HPE HPE Fresenius Kabi handbook - Page 13

PHARMACOVIGILANCE Traceability and pharmacovigilance An important requirement for the safety monitoring of all biologics (including biosimilars) is the need for awareness of adverse events, and product and batch traceability during clinical use and at all levels in the supply chain Alain Astier PharmD PhD Vice-President ESOP; Honorary Head of the Department of Pharmacy. Member of the French Academy of Pharmacy, Henri Mondor University Hospitals, School of Medicine, Paris, France Pharmacovigilance is defined as the practice of monitoring the effects of licensed drugs, especially in order to identify and evaluate previously unreported adverse reactions. 1 To do this, it is crucial to ascertain if the adverse event is actually caused by a drug and, in the case of polytherapy, to identify which drug might be responsible. The batch must also be identified, because a specific impurity or degradation product present in a specific batch could be involved. Thus, for a proper pharmacovigilance, the traceability of the drug (knowing the batch reference, its history, storage conditions, identification of the patient who received it, etc) is mandatory. Traceability and risk management Traceability is a key element in monitoring the safety of biologics by enabling pharmacovigilance measures. Real life conditions, such as risks of drug– drug or drug–food interactions are not accurately evaluated by clinical trials. Thus, long-term follow- up is essential to establish a risk management plan (RMP). The aim of risk management is to address uncertainties in the safety profile at different points in the lifecycle, and to plan accordingly. This procedure was put in place in 2005 as part FIGURE 1 Risk management plan Risk management plan Marketing authorisation Safety specification Pharmacovigilance planning Risk minimisation planning Adverse drug reactions Reporting Epidemiological studies Regulatory decisions of European pharmacovigilance legislation and comprises part of the marketing authorisation application of a drug. 2 RMPs include plans for pharmacovigilance activities designed to gain greater knowledge and explain how risks will be minimised in patients, and how those efforts will be measured (see Figure 1). An RMP is required for all drugs containing a new active substance. The RMP might also be implemented after the product has been marketed if significant changes occur (for example, new indication, new dosage, new route of administration, new manufacturing process) or if a significant risk has been identified after the drug has reached the market. The RMP is also required for biosimilar products registered in the EU. The World Health Organization has published guidance on scientific principles for regulatory risk assessment of biotherapeutic products, including RMPs. 3 For a biosimilar, as for any biologic, variability between products from different manufacturers with the same active substance and batches of the same product from the same manufacturer need to be considered. 4 Moreover, numerous changes in the production process during the life of the biologic might induce large modifications in its composition, as demonstrated, for example, for rituximab originator. 5 Thus for each physicochemical or biological parameter, a biosimilar must fall in the range of variability observed for the originator. 3,6 Through the extensive comparability exercise for the originator drug and its biosimilar candidate, including a Phase III clinical trial, the tolerance and the classical side effects can be demonstrated as identical for both originator and biosimilar. However, immunological side effects remain a key, even controversial, issue, and are frequently cited by opponents of the use of biosimilars, particularly with regards to switching, interchangeability and extrapolation procedures. 5,6 Thus, it is paramount to verify whether a biosimilar has more or fewer immunological side effects compared with the reference drug. For biologics that are the subject of a suspected adverse event, it is of particular importance that the batch number, in addition to the brand names or name of the manufacturer, is reported. 7 Some immunological side effects, such as the presence of neutralising antibodies, are due to factors not directly related to the drug. For example, the production of neutralising antibodies for a biologic is not only related to the drug itself (that is, specific antigenic sequences, presence of foreign proteins and aggregates) but also to the patient’s characteristics, co-medications and pathology. 8,9 hospitalpharmacyeurope.com | 2019 | 13