Thus, an objective comparison between reference and a biosimilar must determine not only the frequency of an undesirable event but also the relative occurrences of the drug-related and non- drug-related causes. The RMP is the responsibility of the manufacturer and the use of the drug must adhere to conditions outlined in the Summary of Product Characteristics. However, drugs are used in many locations and under differing circumstances (for example, medicines dispensed through a hospital pharmacy in the inpatient setting are administered to the patient by a healthcare professional within the hospital, whereas medicinal products dispensed through an outpatient or community pharmacy in primary care are administered by the patient at home) and it is therefore extremely difficult to monitor all side effects that occur in all these situations. As a consequence, only serious adverse events can be identified and recorded but monitoring is very dependent on the local organisation of pharmacovigilance. The recent introduction of serialisation following EU directives (falsified medicines directive; FMD) should theoretically facilitate traceability. The EU FMD (2011/62/EU) was adopted in 2011 and introduced new harmonised measures to ensure that the use of medicines in the EU is as safe as possible, and that trade in medicines is controlled properly. 10 Safety features introduced for the packaging of medicines include: a unique identifier (a 2D data matrix code and human readable information) that must be scanned at fixed points along the supply chain; and an anti-tampering device, allowing verification of whether the packaging of a medicine has been compromised. However, this system has been developed to ascertain that medicines are genuine and not counterfeit, but not for pharmacovigilance purposes. The RMP required by the European Medicines Agency for a biosimilar is expected to take into account any identified or potential risks also covered in the RMP of the reference product. 2,11 Therefore, implementing traceability at the level of hospital and community pharmacies, both for reference drugs and biosimilars, is complex. Indeed, at present, traceability by batch is not required for reference biologics. 12 The anticipated great increase in the number of authorised biosimilars would necessitate development of specific systems to trace all batches regardless of their origin (reference or biosimilar) but also across different brands of a specific biosimilar. At the community pharmacy level, all brands 14 | 2019 | hospitalpharmacyeurope.com of a biosimilar plus the reference drug should be available because substitution by the pharmacist (such as for generics) is not allowed in many countries (see key concepts chapter in this handbook). Implementation at community levels is therefore likely to be problematic and costly. 12,13 Questions arise regarding the availability of the traceability data generated by hospital and community pharmacies. 14 Whose property are these data? Will these data be freely accessible even though they will comprise data specific to each biosimilar and reference? Considering the decline in available health resources in many countries, mainly related to increasing costs of medicines and innovations, it is unlikely that public funds would be made available to help implement widespread traceability systems. The manufacturer of a specific biosimilar might perhaps be willing to pay to obtain traceability data of their own product but might be unlikely to support the expenditure required to follow all prescriptions or switching activities. At a community pharmacy level, the problem seems quite unsolvable. Conclusions These practical, but fundamental, considerations might impact on the implementation of biosimilars in several countries. In contrast to biosimilars, which are considered as new compounds, traceability data are not required for reference drugs more than 20 years old. Therefore in community pharmacies, there might be a temptation to prescribe and dispense the reference instead of the biosimilar to avoid complicated procedures. However, at the hospital level, financial incentives to prescribe bisosimilars, such as those being implemented in many countries, could help mitigate this risk. Healthcare professionals can improve pharmacovigilance through a number of ways, including: • Recording the trade name and batch number at all levels, including at dispensing and patient administration. • Ensure that trade name and batch number are reported in case of suspected adverse events, according to local practice and national regulations • In primary care and community pharmacies, the trade name and batch number of the biologic medicine should be provided to the patient • In any cases of switching, it is important to record the trade name and batch number for each of the medicines. Furthermore, what about risk analysis and related cost–benefit analyses? Indeed, as previously discussed, biosimilarity is ascertained by rigid, extensive physicochemical and biological tests, and clinical trials. 2-4 Some of these preclinical tests allow all the drug-related parameters implicated in immunological tolerance to be determined. The primary structure of the reference and biosimilar are the same, therefore, by definition, the antigenic properties of all particular sequences should be identical. The level of foreign protein, and also the level and the characteristics of aggregates that can induce antigenic behaviour, must also lie in the range observed for the reference, and biosimilars and reference products should have comparable levels of safety. Thus, to believe that the risk of a biosimilar, which conforms to the characteristics of the reference, inducing more or new side effects compared with the reference, has no real meaning from a scientific point of view. References 1 Lindquist M. The need for definitions in pharmacovigilance. Drug Saf 2007;30:825. https:// doi.org/10.2165/00002018- 200730100-00001 (accessed October 2018). 2 European Medicines Agency. EMEA guideline on similar biological medicinal products, London, 2005, 39 (CHMP/437/04). www.ema.europa.eu/documents/ scientific-guideline/guideline- similar-biological-medicinal- products_en.pdf (accessed October 2018). 3 World Health Organization. Guidance on scientific principles for regulatory risk assessment of biotherapeutic products. WHO/ RRA BT_DRAFT/10 December 2014. www.who.int/biologicals/ WHO_Risk_Assessment_for_ BTP_2nd_PC_10_Dec_2014.pdf (accessed October 2018). 4 Mccamish M, Woollett G. The continuum of comparability extends to biosimilarity: How much Is enough and what clinical data are necessary? Clin Pharmacol Ther 2013;93(4): 315–17. 5 Schiestl M et al. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol 2011;29:310–12. 6 Sharma B. Immunogenicity of therapeutic proteins. Part 3: impact of manufacturing changes. Biotechnol Adv 2007;25:325–31. 7 European Parliament and Council of the European Community. Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010, amending as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use. http://ec.europa.eu/health/files/ eudralex/vol-1/dir_2010_84/ dir_2010_84_en.pdf (accessed October 2018). 8 Baker MP et al. Immunogenicity of protein therapeutics. The key causes, consequences and challenges. Self Nonself 2010;1(4):314–22. 9 Ratanji KD et al. Immunogenicity of therapeutic proteins: Influence of aggregation. J Immunotoxicol 2014;11(2): 99–109. 10 European Parliament and Council of the European Community. Falsified Medicines Directive. https://ec.europa.eu/ health/sites/health/files/files/ eudralex/vol-1/dir_2011_62/ dir_2011_62_en.pdf (accessed October 2018). 11 Calvo B, Zuñiga L. EU’s new pharmacovigilance legislation: considerations for biosimilars. Drug Saf 2014;37:9–18. 12 Klein K et al. Traceability of biologics in The Netherlands: An analysis of information-recording systems in clinical practice and spontaneous ADR reports. Drug Saf 2016;39:185–92. 13 Vermeer NS et al. Traceability of biologicals: present challenges in pharmacovigilance. Expert Opin Drug Saf 2015;14:63–72. 14 Ventola CL. Big data and pharmacovigilance: Data mining for adverse drug events and interactions. PT 2018;43(6): 340–51.