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The European Experience W

Follow-on Biologics Legislati

Federal Trade Commission Roundtable 

Follow-on Biologic Drugs: Framework 

Competition and Continued Innovat

Linda R. Horton, Par

Hogan & Hartson 

Washington, 

LRHorton@hhlaw.c

Washington

November 21, 2
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The topics I have been asked to address:• European experience with the legislation• European approach to exclusivity• Exclusivity for new indications• Exclusivity for product improvements and 

second-generation products

• How interchangeability is handled_______The views presented are mine, not those of Hogan & Hartson LLP 

of our clients.
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Introduction: EU / U.S. 

Biosimilars: “similar biological m• One set of laws for all “medicinal 

separate biologics law

• Since 2004/05, a regulatory path• General exclusivity period of 8+2

Follow-on biologics (or follow-o• Two laws for pharmaceutical app• Public Health Service Act: No bio• Federal Food, Drug and Cosmet

believes it has authority to approthose therapeutic proteins handlethe FDCA, e.g., Omnitrope somahuman growth hormone); Hatch-
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Similarities and Differences: EU / U

Relevant similarities• All biotech products, including biosimilars, go through ce

(national Member State agencies might approve non-bioreference product was not one assessed by the EMEA)

• Rigorous review; much harmonization (ICH) and coopera• 20 years patent life; belief in strong IP system and in reg

Relevant differences and a few cautionary notes

• Each of the 27 EU Member States has its own healthcare 

own decisions about reimbursement, pricing etc., and me

• In the EU, national differences persist in the patent syste• No linkage, no Orange Book, no Paragraph IV, no 180-da

the EU: EU pharma regulators ignore patents and patent 

• Origin of EU 10-year exclusivity was 1987 “EU Hatch Wa

approval pathway came separately and much later (2004benefit of studies that might more accurately predict time
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EU Biosimilar Experience

A quick overview
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Biosimilar medicinal products: EU REGULATORY PATHWAY:• Article 10(4), Community Code on Medicinal Products (D

– “Where a biological medicinal product which is similar to a referenc

meet the conditions in the definition of generic medicinal proddifferences relating to raw materials or differences in manufactur

biological medicinal product and the reference biological medicinal appropriate pre-clinical tests or clinical trials relating to these 

provided. The type and quantity of supplementary data to be provid

relevant criteria stated in the Annex and the related detailed guidtests and trials from the reference medicinal product's dossier 

• The Annex referred to is the EU version of the Internation

Harmonization’s Common Technical Document (CTD). It requirements for biologicals & “similar biological medical 

• Under EU law there could, in theory, be a “biogeneric” if t

bioequivalence requirements in Article 10.1 were met. Thpossible today, unless the innovator/marketing authorizatapproval under the generic pathway of a product completdirectly or through a licensee. 
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Overview of Regulatory SystemBiosimilars are authorized:

– by the European Commission – through the centralized authorization procedure

on Medicinal Products for Human Use (CHMP) application

– the Reference Product must have been authori

• Comparability studies are needed to generate evide

similar nature, in terms of quality, safety and efficacbiological medicinal product and the chosen referen

• Whether a medicinal product would be approvable 

biological medicinal product” approach depends on development of analytical procedures, the manufacemployed, and clinical and regulatory experiences. 

• The EMEA has issued a series of guidelines, includ

to product classes, to guide sponsors, rapporteurs, whole. The EMEA emphasizes a “case by case” ap
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Biosimilar 

biotechnologyderived proteins

(S&E)

Product-class-specific annexes

Somatropin Epoietin Insulin G-CSF** 

Similar biological 

medicinal products

Biosimilar 

biotechnologyderived proteins 

(Quality)

Courtesy of Dr. P. Kurki

* Low-molecular weight ** Filgrastim*** Alfa interferon
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Overview of 5 EU Biosimilar Products: 2 HGHs (frmfrs), 5 EPOs (from 2 mfrs), 4 filgrastims (from 1 Authorized biosimilars: • Omnitrope® (somatropin) (Sandoz): Recombinant human growth hormon

Pfizer’s Genotropin®.

• Valtropin® (somatropin) (BioPartners): Recombinant human growth horm

Lilly’s Humatrope

• Binocrit® (epoetin alfa) (Sandoz)-Reference product J&J’s Eprex for all au• Epoetin alfa Hexal® (epoetin alfa) (Hexal Biotech Forschungs)• Abseamed® (epoetin alfa) (Medice Arzneimittel Pütter)• Silapo® (epoetin zeta) (Stada Arzneimittel AG)• Retacrit® (epoetin zeta) (Hospira Enterprises B.V.)• Ratiograstim (filgrastim) (ratiopharm GmbH)-Reference product Amg• Biograstim (filgrastim) (CT Arzneimittel GmbH)• Tevagrastim (filgrastim) (Teva Generics GmbH)• Filgrastim ratiopharm (filgrastim) (ratiopharm GmbH)

Rejected as biosimilar; negative opinion: Alpheon ® (BioPartners): Reco

– Reference product Roche’s Roferon-A ®

Withdrawn by applicant: 3 biosimilar versions of insulin from Marvel LifeS

Mumbai) when EMEA committee would not extend time for answering queextension: intended reference product—reference product Lilly’s Humulin
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European Approach to 

Exclusivity

What does the “8 + 2 + 1” mean an

where did it come from
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“8+2+1”

• 8 years data exclusivity dating from the European Com

decision: before that, no generic applications are filea

• +2 years marketing protection: no generic applications • + 1 year: new indication(s) if it constitutes a significan• For all products, regardless of centralized or Member 

procedure

• Not retroactive; does not affect exclusivity periods for 

applications were submitted before effective date (late 
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Exclusivity: types

• With data exclusivity, there can be neither dis

regulatory data to a competitor nor regulatory data.

• However, unless a patent blocks the way, a co

the market by generating his own data on his v(“testing his way to market”).

• With marketing exclusivity, agency cannot a

product to enter the market during a time perioinnovator has a right of exclusivity

• Competitor cannot generate own data to get a

exclusivity
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Purpose of exclusivity• Whether in the form of data protection or market protectio

purpose of exclusivity is to provide an incentive for compato undertake the expensive and lengthy process to develonew product and bring it to market. 

• Exclusivity is independent of patents and runs concurrent• For medicinal products in the EU under patents, the 20-y

patent period with a 5-year Supplementary Protection Certificate may run longer than 10 years, post-approval. 

• However, not all medicinal product innovations are cover

patents and regulatory exclusivities are intended to providmeasure of certainty that investments in product developcan be recouped. Also patent law alone is viewed as not providing adequate certainty in this regard.
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For centrally authorized products assessed by EM

• Art. 14.11 of the EMEA Regulation:• Without prejudice to intellectual property law, medicines authorized 

Regulation shall benefit from an 8 year period of data protection anmarketing protection. 

• The latter period shall be extended to a maximum of 11 years if, d

years, the marketing authorization holder obtains an authorization 

therapeutic indications which are held to bring a significant clinical 

with existing therapies.

• All biotech biosimilars are assessed by EMEA.

This provision applies to all applications submitted to the EMEA afte
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For generic products (not biosimilars) authorized by Member State agencies

• Art. 10(1),Community Code on Medicinal Products: Wi

intellectual property, the applicant shall not be required results of pre-clinical tests and of clinical trials if he can that the product is a generic of a reference medicinal phas been authorized for not less than 8 years in a Memthe Community.

• A generic authorized under this provision shall not be p

market until 10 years have elapsed from the initial authreference product.

• As with centrally authorized products assessed by the 

year is available, governed by the same criteria.

• Note: this provision governs approvals by national Mem

agencies and by its terms relates to generics, not to biapply in rare cases where a national agency approves biologic whose reference product was not one assesse

• This provision should apply to all applications submitte

State agencies after October 30, 2008 [European Comsays after Member State implementation of Directive.]
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Where the 8:2+1 came from: Legal Landmarks: EU Exclusivity Law

• 1965: First European Community medicines law, Directive 6

framework requirements for authorization of medicinal produ

• 1987 amendments, Directive 87/21: generic pathway and D- “The applicant shall not be required to provide the results o

toxicological tests or the results of clinical trials if he can demmedicinal product is ‘substantially similar’ ...or that the me

essentially similar to a product which has been authorized wnot less than six years and is marketed in the Member Sapplication is made; this period shall be extended to 10 high-technology medicinal products ...furthermore, a Meextend this period to 10 years by a single decision cove

marketed on its territory where it considers this necessary in health.” Art. 4.8.a.iii

- Case law: Generics (1998) and Novartis (2004) cases in Eu

1965 1987
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1993 Regulation establishing the European Agency for th

Medicinal Products (EMEA) provided:

– 10 years of DATA PROTECTION for centrally autho– This continued the 10-year period for high-tech prod

through an earlier expert committee (“ex-concertatio

– All biotech products are required to go through the “

authorization procedure”, assessed by EMEA and thEuropean Commission Decision

• Orphan Medicinal Products Regulation141/2000: MARKE

– The first product to obtain an approval in the EU blo

existing marketing authorization for the “same therarespect of a “similar medicinal product.”

1993

Legal Landmarks: EU Exclusivit

2000
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• In 2000, the WTO issued a panel report in EU vs. Canada 

plus” law allowing not only regulatory testing in Canada but 

• The WTO Panel concluded that Canada's law is a "limited e

the meaning of TRIPS Article 30 only “[a]s long as the exceconduct needed to comply with the requirements of the regprocess.”

• However, the Canadian law went too far in allowing stockp• During the patent life of the pioneer drug, the generic comp

make the drug only for regulatory review purposes.

• Stockpiling is not allowed. Selling drugs made and stockpile

term also is not allowed.

• Afterward: Canada eliminated stockpiling provision AND Eu

Commission decided to propose its own Bolar testing provi2001draft legislation.

2000

WTO EU v. Canada “Bolar” cas
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• November 2001 recodification: Community Code on 

Medicinal Products 2001/83 codified a huge numbepost-1965 EU pharma laws (including 1987 law)

• Earlier that year, in July 2001, Pharmaceutical Revi

Legislation was proposed by the European Commis

• Proposed Bolar provision• Proposed harmonization of exclusivity periods 

EU authorizations to 10 + 1—the +1 for a new indication

2001

Legal Landmarks: EU Exclusivity 
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•2003/63:New Annex 1 to Directive 2001/83 (ICH Com

Document; different requirements for biologics, scaled products)

•2003: EMEA Guidance documents on comparability: E

“inter-company-comparability” in addition to the “intra-ccomparability” encompassed by FDA guidance and IC

•2003: Favorable opinion by EMEA Committee on Prop

Products on Sandoz Omnitrope; Commission did not g

to lack of legal basis

2003

Landmarks: Biosimilars
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•March 31, 2004 Action completed on Pharmaceutical Review includ•2004 Amendment Community Code on Medicinal Products Directiv

– harmonized exclusivity period of 8+2+1 for nati– Bolar testing provision– definition of “similar biological medicinal produc

•2004 EMEA Regulation replacing 1993 regulation: exclusivity in Art•Notes: 10 new Member States were scheduled to join the EU on Ma

States and major stakeholders wanted the legislation concluded prio

•All 10 of the new States favored 6 years over 10 years; some reque•Achieving a harmonized exclusivity period--eliminating the choice o

was a major priority for industry, although the 10+1 period would hav

•During legislative process, Commission resisted having a disparity i

centralized approvals as compared to national approvals. 

•Commission also refused to insert in the EMEA Regulation a cross 

Code provision on 8+2+1--so EMEA Article 14.11 is a self-contained

Legal Landmarks: EU Exclusivity 
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Other Exclusivity or Related Provisions

• New combinations of old medicinal products are treated 

eligible for 8+2+1 years exclusivity (Art. 10b Community CoApplicants Volume 2A Procedures for Marketing Authorizati

• 1 year data exclusivity for a new indication for a well-esta• 1 year data exclusivity for change of the classification fro

versa 

• Orphan drugs 10 years market exclusivity remains unchang

have 10 years market exclusivity for orphan indications and 

• New pediatric regulation: marketing authorization holder ca

supplementary protection certificate from 5 years to 5.5 yea

– OR use the +1 extension of exclusivity (not both) – OR add +2 years to orphan drug market exclusivity fo

• Also new Pediatric Use Marketing Authorization (PUMA) 

products offers 8+2 exclusivity period

• Since 1992, there has been the possibility of a 5-year Supp

Protection Certificate for a patent in force, covering an aupharmaceutical (somewhat analogous to U.S. patent term rpotential 20+5 patent/SPC period runs separately from regu
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EU exclusivity periods are in transi• From 1987 until October 30, 2005, EU Member States ha

implement 6 years of data protection or 10 years. 

– 10 years: Belgium, France, Germany, Italy, Luxemb

Netherlands, Sweden and the UK

– 6 years: Austria, Denmark, Finland, Greece, Ireland, 

all the new Member States who joined EU in 2004 (CRepublic, Estonia, Hungary, Latvia, Lithuania, Maltaand Slovenia); also Iceland and Norway (linked to thEconomic Area treaty) 

• The old “10/6” system continues to govern all applications 

Member State agencies prior to October 30, 2005.

• The old 10 year system continues to govern all applicatio

submitted prior to November 20, 2005, under the centraliz

• Therefore, the old exclusivity system will continue to 

long time, until late 2011 in the Member States with 6 2015 for other Member States and for EMEA-assesse
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Exclusivity

New Indication

Next Generation Product
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Legal provisions on improvements

• All biotech biologicals, including biosimilars, go through the centra

Therefore the exclusivity provision for centralized products is relev

• Art. 14.11 of the EMEA Regulation:• Without prejudice to intellectual property law, medicinal products 

EMEA Regulation “shall benefit from an eight-year period of dten- year period of marketing protection, in which connection thextended to a maximum of 11 years if, during the first 8 of the 10 authorization holder obtains an authorization of one or more new twhich are held to bring a significant clinical benefit in comparison w

• It would appear that every medicinal product that enters the EU ma

centralized procedure should receive a full 8+2+1 period. On the famedicinal product authorized under the EMEA Regulation “shall” b

Applicants wishing to market their own versions of biotech biologics 

could, by submitting full applications, enjoy the benefits of Article 1

This does not appear to be possible for applicants that use the biosi
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For generic products (and non-biotech biosimilarsauthorized by Member State agencies

• Art. 10(1),Community Code on Medicinal Products: Wi

prejudice to IP, the applicant shall not be required to pthe results of pre-clinical tests and of clinical trials if he demonstrate that the product is a generic of a referencmedicinal product which is or has been authorized for than 8 years in a Member State or in the Community.

• A generic authorized under this provision shall not be p

on the market until 10 years have elapsed from the initauthorization of the reference product.

• As with centrally authorized products assessed by the 

an 11th year is available.
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“Global marketing authorizatio• There is debate as to whether a legal construct—”global 

in the 2004 amendment to the Community Code on MediArticle 6(1)) will apply to biosimilars authorized through thprocess. 

• “When a medicinal product has been granted an initial m

any additional strengths, pharmaceutical forms, administr

presentations, as well as any variations and extensions sauthorization ...or be included in the initial marketing authmarketing authorizations shall be considered as belonginmarketing authorization, in particular for the purpose of th10(1).

• Note: European Commission guidance states that applica

marketing authorization holders are not treated as being marketing authorization. 

_____________* Article 10(1) is the generics provision that includes the 8+

was intended to codify case law that arose from generic aprevious EU pharma laws (Generics case).
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“Global marketing authorizatio• The term “a medicinal product” in the provision on “globa

is a key term. 

• Changes that are treated as “line extensions” of the origin

than the indication +1) do not entitle the marketing authornew exclusivity period.

• However, where a 2nd generation product is a different pr

version of an older biotech product—the EMEA has treatedistinctive products and thus not the same “medicinal proconcept of “global marketing authorization” should not staexclusivity period for the 2nd product.

• However, it should be noted that there is uncertainty on th

interpreting the 1987 Directive (Novartis case).
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Case Law: Generics Case

• The “global marketing authorization” concept was mea• GENERICS European Court of Justice (ECJ) Case C-3• Do additional data, which allow the registration of an im

essentially similar to the reference product, benefit from 

• No.

a) 10/6 years after the first marketing authorization of th

generic products that are essentially similar can benefiimprovement (new indications, doses etc.), registered related to the improvement do not benefit from a prote

b) Set forth the criteria for essential similarity: same ac

pharmaceutical form ; bioequivalence.

• Note: case was under 1987 Directive; concerned a Me

authorization; did not involve a biosimilar.
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Case law: Novartis case

• Do additional data, which allow the registration of an im

not essentially similar to the reference product, benefit f

NOVARTIS / SANGSTAT ECJ Case C-106/01 (2004)

• Is a full dossier required for the registration of a second

not essentially similar to the reference product? Or are 

• Products that are not bioequivalent are not essentially s• After the expiry of the Data Exclusivity term, a second-e

bioequivalent to the reference product, due to the fact tdifferent route or in different doses, could be approved data.

• Broad definition of the concept of pharmaceutical form. • Note: case was under 1987 Directive; concerned a Mem

authorization; did not concern a biosimilar.
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EU exclusivity

New Indication
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Guidance on 11th year in 8+2+1

• It is too soon for experience with this provision.• However, the European Commission has issued guidance, Nov. 2

centrally authorized products and products authorized by Member 

• Guidance takes a broad view of significant benefit:• New target disease, different stages or severity of disease, extend

disease

• Change from 1st line to 2nd line treatment or vice versa or from com

monotherapy

• Change from treatment to prevention or vice versa• Change from short-term to maintenance treatment• Improved safety, efficacy, contribution to patient care• Applicant must justify 11th year, address existing therapy
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Interchangeability

How this is handled in the EU
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EMEA CHMP Guideline• 

“It should be recognised that, by definition, similar b

medicinal products are not generic medicinal producould be expected that there may be subtle differensimilar biological medicinal products from different mor compared with reference products, which may noapparent until greater experience in their use has bestablished.”

EMEA CHMP Guideline on Similar Biological M

CHMP/437/04, 
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Interchangeability - EMEA View• “It is not possible we would guarantee a biosimilar i

interchangeable (with its originator). Substitution is competency and needs to be discussed at the natio

EMEA Executive Director Thomas Lönngren, 21 July 

• EMEA/74562/2006, 19 April 2007 

“Since biosimilar and biological reference medicine

similar but not identical, the decision to treat a patiereference or a biosimilar medicine should be taken the opinion of a qualified healthcare professional.”
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Views of former chair of working paDr. P. Kurki• Substitution is a national decision in EU• Generic substitution is not harmonised• Evidence-based guidance may not be possible• Decision to substitute can be seen from an individual and 

public health point of view

• Substitution is a result of a mixture of ethical, political, 

economical, and scientific considerationsThus:EU-wide or local guidance? 

Regulatory agencies or learned societies/hospitals?
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New EU pharmacovigilance guideline advises incof brand-specific information in adverse event re

September 2008, Volume 9A Rules for Medicinal Products on Phar• “For adverse reactions relating to biological products, the definite 

with regard to its manufacturing is of particular importance. There[1] should give advice to reporters[2] to provide the name[3] of the 

batch number and should follow-up the reports when this informa

• This advice contemplates that the doctor has prescribed by brand 

possible substitution by pharmacist OR, if substitution is allowed, back and check dispensing records in the pharmacy or hospital awhat was actually dispensed to the patient.

• This is just one part of substantial post-marketing pharmacovigila

__________[1] i.e., national drug regulatory agencies.[2] those who report adverse reactions, generally the market autho

professionals.

[3] “The name, which may be either an invented name [“brand nam

with the common name [INN or “generic name”], or a common or accompanied by a trade mark or the name of the marketing authoCommunity Code 
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EU countries forbidding substitutio• Austria: Physicians are obliged to prescribe by brand name• Czech Republic: Physicians are obliged to prescribe by brand • Denmark: Official guidelines against substitution.• Finland: By law, no injectable drug may be automatically subst• France: law prohibits the automatic substitution of one biologica

another, without the consent of the treating physician (reason givbiotech products and follow-on medicines are not identical).

• Germany: Since biosimilars are not generics, they are not autom

substitutable.

• Greece: Physicians are obliged to prescribe by brand name.• Hungary: Since biosimilars are not generics they are not autom

substitutable. 

• Italy: The Italian Medicines Agency (AIFA) recommends, for clin

no substitution of these products take place
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EU countries forbidding substitutio

• The Netherlands: The Royal Society of Pharmacists has iss

automatic substitution of biologics.

• Norway: The Medicines Agency has stated that “biosimilars” 

products and should not be substituted.

• Slovakia: An official list sets forth products which cannot be 

includes many biotech medicines (e.g. epoetins, Factor VII, G

• Slovenia: A law has been adopted that prohibits substitution • Spain: A recent amendment to the law includes all biotech m

products that cannot be automatically substituted.

• Sweden: Regulatory authorities have informed the pharmac

writing that biologics are not to be substituted automatically.

• UK: The UK Medicines and Healthcare products Regulatory 

stated that biologics should be prescribed by brand name to esubstitution of a biosimilar does not occur when the medicine pharmacist.
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Reminder: U.S. exclusivities• Hatch-Waxman °New molecular entity - 5 year data exclusivity New use - 3 year 

applicationssupplements

1st filed Abbreviated New Drug Application - 180 da

marketing

• Orphan Drug Exclusivity - 7 years market exclusivity• Pediatric Exclusivity
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