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? 2

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



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.



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.



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.



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 KEY POINTS DIFFERENCE IDENTICAL

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.



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.



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.



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 analysis2concludes 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



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?



FIRST PART: METHODOLOGY



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.



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 http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe 6 Shaping the biosimilars opportunity-december 2011



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



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?



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?



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 :



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?



SECOND PART:

EMPIRICAL CONTEXT: COMPARISON BETWEEN




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.



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



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



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



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



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



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 18http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000318.jsp



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.



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



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



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



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

KEY POINTS DIFFERENCE IDENTICAL

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/



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



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/



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



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 http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe 36 Source: EMA (June 2015) 37 Colloque du 2 octobre 2014 – médicaments biosimilaires : enjeux et perspectives- GEMME BIOSIMILAIRES



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



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 KEY POINTS DIFFERENCE IDENTICAL

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 Colloque du 2 octobre 2014 – médicaments biosimilaires : enjeux et perspectives- GEMME BIOSIMILAIRES



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.



THIRD PART: RESULTS AND ILLUSTRATION



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







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



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



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



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



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



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


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.



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



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



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



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

Bil

lion

$



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



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.



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



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



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



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.

42http://www.codage.ext.cnamts.fr/codif/bdm_it//fiche/index_fic_medisoc.php?p_code_cip=3400937749206&p_site=AMELI 43http://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



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



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



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 http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe 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 Colloque du 2 octobre 2014 – médicaments biosimilaires : enjeux et perspectives- GEMME BIOSIMILAIRES 51 IMS data



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

Haematopoietic stem cell transplantation

6 Feb 2009 Hexal

Biograstim filgrastim Cancer, Neutropenia Haematopoietic stem cell

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

1716

7

18

0

4

8

12

16


Nu

mb

er o

f ye

ars

Years



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

1



Focus on France

Amgen needs to adapt his price to face this situation. We clearly see that we have a

difference in terms of price between biosimilar and originators. Amgen has tried to adapt his

price to remain competitive, but we still have differences. (See graph 2352). The price53of the

two types of drugs decrease over time, biosimilar and originators follow each other.

Graph 23: The evolution of Neupogen and Tevagrastim price over 2006-2015

Patent

Over time Amgen has developed 5 indications for his product (incremental patenting).

Legal action

Novartis' Sandoz is the first drug maker to win U.S. approval of a biosimilar product.

But the United States court of appeals for the federal circuit gave an injunction against

Sandoz, preventing that company from marketing, selling, offering for sale, or importing into

the United States its FDA-approved ZARXIO® biosimilar product until the court resolves the

appeal54. This give more time to Amgen to sell his product.

52 http://www.codage.ext.cnamts.fr/codif/bdm_it//fiche/index_fic_medisoc.php?p_code_cip=3400935395214&p_site=ameli 53 http://www.codage.ext.cnamts.fr/codif/bdm_it//fiche/index_fic_medisoc.php?p_code_cip=3400935395214&p_site=ameli 54 http://www.patentdocs.org/2015/05/amgen-wins-injunction-against-neupogen-biosimilar-pending-appeal.html

866,08 € 858,47 € 858,47 €

749,01 € 746,17 €

691,91 € 688,28 € 703,74 € 700,89 €

0

300

600

900

2006 2008 2009 2012 2015

Pric

e (

eu

ro)

NEUPOGEN 48 MU (0,96 MG/ML)

TEVAGRASTIM 48 MUI/0,8 ML

2

3



Amgen based his action on the fact that the pre-litigation information-exchange

provisions of the Biologics Price Competition and Innovation Act of 2009 (BPCIA) are

mandatory and for Sandoz this is optional. The BPCIA states that a biosimilar applicant "shall

provide" a copy of its FDA application and manufacturing information to the Reference

Product Sponsor (RPS) here, Amgen. The statute further states that in the event that a

biosimilar applicant fails to provide its application and manufacturing information, the RPS

may file a declaratory judgment action against the applicant55.

Cooperation

The company’s CEO Kevin Sharer stated in January 2011 that in order to drive

growth, the company was going to consider entering the biosimilars sector but “in a controlled

way,” (Beasley, 2011).

In December 2011, Amgen announced it had signed a deal with Watson to develop

and commercialize a number of oncology biosimilar monoclonal antibodies (MAbs)56. Under

the agreement, Amgen will be primarily responsible for developing, manufacturing and

initially commercializing the products, while Watson will put in up to $400m in co-

development costs and will share product development risks. Biosimilars from the

collaboration are expected to be sold jointly by both companies.

Amgen has secured a clause which prevents the collaboration from making biosimilar

versions of its drugs including Enbrel (etancercept), Aranesp (darbepoetin alfa) and Epogen

(epoetin alfa).

This deal gives the opportunity to Amgen to enter the biosimilars arena, to develop his

know how and to know more how his can protect his product, Neupogen.

Product

Neulasta (pegfilgrastim) can be considered as a new version of Neupogen. They are

both made of a natural protein known as granulocyte-colony stimulating factor (or "G-CSF").

Pegfilgrastim (Neulasta) has a polyethylene glycol, "PEG," unit added to it, which makes the

molecule larger, so that it stays in your system longer than filgrastim (Neupogen). Two forms

of G-CSF are approved for use in pediatric cancer patients.

55 http://www.orangebookblog.com/2015/05/amgen-wins-temporary-injunction-against-sandoz-in-landmark-biosimilars-case.html 56 http://gabionline.net/Biosimilars/Research/The-future-of-biosimilar-mAbs-in-Europe

4

5



The needs for fewer injections with Neulasta (pegfilgrastim) improve quality of life for

pediatric oncology patients and their families57.

New market

Amgen bought the rights of Neupogen and Neulasta in more than 100 emerging

markets where the drugs were sold by Roche58.

Amgen believes it can drive growth of Neupogen (filgrastim) and Neulasta

(pegfilgrastim) more effectively in the Roche territories, which cover the world's emerging

economies including Eastern Europe, Latin America, Asia, the Middle East and Africa.

For Robert Bradway the chief executive of Amgen "This agreement will enable

Amgen to reach more patients around the world with two of its innovative medicines."

All this 6 levers help Amgen to maintain a high level of sell for his product Neupogen:

1.2 billion in 201459 dollars.

Graph 24: The evolution of sell of Neupogen from 200860 to 2014

The benchmarking on generics and biosimilars help us to identify 8 levers used by

originators producer (Table 18).

57 http://www.oncologynurseadvisor.com/side-effect-management/filgrastim-vs-pegfilgrastim-a-quality-of-life-issue-for-children/article/241198/2/ 58 http://www.pmlive.com/pharma_news/amgen_buys_total_filgrastim_rights_from_roche_512290 59 http://www.bloomberg.com/news/articles/2015-03-19/amgen-loses-bid-for-order-blocking-sandoz-copy-of-neupogen 60 http://www.pharmaceutiques.com/phq/mag/pdf/phq169_48_dossier.pdf

1,41,2

0

0,4

0,8

1,2

2008 2014

Bill

ion

$

Sales of Neupogen

6



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 -

The table 18 shows us that 5 levers are clearly used without distention in biosimilars and

generics case: price, patent, legal action, cooperation and product.

New market is employed to face biosimilars whereas prescription and market saturation is

involved in the case of generics competition.



C. Interpretation of our interviews

The cross analysis of our interviews allows to identify 2 levers

Graph 25: The 2 levers: Brand and Environmental Strategy

Brand strategy

The brand strategy is divided into two actions:

Create more adhesion of patients and healthcare professionals to their drugs (adhesion

to the brand)

Bring more services to patients and healthcare professionals on their drugs (For

example monitoring)61

61 Interview with Mr Stefano Dibiase, Senior Consultant, Thought Leadership EMEA, IMShealth

2 Levers

Brand Strategy

Environmental Strategy

1

1

2



Environmental strategy

Environmental strategy is based on 3 actions:

Promote the obligation of the four-letter code (BQ) at the end of the name of

biosimilars

Promote for the biosimilar a different Summary of Product Characteristics (SmPC)

from the generics and originators

Promote the substitution of biosimilars by physicians

All this will contribute to highlight that biosimilars unlike generics are not identical to

originators, but different products.

2



PART FOURTH: CONCLUSIVE DISCUSSION



CONCLUSIVE DISCUSSION

1. DISCUSSION

In this research work, one of our aims was to understand the regulation of biosimilars,

the position of the main healthcare actors, and how it could change in the future, by making

a comparison between the empirical context and the results of our interviews:

Comparison between biosimilars and generics

In the literature and in the mind of healthcare professionals of our panel, it is clear that

comparison in terms of regulation, market penetration and sales are possible. That is why

regulation has an important role to play in the European market for biosimilars.

Naming system for biosimilars

More than half of healthcare professionals agree with the position of World Health

Organization on the use of four-letter code (BQ) at the end of the name.

Labelling (SmPC) of a biosimilar

For the European Medicines Agency (EMA), the label must be in concordance with the

label of the reference product. This is aligned with the position of healthcare professional

of our panel.

Extrapolation for biosimilars

Main healthcare actors have the same position as the European Medicines Agency on the

possibility for biosimilars to be used in several indications like the reference product.

Substitution of biosimilars by pharmacists

There is a global consensus between national authorities of each country and respondents of

our panel, on the fact that pharmacists can’t make substitutions.

On the topic where we have a consensus between literature and healthcare professionals, we

can think that regulation will evolve in that way.



One of the hottest topics concerning the regulation of biosimilars is the

interchangeability62, the medical practice of changing one medicine for another that is

expected to achieve the same clinical effect in a given setting and in any patient on the

initiative, or with the agreement of the prescriber. This is totally different from substitution

which is the practice of dispensing one medicine instead of another equivalent and

interchangeable medicine at the pharmacy level without consulting the prescriber63.

Germany has accepted the principle of interchangeability, for the Paul-Ehrlich-Institute

“Biosimilar medicines can be prescribed to patients, who previously have not received any

treatment with biologics, as well as those patients who have previously received the original

molecule.”

In the United Kingdom, interchangeability is permitted for biosimilars and it depends on

physician’s choice64.

Italy and France have refused the principle of interchangeability, but the situation will evolve

in the future influence by the international context (many countries using the principle of

interchangeability), the scientific data available and continue to accumulate with use of

biosimilars.

Biosimilars and originators manufacturers need to keep in mind an important element:

the economic situation in all Organization for Economic Co-operation and Development65

(OCDE) countries.

In one country out of three, the total spending of health is declining since 2009, and the most

affected by the economic crisis are the main concerned.

The tendency is thus sharply reversed after strong increases observed in the years preceding

the crisis, according to a new report of the OECD.

For 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.

62 Bilan at Actualités sur les Médicaments Biosimilaires, Mrs Suzette Kox, Coordinator EGA European Biosimilars Group 63 PCWP and HCPWP joint meeting : information session on biosimilars-Interchangeability-EMA-Finnish Medicines Agency Fimea 64 Interview with Mr Stefano Dibiase, Senior Consultant, Thought Leadership EMEA, IMShealth 65 Panorama de la santé 2013 : Les indicateurs de l’OCDE



For example, in France and Germany health costs in percentage of the gross domestic product

(GDP) increased from 2000 to 2009 then decreased since 2009 (see graph 26).

Graph 26: The evolution of health costs in percentage of the gross domestic product

(GDP) from 2000 to 201166

This research work also has limits, the first one is the size of the sample which is not

the same on each country and related to that of the number of countries in the study which

reduce the possibility to make an extrapolation on all European countries.

Some of the answers in this report are pictures of a precise moment and we now that

regulation issues of biosimilars evolve quickly. For example, based on our interviews we were

waiting a discount of 30% for the tender in Hospital in France. But Hospira wins french

Assistance Publique - Hôpitaux de Paris biosimilar drug tender at 45% discount.

66 Source : Statistiques de l’OCDE sur la santé 2013, http://dx.doi.org/10.1787/health-data-fr.



2. CONCLUSION

Our research helps us to see that we have clear difference between biosimilars and

generics in terms of regulation and market trends. Even if, the biosimilars and the generics are

drugs which came in the market after the end of originators patent.

With 19 biosimilars in Europe, the EU is the most advanced market for biosimilars,

accounting for 80% of global spending (Global market: $2.6 billion in 2016 to $25 billion in

2020). In terms of volume and value market for biosimilars in Europe, Germany is the first

one; followed by France, Italy and United Kingdom.

The focus on France, United Kingdom, Italy and Germany allows us to deeply

understand the regulation of biosimilars and the issues regarding this new type of drug.

It is clearer that that the regulation of biosimilars is still in discussion in many

countries, on subjects like naming, role of regulation, substitution, summary of product

characteristics, extrapolation and interchangeability.

Our interviews helped us to have the position of authorities, national and European

pharmaceutical unions, learning societies and patient associations. It has allowed us to have a

clearer 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.

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


Regarding the substitution of biosimilars by pharmacists, there is a global consensus on the

fact that it is impossible. But in countries like France discussions are in place to allow the

substitution by pharmacist67.

One of the hottest topics on biosimilar regulation, interchangeability is still in discussion.

Germany and United Kingdom have accepted the principle of interchangeability but Italy and

France have refused this principle.

67 http://www.assemblee-nationale.fr/14/amendements/2252/AN/305.asp



Based on our observation on 13 companies from 2000 to 2015 and our interviews, we

were able to identify 10 levers which have been used by originators producers over time to

face biosimilars and maintain their positions:

Price Prescription







ANNEX

1. Reference

2. List of illustration

3. Definition



1. Reference

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

3. http://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


6. Shaping the biosimilars opportunity-december 2011

7. http://www.sante.gouv.fr/qu-est-ce-qu-un-generique.html

8. Rapport 2012 sur les médicaments génériques-Mutualité Française

9. EMA Procedural advice for users of the centralized procedure for generic/hybrid applications

10. Lessons learned from the review of the labelling of 5 centrally authorised pandemic vaccines- 10 February 2014 EMA

11. Rapport 2012 sur les médicaments génériques- Mutualité Française

12. http://gabionline.net/Biosimilars/General/Germany-wants-to-increase-biosimilars-penetration

13. http://ec.europa.eu/health/authorisation-procedures_en.htm

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

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

24. http://gabionline.net/Biosimilars/General/Germany-wants-to-increase-biosimilars-penetration

25. http://gabionline.net/Biosimilars/Research/Extrapolation-for-biosimilars

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

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/

29. http://www.britishgenerics.co.uk/about-generics/the-generics-industry

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/

33. http://www.egagenerics.com/index.php/about-us/members

34. Colloque du 2 octobre 2014 – médicaments biosimilaires : enjeux et perspectives- GEMME BIOSIMILAIRES


36. Source: EMA (June 2015)


38. Shaping the biosimilars opportunity-december 2011

39. Biosimilars:Market Entry Strategies- Leading pharma companies tap into biosimilars- December 2011-Datamonitor


41. IMShealth-Information presse-Jeudi 12 mai 2015

42. http://www.codage.ext.cnamts.fr/codif/bdm_it//fiche/index_fic_medisoc.php?p_code_cip=3400937749206&p_site=AMELI


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. Exclusivity Strategies in the United States and European Union by Carolyne Hathaway, John Manthei and Cassie Scherer

46. 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


48. 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. http://www.amgen.fr/french/about/milestones.html

51. http://www.pharmaceutiques.com/phq/mag/pdf/phq169_48_dossier.pdf

52. IMS data



55. http://www.patentdocs.org/2015/05/amgen-wins-injunction-against-neupogen-biosimilar-pending-appeal.html

56. http://www.orangebookblog.com/2015/05/amgen-wins-temporary-injunction-against-sandoz-in-landmark-biosimilars-case.html

57. http://gabionline.net/Biosimilars/Research/The-future-of-biosimilar-mAbs-in-Europe

58. http://www.oncologynurseadvisor.com/side-effect-management/filgrastim-vs-pegfilgrastim-a-quality-of-life-issue-for-



children/article/241198/2/

59. http://www.pmlive.com/pharma_news/amgen_buys_total_filgrastim_rights_from_roche_512290

60. http://www.pharmaceutiques.com/phq/mag/pdf/phq169_48_dossier.pdf

61. http://www.bloomberg.com/news/articles/2015-03-19/amgen-loses-bid-for-order-blocking-sandoz-copy-of-neupogen

62. Interview with Mr Stefano Dibiase, Senior Consultant, Thought Leadership EMEA, IMShealth

63. Bilan at Actualités sur les Médicaments Biosimilaires, Mrs Suzette Kox, Coordinator EGA European Biosimilars Group

64. PCWP and HCPWP joint meeting : information session on biosimilars-Interchangeability-EMA-Finnish Medicines Agency

Fimea

65. Interview with Mr Stefano Dibiase, Senior Consultant, Thought Leadership EMEA, IMShealth

66. http://www.assemblee-nationale.fr/14/amendements/2252/AN/305.asp

67. Panorama de la santé 2013 : Les indicateurs de l’OCDE

68. Source : Statistiques de l’OCDE sur la santé 2013, http://dx.doi.org/10.1787/health-data-fr.

69. http://www.bloomberg.com/news/articles/2014-07-09/servier-to-teva-fined-582-2-million-on-generic-delays

2. List of illustration

List of graphs

Graph 1: The life cycle of generics

Graph 2: The life cycle of biosimilars

Graph 3: The generic market share in Europe

Graph 4: The biosimilars market evolution from 2010 to 2020 Graph 5: A comparison between biosimilars and generics

Graph 6: A comparison between biosimilars and generics

Graph 7: The role of regulation: country level

Graph 8: The naming system of the world health organization

Graph 9: The naming system of the world health organization: country level

Graph 10:The SmPC of a biosimilar: country level

Graph 11: The extrapolation of biosimilars

Graph 12: The extrapolation of biosimilars: country level

Graph 13: Substitution of biosimilars: country level

Graph 14: Quotas or tenders for biosimilars: country level

Graph 15: Evolution of biosimilars market share in volume - Europe

Graph 16: Evolution of biosimilars market share in value - Europe Graph 17: Evolution of retail originators manufacturer price after the introduction of biosimilars

Graph 18: Evolution of biosimilars manufacturing price

Graph 19: Sample of the benchmark

Graph 20: The price evolution of Zocor and simvastatine Teva over 2006-2015 in France

Graph 21: The duration of market exclusivity for Neupogen

Graph 22: The 6 levers of Neupogen

Graph 23: The evolution of Neupogen and Tevagrastim price over 2006-2015

Graph 24: The evolution of sell of Neupogen from 2008 to 2014

Graph 25: The 2 levers: Brand and Environmental Strategy

Graph 26: The evolution of health costs in percentage of the GDP from 2000 to 2011



List of tables

Table 1: Sample of the interviews

Table 2: Comparison between countries in term of price and substitution

Table 3: Comparison between countries in term of tenders

Table 4: Comparison of the marketing authorization between generics and originators

Table 5: Comparison between countries in term of quotas and substitution

Table 6: Comparison of the market authorization between originators, generics, and biosimilars

Table 7: Comparison of difference and common points between biosimilars and generics-Regulation

Table 8: Ranking of generics market Table 9: Evolution of pack of drugs from 2002 to 2013

Table 10: Example of Generics companies

Table 11: List of currently EU approved biosimilar medicines in 2014

Table 12: The biosimilars market in volume and value in 2011

Table 13: Comparison of difference and common points between biosimilars and generics-Market trend

Table 14: Sample of the benchmark in US and EU

Table 15: Strategies of pharmaceutical company to protect the place of their medicine

Table 16: List of Neupogen biosimilars in 2014

Table 17: Price of biosimilars and filgrastim in 2009

Table 18: Comparison of levers used by originators producer to face biosimilars and generics competition

Table 19: Comparison of difference and common points between biosimilars and generics-Structure

3. Definition

Phase of a clinical study

Phase Aim Notes

Phase 0 Pharmacodynamics

And

pharmacokinetics in humans

Phase 0 trials are the first-in-human trials. Single subtherapeutic

doses of the study drug or treatment are given to a small number

of subjects (10 to 15) to gather preliminary data on the agent's

pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs). For a test

drug, the trial documents the absorption, distribution,

metabolization, and removal (excretion) of the drug, and the

drug's interactions within the body, to confirm that these appear

to be as expected.

Phase 1 Screening for safety. Testing within a small group of people (20–80) to evaluate

safety, determine safe dosage ranges, and begin to identify side

effects. A drug's side effects could be subtle or long term, or

may only happen with a few of people, so phase 1 trials are not

expected to identify all side effects.

Phase 2 Establishing the efficacy of the drug, usually

against a placebo.

Testing with a larger group of people (100–300) to see if it is

effective and to further evaluate its safety. The gradual increase

in test group size, allows less common side effects to be

progressively sought.

Phase 3 Final confirmation of safety and efficacy. Testing with large groups of people (1,000–3,000) to confirm its

effectiveness, monitor side effects, compare it to commonly

used treatments, and collect information that will allow it to be used safely.

Phase 4 Sentry studies during sales. postmarketing studies delineate additional information, including the treatment's risks, benefits, and optimal use. As

such, they are ongoing during the drug's lifetime of active

medical use.

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

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

biosimilars: regulation issues

Health & Medicine