Biosimilars in the EU

Information guide for healthcare professionals

Prepared jointly by the European Medicines Agency
and the European Commission

Table of contents
Foreword

2

Summary3

Biological medicines: overview

5

Key features of biological medicines

5

Biosimilar medicines: definition and features

8

Why biosimilars are not considered generic medicines

10

Development and approval of biosimilars in the EU

12

A robust regulatory framework for biosimilars

12

Process for approval of biosimilars in the EU

12

Data requirements for approval: a scientifically tailored package

12

Immunogenicity

20

Extrapolation

22

Safety of biosimilars

24

General considerations on safety for biosimilars

24

Safety monitoring for all biological medicines, including biosimilars

24

Traceability: importance of identifying biological medicines by tradename and batch number

25

How healthcare professionals can help improve pharmacovigilance for biological medicines:

26

Data included in the prescribing information and EMA assessment reports for biosimilars

27

Data for prescribing: summary of product characteristics (SmPC)

27

Data on biosimilarity: published in the assessment report

27

Implications of the availability of biosimilars

28Interchangeability, switching and substitution: EMA and Member States’ responsibilities

29

Definitions

29

EMA and Member States’ responsibilities

29

Communicating with patients on biosimilars

30

EU contribution to the regulation of biosimilars worldwide

31

References32

Abbreviations

33

Glossary34

Forewordby Prof. Guido Rasi
EMA Executive Director

Biological medicines, often produced by cuttingedge biotechnology, have transformed the outlook
for patients with many chronic and often disabling
conditions. An increasing number of biological
medicines are ‘biosimilars’ - medicines highly similar in
all essential aspects to an already approved biological
medicine.
The EU has pioneered the regulation of biosimilar
medicines by establishing a solid framework for theirapproval and by shaping biosimilar development
globally. Since the EU approved the first biosimilar in
2006, healthcare professionals have gained increasing
experience with their use. Today, biosimilars are
an integral part of the effective biological therapies
available in the EU, supported by adequate safeguards
protecting patient safety.
As healthcare professionals are at the forefront ofpatients’ care, it is vital that they have access toreliable information on these medicines: what they
are and what scientific principles support their clinicaldevelopment, approval and safety monitoring. This
guide has therefore been prepared with the important
objective of providing healthcare professionals
with reference information on both the science andregulation underpinning the use of biosimilars.

Contributors
This guide has been prepared by the European
Medicines Agency in collaboration with the European
Commission and scientific experts from EU Member
States.
Information needs and feedback from EU healthcare
professionals’ organisations have been sought
throughout the preparation of this document.

2

Summary Since the EU approved the first biosimilar medicine (‘biosimilar’) in 2006, the EU has pioneered
the regulation of biosimilars. Over the past 10 years, the EU has approved the highest numberof biosimilars worldwide, amassing considerable experience of their use and safety.

 The evidence acquired over 10 years of clinical experience shows that biosimilars approved through
EMA can be used as safely and effectively in all their approved indications as other biological
medicines.

 A biosimilar is a biological medicine highly similar to another biological medicine already approvedin the EU (the so-called ‘reference medicine’).

 Because biosimilars are made in living organisms there may be some minor differences from thereference medicine. These minor differences are not clinically meaningful, i.e. no differences are
expected in safety and efficacy. Natural variability is inherent to all biological medicines and strict
controls are always in place to ensure that it does not affect the way the medicine works or its safety.

 Biosimilars are approved according to the same standards of pharmaceutical quality, safety andefficacy that apply to all biological medicines approved in the EU.

 The aim of biosimilar development is to demonstrate biosimilarity - high similarity in terms ofstructure, biological activity and efficacy, safety and immunogenicity profile.

 By demonstrating biosimilarity, a biosimilar can rely on the safety and efficacy experience gained withthe reference medicine. This avoids unnecessary repetition of clinical trials already carried out withthe reference medicine.

 Demonstration of biosimilarity relies on comprehensive comparability studies with the reference
medicine.

 If a biosimilar is highly similar to a reference medicine, and has comparable safety and efficacy in
one therapeutic indication, safety and efficacy data may be extrapolated to other indications alreadyapproved for the reference medicine. Extrapolation needs to be supported by all the scientificevidence generated in comparability studies (quality, non-clinical and clinical).

 Extrapolation is not a new concept but a well-established scientific principle used routinely when
biological medicines with several approved indications undergo major changes to their manufacturing
process (e.g. to introduce a new formulation). In most of these cases, clinical trials are not repeated for
all indications and changes are approved based on quality and in vitro comparability studies.

 All indications of biological medicines (including biosimilars) have been granted based on soundscientific evidence.

 Safety of biosimilars is monitored through pharmacovigilance activities, in the same way as for any
other medicine. There is no specific safety requirement applicable only to biosimilars because of theirdifferent development route.

3 Over the last 10 years, the EU monitoring system for safety concerns has not identified any relevant
difference in the nature, severity or frequency of adverse effects between biosimilars and theirreference medicines.

 Biosimilar competition can offer advantages to EU healthcare systems, as it is expected to improve
patients’ access to safe and effective biological medicines with proven quality.

 EMA does not regulate interchangeability, switching and substitution of a reference medicine
by its biosimilar. These fall within the remit of EU Member States.

4

Biological medicines: overview
Biological medicines (‘biologicals’) contain active

cell systems and recombinant DNA technology.

substances from a biological source, such as

The EU legislation imposes strict requirements forliving cells or organisms. Biological medicines are

the manufacture of all medicines:

well established in clinical practice and in manycases they are indispensable for the treatment

 EU manufacturers must hold a manufacturer’sof serious and chronic conditions such as diabetes,

license and are legally obliged to comply with

autoimmune diseases and cancers.

Good Manufacturing Practice (GMP), the agreed
standards to obtain a medicine with proven

Key features of biological medicines

quality.

 National regulatory authorities in the EU

Most biological medicines in current clinical use

regularly inspect manufacturing sites forcontain active substances made of proteins. These

compliance with GMP requirements.

can differ in size and structural complexity, from
simple proteins like insulin or growth hormone to If some manufacturing steps take place outside

more complex ones such as coagulation factors or

the EU, then non-EU manufacturers, importers

monoclonal antibodies (figure 1).

and wholesale distributors are obliged to follow
the same strict requirements and are also
regularly inspected.

Biomanufacturing strictly regulated
For biological medicines, some of the GMP
The manufacture of biological medicines tends

requirements have been adapted to taketo be more complex than for chemically-derived

into account their specific nature (e.g. use ofmolecules. Most biological medicines are madeappropriate aseptic techniques, refrigeration andby biotechnology, often using sophisticatedother storage conditions, stability, transport etc.).

Figure 1. Examples of types of proteins in biological medicines approved in the EU

Insulin
5,808 daltons

Growth hormone
22,000 daltons

Monoclonal antibody
150,000 daltons

5Large molecular structure(‘microheterogeneity’). This minor variability must
fall within the acceptable range to ensure consistentCompared with small chemical substances,safety and efficacy. This is done by adjusting thebiological medicines consist of large and often

manufacturing process to guarantee that the active

complex molecular structures. Sophisticatedsubstance fits into the desired specifications range.

analytical methods (e.g. peptide mapping, mass
spectrometry and assays in cells) are used to study

This degree of minor variability can be present

their physicochemical and functional properties suchwithin or between batches of the same

as molecular structure, protein modifications andbiological medicine (figure 2), particularly when

biological activity.

manufacturing processes are modified during thecommercial life of the medicine (e.g. increasing
production scale). Strict controls are always applied

Inherent degree of variability

to ensure that, despite this variability, there isbatch-to-batch consistency and that the differences

Biological medicines are made by living organisms,

do not affect safety or efficacy. In practice,which are naturally variable. Thus, the active

variability (within a batch or batch-to-batch) is very

substance in the final biological medicine canlow when using the same manufacturing process.

have an inherent degree of minor variability

Figure 2. Example of variability between different batches of a biological medicine
Consecutive batches of the same biological medicine may show a small degree of variability (yellow
shadow) within the accepted ranges, for example in glycosylation (sugar molecules attached to theprotein, which are represented by small blue triangles). The amino acid sequence (represented bycircles) and biological activity of the protein remain the same in all batches, even when these minor
differences in sugar chains are present.

Batch 1

6

Batch 2Batch 3

Strict control of the quality of biological
medicines
The quality of all medicines (biological and nonbiological) approved in the EU is rigorously proven.
For biological medicines, this includes studying

Natural variability is inherent toall biological medicines and strict
controls are always in place during
manufacturing to ensure that it does
not affect the way the medicine
works or its safety.

their specific physicochemical properties, biologicalactivity, purity, sterility and stability to ensure that
all the required standards are met before batches
are released for marketing.

Potential immunogenicity
The immune system has the ability to recognise
foreign proteins and react against them. Biological
medicines usually cause no or only a limited
immune response (e.g. transient appearance ofantibodies). Adverse reactions of an immune nature(e.g. infusion-related reactions or injection-site
reactions) are normally not severe. Rarely, however,
an immune reaction against a biological medicine
could be serious and life-threatening.
Also, antibodies directed against the biological
medicine (‘anti-drug antibodies’ or ADAs) could
neutralise the medicine’s activity and reduce its
efficacy. Thus, potential immunogenicity needs
to be always evaluated for all biological medicines.

7Biosimilar medicines: definition and features
A biosimilar medicine (‘biosimilar’) is a medicine

Due to the natural variability of the biologicalhighly similar to another biological medicine alreadysource and to the manufacturing process uniquemarketed in the EU (the so-called ‘reference

to each manufacturer, minor differences can occur

medicine’)

between the biosimilar and its reference medicine

1, 2. Companies can market approved

biosimilars once the period of market protection of(table 1 and figure 3). Strict controls are always in

the reference medicine expires (after 10 years).

place during manufacturing to ensure that minor
differences do not affect the way the medicine

Since biosimilars are a type of biological medicine,works or its safety. Thus, these differences are not

all features pertinent to biological medicines apply.

clinically meaningful in terms of safety or efficacy.

Table 1. Specific features of biosimilar medicines
Highly similar to the

The biosimilar has physical, chemical and biological properties highly similarreference medicine

to the reference medicine’s. There may be minor differences from thereference medicine which are not clinically meaningful in terms of safety or
efficacy.

No clinically

No differences are expected in clinical performance. Clinical studies thatmeaningful differences

support the approval of a biosimilar confirm that any differences will notcompared with thehave an effect on safety and efficacy.

reference medicine
Variability of

Minor variability is only allowed when scientific evidence shows that it does

biosimilar kept within

not affect the safety and efficacy of the biosimilar. The range of variability

strict limits

allowed for a biosimilar is the same as that allowed between batches of thereference medicine. This is achieved with a robust manufacturing process toensure that all batches of the medicine are of proven quality.

Same strict standards

Biosimilars are approved according to the same strict standards of quality,of quality, safety

safety and efficacy that apply to any other medicine.

and efficacy

When the active substance is a protein, both the

be allowed if they have no effect on safety andbiosimilar and the reference medicine must containefficacy - for example differences in the formulation

the same protein (i.e. amino acid sequence) and theof the medicine (e.g. excipients), presentation (e.g.

same ‘3D’ structure (folding of the protein). Amino

powder to be reconstituted versus solution readyacid sequence and folding are the main factors thatfor injection) and administration device (e.g. type ofdetermine biological activity, which must be thedelivery pen).

same for the biosimilar and the reference medicine.
To date, the great majority of biosimilars approved in
For the finished medicine, both biosimilar andthe EU contain proteins as active substances. Tablereference medicine must have the same posology

2 lists the classes of biological medicines for which

and route of administration. Some differences may

biosimilars have been approved in the EU.

8

Figure 3. Example of variability between a biosimilar and the reference medicine
Variability (yellow shadow) between a biosimilar and the reference medicine is comparable to what
may occur between different batches of the same biological medicine (figure 2). Minor variability, e.g.
in glycosylation (represented by small blue triangles) may be allowed, while the protein’s amino acidsequence (circles) and biological activity are the same.

Reference medicine

Biosimilar medicine

Table 2. Classes of biological medicines for which a biosimilar is currently approved in the EU
Classes of biological medicines

Biosimilar approved in the EU(as at October 2019)

Polysaccharides
Low-molecular weight heparins Enoxaparin sodium

Proteins
Growth factors

 Epoetin Filgrastim
 Pegfilgrastim

Hormones

 Follitropin alfa
 Insulin glargine
 Somatropin (growth hormone) Teriparatide Insulin lispro

Fusion proteins Etanercept

9Classes of biological medicines

Biosimilar approved in the EU (as at October
2019)

Proteins
Monoclonal antibodies

 Adalimumab Infliximab
 Rituximab
 Bevacizumab Trastuzumab

Why biosimilars are not considered generic
medicines
A biosimilar is not regarded as a generic of aConsequently, more studies are needed forbiological medicine. This is mostly because theregulatory approval of biosimilars than for generics

natural variability and more complex manufacturing

to ensure that minor differences do not affect safetyof biological medicines do not allow an exact

or efficacy. Table 3 compares development andreplication of the molecular microheterogeneity.

characteristics of generics and biosimilars.

Table 3. Comparison of development and characteristics between generics and biosimilars
Generic medicine

Biosimilar medicine

Usually produced by chemical synthesis

Obtained from a biological source

Generally possible to obtain exactly the same

Possible to reproduce the molecule to amoleculehigh degree of similarity due to uniquebiomanufacturing methods and natural biologicalvariability

Mostly smaller molecules, easier to characterise

In general, larger, structurally more complex
molecules, which require multiple technologies fortheir characterisation

Full data requirements on pharmaceutical quality

Full data requirements on pharmaceutical quality,
plus additional quality studies comparing thestructure and biological activity of the biosimilar
with the reference medicine

10Development based on demonstration of

Development based on demonstration of

bioequivalence (i.e. that the generic and thebiosimilarity using comparability studies

reference medicine release the active substance(comprehensive head-to-head comparison of theinto the body at the same rate and to the samebiosimilar with the reference medicine to show

extent under similar conditions)high similarity in chemical structure, biological
function, efficacy, safety and immunogenicity)

Generic medicine

Biosimilar medicine

Clinical data requirements are mainly

In addition to comparative pharmacokinetic andpharmacokinetic bioequivalence studies

pharmacodynamic studies, safety and efficacy
data may be required, particularly for more
complex biological medicines

All indications approved for the reference

Efficacy and safety have to be justified in each

medicine can be granted based on demonstrated

indication. However, confirmatory clinical trials

bioequivalence, without the need for further

with the biosimilar are usually not needed inclinical data

every indication that has been approved forthe reference medicine. After demonstrationof biosimilarity, extrapolation of data to otherindications is possible if the scientific evidence
available addresses all specific aspects of these
indications

11

Development and approval of biosimilars in the EU
A robust regulatory framework
for biosimilars

When a company applies for marketing
authorisation at EMA, data are evaluated by EMA’s
scientific committees on human medicines andApproval of medicines in the EU relies on a solidon safety (the CHMP and PRAC), as well as by EU

legal framework, which in 2004 introduced aexperts on biological medicines (Biologics Working

dedicated route for the approval of biosimilars.

Party) and specialists in biosimilars (Biosimilar

The EU has pioneered the regulation of biosimilars

Working Party).

since the approval of the first one (the growth
hormone somatropin) in 2006. Since then, the EU

The review by EMA results in a scientific opinion,

has approved the highest number of biosimilars

which is then sent to the European Commission,

worldwide, and consequently has the mostwhich ultimately grants an EU-wide marketing

extensive experience of their use and safety.

authorisation.

Over the years, EMA has issued scientific guidelines
to help developers conform to the strict regulatory
requirements for approving biosimilars. The

Data requirements for approval:a scientifically tailored package

guidelines have evolved to keep pace with rapid
advances in biotechnology and analytical sciences,

Medicines are approved when studies on theirand they take on board increasing experience ofpharmaceutical quality, safety and efficacy

clinical use.

convincingly demonstrate that the medicine’s
benefits outweigh the risks (‘positive benefit-risk

The expertise acquired over the last
10 years has enabled EU regulators
to integrate experience-basedknowledge with the initial sciencedriven concept. This has helped
to shape current requirements forapproval.

balance’). For any biological medicine with a newactive substance, a positive benefit-risk balanceis determined mainly from evidence of safety
and efficacy in pivotal trials in humans (figure 4),
supported by solid pharmaceutical quality data andnon-clinical data.
For biosimilars, a positive benefit-risk balanceis based on demonstrating biosimilarity, i.e.

Process for approval of biosimilars
in the EU

that the active substance is highly similar to thereference medicine (figure 4). This is achieved
via comprehensive comparability studies with thereference medicine (figure 5), and on the basis of

All medicines produced using biotechnology andsolid pharmaceutical quality data. By demonstrating

those for specific indications (e.g. for cancer,

high similarity with the reference medicine, theneurodegeneration and auto-immune diseases)

biosimilar can largely rely on the efficacy and safety

must be approved in the EU through EMA (viaexperience gained with the reference medicine.

the so-called ‘centralised procedure’). Nearly all
biosimilars approved for use in the EU have been

An overview of biosimilar development comparedapproved centrally, as they use biotechnology forwith the development of reference medicines istheir production. Some biosimilars may be approved

provided in table 4.

at national level, such as some low-molecularweight heparins derived from porcine intestinal
mucosa.

12

Figure 4. Comparison of data requirements for approval of a biosimilar versus the reference medicine

Risk management plan

Risk management plan

Clinical studies
 Safety and efficacy
 PK/PD Immunogenicity

Comparative clinical studies
 Safety and efficacy
 PK/PD Immunogenicity
Comparative
non-clinical studies

Non-clinical studies

Comparative quality studies

Pharmaceuticalquality studies

Pharmaceuticalquality studies
Reference medicine

Biosimilar medicine

The non-clinical and clinical dataneeded to approve a biosimilar are
different from those needed for abiological medicine with a new active
substance.
This is because, by demonstratingbiosimilarity, the biosimilar relies on
the safety and efficacy experience
gained with the reference medicine.

13

Table 4. Overview of biosimilar development compared with a reference medicine
Biological medicine with new active

Biosimilar medicine

substance (e.g. reference medicine)
No previous knowledge of safety and efficacy

Builds on knowledge of safety and efficacy fromyears of clinical use with reference medicine

Development aims at demonstrating safety andDevelopment aims at demonstrating comparable

efficacy directly in patientssafety and efficacy by establishing biosimilarity

Comparability studies only for manufacturing

Comprehensive comparability studies with thechanges during development (e.g. producing

reference medicine

larger batches for clinical trials)
Full non-clinical data (pharmacology andAmount of non-clinical data determined by the

toxicology)

outcome of quality studies

Conventional clinical trials to demonstrate efficacy

Comparative clinical trials to exclude clinicallyand safety in all claimed therapeutic indications

meaningful differences

Trials designed mainly to compare with placebo

Trials designed mainly to show clinical equivalenceor current standard of therapy using ‘hard’with the reference medicine using sensitive

endpoints (e.g. long-term outcome, mortality,

endpoints in a population where product-related

structural damage) and a relevant patient

differences in clinical performance can be detected

population to demonstrate benefit
Positive benefit-risk mainly established on the

Positive benefit-risk based on demonstratingbasis of safety and efficacy studies in the intended

biosimilarity (using comparability studies)

population

14

1Same pharmaceutical quality standards forstudies (step 1) is used to determine the extent

all medicines

and type of non-clinical (step 2) and clinical studies

2(step 3) required in the next step of development,
Companies developing medicines in the EU,

always with the aim of ruling out differences inincluding biosimilars, must demonstrate withclinical performance between the biosimilar and thea large body of data that the medicine isreference medicine.

manufactured to agreed standards and that it issuitable for its intended clinical use (what is known
as ‘pharmaceutical quality’).
The studies to prove pharmaceutical quality should
provide detailed data on:

 structural characterisation and other

Comparability is a well-establishedscientific principle of regulatory
science: comprehensive comparative
quality studies prove thatphysicochemical properties andbiological activity are highly similar.

physicochemical properties

 purity (traces of residues from the
manufacturing process have to be controlled
and must not exceed acceptable levels)

 biological activity

Comparative clinical and non-clinicalstudies that support the approvalof a biosimilar rule out differences
which may affect the medicine’s
safety and efficacy.

 excipients and starting materials
 strength and formulation
 the control of the manufacturing process (toensure that the active substance and finishedproduct conform with the accepted ranges fortechnical specifications) stability of the active substance and finishedproduct during shelf-life under defined storage
conditions

Comparability studies: the cornerstoneof biosimilar development
Biosimilar development relies heavily on‘comparability studies’ to establish biosimilarity
to the reference medicine. This involves acomprehensive head-to-head comparison of thebiosimilar and the reference medicine (figure 5).
Comparability is conceived as a step-wise processthat is tailor-made for each product (figure 5);knowledge from the initial quality comparability

15

Step 1 Comparative quality studies

inhibition) of physiological targets and immediate
physiological effects in cells. Pharmacodynamic

In vitro studies compare the protein structurestudies in vivo (animal models) are only done if noand biological function using sensitive techniquessuitable in vitro model exists. In vivo toxicologicalcapable of detecting minor differences with clinicalstudies are only required in certain cases, forrelevance between the biosimilar and its reference

example when the biosimilar is produced in a new

medicine. These studies are much more sensitive

type of cell or organism, or when the formulation

than clinical trials for detecting such differences,includes new excipients not used previously.

as there is often variability among human subjects
participating in trials. Differences that may affectclinical safety, efficacy or immunogenicity need to

Step 3 Comparative clinical studies

be further studied (e.g. in comparative non-clinicalor clinical studies, step 2 and 3).

The aim of studies in humans is not to demonstratesafety and efficacy in patients, as these havealready been established for the reference

Step 2 Comparative non-clinical studies

medicine. Clinical trials are tailored to confirm
biosimilarity and to address any questions that

These studies include pharmacodynamic studies

may remain from previous analytical or functionalin vitro, which look at binding and activation (orstudies.

Step 1

Step 2

Step 3Figure 5. Biosimilar development is comparative and progresses in a step-wise manner

Reference medicine

16

Comparative clinical studies
 Pharmacokinetic/pharmacodynamic
 Efficacy + safety + immunogenicity

Comparative non-clinical studies
 Pharmacodynamic
 Toxicology

Comparative quality studies
 Analytical: physical + chemical properties
 Functional: biological/pharmacological activity

Biosimilar medicine

Approval of biosimilars builds on
existing scientific knowledge on
safety and efficacy of the reference
medicine gained during its clinicaluse, so fewer clinical data areneeded.

used for decades in the manufacture of medicines
3, 4, 5made by biotechnology. Companies producing

biological medicines are likely to adapt or improvethe manufacturing process several times during
the commercial life of a product (e.g. by increasing
production scale). Comparing batches before andafter a manufacturing change ensures consistency,

From a scientific and regulatory pointof view, the reference medicine’s
entire clinical development
programme does not need to berepeated. This means that patientsand healthy volunteers will not be
subjected to unnecessary clinical
trials.

so that there are no changes in safety or efficacy.
A change to the manufacturing process must
always be approved by regulators. The extent
of the comparability studies required following a
manufacturing change to a biological medicine will
depend on the expected impact on quality, safety
and efficacy of the medicine. Most often, analyticaland functional data are sufficient, and clinical trials
to prove safety and efficacy are not needed (table5, scenario 1 and 2). Clinical trials are needed only

Comparability: a scientific principle routinely

if an impact on safety and efficacy is anticipatedused after manufacturing changes to(scenario 3).

medicines on the market
Comparability is not a new regulatory concept, buta well-established scientific principle that has been

Table 5. Comparability studies needed following changes to the manufacturing process of a medicine
produced by biotechnology
Type of manufacturing

Expected impact

changeComparability studies
needed

1. Minor change (e.g. adding

Does not affect theLimited physicochemical studies

a more sensitive test method

pharmaceutical quality of thecomparing batches before andto characterise the active

medicine (no impact on productafter the change

substance)

specifications)

2. Significant change (e.g.

May affect productComprehensive physicochemicalchanges to the cell system usedcharacteristics or specifications

and functional in vitro studies

to produce the active substance)

but not expected to affect safety
or efficacy

3. Major change (e.g. certain

May possibly affect safety or

Comprehensive physicochemicalchanges in the medicine’s

efficacy

and in vitro functional studies

formulation)complemented as needed by
non-clinical and clinical studies

17

Most of the widely used biological
medicines on the market haveseen several changes to their
manufacturing process and theseoften result in minor differences fromthe version initially approved or theversion used in the clinical trials filed
for approval.

 The goal is to rule out potential product-relateddifferences that could affect pharmacokinetics(PK), efficacy or safety, including
immunogenicity.

 PK studies should be conducted in a
homogeneous and sensitive population (healthy
volunteers or patients) to detect any possible
differences between the biosimilar and its

Regulators have built up extensive
experience to conclude that suchdifferences do not affect the
medicine’s quality, safety andefficacy.

reference medicine. Healthy volunteers can beselected if they represent the most appropriate
population to detect such differences and if the
medicines’ toxicity is not a cause of concern.

 To compare the pharmacological effects, asensitive endpoint that allows detection of
product-specific differences should be chosen.

Comparative trials are designed to confirm
biosimilarity and clinical performance Endpoints measuring pharmacodynamic activity(‘PD endpoints’) can be used when available

Comparison of the biosimilar with the reference

and when relevant for the medicine’s clinicalmedicine involves extensive comparability studies toeffect. In many settings, these endpoints areassess any possible impact on safety and efficacy.

more sensitive than clinical outcomes to detect

The approach is equivalent to when major changes

potential differences between a biosimilar

are introduced to the manufacturing process forand the reference medicine. PD endpoints area medicine made by biotechnology (scenario 3 inusually based on laboratory tests. Examples

table 5).

include:Clinical trials for biosimilars do notneed to include all the pivotal studies
conducted for the reference medicine
to prove safety and efficacy inhumans.

 glucose infusion rate in a glucose clamp
study for biosimilar insulins (rather
than measures of HbA1c or long-term
consequences of diabetes)

 absolute neutrophil count for biosimilar
granulocyte-colony stimulating factor

Comparative clinical trials are
specifically designed to rule out
clinically relevant differences insafety or efficacy between thebiosimilar and the reference
medicine, and to confirm
biosimilarity.

(rather than number of serious infections) number of oocytes retrieved during invitro fertilisation for biosimilar folliclestimulating hormone (rather thanpregnancies or live births)

 If there are no suitable PD endpoints, a clinicalefficacy trial comparing the biosimilar and

There are certain key aspects that need to be

its reference medicine is generally needed.

considered for the design of comparative clinicalThis trial should be adequately powered,trials:randomised, parallel-group, preferably doubleblind, and should use efficacy endpoints. These18

endpoints should preferably measure thethus be acceptable because they have nopharmacological activity of the medicine and beclinical relevance. The principles of selecting

less influenced by patient- or disease-related

equivalence margins are not unique to biosimilar

factors.

testing: they are routinely used in clinical trials
when comparing treatment alternatives, or Adequate equivalence margins should be chosenwhen comparing the same medicine before andfor the primary efficacy endpoint. Margins

after manufacturing changes that may have a

are established on the basis of knowledge ofclinical effect .

3efficacy with the reference medicine, as well as
on clinical judgement. Equivalence margins areset specifically for the indication studied and As for all clinical trials, legal requirements (e.g.
Good Clinical Practice) have to be met.

depend on the endpoint chosen. They should
represent the largest difference in efficacy

The extent of clinical studies needed for approvalthat would not matter in clinical practice;depends on several factors, including those outlined

treatment differences within this range would

in table 6.

Table 6. Factors affecting the number and types of clinical studies to be carried out for approval
Determining factor

Reason for varying amount/type of data

Complexity of the molecule and comparability

For simpler molecules with well-established action

data available(e.g. filgrastim) and where comparative quality
data are solid, it may be sufficient to compare theeffect of the biosimilar and reference medicine
with PK and PD studies in healthy volunteers.
For larger molecules (e.g. monoclonal
antibodies), even when robust quality and in vitro
comparability data are provided, a comparative
study in patients using a conventional clinicalefficacy endpoint is usually required.

Availability of a PD endpoint which correlates with

Conventional clinical efficacy endpoints are

efficacy

generally not needed if the PD endpoint correlateswith clinical benefit.

Safety concerns with the reference medicine or

Safety data are collected throughout the clinicalpharmacological classdevelopment programme, including during PK and
PD studies. The amount of data normally depends
on the type and severity of the safety concerns
identified for the reference medicine. In principle,
adverse reactions related to the pharmacologicalaction can be expected at similar frequency forthe biosimilar and reference product, if functional,
analytical, PK, PD and efficacy comparability data
are robust.

19

Determining factor

Reason for varying amount/type of data

Potential for immunogenicity

Analytical studies are the first step in assessing
potential for immunogenicity. To complement this,clinical data on immunogenicity are generally
required; animal studies are of limited value inpredicting immune response in humans.

Possibility of extrapolating to other indications

Indications of the reference medicine can beapproved for the biosimilar in the absence ofspecific clinical data generated with the biosimilar(‘extrapolation of indications’). This can be
accepted if all the scientific evidence available
from the comparability studies establishes
biosimilarity and can address the specificaspects of the ‘extrapolated’ indication (e.g.
mode of action, potentially unique safety or
immunogenicity aspects).
Extrapolation of data to other indications is always
supported by robust physicochemical and in vitro
studies to assess all the possible mechanisms ofaction.

Immunogenicity

Immunogenicity is not a safety concern
in itself

Immunogenicity is always studied for biological
6, 7

medicines. This is because of the intrinsic ability

Severe reactions due to an increased immuneof proteins and other biological medicines to cause

response are very rare and most often an immune

an unwanted immune response, which, in rare

response against a biological medicine is notcases, could cause a serious adverse reaction (e.g.

associated with clinical consequences (e.g. anti-

anaphylaxis or delayed hypersensitivity) or reduced

drug antibodies could be transient).

efficacy.
The nature of immune reactions depends
Key considerations on potential

on many factors

immunogenicity of biological medicines
Immunogenicity may be influenced by product
Although immunogenicity could be a potential

characteristics (e.g. changes to the structure ofconcern for all biological medicines, there are

the protein may occur during improper storage

several important considerations:or transport, or proteins could form aggregates),
but also by treatment-related factors (e.g. the risk
may vary with subcutaneous versus intravenous
administration or with continuous versus
intermittent treatment regimen) and patient- or20disease- related factors (e.g. age, genetic and

Immunogenicity data required for approval

immune status or concomitant treatments).

include incidence, titre and persistence ofantibodies against the biological medicine (ADAs),
neutralisation assays (because neutralisingHarmful immunogenicity is unlikely after

antibodies may reduce the effect of the medicine),

manufacturing changes or after switchingassessment of the clinical impact and measures tomanage the potential risk of immunogenicity (e.g.

Many biological medicines are intended for long-special monitoring of immune-mediated adverse

term management of chronic conditions, andreactions or use of concomitant medication totherefore, over time the patient may receive

mitigate infusion reactions).

biological medicines with slight differences.
In general, the amount and type of data will depend
Experience shows that a harmful immune responseon several factors, including:is unlikely after a change to the manufacturing
process of a biological medicine, since comparability
studies prove that the batch from the new process the type of biological medicine and its intended
use

is of the same quality and free of impurities or
8

aggregates that can trigger immunogenicity .

 product characteristics: the great majorityof immunogenicity studies focus on how

There is also no reason to believe that harmful

differences at product level may affect an

immunogenicity should be expected after switching

immune response. These include studying

between highly similar biological medicines .

changes to the structure or minor variability

8in the protein (microheterogeneity), or
how protein aggregation could occur due to
Immunogenicity is always monitored post-components derived from the formulation ormarketingpackaging.

Immunogenicity of biological medicines is always previous knowledge of immunogenicity: formonitored by regulatory authorities once thebiological medicines with a low immunogenicity

medicine is on the market. This is particularly

profile (e.g. filgrastim), patients are usuallyimportant to learn of rare immune reactions that

tested for antibodies frequently at thecan only be detected after a long follow-up period in

beginning and at the end of the clinical study

larger numbers of patients.

with a shorter follow-up period and routine
pharmacovigilance measures to manage any
potential risk. In cases where clinically relevant

Immunogenicity data needed for approval

immunogenic responses have been observedof a biosimilar(e.g. epoetins) immunogenicity testing is more
frequent, there is a longer patient follow-up

Clinical immunogenicity studies are generallywith intensified clinical monitoring, and specificrequired for biological medicines. In the case of

post-marketing studies may be required.

monoclonal antibodies they are always required,as it is more difficult to predict the incidence of
unwanted immunogenicity, the characteristics of
the immune response or the clinical consequences.
Such studies look both at short-term immune
responses (e.g. infusion-related reactions), as well
as long-term (e.g. delayed responses due to an
evolving immune reaction).

21

Extrapolation

Criteria for extrapolation

If a biosimilar is highly similar to a reference

Important considerations need to be borne inmedicine and has comparable safety and efficacy

mind before an indication for a biosimilar can bein one therapeutic indication, safety and efficacy

approved based on extrapolated safety and efficacy

data may be extrapolated to other indications

data. These include:

approved for the reference medicine. This meansthat fewer clinical trials or no trials at all need to be
carried out with the biosimilar in certain indications.

Mechanism of action

Extrapolation of data to other indications is always
supported by scientific evidence generated in robust

The mechanism of action of the active substancecomparability studies (quality, non-clinical andshould be mediated by the same receptor(s) in bothclinical).

the initial and the extrapolated indication.

Extrapolation is a well-established scientific principle

If the mode of action of the active substancewhich has been used for many years , for example

is complex and involves multiple receptors or

whenever a biological medicine with several

binding sites (as is often the case with monoclonal

approved indications undergoes major changes toantibodies), it may be difficult to establish theits manufacturing process (e.g. new manufacturingcontribution of each receptor or binding site to eachsite or development of new formulations). The

indication. In this case, additional studies (non-potential effect of these changes on the biologicalclinical or clinical) will be needed to prove that

medicine’s clinical performance is carefully

the biosimilar and reference medicine will behave

evaluated with comparability studies (mainly quality

similarly in the extrapolated indication.

9and in vitro studies). If clinical studies are needed,
these are conducted in one relevant indication and,based on all these data, extrapolation to the other

Relevant study population

indications is usually possible.
Comprehensive comparability studies must

Extrapolation is not a new concept
but a well-established scientificprinciple used routinely when
biological medicines with several
approved indications undergo majorchanges to their manufacturing
process.
In most of these cases, regulators
approve manufacturing changes
based on comparability studies andclinical trials are not repeated for all
indications.

show that the biosimilar is highly similar to thereference medicine (by means of safety, efficacy
and immunogenicity data) in a key indication in a
population in which potential differences in clinicalperformance can be detected.

Extrapolation across different clinical settings
Data from a given indication (e.g. rheumatoid
arthritis) may not be directly applicable in termsof safety or efficacy to an indication falling within
another therapeutic area where the mode of action,
posology or pharmacokinetics may be different (e.g.
oncology). In this case, additional studies may beneeded.

22

Extrapolation of safety data
Safety data can only be extrapolated after acomparable safety profile has been established
for the biosimilar in one therapeutic indication. If
comparability is shown at structural, functional,

Prescribers can have confidence
in using biological medicines(including biosimilars) for all theirapproved indications, as all approved
indications of a medicine are granted
based on scientific evidence.

pharmacokinetic and pharmacodynamic level, andefficacy is comparable, then adverse reactions dueto the biosimilar’s pharmacological action can be
expected to be the same and to occur at similarfrequencies.

Extrapolation of immunogenicity data
Extrapolation of immunogenicity data is not
automatic, as it always requires justification.
This is because immunogenicity is determinedby more than product-related characteristics.
Factors relating to patients (age, immune status),disease (comorbidities, concomitant treatments) ortreatment-related factors (route of administration,
length of exposure) also have to be considered.

The scientific criteria for
extrapolation of efficacy and safety
data are supported by over 10 years
experience of safe and effective useof biosimilars in the EU.
Extrapolation is also supported byregulators’ extensive experiencein the routine evaluation of
manufacturing changes forbiologicals, most often without theneed to repeat clinical studies in all
indications.

23

Safety of biosimilars
General considerations on safety
for biosimilars

Same safety monitoring for all biologicalSince the introduction of the first biosimilar in

Safety monitoring of biosimilars follows the same

clinical use in 2006, an increasing number ofrequirements that apply to all biological medicines .

biosimilars have been approved and safely used in

There is no specific requirement just for biosimilars.

medicines

10

the EU.
Apart from reactions of an immunological nature,

A plan to manage risks always in placemost adverse drug reactions (ADRs) can bepredicted from the pharmacological action, andCompanies applying for marketing authorisation

occur with both the reference medicine and thein the EU must submit a risk management planbiosimilar (e.g. high haemoglobin levels with(RMP) for each new medicine, including biologicalepoetins). Of more than 50 biosimilars approved

medicines. The RMP, which is tailored for eachin the EU to date, none has been withdrawn or

product, includes a pharmacovigilance plan and risk

suspended for reasons of safety or efficacy.

minimisation measures to identify, characterise andminimise a medicine’s important risks. The RMP of

Over the last 10 years, the EU
monitoring system for safetyconcerns has not identified any
relevant difference in the nature,
severity or frequency of adverse
effects between biosimilar medicines
and their reference medicines.

a biosimilar is based on knowledge and experience
gained with the reference medicine.
For all medicines approved in the EU, in addition
to the conditions of use in the product information,
additional measures (e.g. educational brochures,
patient alert cards or inclusion of patients inregistries) may be needed to manage a specificrisk. When any extra measure is applied to the

Safety monitoring for all biological
medicines, including biosimilars

reference medicine (e.g. educational material), it
should also be considered for the biosimilar.

Safety studies after marketing
A robust regulatory framework to protect
patients’ safety

Post-marketing studies allow monitoring of known
risks and also permit detection of rare adverse drug

The EU has a well-established system forreactions that emerge only when large numbers ofmonitoring, reporting, assessing and preventing

patients have been treated for a long period. This is

adverse drug reactions for all medicines, including

why at the time of approval regulators may impose

all biological medicines. Authorities continuouslyon the company an obligation to carry out a post-

evaluate the benefit-risk balance of all medicines

authorisation safety study (PASS). This also binds

and take necessary regulatory action (e.g.

the company to register the study in the publicly

introducing new warnings in the product information

available EU PAS Register: http://www.encepp.eu/

or restricting use) to safeguard public health.

encepp_studies/indexRegister.shtml.
The criteria for deciding whether a post-marketing
safety study is needed are the same for all24

medicines, including biosimilars and their reference

The black triangle symbol identifies medicines under

medicines. If a PASS has been requested for aadditional monitoring. It is displayed in the SmPC

reference medicine, it will normally be requested

and package leaflet together with the sentence:

also for the biosimilar.
“This medicinal product is subject to additional
monitoring”
Collecting spontaneous adverse drug reactions
and submitting PSURs

Additional monitoring encourages healthcare
professionals and patients to report any suspected

As for all medicines, companies marketing

adverse drug reactions of new medicines. Thisbiosimilars must collect all reports of suspectedenables prompt identification and analysis ofadverse drug reactions and submit periodic safety

information about the medicines to add to the

update reports (PSURs) to regulators. Regulatory

knowledge gained during clinical trials. If aauthorities review reports for any signal suggestive

biological medicine (or biosimilar) is labelled withof a possible unwanted effect. If a signal isa black triangle, it does not necessarily mean thatsuspected, it is evaluated by EMA’s scientific

there are additional safety concerns with it.

committees, which will determine if any action isneeded.
Monitoring long-term or long-latency adverse
eventsAdditional monitoring and black triangle
Safety monitoring of long-term or long-latency
All new medicines are closely monitored after being

events for biological medicines follows the same

introduced to the market. Biological medicinesprinciples as for small-molecule medicines.

approved after 1 January 2011 are subject to so-

However, detecting and characterising the long-called ‘additional monitoring’ and are included interm adverse drug reactions of biological medicines

a list of medicines under ‘additional monitoring’.

may be difficult using only spontaneous reporting.

This list includes medicines authorised in the EU

This is why additional pharmacovigilance activities

that are being monitored particularly closely by(such as including patients in registries) could be

regulatory authorities, for example because therequired in certain cases.

active substance is new to the market or there arelimited data on its long-term use. In this case, they
are monitored particularly closely during the firstyears after approval.

Traceability: importance ofidentifying biological medicines bytradename and batch number
An important requirement for the safety monitoring

What does theblack triangle mean?

of all biological medicines is the need for productand batch traceability during clinical use and at all
10levels in the supply chain . This covers the timefrom release by the manufacturer and progress
through the entire distribution chain until the
medicine is administered to the patient.
As required by EU law, every medicine will havean invented name (tradename or brand name)together with the active substance name (i.e. the25international nonproprietary name, or INN, which isof product characteristics (SmPC) and package

assigned by WHO).

leaflet. If a suspected ADR is identified for abiological medicine, healthcare professionals should

For identifying and tracing biological medicines

report it, taking care to include the tradename andin the EU, medicines have to be distinguishedbatch number of the medicine. It is important thatby the tradename and batch number and thishealthcare professionals report any suspected ADR

is particularly important in cases where moreof a biosimilar even if the reaction is already listed

than one medicine with the same INN exists onin the reference medicine’s SmPC.

the market. This ensures that, in line with EU
requirements for ADR reporting, the medicine can

For a biological medicine, its tradename, INN

be correctly identified if any product-specific safety

and batch number can be found in the product(or immunogenicity) concern arises.

packaging. A statement has been introduced in the
SmPC to remind healthcare professionals of the

Healthcare professionals play an essential role inneed to clearly record the tradename and batch

contributing to the understanding of a medicine’s

number in the patient’s healthcare records.

safety profile during clinical use. Biological
medicines are approved on the basis of an
acceptable safety profile and they should be usedaccording to the recommendations in the summary

How healthcare professionals canhelp improve pharmacovigilance
for biological medicines: It is important that the

medicine’s tradename andbatch number are recordedby healthcare professionals at
all levels, including dispensing
and patient administration.

 Prescribers should include thetradename of the medicine in
the prescription.

 Healthcare professionals

should ensure that tradename
and batch number are reported
in case of suspected adverse
drug reactions, according tolocal practice and national
regulations.

26

 In cases where the productis dispensed at a community
pharmacy, the tradename andbatch number of the biological
medicine should be provided tothe patient.

 If a patient is switched fromone biological medicine toanother with the same active
substance, it is important torecord the tradename andbatch number for each of the
medicines.

 Healthcare professionals

should contact their national
medicines regulatory
authorities for advice on
how to report adverse drug
reactions.

Data included in the prescribing information and
EMA assessment reports for biosimilars
Data for prescribing: summary of
product characteristics (SmPC)

Data on biosimilarity: published in
the assessment report

The EU SmPC includes information and

For each medicine approved through EMA, including

recommendations to enable healthcare

biosimilars, EMA publishes a group of documents

professionals to prescribe the medicine and to give

known as the european public assessment report

advice to patients on its use.

(‘EPAR’). In addition to the EU product information(SmPC, package labelling and package leaflet), theSection 5.1 (pharmacodynamic properties) of the

EPAR documents contain assessment reports on the

SmPC will identify a medicine as a biosimilar with

scientific evaluation of the medicine at the time of

the following wording:approval and when major changes are introduced(e.g. when a new indication is added).

[Brand name] is a biosimilar medicinal product.
Detailed information is available on the website

Details of how each biosimilar was developedof the European Medicines Agency http://www.ema.

and on the comparability studies to demonstrateeuropa.eu.

biosimilarity are given in their assessment
reports. These include information on analyticalIn the EU, the SmPC of a biosimilar is aligned withand functional comparability, pharmacokinetics,

that of the reference medicine. The biosimilar’sclinical comparability and immunogenicity. Where

SmPC mentions the name of the active substanceapplicable, the assessment report also includes the(i.e. INN) and not the tradename of the reference

scientific rationale for extrapolation of data.

medicine. Details of the studies with the biosimilar
as well as the tradename of the reference medicine

Over 50 biosimilars have been approved throughcan be found in EMA’s assessment report, available

EMA for use in the EU as at April 2017. Their

on EMA’s website.

assessment reports can be accessed on EMA’s
website, on the landing page of each medicine,

A biosimilar can be approved for some or all of theunder the tab ‘assessment history’.

authorised indications of the reference medicine,as a company may choose not to apply for all
the reference medicine’s indications. Healthcare
professionals should check that the biosimilar isauthorised for the intended indication.
When a company does not apply for all theindications of the reference medicine, efficacy
data on the additional indications are not includedin the biosimilar’s SmPC, however safety data
are reflected.

27

Implications of theavailability of biosimilars
Once the period of market protection of the reference
medicine expires (usually 10 years), companies canmarket approved biosimilars. In general, it is expectedthat biosimilars will be introduced to the market at alower price than their reference medicine. Thus, they
are expected to be less costly for healthcare systems
in the EU. This is partly due to a tailored development
programme that builds on scientific knowledge gainedwith the reference medicine and so avoids unnecessary
repetition of non-clinical and clinical studies. It canalso be due to increased market competition.
11

The experience over the past 10 years indicatesthat biosimilar competition can offer advantages to
EU healthcare systems, as having more treatment
alternatives available is expected to improve
patients’ access to biological medicines with provenpharmaceutical quality.

28

Interchangeability, switching and substitution:
EMA and Member States’ responsibilities
Definitions

In the EU, prescribing practices and advice toprescribers fall under the responsibility of Member

In the context of biosimilars and referenceStates, which have the necessary legal framework

medicines, it is important for healthcare

in place and issue regulations, guidelines and advice

professionals to be aware of the terminology toin their areas of competence. As for any medicine,refer to interchangeability and substitution practices

healthcare professionals should choose carefullyin the EU.

when prescribing, taking into account the patient’s
medical history.

Interchangeability refers to the possibility of
exchanging one medicine for another medicine thatis expected to have the same clinical effect. This
could mean replacing a reference product with abiosimilar (or vice versa) or replacing one biosimilar
with another. Replacement can be done by: Switching, which is when the prescriber

For questions on prescribing
or interchangeability practices,
information may be available at thenational competent authority in therelevant Member State (the list canbe found on EMA’s website).

decides to exchange one medicine for anothermedicine with the same therapeutic intent.

 Substitution (automatic), which is the practiceof dispensing one medicine instead of anotherequivalent and interchangeable medicine
at pharmacy level without consulting theprescriber.

EMA and Member States’
responsibilities
When EMA carries out the scientific review of

Any decision on switching should
involve the prescriber in consultation
with the patient, and take into
account any policies that the country
might have regarding the prescribing
and use of biological medicines.

This section should be read together with theInterchangeability Statement and the accompanying
Questions and Answers document available here.

a biosimilar, the evaluations do not include
recommendations on whether the biosimilar isinterchangeable with the reference medicine,and thus whether the reference medicine can beswitched or substituted with the biosimilar.
The decision on whether to allow interchangeable
use and substitution of the reference biological
medicine and the biosimilar is taken at national
level. Information on the scientific evaluation
performed by EMA’s scientific committees isavailable on EMA’s website and could be used tosupport decisions.

29Communicating withpatients on biosimilars
If patients have questions on whether a particularbiological medicine is a biosimilar, their healthcare
professionals can find this information in section
5.1 of the SmPC. The package leaflet, which contains
key recommendations for patients on how to use
the medicine properly, does not include mention ofbiosimilarity, as this only refers to the medicine’s
development route and is not related to the use of the
medicine.
If patients receiving biosimilars in a clinical setting(e.g. in hospital) want information on their biosimilar,
they can ask their healthcare professionals for the
package leaflet. Alternatively, they can download itfrom EMA’s website.
For questions from patients on what is a biosimilar,
and how its safety and efficacy are ensured, patients12

can consult a questions-and-answers document inpatient-friendly language available on the European
Commission’s website.
When a new medicine is approved by EMA, theAgency also publishes a summary for the generalpublic explaining why the medicine is approved in
the EU. These summaries (called ‘EPAR summaries’),are available on each medicine’s landing pageon EMA’s website in the form of questions-andanswers documents in all official EU languages.
EPAR summaries for biosimilars can be accessedby searching for the medicine’s name on EMA’s
homepage. Alternatively, a live list of EPAR summaries
for all biosimilars can be found on EMA’s website.
Several national regulatory authorities also provide
information on biosimilars in their local language.

30

EU contribution to theregulation of biosimilars
worldwide
The EU’s regulation of biosimilars has shapedbiosimilar development globally, by establishing thecore principles that underpin biosimilar development inother highly regulated areas of the world.
The requirements for biosimilar approval in the US by
the FDA are based on the same scientific rationale asin the EU, although specific data requirements may
differ between these two regions due to different legal
frameworks. Other international regulators such as
Australia’s TGA directly apply the principles set out inthe EU legislation for the development and approval ofbiosimilars.
The World Health Organization (WHO) has developed
its own guidelines for biosimilars (called ‘similarbiotherapeutic products’ or SBPs) and biosimilar
monoclonal antibodies, with the aim of providing
guidance to regulatory agencies worldwide. These
WHO guidelines incorporate many of the scientificprinciples used by EMA and its scientific committees
in EU guidelines, as EU experts have been closely
involved in the preparation of the WHO guidelines.
EMA continues to share the extensive experience
gained in the EU on biosimilars with other regulators
around the world and participates in a numberof international forums such as the International
Pharmaceutical Regulators Forum.

31

References

1. European Medicines Agency: Similar biological

7. European Medicines Agency: Immunogenicity

medicinal products (overarching guideline).

assessment of monoclonal antibodies intended for

CHMP/437/04 Rev. 1. http://www.ema.europa.

in-vivo clinical use. EMA/CHMP/BMWP/86289/2010.

eu/docs/en_GB/document_library/Scientific_

http://www.ema.europa.eu/docs/en_GB/document_

guideline/2014/10/WC500176768.pdf. Accessed on 6

library/Scientific_guideline/2012/06/WC500128688.

March 2017.

pdf. Accessed on 6 March 2017.

2. European Medicines Agency: Similar biological

8. Kurki P, van Aerts L, Wolff-Holz E, et al.

medicinal products containing biotechnology-

Interchangeability of biosimilars: a European

derived proteins as active substance: non-clinicalperspective. BioDrugs 2017;31:83-91.

and clinical issues. EMEA/CHMP/BMWP/42832/2005
Rev. 1. http://www.ema.europa.eu/docs/en_GB/

9. Weise M, Kurki P, Wolff-Holz E, et al.

document_library/Scientific_guideline/2015/01/

Biosimilars: the science of extrapolation. Blood

WC500180219.pdf. Accessed on 6 March 2017.

2014;124(22):3191-6.

3. Weise M, Bielsky MC, De Smet K, et al.

10. European Medicines Agency: Guideline on good

Biosimilars: what clinicians should know. Blood

pharmacovigilance practices (GVP), Product- or2012;120(26):5111-7.

Population-Specific Considerations II: Biological
medicinal products. EMA/168402/2014. http://www.

4. European Medicines Agency: ICH Q5E

ema.europa.eu/docs/en_GB/document_library/

Biotechnological/biological products subject

Scientific_guideline/2016/08/WC500211728.pdf.

to changes in their manufacturing process:Accessed on 14 March 2017.

comparability of biotechnological/biologicalproducts. CPMP/ICH/5721/03. http://www.ema.

11. IMS Health, The impact of biosimilar

europa.eu/docs/en_GB/document_library/competition, June 2016. http://ec.europa.eu/

Scientific_guideline/2009/09/WC500002805.pdf.

growth/tools-databases/newsroom/cf/itemdetail.

Accessed on 6 March 2017.

cfm?item_id=8854. Accessed on 10 April 2017.

5. European Medicines Agency: Comparability

12. European Commission: What I need to knowof biotechnology-derived medicinal products

about biosimilar medicines. Information for

after a change in the manufacturing process

patients. 2016. http://ec.europa.eu/growth/tools-- non-clinical and clinical issues. EMEA/CHMP/

databases/newsroom/cf/itemdetail.cfm?item_

BMWP/101695/2006. http://www.ema.europa.

id=9066. Accessed on 6 March 2017.

eu/docs/en_GB/document_library/Scientific_
guideline/2009/09/WC500003935.pdf. Accessed on
6 March 2017.
6. European Medicines Agency: Immunogenicity
assessment of biotechnology-derived therapeuticproteins. EMEA/CHMP/BMWP/14327/2006. http://
www.ema.europa.eu/docs/en_GB/document_
library/Scientific_guideline/2009/09/WC500003946.
pdf. Accessed on 6 March 2017.

32

Abbreviations

ADA

Anti-drug antibody

ADR

Adverse drug reaction

BMWP

Biosimilar Working Party (EMA’s working party of EU experts on biosimilars)

CHMP

Committee for Medicinal Products for Human Use (EMA’s scientific committee
formed by EU experts who review and recommend marketing approval)

DNA

Deoxyribonucleic acid

EMA

European Medicines Agency

EPAR

European public assessment report

EU PAS Register

EU post-authorisation study register

FDA

Food and Drug Administration (the US medicines regulatory authority)

GMP

Good manufacturing practice

INN

International nonproprietary namePASS

Post-authorisation safety study

PD

Pharmacodynamic(s)PK

Pharmacokinetic(s)PRAC

Pharmacovigilance and Risk Assessment Committee (EMA’s scientificcommittee formed by EU experts on safety of medicines)

PSUR

Periodic safety update report

RMP

Risk management plan

SBP

Similar biotherapeutic products (WHO term for biosimilars)

SmPC

Summary of product characteristics (the EU prescribing information)

TGA

Therapeutic Goods Administration (Australia’s medicines regulatory authority)

WHO

World Health Organisation

33

Glossary*

Anti-drug antibody

Antibodies produced by the body’s immune system against an active
substance (particularly a large molecule, such as a protein). ADAs against
a medicine can result in loss of efficacy or in immunological reactions.

Adverse drug reaction

An unwanted medical event following the use of a medicine. Suspected ADRs
are those that have been reported to authorities but which are not necessarily
caused by the medicine.

Bioequivalence

When two medicines release the same active substance into the bodyat the same rate and to the same extent under similar conditions.

Biosimilarity

Demonstration of high similarity to a reference biological medicine interms of chemical structure, biological activity and efficacy, safety andimmunogenicity profile, mainly based on comprehensive comparability
studies.

Biotechnology

Technology that relies on biological systems, living organisms or components
from living organisms (such as genes or enzymes) to make a specific product.
A medicine obtained by biotechnology often has been produced by insertinga gene into cells so that they can produce the desired protein.

Centralised procedure

Approval process of medicines which involves a single application,a single evaluation and, for successful applications, a single authorisation
valid throughout the European Union. It is mandatory for certain typesof medicines, including all medicines produced by biotechnology andmedicines for specific conditions such as cancer, neurodegeneration andautoimmune diseases.

Comparability

Head-to-head comparison of a biosimilar with its reference medicine to ruleout any significant differences between them in terms of structure andfunction. This scientific principle is routinely used when a change is introduced
to the manufacturing process of medicines made by biotechnology, to ensurethat the change does not alter safety and efficacy.

Extrapolation

Extension of the efficacy and safety data from a therapeutic indication
for which the biosimilar has been clinically tested to another therapeutic
indication approved for the reference medicine.

Glycosylation

Modification of a protein after its production, which involves the additionof carbohydrate (sugar) groups. Depending on the amount and type of sugargroups added, the biological activity can change.

* The definitions included in this document and in the glossary are descriptions, not regulatory definitions.
34

INN

International nonproprietary name, a unique name that identifies active
substances. The list of INNs, which is globally recognised and public property,
is maintained by WHO.

Interchangeability

Refers to the possibility of exchanging one medicine for another medicine thatis expected to have the same clinical effect.

Microheterogeneity

Minor molecular variability among biological substances due to natural
biological variability and slight alterations to production methods.

Pharmacodynamic

Studies of the biochemical and physiological effects of a medicine in the body,studies

including mechanism of action.

Pharmacokinetic

Studies of how a medicine is processed by the body, including its absorption,

studies

distribution, biotransformation and excretion.

Pharmacovigilance

Activities to detect and assess adverse reactions and other effectsof medicines in use.

Periodic safety update

Report that a company marketing medicines in the EU must submit

reportto regulatory authorities periodically (e.g. every six months) that includes
new reports of suspected adverse drug reactions.

Post-translational

Modification of a protein after its production, which involves the attachmentchangeof molecules or groups such as phosphates or carbohydrates (sugars).

Recombinant DNA

Technology that involves combining sequences of DNA that do not occur

technology

naturally, for example inserting a gene for producing a therapeutic protein.

Reference medicine

A biological medicine approved in the EU, which is chosen by a company
developing a biosimilar as a reference for the head-to-head comparison ofquality, safety and efficacy.

Specifications

Acceptance limits for important quality standards which an active substanceor a finished medicine must meet.

Substitution

Practice of dispensing one medicine instead of another equivalent andinterchangeable medicine at pharmacy level without consulting the prescriber.

Switching

When the prescriber decides to exchange one medicine for another medicine
with the same therapeutic intent.

35

European Medicines Agency
Domenico Scarlattilaan 61083 HS Amsterdam
The Netherlands
Address for visits and deliveries:
Refer to www.ema.europa.eu/how-to-find-us
Telephone +31 (0)88 781 6000
Send a question www.ema.europa.eu/contact
www.ema.europa.eu© European Medicines Agency, 2019.
Reproduction is authorised provided the source is acknowledged.