Biosimilars – So where are we in the EU?

Robert Williams,Partner, Bird & Bird LLP (London)

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EU Legislation : Basic Rules

Basic Rule No medicinal product can be placed on the market without a MAApplicant must provide the results of:

Pharmaceutical tests (physico-chemical, biological or microbiological tests);Pre-clinical tests (toxicological & pharmacological tests); andClinical data

Article 10.1 Directive 2001/83Applicable to Generics

Compared to the reference product : Same qualitative and quantitative composition in active substances Same pharmaceutical form Bioequivalence (demonstrated by bioavailability studies)

The applicant is not required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorized under Article 6 for not less than 8 years in a Member State or in the CommunityNB “old” rules still in place for reference products applied for pre-Nov 05 (ie 10 years RDP for products applied for centrally)

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What is a biosimilar?

According to article 10.4 of Directive 2001/83

Where a biological medicinal product which is similar to a reference biological product does not meet the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or manufacturing processes, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.

Type and quantity of supplementary data provided must comply with relevant criteria stated in the Annex; and related detailed guidelines.

The results of other tests and trials from the reference medicinal product's dossier cannot be provided.

Consequence: a biosimilar is defined by what is accepted (or not) by the EMEA (or other competent authorities)

No a priori definition of the acceptable differences between a biosimilar and the reference product

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What is a biosimilar ? “Biological medicinal product”

Means that the active substance is a biological substance“Biological substance”

Substance produced or extracted from a biological sourceCombination of physico-chemical-biological testing, production process and its control are needed for its characterization and determination of quality

Examples of biological medicines:Immunological medicinal products and medicinal products derived from blood and human plasma (article 1.4 & 1.10 of Directive 2001/83)Medicinal products developed by recombinant DNA technology, controlled expression of genes coding for biologically active proteins from a cell culture, hybridoma and monoclonal antibody methods ATMP

Biologicals are among best-selling/fastest growing drugs in the world

Epogen/Procrit®, Enbrel®, Humira®, Remicade®, Herceptin®, Avastin®

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Active substance for biological medicinal products

“Biosimilar”

“similar” product made according to a different process

For example different construct, host, cell line, protocol and/or purification steps

In practice: impossible to know without access to original process

But developers of biosimilars normally have no direct access to originator’s data

Have to reverse engineer

(i.e. made using different process): additional pre-clinical tests or clinical trials required to show similarity

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Overarching GuidelineDefines basic principles, philosophy + « User guide »

General Guidelines

General principles for assessing quality,

non-clinical, clinical aspects

Product Specific Guidelines

Annexes to General Guideline on (non-) clinical issues

Address specific pre-clinical and clinical issues re. specific products

Guidelines on biosimilars

Somatropin

Insulin

Granulocyte-colony Erythropoietins

IFN-alpha

LMW heparin, etc.

Quality issues

(Non-) Clinical issues

Apply to all biosimilars

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Information required for a biosimilar MA

Quality dataQuality data Complete self-standing quality dossier

+ Comparability exercise Complete self-standing quality dossier

+ Comparability exercise

Non-clinical dataNon-clinical data

Clinical dataClinical data

PharmacovigilancePharmacovigilance

Case-by-case basisAbridged programs (in vitro/in vivo)+ Comparability exercise

Case-by-case basisAbridged programs (in vitro/in vivo)+ Comparability exercise

Abridged programs but most of the time: extensive trials are requiredAll results must be submitted ( + and -)

+ Comparability exercise

Abridged programs but most of the time: extensive trials are requiredAll results must be submitted ( + and -)

+ Comparability exercise

Monitoring is necessary, as for all other medicinesMonitoring is necessary, as for all other medicines

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Experience so far:Overview of EU authorized biosimilars

SomatropinSomatropin

INNINN BiosimilarBiosimilar

Epoetin alfaEpoetin alfa

Epoetin zetaEpoetin zeta

FilgrastimFilgrastim

Omnitrope® (Sandoz)Omnitrope® (Sandoz)

Valtropin® (BioPartners)Valtropin® (BioPartners)

Binocrit® (Sandoz) Binocrit® (Sandoz)

Epoetin alfa Hexal®Epoetin alfa Hexal®

Abseamed® (MAP)Abseamed® (MAP)

Silapo® (Stade Arzneimittel)Silapo® (Stade Arzneimittel)

Retacrit® (Hospira)Retacrit® (Hospira)

Biograstim® (CT Arzneimittel)Filgrastim Ratiopharm®, Ratiogastim®, Tevagrastim®

Biograstim® (CT Arzneimittel)Filgrastim Ratiopharm®, Ratiogastim®, Tevagrastim®

Reference ProductReference Product

Genotropin® (Pfizer)Genotropin® (Pfizer)

Humatrope® (Eli Lilly)Humatrope® (Eli Lilly)

Eprex®/ Erypo® (J&J)Eprex®/ Erypo® (J&J)

Neupogen® (Amgen) Neupogen® (Amgen) Filgrastim Hexal®, Zarzio® (Sandoz)Nivestim ® (Hospira)

Filgrastim Hexal®, Zarzio® (Sandoz)Nivestim ® (Hospira)

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Experience so far:Refusal/Withdrawals of biosimilars

Interferon alfaInterferon alfa

INNINN BiosimilarBiosimilar

Human insulinHuman insulin

Alpheon (Biopartners)Alpheon (Biopartners)

Insulin Marvel shortInsulin Marvel short

Insulin Marvel IntermediateInsulin Marvel Intermediate

Insulin Marvel longInsulin Marvel long

StatusStatus

Refused in June 2006Refused in June 2006

WithdrawnWithdrawn

Not all biosimilar applications have been successful

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Acceptable differences between biosimilars and reference product

Different host cellsDifferent host cells

Differences between biosimilars and reference drug products Differences between biosimilars and reference drug products

Different levels of impurities

Different levels of impurities

Different formulationDifferent

formulationDifferent

glycosylationDifferent

glycosylation

ValtropinValtropin Abseamed, Binocrit,Epoetin alfa Hexal

Abseamed, Binocrit,Epoetin alfa Hexal Retacrit and SilapRetacrit and Silap

Source: H. Schellekens & E. Moors, « Clinical comparability and European biosimilar regulations », in Nature Biotechnology January 2010nr. 1, vol. 28, p. 29

Zarzio and Filgrastim Hexal

Zarzio and Filgrastim Hexal

Biograstim, Filgrastim,

Ratiopharm, Ratiograstim

and Tevagrastim

Biograstim, Filgrastim,

Ratiopharm, Ratiograstim

and Tevagrastim

Abseamed, Binocrit,Epoetin alfa Hexal

Abseamed, Binocrit,Epoetin alfa Hexal

Retacrit and SilapRetacrit and Silap

Zarzio and Filgrastim Hexal

Zarzio and Filgrastim Hexal

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Acceptable differences between biosimilars and reference product

These variations can have a potential major effect on a product's safety and efficacy

So far: clinical studies show no negative effectThe differences have not compromised the efficacy or increased the level of adverse effects

compared with the reference product

Raise the question of the relevance of the comparison exerciceComparison of quality characteristics between biosimilar and reference product will always show differences (product is the process)

Comparative clinical data is mandatory

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Biosimilars: specific RDP rules

Usually requires data from a bio-assay (set by EMEA)

Which may again not be available to the generic

And will data from another (similar) bio-assay be accepted ?

Choice of comparator is crucial

Reference product should be approved in the EU

and not be changed during development

New technical assay and analytical tools may mean that more “differences” between the reference product and the biosimilar can be detected

Regulators will need to decide how relevant they are

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Biosimilars: the next steps

Application of the current regulatory framework to monoclonal antibodies (MAbs)?

In principle: the "biosimilar" approach applies to any biological medicine Overarching guideline only excludes blood or plasma-derived products

No exclusion regarding development of biosimilars mAbs

But comparablity exercise is more easily applied to highly purified products (easy to characterize, >< more complex biologics)

So: in reality will it depend on the ability to characterize the product?

Feasibility?High molecular weight proteins

Considerably more complex molecules than the currently developed biosimilars

Contain process and product related impurities

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Further Guidelines.....

“Biosimilar antibodies”: concept paper by CHMP dated 22 October 2009

Deadline for comments has expired and draft guideline due out in November 2010 (hopefully)

May be different guidelines for cytotoxic and immunomodulatory MAb’s ?

Other pending concept papers by CHMP (dated 18 March 2010)

Recombinant follicle stimulation hormoneDeadline for comments expired on 1st June 2010

Recombinant interferon beta Deadline for comments expired on 11 June 2010