD Silvia Franzè PhD Francesca Selmin PhD Department of Pharmaceutical Sciences, Università degli Studi di Milano, Italy When patent and data protection of a medicinal product have expired, new manufacturers might choose to market a copy of the product. Because the copy of a biologic medicinal product can only be demonstrated to be similar, but not identical, to the one previously authorised, it is defined as a biosimilar. 1 Marketing authorisations and biosimilars The requirements for the marketing authorisation (MA) of a biosimilar medicinal product include the demonstration of the similar nature to the reference product in terms of quality, efficacy and safety (biosimilarity). Biosimilarity is demonstrated through an in-depth comparison of physical, chemical and in vitro biological characteristics, and comparative non-clinical and clinical studies, which together comprise the comparability exercise. 2 As for any complex drug, the physicochemical characteristics of a biologic are influenced greatly by the manufacturing process, and they cannot be exactly duplicated when producing a copy, or necessarily even maintained when a change in manufacturing occurs. 1 Even without changes in the manufacturing process, batch-to-batch variability is to be expected and should be monitored. Moreover, biologics cannot be completely characterised using available analytical methods, and bioequivalence is not enough to guarantee therapeutic equivalence because the pharmacodynamics can be different. 3 The conclusions of a comparability exercise are valid for a given time only; thus, it would be preferable to demonstrate the similarity over the whole product lifecycle with regard to the effects on the biosimilar’s characteristics, such as therapeutic equivalence. For this reason, the assessment of therapeutic equivalence should not end with the MA, but should be managed for the entire lifecycle of the product. 4-6 The assessment of therapeutic equivalence influences the way a medicinal product is managed, namely the policies on interchangeability and substitution, and the possibility of pharmacist and clinician intervention at the dispensing level. Moreover, a substitution programme can be introduced by the public administration on the basis of interchangeability. Regulatory issues Interchangeability is a scientific concept directly related to intrinsic drug characteristics, and it follows from therapeutic equivalence. Due to its complexity, the assessment of interchangeability requires the scientific knowledge that only regulatory agencies possess at an institutional level. Unlike generics, which are interchangeable by definition, biosimilars are not interchangeable per se. The policy of the European Medicines Agency (EMA) comprises a mandatory comparability exercise to grant a MA for biosimilars, but the regulatory guidelines do not include recommendations on interchangeability because all decisions are regulated at the national level. The term ‘substitution’ could be used to indicate the prescription of a biosimilar to naive patients, or the switch, made by the prescribing physician, between two medicinal products. Because in these cases the prescriber’s choice is not limited to interchangeable products, this term is better avoided, and only used with the meaning of ‘automatic substitution’ at the dispensing level. The term ‘substitution’ should be avoided even when, due to the payer’s policies, physicians might be forced to prescribe a biosimilar instead of the reference product; the term ‘constrained prescription’ could be used instead. 7 In the EU, the policy of automatic substitution is left to local authorities, which can introduce it based on a demonstration of interchangeability, even though many countries do not allow automatic substitution at the dispensing level. 7 Even in countries where it might be allowed, automatic substitution at the dispensing level makes traceability more difficult to deal with, as it can imply the loss of essential information for this class of medicines and might compromise traceability during the product’s lifecycle and its identification in the pharmacovigilance report. While this is accepted in the case of small molecule generics, it might raise concerns when extended to biologics. The publication of the results from NOR-SWITCH, a randomised, non-inferiority, double-blinded, Phase IV trial addressing the issue of switching from the reference infliximab to a biosimilar in stable patients, has shed some light on a highly debated topic. The conclusions of the study can be seen as reassuring for prescribing physicians, at least in the case of infliximab. 8 From a product liability perspective, ‘failure to warn’ or ‘design defect’ liabilities cannot be considered ascribable to the generic MA holder. Indeed, the generic must have the same labelling as the originator. Redesign or label modification, intended to improve the risk–benefit ratio, are not possible for generics, because the generic drug is required to have the same active ingredients, route of administration, dosage form, strength, and labelling as the reference (21 U.S.C. 355(j)). As a consequence, the extent to which a generic hospitalpharmacyeurope.com | 2019 | 15