Bio Similar Factsheet December 2008

7/31/2019 Bio Similar Factsheet December 2008

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EuropaBio&Biosimilar

Medicines


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Contents

Welcome letter rom the Secretary General

o EuropaBio

Healthcare biotechnology and biosimilars

Glossary o key terms

Reerences

Further inormation

Healthcare biotechnology and biosimilars

I - The Science

1. Healthcare biotechnology introduction

2. Why do biological medicines dier rom chemical medicines?

3. How are biological medicines manuactured?

4. Intellectual property or biotech medicines

II - Biosimilar Medicines Current Issues

1. Naming

2. Health Economics & Pricing

3. Immunogenicity

4. Interchangeability

5. Substitution

III The Regulation of Biosimilars

1. In Europe

2. Outside o Europe

IV - The market for biosimilars

1. Which biosimilars are currently available in Europe?

2. When are the next biosimilars coming on to the market?

3. What does the market entry o biosimilars mean or the original innovator products?

V - The impact of biosimilars

1. What do patients need to know?

2. What do healthcare proessionals need to know?

3. What do payers need to know?

E U R O P A B I O A N D B I O S I M I L A R M E D I C I N E S


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have accessto more

than 155biotechnologymedicines andvaccines...

...patients


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Biotechnology uses biological systems and living

organisms to make or modiy products or processes

or specic useii. Biotechnology medicines are just

one o the many applications o biotechnology in

healthcare. There are several prominent categorieso biotechnological medicines:

Recombinant proteins can replace insucient

or malunctioning proteins in the human body.

One example o a recombinant protein is insulin,

which is commonly used in the treatment o

diabetes. Other recombinant proteins like

antibodies or vaccines are used in the treatment

or prevention o serious diseases such as cancer.

Nucleic acids like DNA or RNA are used in

gene-therapy treatments to restore or modulate

specic disease-related genes.

Tissues and cells are used or tissue repair ater

severe injuries e.g., skin transplants.

Inactivated orms o micro-organisms are used as

vaccines to prevent diseases provoked by these

micro-organisms (mostly viruses). Vaccines work

by stimulating an immune response against a

disease-causing micro-organism.

Complex chemical molecules like antibiotics,

which are used or the treatment o bacterial

inections, can be either directly obtained rom

micro-organisms (e.g. penicillin is produced

by a certain type o ungus), or can be urther

modied by chemical processes (e.g. hal-synthetic

antibiotics like ampicillin).

Furthermore, many biotechnological healthcare

products are used widely or diagnostic purposes.

*For the purpose of this document, we use the term biotech medicine or

biological medicine or biopharmaceutical for recombinant protein products.


I - The Science

1. Healthcare biotechnology introduction

What are biotechnology medicines

and how do they work?

05

*


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The history of healthcare biotechnology

06

Although the modern healthcare biotechnology

industry is only 30 years old, the science o

biotechnology has been explored since the 19th

century when eminent scientists such as Louis

Pasteur and Robert Koch rst developed the

science o microbiology, the orerunner o todays

biotechnology. In 1953, James Watson and FrancisCrick discovered DNA and in 1955, Fred Sanger

determined the amino acid sequence o insulin.

In 1972, Paul Berg created the rst recombinant

DNA molecule. DNA engineering has become the

basis o modern biotechnology as it allows the

re-arrangement (recombination) o so ar

unrelated genetic sequences and the use o those

molecules or the production o recombinant

proteins or medical purposes.

The rst biotech companies were ounded in the

1970s and many more in the early 1980s. Most o

todays healthcare biotech companies began lie

as small start-ups established by a handul o

enthusiastic visionary scientists on a shoe-string

budget. The hard work o the early pioneers has

now come to ruition: today, over 325 million

people have had their lives transormed by

healthcare biotechnology treatments and it is

estimated that by 2010, around 50 percent o

new medicines will be o biological originiii.


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1. Biological medicines show a higher variability.

As biological medicines are produced by living

systems, such as cell lines, they show a higher

variability than traditional (chemical)

pharmaceuticals. As a consequence, each

biological medicine is unique. This could be

likened to the signature o a person; each time

a person (biological) signs something, their

signature will be slightly dierent, whereas a

printed (chemical) signature remains exactly

the same.

2. Biological medicines are more complex.

Proteins consist o one or more chains o

potentially several hundred amino acids with a

complex three-dimensional structure. Their

molecular size is, thereore, bigger than that o

chemical medicines. These large molecules are

diverse and dicult to characterize. In contrast,

the molecular structure o chemical medicines

is relatively simple, which can allow them to beexactly reproduced.

3. Biological medicines have the potential to

provoke immune reactions.

Biological medicines, because o their

composition and large molecular size, have

the ability to stimulate the body to mount an

immune response, i.e. produce antibodies against

a protein that the human body recognizes as

oreign. Small molecule chemical medicines,


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Biological medicines are ar more complex

and usually much bigger in size than chemical

medicines, which are produced by chemical

synthesis. This means that their manuacturing and

precise characterisation tends to be more dicult

than or chemical medicines, the ingredients o

which are more easily identiable and can beexactly reproduced.

2. Why do biological medicines differ from

chemical medicines?

What are the differentiating factors?


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08

on the other hand, are too small to be recognized

on their own by the immune system. Chemical

medicines can sometimes provoke rare negative

immune reactions like allergy or hypersensitivity

when they bind to naturally occurring proteins in

the body. However, these reactions are generally

short-lived; once levels o the chemical medicinehave decreased in the body, the negative immune

response will, in most cases, disappear and no

longer harm the patient as long as no urther

exposure to the medicine occurs.

The potential to provoke an immune response in

the body (immunogenicity) is a double-edged sword

or all biological medicines. Vaccines specically

exploit this immunogenic potential by provoking an

immune response that recognizes and ghts o an

invader substance. However, or most medicines

based on recombinant proteins, stimulating an

immune response is regarded as undesirable.

Immune responses are complex reactions o the

body and can dier rom patient to patient (due to

genetic actors), as well as rom disease to disease

(depending on the immune status o the patient).

The likelihood o an immune response can also

be infuenced by characteristics o the biological

product itsel, such as its ormulation, stability and

manuacturing process. The individual manuacturing

process has infuence, or example, on the activesubstance and the quality and quantity o impurities.

Most o the immune responses that occur are mild

and do have negative eects on the patient, e.g.

in the majority o cases where transient antibodies

to a therapeutic protein are ound in the blood. In

rare cases, however, unwanted immune reactions

can have severe, detrimental eects on the health

o a patient, e.g. when so-called neutralizing

antibodies appear and make the therapeutic protein

in the biotech medicine ineective.

With biological medicines that resemble the

patients own proteins and are intended to replace

insucient levels o that substance in the patient,

such neutralizing antibodies can even trigger the

body to ght o what remains o the protein

produced by the patients body. This immunogenic

reaction can persist or years ater the biologicalmedicine has stopped being administered to the

patient. This potential to elicit a sustained immune

response to a patients own protein and block

important biochemical pathways or long periods

o time makes immunogenicity o biological

medicines a particular saety concern.

4. Biological medicines are often administered

via injections.

When taken orally, the digestive system breaks

down proteins (o which biotech medecines

are composed), into their building blocks called

amino acids. This progess would prevent the

protein rom reaching the part o the body it

should treat and exerting its therapeutic

unction. Thereore biotech medicines must

generally be administered by injection and

cannot be taken orally in the shape o a pill or

capsule like chemical medicines. Antibiotics,

which are complex structures, but not proteins,

can be taken orally or via injections, depending

on the specic need.

5. Biological medicines need special transport and

storage conditions.

Biological material is generally subject to ast

degradation when handled inappropriately.

Thereore, biological medicines usually need

to be stored in a rerigerator and should be

handled under specic conditions.


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...biotechmedicines

must generally

be administeredby injection...


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10

3. How are biological medicines manufactured? Manuacturing biological medicines is generally

more complex than the production o traditional

(chemical) pharmaceuticals. Biological medicines

show a higher batch-to-batch variability than

chemical medicines. There are a number o reasons

or this, including the nature o the starting

material and the very high level o precisionrequired in the manuacturing process.

The starting material or most biological medicines

is a genetically modied cell line. Each biotech

company uses unique cell lines and develops its

own proprietary (unique) manuacturing processes

to produce biological medicines.

The production o biological medicines involves

processes such as ermentation and purication.

Even very small changes to these manuacturing

processes such as minor variations during production

e.g. temperature variations, can result in signicant

changes in the clinical properties o the biological

medicine produced. It is thereore vital to precisely

control the manuacturing processes and the

environment inside a production acility, in order to

obtain consistent results and to guarantee the saety

and ecacy o the end product.

The production o biotechnology medicines

requires a high level o monitoring and quality

testing: typically around 250 in-process tests areconducted or a biological, compared with around

50 tests or a traditional (chemical) medicine.

The unique starting material and the complex

manuacturing processes mean that it is not

possible to exactly reproduce a biological in the

same way a pharmaceutical (chemical) generic can

be produced.


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4. Intellectual property for biotech medicines Innovative medicines generally benet rom a

certain period o intellectual property protection

via patents and other exclusive rights such as data

protection and market exclusivity. Patent rights

give the patent holder (oten, but not always, the

manuacturer), the right to prevent others rom

manuacturing, selling, using and importing aproduct, or using a process or selling a product

made by that process during a limited period o

time, e.g. 20 years rom the date o application.

Data and market exclusivity mean that there is a

period o time ater approval beore a competitor

can enter the market with a ollow-on product that

relies wholly or partly on the originators data on

saety and ecacy or its regulatory approval. The

ollow-on product can oten use an abbreviated

regulatory approval procedure.

Such orms o intellectual property protection

are important or companies that develop and

manuacture new medicines, as it enables them to

recoup their investments and urther invest in the

research and development o new medicines.

Follow-on versions o chemical medicines that enter

the market ater expiry o IP protection are

called generics. Follow-on versions o biological

medicines are called similar biological medicinal

products or biosimilars. In both cases, the

originator product is called the reerence product.

Due to certain special eatures that characterise a

biological medicine, the European Union decided

that the name o ollow-on biological medicines

(biosimilars) and their regulatory approval pathway

had to be dierent rom chemical generics.


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II - Biosimilar medicines - current issues

1. Naming

All medicines have an International Non-proprietary

Name (INN) and most have a brand name, too.

Chemical pharmaceuticals have the same INN as

the originator product as they are exact copies o

the originator. Due to the complexity o biologicalmedicinal products, EuropaBio advocates a

revision o the INN nomenclature system so that

each biotechnology-derived medicine is assigned

a distinct INN. Another alternative would be to

ensure that biologicals are always commercialised

with a brand name or the INN plus the

manuacturers name.

In some countries, physicians are obliged or

encouraged to prescribe by INN. In such situations

i two biologicals have the same INN, this could

result in products being considered identical

and thus switched, when there might be no

scientic evidence to support that switch. Such a

switch could have negative clinical consequences

or the patient, as typically the two products

are similar but not identical, and the dierences

between them may have a therapeutic impact.

The European Commissions proposal or improving

the EU pharmacovigilanceiv system stresses the

importance o being able to precisely trace a

biological product. Specically, the Commissionsuggests that marketing authorisation holders

should advise those completing adverse event

reports to provide the (invented) name and the

batch number. Also, in order to improve the

pharmacovigilance o biological products including

biosimilars, the Commission has proposed that

Member States ensure that biological medicinal

products that are the subject o adverse reaction

reports be identiable i.e. traceable.v

2. Health Economics and Pricing

Biosimilars are unlikely to result in the same

price competition as has occurred with the

introduction o generic medicines or a number

o reasons. Firstly, biological medicines including

biosimilars are generally more complex andcostly to produce, e.g. unlike generic medicines,

biosimilars require independent clinical trials to

be undertaken.

Furthermore, the pre-approval regulatory

requirements and post-marketing surveillance

or biosimilars are more rigorous than or

generic medicines, thus adding a urther layer to

the cost o producing a biosimilar.

The exact price level o a biosimilar will depend

on the pricing and reimbursement environment

o each country, the competitiveness o the

market and the desire to encourage the uture

development o new products.

3. Immunogenicity

what is it and why does it matter?

Biologicals have the inherent potential to

provoke (unwanted) immune reactions (see

chapter I part 2 above). This potential is one o

the major reasons why biologicals are generallytreated dierently to chemical medicines by

regulatory authorities.

While a lot is known today about certain

eatures o biological products that make them

more likely to provoke immune reactions e.g.

high content o host cell proteins and certain

routes o administration, it is currently not

possible to accurately predict immunogenicity in

humans only through non-clinical assessment in


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13

animals. Thereore, immunogenicity assessment

through clinical studies plays a major role in the

development o biological medicines.

At the time a biosimilar receives market approval, a

lot is already known about the saety and ecacy o

the product class and the reerence product, whichat this point has usually been on the market or

years (or even decades). However, the potential to

provoke immune reactions can dier rom product

to product and rare eects can only be detected and

assessed when large numbers o patients have been

treated with a product. At the time o approval,

inormation on the saety o a medicinal product

is relatively limited or several reasons, such as a

limited number o patients in clinical trials, a limited

time o exposure to the medication and, generally, a

rather strictly dened patient population.

Unlike chemical generics, biosimilars need to have a

Risk Management Plan in place. This acknowledges

the special characteristics o biologicals. As with

other new medicines, this Risk Management Plan

denes a set o pharmacovigilance activities and

interventions designed to identiy, characterise,

prevent or minimise risks relating to medicinal

products, and the assessment o the eectiveness o

these interventions.vi

The potential o biologicals to provoke immunereactions has been the major reason or treating

biosimilars in the same way as new (biological)

products with regard to post-marketing surveillance.

4. Interchangeability

Interchangeability o medicinal products reers to

the situation where one product is switched or

another equivalent product in a clinical setting,

without a risk o an adverse health outcome.

Generic medicines, which are considered

bioequivalent, are regarded as therapeutically

equivalent and thereore, interchangeablevii.

The current state o scientic knowledge means

that, in general, (chemical) generic medicines

can be deemed interchangeable with their

reerence product. Regulatory agencies such asthe European Medicines Agency (EMEA) do not

assess the interchangeability or substitutability o

a biosimilar when granting a positive opinion or

a marketing authorisation application. In other

words, the granting o approval does not mean

that the biosimilar product can be interchanged or

substituted with the reerence product.

Currently, no clinical studies have been designed

or undertaken to assess the clinical outcome

o repeated switches (changes) o a biological

medicine, whether using two original biological

medicines or an original and a biosimilar.

5. Substitution

Automatic substitution (or generic substitution) is

where the pharmacist substitutes a brand name

(chemical) medicine or a generic version o the

same drug. Some countries make generic substitution

mandatory under certain conditions, or example

where the doctor prescribes by INN. Generic

substitution is oten linked to reimbursement; orexample, some health insurance schemes will only

reimburse the patient or the cost o the generic

version o a product. The result o this is that a

patient reusing the generic version and insisting on

the original product must pay the dierence in cost.

Generic versions o chemical pharmaceuticals which

have demonstrated their bioequivalence may be

substituted with no risk to patient saety.


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The EMEA has specically stated that since

biosimilars and biological reerence products are

not identical, the decision to treat a patient with a

reerence product or biosimilar medicine should be

taken ollowing the opinion o a qualied health

proessional*. In addition, there is currently no

convincing scientic data to prove that repeatedproduct switching o biological medicines

(whether biosimilar versions or not) does not

lead to negative clinical consequences. Moreover,

regulators need to remain prudent in matters

relating to the protection o public health.

A number o countries such as France, Italy, Spain,

UK, Netherlands, Germany, Sweden, have either

established legislative measures to prohibit the

automatic substitution o biotech medicines or

have given regulatory advice on the use o biologics

(including prescription by brand). The justication

or such measures is that o patient saety.

EuropaBio rmly believes that other countries that

allow automatic substitution o generic medicines

should take the necessary measures to prevent

automatic substitution o biologics.

*http://www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf


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III - The Regulation of Biosimilars

1. In Europe

Chemical medicines can be approved by the national

medicines authorities o individual EU member states.

In contrast, biological products, including biosimilars,

have to ollow the centralized procedure or

approval carried out by the European MedicinesAgency (EMEA). Applications submitted to the EMEA

are assessed by its Committee or Human Medicinal

Products (CHMP), which can give a positive or negative

opinion. Upon receipt o a positive opinion rom the

EMEA, the European Commission issues a marketing

authorisation which is valid or all EU countries.

Since 2003, the European Union has created

a legal and regulatory pathway to enable the

development and marketing o biosimilar

medicines. Directives 2003/63/ECviii and 2004/27/

ECix, created a legislative route and the EMEA has

subsequently developed a number o regulatory

guidelines concerning the required data needed or

approval o a biosimilar. Besides the overarching,

general guideline on biosimilars, the EMEA has

developed guidelines on quality, on non-clinical

and clinical issues, and product-specic annexes

to those on e.g., insulin, epoetin, somatropin and

granulocyte-stimulating growth actor. At the time

o publication o this document, urther guidelines

were close to being nalised, including guidelines

on intereron-ala and low-molecular heparinx

.

EMEAs overarching guideline on biosimilarsxi

specically states that biosimilar products are

by denition not generics, and that the

generic approach to approval is scientically not

appropriate or biosimilars.

In its document Questions and Answers on

biosimilar medicines, the EMEA denes biosimilars

as ollowsxii:

A biosimilar medicine is a medicine which is

similar to a biological medicine that has already

been authorized (the biological reerence

medicine). The active substance o a biosimilar

medicine is similar to the one o the biological

reerence medicine. Biosimilar and biologicalreerence medicines are used in general at

the same dose to treat the same disease. Since

biosimilar and biological reerence medicines

are similar but not identical, the decision to

treat a patient with a reerence or a biosimilar

medicine should be taken ollowing the

opinion o a qualied healthcare proessional.

The name, appearance and packaging o a

biosimilar medicine dier to those o the

biological reerence medicine.

The EMEA Q&A document urther states that

the legislation denes the studies that need

to be carried out to show that the biosimilar

medicine is similar and as sae and eective as the

biological reerence medicine. To this end, the

biosimilar approval pathway requires a biosimilar

manuacturer to demonstrate similarity with the

reerence product or quality, saety and ecacy.

Specically, the biosimilar must demonstrate,

through clinical studies, that it has no signicant

clinical dierences with the reerence product.Biosimilar manuacturers must provide all o

the pre-clinical and clinical data required to

demonstrate the similarity o their product with

the reerence product, without the need to repeat

unnecessary tests and trials.

The EMEA assesses the level o data required or a

biosimilar marketing authorisation application on a

case-by-case basis, but the level o data required is

still less than or an original biological.


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A biosimilar manuacturer must undertake

pre-clinical and clinical studies in order to submit

relevant data that establishes the quality, saety and

ecacy o the product, as well as its similarity with the

reerence product. The biosimilar must demonstrate

the similarity o its active substance in molecular

and biological terms, to the active substance inthe reerence product. In addition, the biosimilars

similarity with the reerence product should extend

to the pharmaceutical orm, strength and route

o administration. The data required can include

pre-clinical data rom in-vitro and in-vivo (animal)

testing and data generated by clinical trials in healthy

individuals and the target patient population.

When the reerence product has more than one

therapeutic indication, i.e. treats more than one

disease,the ecacy and saety o the biosimilar

medicine may also have to be assessed using

specic tests or studies or each disease.xiii

Under certain circumstances, the EMEA allows

extrapolation o indication, i.e. a biosimilar that

has demonstrated comparable saety and ecacy

in the most sensitive indication can be assumed

to be able to extrapolate that saety and ecacy

to other indications o the reerence product.

However, this extrapolation is only allowed i the

indications share the same mode o action and i

it is appropriately justied by current scientic

knowledgexiv

, without conducting specic clinicalstudies or each o those indications.

As with all biopharmaceuticals, the EMEA requires

biosimilar manuacturers to prepare a risk

management programme (RMP), which comprises

a saety specication, a pharmacovigilance plan,

an evaluation o the need or risk minimisation

activities and (i deemed necessary), a plan or risk

minimisation activities. The pre-clinical and clinical

testing required as part o the abridged biosimilar

approval procedure may not reveal all possible

immunogenicity.

This means that preparing a marketing

authorisation application or a biosimilar is more

costly and complex than or a generic medicine.

Generic manuacturers do not usually have to carryout non-clinical (i.e., animal) studies or clinical

trials when requesting authorisation. Instead, they

need only demonstrate the bioequivalence o their

product with the reerence product. For (chemical)

generic pharmaceuticals, this is normally done by

showing that the blood levels o the two products

are the same when given to a small number o

healthy volunteers.

2. Outside of Europe

At the time o publication, the European Union

is the only region that has established a specic

approval pathway or biosimilar medicines. The

US congress is still in the process o developing

legislation that would lead to an approval pathway.

The World Health Organisation and numerous

countries around the world such as Argentina,

Canada, Malaysia, Turkey and Saudi Arabia have

produced drat guidelines on biosimilar medicines.

Regulators in Japan and Korea, amongst other

countries, are currently examining the issue o

biosimiliars.


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IV - The Market for Biosimilars

1. Which biosimilars are currently available in Europe?

The ollowing table shows the biosimilar medicines that have been approved by the EMEAxv :

TRADE NAME INN SPONSOR REFERENCE

PRODUCT

DECISION DATE

Omnitrope somatropin Sandoz Genotropin Approve 12/04/2006

Valtropin somatropin BioPartners Humatrope Approve 24/04/2006

Alpheon Intereron ala-2a BioPartners Roeron-A Reject 28/06/2006

Abseamed1 epoetin ala Medice Eprex Approve 28/082007

Binocrit1 epoetin ala Sandoz Eprex Approve 28/08/2007

epoetin ala Hexal1 epoetin ala Hexal Eprex Approve 28/08/2007

Retacrit2 epoetin ala Hospira Eprex Approve 18/12/2007

Silapo2 epoetin ala STADA Eprex Approve 18/12/2007

Insulin Rapid Marvel, Long Marvel

30/70 Mix MarvelInsulin Marvel Humulin Withdraw 16/01/2008

Ratiograstim Filgrastim Ratiopharm Neupogen Approve 16/09/2008

Biograstim Filgrastim CT Arzneimittel Neupogen Approve 16/09/2008

Tevagrastim Filgrastim Teva Neupogen Approve 16/09/2008

Zarzio Filgrastim Sandoz Neupogen Positive opinion 20/11/2008 (MA

expected 01/2009)

Filgrastim Hexal4 Filgrastim Hexal Neupogen Positive opinion 20/11/2008 (MA

expected 01/2009)

2. When are the next biosimilars coming onto

the market?

The EMEAs Committee or Human MedicinalProducts (CHMP) is currently assessing several

applications or biosimilars and it is expected that

these products will be approved during the course

o 2008. The CHMP gave a positive opinion on

three biosimilar versions o lgrastim (reerence

product: Amgens Neupogen) in February 2008

and a revised opinion in July 2008. These three

biosimilars then received a marketing authorisation

rom the European Commission in September 2008.

3. What does the market entry of biosimilars mean

for the original innovator products?

Biosimilar products will compete with originatorbiologicals, many o which already compete with

other originator products made by dierent biotech

companies. However, in many cases, biosimilars

are copies o older biological medicines, or which

second-generation biological medicines are already

available. This means that the biosimilar products will

mainly compete with the older biological medicines,

rather than with the most recent treatments

developed by originator companies, which can oer

increased therapeutic benet to patients.

1

The EMEA approved three licenses for the same EPO made by Sandoz, with two additional licenses being granted to marketing partners Hexal and Medice Arzneimittel.2 The EMEA approved two licenses for the same EPO made by Hosp /STADA3 The EMEA approved three licenses for the same Filgrastim made by Ratiopharm/Teva/CT Artzneimittel4 The EMEA approved two licenses for the same Filgrastim made by Sandoz/Hexal


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must beallowed

to exerciseappropriateclinicaljudgement...

...physicians


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1. What do patients need to know? Patients need and deserve to be ully inormed

about any medical treatment they are receiving.

I a physician chooses to prescribe a medicine

to a patient, the patient should be involved in

that decision, understand why that choice has

been made, and what it will mean or his or her

treatment.

Patients may not be completely aware o the

complexities o biologicals, including biosimilars,

and the implications o using them. These

implications include the potential o dierent

products provoking dierent immunogenic

reactions in individual patients. It is important

that patients are not obliged to switch their

treatment rom an originator to a biosimilar purely

on cost grounds, but that the specic therapeutic

needs o the patient are always taken into account.

According to a survey by the International Alliance

o Patients Organizations (IAPO), the key concerns

o patients with regard to biosimilars arexvi:

Cost and the potential to increase access to

biological treatments

Saety and ecacy

Patient inormation and decision-making

Regulatory process

Interchangeability

For these reasons it is very important that the label

and other product inormation relating to the

biosimilar refect the specic characteristics (clinical

data, reerence product, switching advice etc) o

the biosimilar in question.

V - The Impact of Biosimilars


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2. What do healthcare professionals need to know? Healthcare proessionals need to understand the

EMEA approval process or biosimilars, in particular

the abridged clinical data requirements, which can

allow the extrapolation o indication or biosimilars

in certain circumstances.

Furthermore, in relation to interchangeability andsubstitution, healthcare proessionals should be

aware that the two dierent products may provoke

dierent immune reactions in dierent patients.

Physicians should not eel obliged to prescribe a

certain medication purely on the grounds o cost,

but should be allowed to exercise appropriate

clinical judgement.

For these reasons it is very important that the label

and other product inormation o the biosimilar

refect the specic characteristics (clinical data,

reerence product, switching advice, etc.) o the

biosimilar in question.


20


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3. What do payers need to know? Payers, such as national health systems and health

insurance unds, may be interested in cost-saving

potential. Biological medicines tend to be more

expensive than traditional pharmaceuticals or

a number o reasons. These reasons include the

high costs involved in researching, developing,

producing and marketing biological medicines.It is important or payers to understand the

cost structure o biological medicines, including

biosimilars, with regard to complex manuacturing

procedures and regulatory requirements, which can

require enhanced post-marketing surveillance.

Evidence so ar shows that biosimilars will not

result in the same cost savings that generic

medicines have brought. Due to the act that

biosimilars have been on the market or a relatively

short period o time, it is not possible to accurately

estimate the average price discount compared to

the originator products. In Germany, the biosimilars

that have been launched so ar are available at a

price that is around 25% lower than the originator.

However, it is also true that some biosimilars have

the same price as the originator product.

In addition, it is important that payers understand

that, due to the need to remain prudent in matters

o patient saety, automatic substitution or

biologics should not occur and the choice to use

any biological product should remain in the handso the treating physician. The physician must be

allowed to exercise appropriate clinical judgement

to select the best available treatment or the

individual patient. Treatment choice should not be

mandated purely or reasons o cost.


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Glossary of key terms

Adverse event: The occurrence o an undesirable,

unpleasant or lie-threatening reaction to a

medicinal product.

Allergy: A disorder o the immune system that

causes reactions such as itching, swollen or

infamed skin or eyes, runny nose. More extremeallergic reactions such as anaphylactic shock, which

can be lie threatening.

Amino acid: One o several molecules that join

together to orm proteins. There are 20 common

amino acids ound in proteins.

Antibody (pl: antibodies): Antibodies (also known as

immunoglobulins, abbreviated to Ig) are proteins that

are ound in blood or other bodily fuids. Antibodies

are used by the immune system to identiy and

neutralize oreign objects, such as bacteria and viruses.

Biological/biotech medicine: A substance made rom

a living organism or its products. Biologicals/biotech

medicines may be used to prevent, diagnose, treat

or relieve the symptoms o a disease. For example,

antibodies, interleukins, and vaccines are biologicals.

Biosimilar: A similar but not identical version o an

existing biological made ollowing patent expiry by

a dierent manuacturer than the producer o the

original product.

Biotechnology: Any technological application

that uses biological systems, living organisms, or

derivatives thereo, to make or modiy products or

processes or specic use.

DNA: Deoxyribonucleic acid (DNA) is a nucleic acid

that contains the genetic instructions used in the

development and unctioning o all known living

organisms and some viruses.


22

Generic (medicine): A copy o an existing (chemical)

medicine, which is bioequivalent to the original

medicine, but is made by a dierent rm.

Gene therapy: The practice inserting o genes into

an individuals cells and tissues in order to treat a

disease or correct a generic deciency.

Genetics: The science o heredity and variation in

living organisms.

Hypersensitivity: The occurrence o undesirable

(damaging, discomort-producing and sometimes

atal) reactions produced by the immune system.

Immune system: The collection o mechanisms

within the body that protect against disease by

identiying and killing pathogens and tumour cells.

Immunogenic: The potential to cause immune

reactions.

Indication: A valid reason to use a certain test,

medication, procedure, or surgery, which is oten

subject to ocial (regulatory) approval.

Insulin: A hormone that aects metabolism and

causes the bodys cells to take up glucose (sugar)

rom the blood and store it as glycogen in the liver

and muscles.

INN: International non-proprietary name.

In-vitro: In the laboratory (outside the body).

In-vivo: In the body (the opposite o in-vitro).


23/24


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Marketing authorisation: The permission granted

by a regulatory authority to a company to market

a medicinal product ollowing the companys

submission o required documentation and data

relating to testing and clinical trials o the product.

Medical biotechnology: The production o saeand eective versions o biological substances

that occur naturally in the human body, in a

scientically controlled environment in order to

make medicinal products.

Microbiology: The science o studying micro

organisms or microscopic organisms.

Micro-organism: An organism that is so small it

cannot be seen by the human eye.

Molecule: The smallest particle o a substance that

has all o the physical and chemical properties o

that substance. Molecules are made up o one or

more atoms. I they contain more than one atom,

the atoms can be the same (an oxygen molecule

has two oxygen atoms) or dierent (a water

molecule has two hydrogen atoms and one oxygen

atom). Biological molecules, such as proteins and

DNA, can be made up o many thousands o atoms.

Molecular: O a molecule

Nucleic acid: A macromolecule composed o chains

o monomeric nucleotides. In biochemistry these

molecules carry genetic inormation or orm

structures within cells.

Patent: A patent is a set o exclusive rights granted

by a state to an inventor or his assignee or a xed

period o time in exchange or a disclosure o an

invention.

Pharmacovigilance: Saety control procedures

which medicines are subject to both beore, during

and ater their approval by regulatory authorities.

Protein: Large organic compounds made o

amino acids arranged in a linear chain and joined

together by peptide bonds between the carboxyland amino groups o adjacent amino acid residues.

Recombinant: In genetics, recombinant means

DNA, proteins, cells, or organisms that are made

by combining genetic material rom two dierent

sources. Recombinant substances are made in the

laboratory and are being studied in the treatment

o cancer and or many other uses.

Reference product: The original product on which a

biosimilar or generic drug bases its application or

marketing approval.

RNA: Ribonucleic acid is a nucleic acid which is

central to the synthesis o proteins.

Vaccine: A biological preparation which is used

to establish or improve immunity to a particular

disease.


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Further information

EMEA working group on biosimilars:

http://www.emea.europa.eu/htms/general/contacts/CHMP/CHMP_BMWP.html

EMEA guidelines on biosimilar medicines:

http://www.emea.europa.eu/pds/human/biosimilar/043704en.pd (overarching guideline on biosimilars)

http://www.emea.europa.eu/pds/human/biosimilar/17073408en.pd (Erythropoietin products)

IAPO view on biosimilars:

http://www.patientsorganizations.org/showarticle.pl?id=767

Wikipedia entry on biosimilars:

http://en.wikipedia.org/wiki/Biosimilars

References

i PhRMA Report, 14 August 2006

ii

Adapted rom Convention on Biological Diversity (1992)

iii Add PhRMA reerence.

iv European Commission proposals to revise EudraLex Volume 9A. For more details please see:

http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/docs/doc2008/2008_03/pc_vol9_03-2008.pd

v http://ec.europa.eu/enterprise/pharmaceuticals/pharmacovigilance/docs/public-consultation_12-2007.pd

vi EMEA Guideline on Risk Management Systems or Medicinal Products or Human Use

vii US, Orange Book

viii In case the originally authorized medicinal product has more than one indication, the ecacy and saety o the medicinal

product claimed to be similar has to be justied or, i necessary, demonstrated separately or each o the claimed indications

(part II, 4 o Directive 2003/63/EC).

ix Where a biological medicinal product which is similar to a reerence medicinal product does not meet the condition in

the denition o generic medicinal products, owing to, in particular, dierences relating to raw materials or dierences in

manuacturing processes o the biological medicinal product and the reerence biological medicinal product, the results o

appropriate pre-clinical tests or clinical trials relating to these conditions must be provided (article 10 o Directive 2004/27/EC).

x For guidelines on biosimilars see: http://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm

xi EMEA Guideline on Similar Biological Medicinal Products (CHMP/437/04)

xii EMEAs Questions and Answers on biosimilars (similar biological medicinal products)

xiii EMEAs Questions and Answers on biosimilars (similar biological medicinal products)

xiv Guidance on Biosimilar Medicinal Products Containing Erythropoietins; EMEA/CHMP/94526/2005

xvi See: http://www.patientsorganizations.org/

Avenue de lArme 6, B-1040 Brussels - Belgium

Tel : (+32.2) 735.03.13 Fax : (+32.2) 735.49.60

E mail : ino@europabio org www europabio org

Bio Similar Factsheet December 2008

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