michael marshall ph d regulatory affairs novo nordisk a/s
DESCRIPTION
BioSimilars in EU and US Scientific, Legal and Regulatory Issues. Michael Marshall Ph D Regulatory Affairs Novo Nordisk A/S. Whats in the name?. Generics. Biogenerics. Generic biotech products. Similar biological medicinal products. Follow-On Biologicals. Generic Product. - PowerPoint PPT PresentationTRANSCRIPT
Slide no 1 • •
Michael Marshall Ph DRegulatory AffairsNovo Nordisk A/S
BioSimilars in EU and USScientific, Legal and Regulatory Issues
Slide no 2 • •
Whats in the name?
Slide no 3 • •
InnovatorProduct
GenericProduct
Quality
Clinical
Non-clinical
Bioequivalence
Slide no 4 • •
Article 10
“Generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product
and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies
Directive 2004/27/EC amending 2001/83/EC
Note: Directive 2003/63/EC refers to generics as “essentially similar”
Slide no 5 • •
InnovatorProduct
BioSimilarProduct
Quality
Clinical
Non-clinical
Bioequivalence
Slide no 6 • •
Structure of Biologicals is complex
OH
O
O
O
Aspirin
Insulin Factor VII
Slide no 7 • •
ActiveSubstance
Impurities Formulation
PurificationRecovery
FermentationCell BankHost Cell
Antibodies to drug
Clinical effectNo clinical effect
Impurities
Slide no 8 • •
Whereas (15)
Biological medicinal products similar to a reference medicinal product do not usually meet all the conditions to be considered as a generic medicinal product maínly due to manufacturing process characteristics, raw materials used, molecular characteristics and therapeutic modes of action. When a biological medicinal product does not meet all the conditions to be considered as a generic medicinal product the results of appropriate tests should be provided in order to meet the requirements related to safety (pre-clinical) or efficacy (clinical), or both.
Directive 2004/27/EC amending 2001/83/EC
Slide no 9 • •
‘
Article 10
Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided.’
Directive 2004/27/EC amending 2001/83/EC
Slide no 10 • •
Annex 1 relating to documentation requirementsPart II.4: Similar Biological Medicinal Products
• When a biological medicinal product, which refers to an original medicinal product having been granted a marketing authorisation in the Community, is submitted for a marketing authorisation by an independent applicant after the expiry of data protection period, the following approach shall be applied
• If the information required in the case of essentially similar products (generics) does not permit the demonstration of the similar nature of the two biological medicinal products, additional data, in particular, the toxicological and clinical profile shall be provided.
• Modules 1, 2, 3 plus bioequivalence/bioavailability.Additional data (non-clinical/clinical: case by case basis in accordance with relevant scientific guidelines
Directive 2003/63/EC amending 2001/83/EC
Slide no 11 • •
The Guidelines
General (3207)Non-clinical/clinical (3097)
General (ICH)General (437)
Quality (49348)
Comparability BioSimilars
Non-clinical/clinical (42832)
Insulin (32775)
h-GH (94528)
EPO (94526)G-CSF (31329)
Annexes
Slide no 12 • •
The standard generic approach (demonstration of bioequivalence with a reference medicinal product by appropriate bioavailability studies) is normally applied to chemically derived medicinal products. Due to the complexity of biological/biotechnology derived products, the generic approach is scientifically not appropriate for these products.
The “similar biological medicinal products” approach, based on a comparability exercise, will then have to be followed.
Guideline on Similar Biological Medicinal Products (CHMP/437/04)
Slide no 13 • •
Quality
Clinical
Non Clinical
Comparability Data
Slide no 14 • •
Safety and Efficacymust be ensured
Reduced testingjustified
Scope of Non-clinical and Clinical Studies
RegulatorInnovator
BioSimilarManufacturer
Slide no 15 • •
ReferenceMedicinalProduct
BioSimilarMedicinalProduct
•Characterisation of DSStructure PTM
•Physicochemical•Impurities- Product related•Accelerated stability
Process related Impurities
ActiveSubstance
ActiveSubstance
Comparability
Validate Validate
The Quality Guideline
Slide no 16 • •
Product Non-clinical Clinical
PK/PD
Efficacy Safety
Insulin In vitro PDTox: 4 weeks repeat dose
No Immunogenicity:12 months(6 months comparative)
Local reactionsh-GH In vitro/vivo PD
Tox: 4 weeks repeat dose
Data from Efficacy trialand 12 months Immunogenicity
GCSF In vitro/vivo PDTox: 4 weeks repeat dose
6 months study includingImmunogenicity
EPO In vitro/In vivo PD
Tox: 4 weeks repeat dose
Data from Efficacy trial and12 months Immunogenicity
Comparative Non-Clinical and Clinical studies
Slide no 17 • •
• Strong legal and political struggle both for and against FOBs
• No FOB guidelines yet• FDA workshops have been held
• Two legal systems for approval of drugs• Food, Drug and Cosmetic Act
• Public Health and Safety Act
• Only FDCA has regulatory route available for generics
Status in U.S.
Slide no 18 • •
Food, Drug and Cosmetic Act
Insulin, h-GH
Hatch Waxman Act 1985:Abridged regulatory routefor Generics
1. FD&C Act Section 505 (b)(2)2. FD&C Act Section 505 (j)
Not decided if FOBs can usethese routes
Public Health Service Act
Most Biologicals
No Regulatory route for FOBs
Regulatory legislation in US
Slide no 19 • •
•Provides for data on safety and efficacy• May rely in part on literature or on an earlier
finding by FDA that a drug is safe and effective
• Typically used for changes in dosage form, strength or route of administration, new indication, change to excipient
• Potentially applicable for FOBs but this is being challenged legally (by interests of the innovator companies)
FD&C Act Section 505 (b)(2)
Slide no 20 • •
•“Sameness”• “An abbreviated application for a new drug
shall contain information to show that the active ingredient of the new drug is the same as that of the listed drug….”
• Unlikely or impossible to prove for a biotech derived product
FD&C Act Section 505(j)
Slide no 21 • •
• BioSimilars are not genericsScientific barriers to demonstration of Comparability
• EUThe legislation and regulatory guidelines are in placeOne BioSimilar has already been approved and more
approvals are in the pipeline
• USScientific, legal and political issues not yet resolvedSlower than EU but FOBs will eventually come
Conclusions