biosimilar medicinal products eu experience and perspectives
TRANSCRIPT
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"Biosimilar" medicinal products
EU experience and perspectives
Jean-Hugues Trouvin, Pharm. D, PhD.Scientific adviser for biological products, AFSSAPS
BWP chairman, EMA, London
Disclaimer
Although being a member of EMA committees and working parties, my
t ti i ht t b th i f thpresentation might not be the view of the CHMP and the EMA, nor that of the French Medicines Agency (Afssaps). This presentation reflects only personal views and binds in no way the organisations
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views and binds in no way the organisations mentioned above.
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Outlook
Why "Biosimilars"The challenges of being a biological productThe concept of “biosimilarity” and development of the EU regulationThe biosimilar guidelinesCurrent experience
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Current experienceUnresolved issuesConclusions
Why the concept of biosimilar emerged in Europe -1-
In the early 2000s, for some biological products, marketing authorisation protection
t i hGh EPO G CSF twere to expire soon: hGh, EPO, G-CSF, etc.
Would the generic approach be applicable?
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Acknowledgment that biological products are complex macromolecules
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Why the concept of biosimilar emerged in Europe -2-
Complexity at three levels:Molecular (biological product)Origin production process and heterogeneityOrigin, production process and heterogeneityCharacterisation and quality control of the quality attributes contributing to Safety and Efficacy
Recent examples of safety-efficacy consequences after a change in production process
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processThe bioequivalence parameter used for assessing generics is not sufficient and relevant for biologicals
Definition of a biological medicinal product
A biological medicinal product is a product, the active substance of which is a biological substance.A biological substance is a substance
that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control.
Biological medicinal products: immunological medicinal products medicinal products derived from human blood, human plasma or h i
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human urinemedicinal products defined in Part A of the Annex to Regulation 2309/93 (Biotechnology derived products) advanced therapy medicinal products as defined in regulation 1394/2007
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Biological products and their challenges
Complex structure
Complex production process
Complex quality profile: analytical testing
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Immunogenic properties
Biological products and their challenges
Complex structure
Complex production process
Complex quality profile: analytical testing
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y gImmunogenic properties
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Complex structure
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IgG~660AA, MW: ~150 000 Da
Interferon alfa,165AA, MW: 19 625 Da
Aspirin, MW: 180 Da
Molecular weight
Molecular weight Number of
Paracetamol
Calcitonin
Epoetin-α
0.151
4.5
30.4
N/A
32
165
ProductMolecular weight
(kDa)Number of
amino acids
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Factor VIII 264.0 2,332
Crommelin DJA, et al. Int J Pharm 2003;266:3-16.
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Protein structure
DIA - MERC 2011, Amman - BiosimilarsHorton HR, et al. Principles of Biochemistry. 3rd ed. 2002.
3D structure of epoetin alfa
DIA - MERC 2011, Amman - BiosimilarsCheetham JC, et al. Nat Struct Biol 1998;5:861-6.
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Post-translational modification
After translation the protein backbone is further processed in the cell:
GlycosylationGlycosylationSulphatation, Amidation, etc.
Glycosylation is also complex: more than one glycosylation form (isoforms)
glycan pattern and microheterogeneity S ti t i h i ll difi d
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Sometimes, proteins are chemically modified (post production modification)
PEGylationConjugation
glycosylation> complex carbohydrate structures -1-
carbohydrates
glycans
carbohydrates
sialic acid
gal
glcNAc
man
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protein
man
fuc
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glycosylation> complex carbohydrate structures -2-
NeuAc NeuAca 2,3 or 6 a 2,3 or 6
Gal Gal Gal Man Man Manα 1,4 α1,4 α1,4
GalNAc GalNAc GalNAc Man Man Man Man Manß 1,2 ß 1,2 ß 1,2 a 1,3 a 1,6 a 1,2 a 1,3 a 1,6
Man Man Man Man Man Man
a 1,3 a 1,6 a 1,3 a 1,6 a 1,3 a 1,6 GlcNAc Man Man GlcNAc Man ß 1,4 ß 1,4
ß 1,4 ß 1,4 ß 1,4 GlcNAc GlcNAc GlcNAc
ß 1,4 ß 1,4 ß 1,4
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ß 1,4 ß 1,4 ß 1,4 a 1,6 Fuc GlcNAc GlcNAc GlcNAc
N N N
Asn-X-Ser/Thr Asn-X-Ser/Thr Asn-X-Ser/Thr
Complex Hybrid High-Mannose
An “Isoform” is a Complex Mixture of Glycosylated Species
(4) (3) (3) (2)
Sialylation of Glycan Structures on Epoetin alfa
N24 N38 N83 SER126
N24 N38 N83 SER126
(4) (4) (4) (0)Isoform 12 =1313121211111010
1414
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+ other permutations and combinations including structures with sulfates and lactosamine extensions.
• Additional combinations of structures
By permission Andrew Fox, Amgen
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BA
Cathode
Microheterogeneity of EPO Products -1-
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Sample E IA IB IIA IIB IIIA IIIB IV V VII VIII E E VI
Anode
Source: H. Schellekens (2004) Eur. J. Hosp. Sci. 3, 43-47
Isoelectric focussing profiles of EPO preparations from various manufacturers
Microheterogeneity of EPO Products
IEF pattern and sialic acid content of the two EPO isoform
huEPO-(1) huEPO-CHO (2)
preps may appear very similar but
Bioactivity is different
1
8
765432
1
8
765432
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Isoform 2 Isoform 2
Sialic acid14.0 14.2
226,000 in vivo activity(U/mg)
400,000
Source: Burg, J. et al. 1998 PCT/EP/98/07876
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Glycosylation and Monoclonal antibody isoforms
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30
35
40
45
50
s
Poly-D WinRhO
R297 AD1
Monoclonal antibodiesbiological activity glycosylation-dependant
R297
-5
0
5
10
15
20
25
0 10 20 30 40 50 60 70 80
anti-D ng/ml
% ly
sis
ADC 256 01 058DF5
AD1
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GN
F GSA
Dr. Prost, LFB, by permission
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Impact of glycosylation on Mc Ab bioactivity
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Source: GB Kress, EMEA workshop on biosimilar MAB, 2009
Variability in N-linked carbohydrate side chainsA 527-amino acid residue protein containing 17 S-S bridges and 3 glycosylation sites
Possible sources of Si l h i d
Parekh, RB et al. (1989) Biochemistry 28, 7670–7679Spellman, MW et al. (1989) J. Biol. Chem. 264, 14100–14111Wittwer, AJ et al. (1989) Biochemistry 28, 7662–7669
Other sources of variability/microheterogeneity: t-PA (Alteplase) -1-
Possible sources of heterogeneity (experimentally observed variations only !)
Single-chain and two-chain forms
Additional O-Glycosylation
Proteolysis at Arg-XOxidation of
Rijken, DC & Collen, D (1981) J. Biol. Chem. 256, 7035–7041
Harris, RJ et al. (1991) Biochemistry 30, 2311–2314
Ng en TH & Ward C (1993)
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COOHNH2
N-terminal sequence length variation (non-recombinant t-PA only)
Deamidation of Asn residues
Cys or Met residues
Wallen, P et al. (1983)Eur. J. Biochem. 132, 681 - 686
Nguyen, TH & Ward, C (1993) Pharmaceutical Biotechnology 5, 91–134
Zhang, W & Czupryn, MJ (2003) J. Pharmaceutical and Biomedical Analysis 30, 1479 -1490
Wang, 1999, Int. J. Pharmaceutics 185, 129-188
By permission, J.Mascaro
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Spontaneous modifications: instability, aggregation
Monomer Multimer Small aggregate
Large aggregate
?
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Precipitation
L.Paul, IABS meeting, Washington, June 2003
Variability
Molecular structure: source of variability and heterogeneity
These complex structural elements contribute• to the bioactivity Clinical efficacyVariability
Structure III & IV
Post-translationalmodifications
Sequence
AA composition and sequenceSource of variability
SubstitutionOxidationDeamidation
Type of modificationGlycosylation (–N & O-linked)Methylation / Acetylation / Type of variability
to the bioactivity Clinical efficacy• to the biodistribution Clinical pharmacokinetics• to the immunogenicity profile Clinical safety
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Truncated formN- and C-terminal heterogeneousness
…
y yAcylationPhosphorylation / Sulfatation
…
Type of variabilityConformationAggregatesdissociation
…
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Biological products and their challenges
Complex structure
Complex production process
Complex quality profile: analytical testing
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y gImmunogenic properties
Complexity of the production process
A biological substance “is a substance that is produced by or extracted from a biological source EU Dir 2003/63”source… EU Dir. 2003/63
Biological natural source (extraction and variability of the sources)Biotechnology methods Cell substrate
For cultivation (growth) of bacteria, virus, etc. As expressing/producing cells:
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As expressing/producing cells:– genetically modified to express a foreign gene– Induction of secretion
Transgenic animalsTransgenic plants
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Complexity of the production process -1-
DNA Vector Cl nin intDNA Vector Cloning into DNA Vector
Downstreaming
Transfer into Host Cell,Expression
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Large-Scale Fermentation
Formulatione.g., bacterial or mammaliancell
From J. Mascaro - Roche
Complexity of the production process -2-Cell culture conditions
Spinners Bioreactor
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Cell culture conditions may affect several quality attributesyield, glycosylation, integrity, etc.
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Complexity of the production process -3-Purification steps
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Purification process may affect several quality attributesSelection of variants, process-related impurities, etc.
The process: key elements to consider
Production systemExtraction Expression system
Purification systemPurity profileProduct-related substancesProcess related substances
All these elementscontribute to the"purity-impurity"
profile
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Process-related substancesIn Process controlsBatch release specifications
profile
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“The process is the product. “
DIA - MERC 2011, Amman - BiosimilarsSource: Talk Inger Mollerup, Novo Nordisk A/SJoint EMEA/DIA Workshop on Biosimilars, Paris 2005
Protein of
PURITY PROFILEPURITY PROFILE
Quality of biological products
Peptid variants
interest
Post-translational variantsPROFILE ???PROFILE ???
degradationProcess-related impurities
3D structure
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IMPURITY PROFILEIMPURITY PROFILE
g
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Biological products and their challenges
Complex structure
Complex production process
Complex quality profile: analytical testing
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analytical testingImmunogenic properties
Characterization: structure and physico-chemical properties
Complex molecular structures and various quality attributes to be monitored :IdentityPurity / contaminantsVariants and product-related substancesConformation / aggregationBi l i l ti itBiological activity
Wide range of analytical tools to be considered:UV absorptionCircular dichroism spectroscopyFourier transform IRFluorescence spectroscopyNMR spectroscopyCalorimetric approachesImmunochemical assays: ELISA; immunoprecipitation; biosensorsBiological activity: in cell lines and animalsChromatographic techniques: various types of HPLC; peptide mapping
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g p q yp ; p p pp gElectrophoretic techniques: SDS-PAGE; IEF; CZEField flow fractionationUltracentrifugationStatic and dynamic light scatteringElectron microscopyX-ray techniquesMass spectrometry
Adapted from Crommelin DJA, et al. Int J Pharm 2003;266:3-16.
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Analytical testing and quality attributes
Method Size Charge 1° struct.
2°/3° struct.
Purity Potency
HPLC Size exclusion +++ - - ++ ++ - Ion exchange - ++++ +++ - +++ - Reverse phase +++ +/- +++ ++ +++ - Electrophoresis SDS-Page +++ - +++ - +++ - IEF - +++ + ++ +++ + W-Blot +++ - ++ +++ +++ -
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Assays Immunoassays - - +/- +/- - ++ Receptor binding
- - ++ +++ - ++
In vivo assay - - +++ ++++ +/- +++++
from R. Thorpe, personal communication
Whole protein
HPLC
Electrophoresis
Monosaccharides
HPLC, GC
The Analytical chemistry challenge: glycoform analysis
Courtesy from M. Schiestle – EGA-
Lectin binding
Mass spectrometry
Electrophoresis
Potency
Enzymatic orchemical cleavage
Glycan pools
Mass spectrometry
HPLC, CEGlycan mapping
Isolation of individual glycans
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De-N/O- glycosylated protein
HPLC
Peptide mapping
Electrophoresis, CE
individual glycansGlycopeptides
Enzymatic or chemical cleavage
HPLC, CE
Mass spectrometry
Structural characterization:
Mass spectometry,enzymatic, NMR
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Quality profile: what do we know of the iceberg?
Need for a relevant
control strategy at all stages
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Biological products and their challenges
Complex structure
Complex production process
Complex quality profile: analytical testing
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analytical testingConsequences on the immunogenic properties
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The key question: Immunogenicity
All therapeutic proteins have the potential to be immunogenic
Risk factors for immunogenicity: Nature of the active substancePrevious history of the product (class effect)Target patient populationMode/route of administrationProduct- and process-related impurities: “purer”
ti f t i l lik l t i i t
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preparations of proteins are less likely to give rise to immune reactions
Important to consider presence of other "related" or "unrelated" substances that may play the role potential adjuvant Less immunogenicity if greater homology (similarity) with the endogenous human protein
The key question: Immunogenicity
The immune system can detect alterations in proteins missed by analytical methods Immunogenicity of biopharmaceuticals may have serious clinical consequences
Non-neutralizing Antibodies no impact on clinical efficacyNeutralizing antibodies inhibition (up to
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Neutralizing antibodies inhibition (up to complete loss) of the therapeutic effect
Prediction of (non) immunogenic potential from quality data is inappropriate
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The key question: Immunogenicity
This question is considered as a key issue for proteins of therepeutical interestShould always to be addressed in the framework of clinical trials
Th i l d l i t di tiThe animal model is not predictiveMust take into account the different target populations (indications)To establish correlations between appearance of antibodies and (loss of) efficacyNeed to establish detection methods and assays for antibodies
Need to establish the clinical meaning of the detected immune reaction against the therapeutic protein
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Need to include, within the pharmacovigilance programme, a follow-up of the immunogenic response
Biological products and their challenges
Complex structure impact on the safety and efficacy profile
Complex production process impact on the quality profile and consistency
Complex quality profile
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Complex quality profile difficulties to monitor and quality control the final productImmunogenicity potential
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The question
Considering all the “biological challenges”
I th i h ibl f bi l i lIs the « generic » approach possible for biological products ?
The answer would be: NO
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From innovators to « biosimilars »From innovators to « biosimilars »
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Biosimilars:European Legislative framework
Directive 2004/27 Article 10.4 Biological Medicinal Products :
Where a biological Medicinal Product which is similar to a reference biological product does not meet the conditions in the definition of a generic medicinal product owing to differences relating to raw materials or differences in manufacturing
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processes of the biological medicinal product. The results of appropriate pre-clinical and clinical trials relating to these conditions must be provided.
Biosimilars – development of guidelines
Need guidelines to accompany the « biosimilar » status.The first guideline (2000) was dealing with the question of « comparison »
Following a change introduced in the manufacturing process of a biological medicinal product
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medicinal productFor a biological product prepared by a new manufacturer
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The biosimilar concept: the comparability exercice
How much do we need to know for a biological?
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From C. Schneider, CHMP, by permission
How much „similarity“ do we need?
The key words of the "Comparability Exercise" -1-
"Comparability" in terms of quality, safetysafety efficacy
Generally, same pharmaceutical form, strength and route of administration(non)Clinical data requirements depend on
E t t f ibl h t i ti ( lit tt ib t )
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Extent of possible characterisation (quality attributes) Observed / potential differences in the quality attributesClinical experience with the substance and its classBut also ……case by case approach
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The key words of the "Comparability Exercise" -2-
All studies are comparativeReference product authorized in the EUSame reference product for all aspects of the comparability exercisePivotal studies: use final formulation derived from the final process
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Series of guidelines developped
Overarching guideline
Quality guideliney g
Non-clinical and clinical guidelines
Product specific guidelines (annex)SomatropinEpoetin
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pGranulocyte-colony stimulating factor (G-CSF) Insulin Low molecular weight heparins IFN α (draft)IFN b (position statement)
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« Overarching guideline » (CHMP/437/04)
Scope: Any biological medicinal product Biotechnology derived protein Immunogicals (e.g. vaccines and allergens): unlikely, but case by case…Blood products or recombinant alternatives: reduced clinical dossier not acceptableacceptableOthers (e.g. gene, cell therapy): considered in the future in the light of scientific knowledge and regulatory experience gained at the time…
"Generic approach": not appropriate to biologics due to complexity of molecular structure and/or production
Biosimilarity to be established at all levels: Q / S / E
Importance to clearly identify the product to support pharmacovigilance monitoring
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o to g
When pharmaceutical form or strength or route of administration are not the same: must be supported by non-clinical/clinical trials
Reference medicinal product: must be authorised in the Community on the basis of a complete dossier
Quality guidelineQuality guideline (CHMP/BWP/49348/2005)
Comparability exercise versus reference product Comparison against official data (e.g. pharmacopoeial monographs or against other published scientific data): not sufficientQuality attributes:Quality attributes:
– not expected to be identical. – Limits: not wider than the range of variability of the reference product– Differences: to be justified in relation to safety and efficacy.
Reference product:– Comparability for medicinal product + active substance– Same reference for all three parts of the dossier (Q/S/E)– To be clearly identified (brand name, pharmaceutical form, formulation and strength …) – Shelf life of the reference product to be considered
Manufacturing process of the biosimilar product:Own development + state of the art information
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Own development state of the art informationOwn process related impuritiesSuitability of the proposed formulation to be demonstrated, even if same as reference product. Generate clinical data for the comparability study with product manufactured with the final manufacturing process (i.e. representing quality profile of the batches to be commercialised)
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Similar biological medicinal productNon-clinical / Clinical CHMP/BMWP/42832/2005
Non-clinical studiesComparative in nature; designed to detect differencesI it t diIn vitro studies:
Usually necessary to assess any possible differences in reactivity
In vivo studiesPharmacodynamic effect/activity Non-clinical toxicity: ≥1 repeat-dose including toxicokinetiIf specific concerns (e g local tolerance) may be addressed in
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If specific concerns (e.g. local tolerance) may be addressed in the same repeat dose toxicity study
Usually safety pharmacology, reproduction, mutagenicity and carcinogenicity not required
Similar biological medicinal productNon-clinical / Clinical
Efficacy -1-Pharmacokinetics (PK) studies
Generally for all routes of administration applied forGenerally, for all routes of administration applied forAbsorption and clearance and/or half life (elimination rate may differ)Pre-specified equivalence margins, (acceptance range for generics may not be applicable)
Pharmacodynamics (PD) studiesClinically relevant PD marker
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Combined PK/PD study (information on dose-response relationship)Dose in the linear part of the dose-response curve
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Similar biological medicinal productNon-clinical / Clinical
Efficacy -2-Confirmatory comparative trial(s)
Equivalence margins– Equivalence margins » Pre-specified» Adequately justified, primarily on clinical grounds
Comparative PK/PD studies may suffice to demonstrate clinical comparability, if
– PK of the reference product is well characterizedSufficient knowledge of PD properties
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– Sufficient knowledge of PD properties– ≥1 PD marker(s) accepted as surrogate marker(s) for
efficacy– Equivalence margin appropriately justified– Dose-response sufficiently characterised
Similar biological medicinal productNon-clinical / Clinical
Extrapolation of the clinical indicationsEach claimed indication should be justifiedEach claimed indication should be justified, or if necessary demonstrated separatelyExtrapolation to other indication(s) depends on
clinical experienceavailable literature data
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available literature datasame mechanisms of action or receptor(s) involved in all indications
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Similar biological medicinal productNon-clinical / Clinical
Clinical Safety and pharmacovigilanceSafety clinical data to be provided, even if comparable efficacyefficacyUndesirable effects: comparison of type, frequency and severityNot all differences can be detected pre-licensingRisk specification to be provided (including issues related to tolerability)
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Risk management programme / Pharmacovigilance plan to be provided:
Focus on rare adverse reactionsSpecific PhV measures for the reference product usually to be adopted
Similar biological medicinal productNon-clinical / Clinical
ImmunogenicityImportant issue for protein therapeuticsMust always be investigated within all clinical trials
Cannot be predicted from animal studiesShould be considered in different therapeutic indications (i.e. for each indication)
Requires validated assay for determination of binding/neutralising antibodiesOptimal antibody testing strategy
periodicity and timing of sampling,
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interference with antigen, qualified assay(s) (sensitivity, specificity)Clinical implications of antibodiesChronic administration
usually one-year data pre-licensing
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EMA webpage
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http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000086.jsp&murl=menus/regulations/regulations.jsp
&mid=WC0b01ac058002754a
Similar biological medicinal productBiosimilar MAA (status November 2008)
1. Omnitrope (somatropin) Sandoz Authorised2. Valtropin (somatropin) Biopartners Authorised3. Alpheon (interferon alfa) Biopartners Negative4. Bionocrit (epoetin alfa) Sandoz Authorised( p )5. Epoetin alfa Hexal (epoetin alfa) Hexal Authorised6. Abseamed (epoetin alfa) Medice Authorised7. Silapo (epoetin zeta) Stada Authorised8. Retacrit (epoetin zeta) Hospira Authorised9. Insulin Marvel Short (insulin) Marvel Life Science Withdrawn10. Insulin Marvel Intermediate (insulin) Marvel Life Science Withdrawn11. Insulin Marvel Long (insulin) Marvel Life Science Withdrawn
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g ( )12. Filgrastim Ratiopharm (filgrastim) Ratiopharm Authorised13. Ratiograstim (filgrastim) Ratiopharm Authorised14. Biograstim (filgrastim) CT Arzneimittel Authorised15. Tevagrastim (filgrastim) Teva Authorised16. Filgrastim Hexal (filgrastim) Hexal Authorised17. Zarzio (filgrastim) Sandoz Authorised
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Some questions on the biosimilar status
Would the concept be applicable to "all biologicals"?
The regulation applies to “biological medicinal products” any type of biologics could be licensed as a biosimilaras a biosimilar, For scientific reasons, the approach will be more likely successful for products which can be thoroughly characterised, such as proteins produced by recombinant DNA technology More difficult to apply to other types of biologics:
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More difficult to apply to other types of biologics:by nature are more complex (e.g. vaccines), for which there is little regulatory experience gained so far (e.g. gene therapy).
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Interchangeability – Substitution
As regards substitution or interchangeability on a scientific basis, biosimilars should not be
i il t d t iassimilated to generics as such the term biogeneric is not considered appropriate in the EU. Interchangeability is not a point that EU legislation currently addresses. This policy
ti i l ft t th i iti ti f th N ti l
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question is left to the initiative of the National competent authorities.
Similar biological medicinal productConclusion
Similar biological medicinal productLegal framework introduced in 2003Applicant may choose to file as stand alone applicationApplicant may choose to file as stand-alone application Biosimilar approach: reduction of non-clinical and clinical data compared to a full dossier
Comparability exercise:Similar ≠ identicalStudies should be comparative Q + S + E
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Studies should be comparative Q S EReference product must be authorized in the EUSame reference product for all aspects of the comparability exercisePivotal studies: use the final process material
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Biosimilar conclusion
"Biosimilar" does not mean "generic"In « biosimilar », you get BIO and SIMILAR
SIMILAR indicates the administrati e andSIMILAR indicates the administrative and regulatory statusBIO means and reminds that this is a biological product, with all its complexity and consequences in terms of safety and efficacy
– not recommended to switch patients from a biological product to another without therapeutic justification
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another without therapeutic justification– No reason, for biosimilars, to deviate from general recommendations
for biologics– The « biosimilarity » concept (as well as the « comparability »
programme) are not aimed at concluding that the two products are «identical»
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Back up slidesBack up slides
Preclinical studies Comparative non-clinical studies28-day toxicology
Note explicative “Erythropoietine”EMEA/CHMP 94526/05
Human PK & PD studies
Single dose in healthy volunteers using SC and IVInclude PD evaluation (reticulocytes) in PK studies
Efficacy studies 2, randomised, double blind studies in nephrologyBoth routes of administration (SC and IV)Dose and Hb levels to be collected
Extrapolation Yes – equivalence in renal anaemia may allow extension to other indications if justified by applicant
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extension to other indications, if justified by applicantSafety Safety from efficacy studies is adequate for approval
12-month, comparative immunogenicity dataPharmacovigilance PRCA to be addressed
Safety in cohort of patients from all indications (ie. including extrapolated indications)
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Note explicative “G-CSF”EMEA/CHMP 31329/05
Preclinical studies Comparative non-clinical studies28-day toxicology
Human PK & PD studies
Single dose in healthy volunteers using SC and IVANC and CD34+ in healthy volunteers
Efficacy studies 2-arm (vs. reference product) OR 3-arm (vs. reference product + placebo) equivalence trial in CINORPD study in healthy volunteers (if justified)
Extrapolation Yes – Equivalence in CIN will allow extrapolation to other indications if mechanism of action is the same
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indications, if mechanism of action is the sameSafety Evaluate AE’s and immunogenicity in CIN study
6-month follow-upPost-Approval Commitments
Specific monitoring for LoE in extrapolated indications