Biosimilars So where are we in the EU?

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

EU Legislation : Basic Rules

Basic Rule
No medicinal product can be placed on the market without a MA
Applicant must provide the results of:
Pharmaceutical tests (physico-chemical, biological or microbiological tests);
Pre-clinical tests (toxicological & pharmacological tests); and
Clinical data

Article 10.1 Directive 2001/83

Applicable 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 Community
NB 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

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 source
Combination 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

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

Guidelines on biosimilars
Overarching Guideline
Defines basic principles, philosophy + User guide

Apply to all
biosimilars

Quality
issues

General Guidelines
General principles for assessing quality,

(Non-) Clinical
issues
Somatropin
Insulin
Granulocyte-colony
Erythropoietins

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

IFN-alpha
LMW heparin, etc.

Information required for a biosimilar MA

Quality data

Complete self-standing quality dossier

+ Comparability exercise

Non-clinical data

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

Clinical data

Abridged programs but most of the time:

extensive trials are required
All results must be submitted ( + and -)
+ Comparability exercise

Pharmacovigilance

Monitoring is necessary, as for all other

medicines

Experience so far:
Overview of EU authorized biosimilars
INN
Somatropin

Biosimilar

Reference Product

Omnitrope (Sandoz)

Genotropin (Pfizer)

Valtropin (BioPartners)

Humatrope (Eli Lilly)

Binocrit (Sandoz)
Epoetin alfa

Epoetin alfa Hexal

Abseamed (MAP)

Epoetin zeta

Filgrastim

Eprex/ Erypo (J&J)

Silapo (Stade Arzneimittel)

Retacrit (Hospira)
Biograstim (CT Arzneimittel)
Filgrastim Ratiopharm,
Ratiogastim, Tevagrastim
Filgrastim Hexal,
Zarzio (Sandoz)
Nivestim (Hospira)
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Neupogen (Amgen)

Experience so far:
Refusal/Withdrawals of biosimilars
Not all biosimilar applications have been successful
INN
Interferon alfa

Biosimilar

Status

Alpheon (Biopartners)

Refused in June 2006

Insulin Marvel short

Human insulin

Insulin Marvel Intermediate

Insulin Marvel long

Withdrawn

Acceptable differences between biosimilars

and reference product
Differences between biosimilars and reference drug products
Different host cells

Different levels
of impurities

Different
formulation

Different
glycosylation

Valtropin

Abseamed, Binocrit,
Epoetin alfa Hexal

Retacrit and Silap

Abseamed, Binocrit,
Epoetin alfa Hexal

Zarzio and
Filgrastim Hexal

Biograstim,
Filgrastim,
Ratiopharm,
Ratiograstim
and Tevagrastim

Retacrit and Silap

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

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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 effect
The 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 exercice

Comparison 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
MAbs ?

Other pending concept papers by CHMP (dated 18

March 2010)
Recombinant follicle stimulation hormone
Deadline for comments expired on 1st June 2010

Recombinant interferon beta

Deadline for comments expired on 11 June 2010

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