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-
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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
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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. The
gaps in the knowledge of biosimilars in the biomedical community
and in patients are an obstacle to the adoption of these useful drugs.
263
Funding sources
This work was funded by the Ministerio de Economía y Competitividad (BFU2014-57736-P, AGL2014-58883-R), Junta de Andalucía
(CTS164, CTS235). RGB, CHC, MAA and CJA are funded by Ministery
of Education. CHC and CJA were additionally funded by the Contrato Puente program of the University of Granada (Plan Propio).
CIBERehd is funded by the Instituto de Salud Carlos III.
Conflict of interest
FSM and OMA have received lecture fees and/or research support from Hospira, Pfizer, Sanofi, Biosearch Life, Bioiberica, Amino
Up Chemical, APC Europe, various scientific societies, and the Spanish Generics Association.
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