biosimilars – so where are we in the eu? robert williams, partner, bird & bird llp (london)
TRANSCRIPT
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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