Biosimilars dismantling a myth.pptx

Highlights
Key Points in Biosimilars

Table of contents
10 key points + dismantling a myth
9
“
“
1 Why do we need Biosimilar medicines?
Biosimilars contribute to increasing the efficiency of the national health
system They consequently promote the system's sustainability and
make it easier for more patients to access biological therapies.
2 What is a biosimilar medicine?
A biosimilar medicine is, in essence, the same as the reference
medicine; the small differences are clinically insignificant.
3 How are Biosimilars developed?
Developing a biosimilar means demonstrating biosimilarity, that is,
therapeutic equivalence through an exhaustive comparative process.
4 What are the criteria for authorising a biosimilar?
With respect to authorisation criteria, the requirements in terms of
quality, efficacy and safety are the same as for any medicine.
Likewise, an active pharmacovigilance is required, as with reference
medicines.
5 What is the approval process for a biosimilar?
A biosimilar can be approved for all indications of its reference medicine
after an exhaustive evaluation of the regulatory agencies, without it
being necessary to perform clinical trials in each of them (extrapolation).
6 Are biosimilars more immunogenic than a reference medicine?
The immunogenicity risk of the biosimilar and the reference medicine is
the same.
7 Do efficacy and safety stay the same if the patient started
treatment with a biosimilar?
In terms of efficacy and safety, starting with the biological treatment is
the same as starting with the reference medicine.
Switching from a reference medicine to a biosimilar must be carried
out on the initiative of the prescribing doctor or with their consent and
with the patient’s knowledge.
10Appropriate communication with the patient is essential for
preventing or minimising the possible nocebo effect caused by
switching between the reference and biosimilar medicine.
Myth: Biosimilars are lower-quality
'second-class' medicines, which
have less efficacy and safety than
reference medicines.
8 Is switching safe?
Switching from a reference medicine to a biosimilar is safe.

Biosimilars contribute to increasing the efficiency of the
national health system. They consequently promote the
system's sustainability and make it easier for more patients
to access biological therapies.
1
They allow
more patients
to be treated
Benefits of
BIOSIMILARS
They
promote
competition
They help sustain
the national health
system
Biosimilars are marketed once the
reference medicine patent is finalised
and enter the market at a lower price
(in Spain, around 30% less)1.
Development is based on scientific
knowledge of the reference medicine,
which avoids unnecessary repetition
of studies and lowers costs.
The commercialisation of biosimilars
encourages competition in the
market and often causes a reduction
in the price of reference medicines1.
It is estimated that the use of
biosimilars will generate total savings
in excess of €2.4 billion in Spain
between 2009 and 2020.1
The lowest price generated by
biosimilars and in the context of a
larger therapeutic arsenal of
biological treatments allows more
people to be treated for the same
health budget.
The saving can be used to finance
access to newer treatments which,
among other mechanisms, promotes
pharmaceutical innovation2.
They free up
resources to finance
other treatments
They reduce
prices
They promote
innovation
1 González A, Ivanova Y, Zozaya N, Jiménez M, Hidalgo Á. La introducción de los biosimilares en España. Estimación del ahorro
para el Sistema Nacional de Salud. Madrid: Fundación Weber; 2017.
2 Mestre-Ferrandiz J. The Economics of Innovation and Incentives for Encouraging Medical
R&D [Internet]. 2014.

A biosimilar medicine is, in essence, the same
as the reference medicine; the small
differences are clinically insignificant.
2
1
Batch 1 Batch 2 Batch 3
Variability between batches of the
same biological medicine
Reference Biosimilar
medicine medicine
A biosimilar is a biological medicine
which contains a version of the active
substance of an original or reference
biological product authorised in the
European Union and whose patent
has expired. The same route of
administration and the same dose as
the reference medicine is used1.
Biosimilars are not generic
medicines. Generics are small,
simple molecules that are chemically
synthesised, which ensures that they
are identical to the reference
medicine. Biosimilars are
macromolecules with a complex
structure that is essentially the same
as that of the reference medicine.
Given that they are produced in a
living organism, all biologicals have
some variability. There are small
differences both between different
batches of the same biological and
between the biosimilar and its
reference medicine. The margin of
variability permitted for a biosimilar is
the same as that permitted between
batches of the reference medicine in
the critical structural and functional
attributes2.
The differences between the
biosimilar and the reference medicine
are minor and do not affect safety
and efficacy. The clinical studies on
which the biosimilar approval process
is based confirm that variability does
not affect efficacy, safety or
immunogenicity2.
Variability between a biosimilar and
its reference medicine
Image adapted from
Reference 2
1 Spanish Biosimilar Association (BioSim). Guide to biosimilar medicines for doctors. Madrid: 2017.
2 European Medicines Agency and European Commission. Biosimilars in the EU. Information guide for healthcare
professionals. 2017.

Developing a biosimilar means demonstrating biosimilarity;
that is, therapeutic equivalence through an exhaustive
comparative process.
3
Step Comparative clinical studies
• Pharmacokinetics / Pharmacodynamics
• Efficacy + safety + immunogenicity
1
Step Comparative quality study
• Analytical: Physical and chemical properties.
• Functional: Biological / pharmacological activity
2
Step Comparative preclinical study
• Pharmacodynamic
• Toxicology
3
Reference
medicine
Biosimilar
medicine
Development of the biosimilar is
different to that of the reference
medicine. It is based on
demonstrating the biosimilarity, i.e.
that it is comparable in terms of
quality, safety and efficacy to a
previously authorised reference
product1.
Since the safety and efficacy of the
reference medicine have already
been demonstrated, it is not
necessary to do the same with the
biosimilar. It must be proved that the
biosimilar is very similar to the
original. This is done through an
extensive comparison exercise1.
Comparison of the biosimilar and the
reference medicine is based on a
staggered process; the results of
some studies determine the type and
scope of the subsequent studies.
This process has a preclinical phase
and a clinical phase2.
Preclinical studies compare
physicochemical characteristics,
biological activity, and sometimes
pharmacokinetics and toxicity. They
are in vitro studies and, only in some
cases, in vivo studies (with
animals)1.2.
Clinical studies can confirm
biosimilarity. They do not need to be
as extensive as those performed with
the biological reference, since most
of the parameters (dose, efficacy,
safety) have already been
established with this1.2.
1 European Medicines Agency and European Commission. Biosimilars in the EU. Information guide for healthcare
professionals. 2017. 2 AL-Sabbagh A, Olech E, McClellan JE, Kirchhoff CF. Development of biosimilars. Seminars in
Arthritis and Rheumatism. 2016;45:S11-S18.

With respect to the criteria for authorising the biosimilar, the
requirements in terms of quality, efficacy and safety are the
same as for any medicine. An active pharmacovigilance
programme is required, as with the reference medicine.
4
Studies of the quality of
pharmaceutical products
Studies of the quality of
pharmaceutical products
• FC / FD
Risk
management
plan
Clinical
studies
• Safety
and efficacy
• FC / FD
• Immunogenicity
Preclinical quality studies
Risk
management
plan
• Safety and
Efficacy studies
Comparative
clinical
studies
• Immunogenicity
Pre-clinical
comparative studies
Comparative study
All medicines produced through
biotechnology are authorised in the
European Union through the
European Medicines Agency (EMA),
by means of a centralised procedure.
Biosimilars and reference medicines
are evaluated by the same experts.
Biosimilar authorisation is subject to
the same requirements regarding
pharmaceutical quality, safety and
efficacy as that which applies to other
biological medicines approved in the
European Union1.
The post-authorisation safety control
of the biosimilars is the same as that
of all the biologicals. It includes a
system of pharmacovigilance with an
especially strict follow-up during the
first years after its authorisation
(inverted black triangle), which allows
possible adverse effects to be rapidly
identified1.
All biologicals (reference and
biosimilar) approved by the EMA
have a post-commercialisation risk
management plan.
Biological medicines, both reference
and biosimilar, should be prescribed
by the trade name, to ensure
traceability2.
None of the biosimilars authorised in
the European Union over the last 10
years has been withdrawn for
reasons of safety or efficacy1.
Reference medicine Biosimilar medicine
Image adapted from Reference 1
European Medicines Agency.
1 European Medicines Agency and European Commission. Biosimilars in the EU. Information guide for healthcare professionals. 2017.
2 Royal Decree 1718/2010, of 17 December, on medical prescription and dispensing orders, modified by Royal Decree 81/2014, of 7 February.

A biosimilar can be approved for all indications of its reference
medicine after an exhaustive evaluation of the regulatory agencies,
without it being necessary to perform clinical trials in each of them
(extrapolation).
Psoriatic
arthritis
Ankylosing
spondylitis
Rheumatoid
arthritis
Rheumatoid
arthritis
Psoriatic
arthritis
Ulcerative
colitis
Ulcerative
colitis
Ankylosing
spondylitis
ORIGINAL
1. AUTHORISATION
1. Authorisation: Clinical trials in the most sensitive indication
= BIOSIMILAR
At the molecular, functional,
pharmacokinetic and clinical level, a
biosimilar is essentially the same as
the reference medicine. After an
exhaustive evaluation of the
mechanism of action in the indication
studied and the characteristics of the
population for which it is intended,
the regulatory agencies can approve
the extrapolation of the equivalence
data to an indication for which no
comparative clinical trials have been
conducted in patients1.2. Each
medicine and each indication is
studied on a case-by-case basis3.
The biosimilars have demonstrated
efficacy equivalent to the reference
medicine when they have been
studied in more than one indication.
They have also proven to be effective
and safe when they have been used
in clinical practice in indications for
which no comparative studies have
been performed in patients with the
reference medicines1.
2. Extrapolation: authorisation for other indications after thorough evaluation of the MoA and the population
characteristics
2. EXTRAPOLATION
The scientific principle of
extrapolation allows the biosimilar to
be authorised for the same
indications of the reference medicine,
without having been expressly
studied in all of them using clinical
trials2.
National and European scientific
societies (SER, ECCO, EULAR, etc.)
support extrapolation4.
1 Kay J, Schoels MM, Dörner T, Emery P, Kvien TK, Smolen JS, et al. Consensus-based recommendations for the use of
biosimilars to treat rheumatological diseases. Ann Rheum Dis. 2018;77:165-174.
3 Spanish Biosimilar Association (BioSim). Guideline to biosimilar medicines for doctors. Madrid: 2017.
4 Medicines for Europe. Positioning Statements on Physician-led Switching for Biosimilar Medicines [internet]. Updated
in January 2019.
5

The immunogenicity risk is the same for both the biosimilar
and the reference medicine.
6
REFERENCE BIOSIMILAR
Immunogenicity risk
=
All biological medicines can trigger
an immune response and produce
anti-drug antibodies (ADA),
especially in prolonged use1.
Immunogenicity depends on factors
related to the patient, to the medicine
and to the manufacturing process1.
The clinical consequences of ADAs
vary; in most cases they are
irrelevant, but sometimes they are
neutralising and may affect efficacy
and/or safety. Immunogenicity is
therefore always evaluated during
the development of biological
medicines and is also subject to
follow-up after its commercialisation.
To approve a biosimilar, the
immunogenicity must be comparable
to the reference medicine1.
However, it is highly improbable that
harmful immunogenicity occurs due
to switching the treatment between
two versions of a medicine whose
production process has been
modified, or due to switching
treatment from a biological to a
biosimilar2.
In terms of immunogenicity, no
clinically significant differences have
been found between a biosimilar and
its reference medicine. The
immunogenicity risk is similar.
Therefore, after switching from the
reference medicine to the biosimilar it
is not necessary to determine the
level of ADAs3.
1 Abad Hernández MA, Andreu JL, Caracuel Ruiz MA, Belmonte Serrano MA, Díaz-González F, Moreno Muelas JV. Documento de
posicionamiento de la Sociedad Española de Reumatología sobre fármacos biosimilares. Reumatol Clin. 2015;11(5):269-278.

In terms of efficacy and safety, starting with the
biological treatment is the same as starting with the
reference medicine.
7
3
In a patient who must start treatment
with a biological medicine, the
reference medicine and the biosimilar
offer the same guarantees in terms of
quality, safety and efficacy1.
Choosing one or the other is up to
the doctor and must take place in the
context of a conversation with the
patient, who must be in agreement3.
Dose
=
Administration
route
Once the biosimilar has
demonstrated in the comparability
studies that it is structurally and
functionally equivalent to the
reference medicine - and, therefore,
the regulatory agencies have
authorised it -, it is basically
considered to be a version of the
same medicine, in the same way as
two batches of any original medicine
can also be considered versions of
the same medicine2.
The most important difference
between a biosimilar medicine and its
reference medicine is the price. The
lower cost of biosimilars allows more
patients, on an equal budget, to
benefit from treatment with
biologicals and other novel
medicines, and contributes to the
sustainability of the health system3.
Efficacy
Price
=
Safety
Given the equivalence in terms of
efficacy and safety, the economic
factor and other aspects should be
taken into account in the decision to
start a treatment with a
Since they are considered
equivalent, the biosimilar medicine
can be used in the same conditions
and in the same patients in which the
reference medicine would be used2.
Original Biosimilar 3 Abad Hernández MA, Andreu JL, Caracuel Ruiz MA, Belmonte Serrano MA, Díaz-González F, Moreno Muelas JV. Documento de
posicionamiento de la Sociedad Española de Reumatología sobre fármacos biosimilares. Reumatol Clin. 2015;11(5):269-278.

Switching from a reference medicine to a biosimilar is
safe.
8
4
Medicine
Biosimilar
Medicine
Reference
There is much evidence coming from
both clinical trials and real-life data of
switching from a reference medicine
to a biosimilar for non-clinical
reasons, in stable patients. The
conclusions are that switching is
effective and safe1,2,3.
Rheumatology - are in favour of
switching from the reference
medicine to the biosimilar, provided
the decision is shared between the
doctor and the patient5.
As a precaution, switching must be
prescribed by the doctor; and the
automatic substitution. in a pharmacy
of one biological by another is
prohibited by law6. The acceptance of
switching requires that doctors and
patients be trained and given
information on biosimilars1.2.
There should not be any scientific
rational that would make us think that
such switching between biosimilars
of the same reference medicine
could produce a different clinical
outcome4.
Data on multiple switches between
biosimilar and reference medicine
(multi-switch) are still scarce2.4.
Most scientific organisations - for
example, the European League
Against Rheumatism (EULAR), the
EMA and the Spanish Society of
1 Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching Reference Medicines to Biosimilars: A
Systematic Literature Review of Clinical Outcomes. Drugs. 2018;78:463-478.
2 Wiland P, Batko B, Brzosko M, Kucharz EJ, Samborski W, Świerkot J, et al. Biosimilar switching –current state of
knowledge. Reumatologia. 2018;56(4):234-242.
3 La Noce A, Ernst M. Switching from Reference to Biosimilar Products: An Overview of the European Approach and Real-World
Experience So Far. EMJ. 2018;3(3):74-81.
5 Medicines for Europe. Positioning Statements on Physician-led Switching for Biosimilar Medicines [internet]. Updated in January 2019.
6 Order SCO / 2874/2007, of 28 September.

Switching from a reference medicine to a biosimilar
must be carried out on the initiative of the prescribing
doctor or with their consent and with the patient's
knowledge.
9
Most countries, including Spain, have
banned (under the law) the
replacement of one biological with
another in a pharmacy without the
endorsement of the prescribing
doctor. The pharmacist cannot
therefore switch biological medicines
without the authorisation of the
doctor.1
Switching must be carried out within
the context of a transparent doctor-
patient relationship. The decision
must be agreed between the doctor
and the patient2. This is
recommended by different scientific
societies (SER, ECCO, etc.)3.
Some patients with rheumatic
diseases may be reluctant to switch
from the reference medicine to the
biosimilar, for fear that it is less
effective or has more
adverse effects. It is important to
explain that the scientific evidence
shows that this fear is unfounded2.
Switching is more likely to succeed if
it is performed in a structured way -
with face-to-face visits, written
information, possibility of having
queries answered - and involves
various professionals (doctor, nurse,
pharmacist)4.
The first step to switching is for the
doctor and other professionals to
acquire the appropriate knowledge
about biosimilars and trust them.
There are many sources of
information: scientific studies, guides,
courses, etc.5.
1 Order SCO / 2874/2007, of 28 September.
3 Medicines for Europe. Positioning Statements on Physician-led Switching for Biosimilar Medicines [internet]. Updated in January 2019.
4 Edward C. Switching patients from originator to biosimilar medicines in rheumatoid arthritis: limiting the nocebo effect. EMJ Rheumatol.
2017;4(1):42-48. 5 Rezk MF, Pieper B. Treatment Outcomes with Biosimilars: Be Aware of the Nocebo Effect. Rheumatol Ther. 2017;4:209-218.

Appropriate communication with the patient is
essential to prevent or minimise the possible nocebo
effect caused by switching between the reference and
biosimilar medicine.
10
1
The nocebo effect is the worsening or
appearance of adverse effects to a
treatment, which is not related to the
medicine but is due to the patient's
negative expectations. One of the
factors that favour it most are the
negative attitudes of the doctor
(comments or non-verbal
manifestations that show distrust of
the biosimilar), usually due to lack of
knowledge1.
Communication from the doctor and
other healthcare professionals to the
patient is essential to prevent the
nocebo effect and encourage the
patient to accept the switch1.
essentially the same product.
Enquiries must be made about the
patient’s beliefs, fears and
expectations in order to focus the
message on these. Warnings can be
made about the nocebo effect2.
How the message is formulated is
also influential. It is better to use
positive words and avoid negative
words. The messages should be
clear and short. Make sure that the
patient has understood and
encourage them to ask questions. It
is important to take note of gestures;
non-verbal communication1,2.
Good communication and adequate
information favours adherence to the
treatment.2
The information must be true, but
focused on positive aspects, rather
than on adverse effects. The idea
must be emphasised that biosimilar
and reference medicines are
1 Rezk MF, Pieper B. Treatment Outcomes with Biosimilars: Be Aware of the Nocebo Effect. Rheumatol Ther. 2017;4:209-218. 2
Bingel U. Avoiding Nocebo Effects to Optimize Treatment Outcome. JAMA. 2014;312(7):693-694.

Dismantling a myth. Biosimilars are medicines that are
"second class”, lower quality and less effective and safe
than reference medicines.
+
1
Biosimilars are biological medicines
that are highly similar to the original
ones. The small differences - due to
the complexity of the molecule and
the production process - are
equivalent to those between the
different batches of the reference
medicine and do not affect the
medicine's quality, efficacy or safety.
Variability is intrinsic to all
biologicals1.
The data necessary for authorising a
biosimilar are different from those
necessary to approve a reference
medicine, since they are based on
comparison studies designed to
demonstrate biosimilarity (that is,
they have the same physicochemical
properties, safety and efficacy as the
original). Although different, these
requirements are equally rigorous
and exhaustive, and are
also based on scientific data. The
pharmacovigilance to which they are
subjected is also the same1.
The fundamental difference lies in
the lower price of biosimilars, given
that the development process
requires fewer resources. This does
not diminish their quality or mean that
they are worse medicines.
Biosimilars use the same route of
administration as their reference
medicines, since, in essence, they
are the same product2.
Many studies have shown that
switching from a reference medicine
to its biosimilar is a safe practice
which does not affect the treatment's
efficacy or safety3.
2 Kay J, Schoels MM, Dörner T, Emery P, Kvien TK, Smolen JS, et al. Consensus-based recommendations for the use of biosimilars to
treat rheumatological diseases. Ann Rheum Dis. 2018;77:165-174.
3 Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching Reference Medicines to Biosimilars: A Systematic
Literature Review of Clinical Outcomes. Drugs. 2018;78:463-478.

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