biosimilars and generics: a comparison

1

Biosimilars and Generics-------------------

A comparison

Joseph Pategou

International Strategy and Influence

[email protected]

23/05/2016 GENERICS AND BIOSIMILARS – Joseph Pategou 2

SUMMARY

Introduction

I. Regulation: GENERICS AND BIOSIMILARS

II. Market Trends: GENERICS AND BIOSIMILARS

Conclusion

Information about the Author

Appendix

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introduction

GENERICS AND BIOSIMILARS – Joseph Pategou

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generics


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Generics: Definition and Life cycle

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

A generic medicine 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.


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Generics: Definition and Life cycle



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BIOSIMILARS


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Biosimilars: Definition and Life cycle

Source: Directive 2001/83/EC, as amended by Directive 2003/63/EC and Directive 2004/27/EC

Biosimilars Marketing Authorisation status as of January 2013: 22 Marketing Authorisation Applications

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

The concept of a “similar biological medicinal product” was adopted in EU

pharmaceutical legislation in 2004 and came into effect in 2005. The first biosimilar

medicine was approved by the European Commission in 2006.

A biosimilar medicinal product is a biological medicine which is similar to another

biological medicine that has already been authorized for use, the “reference medicinal

product”.

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).


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Biosimilars: Definition and Life cycle



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REGULATION


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Generics


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Naming

Source: EMA Procedural advice for users of the centralized procedure for generic/hybrid applications

The naming of a drug is important; it allows their differentiation and gives confidence to

patients.

The use of a single name 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.

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


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Labelling

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

The label 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.


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Substitution

Source: Rapport 2012 sur les médicaments génériques- Mutualité Française

The substitution 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).


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Substitution

Source: Observatoire du médicament FNMF à partir des données de l’EGA et de l’AIM, 2011 et 2012

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

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


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Quotas and Tenders

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

In France, in United Kingdom, in Germany 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.


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Quotas and Tenders

Source: Observatoire du médicament, FNMF à partir des données EGA 2011, AIM 2012, ESIP 2012

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

Table 3: Comparison between countries in term of tenders


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Marketing Authorization/Clinical trials

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

Any drug, to be marketed, must obtain a Marketing Authorization. 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


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Source: Guideline on the investigation of bioequivalence- London, 20 January 2010- European Medicines Agencyhttp://www.australianprescriber.com/magazine/26/4/article/712.pdf

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 bioequivalence in regards to the

reference medicine.

For Professor Donald J. Birkett, “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.”


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Source: Guideline on the investigation of bioequivalence- London, 20 January 2010- European Medicines Agencyhttp://www.australianprescriber.com/magazine/26/4/article/712.pdf

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

Table 4: Comparison of the marketing authorization between generics and

originators


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BiOSIMILARS


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Naming

Source: Individual case safety report: Article 28 of Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012

Biological Qualifier An INN Proposal-July 2014- World Health Organization, Geneva

As required by EU law, 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 code 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)


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Labelling

Source: http://www.gabionline.net/Biosimilars/Research/Improved-labelling-sought-for-biosimilar-acceptance

The European Medicines Agency approaches on biosimilar labelling

requiring the label of the biosimilar product, which describes its medical use. It

isto be consistent with the label of the reference product.


Substitution is the pratice of dispensing one medicine instead of another

equivalent and interchangeable medicine at the pharmacy level without

consulting the prescriber

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Substitution

Country Substitution

United Kingdom Not authorized

France Decree Pending

Italy Not authorized

Germany Possible between Biosimilars

Position of each country on Substitution

Source: See appendix


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Interchangeability

Interchangeability: an important topic

Interchangeability is the medical practice of changing one medicine for another that is

expected to achieve the same clinical setting and in any patient on the initiative, or with the

agreement of the prescriber

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 rests with the

responsible clinician in consultation with the patient

In France, interchangeability is permitted for Biosimilars and rests with the responsible

clinician in consultation with the patient (patient consent and clinical monitoring)

Absence of interchangeability in Italy

This situation will evolve due to the international context (scientific data available and other

countries)

Source: FDA


European Medicines Agency

Extrapolation is the scientific concept of granting a clinical indication to a

medicine without requiring new clinical efficacy and safety data to support

an indication

If Biosimilarity has been demonstrated in one indication, extrapolation to

other indications of the reference product could be acceptable with

appropriate scientific justification ( eg: clinical experience)

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Extrapolation

Source: EMA


Comparison of the MA between Originators, Generics, and Biosimilars

Comparative studies in terms of :

Quality

Safety

Efficacy

Aim to demonstrate that these three parameters are similar to the Originator

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Marketing Authorization

File of the demand of MA Originators Generics Biosimilars

Module 1Administrative Information

Yes Yes Yes

Module 2Summary of Module 3, 4

and 5Yes Yes Yes

Module 3Quality (manufacturing

process)Yes Yes Comparative studies

Module 4Safety (non-clinical studies)

Yes Not required Comparative studies

Module 5Efficacy (clinical studies )

Yes Bioequivalence Study Comparative studies

Source: EMA


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MARKET TRENDS


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GENERICS


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Globally, there are eight major world markets: 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 market 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

Global Picture

Source:Where the opportunities are and what role will they play? EGA Lisbon 2011-IMS

http://healthcare.blogs.ihs.com/2012/01/06/generic-drug-price-trends-france-germany-italy-spain-uk/


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Global Picture

Source:Where the opportunities are and what role will they play? EGA Lisbon 2011-IMS

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)).

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

Table 10: Example of Generics companies in Europe


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Global Picture

Source: IMS Health

Graph 3: The Generic market share in Europe

Country Ranking

United Kingdom 1st

Germany 2nd

France 3rd

Italy 4th

Table 8: Ranking of generics market


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Global Picture: United Kingdom

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

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 Kingdom 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.

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.


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Global Picture: Germany

Source: http://translate.google.fr/translate?hl=fr&sl=de&u=http://www.progenerika.de/&prev=search

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 needs 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.


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Global Picture: 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 average.

In 2013, the savings from generics 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.


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Global Picture: France


Generics in France

Year Number of pack of drug

2002 1 pack medicine on 20



The generics market prescribed and refundable

YearNumber of pack

(Million packs)

2012 675

2013 785

Table 9: Evolution of pack of drugs from 2002 to 2013


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Global Picture: 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.


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BiOSIMILARS


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Global Picture

Global market:

2,6 billion$ in 2015

25 billion$ in 2020

Due to a new market

Biosimilars sales by Region

First Biosimilar medicine approved by European Commission Source: IMS and EGA

Focus on EU :

Most advanced market

11% of total biologics sales in 2011

50% of the off-patent biological market in 2020

20 Biosimilars (7 actives substances) in 2015

Biosimilars market in volume and value in 2011


New market.pptx

Total Biosimilar Sales by Region (2013-2023).pptx

23/05/2016

Source: IMS

40

Anti-TNF, Insulins and Onco MABs are the key biologics

LIEN HYPERTEXTE


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Source: BioTrends Research Group A: Actual ; F: Forecast

$ billion

USA

EU

Japan

Biosimilars Sales by Region

LIEN HYPERTEXTE


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Main Actors

Source: IMS and EGA

4 Categories of Players

Top 3 Innovator Companies affected by Biosimilars


4 Categories of Players.pptx

Top 3 innovator companies affected by Biosimilars.pptx

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4 Categories of Players

LIEN HYPERTEXTE


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Source: IMS and EGA

Amgen

AbbVie

Roche

Top 3 innovator companies affected by Biosimilars

Innovator companies affected by Biosimilars

LIEN HYPERTEXTE


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Conclusion

Even if, the biosimilars and the generics came in the market after the end of originators patent,

the comparison between them clearly shows that these two types of drugs are different in terms of

regulation and market trends.

Biosimilar medicines are biologicals developed to be similar to an existing biological medicine.

Whereas generics have simple chemical structures and are considered to be identical to their reference

medicines.

On the regulation part, we see big difference.The marketing Authorization of generics is mainly

based on bioequivalence studies unlike biosimilars based on comparative study. Moreover, the

regulation of biosimilars is still not clear and still in discussion in many countries, unlike to generics

drugs.

In term of sales, generics are driven by eight major world markets accounting for 84% of global

sales (United States, Germany, France, Britain, Canada, Italy, Spain and Japan).

The United States is the largest generics market with 42% of global sales (global sales $123.85 billion

in 2010 and will reach $231.00 billion in 2017.

The most advanced market for biosimilars, is the EU representing 80% of global spending

(Global market: $2.6 billion in 2016 to $25 billion in 2020) with 19 biosimilars already marketed and

representing 6 actives substances. Germany is the first largest market in volume and value; followed

by France, Italy and United Kingdom.


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Information about the author

I am fascinated by healthcare and the experience of many companies

to develop new types of drug with the aim of saving lives around the

world.

Main topics of passion in the healthcare:

- Strategy

- Digital

- Innovation

- Biosimilars

If you want to know more, please contact me:

[email protected]

M. Joseph Pategou


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THANK YOU FOR YOUR ATTENTION


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APPENDIX


23/05/2016 Regulatory issues on the development of Biosimilars – Joseph Pategou 49

GLOBAL ECONOMIC SITUATION: Reduction of health spending

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NAMING


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COMPARISON OF DIFFERENCE AND COMMON POINTS BETWEEN

BIOSIMILARS AND GENERICS-STRUCTURE

KEY POINTS BIOSIMILARS Generics

NatureDrug extracted from a biological

environmentChemical 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


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MARKET TRENDS: Global picture

KEY POINTS DIFFERENCE IDENTICAL

The leading countries x

Market value x

Number of product x

Production cost x

Comparison between Biosimilars and Generics

Focus on EU :

Most advanced market 80% of global spending in 2011 11% of total biologics sales in 2011 50% of the off-patent biological market in 2020

Countries Sales in volume(M)

Sales in value( M€)

Germany 6,1 68

France 2,7 40

Italy 2,5 22

UK 0,5 19

Biosimilars market in volume and value in 2011

Source: IMS


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THE FUTURE BIOSIMILARS


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BIOSIMILARS MARKET IN VOLUME AND VALUE


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MANUFACTURING OF BIOSIMILARS

Un processus de fabrication en 6 étapes:

Les biosimilaires sont composés de protéines recombinantes dont la fabrication se décline en 6 étapes. Chacune de ces étapes implique d’importants efforts en R&D et en contrôle qualité : les propriétés thérapeutiques des molécules dépendent fortement de leur processus de fabrication.

1. Sélection du gène et de la cellule-hôte

2. Création d’une culture cellulaire à partir d’une banque de cellules

3. Synthèse de la protéine recombinante par les cellules hôtes

4. Purification de la protéine synthétisée

5. Formulation du médicament

6. Conditionnement pharmaceutique


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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

5. 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/


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REFERENCE


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REFERENCE


biosimilars and generics: a comparison

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