Pharmacological Research 133 (2018) 251–264 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Invited Review Biosimilars: Concepts and controversies Reyes Gámez-Belmonte a , Cristina Hernández-Chirlaque b , María Arredondo-Amador a , Carlos J. Aranda b , Raquel González a , Olga Martínez-Augustin b , Fermín Sánchez de Medina a,∗ a Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Spain Department of Biochemistry and Molecular Biology II, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Spain b a r t i c l e i n f o Article history: Received 3 October 2017 Received in revised form 31 January 2018 Accepted 31 January 2018 Available online 8 February 2018 Keywords: Biosimilar Comparability exercise Extrapolation of indications Immunogenicity a b s t r a c t Biosimilars are copies of reference biological drugs, developed as the patents for original biologicals expire. They are thus developed to replicate an original biological medicine just a generics are intended to replicate a chemically-synthesized medicine; however, there are important technical and regulatory differences between the two. Unlike chemical drugs, molecular identity cannot generally be established for any two biological drugs. Accordingly, their pharmacological properties cannot be assumed to be the same. This is due to the complexity of the production of biologicals and to the presence of minor natural variations in the molecular structure (collectively known as microheterogeneity). Further, biological production yields slightly different versions of the drug over time, particularly when changes are introduced in the production process. In this case the prechange and postchange versions of the biological are analyzed in what is called a comparability exercise. The comparable versions thus validated are considered not to have any significant differences at the clinical level. Likewise, biosimilars are not identical copies but comparable versions of the original biological drug, also validated through a comparability exercise, although of a much broader scope. Although current knowledge about biosimilars has increased significantly, they still arise a number of controversies and misconceptions, particularly regarding issues like extrapolation of indications, immunogenicity and substitution. This review deals with concepts and controversies in the biosimilar field. © 2018 Elsevier Ltd. All rights reserved. Contents 1. 2. 3. 4. 5. 6. 7. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 What is a biosimilar? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 What is not a biosimilar? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 The issue of molecular identity – chemical vs. biological drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 Process meets product – the comparability exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Development of biosimilars – the biosimilar pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 Controversies in the use of biosimilars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 7.1. Controversy 1: similar but not the same . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 7.2. Controversy 2: immunogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 7.3. Controversy 3: extrapolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 7.4. Controversy 4: substitution and interchangeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 7.5. Controversy 5: nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 Abbreviations: ADA, anti-drug antibodies; CHMP, Committee for Medicinal Products for Human Use; DIN, Drug Identification Number; ECCO, European Crohn’s and Colitis Organisation; EMA, European Medicines Agency; FDA, Food and Drug Administration; INN, International Nonproprietary Name; MAH, Manufacturing Authorisation Holder; WHO, World Health organisation; TGA, Therapeutic Goods Administration. ∗ Corresponding author at: Dpt. Pharmacology, School of Pharmacy, 18071, Granada, Spain. E-mail address: fsanchez@ugr.es (F. Sánchez de Medina). https://doi.org/10.1016/j.phrs.2018.01.024 1043-6618/© 2018 Elsevier Ltd. All rights reserved. 252 R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 8. Biological drift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 9. Knowledge about biosimilars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 10. Economic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 1. Introduction approval and clinical application of biosimilars, with a focus on EMA regulations. Biological drugs are high molecular size, structuraly complex drugs that are obtained from live organisms and which cannot be fully characterized from an analytical point of view. Similar biological medicinal products or biosimilars, were first introduced in the European Union through the European Medicines Agency (EMA) in 2005, as the response to the challenge of the approaching patent expiration dates of the first few biologicals approved. This procedure, i.e. the generation of copies of biological medicines, is in some ways comparable to the development of generic medicines associated with patent expiration of nonbiological (or chemical) drugs (see below and Fig. 1), but it is also fundamentally different both in technical and regulatory terms (Fig. 2). Europe has led the technical, administrative and legal path in the biosimilar field, and the main regulatory agencies, as well as the World Health Organization (WHO), have followed through with similar regulations. At the same time, some agencies have established less stringent regulations for the development of copies of biological medicines, resulting in medicines which may differ substantially from the original product. These are known as ‘intended copies’, the denomination adequately conveying the meaning that these copies are not quite accomplished and/or validated, and therefore they are not biosimilars (see below and Table 1 for a glossary of terms). However, for a variety of reasons they may be wrongly referred to as biosimilars in some instances. Awareness and general knowledge about biosimilars have increased greatly in the last few years. In spite of this, numerous doubts and misconceptions abound in this field. The purpose of this review is to present in a straightforward fashion the main concepts in this burgeoning field of pharmacology, and to discuss the most debated controversies regarding the 2. What is a biosimilar? The EMA defines a biosimilar, or similar biological medicinal product, as ‘a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product)’, with similarity established ‘in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise’. That is, original and biosimilar are versions of the same biological drug which are essentially the same, i.e. they must not differ substantially from their reference in terms of quality, efficacy or safety [1]. Implied in this definition is the fact that a biosimilar need not be an exact, but a close enough, copy of the original biological, a concept that is commonly summed up in the ‘similar but not the same’ phrase (discussed below). Despite the possibility of minor differences, ultimately the biosimilar must not behave any differently from their reference biological drug in clinical terms. Thus, a biosimilar is intended to work as a therapeutic equivalent to the reference product; however, there are important issues to consider in this regard, as explained in the following sections. The development of biosimilars contrasts sharply with that of generic medicines, in that the active substance in generic and reference products is identical (Fig. 2). As a result, the pharmacological activity and toxicity of the two medicines are also identical, provided that pharmacokinetics, mostly depending on galenic characteristics, is reproducible, and overall manufacturing high standards are maintained. Pharmacokinetic reproducibility is established by bioequivalence studies, which are designed to confirm that the pharmacokinetic profile of two given medicines is Fig. 1. Types of drugs: chemical vs. biologic. R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 253 lars approved by EMA up to September 2017. Table 3 shows those approved in the United States, Canada, Australia and Japan. 3. What is not a biosimilar? Fig. 2. Development of replicas of chemical and biological drugs. In the first case molecular identity can be established between originator and copy, and therefore demonstration of bioequivalence suffices, giving rise to a generic medicine. In the case of biologicals, molecular identity cannot be established, hence a global comparison between originator and copy must be carried out, the result being the biosimilar. comparable, that is, identical within a certain, predefined margin. This is typically ±20% [2,3]. Because the comparison involves the use of geometric means, the values are logarithmically transformed for analysis and then back-transformed to the original scale, resulting in an asymmetrical 80–125% margin. The ratio of the relevant pharmacokinetic parameters, such as AUC0-t and Cmax , must be within the 80% and 125% limits, with 90% confidence intervals. AUC0-t is the area under the concentration time curve, reflecting systemic exposure to the drug, between administration and a given time, while Cmax is the peak plasma concentration of the drug. It is generally considered that key pharmacokinetic parameters may be accepted to vary within this range because this sort of variation is considered not to lead to clinically significant changes in efficacy or safety. This margin may be viewed as a compromise between statistical power (and its associated costs), safety, and practicality [4]. For drugs with a narrow therapeutic index the bioequivalence limits are tightened to 90–111%. Of note, bioequivalence studies are not applied solely to the development of generic medicines, but also to other aims such as the validation of new drug formulations, of fixed combinations, or to establish comparable behaviour of medicine batches before and after a significant change in the production process, among other uses [2]. Bioequivalence studies are suitable and sufficient to validate any change in the production process that might impact pharmacokinetics because the drug itself is unchanged. They have been the basis of the validation of generic medicines from the early 80s [4]. Since characterizing pharmacokinetics is substantially easier and cheaper than assessing either efficacy or toxicity, and the production costs of chemical drugs are limited, generics may be developed at very competitive prices. The term ‘biosimilar’ or ‘similar biological medicinal product’ is applied in EMA regulated countries. Equivalent denominations include ‘subsequent entry biologics’ (Canada), ‘follow on biologics’ (USA) and ‘similar biotherapeutic products’ (WHO). However, the term ‘biosimilar’ appears to be gaining acceptance in the USA and Canada even at an official level [5–7]. Table 2 shows the biosimi- Biosimilars should not be confused with related but wholly different concepts, including intended copies, biobetters, and standalone products [8]. Intended copies are biosimilar-type of biologicals, in that they are copies of a reference drug, but they have not been submitted to an stringent comparability exercise as that established and required by the EMA, Food and Drug Administration (FDA) and other agencies, and therefore they are not authorised in the countries regulated by them. In consequence, they are not proven to have an equivalent profile in terms of quality, efficacy and safety, and differences at the clinical level cannot be ruled out [9–11]. This does not mean that intended copies are inferior, simply that they are not biosimilars. Even though the aminoacid sequence may be in fact the same, differences in postranslational modifications, the presence of impurities, the formation of aggregates, and so forth, may impact the pharmacological profile of the molecule significantly (see below), to the point that intended copies may be considered to be actually different drugs altogether or, at the very least, not proven to be comparable to the original. To add to the confusion, the term ‘biosimilar’ may be loosely applied to intended copies, thus introducing uncertainties about bona fide biosimilars. Biobetters are biologicals that are significantly and consciously modified versions of other biologicals, in an attempt to improve their pharmacological profile in one way or another. For instance, darbepoetin alpha is an altered version of epoetin which features an alternative glycosylation pattern that prolongs the elimination half-time [12]. Insulin glargine is similarly designed to delay the release of insulin monomers upon subcutaneous administration, attained by a change in the aminoacid sequence [13]. Hence the similarity is superseded by the improvements in design. Standalone biologicals are those that are developed and approved not as copies of a reference product but as a new medicine. This denomination may be applied to any biological (biobetters, for instance), but particularly when the drug in question is akin to one already approved and used therapeutically, but without validation of similarity by an extensive comparability exercise. Instead, the standalone is characterized as a new biological agent and its efficacy and safety tested against a placebo or another valid comparator. Thus a standalone is a biological me-too [14]. It is important to note that this is strictly an strategic and regulatory decision, in that the biological product may in fact be perfectly suitable to be considered a biosimilar (technically). One example is epoetin theta, which was started originally as a biosimilar of epoetin beta but was developed and commercialized ultimately as a standalone (EPORATIO, RATIOEPO, BIOPOIN), presumably because of differences in glycosylation [11]. 4. The issue of molecular identity – chemical vs. biological drugs Drugs may be of two major types (Fig. 1). Synthetic drugs, also known as chemical drugs or small molecules, are molecules of small size (typically < 3 kD) and low structural complexity displaying little or no heterogeneity and which are obtained by chemical synthesis. This applies also to small molecules obtained partly (semisynthesis) or solely from biological sources for which a precise molecular structure can be established in analytical terms (examples include antibiotics, statins, and others). This latter crucial characteristic signifies that these products can be defined strictly by analytical parameters, regardless of product source or method 254 R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 Table 1 Glossary. Anti-drug antibodies (ADA) Batch Biobetter Bioequivalence Biological Biosimilar Biosimilar pathway Biosimilarity Comparability Extrapolation of indications Generic medicine Immunogenicity INN Intended copy Interchangeability Longitudinal variation Macroheterogeneity Microheterogeneity Pharmacokinetic/pharmacodynamic (PK/PD) study Pharmacovigilance Reference medicine Traceability Transversal variation Synthetic drug Stand-alone pathway Substitution Switching Antibodies produced by the body’s immune system against an active substance (particularly a large molecule, such as a protein). A defined quantity of a starting material or product generated in a single process or series of processes so that it can be expected to be homogeneous. A significantly and consciously modified version of a biological designed to improve its attributes. Quality of two medicinal products containing the same active substance (including, in a broad sense, biosimilar vs. original biological) that have a comparable pharmacokinetic profile when administered in the same circunstances. Drug produced or extracted from a biological source and that requires for its characterization and determination of quality, a combination of physical-chemical and biological assays, together with the characterization and control of the production process. A biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product). Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established. The regulatory procedure, involving the demostration of similarity through an extensive comparatibility exercise between the proposed product and the reference product, that leads to approval as a biosimilar. Demonstration of high similarity of a biosimilar to a reference biological medicine in terms of quality, biological activity, efficacy and safety, via a comprehensive comparability exercise. Head-to-head comparison of two versions of a biological drug to rule out any clinically significant differences between them. This term is routinely used when a change is introduced to the manufacturing process of medicines made by biotechnology, to ensure that the change does not alter safety and efficacy. It is also applied to biosimilar vs. reference drug. Approval of an indication for a biosimilar drug based on overall similarity with the reference drug, but no direct/specific supportive clinical evidence. A medicinal product whose active substance is identical to that of the reference product, is used at the same dose and pharmaceutical form, and has demonstrated bioequivalence. Some exceptions to this general principle are accepted. The ability of a molecule or substance to provoke an immune response. International Nonproprietary Name, a unique name that identifies active substances, administered by the WHO. A copy of a biological drug that has not been validated via a comprehensive and stringent comparability exercise as established and required by the EMA and other agencies. The possibility of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient. Changes in the pharmaceutical properties of a biological that tend to occur with time, particularly in relation to modifications introduced in the production process. Major molecular variations in a biological that are considered biochemically and pharmacologically relevant (and thus incompatible with the biosimilar status). Minor molecular variations in a biological due to natural, inherent variability and slight alterations in production methods. A clinical study that characterizes the pharmacokinetic profile of a drug and its pharmacological action, typically as a surrogate of the desired ultimate effect. The science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem during the commercial lifetime of a medicinal product. A medicine chosen as a comparator for the development of a generic or a biosimilar. Monitoring of medicines during clinical use and at all levels in the supply chain. This covers the time from release by the manufacturer and progress through the entire distribution chain until the medicine is administered to the patient. Occurrence of different, closely related molecular variants (i.e. microheterogeneity), of a biological at any given time due to natural modifications or alternatives in the production process. A drug obtained generally by chemical synthesis or semisynthesis whose structure can be established by state of the art analytical tools. The regulatory procedure involving demonstration of drug efficacy and safety leading to approval as a new, me-too kind of medicine product. Practice of dispensing one medicine instead of another at the pharmacy level, without consulting the prescriber. Medical practice of changing one medicine for another in a given patient with the same therapeutic intent. of synthesis, as their structure can be perfectly established by state of the art techniques, with essentially no margin of error. Chemical drugs constitute the majority of active substances available in pharmacological history, as well as at present. Although some degree of heterogeneity may be, and is usually, present (stereoisomery), this does not preclude precise molecular characterization. For instance the classical betablocker propranolol is a racemic mix of two stereoisomers, so that the drug product contains 2 molecules instead of a single molecule, but both are perfectly well defined at the molecular level. On the other hand, biological products are of a much bigger molecular size and present a high degree of complexity, entailing 3-dimensional structure conformational information, such that chemical synthesis is either not possible or extremely expensive. Importantly, the molecular structure of biologicals cannot be fully established by state of the art techniques. Thus a biological is defined by Directive 2003/63/CE (EMA region) as a substance ‘produced or extracted from a biological source and that needs for its characterization and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control’ [15]. The tradeoff of this complex approach is that biologicals are both very specific mechanistically, and often quite effective drugs. In addition to high molecular size and complexity, biological drugs display substantially increased molecular heterogeneity compared to small molecules. Minor variations of a basic structure are naturally produced in the course of biological synthesis of proteins, giving rise effectively to a number of different molecules that are almost identical. This phenomenon is known as microheterogeneity, to differentiate it from macroheterogeneity, which refers to major variations in the molecular structure which are potentially relevant from a biochemical and pharmacological standpoint. Microheterogeneity pertains various aspects of the biological, including the frequency and types of glycosydes attached to the protein or the occurrence of oxidative and deaminative modifications. In contrast, the introduction of new glycosylation sites or an alteration in the aminoacid sequence are Table 2 Biosimilars approved by the EMA with representative immunogenic potential data. Active substance MAH Code name Authorized Disease Immunogenicity Time Reference ABASAGLAR insulin glargine LY2963016 2014 ABSEAMED/BINOCRIT/EPOETIN ALPHA HEXAL epoetin alpha HX575 2007 diabetes mellitus, type 1 diabetes mellitus, type 2 healthy chronic renal failure 29.8 vs. 33.7% 15.3 vs. 11.0% 0 vs. 0% 0.8 vs. 2.8% 24 w 24 w 4w 54 w LANTUS LANTUS EPREX/ERYPO EPREX/ERYPO ACCOFIL/GRASTOFIL filgrastim apo-filgrastim 2014 AMGEVITA/SOLYMBIC adalimumab Eli Lilly Regional Operations GmbH Medice Arzneimittel Pütter GmbH & Co. KG/Sandoz GmbH/Hexal AG Accord Healthcare Ltd/Apotex Europe BV Amgen Europe B.V. ABP501 2017 healthy chemotherapy related neutropenia healthy 0 vs. 0% 0% 53.7 vs. 67.2 vs. 55.1% (neu 18.0 vs. 21.0 vs. 22.0%) 38.3 vs. 38.2% (neu 9.1 vs. 11.1%) 55.2 vs. 63.6% (neu 9.8 vs. 13.9%) 0 vs. 0% 0 vs. 15.6% (neu 14.3%) 0.7 vs. 13.2% 13.6 vs. 27.6 vs. 23.3% 10 d 48 w 63 d NEUPOGEN – HUMIRA (EU/US) 24 w HUMIRA (US) 16 w HUMIRA (EU) 12 w 71 d rheumatoid arthritis ankylosing spondylitis rheumatoid arthritis venous thromboembolism 4.3 vs. 2.9% (neu 80%) 93 vs. 84 vs. 88% (neu 59.8 vs. 58.3 vs. 63.9%) 43.2 vs. 47.8% (neu 16.0 vs. 20.6%) 0 vs. 1.9% (generally not neutralizing) 0 vs. 0% 0% 47.2 vs. 37.7 vs. 37.7% (neu 56 vs. 70 vs. 35%) 54.4 vs. 48.4% (neu 92.7 vs. 97.5%)* 98.4 vs. 95.2 vs. 100.0% (neu 79.0 vs. 80.0 vs. 82.5%) 32.0 vs. 31.0% 34.4 vs. 32.0% 55.6 vs. 54.3% – rheumatoid arthritis plaque psoriasis BEMFOLA BENEPALI follitropin alpha etanercept BLITZIMA/RITEMVIA/ RITUZENA/TRUXIMA rituximab CYLTEZO adalimumab Gedeon Richter Plc. Samsung Bioepis UK Limited Celltrion Healthcare Hungary Kft. Boehringer Ingelheim International GmbH AFOLIA-150 SB4 2014 2016 CT-P10 2017 anovulation healthy rheumatoid arthritis rheumatoid arthritis BI695501 2017 advanced follicular lymphoma healthy rheumatoid arthritis ERELZI etanercept Sandoz GmbH GP-2015 2017 plaque psoriasis FILGRASTIM HEXAL/ZARZIO FLIXABI filgrastim Hexal AG/Sandoz GmbH EP2006 2009 infliximab Samsung Bioepis UK Limited (SBUK) SB2 2016 healthy chemotherapy related neutropenia healthy rheumatoid arthritis IMRALDI adalimumab Samsung Bioepis UK Limited SB5 2017 INFLECTRA/REMSIMA infliximab Hospira UK Limited CT-P13 2013 INHIXA/THORINANE enoxaparin sodium insulin lispro Techdow Europe AB/Pharmathen S.A. Sanofi Aventis – 2016 SAR342434 2017 LUSDUNA insulin glargine MOVYMIA/TERROSA teriparatide NIVESTIM filgrastim Merck Sharp & Dohme Limited STADA Arzneimittel AG/ Gedeon Richter Plc. Hospira UK Ltd OMNITROPE OVALEAP RATIOGRASTIM/TEVAGRASTIM somatropin follitropin alpha filgrastim RETACRIT/SILAPO epoetin zeta RIXATHON/RIXIMYO rituximab INSULIN LISPRO SANOFI Sandoz GmbH Teva Pharma B.V. Ratiopharm GmbH/ Teva GmbH Hospira UK Limited/Stada Arzneimittel AG Sandoz GmbH healthy 21 d 24 w 24 w 24 w 52 w Up to 9 d 3m 10 w GONAL-F ENBREL ENBREL MABTHERA/ RITUXAN RITUXAN HUMIRA (EU/US) HUMIRA (US) ENBREL 54 w NEUPOGEN – REMICADE (EU/US) REMICADE (EU) 10 w HUMIRA (EU/US) 24 w 54 w 54 w – HUMIRA (EU) REMICADE REMICADE CLEXANE 22.3 vs. 20.3% 18.4 vs. 15.1% 40.6 vs. 39.8% (neu 2.9 vs. 0%)* 19.3 vs. 14.9% (neu 0.0 vs. 0.5%) – 52 w 26 w 52 w 24 w – HUMALOG HUMALOG LANTUS LANTUS FORSTEO MK-1293 2017 RGB-10 2017 diabetes mellitus, type 1 diabetes mellitus, type 2 diabetes mellitus, type 1 diabetes mellitus, type 2 osteoporosis PLIVA/Mayne filgrastim Api Sandoz XM17 XM02 2010 healthy 1.6 vs. 0.0% 5d NEUPOGEN 2006 2013 2008 groth hormone deficiency anovulation chemotherapy related neutropenia 9m 3m 2w GENOTROPIN GONAL-F NEUPOGEN SB309 2007 renal anemia chemotherapy related anemia 0-2.0** vs. 2.3%*** 7.2 vs. 3.4% 0.8 vs. 0.0% (neu 0%) 0 vs. 0% 0% 24 w 12 w ERYPO GP2013 2017 rheumatoid arthritis follicular lymphoma 11.0 vs. 21.4% (neu 3.7 vs. 1.2%) 1.9 vs. 1.1% (neu 0.7 vs. 0.7%) 50 w >6 m MABTHERA MABTHERA 255 Source: EPAR and [78]. Figures are indicative of the overall profile of immunogenicity for EMA approved biosimilars. For specific details please consult. Immunogenicity data can only be compared between biosimilar and its reference but not across studies, as different methods and protocols are used. * Excluding positive baseline. **0% drug, 2.0% cell proteins. ***Indirect comparison. neu: neutralizing antibodies. R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 Medicine name 256 R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 Table 3 Biosimilars approved in the United States, Canada, Australia and Japan (September 2017). United States Active substance Medicine Authorized MAH adalimumab-adbm adalimumab-atto etanercept-szzs filgrastim-sndz infliximab-abda infliximab-dyyb insulin glargine insulin glargine CYLTEZO AMJEVITA ERELZI ZARXIO RENFLEXIS INFLECTRA BASAGLAR TOUJEO SOLOSTAR 2017 2016 2016 2015 2017 2016 2015 2015 Boehringer Ingelheim Amgen Inc Sandoz Sandoz Inc Samsung Bioepsis Co Ltd Celltrion Inc Eli Lilly Canada Inc Sanofi Active substance Medicine Authorized MAH etanercept filgrastim infliximab BRENZYS GRASTOFIL INFLECTRA REMSIMA BASAGLAR TOUJEO SOLOSTAR 2016 2015 2014 2014 2017 2015 Merck Canada Apotex Hospira Celltrion Eli Lilly Canada Inc Sanofi Active substance Medicine Authorized MAH epoetin lambda ACZICRIT GRANDICRIT NOVICRIT BASAGLAR BEMFOLA BRENZYS INFLECTRA RENFLEXIS NIVESTIM TEVAGRASTIM ZARZIO OMNITROPE SCITROPIN A 2010 2010 2010 2014 2015 2016 2015 2016 2010 2011 2013 2010 2010 Sandoz Sandoz Novartis Pharmaceuticals Australia Eli Lilly Australia Finox Biotech Samsung Bioepis Hospira (Pharmabio) Samsung Bioepis Hospira Aspen Pharmacare Australia Sandoz Sandoz SciGen Australia Canada insulin gargline Australia insulin glargine follitropin alfa etanercept infliximab filgrastim somatropin Japan Active substance Proprietary name Authorized MAH epoetin alfa biosimilar 1 Epoetin alfa BS Injection 750/1500/3000 syringe [JCR] Epoetin alfa BS Injection 750/1500/3000 [JCR] Filgrastim BS Injection 75/150/300 g Syringe “Mochida” Filgrastim BS Injection 75/150/300 g Syringe “F” Filgrastim BS Inj. 75/150/300 g Syringe “NK” Filgrastim BS Injection 75/150/300 g Syringe “Teva” Filgrastim BS Inj. 75/150/300 g Syringe “Sandoz” Infliximab BS for I.V. Infusion 100 mg “NK” Infliximab BS for I.V. Infusion 100 mg “CTH” Insulin glargine BS Inj. Cartridges [Lilly] Insulin glargine BS Inj. MirioPen [Lilly] Insulin glargine BS Injection Kit “FFP” Insulin glargine BS Injection 100 Unit/ml “FFP” Somatropin BS S.C. Injection 5/10 mg [Sandoz] 2010 JCR Pharmaceuticals 2012 Fuji Pharma/Mochida Pharmaceutical 2013 Teva Pharma Japan/Nippon Kayaku 2014 Sandoz 2014 Celltrion/Nippon Kayaku 2014 Eli Lilly 2016 Fujifilm Pharma 2009 Sandoz filgrastim biosimilar 1 filgrastim biosimilar 2 filgrastim biosimilar 3 infliximab biosimilar 1 insulin glargine biosimilar 1 insulin glargine biosimilar 2 somatropin Active substance is listed as Japanese approved name for Japanese biosimilars. The names of the corresponding products are combined for brevity. considered changes of a higher magnitude (macroheterogeneity). These considerations apply fundamentally to biotechnologically produced proteins; other biologicals show a much higher heterogeneity, including low molecular weight and regular heparins, vaccines, and so forth. Of note, not only is microheterogeneity inherent to the structure of biologicals at any given time (transversal variation), but there is also a well acknowledged tendency for variation of microheterogeneity over time (longitudinal variation, Fig. 3). This is due to the natural oscillations that are present in the synthesis of pro- R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 257 Fig. 3. Variability in biological drugs. At any given time a biological exhibits a certain degree of molecular variability, in that it features a set of almost identical molecular variations (transversal variability). As an example, different variants of a given glycoprotein may result from the incorporation of various glycosydic fractions (top). On the other hand, variations tend to occur over time due to natural fluctuations in the production process, particularly when there are changes in the process involved (longitudinal variability). These variations are kept within relatively narrow limits by close monitoring of critical parameters and, when necessary, a comparability exercise. This variation affects both original and biosimilar drugs (bottom). teins by cells in culture (as in the living organism, for that matter) [16,17]. In the setting of biological drug production, this gives rise to some degree of batch to batch variation, which must therefore be carefully monitored and kept within a relatively narrow margin, as shown in Fig. 3. Longitudinal variation is particularly relevant when changes are introduced in the production process (see below) [18,19]. Therefore, any given biological is produced as a set of slightly different variations of the basic molecule, which then is itself subject to changes to a certain extent over time. The resulting versions of the biological are not identical, but comparable, that is, they exhibit no significant differences at the clinical level in either efficacy or safety. For the reasons just stated, the principle of molecular identity which applies in the development of generics does not hold for biological drugs. This means that their biological/pharmacological properties cannot be assumed to be identical. Rather, extensive testing is required in order to establish that any existing differences are not clinically relevant. The set of assays required to achieve this aim is known as the comparability exercise. 5. Process meets product – the comparability exercise Our capacity to define a biological drug in purely analytical terms, although substantially enhanced in recent years, is still limited today. This limitation is compensated, or complemented, by the knowledge and characterization of the production process, as noted. The principle is that the final product is more accurately defined if: (1) the protein has a well defined aminoacid sequence and is characterized to the state of the art in terms of tridimensional structure, postranslational modifications, aggregates, and so forth; (2) it has been generated by a well delineated process, where the cell type and bank, culture medium, purification columns, etc., are detailed and monitored continuously. Thus process details are not important only as the know-how of the manufacturer making synthesis possible, but also as part of the very definition of the biological. It is well known that even relatively minor changes in the process can alter substantially the molecule produced, particularly regarding microheterogeneity, aggregates and impurities, stressing the importance of maintaining the production process as constant as possible. Of note, microheterogeneity does not depend solely on the production process, but also on stability and conservation, which have an impact on protein degradation and aggregation. Therefore while the characteristics of the process have a (limited) role in the production of chemical drugs, they become critical in the case of biological drugs. This principle has crystallized in the ‘the process is the product’ adage, which has been extensively used in the field. While useful to convey the importance of the control of the process in biological development, this expression unfortunately gives the wrong impression that the process-product relationship is fixed and bidirectional. As mentioned above, rather than fixed, the process is naturally subject to changes, as all biologicals undergo some modifications in the manufacturing process which have the potential to affect the pharmacological properties of the drug. This is therefore the norm, not the exception [20]. On the other hand, rather than bidirectional, the process-product relationship is unidirectional, in that while an unaltered process gives rise a constant product (with minor variations), a biological can be produced by more than one process (thus making biosimilar development possible). Early in the development of biotechnological proteins as drugs, the realization that changes in the process of production may affect the final product called for a means to validate the product generated after such changes. In order to do this, the comparability exercise was formulated [19,21]. This consists in a more or less extensive series of assays (depending on the extension and characteristics of the modifications) which are applied to the product pre- and post-change. In virtually all cases a limited series of in vitro tests suffices to establish that the changes are not clinically relevant (in what is in effect an extrapolation) [22]. Of note, the two versions need not be identical, what is required is that there is no significant alteration in clinical terms (i.e. that they are comparable). In virtually all cases no extra assays need be performed, but in prin- 258 R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 ciple, in vivo animal and even clinical trials may be also involved, although this is exceptional [23]. All relevant changes in the production process are communicated to, and sanctioned by, the regulatory agencies, on the basis of the comparability exercise. The existence of the changes is public, but the details are privy to the manufacturer and agencies. These changes are due to the necessity to adapt to different technical, practical and regulatory challenges, and may include modifications at any point of the production process, even the cell line stock in some rare cases, for instance because of a change of the scale of production, elimination of a problematic reagent, introducing a second plant, and so forth. It should be noted that quite a few of these changes are merely formal and do not affect the product as such. The number of significant changes in EMA approved biologicals has been recently detailed by Vezér et al. [20]. The impact of manufacturing changes has been evaluated externally for some (reference) biologicals, and it reportedly includes modifications in glycosylation, charged species, and bioactivity [24]. One possible problem in this regard is biological drift (see below). Contrary to the extreme interpretation of the ‘process is product’ adage, the biological is still the same (i.e. comparable) even after these unavoidable modifications are introduced, as long as they are validated through the comparability exercise. Furthermore, a version of the biological may be obtained through an entirely new production process, carried out in a completely separate installation, and by different technicians and scientists, which is what the development of biosimilars entails. Needless to say, this is a challenging and costly enterprise, because the manufacturer of the biosimilar does not have access to the know-how of the originator, except in its most basic details, nor the experience and historical production data. In addition, as literally all aspects of the production have to be validated, the corresponding comparability exercise is of much bigger dimensions than any such exercise used to validate a simple change in a well established and documented system. That is, the comparability exercise is in principle the same in both cases, but the size and scope are very different. Perhaps to reflect better this difference the FDA and Health Canada are proposing to actually using different names for the two, i.e. ‘comparability exercise’ vs. ‘demonstration of biosimilarity’ or ‘studies to demonstrate similarity’ [5,25]. 6. Development of biosimilars – the biosimilar pathway The development and approval of a biosimilar differ substantially from those of both innovative drugs and generic medicines. Fig. 4 displays the process followed by innovative drugs, either chemical or biological; there is a relatively lengthy research and development phase to yield an appropriate candidate molecule, which is then characterized extensively in the preclinical phase. The clinical development follows the established phase I-II-III progression, followed by phase IV after commercialization. The development of a generic medicine starts with the drug molecule (already established and characterized) and requires only the production of the finished medical product and bioequivalence testing. The biosimilar pathway lies somewhere in between that of innovative and generic medicines. As with generics, the molecule is established from the start; unlike generics, the molecule is not easily reproduced nor characterized. Rather, the manufacturer must carry out a complex exercise of fine tuning the manufacturing process based on knowledge of the state of the art, reverse engineering and technical adjustments, in order to generate a final product that is comparable to the originator. The preclinical phase involves, in addition to the refining of the production process, the comparative assessment of the candidate biosimilar vs. the originator. This involves multiple physicochemical, biochemical and bioac- Fig. 4. Development of original, generic and biosimilar medicines. The making of a brand new drug, either chemical or biological, involves a relatively extended preclinical phase for molecule generation, in vitro assays and animal testing, followed by the classical phases I, II and III. In this process phase III is critical as it establishes the efficacy/safety of the drug, while the remainder steps have the role of leading to it. In the case of generic medicines the molecule is already established and constitutes the start point, followed by state of the art pharmaceutical production and the validation of bioequivalence (BE) by a pharmacokinetic trial. The development of biosimilars also builds from an already established molecule, but the production process is far more complex than in chemical drugs. As in generics, comparison with the reference product is key, but in this case bioequivalence is just one part of an exhaustive set of assays covering essentially all aspects of the drug: quality, bioactivity, efficacy and safety, which collectively constitute the comparability exercise. Since in vitro assays are far more sensitive than clinical trials to detect possible differences, they are the core of the demonstration of biosimilarity. Thus one important difference with original drugs is that clinical trials are mainly confirmatory. Please note that the 3 development diagrams are not precisely drawn to scale. tivity/pharmacological assays, covering the entire profile of the molecule, i.e. its aminoacid sequence, tridimensional conformation, subunit assembly, presence of aggregates, impurities, affinity for receptor, pharmacological activities, stability, etc. The exact type of assays depends on the kind of biological considered, i.e. quite different for erythopoyetins, insulins or monoclonal antibodies for instance. In any case, they are expected to cover every conceivable aspect of the molecule according to the state of the art at the time of development. Furthermore, multiple batches of both originator and biosimilar are analyzed. Animal testing may or may not be involved [1]. For instance, it is of importance for the evaluation of biosimilar insulins, as human insulin is bioactive in rodents, and relatively irrelevant for monoclonal antibodies, which show no such crossed species activity. Clinical testing is an integral part of the development process. The EMA requires in most cases a phase I followed by a phase III study, with a comparative design in which patients are randomly assigned to receive the originator or the biosimilar. For some drugs, such as biosimilar insulins, for which there is a close relationship between clinical endpoints and a surrogate marker, a pharmacokinetic/pharmacodynamic trial suffices. The entire set of preclinical (in vitro and animal) and clinical tests constitutes the comparability exercise (Fig. 4). If the results obtained are similar, i.e. within the predefined margins of variation, the biosimilar is validated. Of note, the biosimilar concept is not only technical/scientific, but also regulatory. The demonstration of similarity (biosimilar R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 259 Fig. 5. Immunogenicity of biosimilar vs. original biological drugs. Biological drugs are prone to elicit an immune response. The risk depends partly on the type of molecule and the epitopes present, and partly on the formation of noncovalent aggregates, the presence of immune boosting impurities, and so forth. The overall capacity to predict immunogenicity is low, and clinical assays are key to ultimately establish the immunogenic potential of the biologic. In turn, a biosimilar is expected to present a similar or even identical set of epitopes as the reference drug, inasmuch as the molecule is closely reproduced. Therefore, demonstration of comparability in terms of quality (in vitro assays) is highly predictive of the immunogenicity of the biosimilar, which is expected to match that of the reference drug. However, the occurrence of biosimilar specific immunogenic responses cannot be excluded. pathway) results in the approval of a medicine that essentially adopts the profile of the originator. That is, the biosimilar is expected to have comparable efficacy and toxicity, although to what extent this happens depends on the extrapolation of indications and the adequate follow up in phase IV. Alternatively, a biological with substantial similarity to another may be developed and marketed as a standalone product, as discussed above. As the biosimilar pathway requires that the copy and the original biological product be analyzed in depth in order to show similarity through the comparability exercise, it follows that the original biological must be susceptible to be characterized to a great extent [1]. As a result, biosimilars are almost exclusively proteins generated by biotechnology, although the EMA considers copies of low molecular weight heparins as biosimilars as well. 7. Controversies in the use of biosimilars 7.1. Controversy 1: similar but not the same ‘Similar but not the same’ constitutes a catch phrase as widely used in the biosimilar field as the aforementioned ‘the process is the product’. It refers to the fact that biosimilars are not identical to the original, which is meant as ‘same’ in this context. Thus the phrase gives the impression of an attempt falling short in some way (since ‘similar’ is not quite the same as ‘identical’). In a way, if out of context it may be interpreted to signify something very much like ‘intended copy’. It is important therefore to remember what ‘similar’ and ‘same’ mean in the biological field. As discussed above, the extensive comparability exercise applied to validate (bio)similarity does not establish molecular identity, which in itself is virtually impossible to achieve with biologics, but similarity, which results in comparable clinical outcomes (see also controversy 4). In short, ‘similar’ is as good as it gets (for biologicals). The ‘similar but not the same’ phrase is also deceptive in a second way, inasmuch as it attaches the ‘same’ label to the originator. Although the reference biological product has a continuous track of production and clinical use, which builds its reputation as a product, it does not remain unaltered during its commercial life. In other words, there is arguably no ‘same’ for biologicals [26]. 7.2. Controversy 2: immunogenicity Any drug may be potentially recognized as foreign by the immune system and produce a significant response. This applies to both synthetic and biological drugs, but the latter are typically more prone to elicit an immune response due to their high molecular size, their parenteral route of administration and, in some cases, their featuring nonhuman sequences. Examples of small molecules with immunogenic responses include penicillin, metamizol, or sulfasalazine. The immunogenic response to biologicals generally involves the generation of anti-drug antibodies (ADA). These may be either neutralizing or non neutralizing, depending on their capacity to block the binding of the biological to its receptor. ADA are relevant to the clinical use of biologicals (either original or biosimilar) because they may potentially affect efficacy and/or safety. Efficacy may be compromised by accelerated elimination (which tends to happen with all ADA), or by impeding receptor binding (which is exclusive of neutralizing ADA) [27,28]. Safety may be limited by the development of anaphylactic or anaphylatic-like reactions [29]. It should be noted that there are wide differences in immunogenicity among biologicals. One well studied case of the consequences of ADA formation is that of infliximab, where the role of both ADA and serum drug levels (therapeutic drug monitoring) has been extensively studied in recent years [30–32]. In addition, when the biological is a replacement for an endogenous protein, such as erythropoetin or G-CSF (although filgrastim immunogenicity is extremely low, see Table 2), the development of ADA carries the added risk of causing a total suppression of both endogenous and exogenous protein by cross–reaction, causing potentially catastrophic effects. In this regard, pure red cell aplasia is a known risk of erythopoetin treatment, although its incidence is very low. Increased incidence was detected around 2001 with epoetin alpha (original), which was attributed to changes in the manufacturing process. The result was increased aggregation of the protein product, resulting in enhanced ADA formation [11,33]. Drug immunogenicity is a probability phenomenon, with well known risk factors which augment the chance that a given patient develops ADA. The risk factors have been classically classified as patient (age, idiosyncrasy), treatment (dosing, concurrent drugs) and drug related. Of note, the latter are not derived solely by the molecular structure of the biological, but also by characteristics that are largely independent of structure, such as the presence of aggregates or process derived substances (tungsten, cell proteins, endotoxin, etc.). Product conservation and reconstitution are also of importance in this regard. Because the biosimilar is destined to be used in the same patients and with the same treatment protocols as the original, any differences in immunogenicity vs. the original must arise from drug related factors. One key issue here is that, for a new biological drug, immunogenicity can be predicted (i.e. before clinical testing) only to a certain extent, and we 260 R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 depend on the clinical trials to know how the organism reacts to the drug. The same is not true of the biosimilar, because the well established immunogenicity profile of the original is expected to predict to a large extent that of the biosimilar, as mentioned above (Fig. 5). In other words, there is a logical correlate between the similarity both products and how the immune system reacts to them. Because the immune system may be stimulated by minute amounts of an immunogenic substance, and there may exist such slight modifications in the biosimilar compared with the original molecule, immunogenicity differences between the biosimilar and the reference drug cannot be excluded a priori. Thus the risk of immunogenicity is largely, albeit not completely, predicted by that of the original drug. The final answer is provided by the clinical evidence (including postmarketing pharmacovigilance). The monitoring of ADA development and ADA characterization are required in each step of biosimilar clinical testing, and samples should be kept for future assessment as well [34,35]. EMA establishes that the biosimilar cannot have increased immunogenicity (generally meaning higher ADA incidence) vs. the reference drug, but exceptionally it does allow the biosimilar to show a lower immunogenicity, this being the only major difference permitted for a biosimilar [34,36]. Because safety may theoretically be improved by a biosimilar with lower immunogenicity than the original, it is logical to consider whether such an advantage is accepted or not by the regulator. However, to the best of our knowledge, this point has not been contemplated to date. Lower immunogenicity is claimed to be facilitated (at least in theory) by the advances in manufacturing procedures and the state of the art from the time of approval of the reference drug. Nevertheless, this provision by the EMA has not materialized so far, as biosimilars generally show comparable rates of ADA+ patients than the respective reference drugs (Table 2), perhaps because technical advances are gradually incorporated to the manufacturing process over the years, or because the molecular structure carries more weight in this regard. One possible exception to this rule is the recently EMA- approved etanercept biosimilar, BENEPALI (SB4), which was found to have decreased immunogenicity compared to the original, ENBREL [37]. Namely, 0.7% vs. 13.1% (p < 0.001) of patients showed at least one positive sample during the 24 week study. This correlated with a lower presence of protein aggregates in SB4, which would be expected to lower the immune response [38]. Lower ADA incidence was also shown in a single dose pharmacokinetic study [39]. However, the Committee for Medicinal Products for Human Use (CHMP) assessment questioned the lower immunogenicity claim, based on a correlation between positive samples, most of which were obtained at week 4 and 8, and low drug levels, suggestive of possible drug interference issues. Drug interference occurs when the presence of drug (i.e. the biological) in the sample analyzed hampers the detection of ADA. This is a common problem, as most tests used to measure ADA require that they are in free solution i.e. not drug bound, since drug-ADA complexes go undetected. Drug interference may be prevented by separation of the complexes present in plasma in acid medium prior to analysis (acid dissociation). This was actually the approach followed in ADA analysis in this particular study, rendering drug interference less likely, at least in principle. However, when data from weeks 4 and 8 were excluded from analysis there were no differences in immunogenicity [39], and the CHMP concluded that due to low drug tolerance of the ADA assay, immunogenicity could not be established as being lower than the comparator. Several comments on this issue have been published [40–44], and the authors of the study have announced that they are reanalysing the samples with an improved method with better drug tolerance [41,45], but this remains an unsettled issue. At any rate, etanercept antibodies are not considered to affect safety or efficacy [39,46]. Similarly, AMGEVITA/SOLYMBIC also showed a tendency for lower immunogenicity compared to EU HUMIRA (Table 2). Another point worth considering is that, even though the biosimilar and the original have comparable immunogenicity, showing similar incidence of ADA, including neutralizing/not neutralizing types as well as antibody isotypes, it is generally unknown to what extent they recognize the same or different epitopes. For the reasons already explained, high ADA cross-reactivity is expected between originator and biosimilar, but it is quite possible that patients develop antibodies to different epitopes to some extent. The clinical significance of the development of such biosimilar-specific ADA is unknown. If, on the contrary, ADA developed in patients bind to both biologicals (100% cross-reactivity), the epitopes recognized are the same, and the probability that any ADA related effects may differ between the two drugs is minimized. Immune cross-reactivity with the original can be assessed during the in vitro characterization of the biosimilar by using a panel of murine monoclonal anti-drug antibodies recognizing various epitopes in the molecule (immunological fingerprint). This has been applied for instance to the infliximab biosimilar CT-P13 [47], with 34 antibodies directed against 24 epitopes showing comparable reactivity towards a number of batches of either REMICADE or the biosimilar (CT-P13). Comparable results have been obtained with infliximab FLIXABI (SB2) vs. REMICADE [48] or with IMRALDI vs. HUMIRA [49]. Cross-reactivity involving clinically developed ADA has also been studied with CT-P13 in three different papers [31,50,51]. In the first one, Ben-Horin et al. analyzed 86 samples of inflammatory bowel disease (IBD) patients treated with REMICADE, both ADA+ and ADA-, and 22 control samples obtained from anti-TNF naïve IBD, rheumatic and healthy patients [50]. REMICADE or CT-P13 (different batches) were captured with TNF and probed in parallel with patient serum, and the amount bound to either biological showed good correlation, regardless of batch, and with REMICADE interbatch correlation being comparable to that of REMICADE vs. CT-P13. In these analyses the authors found a higher background signal in the CT-P13 samples, but could not reach any conclusions as for the cause. This may represent some type of interference of CT-P13 with the plate, or be the result of minute differences in aggregate content. In a second study, Gils et al. took advantage of a panel of 55 (murine) monoclonal antibodies previously developed by this group to test reactivity to either REMICADE or CT-P13 as capture antibody in parallel, in an antibody fingerprint sort of analysis, finding close cross-reactivity [31]. This experiment was repeated using serum from a small cohort of IBD patients (36 samples from 22 patients), using one of the murine monoclonals, MA-IFX10F9, as calibrator, again showing excellent correlation. The third study analyzed 250 serum samples from rheumatoid arthritis patients, both ADA+ and ADA-, and 77 control samples from infliximab naïve rheumatic or healthy patients, using ADA determination kits developed for REMICADE (PROMONITOR, Progenika-Grifols), and the two CT-P13 brands, INFLECTRA (Hospira/Pzifer) and REMSIMA (Orion Pharma) [51]. The 3 kits are ELISA based, with infliximab used for both capture and detection. The results were correlated in pairs, showing excellent correlation in each case, and with no single discrepancy in sample labeling as ADA+ or ADA-. Of note, in neither of these two latter studies was there a difference in background signal found, suggesting that the finding of Ben-Horin et al. is probably of little significance [50]. 7.3. Controversy 3: extrapolation The approval of a biosimilar requires clinical data. It should be noted that, although considered an important integral part of the comparability exercise for biosimilars, clinical trials have a relatively minor role (due to low sensitivity to pick up differences) R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 compared to their paramount importance in the development and approval of new drugs (Fig. 4). When the reference biological drug has more than one indication, an important decision to be taken by the regulator is whether to demand a confirmatory clinical trial of efficacy/safety for the biosimilar for each separate indication, or to assume that the comparability exercise up to this point (i.e. featuring one clinical trial for one of the indications) is enough guarantee (i.e. extrapolation of indications) [1]. The first scenario may be viewed by some as more appropriate as it undoubtedly has a more extensive and directly relevant clinical evidence base. However, this approach ignores the essential fact that the biological being tested is not a new molecule, but rather the ‘same’ as the reference product (within the margin of change allowed, as discussed). Thus, if the biosimilar has already established to be similar to the original in the preclinical phase (which as we have shown is the most sensitive), plus one disease in a clinical trial, it is unlikely that it behaves differently in a second disease. In fact, for this latter possibility to happen, there must be some aspect of the drug that is not adequately covered by the comparability exercise. This is a remote but real possibility. Therefore EMA does not assume extrapolation of indications automatically. Rather, it is considered on a case-bycase basis. The rule is that extrapolation is contingent on a lack of substantial differences of the drug profile in the various disease indications, for instance in terms of pharmacokinetics, mechanism of action, immunogenicity, and so forth [35,52]. However, in many cases there may be differences, be it in the drug dose in different diseases, accompanying medications (including immunosuppresants, which affect immunogenicity), minor pharmacokinetic shifts, etc. Because of this and of the traditional pivotal role assigned to clinical trials in drug development there has been significant resistance to the extrapolation of indications in the health care professions [53], although it appears to be fading over time [54]. It should be noted that extrapolation is a sound scientific principle that is applied for instance when extending clinical trial findings to the population, adult trials to pediatric patients, etc. And, as noted above, to the in vitro findings in the comparability exercise dealing with prepost-change versions of a given biological to the clinical use. This issue was elegantly covered by Weise et al. [55]. Some general principles apply for the extrapolation of indications. Thus, for instance, if a biosimilar has been shown to have comparable immunogenicity to the original in an indication characterized by an intact immune system, this can be extrapolated to a second indication in which the immune response is depressed. This is because any possible differences in immunogenicity will be picked up more likely in the former case. For the same reason, extrapolation cannot be done in the opposite direction. For biological drugs that have more than one indication, the question arises as to which disease should be targeted in the pivotal clinical trial. The EMA establishes that a sensitive disease should be selected, i.e. that with a high probability to detect any existing difference between the drugs [56]. In practice however it may not be easy to pinpoint the disease, because there is not a single criterium in this regard. For instance, in the case of INFLECTRA/REMSIMA, rheumatoid arthritis was selected for the phase III trial, but it has been claimed that infliximab has a relatively low efficacy vs. placebo effect in this indication [57]. Mechanistically, because of the intricacies of incomplete knowledge of the mode of action of anti-TNF drugs in inflammatory bowel disease compared with rheumatic diseases, Crohn’s disease might have been a better choice. Indeed, this very fact underlied a great deal of the criticism over extrapolation of indications in this case, because not all anti-TNF drugs work in inflammatory bowel disease, whereas arthritic conditions appear to be more uniformly responsive [53,58]. 261 7.4. Controversy 4: substitution and interchangeability As a rule, generic medicines can be dispensed instead of the prescribed reference products (or instead of a second generic, for that matter) without the consentment or knowledge of the prescribing physician, a procedure known as substitution. When this happens on a systematic basis, automatic substitution is in place. In both instances the assumption is that the effects, beneficial or harmful, of the generic and original medicine products are identical, and in effect the two products can be used interchangeably, at any order and in any patient. It should be noted however that equivalence is established at a poblational rather than individual level, i.e. there is no strict guarantee that the response may differ in a particular patient, even though this is relatively unlikely. Substitution is generally not allowed for biosimilars, because of the uncertainties mentioned in the preceding sections (it should be noted that it is also generally not allowed for any biological). Thus the legal capacity to decide on biological treatment lies with the prescriber. Substitution should not be confused with interchangeability, which may be defined as the legal and/or scientific capacity to use biosimilars instead of the reference biological to treat a given patient, expecting to achieve the same clinical effect. Interchange may take place at different levels. One is the start of a biological in a naïve patient, possibly the least contended. Another is the practice of starting a biosimilar in a patient previously treated with the reference biological, commonly known as switching, although this is not an official denomination. It also applies to a change from one biosimilar to another (of the same original biological product), or from a biosimilar to the reference medicine. Biosimilar switching may take place in patients treated intermittently with the biological (erythropoyetin, G-CSF) or chronically (infliximab, rituximab). As noted, switching requires the prescribing physician’s aquiescence, so that in fact it implies a change in the prescription itself. The question is therefore to what extent biosimilars are interchangeable. In this regard, full interchangeability would correspond to a situation in which the biosimilar can be used at any given time and in any patient, as an alternative to the reference biological (or another biosimilar). Not surprisingly, switching involving chronically treated patients is the most controversial modality. The two main reservations are: one, that differences in efficacy/toxicity, however minor, may impact unfavorably; two, that the change may precipitate an immunogenic reaction (commented above). The EMA has abstained from issuing recommendations on interchangeability, leaving this issue to national authorities/agencies, while establishing that biosimilar and reference biological are of comparable quality, efficacy and safety. WHO guidelines have the same viewpoint. This prudent position has created a certain void, as it tends to fuel uncertainties about the use of biosimilars (i.e. if they are comparable, why are they not interchangeable?). The very definition of biosimilarity negates the possibility that efficacy or toxicity may differ significantly from that of the reference drug. At the same time, since the biosimilar is a new drug, it is justified to handle it accordingly. The possibility of immunogenicity issues is real but not particularly likely, and it has not been substantiated so far. The FDA has instead defined a double category, i.e. interchangeable and non-interchangeable biosimilars, the former constituted by those which ‘can be expected to produce the same clinical result as the reference product in any given patient’ and if ‘administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation 262 R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 or switch’ [59]. In order for the biosimilar to be labelled as interchangeable, the sponsor must carry out switching studies between the reference biological and the biosimilar, according to productspecific details, unless it is intended to be used only once in a given patient [60]. As a result, section 351(i) of the US Public Health Service Act allows for interchangeable biosimilars to be substituted for their reference product at the pharmacy level. There are also state-specific regulations on this matter. It is likely that the doubts cast on the interchangeability of biosimilars are cleared to a great extent in the next few years, as experience and data accumulate. Even so, it should be noted that, from a pharmacovigilance standpoint, switching between same active substance brands poses an objective difficulty in locating the source of possible adverse effects, specially long term, where the time connection is specially tenuous. Thus the extent to which interchangeability is facilitated in the future will probably depend on the identification of a suitable threshold of patientmonths/years that guarantee an appropriate assessment of such differences. Adding to the confusion, whenever there are US and EU versions of the same biological reference product, they are generally considered separately for the purposes of analysis as applied to the comparability exercise. Similarly, the FDA draft for interchangeability establishes that the US biological of reference ought to be used for switching studies, thus considering the EU version as a separate product [60]. This approach would by logic take us to separate international nonproprietary names (INNs) for the different international versions of the same biological product produced by the same manufacturer (more on nomenclature in the next section). The interchangeability of biosimilars has been recently covered very nicely by Kurki et al. [61]. 7.5. Controversy 5: nomenclature As the EMA defines a biosimilar as a version of a biological product of reference, it accordingly establishes that the drug name (INN) is the same as that in the original (i.e. filgrastim, infliximab, rituximab, and so forth). This straightforward approach has been contested by some regulatory agencies. For instance, the FDA has not totally decided on the naming policy but currently uses the same drug name but adding a suffix indicating the drug maker for some (filgastrim-sndz ZARXIO, infliximab-dyyb INFLECTRA, infliximab-abda RENFLEXIS, etanercept-szzs ERELZI, adalimumab-atto AMJEVITA), but not all biosimilars (insulin glargine BASAGLAR). Although this practice is not said to be meant to denote a difference, it may be argued that this is exactly the message it transmits. The Australian agency, Therapeutic Goods Administration, currently applies a naming system using the tradename together with the INN (for instance ‘SANDOZ filgrastim’), to ultimately adjust to the new WHO system, and previously contemplated using the reference drug INN followed by a second word composed by sim- plus the then-standard 3 letter WHO suffix (for instance, filgrastim simsdz −imaginary name–) [62]. The Japanese agency uses the INN plus a modifier in the form (genetical recombination) [INN Biosimilar x], where x designates the different biosimilar available by order of approval. Nonglycosylated proteins can however receive the same INN as the reference biological [63]. Health Canada has still to decide on a definitive naming system, and in the interim has established that biosimilars are identified by brand name, common (non-proprietary) name and Drug Identification Number (DIN) [5]. The WHO hosted an early discussion conference and issued a document considering this subject, with fairly discrepant views [64]. More recently, it issued a new document on INN for biosimilars [65], in which a random four letter suffix to the regular biological INN, known as the biological qualifier, is proposed (with an additional optional two digits as a checksum). This is considered for use on a voluntary basis, but stemming from regulations by the FDA and also the regulatory agencies in Australia and Japan just commented. The WHO justification for introducing the INN suffix is arguably somewhat inconsistent. Based on the assignment of Greek letter suffixes to the INN of some protein drug products due to postranslational differences (as in epoetin ␣/ or interferon ␣ 2a/2b), started in 1991, it argues that the INN single word system does not suffice for naming of biologicals. Consistent with this principle, the biological qualifier has not been applied to nonglycosylated proteins. However, the biological qualifier is designed to ‘uniquely identify the active substance in a biological product distributed by a marketing authorization holder’. That is, it really has to do with the manufacturer rather than the glycosylation or other postranslational modifications worthy of naming. What are the advantages of using different nonpropietary names for the biosimilars and their reference drugs? The justification for the naming systems alternative to that followed by EMA lies mainly in traceability and avoiding naming confusion. Arguably, traceability may improve to some extent by using different nonproprietary names, however it is difficult to see how much it can add to the already (widely) different trade name [66,67]. Further, batch number is just as important and there is no impact of this denomination system at this level. Whether traceability is actually improved remains to be established. However, it would seem that any system in which the trade name and batch number may be missed for tracking purposes would similarly fail to record an additional bit of information in the shape of a longer nonproprietary name. In turn, the use of different, biosimilar specific nonproprietary names suggests that the drugs are actually different, which is exactly what the biosimilar approach tries to avoid. Traceability issues notwithstanding, it is currently unclear what the boundaries of biologicals are for the sake of naming conventions. In other words, how different must two biological drugs be to receive distinct INNs? Of note, specific naming may make more sense when considering different degrees of similarity, as contemplated by the FDA, but this remains to be established [68]. This issue dovetails with that of interchangeability (see previous section). Hence there is at present no universal INN system for biosimilars, with the WHO biological qualifier and the simplified versions coexisting at this time in their respective areas. This will probably remain being the case for the near future. 8. Biological drift One caveat of the biosimilar/comparability approach is that, since each version is compared with the preceding one, even though there may be no substantial change pairwise, modifications might potentially build over time. This is similar to the classic classroom exercise where one student is asked to pass a certain message to the next student, this apparently goes smoothly but with sufficient students participating minute alterations accumulate, distorting the original version. This is an acknowledged potential problem with all biologicals, successfully mitigated by strict control of quality parameters and use of standards whenever possible [69]. It additionally pertains biosimilars because they are validated via a comprehensive comparability exercise using a number of different batches of both original and biosimilar products, but only at a particular time. Thus there is not only the possible drift of the original (and the biosimilar) over time, but also the possibility that the respective drifts take them apart [18]. 9. Knowledge about biosimilars Knowledge of biosimilars has increased substantially in the last few years, based on the evolution of position papers by med- R. Gámez-Belmonte et al. / Pharmacological Research 133 (2018) 251–264 ical societies and surveys in the medical profession. As a case in point, the European Crohn’s and Colitis Organisation (ECCO) issued a position statement in 2013 [53] which expressed early concerns about the use of biosimilars, particularly with regard to extrapolation of indications of the infliximab biosimilar CTP13 (INFLECTRA/REMSIMA), which was tested clinically only in rheumatoid arthritis and ankylosing spondylitis. This was actually answered by EMA [70], with a comment by ECCO representatives [71] which showed substantial agreement but questioned the adequacy of the ±15% margin for efficacy of an IBD drug. ECCO issued an updated version of its position paper in 2017 [54] which largely accepted extrapolation and showed agreement with the EMA viewpoint. These changes parallel the increased knowledge among ECCO members as judged from surveys taken in 2013 and 2015 [72,73]. For instance, concern about immunogenicity was expressed by 67% of responders in 2013 but only 27.1% in 2015, and confidence in biosimilars was substantially higher in the latter. In addition, clinical evidence was already accumulating regarding the INFLECTRA/REMSIMA during the interim period, which probably was also reassuring to the participants in the survey (it should be noted that no clinical trial has been performed so far) [74,75]. 10. Economic considerations Biosimilars are developed for the exact same reasons than generics, i.e. to earn a profit by competing with the original drug at a reduced price. The stress in this process is to produce a biological drug that is comparable to the original in every aspect, with the only exception of immunogenicity which, as noted, may be lower for the biosimilar, although this is exceptional to date. Thus the biosimilar is designed to ‘inherit’ all the characteristics of the originator, good and bad. In short, cost, and thereby price, is the only advantage of biosimilars (save for those with attenuated immunogenicity). Biosimilars have resulted in smaller cuts in pharmaceutical expenses compared with generics, allegedly because of the inherently higher costs of biological production. Savings have been higher in countries with more comprehensive plans [76,77]. As biosimilars are introduced in clinical practice, the originators tend to lower their price to match the competition, much in the same way as with generic medicines. Both generics and biosimilars may be at a disadvantage if the reference medicines successfully compete with them by an aggressive pricing strategy, given that in these conditions the original may be preferred in many cases. This is a well known economic scenario, which normally is equilibrated by the existence of small barriers to enter the market (considering pharmaceutical environment as a market, which is debatable in itself). Thus, an original drug manufacturer may outsell the generic/biosimilar competitor, and then increase prices again, but another player may enter the competition if the barriers are not too high. In this regard, the barriers are higher for a biosimilar than a generic maker, because the costs of development are also greater [77]. 11. Conclusions Biosimilars offer a great opportunity to improve health care by lowering pharmaceutical expenses, but this has not been taken advantage of as expected. This lackluster performance may be attributed in part to existing uncertainties, such as those related to immunogenicity and interchangeability, which are expected to be solved gradually as evidence and experience accumulate. 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