HPE HPE Fresenius Kabi handbook - Page 17

• Module 2: summaries of quality, non-clinical and clinical data; • Module 3: chemical, pharmaceutical and biological information (quality); • Module 4: non-clinical reports (safety); • Module 5: clinical study reports (efficacy). 12 For biosimilars, the requirements for MA applications are based on the demonstration of the similar nature of the two biological products, based on the comparability exercise. 2 The number and extent of comparability studies that form the comparability exercise is outlined in guidelines issued by the EMA. 10 In the dossier of biosimilars, comparability studies are required in modules 3, 4 and 5; in the case of generics, non-clinical studies (module 4) are omitted and the demonstration of bioequivalence replaces module 5. 1 Indeed, generics, which are copies of medicinal products based on active ingredients obtained via a synthetic pathway, do not require pharmacodynamic investigations if the pharmacokinetic parameters can be used to demonstrate that the generic and reference are essentially the same. By contrast, because of the complexities of bioproduction, even minor modifications to manufacturing processes can yield substantial differences in pharmacodynamic parameters, so pharmacokinetic data alone are not sufficient for the demonstration of biosimilarity. Conclusions Biosimilars are a reality of the pharmaceutical market. EU regulatory policies, mainly established by guidelines issued by the EMA and revised periodically, can now draw upon more than a decade of experience. Biologics are complex drugs. As such, their characteristics depend considerably on the manufacturing process, and their complete characterisation cannot be achieved by current analytical methods. The complexity of biologic medicinal products has clear repercussions on the assessment of therapeutic equivalence and, consequently, on interchangeability and substitution. For this reason, when copies of biological products are manufactured, they cannot be considered as small molecule generics. The EMA has led the way in the development of a regulatory framework of biosimilars. The EMA has the scientific competence and the broad view required to assess the interchangeability of biotechnological medicinal products. The EMA’s assessment of interchangeability could then be used as a basis, by local regulatory agencies, to allow automatic substitution. The EMA, though, have chosen to leave decisions on interchangeability of biosimilars to national authorities. Therefore, it is of paramount importance to define the pharmacist’s/clinician’s role in the choice of switching between reference and biosimilars, especially in hospitals. It is highly recommended that both the pharmacist and the prescribing physician decide whether to always purchase the cheapest biosimilar or which patients have to be treated with the reference product, as a precautionary measure to assure continuity of care. Where national authorities decide to allow automatic substitution without the prescriber’s prior consent, the traceability of the administered medicinal product should be mandatory, in order to allow the prescribing physicians to monitor which medicinal product is actually dispensed to their patients as specified in good pharmacovigilance practice guidance. TABLE 1 Key EMA scientific guidelines on biosimilars 2,10,11 Overarching biosimilar guidelines • Similar biological medicinal products • Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues • Similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues Product-specific biosimilar guidelines • Biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor (Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues) • Non-clinical and clinical development of similar biological medicinal products containing low- molecular-weight heparins • Non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues • Similar biological medicinal products containing interferon beta • Similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues • Similar biological medicinal products containing recombinant erythropoietins • Similar biological medicinal products containing recombinant follicle-stimulating hormone • Similar medicinal products containing somatropin (Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues) • Non-clinical and clinical development of similar biological medicinal products containing recombinant interferon alpha or pegylated recombinant interferon alpha References 1 Minghetti P et al. Biosimilars and regulatory authorities. Nephron Clin Pract 2011;117: C1–C7. 2 European Medicines Agency. Guideline on similar biological medicinal products (CHMP/437/04 Rev.1) www. ema.europa.eu/docs/ en_GB/document_library/ Scientific_guideline/2014/10/ WC500176768.pdf (accessed September 2018). 3 Rocco P et al. Copies of nonbiological complex drugs: generic, hybrid or biosimilar? Drug Discov Today 2018;pii :S1359-6446(18)30082–5. 4 Schellekens H, Moors E. Clinical comparability and European biosimilar regulations. Nat Biotechnol 2010;28(1):28–31. 5 Schellekens H. Biosimilar therapeutics – what do we need to consider? NDT Plus 2009;(Suppl 1):i27–i36. 6 Ebbers HC et al. Interchangeability, immunogenicity and biosimilars. Nat Biotechnol 2012;30(12): 1186–90. 7 Minghetti P, Rocco P, Schellekens H. The constrained prescription, interchangeability and substitution of biosimilars. Nat Biotechnol 2015;33(7):688–9. 8 Jørgensen KK et al; NOR- SWITCH study group. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet 2017;389(10086):2304–16. 9 Rocco, P, Selletti S, Minghetti P. Biosimilar switching and related medical liability. J Forensic Leg Med 2018;55:93–4. 10 European Medicines Agency. Similar biological medicinal products. Similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/ CHMP/BMWP/42832/2005 Rev. 1) (2014). www.ema.europa.eu/ docs/en_GB/document_library/ Scientific_guideline/2015/01/ WC500180219.pdf (accessed September 2018). 11 European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance – quality issues. (EMA/CHMP/ BWP/247713/2012). www. ema.europa.eu/docs/en_GB/ document_library/Scientific_ guideline/2014/06/WC500167838. pdf (accessed September 2018). 12 Minghetti P et al. The regulatory framework of biosimilars in the European Union. Drug Discov Today 2012;17(1-2):63–70. Other guidelines relevant for biosimilars • Comparability of biotechnology-derived medicinal products after a change in the manufacturing process – non-clinical and clinical issues • ICH Q5E Biotechnological/biological products subject to changes in their manufacturing process: comparability of biotechnological/biological products • I mmunogenicity assessment of biotechnology- derived therapeutic proteins • Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use hospitalpharmacyeurope.com | 2019 | 17