1. SAFETY CONCERNS OF BIOSIMILARS IN TURKEY Serra Vildan Akgül¹, Sevcan Gül Akgün¹, Gülden Z. Omurtag¹, Semra Şardaş¹ ¹ Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey Biological (biotechnological, biopharmaceutical) drugs are defined as drugs which can be produced either in living organism or by biological processes. Biologics are often used to treat severe and/or life threatening diseases which can shift the suspected ADRs (adverse drug reactions) to more serious events. Biosimilar drug is a medicine whose active substance is similar to that of biological medicine that has already been authorized. It is developed after the patent protecting the original product has expired. Licensing The differences between the reference biologic drug and intended copy (biosimilars) must be understood sufficiently studied by preclinical and clinical studies to show its clinical effectiveness and safety before licensing. Legislation While health authority regulations provide general information on the standards to demonstrate the efficacy and safety of drugs used in human diseases, the guideline and legislation for the biosimilars seem to vary between countries (Fig. I). Therefore,regulatory health authorities around the world should standardize the guidelines for approval pathways of biosimilars to assure the safety, efficacy and quality of biosimilar drugs. Risk Management Plan (RMP) Pharmacavigilance is essential for biosimilars, especially to detect rare but serious side effects. Besides the routine PV, carefully designed RMPs should be carried to trace the safety and to minimize the risk f concerned products as demonstrated in Figure III. Pharmacovigilance systems should differentiate between originator and biosimilar products (so that effects of biosimilars are not lost in background of reports on reference products). With the approval as a clinically comparable version of the reference product, the biosimilar product should generally be considered as interchangeable, meaning that a patient can expect an equivalent outcome with regards to safety and efficacy with either treatment. The prescription by INN could result in different products being considered identical. For example, if two biologicals would have the same INN they could be ‘switched’ when there might be no scientific evidence to support that switch. The interchangeability could have negative clinical consequences for the patient as the two products are similar but not identical, and the differences between them may have a therapeutic impact. Ensure traceability commercialized with a brand name the INN plus the manufacturer’s name, country serial number TWN TUR MYS AUS BRA ARG SAU MEX WHO JPN EU Legal Methods CAN EMEA, published first biosimilar regulatory approval method for EU member countries More states began to develop SBP methods as taking WHO’s and EU’s guides template as it is shown for Australia KOR 20082005200920012004200020022006200720102003 2011 2012 USA (draft) IND ZA F CU B COL (draft) EU Inclusive Guides IRI JOR (draft) SIN PER THA (draft) Development of Guide WHO’s SBP (Similar biotherapeutic product) guide aims to provide consistent scientific standard and it s model for ones who just began to develop. Safety Concerns for Biosimilars Compared with the traditional chemically synthesized small molecules, biologicals have specific characteristics that influence their safety profile(Fig. IV). For example, biologicals are large, complicated molecules with a very complex production & purification processes, limited predictability of preclinical data to clinical outcomes, and a high potential for immunogenicity including allergic reactions, infections, infestations, immune system disorders, neoplasms, malign and many types of unspecified reactions, etc., since mechanism of biosimilars are triggered by serious biologic activities. Among these unwanted effects, immunogenicity is the most critical safety concern for biosimilars and is defined as the capacity of leading production of antibody. Safety and Efficacy Studies The quality comparison between the biosimilar and the innovator product is crucial, because the quality of protein product affects is safety and efficacy. The product is affected both by the host cell and the multistep manufacturing process (Fig II). In addition, protein molecules can be degraded during processing steps and impurities created in these steps can contribute to decreased potency and/or increased immunogenicity. The antibody screening should be part of clinical trials protocols. If the immune response observed with a biosimilar medicine differs from the reference product, further analysis must be conducted to characterize antibodies and determine their impact on pharmacokinetics and pharmacodynamics. Pharmacovigilance (PV) of Biosimilars Figure III: Risk management plan development Discussion There is a need for careful pharmacovigilance programs to monitor all biopharmaceuticals (including innovator products and biosimilars) for safety and efficacy issues during the post- approval period. Healthcare professionals must be aware that, biosimilars are not biopharmaceutical generics as they are obtained by specific manufacturing processes and have been even developed with more requirements than the reference drug. Pharmacovigilance is essential in the biopharmaceuticals market because of the limited ability to predict clinical consequences of seemingly innocuous changes in the manufacturing process and the scientific information gap. Detailed pharmacovigilance programs should be implemented according to the Eudravigilance guidelines developed by EMEA. The Turkish pharmacovigilance plan, which also covers the risk management rules for biosimilars has been implemented in the newly published regulation on 15 April 2014 by Turkish Drug and Medical Device Institution, department of Risk management. The present requirements for the safety of biosimilars are in harmony with the safety regulations of EMEA. However regulatory decision on interchangeability has still not been finalized. References 1.Zuniga L., Calvo B.,Biosimilars: pharmacovigilance and risk management. Pharmacoepidemiology and drug safety 2010; 19:661-669 2.Sekhon BS., Saluja V. Biosimilars: an overview. Dovepress Biosimilars 2011; 1: 1-11 3.EudraLex [Homepage]. Volume 9A Guidelines on Pharmacovigilance for Medicinal Products for Human Use. In: The rules governing medicinal products in the European Union. 2007; http://ec.europa.eu [accessed 1 December 2009]. 4.EMEA/192632/06 European Medicines Agency. Template for EU Risk Management Plan (EU-RMP). 2006; http://www.emea.europa.eu [accessed 1 December 2009]. Figure IV: Gel electrophoresis of 12 ‘biosimilar’ products. Results should be similar but this image shows the wide variance in similarity. 1 Figure II: Typical steps in manufacturing of a biologic product.