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Biologics and biosimilars An overview
Biologics and biosimilars An overview

Biologics and biosimilars

An overview

Contents

Contents An introduction to biotechnology 3 A brief history of medicine development 4 What are biologic

An introduction to biotechnology3

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 biosimilars13

13

Approval pathways for biologic and biosimilar medicines

14

Biosimilar regulations

18

Pharmacovigilance, traceability & naming21

21

Naming, tracking and tracing medicines

22

WHO biologic naming policy

23

Substitution and interchangeability25

25

The variation in global substitution guidelines

26

Manufacturing biologics31

31

The manufacturing process is unique to every manufacturer

34

Striving to ensure a consistent supply

35

Glossary37

37

Works cited

43

© 2014 Amgen Inc. All rights reserved. March 2014.

a consistent supply 35 Glossary 37 Works cited 43 © 2014 Amgen Inc. All rights reserved.

An introduction to biotechnology

An introduction to biotechnology

A n i n t r o d u c t i o n t o

An introduction to biotechnology

i n t r o d u c t i o n t o biotechnology Amgen

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.

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 sedative- hypnotic. 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

21 atoms

Acetylsalicylic acid Small molecule 21 atoms IgG1 antibody Biologic medicine > 20,000 atoms What are biologic
Acetylsalicylic acid Small molecule 21 atoms IgG1 antibody Biologic medicine > 20,000 atoms What are biologic

IgG1 antibody

Biologic medicine

> 20,000 atoms

21 atoms IgG1 antibody Biologic medicine > 20,000 atoms What are biologic medicines? A biologic medicine

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.

almost always injected into a patient’s body and individual patient responses can depend on how a

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How are biologic medicines developed?

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)

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 T T A C A G 6 C
Chromosome
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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.

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.

Gene

safety, efficacy and/or shelf life, and to increase the risk of an unwanted immune response. Gene

DNA

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01 Biologic medicines are made in living organisms by genetically engineering DNA. DNA is inserted into

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.

cells, to code for the production of a particular protein. 02 The biologic is modified to

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.

each manufacturer and is the source of all future product. 04 The unique cell line is
each manufacturer and is the source of all future product. 04 The unique cell line is

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

Discover more on the manufacturing of biologic medicines by visiting the Amgen YouTube channel at youtube.com/user/Amgen

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Targeting disease pathways to benefit patients Cancer: Following cancer pathways and determining the molecular basis
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)
An introduction to
biotechnology
biologic medicines and targeted therapies such as monoclonal antibodies. (3) An introduction to biotechnology 9

9

t are biosimilar medicines?

e generic medicines where the active ients are identical, biosimilars are

r to but not identical copies of the

ator biologic. They are similar, but

e same. Biologics made by different

facturers differ from the original

ct and from each other.

omplexity of biologics precludes cal copies and are therefore

e same as generic drugs. Due

complex structure of biologic ines and the processes involved duction, biosimilars must be

mined on the basis of analytical, linical and clinical data to be

r to an original biologic in terms

ctural characteristics, and safety ficacy. Minor differences with tive ingredient are expected and tted so long as any such differences monstrated not to be clinically

ngful. (7) The patents of a growing

er

of biologic medicines have

y

expired or are due to expire, which

d to an increased interest in the opment of biosimilars. (11)

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 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)

riginal biologic

and potency of the product. ( 1 0 ) riginal biologic Biosimilars Similar to snowflakes, biosimilars

Biosimilars

of the product. ( 1 0 ) riginal biologic Biosimilars Similar to snowflakes, biosimilars from different

Similar to snowflakes, biosimilars from different manufacturers differ from their originator biologic medicines and from each other.

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 non- clinical and clinical issues. In addition, class specific guidelines for growth hormones, monoclonal antibodies, GCSFs, recombinant follicle stimulating hormones, interferons, low- molecular 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

but growing proportion at $2-2.5 billion. ( 1 7 ) 12 The cost of developing biosimilars

The cost of developing biosimilars

Biosimilar manufacturers must invest in clinical trials, manufac- turing 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 Regulating biosimilars

Regulating biosimilars

Regulating biosimilars “The approach established for generic medicines is not suitable for development, evaluation and

“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

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
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)

may be necessary in some cases World Health Organization (WHO) guidance on biosimilar development standards (

14

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

must demonstrate that it has no significant clinical differences to the reference product, but some limited

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)

Non clinical

Quality

European Union

Quality

Originator Biosimilar Cross reference Clinical Cross reference Clinical (extrapolation?) Non clinical Non clinical
Originator
Biosimilar
Cross reference
Clinical
Cross reference
Clinical
(extrapolation?)
Non clinical
Non clinical
Comparability data
Quality
Quality

Not to scale. Comparison of originator and biosimilar marketing approvals process in the US and EU (28) (29)

to scale. Comparison of originator and biosimilar marketing approvals process in the US and EU (

pe

European Medicines Agency (EMA)/European Commission (EC) was the major regulatory authority to implement a framework for the marketing orization of biosimilars and has one of the most detailed and stringent delines for developing biosimilars.

guidelines outline an approach for comparing the proposed biosimilar to original biologic, in terms of quality, safety and efficacy. (7)

duct-specific guidelines for some biosimilar medicines, eg: recombinant hropoietin, are provided by the EMA/Committee for Medicinal Products Human Use (CHMP), outlining the data requirements and studies essary to demonstrate comparability.

EMA/CHMP guidelines are widely considered the gold standard, with ntries such as Australia, Canada, Japan, Korea and South Africa using m as a basis for their own regulations. (31) (32)

Australia, Canada, Japan, Korea and South Africa using m as a basis for their own regulations.

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)

compared to the reference product. » The FDA has discretion to waive any requirement deemed unnecessary.

17

18

2001

2002

2003

2004

2005

2006

2007

18 2001 2002 2003 2004 2005 2006 2007 The EMA published the first directive relating to

The EMA published the first directive relating to differences in raw materials or manufacturing processes between biosimilar and reference products

Guideline development EU EU Legal Overarching Pathway Guidelines
Guideline
development
EU
EU
Legal
Overarching
Pathway
Guidelines

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)
• Monoclonal antibodies
(infliximab)

The EMA published the first biosimilar regulatory approval pathway for the EU member states

regulatory approval pathway for the EU member states AUS As more governments develop biosimilar pathways, the

AUS

regulatory approval pathway for the EU member states AUS As more governments develop biosimilar pathways, the

As more governments develop biosimilar pathways, the WHO and EU’s established guidelines will continue to serve as a template, as demonstrated by Australia’s unadulterated adoption of the 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

2013

development 2008 2009 2010 2011 2012 2013 TUR KOR CAN ARG USA EU (draft) Revised Guidelines*
development 2008 2009 2010 2011 2012 2013 TUR KOR CAN ARG USA EU (draft) Revised Guidelines*
development 2008 2009 2010 2011 2012 2013 TUR KOR CAN ARG USA EU (draft) Revised Guidelines*
development 2008 2009 2010 2011 2012 2013 TUR KOR CAN ARG USA EU (draft) Revised Guidelines*
development 2008 2009 2010 2011 2012 2013 TUR KOR CAN ARG USA EU (draft) Revised Guidelines*
development 2008 2009 2010 2011 2012 2013 TUR KOR CAN ARG USA EU (draft) Revised Guidelines*

TUR

KOR

CAN

ARG USA EU (draft) Revised Guidelines* MEX COL (draft) EU Non-clinical and clinical CUB Guidelines
ARG
USA
EU
(draft)
Revised
Guidelines*
MEX
COL
(draft)
EU
Non-clinical
and clinical
CUB
Guidelines †
JOR
(draft)
IRI
THA
(draft)
IND
PER
EU

Update to Quality Issues Guideline

(draft) IND PER EU Update to Quality Issues Guideline MYS JPN ZAF TWN SIN BRA WHO

MYS

JPN

ZAF

IND PER EU Update to Quality Issues Guideline MYS JPN ZAF TWN SIN BRA WHO SAU

TWN

SIN

BRA

Update to Quality Issues Guideline MYS JPN ZAF TWN SIN BRA WHO SAU The WHO biosimilar

WHO

SAU

to Quality Issues Guideline MYS JPN ZAF TWN SIN BRA WHO SAU The WHO biosimilar guideline,

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

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.

for use within India under an ad hoc abbreviated process. ( 3 4 ) The WHO

19

20

20

Pharmacovigilance,

traceability

& naming

Pharmacovigilance, traceability & naming

P h a r m a c o v i g i l a n c

& naming

Pharmacovigilance,

traceability

a r m a c o v i g i l a n c e ,

“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 post- marketing pharmacovigilance considerations should include:

• Pre and post-authorization comparative testing

• Regular tests to ensure that the manufacturing processes are the same, as biosimilarity and immu- nogenicity are dependent on this

• Risk management in case of adverse drug reactions (35)

and immu- nogenicity are dependent on this • Risk management in case of adverse drug reactions

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 Non- proprietary 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

precisely which medicine a pharmacist gave the patient. 22 Without distinguishable INNs, a reporter may be

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)

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 post- marketing 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

(filgrastim) respectively. ( 4 1 ) ( 4 2 ) 24 The FDA concluded that the

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

S u b s t i t u t i o n a n d interchangeability

interchangeability

Substitution and

interchangeability S u b s t i t u t i o n a n d
interchangeability S u b s t i t u t i o n a n d
interchangeability S u b s t i t u t i o n a n d

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

different brand every time their medicine is dispensed.

a

• the patient may potentially receive different brand every time their medicine is dispensed. a 25

25

26

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.

several different products prior to an immunogenic reaction. This makes tracing the medicine responsible for the
several different products prior to an immunogenic reaction. This makes tracing the medicine responsible for the

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)

The FDA can designate a biosimilar as an interchangeable biologic when the following criteria are

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)

product without such alternation or switch. ( 4 7 ) Europe – EMA Decisions on substitution
product without such alternation or switch. ( 4 7 ) Europe – EMA Decisions on substitution

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)

that a number of issues associated with the use of biologics should be defined by the

27

Canada does not support automatic substitution (25)
Canada does not
support automatic
substitution (25)

The variation in global substitution guidelines

28

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
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)
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.

market expands and biosimilars become more complex, it is important to ensure clarity in prescribing regulations.

29

30

30

Manufacturing

biosimilars

Manufacturing

biologics

M a n u f a c t u r i n g biosimilars Manufacturing biologics

Manufacturing

biosimilars

M a n u f a c t u r i n g biosimilars A biologic

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)

qua y o o og cs. ey can a so cause product recalls and drug
qua
y o
o og cs.
ey can a so cause
product recalls and drug shortages, which
can have profound effects on patients,
treatment practices and overall
confidence in biologics.

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 1 Cell line development DNA - Cloning Transfection Select "best" cell
STEP 1 Cell line development DNA - Cloning Transfection Select "best" cell
STEP 1 Cell line development DNA - Cloning Transfection Select "best" cell

STEP 2

Cell expansion

Media pH, temp cell density

STEP 2 Cell expansion Media pH, temp cell density
STEP 2 Cell expansion Media pH, temp cell density
STEP 2 Cell expansion Media pH, temp cell density

STEP 3

Cell culture

Bioreactor media pH, temperature

STEP 3 Cell culture Bioreactor media pH, temperature
STEP 3 Cell culture Bioreactor media pH, temperature
STEP 3 Cell culture Bioreactor media pH, temperature

STEP 4

Harvest

Remove cells from product

STEP 4 Harvest Remove cells from product
STEP 4 Harvest Remove cells from product
STEP 4 Harvest Remove cells from product

Purification

Remove impurities Highly selective resin Specific process conditions

Purification Remove impurities Highly selective resin Specific process conditions
Purification Remove impurities Highly selective resin Specific process conditions
Purification Remove impurities Highly selective resin Specific process conditions

STEP 5

multiple steps

STEP 6

Virus inactivation/removal

Dedicated steps to ensure virus killing or reduction

STEP 6 Virus inactivation/removal Dedicated steps to ensure virus killing or reduction
STEP 6 Virus inactivation/removal Dedicated steps to ensure virus killing or reduction
STEP 6 Virus inactivation/removal Dedicated steps to ensure virus killing or reduction

STEP 7

Filling

Filling method No human contact

STEP 7 Filling Filling method No human contact
STEP 7 Filling Filling method No human contact
STEP 7 Filling Filling method No human contact

Lyophilization

Lyophilization
Lyophilization
Lyophilization

STEP 8

Finishing

Syringe-fill

STEP 9

Packaging & storage

Controlled temperature Ensure no foaming No particles

 

Quality assurance

Highly precise methods Reference standards

 

STEP 10

& characterization

STEP 11

Stability

Testing to ensure product remains stable through shelf life

STEP 11 S t a b i l i t y Testing to ensure product remains

Good Manufacturing Practice (GMP)

Clean room & sterile equipment (prevention and control of potential bacterial contamination)stable through shelf life Good Manufacturing Practice (GMP) Virus segregation (prevention of potential virus

Virus segregation (prevention of potential virus contamination)and control of potential bacterial contamination) Segregation: Personnel and material Biologics have more

Segregation: Personnel and materialsegregation (prevention of potential virus contamination) Biologics have more GMP-requirements than small molecules 32

Biologics have more GMP-requirements than small molecules

32

virus contamination) Segregation: Personnel and material Biologics have more GMP-requirements than small molecules 32

STEP 1

STEP 2

STEP 3

STEP 4

STEP 5

STEP 6

STEP 7

Small molecule Process GMP requirements (Good Manufacturing Practice) Add ingredients Reaction pressure, temperaure

Small molecule

Small molecule Process GMP requirements (Good Manufacturing Practice) Add ingredients Reaction pressure, temperaure
Process GMP requirements (Good Manufacturing Practice) Add ingredients Reaction pressure, temperaure Weigh API
Process
GMP requirements
(Good Manufacturing Practice)
Add ingredients
Reaction
pressure, temperaure
Weigh API
Weigh
& inactive chemicals
Mix
Mixing speed, time
Compress (solid dosage)
Filling (liquid dosage)
Pressure
Filling method
(no human contact)
Packaging & storage
Room temperature
Quality assurance
Easy methods
& characterization
Stability
Testing to ensure
product remains stable
through shelf life
to ensure product remains stable through shelf life To manufacture safe and effective biologic and biosimilar

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
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.

34

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 genetically- modified 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.

a cell line. Each cell line is unique to the manufacturer. Unit Operation Purified bulk drug

Unit Operation

Purified bulk drug
Purified bulk drug

Cell expansion

Cell production in bioreactors

Recover through filtration or centrifugation

Purification through

chromatopgraphy

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

Striving to ensure a consistent supply Problems or interruptions to the manufacturing process of biologic

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 high- quality science.

and functions. A consistent supply of high-quality products requires commitment, expertise and high- quality science. 35

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

biosimilars. » Amgen has six biosimilar molecules in development. We expect to launch the first biosimilar

Glossary

Glossary

Glossary Glossary
he occurrence of an undesirable, unpleasant, or life- to a medicinal product. of several molecules

he occurrence of an undesirable, unpleasant, or life- to a medicinal product.

of several molecules that join together to form proteins.

on amino acids found in proteins.

ibodies): Antibodies (also known as abbreviated to Ig) are proteins that are found in blood or Antibodies are used by the immune system to identify gn objects, such as bacteria and viruses.

tution and substitution: The practice by which a he one specified on the prescription is dispensed to

the prior informed consent of the treating physician. itution is practiced in some countries where, if the

s by international non-proprietary name (INN), the

pense any product with the same active ingredient.

ct derived from a living organism (from animal products

sources) that is used in the diagnosis, prevention or e. Examples of biologic medicines include recombinant

ots, vaccines and hematopoietic growth factors.

prevention or e. Examples of biologic medicines include recombinant ots, vaccines and hematopoietic growth factors.

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

drug or chemical medicine: Refers to medicines that are manufactured without the involvement of living organisms.

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

medicines are licensed by FDA under the Public Health Service Act. Once licensed by FDA, however,

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

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

treatment, or prevention of disease. Pharmacodynamics: Studies performed to determine what a drug does to the

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

effects. Vaccine: A biological preparation which is used to establish or improve immunity to a particular

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Amgen and biosimilars, visit:

www.amgen.com/science/amgen_biosimilars

Amgen and biosimilars, visit: www.amgen.com/science/amgen_biosimilars
Amgen and biosimilars, visit: www.amgen.com/science/amgen_biosimilars
Amgen and biosimilars, visit: www.amgen.com/science/amgen_biosimilars