Biosimilars: Regulation Issues

Masters of Science in International Strategy and Influence
SKEMA Business School, School of Knowledge Economy and Management
France, China, United States and Brazil
REGULATORY ISSUES ON THE DEVELOPMENT OF
BIOSIMILARS
Research Question:
Which regulatory framework could foster the market development of biosimilars
in Europe? And which strategic positioning for the originators
manufacturers?
Student: Joseph Pategou
Tutor: Healthcare expert at Boston Consulting Group
Co-Tutor: Dr. Benjamin LEHIANY, Research Associate Polytechnic School Paris and
Scientific Director, MSc. International Strategy & Influence
Year: 2014 – 2015

2014/2015 – Joseph Pategou | Which regulatory framework could foster the market development of
biosimilars in Europe? And which strategic positioning for the originatorss producers?
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TABLE OF CONTENT
Acknowledgement ............................................................................................................................3
Executive summary ..........................................................................................................................4
Introduction ......................................................................................................................................9
I. Methodology .......................................................................................................................11
II. Empirical context: comparison between Generics and Biosimilars..................................19
1. Regulation............................................................................................................................21
A. Generics .........................................................................................................................21
B. Biosimilars .....................................................................................................................26
2. Market Trends.......................................................................................................................31
A. Generics .........................................................................................................................31
B. Biosimilars .....................................................................................................................34
III. Results and illustration.......................................................................................................39
1. Results ..................................................................................................................................41
2. Strategic positioning for the originators manufacturers...........................................................53
A. Benchmark on Generics ..................................................................................................53
i. Context ..................................................................................................................53
ii. Action of the manufacturers of originators .............................................................55
B. Benchmark on Biosimilars: the case of Neupogen ..........................................................59
i. Context ..................................................................................................................59
ii. Action of the manufacturers of originators .............................................................61
C. Interpretation of our interviews .......................................................................................66
Conclusive discussion......................................................................................................................68
1. Discussion............................................................................................................................69
2. Conclusion ...........................................................................................................................72
Annex .............................................................................................................................................74
1. Reference .............................................................................................................................75
2. List of illustration .................................................................................................................76
3. Definition.............................................................................................................................77

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ACKNOWLEDGEMENT
I want to thank all those who gave me their help and their support during my
scholarship and in the preparation of my graduation memory.
First, I want to thank in France, the LEEM, the GEMME, the Association France
Colon, the Maison des MICI, the French Society of Cardiology, the French Society of
Rheumatology, the French National Society of Gastroenterology and IMS Paris for their trust
and availability.
In Great Britain, I thank the Medicines and Healthcare Products Regulatory Agency,
the Association of the British Pharmaceutical Industry, National Institute for Health and Care
Excellence, the British Society for Rheumatology and IMS London for their support and
availability.
I want to thank the Italian Federation of Cardiology, the Confederation of the three
Italian Societies of Gastroenterology and the European Federation of Crohn's & Ulcerative
Colitis Associations for their valuable assistance on regulation in Italy.
I am grateful to the Drug Commission of the German Medical Association and the
German Society of Rheumatology.
Thanks to the European Medicines Agency, European Generic Medicines Association
and European Biosimilars Group for the incredible support they have given me in the
realization of this research.
I express my gratitude to Professor Benjamin Lehiany and the Boston Consulting
Group for allowing me to work on this exciting subject.
My sincere acknowledgment to my family for their encouragement.
I also wish to thank the teaching staff of Skema Business School for the teachings and
support.

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EXECUTIVE SUMMARY
Nowadays patients and physicians can have access to three types of drugs: a
originators, a generic or a biosimilar.
Those drugs have different regulatory systems that apply in Europe; moreover the
biosimilars regulation is evolving and may change. Regulation is an important factor that can
give more confidence to patients and healthcare professionals. As a consequence,
biosimilaires will grow.
Therefore the question we shall ask ourselves is
Which regulatory framework could foster the market development of biosimilars in
Europe? And which strategic positioning for the originators producers?
To bring the most accurate answer to this question, we will study the regulation
framework in France, Germany, Italy and United Kingdom.
I. METHODOLOGY
To understand the regulatory issues on the development of biosimilars in France,
Germany, Italy and United Kingdom:
We first determined the main differences between generics and biosimilars using mainly
secondary data, focusing on regulation and market trends.
Then, we concentrated on regulation of biosimilars, by doing 22 interviews of 4 types of
organizations (Authorities, National and European pharmaceutical unions, Learned Societies
and patient associations); we established a questionnaire of 10 questions based on five main
topics:
 Naming  Labelling
 Clinical trials /extrapolation  Switching/ substitution
 Quotas/ tenders
All interviewees received the same questions; we made cross analysis between countries and
actors in order to draw the best lessons.
Finally, we looked which strategic positioning could have a originators producer to face
biosimilars and to maintain its position in the market by studying 13 companies.

5
II. EMPIRICAL CONTEXT : COMPARISON BETWEEN
GENERICS AND BIOSIMILARS
Biosimilars and generics are drugs which enter the market at the end of the originators
patent; our observations help us to see the main differences in terms of regulation and market
trends between these two types of drugs.
Generics have simple chemical structures and are considered to be identical to their
reference medicines. In comparison, a medicine which is developed to be similar to an
existing biological medicine is a biosimilar (see table 19).
Table 19: Comparison of difference and common points between biosimilars and generics-
Structure
KEY POINTS BIOSIMILARS GENERICS
Nature Drug extracted from a biological
environment
Chemical drug
Molecular size Up to 270,000 Da 100 to 200 Da
Development Comparative studies Bioequivalence studies
Duration of development 5-7 years(500 patients) 2-3 years (20-50 patients)
Cost of the development 200-300 million dollars 2-4 million dollars
On regulation, we observed dissimilarity, for example the Marketing Authorization of
generics is mainly based on bioequivalence studies or for biosimilars on comparative study
(see table 7).
Regulation
KEY POINTS DIFFERENCE IDENTICAL
Naming
x
Labelling x
Substitution x
Quotas and tenders x
Marketing authorization x
Moreover, biosimilars regulation is part of important debates in many countries,
compared to generics drugs.

6
Eight major world markets accounting for 84% of their global sales drive the generics
(United States, Germany, France, Britain, Canada, Italy, Spain and Japan). The first market is
the United States with 42% of global sales (global sales $123.85 billion in 2010 and will reach
$231.00 billion in 2017).
When you talk about biosimilars, the EU is the most advanced market, accounting for
80% of global spending (Global market: $2.6 billion in 2016 to $25 billion in 2020). We
observed 19 biosimilars in Europe representing 6 actives substances. In terms of volume and
value, Germany is the largest; followed by France, Italy and the United Kingdom.
All these elements clearly show us that between these two drugs we have different
market trend (see table 13)
Market trend
The leading countries x
Market value x
Number of product x
Production cost x
III. RESULTS AND ILLUSTRATION
Those 22 interviews we made helped us understand the position of Authorities,
National and European pharmaceutical unions, Learned Societies and patient associations in
four European countries (France, Germany, Italy and the United Kingdom).
On a topic like naming, the role of regulation, substitution, market shares, price
evolution of the originators and biosimilars, we have a global consensus between actors.
Positions are more variable between actors on regulatory issues such as summary of
product characteristics, interchangeability and extrapolation.
We made an historical benchmark of 13 companies from 2000 to 2015. And observed
10 levers, which were taken by originators manufacturers facing biosimilars and generics
competition.

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 Price  Prescription
 Patent  Market saturation
 Legal action  New market
 Cooperation  Environmental strategy
 Product  Brand strategy
Some of these levers seem to be used in the context of biosimilars and others in presence of
generics (see table 18).
Table 18: Comparison of levers used by originators producer to face biosimilars and generics
competition
Levers Biosimilars Generics
Price X X
Patent X X
Legal action X X
Cooperation X X
Product X X
Prescription - X
Market saturation - X
New market X -
CONCLUSIVE DISCUSSION
The research on France, United Kingdom, Italy and Germany allows us to understand
the regulation of biosimilars and the issues regarding this new type of drug.
One of the lessons is the fact that the regulation of biosimilars is not clear and still in
discussion in many countries, on topics like naming, role of regulation, substitution, summary
of product characteristics, extrapolation and interchangeability.
Our interviews helped us to have a clear vision on those topics:
For the naming system, the World Health Organization suggests a four-letter code
attached at the end of every drug name.

8
Concerning the label (SmPC) of a biosimilar, it must be in concordance with the label
of the reference product.
In term of extrapolation, biosimilars have the possibility to be used in several
indications like the reference product.
Regarding the substitution of biosimilars by pharmacists, there is a global consensus
on the fact that it is impossible and not allowed at the moment. But in some countries
discussions are in place to allow substitution by pharmacists, for example in France.
One of the hottest topics on biosimilar regulation, interchangeability is still in
discussion. Germany and United Kingdom have accepted the principle of interchangeability
unlike Italy and France who have refused this principle.
The economic situation in OCDE countries is an important element that biosimilars
and originators manufacturers need to bear in mind. Due to the economic crisis, the total
spending of health is declining since 2009 in several countries.
According to the Panorama health 2013 of the OECD, it is essential in this context that
countries make their health systems more productive, more efficient and more affordable.
The countries have sought to reduce spending by lower prices of medical goods,
particularly pharmaceuticals, and by budgetary restrictions and wage cuts in the hospital
sector.
For example, in France and Germany the costs in percentage of GDP evolved from
10% to 12% between 2000 and 2008, then decreased to reach 11% of the GDP in 2011.

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INTRODUCTION
Currently, when a patient wants to be treated for a pathology, depending on the
country, a doctor or a pharmacist can propose different types of drug: an originators, a generic
or a biosimilar with the aim of bringing the best solution to the patient.
In the same time, authorities, learning societies, patient associations, national and
European unions work closely together to set up regulations that will help bring the most
efficient drugs at the lowest price on the market and take care of the patient.
Generic drugs1
are the same drug as the original, but produced and sold under its
International Nonproprietary Name (INN chemical name of the substance) or under a new
trade name. They are produced following the patent expiry, or in the absence of patent.
A global analysis2
concludes that this market has generated more than $ 123 billion in 2010
and will reach $ 231 billion in 2017 with an annual growth rate of approximately 9% from
2011 to 2018. Europe holds a very important place in this market, for example the generics
market in the UK is the second largest generic market globally, after the United States.
A biosimilar3
medicine is a biological medicine that is developed to be similar to an
existing biological medicine (the ‘reference medicine’). Biosimilars are not the same as
generics, which have simple chemical structures and are considered to be identical to their
reference medicines.
The active substance of a biosimilar and its reference medicine are essentially the same
biological substance, though there may be minor differences due to their complex nature and
production methods. Like the reference medicine, the biosimilar has a degree of natural
variability. When approved, its variability and any differences with its reference medicine will
be shown not to affect safety or effectiveness.
Economically, the global biosimilars market represented $1.9 billion in 2013 and will
represent $25 billion in 2020. Europe is the most advanced market, with 80% of the global
market, 21 approved drugs4
and numerous leading companies like Sandoz.
1 http://www.sante.gouv.fr/qu-est-ce-qu-un-generique.html
2 Where the opportunities are and what role will they play? EGA Lisbon 2011-IMS
3http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000318.jsp
4
http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe

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The existence of biosimilars and generics is the result of the end of a drugs loss
exclusivity. Obtaining a patent allows companies to have market exclusivity for 20 years. This
monopoly position must help companies to have return on investments, knowing that the
investment for the development of an originators drug can reach nearly $2 billion.
Different regulations apply to Europe, for example in terms of marketing authorization
or clinical study. Unlike generics, biosimilars regulation is still not fixed. But regulation is an
important element that will give full legitimacy to medicines in the mind of patients and
healthcare professionals.
At the same time, we see a market penetration rate that differs according to the type of
the drug and the country. Generics with a clear regulation possess a very high penetration rate
in the several countries of Europe, which is not the case for biosimilars. In addition, according
to the product concerned, the position of some countries evolves on the market. Germany is
the third largest market in terms of generics and the first for biosimilars in Europe.
The aim of this research work is to identify first the changing regulatory system for
biosimilaire in Europe, more precisely in France, Germany, Italy and United Kingdom.
Therefore, how are companies preparing to face biosimilars.
Research Question:
Which regulatory framework could foster the market development of
biosimilars in Europe? And which strategic positioning for the originators
producers?

11
FIRST PART: METHODOLOGY

12
Summary
To study the regulatory issues on the development of biosimilars in France, Germany, Italy and
United Kingdom:
Firstly, we decided to understand the difference between generics and biosimilars in term of regulation
and market trends using mainly secondary data.
Then, we focus on biosimilars, by doing 22 interviews of 4 types of organizations (authorities, national
and European pharmaceutical unions, learned societies and patient associations); we use a
questionnaire of 10 questions based on five main points:
 Naming  Labelling
 Clinical trials /extrapolation  Switching/ substitution
 Quotas/ tenders
We send the same questions to all the interviewees, those interviews were read several times, we
made cross analyzed between countries and actors in order to draw the best lessons.
Finally, we decide to see which strategic positioning could have a originators producer to face
biosimilars and to maintain his position in the market, mainly based on benchmarking of 13
companies from 2000 to 2015.

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I. METHODOLOGY
Our aim was to understand the regulatory issues on the development of biosimilars in
four European markets: France, Germany, Italy and United Kingdom.
We chose those markets for many reasons:
-EU is the most advanced market for biosimilars, (accounting for 80% of global
spending) and 19 biosimilars were allowed in Europe5
.
-In term of volume and value market for biosimilars in Europe, Germany is the first;
followed by France, Italy and United Kingdom6
.
We decided in a first step to analyse also generics drug because biosimilars and
generics are drugs that come in the market the end of the following the patent expiry of a
originators. We want to know what are the differences between generics and biosimilars drug
in term of regulation and market trends.
To reach our objectives, we put in place two main actions:
-Collection of data in four European countries, France, Germany, Italy and United
Kingdom.
-Data Analysis and interpretation.
Generics
Knowing that the regulation of the generics is already established and clear, that is
why we decided to use secondary data. This helps us to have an overview of this market.
Biosimilars
 Collection of relevant data
We identified people who can share relevant information on biosimilars regulation in
France, Germany, Italy and United Kingdom. We find these people inside four categories of
actors.
 National and European authorities
 National and European pharmaceutical unions
5
6
Shaping the biosimilars opportunity-december 2011

14
 Learned Societies
 Patient Associations
We identified 22 organizations in the four countries (see the table below).
Then, we created an interview guide, based on five main points which are very
important when you talk about drug regulation.
 Naming
 Labelling
 Clinical trials/ extrapolation
 Switching/ substitution
 Quotas/ tenders
Table 1: Sample of the interviews

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The following 10 questions were asked:
1. Generally, a comparison is made between biosimilars and generics in terms of
regulation, market penetration and sales. According to you, what are the aspects of
biosimilars comparable to generics, and which ones are not?
2. In Europe, Germany is the largest market for biosimilars. According to some, this
advance may be explained partly by price regulation and biosimilars repayment terms
in Germany. In your opinion, what is the role of regulation in the European market for
biosimilars?
3. The name of a medication is an important element. It allows their differentiation and
reassure patients. Regarding biosimilars, the World Health Organisation has chosen to
develop a four-letter code at the end of the name (for instance: epoetin alfa bbbb).
This code is entitled to differentiate generic and originators from biosimilar. What do
you think of this approach?
3.1 Some professionals believe that this differentiation will hamper the substitution
needed to reduce health care costs. What is your opinion?
3.2 Will this naming system allow to more easily track the adverse effects that could
be included in the patient records?
3.3 Do you think of other advantages or disadvantages related to this approach?
4. Instructions accompanying medication provides important information for its proper
use and for patient safety. Do you think the instructions of a biosimilar should provide
the same information as the ones of the generic or originators it replaces?
4.1 In order to strengthen trust, some associations recommend a combination of
information about each biosimilar and the reference product in the record. What is
your opinion regarding this proposal?
4.2 Will not a different instruction between the biosimilar and reference lead the
prescriber to the conclusion that biosimilars do not require the same level of proof
that their reference products?
4.3 Do you see other advantages or disadvantages in the fact of differentiating
instruction of a biosimilar from the one of its reference product?

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5. Some reference products already commercialised are used in several therapeutic
indications. Regarding biosimilars, is such a use desirable?
5.1 If extrapolation is desirable, is conducting a clinical study necessary?
5.2 If not, is it necessary to implement the same approach, which is used for generics?
(Meaning setting up bioequivalence studies?)
6. In France, Italy, and in Germany, the replacement of a medication by a generic is
possible through a pharmacist. Do you think that this process should be extended to
biosimilars?
6.1 In your opinion, is replacement by biosimilar not going to threaten medication’s
traceability, and thus the identification of the origin of undesirable reactions in the
patient?
6.2 The process of substitution requires the creation of a regulatory basis for
interchangeability criteria. Do the expected benefits of such regulations allow you
to justify the costs and regulatory risks borne by the stakeholders (government and
companies)?
7. In Germany, in some cities such as Bremen, a quota system encouraging doctors and
health insurance fund to use biosimilars has been set up. It is translated into an
increase in the prescription of biosimilars in this town. What is your point of view
regarding the set-up of quotas or call for tender for biosimilars?
7.1 As part of a call for tender, if a company wins a two-year contract, there is little
incentive for competitors to produce. If the provider chooses not to meet its
obligations, there is a risk of supply disruption. Do you think that it is a major
issue in your country? What would you consider the best way to prevent this
situation?
7.2 In order to improve the penetration of biosimilar in various countries, would not it
be more effective to communicate to physicians and suppliers about the high
quality standards for biosimilars? What would be according to you the best way to
answer it?

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8. In 2013, on the world scene the biosimilars market accounted for $ 1.3 billion of
which 80% in Europe. By 2020 it will account for $ 25 billion. According to you, what
will be the evolution of this market in the upcoming years in Europe, especially in
France, Germany, Italy and in the United Kingdom?
BIOSIMILARS’ MARKET SHARE (Volume and Value)
Volume (%) - 2015
5% 15% 25% 35% 45% Other :
Volume (%) - 2020
5% 15% 25% 35% 45% Other :
Value (billion) - 2015
2 4 7 10 15 Other :
5 15 25 35 50 Other :
9. The introduction of generics has significantly reduced medication prices. For instance,
in Germany the decrease can reach of 71%. Regarding Biosimilars, may we expect
such a decrease?
EVOLUTION OF BIOSIMILAR AND ORIGINATORS MANUFACTURING PRICE
Originators – Year 0 (Y+0)
-2% -4% -6% -8% -10% Other :
Originators - Year 2 (Y + 2)
-5% -10% -15% -20% -25% Other :
Originators - Year 5 (Y+5)
-10% -15% -25 -30% -50% Other :
Biosimilar - Year 0 (Y+0)
-5% -15% -25% -35% -50% Other :
Biosimilar - Year 2 (Y+2)
-10% -20% -30% 45% 60% Other :
Biosimilar - Year 5 (Y + 5)
-15% -25% -35% -50% -70% Other :
Year 0 = Y = Year of loss of the originators’ patent
10. With biosimilars and generics being present on the market, do you think that
originators medications will keep their leadership in France, Germany, Italy and in the
United Kingdom?
ORIGINATORS’ MARKET VALUE (Volume and Value)
Volume (%) - 2015
5% 15% 25% 35% 45% Other :
Volume (%) - 2020
5% 15% 25% 35% 45% Other :
2 4 7 10 15 Other :
5 15 25 35 50 Other :

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22 interviews were achieved in France, Germany, Italy and United Kingdom; and we
made cross analyzed between countries and actors.
Then, we decided to see which strategic positioning could have a originators producer
to face biosimilars and to maintain his position in the market, based on:
 Benchmarking on the experience of pharmaceutical company with generics
 Benchmarking on the experience of pharmaceutical company with biosimilars
 The results of our interviews
All those interviews and strategic analysis helped us to answer our question.
Which regulatory framework could foster the market development of biosimilars
in Europe? And which strategic positioning for the originators producers?

19
SECOND PART:
EMPIRICAL CONTEXT: COMPARISON BETWEEN

20
Summary
Even if, the biosimilars and the generics came in the market after the end of
originators patent, the comparison between them clearly shows that these two types of drugs
are different in terms of regulation and market trends.
Biosimilar medicines are biologicals developed to be similar to an existing biological
medicine. Whereas generics have simple chemical structures and are considered to be
identical to their reference medicines.
On the regulation part, we see big difference.The marketing Authorization of generics
is mainly based on bioequivalence studies unlike biosimilars based on comparative study.
Moreover, the regulation of biosimilars is still not clear and still in discussion in many
countries, unlike to generics drugs.
In term of sales, generics are driven by eight major world markets accounting for 84%
of global sales (United States, Germany, France, Britain, Canada, Italy, Spain and Japan).
The United States is the largest generics market with 42% of global sales (global sales
$123.85 billion in 2010 and will reach $231.00 billion in 2017.
The most advanced market for biosimilars, is the EU representing 80% of global
spending (Global market: $2.6 billion in 2016 to $25 billion in 2020) with 19 biosimilars
already marketed and representing 6 actives substances. Germany is the first largest market in
volume and value; followed by France, Italy and United Kingdom.

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II.EMPIRICAL CONTEXT : COMPARISON BETWEEN
1. REGULATION
A. Generics
A generic medicine7
contains the same active ingredient as the originators product on
which it is based and as such is interchangeable with this originators. It offers the same high
quality and efficacy, together with affordability. In theory, dosage, indications, cons-
indications, side effects and safety guarantees are the same.
This combination has made them increasingly attractive for healthcare systems as a
whole and patients in particular. They can be marketed after the patent expiry of the
originators product on which they are based.
Graph 1: The life cycle of generics
A generic drug has a particular life cycle8
with mainly two steps.
The first one is to obtain the marketing authorization. Generic drugs just need a
bioequivalence study contrary to the originators that need clinical study. Clinical study is a
prospective biomedical or behavioral research studies on human subjects that are designed to
answer specific questions about biomedical or behavioral interventions, generating safety and
7
http://www.sante.gouv.fr/qu-est-ce-qu-un-generique.html
8
Rapport 2012 sur les médicaments génériques-Mutualité Française

22
efficacy data. Clinical study has four phases: 0, 1, 2, 3 and 4 (See appendix for more
information).
The second step is the launch of the generic drug. Having a CCP will increase the
protection of the Originators by 5 years and delay the generics entry.
The aim of this part is to have a general overview of the regulation of generics drug, in
four countries: France, Italy, United Kingdom and Germany.
In terms of regulation, 5 key points have been and are still much debated: naming,
labelling, switching/substitution, quotas/tenders and clinical trials/extrapolation. We will
discuss those points.
 Naming
The naming of a drug is important; it allows their differentiation and gives confidence
to patients.
The use of a single name9
is also a requirement for generic/hybrid medicinal products
regardless of whether the applicant/ Marketing Authorization Holder (MAH) wishes to use an
invented name or a common name or scientific name, together with a trademark or the name
of the MAH.
It should be noted that the applicant/MAH will be required to identify the ‘reference
medicinal product’ and the legal basis for submission of the application within the invented
name notification.
The name review group should also be consulted where the applicant/MAH
(Marketing Authorisation Holder) wishes to use the common or scientific name, together with
a trademark or the name of the Marketing Authorisation Holder.
In such cases the Marketing Authorization Holder should take into account the
following rules:
 If an International non-proprietary name (INN) recommended by the World Health
Organization exists for the active moiety it should be used within the name of the
medicinal product exactly as published without omissions or abbreviations. All the
linguistic versions of the INN (International non-proprietary name), including
9
EMA Procedural advice for users of the centralized procedure for generic/hybrid applications

23
translations officially recognized at the national level, shall be considered to be the
same name. If one does not exist, the usual common name should be used.
 If a Modified INN (INNM) recommended by the World Health Organization exists for
the active moiety, it should be used within the name of the medicinal product exactly
as published without omissions or abbreviations.
 Where the active is an unpublished INNM the name of the medicinal product should
be that as agreed by users of INNs (pharmacopoeia, regulatory bodies, stakeholders),
in accordance with the WHO INNM working document 05.167/3.
 The ‘name of the MAH’ within the name of the medicinal product should correspond
to all or part of the official name of the MAH as presented in the proof of
establishment of the applicant/MAH.
The requirement for a single name for a generic medicinal product of a reference
medicinal product authorized through the Centralized Procedure applies also in the case the
generic medicinal product is authorized by member states via the Mutual Recognition or
Decentralized Procedure.
 Labelling
The label10
of a drug provides important information for the proper use and patient
safety. We can regroup all this information in 5 groups.
1. Definition of the drug
2. Information you must know before taking the drug
3. How to take the drug?
4. What are the possible side effects?
5. How to store it?
The name of those groups can be different in some countries. Consistency and transparency of
labels lead to a better understanding and acceptance of the drug with all stakeholders
(Patients, Professionals….).
In the case of the generic, the label of the drug is an identical copy of the reference product.
10
Lessons learned from the review of the labelling of 5 centrally authorised pandemic vaccines- 10 February 2014 EMA

24
 Substitution
The substitution11
by the pharmacist is allowed in France, in Italy and in Germany but
is forbidden in United Kingdom.
France and Italy have a system of price setting, in Germany we don’t have this king of
system and in United Kingdom also but generic can’t be more expensive than reference drug.
In some of those countries, we have incentive plan in the delivery of generic medicines
by the pharmacists for example in France (see Table 2).
Table 2: Comparison between countries in term of price and substitution
United Kingdom France Italy Germany
System of Price setting Free. But generic
can’t be more
expensive than the
reference drug.
The prices of
refundable
medicine are
administered
Yes Free
Is there a right of
substitution by the
pharmacist?
No, But the
prescriptions are most
of the time
Denominated in DCI
(INN)
Yes, in the
perimeter of the
directory of the
generic groups.
Yes. The
substitution is
legally authorized.
The doctor can
oppose to the
substitution
Yes. The substitution is
compulsory except
opposite mention of the
doctor
Is there a plan of incentive
in the delivery of generic
medicines by the
pharmacists?
No Yes. Preferential
margin and
payment in the
performance.
No No. The amount of the
remuneration is fixed
by prescription
DCI: INN: International non-proprietary name
Source : Observatoire du médicament FNMF à partir des données de l’EGA et de l’AIM, 2011 et 2012
 Quotas and Tenders
In France, in United Kingdom, in Germany12
and in Italy, we don’t have a system of
quotas for drug.
We have tenders in Germany; this concerns only the new type of drugs and many
actors are involved in the mechanism of calls for tender for example: the Health Insurance
Funds. In France, we also have tenders for the hospital market. We observed discussion
concerning the implementation of a system of calls for tender in the United Kingdom and
Italy.
11
Rapport 2012 sur les médicaments génériques- Mutualité Française
12
http://gabionline.net/Biosimilars/General/Germany-wants-to-increase-biosimilars-penetration

25
Table 3: Comparison between countries in term of tenders
United Kingdom France Italy Germany
Existence of an
(ambulatory) mechanism
of calls for tender
No Yes, in hospital No Yes, all over the country
and only for new drugs
If yes, on what criteria are
negotiated the prices?
By active substance
by product,
by therapeutic indication
If yes, which actors are
involved in the mechanism
of calls for tender
Health insurance funds and
industrialists of the
medicine
Discussions concerning the
implementation of a
system of calls for tender
Yes, at the
government level
Yes, at the level of
the compulsory
health insurance
and of the
parliament
Yes, at the local
health authorities
(21 regions)
Yes, in government and
health insurance funds
Source : Observatoire du médicament, FNMF à partir des données EGA 2011, AIM 2012, ESIP 2012
 Marketing Authorization/Clinical trials
Any drug, to be marketed, must obtain a Marketing Authorization13
. For this, the
applicant must file an application with the competent health authorities, that is to say, the
National Security Agency for Drugs and Health Products, as part of a national procedure or
the European Medicines Agency (EMA), as part of a European procedure.
The format of the Marketing Authorization application is standardized internationally
(Europe, USA and Japan), which is why it is called "Common Technical Document" (CTD).
It includes five modules:
Module 1: Administrative Information
Module 2: Summary of module 3, 4 and 5
Module 3: Chemical and pharmaceutical data on the quality of the active substance and the
finished product (Physico-chemical data of the active substance, control, packing and stability
of the active substance and the finished product)
Module 4: Safety data (toxicological data on the basis of non-clinical reports)
Module 5: Data on the efficacy of the drug from the results of clinical studies on humans
13
http://ec.europa.eu/health/authorisation-procedures_en.htm

26
Table 4: Comparison of the marketing authorization between generics and originators
Comparison of the contents of the file of the demand of marketing authorization
File of the demand of marketing
authorization
Originators Generics
Module 1
Administrative Information
Yes Yes
Module 2
Summary of Module 3, 4 and 5
Yes Yes
Module 3
Quality (manufacturing process)
Yes Yes
Module 4
Safety (non-clinical studies)
Yes Not required
Module 5
Efficacy (clinical studies )
Yes Bioequivalence Study
So, generic medicines, in support to their file of demand for marketing authorization,
are dispense of producing the results of clinical study demonstrating the efficiency of the
active ingredient, but they have to demonstrate their bioequivalence14
in regards to the
reference medicine.
For Professor Donald J. Birkett15
, “two pharmaceutical products are bioequivalent if
they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability)
after administration in the same molar dose are similar to such a degree that their effects, with
respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical
equivalence implies the same amount of the same active substance(s), in the same dosage
form, for the same route of administration and meeting the same or comparable standards.”
B. Biosimilars
The concept of a “similar biological medicinal product” was adopted in EU
pharmaceutical legislation in 200416
and came into effect in 2005. The first biosimilar
medicine was approved by the European Commission in 200617
.
A biosimilar18
medicinal product is a biological medicine which is similar to another
biological medicine that has already been authorized for use, the “reference medicinal
product”.
14
Guideline on the investigation of bioequivalence- London, 20 January 2010- European Medicines Agency
15
http://www.australianprescriber.com/magazine/26/4/article/712.pdf
16
Directive 2001/83/EC, as amended by Directive 2003/63/EC and Directive 2004/27/EC
17
Biosimilars Marketing Authorisation status as of January 2013: 22 Marketing Authorisation Applications
18
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000318.jsp

27
The EU is the first region in the world to have set up a legal framework and a
regulatory pathway for “similar biological medicinal products”, more commonly called
“biosimilars”. The EU regulatory framework inspired many countries around the world e.g.
Australia, Canada, Japan, Turkey, Singapore, South Africa, Taiwan, USA etc. as well as the
World Health Organization (WHO).
Graph 2: The life cycle of biosimilars
A biosimilar drug has a particular life cycle with mainly two steps.
The first one is to obtain the Marketing Authorization. For this, biosimilars drugs need
to do comparative studies contrary to the originators which need clinical study. The aim of
these studies is to show that the medicine is similar to the reference medicine and does not
have any meaningful differences from the reference medicine in terms of quality, safety or
efficacy.
The second step is the launch of the biosimilars drugs, having a CCP will increase the
protection of the originators by 5 years and delay the Generic entry.
The aim of this part is to have a general overview of the regulation of biosimilar drug,
in four countries: France, Italy, United Kingdom and Germany.
In terms of regulation, 5 key points have been and are still much debated: naming,
labelling, switching/substitution, quotas/tenders and clinical trials/extrapolation. We will
discuss those points.

28
 Naming
As required by EU law19
, every medicine will either have an invented (trade) name, or
the name of the active substance together with the company name/trademark. The World
Health Organization (WHO) suggests that the current system for choosing INNs remain
intact, but that a four-letter code would be attached at the end of every drug name. The WHO
says the approach, which would apply retroactively, would be voluntary.
The code20
will consist of four letters and each code issued will be assigned randomly.
The choice of letters used will be made to facilitate transliteration into various languages and
to avoid meaningful or inappropriate words being used. The use of four letters offers more
than 160 000 codes (204
). This is expected to provide sufficient flexibility for the foreseeable
future. (Biological Qualifier code = BQ code)
 Labelling
The European Medicines Agency approaches on biosimilar labelling21
requiring the
label of the biosimilar product, which describes its medical use. It isto be consistent with the
label of the reference product.
 Switching/ Substitution
The substitution22
is a practice of dispensing one medicine instead of another
equivalent and interchangeable medicine at the pharmacy level without consulting the
prescriber.
The automatic substitution refers to the practice whereby a pharmacist is obliged to
dispense one medicine instead of another equivalent and interchangeable medicine due to
national or local requirements (without consulting the prescriber).
Some physicians23
can decide to exchange one medicine for another medicine with the
same therapeutic intent for patients who are undergoing treatment. This is known as
19
Individual case safety report: Article 28 of Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012
20
Biological Qualifier An INN Proposal-July 2014- World Health Organization, Geneva
21
http://www.gabionline.net/Biosimilars/Research/Improved-labelling-sought-for-biosimilar-acceptance
22
EC consensus paper 2013- What you need to know about Biosimilar Medicines
23
European Commission consensus paper 2013 : What you need to know about biosimilar medicines

29
switching. In hospitals, decision is made by a multidisciplinary team always including the
clinical community (therapeutic/formulary committee).
Each country in Europe has it is his position on substitution 24
(See Table 5).
Table 5: Comparison between countries in term of quotas and substitution
United Kingdom Substitution is not authorized by the law
France Substitution with biosimilar unauthorized (art 5121-1 of the Public health code), possible
for naïve patients.
Italy The Italian Agency of medicine (AIFA) does not recommend the substitution with
biosimilar in pharmacies.
Germany The biosimilar are not considered as generic medicines. The substitution is possible
between biosimilar containing the same active substance and made according to the same
process.
Quotas for biosimilars use for physicians and sickness funds
Example: Bremen where prescribing quotas have been agreed and where biosimilars now
account for 70% of the market.
 Clinical trials/ Extrapolation
Biopharmaceuticals are often used in more than one therapeutic indication.
Extrapolation of clinical efficacy and safety data to other indications of the reference
medicine that are not specifically studied during the clinical development of the biosimilar
medicine is possible based on the overall evidence of comparability provided from the
comparability exercise and with adequate scientific justification. This includes at least one
clinical study in the most sensitive patient population25
.
The EMA guidance says, "If biosimilarity has been demonstrated in one indication,
extrapolation to other indications of the reference product could be acceptable with
appropriate scientific justification (e.g., clinical experience, available literature data, whether
or not the same mechanisms of action or the same receptor(s) are involved in all indications.)
Whether extrapolation to multiple indications is acceptable (or not) is decided on a case-by-
case.”
 Marketing authorization
The legal and regulatory pathway for approval of biosimilar medicines is different
from generic medicines. Since 1995, all biotechnology-derived medicines must be assessed
centrally by the European Medicines Agency. In the case of a positive scientific opinion
adopted by the scientific committee, the European Commission makes a formal decision for
24
http://gabionline.net/Biosimilars/General/Germany-wants-to-increase-biosimilars-penetration
25
http://gabionline.net/Biosimilars/Research/Extrapolation-for-biosimilars

30
marketing. Since 2003 a specific legal and regulatory pathway exists for the development and
approval of biosimilar medicines. The general principles of drug development and review by
the European authorities apply to biosimilar medicines in the same way as to the reference
biological medicines.
For biosimilar medicines, the company needs to carry out studies to show that the medicine:
 Is similar to the reference medicine;
 Does not have any meaningful differences from the reference medicine in terms of
quality, safety or efficacy.
The format of the Marketing Authorization includes five modules:
Module1: Administrative Information
Module2: Summary of module 3, 4 and 5
Module3 (Chemical and pharmaceutical data): The quality of the product from biosimilar
manufacturing process should be compared with the reference product.
Module 4 (non-clinical reports): Biosimilar safety and toxicity should be compared to the
reference product on the basis of in vitro and in vivo studies (pharmacodynamics and
pharmacokinetics).
Module 5 (reports of clinical studies): The effectiveness of the biosimilar should also be
demonstrated on the basis of comparative studies in relation to the reference product26
.
The studies are comparative. They do not aim to demonstrate the quality, safety and
efficacy of biosimilar, but to demonstrate that these three parameters are similar to those of
the reference product.
Table 6: Comparison of the market authorization between originators, generics, and
biosimilars
File of the demand of AMM Originators Generics Biosimilars
Module 1
Administrative Information
Yes Yes Yes
Module 2
Summary of Module 3, 4 and 5
Yes Yes Yes
Module 3
Quality (manufacturing
process)
Yes Yes
Comparative
studies
Module 4
Safety (non-clinical studies)
Yes Not required
Comparative
studies
Module 5
Efficacy (clinical studies )
Yes Bioequivalence Study
Comparative
studies
26
Directive 2001/83/CE du parlement européen et du Conseil du 6 novembre 2001 instituant un code communautaire relatif
aux médicaments à usage humain

31
We have clear difference in term of marketing authorization between originators, generics and
biosimilars (see table 6).
Table 7: Comparison of difference and common points between biosimilars and generics
Naming
x
Labelling x
Substitution x
Quotas and tenders x
Marketing authorization x
The table 7 shows us the main differences in term of regulation between generics and
biosimilars which, but we have a common point between those drugs which is labelling.
2. MARKET TRENDS
A. Generics
Globally, there are eight major world markets27
: The United States, Germany, France,
United Kingdom, Canada, Italy, Spain and Japan. They represent 84% of global sales.
The United States is the largest generics market in the world with 42% of global sales.
In those countries, the generic drug plays a major role in controlling health spending, balance
and survival of social protection models.
In developing countries, this helps people to have access to healthcare because the
price of the generics drugs is less expensive.
The European market28
for generics varies from a country to another, this is due to:
 The maturity of the market
 The generic definition
 The incitement mechanism
 The organization
27
Where the opportunities are and what role will they play? EGA Lisbon 2011-IMS
28
http://healthcare.blogs.ihs.com/2012/01/06/generic-drug-price-trends-france-germany-italy-spain-uk/

32
A Global analysis finds that the market earned revenues is $123.85 billion in 2010 and
will reach $231.00 billion in 2017 at a compound annual growth rate of 9.29 per cent from
2011-2018. (The United States, Europe (Germany, the United Kingdom, France, Spain, and
Italy) and Asia (India and China)).
Graph 3: The Generic market share in Europe
Source : IMS Health
Table 8: Ranking of generics market
Country Ranking
United Kingdom 1st
Germany 2nd
France 3rd
Italy 4th
 United Kingdom
The generics market in the United Kingdom is the first largest generic market, after the
United States. It is the most mature market with over 60% market share by volume for
generics.
The United Kingdom29
has a competitive, multi-source generic market which keeps
medicine prices at the lowest level in Europe. Generic competition - that occurs when a
branded product loses its patent protection – reduces prices by 90%.
The onset of generic competition also drives innovation because the originators know that
their products will eventually face generic competition leading to a significant fall in sales and
income, they need to research new medicines.
29
http://www.britishgenerics.co.uk/about-generics/the-generics-industry

33
Each year nearly three quarters of prescriptions in England and Wales are met by
generic products, saving the NHS (National Health Service) more than £11billion.
The British Generic Manufacturers Association (BGMA) represents the interests of
UK-based manufacturers, suppliers of generic and biosimilar medicines. BGMA promotes
the development, understanding of the generic and biosimilars medicines industry in the
United Kingdom.
 Germany
The German generic market is the second largest market in the world, with over 60%
market share by volume for generics. The prices of generic drugs are on average 71% lower
than those of their originators.
In Germany, generics companies cover almost 75 percent of the total drug needs30
for
the care of patients. For 100 patients treated with medication, 75 patients used generic
products. Progenerika is the association for generics and biosimilars producers in Germany.
 France
France is considered as a market that has not optimized its generic development
potential, which exceeds 40% market share in volume, but still below the world average31
.
Table 9: Evolution of pack of drugs from 2002 to 2013
Generics in France
Year Number of pack of drug
2002 1 pack medicine on 20
The generics market prescribed and refundable
Year
Number of pack
(Million packs)
2012 675
2013 785
In 2013, the savings from generics32
represent more than € 2.4 billion. Since 2000,
cumulative savings are more than € 15.5 billion. This is due to the price of the generics which
are 75% to 80% lower than the Originators. According to the GEMME growth of 4% is
expected for 2014. GEMME is the association for generics drugs, but it is also the Association
of biosimilars drugs.
30
http://translate.google.fr/translate?hl=fr&sl=de&u=http://www.progenerika.de/&prev=search
31
Rapport 2012 sur les médicaments génériques- Mutualité Française
32
http://www.medicamentsgeneriques.info/le-medicament-generique/chiffres-cles/

34
 Italy
Italy is considered less active from the point of view of generic penetration with over
30% market share by volume for generics. The prices of generic drugs are on average 56%
lower than those of their originators
Assogenerici (National Association of Industries Drugs Generic) is the official
representative body of the industry of generics and biosimilars in Italy, at the forefront in
providing medicines at affordable prices and high quality to millions of citizens. Also helps to
stimulate competition and innovation in the pharmaceutical sector.
Table 10: Example of Generics companies in Europe33
N° Company N° Company
1 CRISTERS 10 SANDOZ
2 ZENTIVA 11 MEDIS
3 VENIPAHRM 12 EG LABO
4 SUBSTIPHARM 13 HOSPIRA
5 ARROW 14 H2PHARMA
6 ZYDUS 15 DELPHARM
8 RANBAXY 16 BIOGARAN
9 TEVA LABORATOIRES
B. Biosimilars
The biological drug market is very important in the pharmaceutical market and
represents a growing share of drug spending for health care systems34
:
In the world:
 170 billion euros in 2014;
 250 billion euros in 2020;
 200 currently available drugs;
 30% of the pharmaceutical pipeline (900 products in development).
 More than 25% of health expenditures;
 7 of the top 10 drugs most expensive drugs for the health system;
 3 years of patent losses on drugs representing over 1 billion € of annual health
expenditures (oncology and autoimmune diseases).
33
http://www.egagenerics.com/index.php/about-us/members
34
Colloque du 2 octobre 2014 – médicaments biosimilaires : enjeux et perspectives- GEMME BIOSIMILAIRES

35
In this context, biosimilar medicines are a critical issue for the future of our healthcare
system and allow:
 Maintaining a high level of patient access to advanced treatments
 Finding savings to finance the innovation in health.
The EU presents the most advanced market for biosimilars, accounting for 80% of
global spending on these molecules.
19 biosimilars are authorized in Europe and they represent 6 actives substances35
(see
Table 10).
Table 11: List of currently EU approved biosimilar medicines in 201436
In Europe:
Biosimilars of Filgastrim are used more than the reference product (Neupogen),
allowing more patients to benefit at lower costs. The savings achieved through the use of
filgrastim biosimilar is estimated at € 318M since 200937
.
35
36
Source: EMA (June 2015)
37

36
In Germany:
EPO biosimilars represent 57% in value of the EPO market, € 551M of savings was
achieved through the actions of the authorities and to greater competition.
In The United Kingdom:
Biosimilar filgrastim represents about 90% of filgrastim volume.
In term of volume and value market for biosimilars in Europe, Germany is the first,
followed by other countries38
(See table 11).
Table 12: The biosimilars market in volume and value in 2011
Countries Sale in volume
(M)
Sale in value
( M€)
Germany 6,1 68
France 2,7 40
Italy 2,5 22
UK 0,5 19
From the launch in 2007 to 2011 the market share of biosimilar has increased in
Europe and represents 11% of total biologics sales. This market will grow as the patent for
several biological medicines will expire over the next 5 years.
Graph 4: The biosimilars market evolution from 2010 to 2020 worldwide
Source: IMS Health
38
Shaping the biosimilars opportunity-december 2011

37
The biosimilars market will increase in the future, (multiplied by 10) and the
American market will be an important driver (See Graph 4).
The overall penetration of biosimilars within the off-patent biological market is
forecast to reach up to 50% by 2020, assuming a price discount in the range of 20-30%.
With sales for the top 50 pharma39
companies forecast to decline by 1.6% during
2010–16, many leading drugmakers are looking to expand into markets that offer long-term
growth, limited competition, and are relatively low risk. One such area is biosimilars,
attracting both innovative biologics players and generics players alike.
Currently, Sandoz is the leader of the world market with 51 % of market shares in
2011. Teva (25 %) and Hospira (17 %) are behind (See Table 12).
Table 12: Example of biosimilar companies
Example of biosimilar companies
Accord healthcare Mylan
Gedeon Richter Infarco/Cinfa Biotech S.L.
Fresenius Kabi Hospira
TEVA Europe EGIS
Stada International GmbH
Sandoz Boehringer Ingelheim
Polpharma Actavis
Manufacturing biosimilars40
is expensive and the uncertainties on return on investment
as well as regulatory requirements slow down the enthusiasm of pharmaceutical companies to
engage into the production.
 Development of a biosimilar drug: 5-7 years
 Development costs: between 200 and 300 million dollar
Table 13: Comparison of difference and common points between biosimilars and generics
The leading countries x
Market value x
Number of product x
Production cost x
39
Biosimilars:Market Entry Strategies- Leading pharma companies tap into biosimilars- December 2011-Datamonitor
40

38
In term of market trends, we don’t have common points between biosimilars and generics
(See table 13). One of the reasons to this situation is the difference of maturity between those
two markets.

39
THIRD PART: RESULTS AND ILLUSTRATION

40
Summary
Those interviews help us to have the position of authorities, national and European
pharmaceutical unions, learning societies and patient associations in four European countries more
precisely in France, Germany, Italy and United Kingdom.
We have a global consensus between actors on topic like naming, role of regulation,
substitution, market share, evolution of price of the originators and biosimilars. Position a more
different between actors on regulatory issues like summary of product characteristics and
extrapolation.
Concerning the levers a originators producer can put in place to face the biosimilars
competition and maintain his position, benchmarking on biosimilars, generics (13 companies from
2000 to 2015) and the results of our interview allow us to observe 10 levers:
 Price  Prescription
 Patent  Market saturation
 Legal action  New market
 Cooperation  Environmental strategy
 Product  Brand strategy

41
III.RESULTS AND ILLUSTRATION
1. RESULTS
All the interviews we made in France, Germany, United Kingdom and in Italy helped us to
bring an answer to our interrogations.
Q1: Comparison between biosimilars and generics in terms of regulation, market
penetration and sales.
75% of respondents tell there is no comparison possible between biosimilars and
generics. For them, the biosimilars differ in the complexity of the manufacturing process and
the inherent variability in the biological systems used. They are large complex molecules
rather than small simple molecules. This means that they are medicines in their own right and
cannot be automatically substituted for a reference product.
Moreover, biosimilars and generics have different approval systems, generics are mainly
approved by national authorities and biosimilars are approved by the centralised procedure.
The requirements are also different, for the approval of generics the documentation of the
quality is sufficient and only for some generics, depending on the requirements in each
member state, bioequivalence studies are required. For biosimilars, the documentation of
quality preclinical and clinical studies are requested and need to demonstrate clinical safety
and efficacy.
The common point between biosimilars and generics is only the drop in drug prices for
25% of the respondents.
Graph 5: A comparison between biosimilars and generics
75%
25%
No comparison
Comparison

42
Graph 6: A comparison between biosimilars and generics: country level
The graph 6 shows us that in all countries we have the idea of comparison between
biosimilars and generics. This is a result of difference of position between national unions and
also learning societies.
National and European authorities, patient association and learned societies in the four
countries all agree on the absence of comparison on this two types of drugs.
Q2: The role of regulation in the European market for biosimilars
The pharmaceutical industry is one of the industries where regulation is the most
complicated. For 91% of the professionals surveyed, as part of biosimilars, it will have a very
important role. It should allow to build a favorable environment for the production of
biosimilars.
The role of the EU regulator is to ensure that only drugs with a sufficient evidence
base for safety and efficacy enter the EU market and that they have a suitable post marketing
surveillance in place. The regulation is therefore essential and State must establish regulations
in line with the objectives.
9% of our panel thinks that the offer of biosimilar on the market will have an
important role in the development of biosimilars not the regulation.
30%
15%
30% 24%
70%
85%
70% 76%
0%
20%
40%
60%
80%
100%
France Italy Germany UK
Comparison
No comparison

43
At the national level, the repartition on this topic is this one:
Graph 7: The role of regulation: country level
Some learning societies in France think that the role of regulation is not important; it is
the type of biosimilars on the market which will be important.
National and European authorities, patient association and unions want to build a clear
regulation and think that regulation is the most important element in France, Italy, Germany
and United Kingdom.
Q3: The naming system of the World Health Organisation on biosimilars with a four-
letter code (BQ) at the end of the name (for instance: epoetin alfa bbbb)
The name of a medication is an important element. It allows their differentiation and
reassures patients. Regarding biosimilars, the World Health Organisation has chosen to
develop a four-letter code (BQ) at the end of the name.
The use of a four letter code (BQ) at the end of the name is a good idea for 62 % of the
panel. The BQ could serve as a tool for identification and traceability.
37% of the respondents think that the approach of the World Health Organization is
not the good one. For them the EU has a robust pharmacovigilance system, product
identification for biologicals is well ensured in the EU, and hence there is no need for the BQ
as additional tool.
Moreover, this additional voluntary codification (i.e. the BQ scheme) could give the
perception of important differences between a biosimilar and its reference product, leading to
confusion and consequent impact on prescribing practices.
14% 0% 0% 0%
86%
100% 100% 100%
0%
20%
40%
60%
80%
100%
No important role
Important role

44
The BQ scheme should not be introduced where things work well, but only where it
provides a demonstrable added value.
Graph 8: The naming system of the world health organization
Our results at a national level show us that it is difficult to find a consensus between
countries on this topic.
Graph 9: The naming system of the world health organization: country level
In France, national unions are against this approach contrary to patient associations and
learning societies which think that this approach is the right one.
In the United Kingdom, for learning societies the naming system of the world health
organization is not the right approach, contrary to the national authorities which see this like a
good evolution.
38%
63%
Right approach
Wrong approach
25%
0%
100%
50%
75%
100%
0%
50%
0%
20%
40%
60%
80%
100%
Right approach
Wrong approach

45
Q4: The summary of product characteristics (SmPC) of a biosimilar
Instructions accompanying medication provides important information for its proper
use and for patient safety.
58% of the interviewees think that the Summary of Product Characteristics (SmPC)
for a biosimilar should be closely aligned to its reference product, similarly to what is done
for generics. Moreover, there are no clinically meaningful differences between the biosimilar
and the reference product.
This approach is not appropriate for 42% of the professional of our panel, some
believe that a two column table (one reference and the other biosimilar) for each topic
(posology, side effects, composition of the drug) will be of help and allow comparison. For
them, there are examples where the wording of SmPC sections for a biosimilar and its
originators product are identical and respondents believe the Summary of Product
Characteristics (SmPC) should clearly show where information was obtained from either from
studies investigating the biosimilar product or where the data was derived from evidence
about the originators product.
At a national level is also difficult to find a consensus on this topic between actors in
the same countries or not.
Graph 10: The SmPC of a biosimilar: country level
75%
0%
100%
30%25%
100%
0%
70%
0%
20%
40%
60%
80%
100%
Identical SmPC
Different SmPC

46
Globally we don’t have the same position between learning societies in France, Germany,
United Kingdom and Italy and also between national unions in those countries.
European pharmaceutical unions think that the SmPC must be identical between biosimilars
and originators.
In France, we have a different position between learning societies as some of them want the
same SmPC between biosimilar and originators other would like different approach. For
patient associations and national unions the SmPC can’t be different.
Learning societies and national unions in the United Kingdom don’t want the same SmPC
between originators and biosimilars, contrary to national authorities.
Q5: The extrapolation of biosimilars
Some reference products already commercialised are used in several therapeutic
indications. Only 67% of the respondents think that biosimilars can be used in several
indications like the reference product for many reasons.
First, the European Medicines Agency gives the Marketing Authorization and on the
Marketing Authorization you have the therapeutic indications for each drug. If a product has a
Marketing Authorization then it must have the same system of reimbursement than the
reference product.
Moreover, when biosimilar comparability has been demonstrated in one indication,
extrapolation of clinical data to other indications of the reference product could be acceptable
and there is no logical reason not to extrapolate the evidence to the same indications as that of
the reference product.
33% of the interviewees see this approach as not appropriate. For them, as biosimilars are not
identical to the originators, being derived from different cell lines and through different
manufacturing processes, it cannot be assumed that they will automatically show the same
safety and efficacy in all indications as the originators. Therefore it is well accepted by
regulators that extrapolation of indications should be considered on a case by case basis.
Furthermore, to maximise the savings in the long term healthcare professional need to be very
vigilant and react quickly if any problems occur. That is why clinical studies by indication
should be made.

47
Graph 11: The extrapolation of biosimilars
Graph 12: The extrapolation of biosimilars: country level
At the European level, unions of the biosimilars producer agree on the necessity of
extrapolation.
Clear difference of position between unions of biosimilars and originators in France,
Germany, Italy and United Kingdom. For originators representatives, extrapolation of
indication must not be allowed to the biosimilars, interviewees want more clinical studies.
Contrary to unions, learning societies show us a global consensus on the necessity to
give extrapolation of indication to biosimilars in the four countries.
In France, patient associations are the most against extrapolation of indication for biosimilars.
67%
33%
Extrapolation
No extrapolation
75%
40%
60%
70%
25%
50%
40%
30%
0%
20%
40%
60%
80%
Extrapolation
No extrapolation

48
Q6: The substitution of biosimilars by pharmacist
For 11% of our panel if the reglementation allows the presence of biosimilar in town
then the pharmacist must have the right of substitution, if it is permitted by the regulation.
89% of the interviewees have another approach on this topic. The substitution by the
pharmacist is not the priority axis for them. The development of biosimilars will be better
with physicians, creating a relationship of trust between patient, doctor and pharmacist is the
priority.
State must establish the medical record for tracking the prescription of patients at least
on 5 years in pharmacy. It would possibly allow to set up the substitution in the case of
biosimilars.
Furthermore, as biosimilar and biological reference medicines are similar but not identical,
the decision to treat a patient with a reference or a biosimilar medicine should be taken at least
not without the agreement of a qualified healthcare professional and the patient.
Graph 13: The substitution of biosimilars: country level
In Italy, Germany and United Kingdom all actors are all against substitution by pharmacist.
Learning societies in France are favorable for the right of substitution.
17% 0% 0% 0%
83%
100% 100% 100%
0%
20%
40%
60%
80%
100%
Substitution
No substitution

49
Q7: The set-up of quotas or call for tender for biosimilars
The quotas solution is the optimal solution for 64% of the respondents. They think that
this will ensure an increase in the penetration of biosimilars. Quotas promote penetration of
biosimilars in volume and call for tenders allow a reduction of costs. All this will help to
reduce health system cost.
The other part of our panel find this approach inappropriate, 36% are against quotas but
for a financial incentive establishment for physicians when prescription is made. Moreover, in
some countries like France the tradition is not to put in place quotas contrary to Germany.
Tenders which are undertaken involving biological medicines should not seek to source a
single product only. It has to be a solid scientific approach, initiative and the prescribers must
have the choice and make their decision on medical grounds with the patient.
At a national level between countries we don’t have a consensus on this question. But
Germany seems to be the most favourable for this approach for biosimilars (see Graph 14)
and the quotas are set up by the Kassenärztliche Vereinigungen. This is a body jointly built up
for each region in Germany by the compulsory health insurances and the medical doctors
working on a contract with the Kassenärztliche Vereinigung. This body is responsible for
covering the ambulatory healthcare in this region. Call for tender is used by the owner of the
hospital.
Graph 14: Quotas or tenders for biosimilars: country level
In France, patient association are favourable to quotas and tenders. For learned
societies and national unions it is more difficult to have a clear picture. Some learned societies
and unions are favourable order are against.
50%
0%
100%
66%
50%
100%
0%
30%
0%
20%
40%
60%
80%
100%
Yes
No

50
In the United Kingdom, the positions of actors are clearer than in France, national
unions and authorities are favourable for quotas and tenders. Learned societies are opposed.
Q8: The Biosimilar’s market share in volume and value
For all the interviewees the share of biosimilars will increase in volume and value in
the coming years. But it is very difficult to have a clear prediction about this evolution.
In term of volume this market will represent 35% in 2015 and reach 45% in 2020. On the
world scene the biosimilars market accounted for $ 1.3 billion of which 80% in Europe in
2013. The value of this market will also increase from $2 billion in 2015 to $15 billion in
2020 (See Graph 15 et 16).
Graph 15: Evolution of biosimilars market share in volume-Europe
For example, in France the central purchasing agency for the Assistance Publique - Hôpitaux
de Paris had decided to buy Inflectra after the company offered a discount of 45 percent
(Inflectra is the biosimilar version of infliximab from Hospira)
Graph 16: Evolution of biosimilars market share in value-Europe
35%
45%
0%
20%
40%
60%
2015 2020
$2
$15
0
3
6
9
12
15
2015 2020
Billion$

51
Q9: The Evolution of biosimilar and originators manufacturing price
The introduction of the biosimilars will have an impact in the manufacturing price of
originators. All the respondents think that in the coming years the price of originators and
biosimilars will decrease.
The price reduction for the originators will range from -8% in Year 0 (Year 0 = Year of loss
of the originators’ patent) to -15% in year 5 (five years after the loss of patent). This is the
retail discount, for the hospital the reduction is from 30% to 45% (See graph 17).
The biosimilar will have a more important decrease of price from -25% (Year 0) to -50% in
year 5(graph 18).
Graph 17: Evolution of retail originators manufacturer price after the introduction of
biosimilars
Graph 18: Evolution of hospital manufacturing price for biosimilars
-8%
-10%
-15%
-16%
-13%
-10%
-7%
-4%
-1%
Y 0 Y 2 Y 5
-25% -30%
-50%
-55%
-35%
-15%
Y 0 Y 2 Y 5
0

52
Moreover, before the arrival of a biosimilar on the market, an originators may already
have made a price cut that is between 10 and 15%.
So the price cut of 20 to 30% of biosimilars is observed on the market is made on the
new price of the originators. In reality, we have a price reduction of 30-45% compared to the
originators.
Q10: The leadership position of originators medications
For all of our panel market share of original medicines will decline, but the magnitude
of the decline will depend on several factors:
 The regulation of biosimilars, if we have a favorable regulation of biosimilars, then it
will encourage the penetration of biosimilars.
 Adaptability of pharmaceutical companies, adaptation to the price of biosimilars and
adaptation to the central issue of substitution.
 The last factor is the trust that the doctors give to original medicines. But if biosimilars
significantly reduce costs and prove themselves scientifically then confidence can and
could change.
Pharmaceutical companies will maybe change strategy and move towards marketing
investments, because they are not going to do research so that other laboratories take
advantage by making biosimilar.
All this result show us which regulation could change the development of biosimilars.
Knowing that these actors which respond to our questions are the users, the prescribers and
regulatory authority of the biosimilars, regulation needs to be in concordance with their
willing, to facilitate the acceptance, the prescription of this new type of drug. Therefore their
penetration in those four different markets: France, Germany, United Kingdom and in Italy.

53
2. STRATEGIC POSITIONING FOR THE ORIGINATORS
MANUFACTURERS
This part will focus on the strategy we have observed a manufacturers of originators
can use to keep the place of his medicine with the arrival of biosimilars. We will base our
thinking on three elements:
 Benchmarking on the experience of pharmaceutical company with generics
 Benchmarking on the experience of pharmaceutical company with biosimilars
 The results of our interviews
In 2014, the global pharmaceutical market grew by 8.8% compared to 2013, exceeding
1,000 billion US dollars41
. In 2018, the annual growth rate should be approximately + 4% to +
7%. This return to growth is related to the passage of the period of significant losses of
patents. « The exposure of pharmaceutical company in the losses of patents in the developed
countries is less strong over the period 2014/2018 than over the period 2009/2013,which was
characterized by the loss of many patents in 2012 » explains Stéphane Sclison, strategy
director Imshealth. It is therefore relevant to observe originators producers’ strategic move to
face patent loss.
A. Benchmark on Generics
i. Context
This wave of patent loss has allowed the development of new generic drugs. A Global
analysis finds that the market earned revenues is $123.85 billion in 2010 and will reach
$231.00 billion in 2017 at a compound annual growth rate of 9.29 % from 2011-2018.
The entry of generics has had huge impact in particular on the price of medecine or the
turnover of some pharmaceuticals companies. For example, in Germany the prices of generic
drugs are on average 71% lower than those of their originators and in France it’s about 75% to
80%. To face this upheaval of the landscape of the medicine, producers of originators have set
up various strategies.
For our benchmark we observe action of 11 companies from 2000 to 2015 (See table
14)
41
IMShealth-Information presse-Jeudi 12 mai 2015

54
Table 14: Sample of the benchmark in US and EU
Company Product
Glaxosmithkline Augmentin, Paxil, Amoxicilline
Lilly Prozac
Hoechst Cardizem
Servier Périndopril
Merck & Co Claritin
Fournier Lipanthyl
Astrazeneca oméprazole
Merck-Lipha Glucophage
MSD Inegy, Zocor
Pfizer Gabapentine
Bristoll Myers Squibb Buspirone
Teva Simvastatine

55
ii. Action of the manufacturers of originators
Our benchmarks help us to identify 7 levers; that we can use individually or combine them.
Graph 19: The 7 levers of originators to face Generics
Price
The price reduction of the originators at the level of the price of the generic medicines
can allow to keep the advantage acquired by the brand and to preserve a part of his market.
This policy is only relevant when demand is price sensitive.
The impact of the strategies of companies differs according to market conditions. We
thus notice a particular evolution of markets upon the arrival of the generic medicines.
 A originators would have many generics when his sales and price are high.
 The evolution of the price of the originators depends on the sensitivity of demand to
the price of the product.
7
Levers
Price
Patent
Legal Action
CooperationProduct
Market
Saturation
Prescription
1
3
4
5
6
7
2
1

56
 The falling price of the originators or the production of generic by the producer of
originators limits the penetration of generic competitors on the market.
For example, in 2006, Merck&Co reduce the price of his product Zocor to face the
competition of generics (see Graph 20)
Graph 20: The price evolution of Zocor and Simvastatine teva over 2006-2015 in France
From 2006 to 2015, the price of Zocor42
lost 77 euros and Simvastatine Teva43
52 euros. The
Graph 20 clearly shows us that Merck&Co always wanted to adapt its price to the price of
Simvastatine teva.
Patent
Early in the life cycle of the drug, patent protection is the major tool to counter the entry
of generic. To increase its protection, the laboratory puts down, after the discovery of the
molecule, a whole series of patents: patent on the molecule, on indications etc. The
multiplicities of patents, as well as their spreading in time, allow the laboratory to make more
complex the identification of the valid patents by the potential producers of generics and to
lengthen the period of exclusivity covered by patents. GlaxoSmithKline (GSK), for example,
filed four new patents for Augmentin in 2000 in the United States, two years before the
expiration of the first patents.
42
http://www.codage.ext.cnamts.fr/codif/bdm_it//fiche/index_fic_medisoc.php?p_code_cip=3400937749206&p_site=AMELI
43
http://www.codage.ext.cnamts.fr/codif/bdm_it//fiche/index_fic_medisoc.php?p_code_cip=3400937290265&p_site=AMELI
76 € 76 €
65 € 62 €
43 €
36 €
27 € 24 €
118 € 118 €
106 € 101 €
65 € 65 €
44 € 41 €
0
20
40
60
80
100
120
2006 2007 2008 2009 2012 2013 2014 2015
SIMVASTATINE TEVA 40 MG
ZOCOR 40 MG
2

57
Legal action
The legal battles between producers of originators and manufacturers of generics are
the most media. The first ones accused the second of violating unexpired patents or dispute
the bio-equivalence claimed by generic companies.
The action44
of justice for violation of the patent has for consequence the suspension of the
marketing of the generics medicines. It allows big laboratories to win some invaluable weeks
of exclusivity on the market. For example: GSK has filed several lawsuits for violation of
patents of Paxil in the US and Lilly sued generic makers of Prozac for the same reasons.
Cooperation
Some pharmaceutical companies have reached financial agreements with producers of
generic to postpone competitors launch on the market.
For the European Commission, Servier45
had work with 5 generics companies
(Niche/Unichem, Matrix ( Mylan), Teva, Krka and Lupin.) to slow down the entrance on the
market of generic versions of his medicine, marketed under the name of Coversyl, to handle
the high blood pressure and the cardiac insufficiency. The European Commission heavily
sanctioned the laboratory Servier with a 331 million euro fine to have hindered the launch on
the market of generic versions of its product
Product
Creation of new formulations and new methods of administration possibly patentable.
The laboratory intensely promotes these innovations before patent expiry of the original
formulation, so that they supplant in the prescriptions or the consumer habits (eg dispersible
Prozac, Prozac Weekly)
They developed new dosages containing for example less active ingredient for a
similar efficiency (Lipanthyl® 160 mg was placed on the market to replace the Lipanthyl®
micronized 200 mg).
They make associations of a molecule with another one. For example, in Germany
Inegy® combines the active ingredients of Zocor ® (simvastatin) and Ezetrol® (ezetimibe).
44
Les laboratoires pharmaceutiques face à l’arrivée des génériques : quelles stratégies pour quels effets ?- Bulletin
d’information en économie de la santé-n° 84 - Octobre 2004
45
http://www.bloomberg.com/news/articles/2014-07-09/servier-to-teva-fined-582-2-million-on-generic-delays
3
4
5

58
They developed new products, very close to the initial product and could be replaced.
For example: In the case of the oméprazole, the isomeric molecule was launched on the
market in the United States two years before the arrival of the generic medicines and allowed
AstraZeneca to keep about three quarters of the market which he had in this indication.
Market saturation
The laboratory can produce itself the generic medicine of one of its originators; like
that the company will have many products on the market and would increase its opportunity
to sell one product of the portfolio.
For example, Merck-Lipha continues to market Glucophage whereas Merck Generics
launched on the market a Metformine Merck.
Prescription
The new European regulations promote this strategy by granting one year additional
exclusivity for products that laboratories decided to switch to OTC46
. Pharmaceutical
laboratory make the drug available without a prescription and bet on attachment to the brand.
The Claritin (loratadine ) medicine of the laboratory MSD became OTC in the United States
in November, 2002. Generic version entered on the market in the end of December, 2002.
Some companies have combined different types of actions, for example GlaxoSmith-
Kline used 3 types of levers patent, legal action and product (See table 15).
Table 15: Strategies of pharmaceutical company to protect the place of their medicine47
DCI Laboratory
name
Patent Legal actions Product Brand Strategy
Amoxicilline-
acide
clavulanique
Glaxo
Smith-Kline X X X
Buspirone Bristoll Myers
Squibb
X X
Gabapentine Pfizer X X X
Omeprazole Astra Zeneca X X X
46
Exclusivity Strategies in the United States and European Union by Carolyne Hathaway, John Manthei and Cassie Scherer
47
Les laboratoires pharmaceutiques face à l’arrivée des génériques : quelles stratégies pour quels effets ?- Bulletin
d’information en économie de la santé-n° 84 - Octobre 2004
6
7

59
B. Benchmark on biosimilars: the case of Neupogen
i. Context
The EMA has approved 19 biosimilars within the product classes of human growth
hormone, granulocyte colony-stimulating factor, erythtropoesis stimulating agent, insulin and
tumour necrosis factor (TNF)-inhibitor, for use in the EU48
. The first biosimilar launch in the
EU (Omnitrope/Somatropin) occurred in Germany in 200649
.
This introduction of the biosimilars on the market has many impacts. For example,
biosimilars of filgastrim are used more than the reference product (Neupogen), allowing more
patients to benefit at lower costs. The savings achieved through the use of filgrastim
biosimilar is estimated at € 318M since 200950
.
In this part we will study how the laboratory Amgen, producer of Neupogen responds
to the arrival of biosimilars.
Amgen is an American company world leader in medical biotechnology industry. It
has over 18 000 employees for a turnover of $ 20 billion in 2014 and his headquarter is in
California.
Amgen has 14 products on different type’s diseases and Neupogen is one of them.
The first commercialization of Neupogen in Europe was in 1991 with the collaboration
of Roche . In 2008, this blockbuster represented 1,4 billion dollars and according to
Symphony Health Solutions, Neupogen had approximately $1,2 billion in sales in calendar
year 2014.
The time of total exclusivity enjoyed by Amgen for the Neupogen depend on the
country51
(Graph 21).
48
49
Sierakoviak and Syed (2009. p.22) claim that Sweden was the first country in the world to grant market approval to a
biosimilar medicine in 2007 (Omnitrope, Sandoz).
50
51
IMS data

60
Graph 21: The duration of market exclusivity for Neupogen
Several biosimilars of Neupogen were developed after the loss of patent in European
countries (Table 16).
Table 16: List of Neupogen biosimilars in 2014
Product name Active
substance
Therapeutic area Authorization date Manufacturer/Company
name
Accofil filgrastim Neutropenia 18 Sep 2014 Accord Healthcare
Grastofil filgrastim Neutropenia 18 Oct 2013 Apotex
Nivestim filgrastim Cancer, Neutropenia
Haematopoietic stem cell
transplantation
8 Jun 2010 Hospira
Zarzio filgrastim Cancer, Neutropenia
transplantation
6 Feb 2009 Sandoz
Filgrastim Hexal filgrastim Cancer, Neutropenia
transplantation
6 Feb 2009 Hexal
Biograstim filgrastim Cancer, Neutropenia
transplantation
15 Sep 2008 CT Arzneimittel
Filgrastim
ratiopharm
filgrastim Cancer, Neutropenia
transplantation
15 Sep 2008
Withdrawn on 20
Apr 2011
Ratiopharm
Ratiograstim filgrastim Cancer, Neutropenia
transplantation
15 Sep 2008 Ratiopharm
Tevagrastim filgrastim Cancer, Neutropenia
transplantation
15 Sep 2008 Teva Generics
17
16
7
18
0
4
8
12
16
Numberofyears
Years

61
ii. Action of the manufacturers of originators
Our benchmark on Neupogen helps us to identify 6 levers:
Graph 22: The 6 levers of Neupogen
Price
When the filgrastim biosimilars enter into the market they provide an average discount of
10.8% in 2008 and 35.0% in 2009.
Table 17: Price of biosimilars and filgrastim in 2009
6 Levers
Price
Patent
Legal Action
Cooperation
Product
New Market
Price of Biosimilars and Filgrastim in 2009
Countries Type of drugs Price (euro)
Italy
Biosimilars 70.2
Filgrastim 90.4
UK
Biosimilars 70.3
Filgrastim 74.1
France
Biosimilars 88.6
Filgrastim 141.8
Germany
Biosimilars 123.1
Filgrastim 149.7
1
3
4
5
6
2
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