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Biologics and biosimilars
An overview
Contents
An introduction to biotechnology................................................................................. 3
A brief history of medicine development.................................................................................... 4
What are biologic medicines?.................................................................................................... 5
How are biologic medicines developed?.................................................................................... 6
The value of biotechnology........................................................................................................ 8
What are biosimilar medicines?............................................................................................... 10
How do biosimilars differ from the original innovator medicines?........................................... 11
The emerging role of biosimilars ............................................................................................ 12
The cost of developing biosimilars ......................................................................................... 12
Regulating biosimilars....................................................................................................... 13
Approval pathways for biologic and biosimilar medicines....................................................... 14
Biosimilar regulations.............................................................................................................. 18
Pharmacovigilance, traceability & naming............................................................ 21
Naming, tracking and tracing medicines.................................................................................. 22
WHO biologic naming policy................................................................................................... 23
Substitution and interchangeability.......................................................................... 25
The variation in global substitution guidelines ........................................................................ 26
Manufacturing biologics.................................................................................................. 31
The manufacturing process is unique to every manufacturer ................................................... 34
Striving to ensure a consistent supply .................................................................................... 35
Glossary .................................................................................................................................... 37
Works cited.............................................................................................................................. 43
©2014
Amgen Inc. All rights reserved. March 2014.
1
2
An introduction to
biotechnology
An introduction
to biotechnology
An introduction to
biotechnology
Amgen was one of the first companies to
recognize the potential of modern biotechnology
in developing valuable medicines for patients
– and to assemble the diverse set of skills
necessary to advance from hard to applied
science. A leader in biotechnology since 1980,
Amgen is focused on serving patients by
discovering, developing and manufacturing
innovative human therapeutics. By pioneering
the development of novel products based on
advances in cellular and molecular biology,
Amgen’s therapeutics have changed the practice
of medicine and helped millions of people
around the world to fight cancer, kidney disease,
rheumatoid arthritis and other serious illnesses.
An introduction
to biotechnology
The term biotechnology was
first coined in 1919 to describe
the interaction between biology
and human technology for the
conversion of raw materials into
socially valuable products.
At the time, the focus was on food
production but by the 1940s early
advances in the technology had led
to the development of medicines;
enabling the mass production of
antibiotics, such as penicillin,
which continue to be used to
control infectious diseases.
The breakthrough that laid
the groundwork for modern
biotechnology came when the
structure of DNA was discovered
in the early 1950s.
A standard definition of
biotechnology was not reached
until the United Nations and World
Health Organization accepted the
1992 Convention on Biological
Diversity and defined biotechnology
as “any technological application
that uses biological systems, living
organisms or derivatives thereof,
to make or modify products and
processes for specific use.” (1)
3
A brief history of
medicine development
The first medicinal drugs came from
natural sources and existed in the
form of herbs, plants, roots, vines
and fungi. Until the mid-nineteenth
century these natural remedies were
all that was available to treat some
conditions. The first synthetic drug,
chloral hydrate, was discovered in
1869 and introduced as a sedativehypnotic. The first pharmaceutical
companies were spin-offs from the
textiles and synthetic dye industry
and owe much to the rich source of
organic chemicals derived from the
distillation of coal (coal-tar). (2)
For many years, the pharmaceutical
industry traditionally developed
chemical drugs (also referred to
as small molecules), including
well-known medicines such as
acetylsalicylic acid, to treat a wide
range of illnesses. Since the 1970s,
a revolution in biotechnology has
resulted in a new class of medicine:
the biologic.
Acetylsalicylic acid
Small molecule
IgG1 antibody
Biologic medicine
21 atoms
> 20,000 atoms
What are biologic
medicines?
A biologic medicine is a large
molecule typically derived from
living cells and used in the
treatment, diagnosis or prevention
of disease. Biologic medicines
include therapeutic proteins, DNA
vaccines, monoclonal antibodies
and fusion proteins. Biologic
medicines are often 200 to 1,000
times the size of a small molecule
drug and are far more complex
structurally. They are also highly
sensitive to their manufacturing
and handling conditions, making
them more difficult to characterize
and produce than small molecule
drugs. Due to both their size and
sensitivity, biologic medicines
are almost always injected into a
patient’s body and individual patient
responses can depend on how a
biologic is made.
5
How are biologic
medicines developed?
DNA to build a functional DNA
sequence. The DNA sequence is
introduced into the host cell of a
living organism, such as bacteria,
yeast or mammal cells, altering
the cell’s genetic makeup and
coding it to produce the chosen
protein. Genetically modified cell
lines are carefully selected and
cultured in large bioreactors before
the biologic medicine is extracted
through complex and lengthy
purification processes.
Biologic medicines are made
in living organisms to produce
proteins to treat various diseases,
often by genetically modifying
cell constructs or cell lines.
DNA technology is often used to
insert desirable genes or remove
undesirable ones within a living
cell or via a vector such as a virus,
prompting a specific function –
such as the production of a protein
to treat disease. Biotechnology has
led to the development of many of
today’s most important medicines,
including monoclonal antibodies
for the treatment of cancer, human
insulin for the treatment of diabetes
and the cloning of the naturally
occurring protein, erythropoietin
to stimulate the production of red
blood cells in the treatment of
chronic anemia. (3)
Each of the thousands of steps
is intricate, sensitive and often
specific to a particular medicine,
requiring robust quality systems,
significant experience, expertise
and financial investment. Even
minor alterations may lead to
changes in cell behavior and
differences in the structure, stability
or other quality aspects of the end
product. Any of these differences
have the potential to affect the
treatment’s safety, efficacy and/or
shelf life, and to increase the risk of
an unwanted immune response.
The genetic code of a chosen
protein, such as human insulin
or an immune system antibody,
is identified and replicated by
combining different segments of
Chromosome
Gene
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01
Biologic medicines are made in living
organisms by genetically engineering DNA.
DNA is inserted into living cells, such as bacteria,
yeast or cultured animal cells, to code for the
production of a particular protein.
02
The biologic is modified to ensure it
functions as intended. Specific chemicals
are added to control the function of the biologic.
Translating high science: from laboratory to better patient care
03
The most effective cell line is selected for
expansion. During selection, the cells that can
produce the biologic most effectively are identified
and expanded to manufacture the medicine. This cell
line is unique to each manufacturer and is the source
of all future product.
04
The unique cell line is grown in
bioreactors and carefully monitored.
The biologic drug is then isolated and
purified using sophisticated technology.
Discover more on the manufacturing of biologic
medicines by visiting the Amgen YouTube
channel at youtube.com/user/Amgen
7
The value of biotechnology
Today’s biologic medicines have
made a significant difference to
the lives of patients with serious
illnesses, including cancer,
blood conditions, auto-immune
disorders such as rheumatoid
arthritis (RA) and psoriasis, and
neurological disorders like multiple
sclerosis. Recreating human
proteins into biologic medicines
has revolutionized how we treat
disease. (5)
underlying causes of disease,
potentially altering the course of
disease rather than simply treating
symptoms. (6)
Worldwide, nearly 200
biologic medicines have
transformed the lives of over
800 million patients with
serious illnesses. (3)
By understanding the mechanisms
of diseases, such as multiple
sclerosis, biologic medicines can
be developed to target and modify
The development of new biologic
medicines may be the best hope
for effectively treating diseases for
which there are currently no cures.
The mapping of the human genome
– one of the most significant
advances in biotechnology –
has led to an escalation in
biotechnology research, including
experimental therapies such as
stem cell and gene therapy.
Today, over 400 biologic medicines
worldwide are being studied in
serious illnesses, such as HIV/
AIDS, Alzheimer’s disease, cancer,
cardiovascular disease and
autoimmune disorders. (3)
A 2013 report (1) from the European
Commission looking at Europe’s strong
regulatory and commercial foundation
for biosimilars found that biosimilars are
helping improve competition and are thus
increasing access to biologic medicines
for patients. Read the report here:
http://ec.europa.eu/enterprise/
sectors/healthcare/files/docs/
biosimilars_report_en.pdf
8
An introduction to
biotechnology
Targeting disease pathways
to benefit patients
Cancer: Following cancer pathways and
determining the molecular basis of cancer
has led to the development of new targeted
diagnostics and treatments. Traditionally, cancer
has been treated with surgery, radiation and
chemotherapy. Biotechnology has contributed
to significant advances in cancer treatment,
including hormone therapies, biologic
medicines and targeted therapies such as
monoclonal antibodies. (3)
9
Defining biosimilars
What are biosimilar medicines?
Unlike generic medicines where the active
ingredients are identical, biosimilars are
similar to but not identical copies of the
originator biologic. They are similar, but
not the same. Biologics made by different
manufacturers differ from the original
product and from each other.
The complexity of biologics precludes
identical copies and are therefore
not the same as generic drugs. Due
to the complex structure of biologic
medicines and the processes involved
in production, biosimilars must be
determined on the basis of analytical,
non-clinical and clinical data to be
similar to an original biologic in terms
of structural characteristics, and safety
and efficacy. Minor differences with
the active ingredient are expected and
permitted so long as any such differences
are demonstrated not to be clinically
meaningful. (7) The patents of a growing
number of biologic medicines have
already expired or are due to expire, which
has led to an increased interest in the
development of biosimilars. (11)
Original biologic
The World Health Organization:
A biotherapeutic product which is similar
in terms of quality, safety and efficacy
to an already licensed reference
biotherapeutic product. (8)
The European Medicines Agency:
A biosimilar is a biological medicinal
product that contains a version of the
active substance of an already authorized
original biological medicinal product
(reference medicinal product). A biosimilar
demonstrates similarity to the reference
product in terms of quality characteristics,
biological activity, safety and efficacy
based on a comprehensive comparability
exercise. (9)
The U.S. Food and Drug
Administration: A biological Product that
is highly similar to a U.S. licensed reference
biological product notwithstanding
minor differences in clinically inactive
components, and for which there are no
clinically meaningful differences between
the biological product and the reference
product in terms of the safety, purity and
potency of the product. (10)
Biosimilars
Similar to snowflakes, biosimilars from different manufacturers differ from their
originator biologic medicines and from each other.
10
How do biosimilars
differ from the original
innovator medicines?
The active ingredient of a
biosimilar is expected to closely
resemble that of the original
biologic. Unlike generic medicines
(small molecules) where the
active ingredient is required to
be identical, the manufacturing
process through which a biologic
(large molecule) is made cannot
be exactly duplicated by another
manufacturer. (12)
There are naturally occurring
differences between an originator
and biosimilar medicine:
•Biologic medicines are not
made using a set of standard
materials, but are developed
using unique biological systems
and living cells. As a result, the
active ingredient is impossible to
recreate exactly and the selected
cell lines from which the biologic
medicine originates are unique to
each manufacturer. (13)
•The manufacturing process for
biologic medicines requires
dozens of steps involving
hundreds of variables and is
generally more complex than
manufacturing processes for
chemical drugs. Any variation
in this complex process can
affect a biologic product’s
stability, efficacy, safety and/
or immunogenicity. Unlike
small molecule drugs, biologic
medicines are produced in
genetically-engineered living
cells that are sustained in a
highly-controlled environment.
The protein produced by the cells
will be influenced by individual
cell characteristics as well as
the environment and nutrients
provided.
•The manufacturer has different
processes that create distinctive
characteristics in the product,
which are specific to the
manufacturer. This creates a
unique relationship between a
biologic’s manufacturing process
and the final product approved by
regulators. (12)
11
The emerging role of biosimilars
Countries around the world face a growing,
aging population and an increase in chronic
disease. (14) With expanding demand for
good-quality healthcare comes the challenge
of controlling healthcare expenditure. The
regulated introduction of biosimilars into the
market has been forecasted to increase access
to much needed biologic medicines and
reduce costs. (12)
Over the next few years, we will continue to
see a new generation of complex biosimilars
being developed as numerous leading biologic
medicines, worth an estimated $81 billion
in global annual sales, will lose their patents
by 2020. (15) Fusion proteins and monoclonal
antibodies used in cancer and autoimmune
diseases are expected to form a substantial
proportion of this new line of biosimilars. (16)
Based on experience gained by the European
Medicines Agency (EMA) since the introduction
of a regulatory mechanism for developing,
reviewing and approving biosimilars in the
European Agency, the EMA has updated its
overarching guidance on the general principles
of Biosimilar development, quality and nonclinical and clinical issues. In addition, class
specific guidelines for growth hormones,
monoclonal antibodies, GCSFs, recombinant
follicle stimulating hormones, interferons, lowmolecular weight heparins and recombinant
insulin products have been developed.
The biologic medicines market is expected
to grow to $190-200 billion by 2015, with
biosimilars a small but growing proportion
at $2-2.5 billion. (17)
12
The cost of
developing biosimilars
Biosimilar manufacturers must
invest in clinical trials, manufacturing and post-approval safety
monitoring programs similar
to that of the original innovator
companies.
According to Sandoz, the cost
of developing a generic small
molecule is around $2-3 million,
whereas biosimilars have been
estimated to cost around
$75-250 million to reach
approval, (18) largely due to the
clinical studies and comparability
exercise required to demonstrate
biosimilarity.
Because of this investment,
cost savings achievable with
biosimilars may not be as great
as can be experienced with small
molecule generics. (12)
Regulating biosimilars
Regulating
biosimilars
Regulating biosimilars
“The approach established for generic medicines
is not suitable for development, evaluation and
licensing of similar biotherapeutic products
(SBPs) since biotherapeutics consist of relatively
large and complex proteins that are difficult
to characterize”. (8)
The World Health Organization
Regulating
biosimilars
In 2009 the World Health Organization developed a set of globally accepted
standards to assure the safety, efficacy and quality of biosimilar medicines.
These have been developed in the wake of increased interest in biosimilars
by local regulatory authorities seeking to develop national standards. (8) (25)
Reference product
The reference product should be authorized in the country or region in question
Quality
All aspects of quality and heterogeneity should be assessed including
head-to-head comparisons with the reference product
Non-clinical data
Should include pharmacodynamic, pharmacokinetic and comparative repeat-dose
toxicity studies in a relevant species
Clinical studies
Required to demonstrate similar safety and efficacy. Immunogenicity should
always be investigated in humans before authorization
Pharmacovigilance and risk management
A pharmacovigilance plan is required when an application is submitted and a risk
management plan may be necessary in some cases
World Health Organization (WHO) guidance on biosimilar development standards (25)
13
Approval pathways for
biologic and biosimilar
medicines
Before marketing authorization is
granted by regulators such as the
U.S. Food and Drug Administration
(FDA) or the European Medicines
Agency (EMA)/European
Commission (EC), originator
companies and biosimilar
manufacturers must submit robust
data to demonstrate a product’s
efficacy and safety profile. Extensive
analytical chemistry, manufacturing
and control (CMC), non-clinical
and clinical evidence will likely
be required for the relevant
therapeutic area. (7) (26)
The approval pathway for a
biosimilar medicine may be
abridged in comparison to the
originator product. Where there
are approval pathways, in order
to gain approval as a biosimilar,
the manufacturer must provide
substantial data to show that its
product is sufficiently similar
to the original product. This
demonstration should be step wise
in approach, firstly demonstrating
similarity in physic-chemical
inspection of the biosimilar to
the reference medicinal product,
then in non-clinical studies and
finally in clinical trials. Overall,
the biosimilar must demonstrate
that it has no significant clinical
14
differences to the reference
product, but some limited variation
is permitted. This is because
biosimilar approval is based on
a demonstration of similarity to
a previously approved originator
product rather than a de novo
demonstration of safety and
effectiveness. (7) (8)
A decision on how extensive
clinical data needs to be depends
on each individual case. However,
the amount of clinical efficacy
and safety data is likely to be less
for a biosimilar than the original
biologic. (27)
The 2012 draft FDA biosimilar
guidance provides a list of factors
that a sponsor should consider
when assessing the similarity of its
proposed products including:
• Expression system
• Manufacturing process
• Physicochemical properties
• Functional activities
• Receptor binding and
immunochemical properties
• Impurities
• Characterization of the reference
product and reference standards
• Characterization of the finished
drug product
• Stability (10)
Due to the varied nature of
biotechnology products and their
potential risks, manufacturers
of both biologic medicines and
biosimilars are required to submit
pharmacovigilance and risk
management plans as part of their
application. (8) (30)
United States
Biosimilar
Originator
Clinical S&E
Clinical S&E
Clinical Pharm
Clinical Pharm
Non clinical
Non clinical
Quality
Quality
European Union
Originator
Clinical
Cross reference
Cross reference
(extrapolation?)
Non clinical
Quality
Biosimilar
Clinical
Non clinical
Comparability data
Quality
Not to scale. Comparison of originator and biosimilar marketing approvals process in the US and EU (28) (29)
15
Guiding the way for biosimilars development
Europe
•The European Medicines Agency (EMA)/European Commission (EC) was the
first major regulatory authority to implement a framework for the marketing
authorization of biosimilars and has one of the most detailed and stringent
guidelines for developing biosimilars.
•The guidelines outline an approach for comparing the proposed biosimilar to
the original biologic, in terms of quality, safety and efficacy. (7)
•Product-specific guidelines for some biosimilar medicines, eg: recombinant
erythropoietin, are provided by the EMA/Committee for Medicinal Products
for Human Use (CHMP), outlining the data requirements and studies
necessary to demonstrate comparability.
• The EMA/CHMP guidelines are widely considered the gold standard, with
countries such as Australia, Canada, Japan, Korea and South Africa using
them as a basis for their own regulations. (31) (32)
16
United States
•In March 2010, the U.S. biosimilar pathway was signed into law as
part of the Affordable Care Act. In February 2012, the Food and Drug
Administration (FDA) issued three draft guidance documents on biosimilar
product development to assist industry in developing such products in the
United States. What, if any, additional guidance FDA may issue, and when,
is uncertain. (26)
•The FDA recommends a stepwise approach to demonstrate biosimilarity
between a proposed medicine and the original biologic. The aim is to
demonstrate no clinically meaningful difference in terms of safety, potency
and purity. The guidance provides advice on the types of rigorous studies
that should be undertaken by the manufacturer to address uncertainty
about the proposed product.
•To comply with this approach, a sponsor should include:
»» Structural analysis: Using state-of-the-art technology to display,
for example, primary and higher order structures, post-translational
modifications and intentional chemical modifications.
»» Functional assays: Appropriate studies including: bioassays,
biological assays, binding assays and enzyme kinetics. FDA
recommends that any functional assays performed should be
comparative “so they can provide evidence of similarity or
reveal differences...”
»» Animal data: Including toxicity studies, pharmacokinetic and
pharmacodynamic measurements and immunogenicity studies.
»» Human clinical studies: Including pharmacokinetic and
pharmacodynamic measurements, immunogenicity results and safety
and efficacy data. Studies should demonstrate that the proposed
product has neither decreased nor increased activity compared to the
reference product.
»» The FDA has discretion to waive any requirement deemed unnecessary. (26)
17
2001 2001 2002 2002 2003 2003 2004 2004 2005 2005 2006 2006 2007 2007
The EMA
Thepublished
EMA published
the firstthedirective
first directive
relatingrelating
to differences
to differences
in raw in
materials
raw materials
or manufacturing
or manufacturing
processes
processes
between
between
biosimilar
biosimilar
and reference
and reference
products
products
Biosimilars are a relatively
new, emerging market.
Regulatory guidelines and
standards are still being
developed in some countries
and they are constantly evolving
as technology develops.
Biosimilar regulations
The EMA was the first Regulatory
Agency to create biosimilar
guidelines in 2005, swiftly followed
by the first approved biosimilar
products in 2006. As of December
2013, 16 biosimilar products were
approved by the EMA. (17)
These approvals cover five classes
of Biosimilar:
•Recombinant erythropoietins
(epoetin alfa, epoetin zeta)
•Recombinant granulocyte-colony
stimulating factors (filgrastim)
•Recombinant human growth
hormone (somatropin)
•Recombinant follicle stimulating
hormone (follitropin alfa)
•Monoclonal antibodies
(infliximab)
18
Guideline
Guideline
development
development
EU
EU
Legal Legal
Pathway
Pathway
EU
EU
Overarching
Overarching
Guidelines
Guidelines
The EMA
Thepublished
EMA published
the firstthebiosimilar
first biosimilar
regulatory
regulatory
approval
approval
pathway
pathway
for for
the EUthe
member
EU member
states states
AUS AUS
As more
As governments
more governments
develop
develop
biosimilar
biosimilar
pathways,
pathways,
the WHO
the WHO
and EU’s
andestablished
EU’s established
guidelines
guidelines
will continue
will continue
to serve
to serve
as a as a
template,
template,
as demonstrated
as demonstrated
by Australia’s
by Australia’s
unadulterated
unadulterated
adoption
adoption
of the of
EUthe
guidelines
EU guidelines
Regulation has evolved rapidly
with many countries establishing
national guidelines based on the
WHO and EMA/EC framework.
Guidelines are helping to open
up the development and approval
of biosimilars worldwide, but
definitions and terminology for
biosimilarity vary, as does guidance
on the original reference product
for comparability studies and
the scope of data required for
marketing approval. (31)
Biosimilar Regulations
Global guideline/regulation development
2008
2009
2010
2011
2012
TUR
KOR
CAN
ARG
USA
(draft)
MYS
JPN
ZAF
MEX
COL
(draft)
TWN
SIN
BRA
CUB
2013
EU
Revised
Guidelines*
EU
Non-clinical
and clinical
Guidelines†
JOR
(draft)
WHO
SAU
The WHO biosimilar guideline, aimed
at providing a consistent scientific
standard, is the reference for many
newly developed biosimilar pathways
WHO = World Health Organization
* Update to the 2006 guidelines; in consultation until October 2013
† Update to the 2006 guidelines; in consultation until November 2013
IRI
IND
PER
THA
(draft)
EU
Update to Quality
Issues Guideline
Some emerging markets have developed their own regulatory pathways
for biosimilars, hoping to meet a growing demand for biologic medicines.
Singapore and Malaysia amended their guidelines mainly in accordance
with the EMA guidelines, while Brazil and Cuba chose the WHO and
Canadian guidelines as the basis for developing regulations. (31) India
released official guidelines in June 2012, (33) before which around 20
biosimilars were approved for use within India under an ad hoc abbreviated
process. (34) The WHO will continue to monitor progress.
19
20
Pharmacovigilance,
traceability & naming
Pharmacovigilance,
traceability & naming
Pharmacovigilance,
traceability & naming
“It should be recognized that, by definition,
similar biological medicinal products are not
generic medicinal products, since it could be
expected that there may be subtle differences
between similar biological medicinal products
from different manufacturers or compared with
reference products, which may not be fully
apparent until greater experience in their use has
been established. Therefore, in order to support
pharmacovigilance monitoring, the specific
medicinal product given to the patient should be
clearly identified.” (36)
The European Medicines Agency
Pharmacovigilance,
traceability & naming
Rigorous pharmacovigilance
programs are needed to protect
patients and ensure any adverse
events are quickly detected,
reported and attributed to the
correct product and manufacturer.
An important concern with all
biologic medicines is the risk of
an unwanted immune response,
where the patient reacts against
proteins in the medicine, limiting
its efficacy or affecting its safety. (30)
Healthcare systems must ensure
all biologic medicines, including
biosimilars, can be rapidly and
accurately identified by national
regulators, healthcare providers
and patients.
Safety monitoring and ongoing
pharmacovigilance of medicines
involves detection, assessment,
understanding and prevention of
adverse effects. As clinical trials
involve a relatively small number of
patients, potential adverse events
may be unknown at the time of
launch. (8) As with all medicines, the
safety of biosimilars is monitored
post marketing to assess and
identify any long-term or rare
adverse events.
In Europe and the U.S., it is
obligatory for the manufacturers of
all biologic medicines to submit
comprehensive pharmacovigilance
and risk management plans when
applying for approval. Potential
pharmacovigilance programs
may be a greater consideration
for biosimilars, where the clinical
safety and efficacy package is likely
to be more limited at launch than
that of the original biologic. (11)
Risk management and postmarketing pharmacovigilance
considerations should include:
•Pre and post-authorization
comparative testing
• Regular tests to ensure that the
manufacturing processes are the
same, as biosimilarity and immunogenicity are dependent on this
• Risk management in case of
adverse drug reactions (35)
21
Connecting worldwide adverse event reporting
The WHO Program for International Drug Monitoring is based on the
principle of international collaboration in the field of pharmacovigilance.
Over 100 member nations have systems in place that encourage
healthcare professionals to record and report adverse drug reactions in
their patients. These reports are assessed locally and may lead to action
within the country. Through membership of the WHO program, one
country can know if similar reports are being made elsewhere. (37)
Naming, tracking
and tracing medicines
The ability to track and trace all
biologic medicines and biosimilars
throughout the product lifecycle is
critical to protecting patient safety.
Physicians need accurate data on
adverse events linked to treatments
to ensure they are prescribing safe
and effective medicines to patients.
Scientific names are the foundation
of product identification and
therefore, accurate record keeping
and attribution of adverse events.
Currently, the International Nonproprietary Name (INN) for a new
biosimilar may be the same as that
of the original biologic medicine.
In such a case, if only the INN,
without a distinguishable name,
is used when prescribing a
biologic medicine, the treating
physician may not know precisely
which medicine a pharmacist gave
the patient.
22
Without distinguishable INNs,
a reporter may be unable to
immediately identify which
medicine was given when a patient
experiences an adverse event.
It could then be unclear which
medicine caused the adverse
event, which may lead to a delay
in establishing the root cause of
the problem. (38)
Regulations are being tightened
to improve identification and
traceability of biologic medicines.
In August 2013 the Therapeutic
Goods Administration in Australia
issued guidance for the evaluation
of biosimilars which includes
guidance on distinguishable names
for biosimilars. A similar naming
program is recommended by the
WHO and national regulatory
bodies, such as the UK’s Medicines
and Healthcare products Regulatory
Agency (MHRA). (40)
In 2012, the European Commission
introduced new pharmacovigilance
legislation (made up of a regulation
and a directive), which was the
biggest change to the regulation
of human medicines in Europe
since 1995.
It is now a legal requirement for
EU Member States to take all
necessary measures to clearly
identify the biological medicines
that are prescribed, dispensed
and sold in their country. Member
States are empowered to impose
these requirements on doctors,
pharmacists and other healthcare
professionals. (39)
Amgen – who develops both
originator and biosimilar medicines –
believes prompt identification and resolution
of product problems can be enabled by
distinguishable, non-proprietary names for
all biologics. This would help:
WHO biologic naming policy
In March 2013 WHO published
minutes from the 55th INN
Consultation meeting in October
2012 that outline the INN
Committee’s proposed options for
adopting a policy of distinguishable
non-proprietary names for biologic
medicines. The minutes outline
the WHO’s objective to improve
the current INN naming system
to allow for global consistency
and avoid inadvertent switching
of products between patients, in a
sustainable way.
Amgen believes that healthcare
systems globally must ensure
all biologic medicines, including
biosimilars, can be rapidly and
accurately identified by national
regulators, healthcare providers
and patients.
• Facilitate prompt identification and
resolution of product problems
• Facilitate manufacturer accountability
• Avoid incorrectly implying that the
molecules are identical
23
Amgen supports policies to create distinguishable
non-proprietary names for all of our biologic
(innovator and biosimilar) medicines.
Distinguishable names for all
biologics will reduce the likelihood
of inadvertent and inappropriate
product switching and strengthen
the accuracy of tracing via postmarketing safety monitoring
systems.
In 2012, the FDA embodied a
patient safety-focused approach to
naming biologic medicines. Two
biologics approved through the
FDA’s 351(a) BLA pathway required
distinguishable, non-proprietary
names by adding a prefix with a
hyphen: ziv-aflibercept (Zaltrap®)
and tbo- filgrastim (GRANIX™).
These biologics are related to
previously approved products –
Regeneron’s Eylea® (aflibercept)
and Amgen’s Neupogen®
(filgrastim) respectively. (41) (42)
24
The FDA concluded that the
non-proprietary names for
ziv- aflibercept and tbo-filgrastim
should be different to their
reference biologics, to avoid
patients receiving the incorrect
product and to reduce confusion
among healthcare providers who
may perceive them to be clinically
the same, because they have the
same non-proprietary name. (41)
The FDA has also made the
broader conclusion that the use of
distinguishable non-proprietary
names will help post-marketing
safety monitoring, allowing better
traceability of medicines in the case
of an adverse event. In addition,
the use of brand names alone
was determined to be insufficient
as brand names are often not
used by healthcare professionals
for prescribing, and many
pharmacovigilance systems do not
require them. (41)
Substitution and
interchangeability
Substitution and
interchangeability
Substitution and
interchangeability
Substitution and
interchangeability
Most generics are considered
to be therapeutically equivalent
(or interchangeable) with their
reference products, (43) meaning
the effects of both drugs are
expected to be identical and that
consequently it doesn’t matter
which drug the patient receives
at any time. (13) In the U.S. drugs
that are interchangeable are given
an AB-rating by the FDA. (44) By
contrast, although biosimilars are
similar to their reference products,
they are not clinically identical and
there is scope for differences in
effects in patients. (12)
Substitution (sometimes called
automatic substitution) is often
permitted for generics that are
considered to be interchangeable
or clinically identical. The
practicalities of substitution
vary from country to country.
In some countries, the doctor
is encouraged to prescribe
substitutable medicines by INN,
leaving the pharmacist to decide
which brand (generic or reference
product) to dispense, whereas in
other countries the pharmacist
may dispense a generic of a
substitutable medicine even where
the doctor has prescribed the
reference product by brand. (38)
In all cases, however, the essential
features of substitution are that:
•it is the pharmacist (and not the
doctor) who decides which brand
the patient receives;
•the doctor is not routinely
informed of which brand the
patient has received;
•the patient may potentially receive
a different brand every time their
medicine is dispensed.
25
Because generic medicines are
therapeutically equivalent with their
reference products, substitution
does not usually have any negative
impact on the patient or on public
health. (13) However, biosimilars
are not identical to their reference
products so substitution of
biosimilars with their reference
biological products can result in
problems, such as:
• A lack of traceability in the case of
an adverse event. If substitution
has taken place, the doctor may
not know which brand was used
and so only the INN can be
included in the adverse event
report. This lack of traceability
may prevent identification of the
particular product responsible for
the adverse reaction. (12)
• Confusion in tracing the cause
of a delayed adverse event. Some
adverse reactions, including many
immunogenic reactions such as
pure red cell aplasia (PRCA), are
delayed in onset and may develop
only after several months of
treatment. (45) (46) With substitution
and frequent switching between
products, a patient may receive
several different products prior to
an immunogenic reaction.
26
This makes tracing the medicine
responsible for the reaction very
difficult, even when each different
product can be identified by
brand. (13)
Regulatory authorities recognize
the risks of substitution for biologic
medicines, and in Europe the EMA
states that for questions related
to switching from one biologic
medicine to another, patients
should speak to their doctor and
pharmacist. (9)
Across the EU, decisions on
prescribing practices such as
substitution are made at the
national level. In many countries
(eg: Italy and Germany), biologic
medicines are specifically excluded
from lists of products suitable
for substitution (15), whereas in
other countries where substitution
is permitted only for INN-only
prescriptions (eg: Sweden and
UK) doctors are urged to prescribe
biologics by brand.(47)
Substitution and interchangeability at a glance
U.S. – FDA
The FDA can designate a biosimilar as an interchangeable
biologic when the following criteria are met:
1.The biologic product is biosimilar to the reference biologic
product; and
2.It can be expected to produce the same clinical results as the
reference product in any given patient; and
3.For a biological product that is administered more than once to
an individual, the risk in terms of safety or diminished efficacy
of alternating or switching between use of the biological product
and the reference product is not greater than the risk of using the
reference product without such alternation or switch. (47)
Europe – EMA
Decisions on substitution are made at national level. In many
EU countries, automatic substitution of biologics is officially
prohibited or not recommended. (9)
WHO
The WHO does not define standards on interchangeability for biologic
medicines. It recognizes that a number of issues associated with the
use of biologics should be defined by the national authorities. (8)
27
Canada does not
support automatic
substitution (25)
The variation in global substitution guidelines
28
UK and
Belgium recommend
prescribing by brand
name to avoid
substitution (15)
Spain and
Germany
prohibit
automatic
substitution (15)
Ireland,
Poland and
Portugal have
no clear
position (49)
In Japan,
substitution should
be avoided during
the post-marketing
surveillance
period (25)
As the biosimilar market expands and biosimilars
become more complex, it is important to ensure
clarity in prescribing regulations.
29
30
Manufacturing
biologics
Manufacturing
biosimilars
Manufacturing
biosimilars
A biologic medicine typically has around
250 in-process tests during manufacturing,
compared with around 50 tests for a small
molecule, to demonstrate safety and equivalent
efficacy and to ensure safe, reliable production
of therapies for patients. (13)
Manufacturing
biologics
Transforming complex therapeutic
proteins from the laboratory into the
large-scale production of safe and
effective medicines requires highly
specialized knowledge, processes,
scientific standards and ongoing
investment in quality.
The challenge in manufacturing
biologic medicines is to control
variability in this process to ensure
compliance with quality standards
so that every patient can be treated
with a medicine of consistent
quality, every time.
Manufacturing and quality control
issues can impact patient safety and
result in a loss of confidence in the
quality of biologics. They can also cause
product recalls and drug shortages, which
can have profound effects on patients,
treatment practices and overall
confidence in biologics.
31
Good manufacturing practice for large
molecules and small molecule medicines
Large molecule
Process
GMP requirements
(Good Manufacturing Practice)
STEP 1
Cell line development
DNA - Cloning
Transfection
Select "best" cell
STEP 2
Cell expansion
Media pH, temp cell density
STEP 3
Cell culture
Bioreactor media pH, temperature
STEP 4
Harvest
Remove cells from product
STEP 5
Purification
multiple steps
Remove impurities
Highly selective resin
Specific process conditions
STEP 6
Virus inactivation/removal
Dedicated steps to ensure virus
killing or reduction
STEP 7
Filling
Filling method
No human contact
STEP 8
Finishing
Lyophilization
Syringe-fill
STEP 9
Packaging & storage
Controlled temperature
Ensure no foaming
No particles
STEP 10
Quality assurance
& characterization
Highly precise methods
Reference standards
STEP 11
Stability
Testing to ensure product
remains stable through shelf life
Good Manufacturing Practice (GMP)
Clean room & sterile equipment (prevention and control of potential bacterial contamination)
Virus segregation (prevention of potential virus contamination)
Segregation: Personnel and material
Biologics have more GMP-requirements than small molecules
32
Small molecule
Process
GMP requirements
(Good Manufacturing Practice)
Add ingredients
pressure, temperaure
STEP 1
Reaction
STEP 2
Weigh
Weigh API
& inactive chemicals
STEP 3
Mix
Mixing speed, time
STEP 4
Compress (solid dosage)
Filling (liquid dosage)
Pressure
Filling method
(no human contact)
STEP 5
Packaging & storage
Room temperature
STEP 6
Quality assurance
& characterization
Easy methods
STEP 7
Stability
Testing to ensure
product remains stable
through shelf life
To manufacture
safe and effective
biologic and biosimilar
medicines, more steps
and more stringent
processes for each
step are required than
for small molecule
medicines.
Much like the way in which
varieties of wine have common
characteristics but may vary in quality
and taste depending upon region, vineyard,
growing conditions and so on, the characteristics
of a protein may vary depending upon the
manufacturing process, including the growing
conditions, for the protein. This sensitivity to
environmental factors in production is an
inherent and important difference between
biologic medicines and traditional,
chemical medicines.
33
Unit Operation
Cell expansion
Cell production in bioreactors
Recover through filtration
or centrifugation
The manufacturing
process is unique to
every manufacturer
There is a strong relationship
between the manufacturing
processes of a biologic medicine
and the characteristics of the
final product. Due to proprietary
knowledge, it is impossible
for biosimilar manufacturers
to precisely replicate the
manufacturing process of the
original biologic or the active
ingredient of the protein product. (50)
The starting materials for most
biologic medicines are geneticallymodified cells. Once scientists
design and select a cell that
produces a medically valuable
protein, they replicate it to create a
cell line. Each cell line is unique to
the manufacturer.
Purification through
chromatopgraphy
Purified bulk drug
Characterisation and stability
The major steps involved with
the manufacture of biologic
medicines include:
• Modifying the selected cell
• Growing a cell line from the
original modified cell
• Growing a large number of
cells from the cell line
• Cultivating them to produce
the desired protein
• Separating the protein from
the cells
• Purifying the collected protein
34
Striving to ensure a
consistent supply
Problems or interruptions to the
manufacturing process of biologic
medicines may not only affect
quality and safety, but could also
lead to delayed supplies and
distribution of urgently needed
medicines.
Along with regulators, manufacturers
have a responsibility to ensure
strategies are in place to minimize
incidences of drug shortages and
possible disruption. Manufacturer
risk management is a continuous
and holistic process designed
to ensure a consistent supply.
Strong governance can also help to
integrate and manage supply risk
across manufacturing plants
and functions.
A consistent supply of
high-quality products
requires commitment,
expertise and highquality science.
35
Amgen biosimilars
»» Biosimilars are therapeutic alternatives for originator
biologic medicines, and offer the potential for increased
access and reduced cost.
»» Amgen is a pioneer in the field of biologic medicines.
Science-based medicine and patient safety are
fundamental to our values.
»» Amgen is uniquely equipped to leverage its leading
position in biotechnology to produce biosimilars.
»» Amgen has six biosimilar molecules in development.
We expect to launch the first biosimilar in 2017.
36
Glossary
Glossary
Glossary
Glossary
Adverse event: The occurrence of an undesirable, unpleasant, or lifethreatening reaction to a medicinal product.
Amino acid: One of several molecules that join together to form proteins.
There are 20 common amino acids found in proteins.
Antibody (pl: antibodies): Antibodies (also known as
immunoglobulins, abbreviated to Ig) are proteins that are found in blood or
other bodily fluids. Antibodies are used by the immune system to identify
and neutralize foreign objects, such as bacteria and viruses.
Automatic substitution and substitution: The practice by which a
product other than the one specified on the prescription is dispensed to
the patient, without the prior informed consent of the treating physician.
A variation of substitution is practiced in some countries where, if the
physician prescribes by international non-proprietary name (INN), the
pharmacist may dispense any product with the same active ingredient.
Biologic: A product derived from a living organism (from animal products
or other biological sources) that is used in the diagnosis, prevention or
treatment of disease. Examples of biologic medicines include recombinant
proteins, allergy shots, vaccines and hematopoietic growth factors.
37
Biologic License Application (BLA): An application submitted to the FDA seeking
approval to market a biologic in the United States. The application contains a description of
the trials and results, formulation, dosage, drug shelf life, manufacturing protocols, packaging
information, etc. There are two different types of BLAs: full, stand-alone BLAs filed for
approval of an originator biological product, and abbreviated BLAs filed for approval of a
biosimilar product.
Biosimilar: Defining biosimilars
THE WORLD HEALTH ORGANIZATION: A biotherapeutic product which is similar in terms of
quality, safety and efficacy to an already licensed reference biotherapeutic product. (8)
THE EUROPEAN MEDICINES AGENCY: A biological medicine that is developed to be similar to
an existing biological medicine (the ‘reference medicine’). When approved, a biosimilar’s
variability and any differences between it and its reference medicine will have been shown not
to affect safety or effectiveness. (9)
THE U.S. FOOD AND DRUG ADMINISTRATION: A biological product that is highly similar to a
U.S. licensed reference biological product notwithstanding minor differences in clinically
inactive components, and for which there are no clinically meaningful differences between the
biological product and the reference product in terms of the safety, purity and potency of the
product. (10)
Biotechnology: Technology based on biology, especially when used in agriculture, food
science and medicine. The United Nations Convention on Biological Diversity defines
biotechnology as “any technological application that uses biological systems, living
organisms, or derivatives thereof, to make or modify products or processes for specific use.”
The Center for Drug Evaluation and Research (CDER): As part of the US Food
and Drug Administration (FDA), CDER regulates over-the-counter and prescription drugs,
including biologic therapeutics and generic drugs.
Chemical drug or chemical medicine: Refers to medicines that are manufactured without
the involvement of living organisms.
38
Chemistry, manufacturing and control (CMC): The CMC stage of product development
focuses on how a drug was created. It should be demonstrated that the manufacturing
method is proper and valid on a technological level and that quality is ensured through
consistent production in accordance with the WHO’s Good Manufacturing Procedure. Many
aspects of both the active ingredients and the product as a whole will be reviewed, including
characterization, control and stability.
Clinical trial: A test in which a drug or biologic is given to humans to establish how it works
in the body and measure the nature and extent of any intended or unintended consequences.
Committee for Medicinal Products for Human Use (CHMP): The CHMP is the
scientific committee responsible for formulating the opinion of the European Medicines Agency
on any question concerning the evaluation of human medicinal products.
Comparability exercise: The head-to-head comparison of a biotherapeutic product with
a licensed originator product, with the goal of establishing similarity in quality, safety, and
efficacy. Products should be compared in the same study using the same procedures.
Data exclusivity: The period of time during which the clinical testing data that supported
approval of the innovator medicine is protected, so that the prior approval of that originator
based on those data may not be relied upon by another applicant to help approve a copy of
that product.
DNA (Deoxyribonucleic Acid): DNA is a nucleic acid that contains the genetic information
used in the development and functioning of all cellular organisms. Molecular systems interpret
the sequence of these nucleic acids to produce proteins.
Efficacy: The desired impact that a medicine or treatment has when administered to a human.
European Medicines Agency (EMA): The EMA is responsible for evaluating marketing
applications for medicinal products to be approved in the European Union.
Federal Food, Drug and Cosmetic Act: The federal law that regulates FDA’s licensing of
drugs but not the majority of biologic medicines. Instead, most biologic medicines are licensed
by FDA under the Public Health Service Act. Once licensed by FDA, however, most of the other
39
provisions set forth in the Federal Food, Drug and Cosmetic Act concerning the marketing and
other regulatory requirements are applicable to both drugs and biologic medicines.
U.S. Food and Drug Administration (FDA): The federal agency responsible for
evaluating marketing applications and/or otherwise regulating the U.S. marketing of medicinal
products, medical devices, food and cosmetics to be approved in the United States.
Fusion protein: A protein made from a fusion gene, which is created by joining parts of two
different genes. Fusion genes may occur naturally in the body by transfer of DNA between
chromosomes.
Generic medicine: A generic drug is the same as a brand name drug in dosage, safety,
strength, how it is taken, quality, performance, and intended use. A generic drug product must
contain the identical amounts of the same active ingredient(s) as the brand name product.
Drug products evaluated as “therapeutically equivalent” can be expected to have equal effect
and no difference when substituted for the brand name product.
Genetic engineering: The direct manipulation of an organism’s genes by introducing,
eliminating or rearranging specific genes using the methods of modern molecular biology,
particularly those techniques referred to as recombinant DNA techniques. These techniques
entail producing a piece of DNA (the recombinant DNA or synthetic rDNA construct) and
introducing it into an organism so that new or altered traits can be imparted to that organism.
Guidance: A document issued by a regulatory agency to provide interpretation of a law that
the regulatory agency is responsible for administering and/or enforcing and recommendations
as to how to proceed with particular issues.
Immune system: The collection of mechanisms within the body that protect against disease
by identifying and attacking foreign substances in the body.
Immunogenicity: The ability of a substance to trigger an immune response or reaction
(eg: development of specific antibodies, T-cell response, allergic or anaphylactic reaction).
INN (International non-proprietary name): Allocated by the World Health Organization,
an INN identifies pharmaceutical substances or active pharmaceutical ingredients. Each INN
40
is a unique name that is globally recognized and is public property. A non-proprietary name is
also known as a generic name.
Innovator: Describes a company that invested considerably in research and development to
develop a new medicine through innovative technologies, such as biotechnology.
Innovator product: Original approved biologic medicine.
Insulin: A hormone that affects metabolism and causes the body’s cells to take up glucose
(sugar) from the blood and store it as glycogen in the liver and muscles.
Interchangeability: Where two products, that are judged to be similar, can be exchanged one
with another without a significant risk of an adverse health outcome.
Large molecule drugs: Are therapeutic proteins – also known as biologic medicines.
Essentially, these are copies or optimized versions of endogenous human proteins.
Mechanism of action: The specific way by which a medicine achieves the desired outcome.
Medicines and Healthcare products Regulatory Agency (MHRA): UK government
agency that is responsible for ensuring that medicines and medical devices work and are
acceptably safe.
Monoclonal antibody: An antibody produced in the laboratory by a single clone of cells or a
cell line and consisting of identical antibody molecules.
Originator: See above for innovator.
Originator product: See above for innovator product.
Pharmaceutical medicine: Also referred to as medicine or medication – any chemical
substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.
Pharmacodynamics: Studies performed to determine what a drug does to the body.
41
Pharmacokinetics: Studies performed to determine what the body does to a drug.
Pharmacovigilance: Procedures that monitor the safety of medicines to detect, assess,
understand, and prevent adverse effects or any other safety-related issue.
Preclinical trials (or studies): Tests that take place in a scientifically-controlled setting
using cell culture and/or animals as disease models.
Proteins: Compounds (chains of amino acids) constituting the ultimate expression product of
a gene. Created through the synthesis performed by ribosomes, proteins are the workhorses of
living systems, causing chemical processes and changing as their environment changes.
Recombinant: In genetics, recombinant means DNA, proteins, cells, or organisms that are
made by combining genetic material from two different sources. Recombinant substances are
made in living cells and are being studied in the treatment of cancer and for many other uses.
Reference product: The innovator/originator product that the biosimilar product is intended
to copy.
RNA: Ribonucleic acid is a nucleic acid which is central to the synthesis of proteins.
Similar biotherapeutic product (SBP): A biotherapeutic product which is similar in terms
of quality, safety and efficacy to an already-licensed, reference biotherapeutic product.
Small molecule drugs: Chemical compounds that have a defined structure and
characteristics.
Switching: The decision of a physician to change a patient from one drug to another drug
with the same therapeutic intent, in order to optimise therapy and reduce adverse effects.
Vaccine: A biological preparation which is used to establish or improve immunity to a
particular disease.
42
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