Guide to Biological Medicines: A Focus on Biosimilar ... - Europabio

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<strong>Biological</strong> 

<strong>Medicines</strong> 

A <strong>Focus</strong> on 

Biosimilar 


TM

EXECUTIVE SUMMARY 

Biotechnology has enabled 

the discovery of treatments 

for a variety of serious diseases. 

Worldwide, over 350 million patients have benefited from approved 

medicines manufactured through biotechnology. Currently, over 650 

new biological medicines and vaccines are be developed <strong>to</strong> treat 

more than 100 diseases. As the exclusive rights for these biological 

medicines expire, similar biological medicines, or “biosimilars”, are 

being developed, with some already available on European markets. 

<strong>Biological</strong> medicines are 

comprised of proteins and 

other substances that are 

often naturally produced in 

the human body. In healthcare, 

biotechnology is being used in 

three primary areas: therapeutic 

medicines, vaccines and 

diagnostics. When compared <strong>to</strong> 

chemical medicines, biological 

medicines are generally more 

complex and usually much larger 

in size than chemical medicines. 

The complexity is predominantly 

due <strong>to</strong> the manufacturing 

process for biological medicine, 

as they are developed in living 

system the exact characteristics 

and properties are highly 

dependent on the manufacturing 

process. Chemical medicines 

can be approved either by 

national medicines authorities or 

by the ‘centralised procedure’ 

carried out by the European 

<strong>Medicines</strong> Agency (EMA), 

however all biological medicines 

products must follow the 

‘centralised procedure’ 

for approval. 

Due <strong>to</strong> the composition and 

large molecule size of biological 

medicines, they have the inherent 

potential <strong>to</strong> induce (unwanted) 

immune reactions. Therefore, 

in order <strong>to</strong> identify unwanted 

immune reactions, and for 

post regula<strong>to</strong>ry approval 

commitments, treating 

physicians should state the 

brand name and batch 

number, as opposed <strong>to</strong> the 

International Non-Proprietary 

Name (INN) when prescribing. 

Furthermore, due <strong>to</strong> the unique 

nature of biosimilars, there 

should not be au<strong>to</strong>matic 

substitution of the reference 

product, this decision should 

be left with the treating 

physician. 

Generics and Biosimilars have 

an important role <strong>to</strong> play in 

fostering competition in the 

market place, and thereby 

contributing <strong>to</strong> the sustainability 

of healthcare budgets. However, 

as the research and development 

costs of biosimilars are much 

higher than generics, suitable 

pricing and reimbursement 

environments are needed <strong>to</strong> 

foster the development of 

new products. Furthermore, 

adequate intellectual property 

protection is vital <strong>to</strong> ensure 

that companies are able <strong>to</strong> fund 

research and development 

of biological medicines, and 

therefore develop and produce 

more potential treatments. 

Upon expiry of such protection, 

biosimilar products (unlike 

chemical generics these are 

not exact copies, as they are 

made in living systems the exact 

characteristics are dependent 

upon the manufacturing process) 

can enter the market <strong>to</strong> compete 

with the original “reference 

product”. 

So far the European Union has 

approved 7 biosimilars, across 

3 product classes. In the United 

States, the Biologics Price 

Competition and Innovation 

Act, signed in<strong>to</strong> law in March 

2010, created a statu<strong>to</strong>ry 

framework for the approval 

of biosimilars by the Food and 

Drug Administration (FDA). 

Over the last two years, the 

biosimilar market shares have 

steadily increased in most 

countries. In several European 

countries, biosimilars now have 

a higher volume market share 

than the reference product, 

and this trend appears <strong>to</strong> be 

accelerating. 

<strong>Biological</strong> 


A <strong>Focus</strong> on 

Biosimilar 

<strong>Medicines</strong>

01 

<strong>Biological</strong> <strong>Medicines</strong> 

A <strong>Focus</strong> on Biosimilar <strong>Medicines</strong> 

TABLE OF CONTENTS INTRODUCTION 

02 INTRODUCTION 

03 HEALTHCARE BIOTECHNOLOGY: INTRODUCTION TO THE SCIENCE 

03 What are biological medicines and how do they work? 

03 How do biological medicines differ from chemical medicines? 

Key differentiating fac<strong>to</strong>rs. 

03 How are biological medicines manufactured? 

05 Intellectual property for biotech medicines 

06 BIOLOGICAL MEDICINES – CURRENT ISSUES 

06 Naming, Pharmacovigilance and Risk Management Plans 

07 Interchangeability 

07 Substitution 

08 Impact on healthcare budget and pricing 

08 The regulation of biologicals in Europe, including biosimilars 

09 THE MARKET FOR BIOSIMILARS 

09 Which biosimilars are currently available in Europe? 

09 What about the rest of the world? 

09 What does the entry of biosimilars in the market mean <strong>to</strong> origina<strong>to</strong>r products? 

10 THE POTENTIAL IMPACT OF BIOSIMILARS 

10 For patients 

10 For healthcare professionals 

10 For payers 

11 GLOSSARY OF KEY TERMS 

12 REFERENCES 

Biotechnology has enabled the discovery 

of treatments for a variety of serious 

diseases. Worldwide, more than 350 

million patients have already benefited 

from approved medicines manufactured 

through biotechnology. 

These medicines help treat or prevent many rare 

and severe diseases including cancers, heart attacks, 

stroke, multiple sclerosis, diabetes, rheuma<strong>to</strong>id 

arthritis and au<strong>to</strong>immune diseases. In addition, 

over 650 new biological medicines and vaccines 

are currently being developed <strong>to</strong> treat more 

than 100 diseases 1 . 

As the exclusive rights (patents and other data 

protection) for certain biological medicines expire, 

similar biological medicines, or "biosimilars", are 

being developed. Several biosimilars are already 

available on European markets. This document 

is intended <strong>to</strong> explain the complexities and 

specificities of biological medicines, including 

biosimilar medicines. 

“ 


comprised of proteins and 

other substances that are 

often naturally produced 

in the human body. 

“ 

1. "Engaging with the global monoclonal antibody 

and biologicals markets" Jean-Claude Muller; 

Special Advisor, Innovation and International 

Relationships; Formerly Senior Vice President, 

R&D Prospective and Strategic Initiatives; 

Sanofi-Aventis 

02

03 



HEALTHCARE BIOTECHNOLOGY: 

INTRODUCTION TO THE SCIENCE 

What are biological 

medicines and how 

do they work? 


comprised of proteins (such 

as growth hormone, insulin, 

erythropoietin, enzymes, 

and antibodies) and other 

substances that are often 

naturally produced in the human 

body. Biotechnology uses the 

great potential in living systems 

(plant or animal cells, bacteria, 

viruses and yeasts) and modern 

technologies <strong>to</strong> produce biological 

medicines <strong>to</strong> treat diseases 

and genetic disorders in humans. 

Biotechnology in healthcare is 

currently being used in three 

primary areas: therapeutic 

medicines (also including 

advanced therapies such as cell 

and gene therapy), vaccines 

and diagnostics. In this brochure, 

we use the term “biological 

medicine” or “biotech medicine” 

as a synonym for therapeutic 

proteins and monoclonal 

antibodies. 

How are biological 

medicines manufactured? 

Manufacturing biological 

medicines is more complex 

than the production of chemical 

pharmaceuticals. There are a 

number of reasons for this, 

including the nature of the 

starting material and 

How do biological medicines differ from 

chemical medicines? Key differentiating fac<strong>to</strong>rs. 


generally more complex and 

usually much larger in size than 

chemical medicines, which are 

produced by chemical synthesis. 

As biological medicines are made 

in living systems, their exact 

characteristics and properties 

are highly dependent on the 

manufacturing process. 

Therefore, manufacturing and 

precise characterisation tends 

<strong>to</strong> be more difficult when 

compared <strong>to</strong> chemical medicines, 

the ingredients of which are 

more easily identifiable and 

can be exactly reproduced. 

<strong>Biological</strong> medicines may have higher variability. 

As biological medicines are produced by living systems, such as cell lines, they 

may show a higher variability in their structure and characteristics than traditional 

pharmaceuticals produced by chemical synthesis, unless processes are carefully 

controlled. This variability is highly dependent on the master cell line selected 

and used by each manufacturer, as well as materials and manufacturing conditions 

used throughout the production process. 

<strong>Biological</strong> medicines are more complex. 

Because biological medicines are generally far more complex than chemical 

pharmaceuticals, modifications <strong>to</strong> their manufacturing process need <strong>to</strong> be 

evaluated carefully, <strong>to</strong> ensure the drug's efficacy and <strong>to</strong>lerability are not 

compromised. Furthermore, the complexity of biological medicines makes their 

analytical characterisation more challenging than that of small molecules 

(chemically synthesised). Small changes in the manufacturing processes of 

biological medicines can lead <strong>to</strong> major changes in the products, as these changes 

could alter their tri-dimensional structure and their safety and efficacy profile. 

<strong>Biological</strong> medicines have the potential <strong>to</strong> provoke immune reactions. 

<strong>Biological</strong> medicines have the potential <strong>to</strong> be recognised by the body as 

‘foreign’ and therefore have the inherent potential <strong>to</strong> induce (unwanted) 

immune reactions, due <strong>to</strong> their composition and large molecular size. Chemical 

medicines, on the other hand, are usually <strong>to</strong>o small <strong>to</strong> be recognised by the 

immune system and are of a different composition. 

The potential <strong>to</strong> induce an immune reaction in the body (immunogenicity) is a 

double-edged sword for biological medicines. Vaccines specifically exploit their 

immunogenic potential by provoking an immune response that recognises and 

"fights off" an "invader" substance. However, for some medicines based on 

the very high level of 

precision required. 

Most biological medicines 

are made using a geneticallymodified 

cell construct or cell 

line. Each biotech company 

has its own master cell bank 

producing unique cell lines 

replicated for manufacturing 

and develops its own proprietary 

(unique) manufacturing processes. 

The production of biological 

medicines involves processes 

such as fermentation and 

purification. Even very minor 

variations <strong>to</strong> these manufacturing 

processes, for example in 

temperature, can result in 

significant changes in the 

physical and clinical properties 

of the biological medicine 

produced. It is therefore vital 

<strong>to</strong> control precisely the 

manufacturing processes 

and the environment inside a 

production facility, <strong>to</strong> obtain 

consistent results and <strong>to</strong> 

guarantee the safety and 

efficacy of the end product. 

Production also requires a high 

level of moni<strong>to</strong>ring and quality 

testing: typically around 250 

in-process tests are conducted 

for a biological medicine, 

compared <strong>to</strong> around 50 tests for 

a traditional chemical medicine. 

proteins, stimulating an immune response is regarded as undesirable (with the 

notable exception of vaccines where this immune response is the expected effect). 

Most of the immune responses that occur are mild and do not have negative 

effects on the patient. However in rare cases, unwanted immune reactions can 

lead <strong>to</strong> severe and detrimental effects on the health of a patient. One example is 

the appearance of so-called "neutralising" antibodies that can make the therapeutic 

protein in the medicine ineffective. Neutralising antibodies can be of particular 

concern for biological medicines that resemble the patient's own proteins (<strong>to</strong> 

replace insufficient substance levels in the patient), as they can trigger the body 

<strong>to</strong> fight off the protein injected in the medicinal product and, in rare cases, any 

remaining protein produced by the patient's own body. This immunogenic reaction 

can take years <strong>to</strong> develop and can happen at any time during treatment (after 

short-, medium and long-term use). This reaction can persist for years after the 

biological medicine has s<strong>to</strong>pped being administered <strong>to</strong> the patient. Therefore, 

immunogenicity assessment through clinical studies plays a major role in the 

development of biological medicines. 

<strong>Biological</strong> medicines are typically administered via injections or infusions. 

A molecule of a biological medicine is typically a protein made of one or several 

chains of several hundred amino acids within a complex three-dimensional 

structure. Because proteins are digested when taken orally, typically biological 

medicines must be administered by injection. <strong>Medicines</strong> based on small molecules 

(traditional pharmaceuticals) usually come in tablet or capsule form. 

<strong>Biological</strong> medicines usually need special transport and s<strong>to</strong>rage conditions. 

<strong>Biological</strong> material generally degrades quickly when handled inappropriately, 

particularly if they are subject <strong>to</strong> high temperature. Therefore, biological medicines 

usually need <strong>to</strong> be s<strong>to</strong>red in a refrigera<strong>to</strong>r and should only be handled under 

specific conditions. 

“ 

the complexity of 

biological medicines 

makes their analytical 

characterisation more 

challenging than that 

of small molecules. 

“ 

04

05 



“ 

<strong>Biological</strong> medicines 

made by unrelated 

manufacturers after 

the expiry of intellectual 

property protection are 

not exact copies of 

the original biological 

medicines. 

“ 

Intellectual property for 

biotech medicines 

Innovative medicines benefit 

from a certain period of 

intellectual property protection, 

via patents and other exclusive 

rights, such as data protection. 

Patent rights give the patent 

holder (often, but not always, 

the manufacturer) the right 

<strong>to</strong> prevent others from 

manufacturing, selling, using 

and importing the product 

during a limited period of time. 

A patent also grants the right 

<strong>to</strong> prevent others from using a 

specific process, or selling a 

product made by that process, 

during a limited period of time. 

Patents benefit both companies 

and society at large, as they 

enable important scientific 

information <strong>to</strong> be made publicly 

available, which might otherwise 

remain hidden. Patents also make 

investments in biotechnology 

R&D more attractive, which in 

turn leads <strong>to</strong> more innovation, 

and therefore more potential 

treatments. 

Data exclusivity grants a 

period of time after Marketing 

Authorisation, during which 

competi<strong>to</strong>rs are not allowed <strong>to</strong> 

enter the market with a followon 

product (i.e. generic or biosimilar). 

The “follow-on” product 

generally uses an abbreviated 

regula<strong>to</strong>ry approval procedure. 

Intellectual property protection 

is vital for companies that 

develop and manufacture new 

medicines, as it enables them 

<strong>to</strong> recoup their investments and 

further invest in the research and 

development of new medicines. 

As such, the provision of an 

adequate intellectual property 

protection system is critical <strong>to</strong> 

ensure a steady stream of new 

medical advances, <strong>to</strong> great 

public benefit. 

Small molecule medicines, 

produced by chemical synthesis, 

can generally be replicated fairly 

easily by unrelated manufacturers 

after the expiry of intellectual 

property protection. Such copies 

of the original chemical medicines 

are called "generics". In contrast, 

biological medicines made by 

unrelated manufacturers after the 

expiry of intellectual property 

protection are not exact copies of 

the original biological medicines 

because they are made in 

living systems and their exact 

characteristics and properties 

are highly dependent on the 

manufacturing process. These 

new versions of biological 

medicines are called "similar 

biological medicinal products" 

or "biosimilars". In both cases, 

the origina<strong>to</strong>r product is called 

the "reference product". 

BIOLOGICAL MEDICINES – CURRENT ISSUES 

Naming,Pharmacovigilance 

and Risk Management Plans 

Each active ingredient in a 

medicine has an International 

Non-proprietary Name (INN – 

for example “acetylsalicylic 

acid” is the INN of the active 

ingredient in “aspirin”) as well 

as a brand name. 

In the case of biological, INN can 

be either identical or different 

for similar products made by 

different manufacturers. 

For instance, the INN for 

recombinant growth hormone, 

is the same (somatropin) for all 

growth hormones made by 

different origina<strong>to</strong>rs or biosimilar 

companies. By contrast, the 

INN for recombinant human 

erythropoietin is different for 

different origina<strong>to</strong>r products 

(epoetin alpha, beta or theta) 

and can be identical or different 

for biosimilar products (epoetin 

alpha or zeta). 

European Medicine Agency 

(EMA) guidance indicates 

standard reporting of brand 

name, manufacturer’s name and 

batch number for all adverse 

events caused by biological 

medicines. Therefore, biological 

medicines should only be 

prescribed by their brand name, 

and not by their INN, which 

identifies medicines by 

their active pharmaceutical 

ingredients. Despite the fact 

that it may be possible for active 

ingredients in different biological 

medicines <strong>to</strong> share the same 

INN, patients may experience 

different immunogenic reactions 

with different products. 

Additionally, not all biological 

medicinal products have the 

same indications, administration 

schedules, administration 

systems or side effect profiles. 

The need for correct and precise 

identification is strengthened 

by the need <strong>to</strong> have robust 

pharmacovigilance carried out 

after marketing authorisation. 

Due <strong>to</strong> the variability of 

biologicals, the correct product 

identification in case of adverse 

events is important. 

Biosimilars may be approved 

by regula<strong>to</strong>ry authorities on 

the basis of demonstrated 

comparability <strong>to</strong> the reference 

product, a limited clinical 

database and often data on the 

main indication only. Holders 

of marketing authorisations for 

biological medicines, reference 

products as well as biosimilars, 

may have post-approval 

commitments defined in risk 

The specific characteristics of biologicals are taken in<strong>to</strong> account 

by the European legisla<strong>to</strong>r and regula<strong>to</strong>r: 

1. The updated European legislation on pharmacovigilance, due <strong>to</strong> be implemented 

mid-2012, establishes that Member States must make sure that “all appropriate 

measures are taken <strong>to</strong> identify when biological medicinal products are prescribed, 

dispensed, or sold in their terri<strong>to</strong>ry which is the subject of a suspected adverse 

reaction report, with due regard <strong>to</strong> the name of medicinal product (…) and the 

batch number.” 

2. All biological medicines, origina<strong>to</strong>r and biosimilar products, need <strong>to</strong> have a 

"Risk Management Plan" in place. This Risk Management Plan defines a set of 

"pharmacovigilance activities and interventions designed <strong>to</strong> identify, characterise, 

prevent or minimise risks relating <strong>to</strong> medicinal products, and the assessment of 

the effectiveness of these interventions". Assessment of the immunogenicity is 

a key measure in the Risk Management Plan of any biological medicine. 

management plans, <strong>to</strong> 

characterise safety profiles more 

fully, <strong>to</strong> establish long-term safety. 

As already discussed, biologicals 

have the inherent potential <strong>to</strong> 

induce (unwanted) immune 

reactions. Immune reactions may 

take years <strong>to</strong> develop, therefore 

biologicals are usually treated 

differently <strong>to</strong> chemical medicines 

by regula<strong>to</strong>ry authorities. Whilst 

much is now known about the 

features of biological medicinal 

products that cause immune 

reactions (for example high 

content of host cell proteins and 

certain routes of administration), 

it is not currently possible <strong>to</strong> 

accurately predict immunogenicity 

in humans. Immunogenicity 

is however assessed through nonclinical 

assessment in animals, 

and in humans within the scope 

of clinical trials and thorough 

post-marketing surveillance. 

At the time of approval (for 

both origina<strong>to</strong>r and biosimilar 

biologicals), information on the 

safety of the medicinal product 

is relatively limited for several 

reasons, including a limited 

number of patients in clinical 

trials, limited time of exposure 

<strong>to</strong> the medication and, usually, 

a rather strictly defined patient 

population. 

06



Interchangeability 

Interchangeability of medicinal 

products refers <strong>to</strong> the situation 

where one product can be 

interchanged for another 

equivalent product in a clinical 

setting, without the risk of a 

negative health outcome. 

In order <strong>to</strong> gain a marketing 

authorisation in Europe, biosimilar 

applicants need <strong>to</strong> demonstrate 

similarity <strong>to</strong> the reference 

product. Assessments of 

interchangeability and 

substitutability are not part 

of the scientific evaluation by 

the European <strong>Medicines</strong> Agency 

(EMA) and therefore, no 

conclusion on interchangeability 

or au<strong>to</strong>matic substitution can be 

made based on the grant of a 

market authorisation. Decisions 

on au<strong>to</strong>matic substitution lie 

within the responsibility of the 

Member States. Unless products 

are designated as substitutable 

(see below), the decision as <strong>to</strong> 

which product should be used 

and whether treatment should 

or could be changed <strong>to</strong> another 

product lies with the treating 

physician. 

Substitution 

Au<strong>to</strong>matic substitution (or 

generic substitution) is when a 

pharmacist substitutes a generic 

medicine for the brand name 

version of the same active 

ingredient, with no obligation 

<strong>to</strong> inform the treating physician. 

Some countries make generic 

substitution manda<strong>to</strong>ry under 

certain conditions, for example 

where the doc<strong>to</strong>r prescribes 

by INN. 

Generic substitution is often 

linked <strong>to</strong> reimbursement, as 

some health insurance schemes 

will only reimburse the patient 

for the cost of the generic 

version of a product. The result 

of this can be that a patient who 

refuses the generic version and 

insists on the original product 

may be liable <strong>to</strong> pay the difference 

in cost. Generic versions 

of chemical pharmaceuticals 

that have demonstrated their 

bioequivalence may generally 

be substituted with no risk 

<strong>to</strong> patient safety. 

However, the EMA has 

specifically stated that "since 

biosimilars and biological 

reference products are not 

identical, the decision <strong>to</strong> treat a 

patient with a reference product 

or biosimilar medicine should be 

taken following the opinion of a 

qualified health professional". 

The physician’s involvement is 

particularly relevant, as not 

all biological medicines will 

necessarily have the same 

indications, administration 

schedules, administration 

devices or side effect profiles. 

Furthermore, if au<strong>to</strong>matic 

substitution were <strong>to</strong> take place, 

it could confound pharmacovigilance 

when adverse reactions 

occur, especially immune reactions, 

as it is more difficult <strong>to</strong> 

evaluate which product is 

responsible for the reaction if 

the product has been repeatedly 

switched during treatment. 

A number of countries have 

either established legislative 

measures <strong>to</strong> prohibit the 

au<strong>to</strong>matic substitution of 

biological medicines or have 

given regula<strong>to</strong>ry advice on the 

use of biologics (including 

prescription by brand names). 

Based on the above, countries 

that currently allow au<strong>to</strong>matic 

substitution of biologicals should 

take the necessary measures <strong>to</strong> 

s<strong>to</strong>p this practice in the absence 

of data that demonstrate interchangeability. 

Therefore, any 

change of treatment with a 

biological medicine should 

currently only be made under 

close medical supervision by 

the physician, with the patient’s 

consent. 

Impact on Healthcare 

Budget and Pricing 

Generics and biosimilars have an 

important role <strong>to</strong> play <strong>to</strong> foster 

competition in the marketplace, 

contributing thereby <strong>to</strong> the sustainability 

of healthcare budgets. 

Price reductions for biosimilars 

are generally not as those for 

generic medicines for a number 

of reasons. Firstly, biological 

medicines, including biosimilars, 

are generally more complex and 

costly <strong>to</strong> produce and develop. 

Secondly, the regula<strong>to</strong>ry approval 

requirements and post-marketing 

surveillance for biosimilars are 

more rigorous than for generic 

medicines, thus adding a further 

layer of cost <strong>to</strong> developing a 

biosimilar (e.g. unlike generics, 

biosimilars usually require 

independent non-clinical and 

clinical trials <strong>to</strong> be undertaken). 

Therefore, R&D costs required 

for the approval of a biosimilar - 

ranging on average from USD 

75 <strong>to</strong> USD 250 (approximately 

€50 <strong>to</strong> €170 million) 2 - are much 

higher than those for a generic. 

The exact price level of a 

biosimilar will depend on a 

number of fac<strong>to</strong>rs, namely the 

pricing and reimbursement 

environment of each country, 

competitiveness of the market 

and the desire <strong>to</strong> encourage 

the future development of 

new products. 

Currently the number of 

biosimilars is low partly because 

only a few biological medicines 

have lost their market exclusivity. 

Potential savings, due <strong>to</strong> their 

lower list prices, are therefore 

limited as the products compete 

in market segments that only 

represent a small portion of <strong>to</strong>tal 

healthcare expenditure. 

The regulation of 

biological in Europe, 

including biosimilars 

Depending on the disease 

category, chemical medicines 

can be approved either by the 

national medicines authorities 

of the individual EU Member 

States or by the "centralised 

procedure" for approval carried 

out by the European <strong>Medicines</strong> 

Agency (EMA). In contrast, 

all new biological medicinal 

products, including biosimilars, 

have <strong>to</strong> follow the centralised 

procedure. 

Applications submitted <strong>to</strong> the 

EMA are assessed by its 

Committee for Human Medicinal 

Products (CHMP), which can give 

a positive or negative opinion. 

Upon receipt of a positive 

opinion from the EMA, the 

European Commission issues a 

marketing authorisation, which is 

valid for all EU Member States. 

Since 2003, the European 

Union has created a legal and 

regula<strong>to</strong>ry pathway <strong>to</strong> enable 

the development and marketing 

of biosimilar medicines. 

Directives 2003/63/EC and 

2004/27/EC created the 

legislative route and the EMA 

has subsequently developed a 

number of regula<strong>to</strong>ry guidelines 

concerning the data required for 

the approval of a biosimilar. 

The EMA defines biosimilars in "Questions and Answers on biosimilar medicines" as: 

Besides the "overarching" 

general guidelines on biosimilars, 

the EMA has also developed 

guidelines on quality, non-clinical 

and clinical issues, as well as 

product-specific guidelines 

annexes (for example insulin, 

epoetin, somatropin, granulocytestimulating 

growth fac<strong>to</strong>r, 

interferon-alfa and low-molecular 

weight heparin). At the time of 

publication of this document, 

further guidelines are being 

prepared, including guidelines 

on follicle stimulation hormone, 

interferon-beta and monoclonal 

antibodies. 

The EMA's "overarching" 

guidelines on biosimilars 

specifically state that biosimilar 

products are "by definition" 

not generics, and that the 

generic approach <strong>to</strong> approval 

"is scientifically not appropriate" 

for biosimilars. 

2. Industry average source: Sandoz internal 

estimates. Conversion in € done in July 2011 

"A biosimilar medicine is a medicine which is similar <strong>to</strong> a biological medicine that has 

already been authorised (the 'biological reference medicine'). The active substance of 

a biosimilar medicine is similar <strong>to</strong> the one of the biological reference medicine. 

Biosimilar and biological reference medicines are used in general at the same dose <strong>to</strong> 

treat the same disease. Since biosimilar and biological reference medicines are similar 

but not identical, the decision <strong>to</strong> treat a patient with a reference or a biosimilar 

medicine should be taken following the opinion of a qualified healthcare professional. 

The name, appearance and packaging of a biosimilar medicine differ <strong>to</strong> those of the 

biological reference medicine." 

Furthermore, the EMA Questions and Answers document states that the "legislation defines 

the studies that need <strong>to</strong> be carried out <strong>to</strong> show that the biosimilar medicine is similar and 

as safe and effective as the biological reference medicine". To this end, the biosimilar 

approval pathway requires the manufacturer <strong>to</strong> demonstrate similarity with the reference 

product for quality, safety and efficacy. Specifically, the biosimilar must demonstrate that it 

has no significant clinical differences <strong>to</strong> the reference product. Biosimilar manufacturers must 

provide all of the non-clinical, pre-clinical and clinical data required <strong>to</strong> demonstrate the 

similarity of their product <strong>to</strong> the reference product, without the need <strong>to</strong> repeat unnecessary 

tests and trials. 

07 08



THE MARKET FOR BIOSIMILARS THE POTENTIAL IMPACT OF BIOSIMILARS 

Which biosimilars are currently available in Europe? 

So far, the European Union has approved 7 biosimilars, across 3 product classes: human growth hormones, 

erythropoietins and granulocyte colony stimulating fac<strong>to</strong>rs. 

Name 

Abseamed 

Binocrit 

Biograstim 

Epoetin alfa Hexal 

Filgrastim Hexal 

Filgrastim 

ratiopharm 

Nivestim 

Omnitrope 

Ratiograstim 

Retacrit 

Silapo 

Tevagrastim 

Valtropin 

Zarzio 

What about the rest 

of the world? 

Active 

substance 

epoetin alfa 

epoetin alfa 

filgrastim 

epoetin alfa 

filgrastim 

filgrastim 

filgrastim 

somatropin 

filgrastim 

epoetin zeta 

epoetin zeta 

filgrastim 

somatropin 

filgrastim 

In the United States, the 

Biologics Price Competition and 

Innovation Act, signed in<strong>to</strong> law in 

March 2010, created a statu<strong>to</strong>ry 

framework for the approval of 

biosimilars by the Food and Drug 

Administration (FDA). Almost all 

guidelines that have either been 

passed or are being discussed in 

other parts of the world (for 

example Australia, Japan, Korea, 

Malaysia, Mexico, Switzerland, 

South Africa, Taiwan and Turkey) 

largely correspond <strong>to</strong> the 

European body of regulations for 

biosimilars. Lastly, the World 

Health Organisation’s guideline 

for biosimilars fundamentally 

follows the EU principles and is 

meant <strong>to</strong> serve as a basis for 

countries <strong>to</strong> develop their own 

biosimilar legislation. 

Therapeutic area 

Kidney Failure, Chronic Anemia Cancer 

Kidney Failure, Chronic Anemia 

Hema<strong>to</strong>poietic Stem Cell Transplantation 

Neutropenia Cancer 

Kidney Failure, Chronic Anemia Cancer 

Neutropenia Cancer Hema<strong>to</strong>poietic Stem 

Cell Transplantation 

Neutropenia Hema<strong>to</strong>poietic Stem Cell 

Transplantation Cancer 

Hema<strong>to</strong>poietic Stem Cell Transplantation 

Cancer Neutropenia 

Turner Syndrome Dwarfism, Pituitary Prader- 

Willi Syndrome 



Cancer Anemia Kidney Failure, Chronic 

Blood Transfusion, Au<strong>to</strong>logous 

Anemia Blood Transfusion, Au<strong>to</strong>logous 

Cancer Kidney Failure, Chronic 



Dwarfism, Pituitary Turner Syndrome 

Cancer Hema<strong>to</strong>poietic Stem Cell 

Transplantation Neutropenia 

What does the entry of 

biosimilars in the market 

mean <strong>to</strong> origina<strong>to</strong>r 

products? 

Market success for all medicines, 

including biological medicines 

and biosimilars, in the EU 

depends upon a number of 

fac<strong>to</strong>rs, including pricing and 

reimbursement and physician 

and patient expectations. 

Biosimilar products compete 

with origina<strong>to</strong>r biologicals, which 

already compete with other 

origina<strong>to</strong>r products made by 

different biopharmaceutical 

companies. Experience so far 

indicates that biosimilar uptake 

varies by product class and 

country. Naturally, biosimilars 

are versions of older biological 

medicines that have lost IP 

protection. Continued innovation 

Date of 

authorisation 

28/08/2007 

28/08/2007 

15/09/2008 

28/08/2007 

06/02/2009 

15/09/2008 

08/06/2010 

12/04/2006 

15/09/2008 

18/12/2007 

18/12/2007 

15/09/2008 

24/04/2006 

06/02/2009 

Status 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Authorised 

Source: European <strong>Medicines</strong> Agency (June 2011) 

has often led <strong>to</strong> secondgeneration 

biological medicines 

providing increased therapeutic 

benefits <strong>to</strong> patients. This means 

that the biosimilar products 

mainly compete with older 

biological medicines, with which 

they are comparable, rather than 

with the most recent innovative 

treatments. 

Over the last 2 years, the 

biosimilar market shares have 

steadily increased in most 

countries. In several European 

countries, biosimilars now have a 

higher volume market share than 

the reference products, and this 

trend appears <strong>to</strong> be accelerating. 

For patients 

Patients need and deserve <strong>to</strong> be 

fully informed about any medical 

treatment that they are receiving. 

If a physician chooses <strong>to</strong> prescribe 

a medicine <strong>to</strong> a patient, the 

patient should be involved in 

that decision, meaning that the 

patient understands why the 

choice has been made as well 

as what it will mean for his or 

her treatment. 

Patients may not be completely 

aware of the complexities of 

biologicals, including biosimilars, 

and the implications of using 

them. This includes the potential 

of different products <strong>to</strong> provoke 

different immunogenic reactions 

in the patient. It is important 

that patients are not obliged <strong>to</strong> 

"switch" their treatment from 

one biological <strong>to</strong> another purely 

on cost grounds, the specific 

therapeutic needs of the patient 

must always be taken in<strong>to</strong> 

account. 

According <strong>to</strong> a survey by the 

International Alliance of Patients' 

Organizations (IAPO), the key 

interests of patients with regards 

<strong>to</strong> biosimilars are: 

Cost and the potential <strong>to</strong> 

increase access <strong>to</strong> biological 

treatments; 

Safety and efficacy; 

Patient information and 

decision-making; 

Regula<strong>to</strong>ry process; and 

Interchangeability. 

Therefore, it is very important 

that the label and other product 

information relating <strong>to</strong> the 

biosimilar reflect the specific 

characteristics (such as 

reference product, potential 

side effects etc). 

For healthcare 

professionals 

Healthcare professionals need 

<strong>to</strong> understand the EMA approval 

process for biosimilars and be 

aware of the scientific data 

underlying their approval (in 

particular the abridged clinical 

data requirements, which can 

allow the extrapolation of 

indications). 

For physicians <strong>to</strong>o, it is very 

important that the label and 

other product information 

relating <strong>to</strong> the biosimilar reflect 

the specific characteristics (such 

as reference product, potential 

side effects, etc). The summary 

of product information on 

biosimilars should also list the 

available data in order <strong>to</strong> 

show which applications were 

substantiated by studies and 

which were derived from the 

biological medicine of the 

original manufacturer without 

separate data via extrapolation. 

Furthermore, healthcare 

professionals must be aware that 

the interchangeability between 

the biosimilar and its reference 

product has not been evaluated 

by the regula<strong>to</strong>ry authority. 

Physicians should not be obliged 

<strong>to</strong> prescribe a certain medication 

purely on the grounds of cost, but 

should be allowed <strong>to</strong> exercise 

appropriate clinical judgment. 

With regards <strong>to</strong> patients, it is 

very important for healthcare 

professionals that the label and 

other product information of 

the biosimilar reflect its specific 

characteristics (clinical data, 

reference product, etc.). 

09 10 

“ 

the specific 

therapeutic needs 

of the patient must 

always be taken 

in<strong>to</strong> account. 

“ 

For payers 

Payers, such as national health 

systems and health insurance 

funds, are interested in the costsaving 

potential of biosimilars. 

<strong>Biological</strong> medicines have 

brought great benefit <strong>to</strong> patients, 

often treating so far untreatable 

or insufficiently treatable, severe 

diseases. Biosimilars offer opportunities 

for savings upon loss of 

IP protection for the origina<strong>to</strong>r 

products. Biosimilars have 

brought enhanced competition 

<strong>to</strong> prices of biological medicines, 

which in turn have resulted in 

significant price decreases in the 

majority of markets. It is important 

however that physicians and 

patients retain the flexibility <strong>to</strong> 

make informed decisions about 

the different treatment options. 

It is important that payers 

understand that, due <strong>to</strong> the 

precautionary principle, 

au<strong>to</strong>matic substitution for 

biologics should not occur and 

the choice <strong>to</strong> use any biological 

product should remain in the 

hands of the treating physician. 

Any future decisions need <strong>to</strong> be 

based on appropriate data. The 

physician must be allowed <strong>to</strong> 

exercise appropriate clinical 

judgment <strong>to</strong> select the best available 

treatment for the individual 

patient, and such choices should 

never be mandated purely on 

the basis of product prices.



GLOSSARY OF KEY TERMS REFERENCES 

Advanced therapies: New and 

emerging therapies, including cell, 

gene and tissue therapies 

Adverse event: The occurrence of 

an undesirable, unpleasant or lifethreatening 

reaction <strong>to</strong> a medicinal 

product 

Amino acid: Building block of 

proteins. There are 20 common 

amino acids found in proteins 

Antibody (pl: antibodies): Antibodies 

(also known as immunoglobulins, 

abbreviated <strong>to</strong> Ig) are proteins that are 

found in blood or other bodily fluids. 

Antibodies are used by the immune 

system <strong>to</strong> identify and neutralise foreign 

objects, such as bacteria and viruses 

Au<strong>to</strong>immune disease: A disease 

caused by the body producing an 

excessive immune response against 

its own tissues. Thereby, the immune 

system ceases <strong>to</strong> recognise one or 

more of the body's normal constituents 

as "self" and will create au<strong>to</strong>-antibodies 

that attack its own cells, tissues, 

and/or organs. Inflammation and tissue 

damage are common symp<strong>to</strong>ms of 

au<strong>to</strong>immune diseases 

Au<strong>to</strong>matic substitution: The practice 

by which a product other than the 

one specified on the prescription is 

dispensed <strong>to</strong> 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 decide <strong>to</strong> dispense any 

product with the same active ingredient 

<strong>Biological</strong>/biotech medicine: 

A medicinal product or a vaccine that 

consists of, or has been produced by 

the use of, living organisms. Often 

recombinant DNA (a form of DNA that 

does not exist naturally and which 

combines DNA sequences that would 

not normally occur <strong>to</strong>gether in order 

<strong>to</strong> establish new functions) forms 

the basis for biotechnologically 

manufactured products. Examples 

include therapeutic proteins such as 

antibodies, insulins or interleukins; but 

also vaccines, nucleic acid or tissues 

and cells. For the purpose of this 

document, the term “biological/biotech 

medicine” refers <strong>to</strong> therapeutic proteins 

Biosimilar: A similar, but not identical, 

version of an existing biological 

medicine made following the patent 

expiry of the original product (must be 

made by a different manufacturer) 

Biotechnology: Any technological 

application that uses biological systems, 

living organisms, or derivatives thereof, 

<strong>to</strong> make or modify products or 

processes for specific use 

Cell line (including master cell line): 

A well-established, living system of 

cultured (grown in a labora<strong>to</strong>ry) cells 

that will continue <strong>to</strong> grow and produce 

new cells indefinitely, so long as the 

cells receive nourishment and have 

space <strong>to</strong> propagate 

Extrapolation: Extending the findings 

from one set of conditions <strong>to</strong> another, 

such as extending and applying the 

data from clinical studies regarding 

one medical condition <strong>to</strong> another 

medical condition or extending data 

from clinical studies in adults <strong>to</strong> children 

Generic (medicine): A copy of an 

existing (chemical) medicine, which is 

bioequivalent <strong>to</strong> the original medicine, 

but which may be made by a different 

firm after patent expiry of the origina<strong>to</strong>r 

product 

Immune system: The collection of 

mechanisms within the body that 

protect against disease by identifying 

and killing pathogens (e.g. viruses 

and bacteria) and tumour cells 

Immunogenic: The potential <strong>to</strong> cause 

immune reactions 

Indication: The medical condition, 

disorder or disease for which a certain 

test, medication, procedure, or surgery 

is used. Such tests and medications 

are often subject <strong>to</strong> official (regula<strong>to</strong>ry) 

approval. Most countries and jurisdictions 

have a licensing body whose 

duty it is <strong>to</strong> determine whether <strong>to</strong> 

approve a drug for a specific indication, 

based on the relative safety of the 

drug and its efficacy for the particular 

indication (use) being investigated 

INN: International Non-proprietary 

Name 

Interchangeability: Where two 

products can be exchanged one with 

another without a significant risk of 

an adverse health outcome 

Marketing authorisation: The 

permission granted by a regula<strong>to</strong>ry 

authority <strong>to</strong> a company <strong>to</strong> market a 

medicinal product in accordance with 

the conditions described in the label, 

following the company's submission 

of required documentation and data 

relating <strong>to</strong> testing and clinical trials of 

the product 

Molecule: The smallest particle of a 

substance that has all of the physical 

and chemical properties of that 

substance. Molecules are made up of 

one or more a<strong>to</strong>ms. If they contain 

more than one a<strong>to</strong>m, the a<strong>to</strong>ms can 

be the same (an oxygen molecule has 

two oxygen a<strong>to</strong>ms) or different (a 

water molecule has two hydrogen 

a<strong>to</strong>ms and one oxygen a<strong>to</strong>m). 

<strong>Biological</strong> molecules, such as proteins, 

can be made up of many thousands 

of a<strong>to</strong>ms 

Molecular: Of a molecule 

Nucleic acid: A macromolecule 

(i.e. a very large molecule) composed 

of chains of monomeric (having a single 

component) nucleotides, which are 

molecules that, when joined <strong>to</strong>gether, 

make up the structural units of RNA 

and DNA. In biochemistry these 

molecules carry genetic information 

or form structures within cells 

Patent: A patent is a set of exclusive 

rights granted by a state (national 

government) <strong>to</strong> an inven<strong>to</strong>r or their 

assignee for a limited period of time 

in exchange for public disclosure of an 

invention. Typically, however, a patent 

application must include one or more 

claims defining the invention which 

must be new, non-obvious, and 

useful or industrially applicable 

Pharmacovigilance: Safety control 

procedures <strong>to</strong> which medicines are 

subject before, during and after their 

approval by regula<strong>to</strong>ry authorities 

Protein: Large organic compounds 

made of amino acids. Proteins are 

essential parts of organisms and 

participate in virtually every process 

within cells 

Reference product: The original 

product <strong>to</strong> which a biosimilar or 

generic drug refers in its application 

for marketing approval 

Vaccine: A biological preparation 

which is used <strong>to</strong> establish or improve 

immunity <strong>to</strong> a particular disease 

Directive 2001/83/EC of the European Parliament and of 

the Council of 6 November 2001 on the Community code 

relating <strong>to</strong> medicinal products for human use. Article 10. 

Available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri= 

CELEX:32001L0083:en:NOT 

Brochure - Biosimilar medicinal products; 2001; 

European <strong>Medicines</strong> Agency. 

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

library/Brochure/2011/03/WC500104228.pdf 

Questions and Answers on biosimilar medicines 

(similar biological medicinal products); Oct 2008; 

European <strong>Medicines</strong> Agency. 

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

library/Medicine_QA/2009/12/WC500020062.pdf 

All the following European <strong>Medicines</strong> Agency’s 

guidelines are available at: 

http://www.ema.europa.eu/ema/index.jsp?curl=pages/ 

special_<strong>to</strong>pics/document_listing/document_listing_000318.jsp 

&murl=menus/special_<strong>to</strong>pics/special_<strong>to</strong>pics.jsp&mid=WC0b01 

ac0580281bf0 

<strong>Guide</strong>lines on Similar <strong>Biological</strong> Medicinal Products containing 

Biotechnology-Derived Proteins as Active Substance: 

Non-Clinical and Clinical Issues; Feb 2006; European 

<strong>Medicines</strong> Agency 

Concept paper on the Revision of the guideline on similar 

biological medicinal products containing biotechnologyderived 

proteins as active substance: quality Issues; Feb 2011; 

European <strong>Medicines</strong> Agency 

<strong>Guide</strong>lines on Similar <strong>Biological</strong> Medicinal Products Containing 

Biotechnology-Derived Proteins as Active Substance: Quality 

Issues; Feb 2006; European <strong>Medicines</strong> Agency 

<strong>Guide</strong>lines on Similar <strong>Biological</strong> Medicinal Product; 

Sep 2005; European <strong>Medicines</strong> Agency 

<strong>Guide</strong>lines on Similar biological medicinal products containing 

recombinant follicle stimulation hormone; Mar 2010; 


<strong>Guide</strong>lines on Similar biological medicinal product 

containing recombinant interferon beta; Mar 2010; 


Concept Paper on <strong>Guide</strong>lines on Similar biological medicinal 

products containing monoclonal antibodies; Nov 2010; 


<strong>Guide</strong>lines on Similar biological medicinal products 

containing recombinant Erythropoietins; Sep 2010; 


<strong>Guide</strong>lines on Similar biological medicinal products 

containing low-molecular-weight-heparins; Oct 2009; 


<strong>Guide</strong>lines on Non-clinical and clinical development of 

similar medicinal products containing recombinant interferon 

alpha; Apr 2009; European <strong>Medicines</strong> Agency 

<strong>Guide</strong>lines on Evaluation of Similar Biotherapeutic Products 

(SBPs); Oct 2009; World Health Organization (WHO). 

Available at: http://www.who.int/biologicals/areas/biological_ 

therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf 

CPME Position on Access <strong>to</strong> <strong>Medicines</strong> – Biosimilars; 

Mar 2011; Comité Permanent des Médecins Européens. 

Available at: http://cpme.dyndns.org:591/database/ 

2011/cpme.2011-027.Position.Biosimilars.pdf 

Biosimilar <strong>Medicines</strong>; International Alliance of Patients’ 

Organizations; May 2006. 

Available at: http://www.patientsorganizations.org/ 

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