Biosimilars – So where are we in the EU?

1
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 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

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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
  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

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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 originators 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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Guidelines on biosimilars
Overarching Guideline Defines basic principles,
philosophy  User guide 
Apply to all biosimilars
General Guidelines General principles for
assessing quality, non-clinical, clinical aspects
Quality issues
(Non-) Clinical issues
Product Specific Guidelines Annexes to General
Guideline on (non-) clinical issues Address
specific pre-clinical and clinical issues
re. specific products
Somatropin Insulin Granulocyte-colony
Erythropoietins IFN-alpha LMW heparin, etc.
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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
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Experience so farOverview of EU authorized
biosimilars
INN
Biosimilar
Reference Product
Somatropin
Omnitrope (Sandoz)
Genotropin (Pfizer)
Valtropin (BioPartners)
Humatrope (Eli Lilly)
Epoetin alfa
Binocrit (Sandoz)
Eprex/ Erypo (JJ)
Epoetin alfa Hexal
Abseamed (MAP)
Epoetin zeta
Silapo (Stade Arzneimittel)
Retacrit (Hospira)
Filgrastim
Biograstim (CT Arzneimittel) Filgrastim
Ratiopharm, Ratiogastim, Tevagrastim
Neupogen (Amgen)
Filgrastim Hexal, Zarzio (Sandoz) Nivestim
(Hospira)
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Experience so farRefusal/Withdrawals of
biosimilars

• Not all biosimilar applications have been
  successful

INN
Biosimilar
Status
Interferon alfa
Alpheon (Biopartners)
Refused in June 2006
Human insulin
Insulin Marvel short
Withdrawn
Insulin Marvel Intermediate
Insulin Marvel long
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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

13
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, gtlt 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